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Acquisitions Editor: Rebecca Gaertner Digital Product Development Editor: Leanne Vandetty Production Project Manager: Priscilla Crater Design Coordinator: Elaine Kasmer Manufacturing Coordinator: Beth Welsh Marketing Manager: Rachel Mante Leung Prepress Vendor: Absolute Service, Inc. 26th edition Copyright © 2017 Wolters Kluwer All rights reserved. This book is protected by copyright. No part of this book may be reproduced or transmitted in any form or by any means, including as photocopies or scanned-in or other electronic copies, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews. Materials appearing in this book prepared by individuals as part of their official duties as U.S. government employees are not covered by the above-mentioned copyright. To request permission, please contact Wolters Kluwer at Two Commerce Square, 2001 Market Street, Philadelphia, PA 19103, via email at [email protected], or via our website at lww.com (products and services). 9 8 7 6 5 4 3 2 1 Printed in China

Library of Congress Cataloging-in-Publication Data available from the Publisher upon request. ISBN-13: 978-1-4963-7465-3 ISBN-10: 1-4963-7465-7

This work is provided “as is,” and the publisher disclaims any and all warranties, express or implied, including any warranties as to accuracy, comprehensiveness, or currency of the content of this work. This work is no substitute for individual patient assessment based on health care professionals’ examination of each patient and consideration of, among other things, age, weight, gender, current or prior medical conditions, medication history, laboratory data, and other factors unique to the patient. The publisher does not provide medical advice or guidance, and this work is merely a reference tool. Health care professionals, and not the publisher, are solely responsible for the use of this work including all medical judgments and for any resulting diagnosis and treatments. Given continuous, rapid advances in medical science and health information, independent professional verification of medical diagnoses, indications, appropriate pharmaceutical selections and dosages, and treatment options should be made and health care professionals should consult a variety of sources. When prescribing medication, health care professionals are advised to consult the product information sheet (the manufacturer’s package insert) accompanying each drug to verify, among other things, conditions of use,

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warnings, and side effects, and identify any changes in dosage schedule or contraindications, particularly if the medication to be administered is new, infrequently used, or has a narrow therapeutic range. To the maximum extent permitted under applicable law, no responsibility is assumed by the publisher for any injury and/or damage to persons or property, as a matter of products liability, negligence law or otherwise, or from any reference to or use by any person of this work. LWW.com

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Born in 1926, H. Winter Griffith became a pioneer in the world of family medicine. He recognized the benefit of fast access to information needed at the point of care. His first book focused on patient education and was published in the early 1970s. Before his death, his patient education book was updated through eight editions and three decades. Dr. Griffith wrote 27 books covering issues including medications, sports medicine, and patient education. In 1993, he published the first edition of The 5-Minute Clinical Consult. Despite his busy practice, his academic work (teaching first in Florida and then in Arizona) and his own health problems, Dr. Griffith, along with coeditor and author, Mark Dambro, MD, continued to help his peers by updating this book every year. He and Mark wrote much of the book and invited volunteer authors to help cover the wide range of the text. Like Dr. Griffith’s other books, The 5-Minute Clinical Consult immediately filled a void in patient care. Their work became the first “fast” method to answer clinical questions of diagnosis and treatment. It is the first “database” of medical information. In fact, their motivation for developing this structured content was to make it available on technology. This year’s 5-Minute Clinical Consult is dedicated to Dr. H. Winter Griffith and to Dr. Mark Dambro. Their efforts were visionary, and their legacy is the book in your hand. Dr. Griffith is gone, but Dr. Dambro continues to work in medicine. Thank you Dr. Griffith and Dr. Dambro. And thank you to all of the volunteer authors of The 5-Minute Clinical Consult. Your dedication and interest have made this book, year after year, a valuable asset to all who practice medicine. As the current editor, my reliance on you is great, and my gratitude greater. Like Dr. Griffith, your efforts will live on in these pages.

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FRANK J. DOMINO, MD

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PREFACE

“If you want to heal the body, you must first heal the mind.” —PLATO ome truths are timeless. Plato was born in 428 B.C. He understood that good physical health can only occur in the presence of sound mental health. We can “cure” a malignancy in someone with end-stage dementia, but are they really healed? Can someone without a single physical illness, but who struggles with paralyzing anxiety or the depths of depression, be considered well? In an era dictated by guidelines and “quality” measures, it is easy to miss the forest for the trees. We can make all the numbers “reach the target” and miss the main problem. The action of chasing targets can also result in the added harm of unpredicted consequences such as overdiagnosis, and its cousin, overtreatment. Sound mental health requires not just adequate treatment but initial recognition. As marijuana becomes more available (medical and otherwise), one wonders if anxiety, insomnia, depression, and dysthymia will become even more hidden as patients self-medicate. Screening for mental health problems is one route to identifying those at risk. Yet, I suspect you have a sense, a gut instinct, when you are with someone who is mentally suffering. One of my former mentors, Bill Damon, used to say that you know when you are with a depressed patient because you begin to feel depressed being with them (countertransference). This is true of anxiety as well; when you have an anxious patient, you begin to feel anxious. The treatment for these folks is not just about addressing their chief complaint but also addressing their hidden, often primary, issue. We teach learners that 95% of patient visits involve a patient’s anxiety. If they have upper respiratory tract infection symptoms, patients often do not want an antibiotic, but mostly to be reassured their condition is nothing serious. If they have chest pain, they want your professional belief that the pain is not their

S

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heart. Even when tests are negative, patients look to us to treat their anxiety with our words. Words have power—to encourage and to do damage. Their absence, not asking, also has consequence. My good friend Sanjiv reminds me to “speak only to create bliss.” That bliss may be to query the anxiety or depression of our patient, to offer a kind word to someone struggling, to compliment an oppositional adolescent, and to lend our voice to those who support health care for all. Another Bill Damon quote is “Always touch the part that hurts, and remember that it’s often the heart.” Words have power to heal the mind. Welcome to the 2018 edition of The 5-Minute Clinical Consult. This is a book of diseases, diagnostic methods, and treatment recommendations. Much of the work provided by primary care providers is focused on helping the patients help themselves to be healthier. Diet, exercise, safety, and prevention are the interventions that provide the greatest number of people with the greatest return on longevity and its enjoyment. This year’s The 5-Minute Clinical Consult is here to assist in fulfilling our role as a health care provider. In each patient interaction, in addition to bringing your clinical expertise, remember how others view you, as a leader, and the power of your words and actions. Encourage them to dream more, learn more, do more, and to be more. Our editorial team has collaborated with hundreds of authors so that you may deliver your patients the best care. Each topic provides you with quick answers you can trust, where and when you need them most, either in print or online at www.5MinuteConsult.com. This highly organized content provides you with the following: • Differential diagnosis support from our expanded collection of algorithms • Current evidence-based designations highlighted in each topic • 540+ commonly encountered diseases in print, with an additional 1,500 online topics, including content from The 5-Minute Pediatric Consult and Rosen & Barkin’s 5-Minute Emergency Medicine Consult • FREE point-of-care CME and CE: 1/2 hour credit for every digital search • Thousands of images to help support visual diagnosis of all conditions • Video library of procedures, treatment, and physical therapy

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• A to Z drug database from Facts & Comparisons • Laboratory test interpretation from Wallach’s Interpretation of Diagnostic Tests • More than 3,000 patient handouts in English and Spanish • ICD-10 codes and DSM-5 criteria; additionally, SNOMED codes are available online. Our website, www.5MinuteConsult.com, delivers quick answers to your questions. It is an ideal resource for patient care. Integrating The 5-Minute Clinical Consult content into your workflow is easy and fast. And our patient education handouts can assist in helping you meet meaningful use compliance. The site promises an easy-to-use interface, allowing smooth maneuverability between topics, algorithms, images, videos, and patient education materials as well as more than 1,500 online-only topics. Evidence-based health care is the integration of the best medical information with the values of the patient and your skill as a clinician. We have updated our EBM content so you can focus on how to best apply it in your practice. The algorithm section includes both diagnostic and treatment algorithms. This easy-to-use graphic method helps you evaluate an abnormal finding and prioritize treatment. They are also excellent teaching tools, so share them with the learners in your office. This book and website are a source to solve problems; to help evaluate, diagnose, and treat patients’ concerns. Use your knowledge, through your words and actions, to address their anxiety. The 5-Minute Clinical Consult editorial team values your observations, so please share your thoughts, suggestions, and constructive criticism through our website, www.5MinuteConsult.com. FRANK J. DOMINO, MD

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EVIDENCE-BASED MEDICINE

WHAT IS EVIDENCE-BASED MEDICINE? emember when we used to treat every otitis media with antibiotics? These recommendations came about because we applied logical reasoning to observational studies. If bacteria cause an acute otitis media, then antibiotics should help it resolve sooner, with less morbidity. Yet, when rigorously studied (via a systematic review), we found little benefit to this intervention. The underlying premise of evidence-based medicine (EBM) is the evaluation of medical interventions and the literature that supports those interventions, in a systematic fashion. EBM hopes to encourage treatments proven to be effective and safe. And when insufficient data exists, it hopes to inform you on how to safely proceed. EBM uses end points of real patient outcomes, morbidity, mortality, and risk. It focuses less on intermediate outcomes (bone density) and more on patient conditions (hip fractures). Implementing EBM requires three components: the best medical evidence, the skill and experience of the provider, and the values of the patients. Should this patient be screened for prostate cancer? It depends on what is known about the test, on what you know of its benefits and harms, your ability to communicate that information, and that patient’s informed choice. This book hopes to address the first EBM component, providing you access to the best information in a quick format. Although not every test or treatment has this level of detail, many of the included interventions here use systematic review literature support. The language of medical statistics is useful in interpreting the concepts of EBM. Below is a list of these terms, with examples to help take the confusion and mystery out of their use.

R

Prevalence: proportion of people in a population who have a disease (in

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the United States, 0.3% [3 in 1,000] people >50 years have colon cancer) Incidence: How many new cases of a disease occur in a population during an interval of time; for example, “The estimated incidence of colon cancer in the United States is 104,000 in 2005.” Sensitivity: Percentage of people with disease who test positive; for mammography, the sensitivity is 71–96%. Specificity: Percentage of people without disease who test negative; for mammography, the specificity is 94–97%. Suppose you saw ML, a 53-year-old woman, for a health maintenance visit, ordered a screening mammogram, and the report demonstrates an irregular area of microcalcifications. She is waiting in your office to receive her test results, what can you tell her? Sensitivity and specificity refer to characteristics of people who are known to have disease (sensitivity) or those who are known not to have disease (specificity). But, what you have is an abnormal test result. To better explain this result to ML, you need the positive predictive value. Positive predictive value (PPV): Percentage of positive test results that are truly positive; the PPV for a woman aged 50–59 years is approximately 22%. That is to say that only 22% of abnormal screening mammograms in this group truly identified cancer. The other 78% are false positives. You can tell ML only one out of five abnormal mammograms correctly identify cancer; the four are false positives, but the only way to know which mammogram is correct is to do further testing. The corollary of the PPV is the negative predictive value (NPV), which is the percentage of negative test results that are truly negative. The PPV and NPV tests are population-dependent, whereas the sensitivity and specificity are characteristics of the test, and have little to do with the patient in front of you. So when you receive an abnormal lab result, especially a screening test such as mammography, understand their limits based on their PPV and NPV. Treatment information is a little different. In discerning the statistics of randomized controlled trials of interventions, first consider an example.

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The Scandinavian Simvastatin Survival Study (4S) (Lancet. 1994;344[8934]:1383–1389) found using simvastatin in patients at high risk for heart disease for 5 years resulted in death for 8% of simvastatin patients versus 12% of those on placebo; this results in a relative risk of 0.70, a relative risk reduction of 33%, and a number needed to treat of 25. There are two ways of considering the benefits of an intervention with respect to a given outcome. The absolute risk reduction is the difference in the percentage of people with the condition before and after the intervention. Thus, if the incidence of myocardial infarction (MI) was 12% for the placebo group and 8% for the simvastatin group, the absolute risk reduction is 4% (12% − 8% = 4%). The relative risk reduction reflects the improvement in the outcome as a percentage of the original rate and is commonly used to exaggerate the benefit of an intervention. Thus, if the risk of MI were reduced by simvastatin from 12% to 8%, then the relative risk reduction would be 33% (4% / 12% = 33%); 33% sounds better than 4%, but the 4% is the absolute risk reduction and reflects the true outcome. Absolute risk reduction is usually a better measure of clinical significance of an intervention. For instance, in one study, the treatment of mild hypertension has been shown to have relative risk reduction of 40% over 5 years (40% fewer strokes in the treated group). However, the absolute risk reduction was only 1.3%. Because mild hypertension is not strongly associated with strokes, aggressive treatment of mild hypertension yields only a small clinical benefit. Don’t confuse relative risk reduction with relative risk. Absolute (or attributable) risk (AR): the percentage of people in the placebo or intervention group who reach an end point; in the simvastatin study, the absolute risk of death was 8%. Relative risk (RR): the risk of disease of those treated or exposed to some intervention (i.e., simvastatin) divided by those in the placebo group or who were untreated • If RR is 1.0, it increases risk—the greater the number, the greater the

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risk increase. Relative risk reduction (RRR): the relative decrease in risk of an end point compared to the percentage of that end point in the placebo group If you are still confused, just remember that the RRR is an overestimation of the actual effect. Number needed to treat (NNT): This is the number of people who need to be treated by an intervention to prevent one adverse outcome. A “good” NNT can be a large number (>100) if risk of serious outcome is great. If the risk of an outcome is not that dangerous, then lower (40 years • Obesity • PCOS • Diabetes mellitus • Nulliparity • Early menarche or late menopause (>55 years of age) • Hypertension • Chronic anovulation or infertility • Unopposed estrogen therapy • History of breast cancer or endometrial hyperplasia • Tamoxifen use • Family history: gynecologic, breast, or colon cancer

DIAGNOSIS HISTORY • Menstrual history – Onset, severity (quantified by pad/tampon use, presence and size of clots), timing of bleeding (unpredictable or episodic) – Menorrhagia with onset of menarche is suggestive of a coagulation disorder. – Menopausal status – Association with other factors (e.g., coitus, contraception, weight loss/gain) • Gynecologic history: gravidity and parity, STI history, previous Pap smear results • Review of systems (exclude symptoms of pregnancy and of bleeding

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disorders, bleeding from other orifices, stress, exercise, recent weight change, visual changes, headaches, galactorrhea) • Medication history: Evaluate for use of aspirin, anticoagulants, hormones, and herbal supplements (1,2).

ALERT Postmenopausal bleeding is any bleeding that occurs >1 year after the last menstrual period; cancer must always be ruled out (2)[C].

PHYSICAL EXAM Discover anatomic or organic causes of AUB. • Evaluate for – Body mass index (obesity) – Pallor, vital signs (anemia) – Visual field defects (pituitary lesion) – Hirsutism or acne (hyperandrogenism) – Goiter (thyroid dysfunction) – Galactorrhea (hyperprolactinemia) – Purpura, ecchymosis (bleeding disorders) • Pelvic exam – Evaluate for uterine irregularities and Tanner stage. – Check for foreign bodies. – Rule out rectal or urinary tract bleeding. – Include Pap smear and tests for STIs (2)[C].

Pediatric Considerations Premenarchal children with vaginal bleeding should be evaluated for foreign bodies, physical/sexual abuse, possible infections, and signs of precocious puberty.

DIFFERENTIAL DIAGNOSIS See “Etiology.”

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Everyone: urine human chorionic gonadotropin (hCG; rule out pregnancy

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and/or hydatidiform mole) and complete blood count (CBC) (1) – For acute bleeding, a type and cross should be obtained (3)[C]. • If disorder of hemostasis is suspected, a partial thromboplastin time (PTT), prothrombin time (PT), activated partial thromboplastin time (aPTT), and fibrinogen level is appropriate (3)[C]. • If anovulation is suspected: thyroid-stimulating hormone (TSH) level, prolactin level (1) • Consider other tests based on differential diagnosis. – Follicle-stimulating hormone (FSH) level to evaluate for hypo- or hypergonadotropism – Coagulation studies and factors if coagulopathy is suspected (1) – 17-Hydroxyprogestrone if congenital adrenal hyperplasia is suspected – Testosterone and/or dehydroepiandrosterone sulfate (DHEA-S) if PCOS – Screening for STI • Endometrial biopsy (EMB) should be performed as part of the initial evaluation for postmenopausal uterine bleeding and in premenopausal women with risk factors for endometrial carcinoma. Medical management can be initiated in premenopausal women with normal TVUS and low risk for malignancy (1)[A]. • TVUS, sonohysterography, and hysteroscopy may be similarly effective in detection of intrauterine pathology in premenopausal women with AUB (1) [A]. • If normal findings following imaging in patients without known risk factors for endometrial carcinoma, a biopsy should be performed if not done so previously (2)[C].

Diagnostic Procedures/Other • Pap smear to screen for cervical cancer if age >21 years (2)[C] • EMB should be performed in – Women age >35 years with AUB to rule out cancer or premalignancy – Postmenopausal women with endometrial thickness >5 mm – Women aged 18 to 35 years with AUB and risk factors for endometrial cancer (see “Risk Factors”) – Perform on or after day 18 of cycle, if known; secretory endometrium

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confirms ovulation occurred. • Dilation and curettage (D&C) – Perform if bleeding is heavy, uncontrolled, or if emergent medical management has failed. – Perform if unable to perform EMB in office (2)[C]. • Hysteroscopy if another intrauterine lesion is suspected

Test Interpretation Pap smear could reveal carcinoma or inflammation indicative of cervicitis. Most EMBs show proliferative or dyssynchronous endometrium (suggesting anovulation) but can show simple or complex hyperplasia without atypia, hyperplasia with atypia, or endometrial adenocarcinoma.

TREATMENT Attempt to rule out other causes of bleeding prior to instituting therapy.

GENERAL MEASURES NSAIDs (naproxen sodium 500 mg BID, mefenamic acid 500 mg TID, ibuprofen 600 to 1,200 mg/day) (1)[B] • Decreases amount of blood loss and pain compared with placebo, with no one NSAID clearly superior

MEDICATION First Line • Acute, emergent, nonovulatory bleeding – Conjugated equine estrogen (Premarin): 25 mg IV q4h (max 6 doses) or 2.5 mg PO q6h should control bleeding in 12 to 24 hours (4)[A]. – D&C if no response after two to four doses of Premarin or sooner if bleeding >1 pad/hr (2)[C] – Then change to oral contraceptive pill (OCP) or progestin for cycle regulation, that is, IUD (5)[A] • Acute, nonemergent, nonovulatory bleeding – Combination OCP with ≥30 μg estrogen given as a taper. An example of a tapered dose: 4 pills/day for 4 days; 3 pills/day for 3 days; 2 pills/day for 2

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days, daily for 3 weeks then 1 week off, then cycle on OCP for at least 3 months. • Nonacute, nonovulatory bleeding (ranked in order based on decision analysis as best option based on efficacy, cost, side effects, and consumer acceptability) (5)[A] – Levonorgestrel IUD (Mirena) is the most effective form of progesterone delivery and is not inferior to surgical management. – Progestins: medroxyprogesterone acetate (Provera) 10 mg/day for 5 to 10 days each month. Daily progesterone for 21 days per cycle results in significantly less blood loss. – OCPs: 20 to 35 μg estrogen plus progesterone • Do not use estrogen if contraindications, such as suspicion for endometrial hyperplasia or carcinoma, history of deep vein thrombosis (DVT), or the presence of smoking in women >35 years of age (relative contraindication), are present. • Precautions – Failed medical treatment requires further workup. – Consider DVT prophylaxis when treating with high-dose estrogens (2)[C].

Second Line • Leuprolide (varying doses and duration of action); gonadotropin-releasing hormone (GnRH) agonist • Danazol (200 to 400 mg/day for a maximum of 9 months) is more effective than NSAIDs but is limited by androgenic side effects and cost. It has been essentially replaced by GnRH agonists. • Antifibrinolytics such as tranexamic acid (Lysteda) 650 mg, 2 tablets TID (max 5 days during menstruation) (1)[A] • Metformin or Clomid alone or in combination in women with PCOS who desire ovulation and pregnancy

ISSUES FOR REFERRAL • If an obvious cause for vaginal bleeding is not found in a pediatric patient, refer to a pediatric endocrinologist or gynecologist. • Patients with persistent bleeding despite medical treatment require reevaluation and possible referral.

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ADDITIONAL THERAPIES • Antiemetics if treating with high-dose estrogen or progesterone (2)[C] • Iron supplementation if anemia (usually iron deficiency) is identified

SURGERY/OTHER PROCEDURES • Hysterectomy in cases of endometrial cancer or if medical therapy fails or if other uterine pathology is found • Endometrial ablation is less expensive than hysterectomy and is associated with high patient satisfaction; failure of primary medical treatment is not necessary (1,4)[A]. – This is a permanent procedure and should be avoided in patients who desire continued fertility.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Significant hemorrhage causing acute anemia with signs of hemodynamic instability; with acute bleeding, replace volume with crystalloid and blood, as necessary (1)[A]. • Pad counts and clot size can be helpful to determine and monitor amount of bleeding. • Discharge criteria – Hemodynamic stability – Control of vaginal bleeding (2)[C]

ONGOING CARE FOLLOW-UP RECOMMENDATIONS • Once stable from acute management, recommend follow-up evaluation in 4 to 6 months for further evaluation (5). • Routine follow-up with a primary care or OB/GYN provider

Patient Monitoring Women treated with estrogen or OCPs should keep a menstrual diary to document bleeding patterns and their relation to therapy.

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DIET No restrictions, although a 5% reduction in weight can induce ovulation in anovulation caused by PCOS.

PATIENT EDUCATION Explain possible/likely etiologies. • Answer all questions, especially those related to cancer and fertility. • http://www.acog.org/Patients

PROGNOSIS • Varies with pathophysiologic process • Most anovulatory cycles can be treated with medical therapy and do not require surgical intervention.

COMPLICATIONS • Iron deficiency anemia • Uterine cancer in cases of prolonged unopposed estrogen stimulation

REFERENCES 1. Sweet MG, Schmidt-Dalton TA, Weiss PM, et al. Evaluation and management of abnormal uterine bleeding in premenopausal women. Am Fam Physician. 2012;85(1):35–43. 2. Committee on Practice Bulletins—Gynecology. Practice bulletin no. 128: diagnosis of abnormal uterine bleeding in reproductive-aged woman. Obstet Gynecol. 2012;120(1):197–206. 3. American College of Obstetricians and Gynecologists. ACOG Committee Opinion No. 557: management of acute abnormal uterine bleeding in nonpregnant reproductive-aged women. Obstet Gynecol. 2013;121(4):891– 896. 4. DeVore GR, Owens O, Kase N. Use of intravenous Premarin in the treatment of dysfunctional uterine bleeding—a double-blind randomized control study. Obstet Gynecol. 1982;59(3):285–291. 5. Marjoribanks J, Lethaby A, Farquhar C. Surgery versus medical therapy for heavy menstrual bleeding. Cochrane Database Syst Rev. 2006; (2):CD003855.

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ADDITIONAL READING • Farquhar C, Ekeroma A, Furness S, et al. A systematic review of transvaginal ultrasonography, sonohysterography and hysteroscopy for the investigation of abnormal uterine bleeding in premenopausal women. Acta Obstet Gynecol Scand. 2003;82(6):493–504. • Kouides PA, Conard J, Peyvandi F, et al. Hemostasis and menstruation: appropriate investigation for underlying disorders of hemostasis in women with excessive menstrual bleeding. Fertil Steril. 2005;84(5):1345–1351. • Lethaby AE, Cooke I, Rees M. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev. 2005;(4):CD002126. • Lethaby A, Farquhar C, Cooke I. Antifibrinolytics for heavy menstrual bleeding. Cochrane Database Syst Rev. 2000;(4):CD000249. • Lethaby A, Irvine G, Cameron I. Cyclical progestogens for heavy menstrual bleeding. Cochrane Database Syst Rev. 2008;(1):CD001016.

SEE ALSO • Dysmenorrhea; Menorrhagia (Heavy Menstrual Bleeding) • Algorithm: Menorrhagia

CODES ICD10 • N93.9 Abnormal uterine and vaginal bleeding, unspecified • N93.8 Other specified abnormal uterine and vaginal bleeding • N91.2 Amenorrhea, unspecified

CLINICAL PEARLS • AUB is irregular bleeding that occurs in the absence of pathology, making it a diagnosis of exclusion. • Anovulation accounts for 90% of AUB. • An EMB should be performed in all women >35 years of age with AUB to

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rule out cancer or premalignancy, and it should be considered in women aged 18 to 35 years with AUB and risk factors for endometrial cancer. • It is appropriate to initiate medical therapy in females 65 years who have had adequate prior screening and no history of CIN 2+ in the last 20 years should not be screened for cervical cancer. Adequate prior screening is defined as three consecutive, negative cytology results or two consecutive, negative HPV + cytology “contesting” results within 10 years before cessation of screening (with the most recent test within the last 5 years).

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• Routine screening should continue for at least 20 years after spontaneous regression or appropriate management of a high-grade precancerous lesion, even if this extends screening past the age 65 years.

Pregnancy Considerations • Squamous intraepithelial lesions can progress during pregnancy but often regress postpartum. • Colposcopy only to exclude the presence of invasive cancer in high-risk women • Endocervical curettage is contraindicated during pregnancy (2). • Unless cancer is identified or suspected, treatment of CIN is contraindicated during pregnancy.

EPIDEMIOLOGY Cervical cancer is the fourth most common type of cancer in women worldwide. • Predominant age: can occur at any age, but incidence of CIN 3 peaks between ages 25 and 29 years; invasive disease peaks 15 years later. Cervical cancer most commonly occurs in women aged 35 to 55 years.

Incidence In United States: Approximately 12,990 new cases of cervical cancer are diagnosed and 4,120 deaths from the disease yearly. The incidence of cervical cancer in the United States has decreased by more than 50% in the past 30 years, likely because of widespread cervical cancer screening tests.

Prevalence • In 2004, in the United States, there were approximately 250,726 women who had a history of cervical cancer. • Point prevalence of HPV positivity is highest in those 18 to 22 years of age (as high as 70%), falling off rapidly as women enter their 30s.

ETIOLOGY AND PATHOPHYSIOLOGY HPV DNA is found in virtually all cervical carcinomas and precursor lesions worldwide. • High-risk HPV types: 16, 18, 31, 33, 35, 45, 52, and 58 are common

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oncogenic virus types for cervical cancer. • HPV 16 is the most carcinogenic HPV genotype and accounts for 55–60% of all cervical cancers. • HPV 18 is the next most carcinogenic HPV genotype. HPV 18 causes a greater proportion of glandular cancers, adenocarcinoma, and adenosquamous carcinoma than squamous cell carcinoma. • Most HPV infections are transient, becoming undetectable within 1 to 2 years. Persistent infections are what place women at significant risk for developing precancerous lesions. • Low-risk types: HPV viral types 6, 11, 42, 43, and 44 are considered common low-risk types and may cause genital warts. HPV 6 and 11 (cause 90% of benign anogenital warts) can lead to low-grade squamous intraepithelial lesion (LSIL) and CIN 1.

RISK FACTORS • Previous or current HPV infection • HIV infection and other immunosuppressive conditions • In utero exposure to diethylstilbestrol • Previous treatment of a high-grade precancerous lesion or cervical cancer • Cigarette smoking • Early age at first coitus (24 years of age) – Option 1: HPV testing (preferred) If HPV +, proceed to colposcopy (2)[B]. If HPV negative, repeat cotesting at 3 years (2)[B]. – Option 2: Repeat cytology at 1 year (acceptable) (2) If repeat cytology ASC or greater, proceed to colposcopy. If repeat cytology is negative, proceed to routine screening in 3 years. • ASC-H: Colposcopy required • LSIL: (>24 years of age) – LSIL with negative HPV test: Repeat cotesting at 1 year (preferred). If repeat cotesting is negative, repeat cotesting in 3 years. If cotesting is positive, proceed to colposcopy. – LSIL with no HPV test or positive HPV test: Proceed to colposcopy. – LSIL in pregnancy: Colposcopy preferred, but it is acceptable to defer colposcopy to postpartum (2). • HSIL: loop electrosurgical excision procedure (LEEP) or colposcopy (2)[B] • AGCs: colposcopy with endocervical sampling and endometrial sampling (if 35 years or older or at risk for endometrial neoplasia) (2)[A] • Atypical endometrial cells: endometrial and endocervical sampling

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– If negative, perform colposcopy. • Women with no lesion on colposcopy or CIN I (preceded by “lesser abnormalities” such as ASC-US, LSIL, HPV 16+, HPV 18+, and persistent HPV) – Follow-up without treatment: cotesting at 12 months – If both HPV and cytology are negative, age-appropriate retesting 3 years later – If either positive, proceed to colposcopy. If persistent CIN 1 for at least 2 years, proceed to treatment with ablative or excisional methods. • Ages 21 to 24: Management is slightly different than above; see “ASCCP guidelines” (2) or algorithm “Pap, Normal and Abnormal in Women Ages 21– 24 Years.” • Age >30: If cytology is negative but HPV is positive, repeat cotesting at 1 year is acceptable.

Test Interpretation Atypical squamous or columnar cells, coarse nuclear material, increased nuclear diameter, koilocytosis (HPV hallmark)

TREATMENT ASCCP guidelines: Evidence-based management algorithms guide Pap smear and postcolposcopic diagnostics and therapeutics and are available online at http://www.asccp.org/Guidelines (2).

GENERAL MEASURES Office evaluation and observation; promote smoking cessation; promote protected intercourse; promote immunization.

MEDICATION • Infective/reactive Pap smear: Treat trichomoniasis, symptomatic candida, or shift in flora suggestive of bacterial vaginosis found on Pap smear results. • Condyloma acuminatum: may be treated with cryotherapy or podophyllin topically q1–2wk or podofilox 0.5% applied BID × 3 days then off 4 days, repeated for 1 to 4 weeks, OR trichloroacetic acid applied topically by a

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physician and covered for 5 to 6 days, OR imiquimod cream 3 times per week at bedtime, up to 16 weeks.

SURGERY/OTHER PROCEDURES • Persistent CIN 1, 2, or 3: ablative or excisional methods. If inadequate colposcopy for CIN 2 or 3 or recurrent CIN 2 or 3, diagnostic excisional procedure is done. For adenocarcinoma in situ, hysterectomy is preferred. • Cryotherapy, laser ablation, LEEP/large loop excision of transition zone, or cold-knife conization are all effective but require different training and with different side effects for patient. If cervical malignancy, see “Cervical Malignancy.”

ONGOING CARE FOLLOW-UP RECOMMENDATIONS After treatment (excision or ablation) of CIN 2 or 3, women may reenter routine screening only after negative cotesting between 12 and 24 months. Screening should be continued for 20 years.

DIET Promote increased intake of antioxidant-rich foods.

PATIENT EDUCATION HPV vaccination, smoking cessation, protected intercourse, regular screening with Pap smear per guidelines

PROGNOSIS • Progression of CIN to invasive cervical cancer is slow, and the likelihood of regression is high: Up to 43% of CIN 2 and 32% of CIN 3 lesions may regress. CIN 3 has a 30% probability of becoming invasive cancer over a 30year period, although only about 1% if treated. • CIN 3 becomes invasive (4). Lesions discovered early are amenable to treatment with excellent results and few recurrences. • 1- and 5-year relative survival rates for cervical cancer patients are 87% and 68%, respectively. The 5-year survival rate for patients diagnosed with

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localized disease is 91% (5).

COMPLICATIONS Aggressive cervical surgery may be associated with cervical stenosis, cervical incompetence, and scarring affecting cervical dilatation in labor.

REFERENCES

1. Yang KY. Abnormal pap smear and cervical cancer in pregnancy. Clin Obstet Gynecol. 2012;55(3):838–848. 2. Massad S, Einstein MH, Huh WK, et al. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis. 2013;17(5 Suppl 1):S1–S27. 3. U.S. Preventive Services Task Force. Cervical cancer: screening. U.S. Preventive Services Task Force Web site. http://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/cervi cancer-screening. Accessed December 6, 2016. 4. McCredie MR, Sharples KJ, Paul C, et al. Natural history of cervical neoplasia and risk of invasive cancer in women with cervical intraepithelial neoplasia 3: a retrospective cohort study. Lancet Oncol. 2008;9(5):425–434. 5. American Cancer Society. Cancer facts & figures 2014. American Cancer Society Web site. http://www.cancer.org/acs/groups/content/@research/documents/webcontent/acspc042151.pdf. Accessed December 6, 2016.

ADDITIONAL READING American Society for Colposcopy and Cervical Pathology. Management guidelines. http://www.asccp.org/asccp-guidelines

SEE ALSO • Cervical Malignancy; Condylomata Acuminata; Trichomoniasis; Vulvovaginitis, Prepubescent • Algorithm: Pap, Normal and Abnormal in Nonpregnant Women Ages 25

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Years and Older; Pap, Normal and Abnormal in Women Ages 21-24 Years

CODES ICD10 • R87.619 Unspecified abnormal cytological findings in specimens from cervix uteri • N87.9 Dysplasia of cervix uteri, unspecified • N87.1 Moderate cervical dysplasia

CLINICAL PEARLS • HPV is present in virtually all cervical cancers (99.7%), but most HPV infections are transient. • Vaccine should be offered prior to onset of any sexual activity for maximum effectiveness. • Know and adhere to recognized screening guidelines to avoid the harms of overscreening. • Optimal screening strategy is in evolution. HPV-primary with cytologysecondary strategies will likely supplant current guidelines in near future.

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ABORTION, SPONTANEOUS (MISCARRIAGE) Clara M. Keegan, MD BASICS DESCRIPTION • Spontaneous abortion (SAb) (miscarriage) is the failure or loss of a pregnancy before 13 weeks’ gestational age (WGA). • Related terms – Anembryonic gestation: gestational sac on ultrasound (US) without visible embryo after 6 WGA – Complete abortion: entire contents of uterus expelled – Ectopic pregnancy: pregnancy outside the uterus – Embryonic or fetal demise: cervix closed; embryo or fetus present in the uterus without cardiac activity. – Incomplete abortion: abortion with retained products of conception, generally placental tissue – Induced or therapeutic abortion: evacuation of uterine contents or products of conception medically or surgically – Inevitable abortion: cervical dilatation or rupture of membranes in the presence of vaginal bleeding – Recurrent abortion: ≥3 consecutive pregnancy losses at 35 years; at age 40 years, the loss rate is twice that of age 20 years.

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Incidence • Threatened abortion (1st-trimester bleeding) occurs in 20–25% of clinical pregnancies. • Between 10% and 15% of all clinically recognized pregnancies end in SAb, with 80% of these occurring within 12 weeks after last menstrual period (LMP) (1). • When both clinical and biochemical (β-hCG detected) pregnancies are considered, about 30% of pregnancies end in SAb. • One in four women will have a SAb during her lifetime (1).

ETIOLOGY AND PATHOPHYSIOLOGY • Chromosomal anomalies (50% of cases) • Congenital anomalies • Trauma • Maternal factors: uterine abnormalities, infection (toxoplasma, other viruses, rubella, cytomegalovirus, herpesvirus), maternal endocrine disorders, hypercoagulable state

Genetics Approximately 50% of 1st-trimester SAbs have significant chromosomal anomalies, with 50% of these being autosomal trisomies and the remainder being triploidy, tetraploidy, or 45X monosomies.

RISK FACTORS Most cases of SAb occur in patients without identifiable risk factors; however, risk factors include the following: • Chromosomal abnormalities • Advancing maternal age • Uterine abnormalities • Maternal chronic disease (antiphospholipid antibodies, uncontrolled diabetes mellitus, polycystic ovarian syndrome, obesity, hypertension, thyroid disease, renal disease) • Other possible contributing factors include smoking, alcohol, cocaine use, infection, and luteal phase defect.

GENERAL PREVENTION

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• Insufficient evidence supports the use of aspirin and/or other anticoagulants, bed rest, hCG, immunotherapy, progestogens, uterine muscle relaxants, or vitamins for general prevention of SAb, before or after threatened abortion is diagnosed. • By the time hemorrhage begins, 1/2 of pregnancies complicated by threatened abortion already have no fetal cardiac activity. • Recurrent abortion: Women with a history of ≥3 prior SAbs may benefit from progestogens (OR 0.39, 95% CI 0.21–0.72) (2)[A]. • Antiphospholipid syndrome: The combination of unfractionated heparin and aspirin reduces risk of SAb in women with antiphospholipid antibodies and a history of recurrent abortion (RRR 46%, 95% CI 0.29–0.71) (3)[A].

DIAGNOSIS HISTORY • The possibility of pregnancy should be considered in a reproductive-age woman who presents with nonmenstrual vaginal bleeding. • Vaginal bleeding – Characteristics (amount, color, consistency, associated symptoms), onset (abrupt or gradual), duration, intensity/quantity, and exacerbating/precipitating factors – Document LMP if known: allows calculation of estimated gestational age • Abdominal pain/uterine cramping, as well as associated nausea/vomiting/syncope • Rupture of membranes • Passage of products of conception • Prenatal course: toxic or infectious exposures, family or personal history of genetic abnormalities, past history of ectopic pregnancy or SAb, endocrine disease, autoimmune disorder, bleeding/clotting disorder

PHYSICAL EXAM • Orthostatic vital signs to estimate hemodynamic stability • Abdominal exam for tenderness, guarding, rebound, bowel sounds (peritoneal signs more likely with ectopic pregnancy)

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• Speculum exam for visual assessment of cervical dilation, blood, and products of conception (confirms diagnosis of SAb) • Bimanual exam to assess for uterine size–dates discrepancy and adnexal tenderness or mass

DIFFERENTIAL DIAGNOSIS • Ectopic pregnancy: potentially life-threatening; must be considered in any woman of childbearing age with abdominal pain and vaginal bleeding • Physiologic bleeding in normal pregnancy (implantation bleeding) • Subchorionic bleeding • Cervical polyps, neoplasia, and/or inflammatory conditions • Hydatidiform mole pregnancy • hCG-secreting ovarian tumor

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Quantitative hCG – Particularly useful if intrauterine pregnancy (IUP) has not been documented by US. – Serial quantitative serum hCG measurements can assess viability of the pregnancy. Serum hCG should rise at least 53% every 48 hours through 7 weeks after LMP. An inappropriate rise, plateau, or decrease of hCG suggests abnormal IUP or possible ectopic pregnancy. • Complete blood count (CBC) with differential • Rh type • Cultures: gonorrhea/chlamydia • US exam to evaluate fetal viability and to rule out ectopic pregnancy (4)[A] – hCG >2,000 mIU/mL necessary to detect IUP via transvaginal US (TVUS), >5,500 mIU/mL for abdominal US – TVUS criteria for nonviable intrauterine gestation: 7-mm fetal pole without cardiac activity or 25-mm gestational sac without a fetal pole, IUP with no growth over 1 week, or previously seen IUP no longer visible – Structures and timing: with TVUS, gestational sac of 2 to 3 mm generally seen around 5 WGA; yolk sac by 5.5 WGA; fetal pole with cardiac activity by 6 WGA

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Follow-Up Tests & Special Considerations • In the case of vaginal bleeding with no documented IUP and hCG 200 mg/kg in children. However, poisoning also occurs after acute and chronic ingestions of lesser amounts in susceptible individuals, including those who regularly abuse alcohol, are chronically malnourished, or take medications that affect hepatic metabolism of acetaminophen. • Therapeutic adult doses are 0.5 to 1 g q4–6h, up to a maximum of 4 g/day. Therapeutic pediatric doses are 10 to 15 mg/kg q4–6h, not to exceed 5 doses in 24 hours. • System(s) affected: gastrointestinal, cardiovascular, renal/urologic, CNS. – Multisystem organ failure can occur. • Synonym(s): paracetamol poisoning

Geriatric Considerations Increased risk of hepatic damage in frail elderly due to decreased hepatic phase II metabolism and hepatotoxic medications. Expert opinion recommendations are to keep dose of acetaminophen at ≤3,000 mg/day in senior citizens, those with liver disease and with alcohol abuse disorders.

Pediatric Considerations Hepatic damage at toxic acetaminophen levels is decreased in young children. This may be due to larger glutathione stores.

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Pregnancy Considerations • Increased incidence of spontaneous abortion, especially with overdose at early gestational age • Incidence of spontaneous abortion or fetal death appears to be increased when N-acetylcysteine (NAC) treatment is delayed. • IV NAC is generally preferred in pregnancy since it may offer greater bioavailability.

EPIDEMIOLOGY • Predominant age: children and adults • Predominant sex: no reported association • Intentional vs. unintentional ingestion (52% vs. 48%)

Incidence The annual incidence of APAP in the ED increased from 2.0 (95% CI: 0.2–7.2) cases per 10,000 patients in 2005 to 3.4 (95% CI: 1.1–8.8) in 2010.

Prevalence • >38,000 hospitalizations per year on average from 1998 to 2011 for acetaminophen-related poisonings in the United States, nearly one half were unintentional largely related to opioid–acetaminophen combinations. • 4 years, usually 4 mg/dose). – IV NAC (Acetadote) may cause anaphylactoid reactions, (3–6%) including rash, bronchospasm, pruritus, angioedema, tachycardia, or hypotension (higher rates seen in asthmatics and those with atopy) (3,4)[C]. • Reactions usually occur with loading dose. Slow or temporarily stop the

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infusion; may concurrently treat with antihistamines

Second Line • Oral racemethionine (methionine) • In cases of massive ingestions (e.g., levels > 1,000 mg/L, acidosis, coma/ hypotension), hemodialysis may be a beneficial adjunct therapy and improve survival (5)[C].

ISSUES FOR REFERRAL • Psychological evaluation in emergency room and close follow-up after intentional ingestions • Consider child abuse reporting if neglect led to overdose.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Toxic and intentional ingestions • Any reported ingestion with increased LFTs, acidosis on ABG, elevated creatinine, and so forth • Initiate aggressive age- and weight-appropriate IV hydration.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS • All patients should be evaluated at a health care facility. • Patients with evidence of organ failure, increased LFTs, or coagulopathy should be evaluated for ELT (emergency liver transplant) at a transplant center. • Activity may be restricted if significant hepatic damage is present. • Outpatient management of nontoxic accidental ingestions.

Patient Monitoring Ask about possible ingestion by others (i.e., suicide pacts).

DIET No special diet, except with severe hepatic damage

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PATIENT EDUCATION • Patients should be counseled to avoid Tylenol if already using combination product(s) containing acetaminophen. • Education of parents/caregivers during well-child visits. • Anticipatory guidance for caregivers, family, and cohabitants of potentially suicidal patients • Education of patients taking long-term acetaminophen therapy

PROGNOSIS • Complete recovery with early therapy • 65], creatinine >3.4 mg/dL [>300 μmol/L]) is associated with a poor prognosis and possible need for liver transplant (6)[C]. Early referral increases the chance for transplant success (4)[A]. • Hepatic failure is very rare in children 150

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μg/mL (993 μmol/L), >75 μg/mL (497 μmol/L), and >40 μg/mL (265 μmol/L) at 4, 8, and 12 hours after ingestion, respectively. • NAC should be started within 8 hours of ingestion for best chance of hepatic protection. Patients presenting near 8 hours should empirically receive NAC while waiting for labs. • All patients with acetaminophen liver injury (even after 8 hours) should receive NAC. • To enhance palatability, oral NAC can be diluted with a beverage of choice and served in a cup with lid and straw. • In January 2016 Cetylev, an effervescent lemon mint flavored tablet was approved by the FDA. Tablets come in strengths of 500 mg and 2.5 g of NAC.

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ACNE ROSACEA Daniel R. DiBlasi, DO • Shane L. Larson, MD BASICS DESCRIPTION • Rosacea is a chronic condition characterized by recurrent episodes of facial flushing, erythema (due to dilatation of small blood vessels in the face), papules, pustules, and telangiectasia (due to increased reactivity of capillaries) in a symmetric, central facial distribution. Sometimes associated with ocular symptoms (ocular rosacea). • Four subtypes: – Erythematotelangiectatic rosacea (ETR) – Papulopustular rosacea (PPR) – Phymatous rosacea – Ocular rosacea • System(s) affected: skin/exocrine • Synonym(s): rosacea

Geriatric Considerations • Uncommon >60 years of age • Effects of aging might increase the side effects associated with oral isotretinoin used for treatment (at present, data are insufficient due to lack of clinical studies in elderly patients ≥65 years).

EPIDEMIOLOGY Prevalence • Predominant age: 30 to 50 years • Predominant sex: female > male. However, males are at greater risk for progression to later stages.

ETIOLOGY AND PATHOPHYSIOLOGY • No proven cause • Possibilities include the following:

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– Thyroid and sex hormone disturbance – Alcohol, coffee, tea, spiced food overindulgence (unproven) – Demodex follicular parasite (suspected) – Exposure to cold, heat – Emotional stress – Dysfunction of the GI tract

Genetics People of Northern European and Celtic background commonly afflicted

RISK FACTORS • Exposure to spicy foods, hot drinks • Environmental factors: sun, wind, cold, heat

GENERAL PREVENTION No preventive measures known

COMMONLY ASSOCIATED CONDITIONS • Seborrheic dermatitis of scalp and eyelids • Keratitis with photophobia, lacrimation, visual disturbance • Corneal lesions • Blepharitis • Uveitis

DIAGNOSIS HISTORY • Usually have a history of episodic flushing with increases in skin temperature in response to heat stimulus in mouth (hot liquids), spicy foods, alcohol, sun exposure (solar elastosis) • Acne may have preceded onset of rosacea by years; nevertheless, rosacea usually arises de novo without preceding history of acne or seborrhea. • Excessive facial warmth and redness are the predominant presenting complaints. Itching is generally absent.

PHYSICAL EXAM

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• Rosacea has typical stages of evolution: – The rosacea diathesis: episodic erythema, “flushing and blushing” – Stage I: persistent erythema with telangiectases – Stage II: persistent erythema, telangiectases, papules, tiny pustules – Stage III: persistent deep erythema, dense telangiectases, papules, pustules, nodules; rarely persistent “solid” edema of the central part of the face (phymatous) • Facial erythema, particularly on cheeks, nose, and chin. At times, entire face may be involved. • Inflammatory papules are prominent; pustules and telangiectasia may be present. • Comedones are absent (unlike acne vulgaris). • Women usually have lesions on the chin and cheeks, whereas the nose is commonly involved in men. • Ocular findings (mild dryness and irritation with blepharitis, conjunctival injection, burning, stinging, tearing, eyelid inflammation, swelling, and redness) are present in 50% of patients.

DIFFERENTIAL DIAGNOSIS • Drug eruptions (iodides and bromides) • Granulomas of the skin • Cutaneous lupus erythematosus • Carcinoid syndrome • Deep fungal infection • Acne vulgaris • Seborrheic dermatitis • Steroid rosacea (abuse) • Systemic lupus erythematosus • Lupus pernio (sarcoidosis)

DIAGNOSTIC TESTS & INTERPRETATION Diagnosis is based on physical exam findings.

Test Interpretation • Inflammation around hypertrophied sebaceous glands, producing papules,

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pustules, and cysts • Absence of comedones and blocked ducts • Vascular dilatation and dermal lymphocytic infiltrate

TREATMENT GENERAL MEASURES • Proper skin care and photoprotection are important components of management plan (1)[B]. Use of mild, nondrying soap is recommended; local skin irritants should be avoided. • Avoidance of triggers • Reassurance that rosacea is completely unrelated to poor hygiene • Treat psychological stress if present. • Topical steroids should not be used, as they may aggravate rosacea. • Avoid oil-based cosmetics: – Others are acceptable and may help women tolerate symptoms • Electrodesiccation or chemical sclerosis of permanently dilated blood vessels • Possible evolving laser therapy • Support physical fitness.

MEDICATION First Line • Topical metronidazole preparations once (1% formulation) or twice (0.75% formulations) daily for 7 to 12 weeks was significantly more effective than placebo in patients with moderate to severe rosacea. A rosacea treatment system (cleanser, metronidazole 0.75% gel, hydrating complexion corrector, and sunscreen SPF 30) may offer superior efficacy and tolerability to metronidazole (2)[A]. • Azelaic acid (Finacea) is very effective as initial therapy; azelaic acid topical alone is effective for maintenance (3)[A]. • Topical ivermectin 1% cream (2)[A] – Recently found to be more effective than metronidazole for treatment of PPR • Topical brimonidine tartrate 0.5% gel is effective in reducing erythema

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associated with ETR (4)[A]. – α2-Adrenergic receptor agonist; potent vasoconstrictor • Doxycycline 40-mg dose is at least as effective as 100-mg dose and has a correspondingly lower risk of adverse effects but is much more expensive (5) [A]. • Precautions: Tetracyclines may cause photosensitivity; sunscreen is recommended. • Significant possible interactions: – Tetracyclines: Avoid concurrent administration with antacids, dairy products, or iron. – Broad-spectrum antibiotics: may reduce the effectiveness of oral contraceptives; barrier method is recommended.

Second Line • Topical erythromycin • Topical clindamycin (lotion preferred) – Can be used in combination with benzoyl peroxide; commercial topical combinations are available • Possible use of calcineurin inhibitors (tacrolimus 0.1%; pimecrolimus 1%). Pimecrolimus 1% is effective to treat mild to moderate inflammatory rosacea (6)[A]. • Permethrin 5% cream; similar efficacy compared to metronidazole (7)[B]. For severe cases, oral isotretinoin at 0.3 mg/kg for a minimum of 3 months.

Pediatric Considerations Tetracyclines: not for use in children male (adult)

Prevalence • 80–95% of adolescents affected. A smaller percentage will seek medical advice. • 8% of adults aged 25 to 34 years; 3% at 35 to 44 years • African Americans 37%, Caucasians 24%

ETIOLOGY AND PATHOPHYSIOLOGY • Androgens (testosterone and dehydroepiandrosterone sulfate [DHEA-S]) stimulate sebum production and proliferation of keratinocytes in hair follicles (3). • Keratin plug obstructs follicle os, causing sebum accumulation and follicular distention. • Propionibacterium acnes, an anaerobe, colonizes and proliferates in the plugged follicle. • P. acnes promote proinflammatory mediators, causing inflammation of follicle and dermis.

Genetics • Familial association in 50% • If a family history exists, the acne may be more severe and occur earlier.

RISK FACTORS • Increased endogenous androgenic effect

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• Oily cosmetics, cocoa butter • Rubbing or occluding skin surface (e.g., sports equipment such as helmets and shoulder pads), telephone, or hands against the skin • Polyvinyl chloride, chlorinated hydrocarbons, cutting oil, tars • Numerous drugs, including androgenic steroids (e.g., steroid abuse, some birth control pills) • Endocrine disorders: polycystic ovarian syndrome, Cushing syndrome, congenital adrenal hyperplasia, androgen-secreting tumors, acromegaly • Stress • High-glycemic load and possibly high-dairy diets may exacerbate acne (3). • Severe acne may worsen with smoking.

COMMONLY ASSOCIATED CONDITIONS • Acne fulminans, pyoderma faciale • Acne conglobata, hidradenitis suppurativa • Pomade acne • SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, and osteitis) • Pyogenic arthritis, pyoderma gangrenosum, and acne (PAPA) and seborrhea, acne, hirsutism, and alopecia (SAHA) syndromes • Behçet syndrome, Apert syndrome • Dark-skinned patients: 50% keloidal scarring and 50% acne hyperpigmented macules

DIAGNOSIS HISTORY • Ask about duration, medications, cleansing products, stress, smoking, exposures, diet, and family history. • Females may worsen 1 week prior to menses.

PHYSICAL EXAM • Closed comedones (whiteheads) • Open comedones (blackheads) • Nodules or papules • Pustules (“cysts”)

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• Scars: ice pick, rolling, boxcar, atrophic macules, hypertrophic, depressed, sinus tracts • Grading system (American Academy of Dermatology, 1990) (3) – Mild: few papules/pustules; no nodules – Moderate: some papules/pustules; few nodules – Severe: numerous papules/pustules; many nodules – Very severe: acne conglobata, acne fulminans, acne inversa • Most common areas affected are face, chest, back, and upper arms (areas of greatest concentration of sebaceous glands) (3).

DIFFERENTIAL DIAGNOSIS • Folliculitis: gram negative and gram positive • Acne (rosacea, cosmetica, steroid-induced) • Perioral dermatitis • Chloracne • Pseudofolliculitis barbae • Drug eruption • Verruca vulgaris and plana • Keratosis pilaris • Molluscum contagiosum • Sarcoidosis • Seborrheic dermatitis • Miliaria

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) Only indicated if additional signs of androgen excess; if so, test for free and total testosterone and DHEA-S and consider LH and FSH (PCOS).

TREATMENT • Comedonal (grade 1): keratinolytic agent (see as follows for specific agents) • Mild inflammatory acne (grade 2): benzoyl peroxide or topical retinoid or benzoyl peroxide +/− topical antibiotic +/− topical retinoid (4) • Moderate inflammatory acne (grade 3): Add systemic antibiotic to grade 2

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regimen. • Severe inflammatory acne (grade 4): as in grade 3, or isotretinoin • Topical retinoid plus a topical antimicrobial agent is first-line treatment for more than mild disease. • Topical retinoid + antibiotic (topical or PO) is better than either alone for mild/moderate acne. • Topical retinoids are first-line agents for maintenance. Avoid long-term antibiotics for maintenance. • Avoid topical antibiotics as monotherapy. • Recommended vehicle type – Dry or sensitive skin: cream, lotion, or ointment – Oily skin, humid weather: gel, solution, or wash – Hair-bearing areas: lotion, hydrogel, or foam • Apply topical agents to entire affected area, not just visible lesions. • Mild soap daily to control oiliness; avoid abrasives. • Avoid drying agents with keratinolytic agents. • Gentle cleanser and noncomedogenic moisturizer help decrease irritation. • Oil-free, noncomedogenic sunscreens • Stress management if acne flares with stress

MEDICATION ALERT Most prescription of topical medications are very expensive, costing from $100 to several hundred dollars per tube. • Keratinolytic agents (alpha-hydroxy acids, salicylic acid, azelaic acid) (side effects include dryness, erythema, and scaling; start with lower strength, increase as tolerated) • Tretinoin (Retin-A, Retin-A Micro, Avita, Atralin) varying strengths and formulations: apply at bedtime; wash skin, let skin dry 30 minutes before application. – Retin-A Micro, Atralin, and Avita are less irritating, and stable with BP – May cause an initial flare of lesions; may be eased by 14-day course of oral antibiotics – Avoid in pregnant and lactating women.

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• Adapalene (Differin): 0.1%, apply topically at night. – Effective; less irritation than tretinoin or tazarotene – May be combined with benzoyl peroxide (Epiduo)—very effective in skin of color • Tazarotene (Tazorac): apply at bedtime. • Most effective and most irritating; teratogenic • Azelaic acid (Azelex, Finevin): 20% topically, BID – Keratinolytic, antibacterial, anti-inflammatory – Reduces postinflammatory hyperpigmentation in dark-skinned individuals – Side effects: erythema, dryness, scaling, hypopigmentation – Less effective in clinical use than in studies – Effective in postadolescent acne • Salicylic acid: 2%, less effective and less irritating than tretinoin • Alpha-hydroxy acids: available over-the-counter • Topical antibiotics and anti-inflammatories – Topical benzoyl peroxide 2.5% as effective as stronger preparations Gel penetrates better into follicles When used with tretinoin, apply benzoyl peroxide in morning and tretinoin at night. Side effects: irritation; may bleach clothes; photosensitivity • Topical antibiotics – Erythromycin 2% – Clindamycin 1% – Metronidazole gel or cream: apply once daily. – Azelaic acid (Azelex, Finevin): 20% cream: enhanced effect and decreased risk of resistance when used with zinc and benzoyl peroxide – Benzoyl peroxide-erythromycin (Benzamycin): especially effective with azelaic acid – Benzoyl peroxide-clindamycin (BenzaClin, DUAC, Clindoxyl) – Benzoyl peroxide-salicylic acid (Cleanse & Treat, Inova): similar in effectiveness to benzoyl peroxide-clindamycin – Sodium sulfacetamide (Sulfacet-R, Novacet, Klaron): useful in acne with seborrheic dermatitis or rosacea

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– Dapsone (Aczone) 5% gel: useful in adult females with inflammatory acne, may cause yellow/orange skin discoloration when mixed with benzoyl peroxide, very rare methemoglobinemia • Oral antibiotics: use for at least 6 to 8 weeks after initiation, discontinue after 12 to 18 weeks’ duration; indicated when acne is more severe, trunk involvement, unresponsive to topical agents, or at greater risk for scarring (5) [A] – Tetracycline: 500 to 1,000 mg/day divided BID; high dose initially, taper in 6 months, less effective than doxycycline or minocycline (4), side effects: photosensitivity, esophagitis – Minocycline: 100 to 200 mg/day, divided daily—BID; side effects include photosensitivity, urticaria, gray-blue skin, vertigo, hepatitis, lupus. – Doxycycline: 20 to 200 mg/day, divided daily—BID; side effects include photosensitivity. – Erythromycin: 500 to 1,000 mg/day; divided BID–QID; decreasing effectiveness as a result of increasing P. acnes resistance – Trimethoprim-sulfamethoxazole (Bactrim DS, Septra DS): 1 daily or BID – Azithromycin (Zithromax): 500 mg 3 days/week × 1 month, then 250 mg every other day × 2 months • Oral retinoids – Isotretinoin: 0.5 to 1 mg/kg/day divided BID to maximum 2 mg/kg/day divided BID for very severe disease; 60–90% cure rate; usually given for 12 to 20 weeks; maximum cumulative dose = 120 to 150 mg/kg; 20% of patients relapse and require retreatment (3)[A], 0.25 to 0.40 mg/kg/day in moderately severe acne Side effects: teratogenic, pancreatitis, excessive drying of skin, hypertriglyceridemia, hepatitis, blood dyscrasias, hyperostosis, premature epiphyseal closure, night blindness, erythema multiforme, StevensJohnson syndrome, suicidal ideation, psychosis Avoid tetracyclines or vitamin A preparations during isotretinoin therapy. Monitor for pregnancy, psychiatric/mood changes, complete blood count (CBC), lipids, glucose, and liver function tests at baseline and every month. Must be registered and adhere to manufacturer’s iPLEDGE program

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(www.ipledgeprogram.com) • Medications for women only – Oral contraceptives (3)[A],(4) Norgestimate/ethinyl estradiol (Ortho Tri-Cyclen), norethindrone acetate/ethinyl estradiol (Estrostep), drospirenone/ethinyl estradiol (Yaz, Yasmin), drospirenone/ethinyl estradiol/levomefolate (Beyaz, Safyral) are FDA approved. Levonorgestrel/ethinyl estradiol (Alesse) and most combined contraceptives effective • Spironolactone (Aldactone); 25 to 200 mg/day; antiandrogen; reduces sebum production

ISSUES FOR REFERRAL Consider referral/consultation to dermatologist. • Refractory lesions despite appropriate therapy • Consideration of isotretinoin therapy • Management of acne scars

ADDITIONAL THERAPIES • Acne hyperpigmented macules – Topical hydroquinones (1.5–10%) – Azelaic acid (20%) topically – Topical retinoids – Corticosteroids: low dose, suppresses adrenal androgens – Dapsone 5% gel (Aczone): topical, anti-inflammatory; use in patients over 12 years – Sunscreen for prevention • Light-based treatments – Ultraviolet A/ultraviolet B (UVA/UVB), blue or blue/red light; pulse dye, KTP, or infrared laser – Photodynamic therapy for 30 to 60 minutes with 5-aminolevulinic acid × 3 sessions is effective for inflammatory lesions. Greatest use when used as adjunct to medications or if can’t tolerate medications

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SURGERY/OTHER PROCEDURES • Comedo extraction after incising the layer of epithelium over closed comedo • Inject large cystic lesions with 0.05 to 0.3 mL triamcinolone (Kenalog 2 to 5 mg/mL); use 30-gauge needle, inject through pore, slightly distend cyst. • Acne scar treatment: retinoids, steroid injections, cryosurgery, electrodessication, micro/dermabrasion, chemical peels, laser resurfacing

COMPLEMENTARY & ALTERNATIVE MEDICINE Evidence suggests tea tree oil, seaweed extract, Kampo formulations, Ayurvedic formulations, rose extract, basil extract, epigallocatechin gallate, barberry extract, gluconolactone solution, and tea extract may be useful (4).

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Use oral or topical antibiotics for 3 months; taper as inflammatory lesions resolve.

DIET Avoid high-glycemic index foods and milk.

PATIENT EDUCATION • There may be a worsening of acne during first 2 weeks of treatment. • Results are typically seen after a minimum of 4 weeks of treatment.

PROGNOSIS Gradual improvement over time (usually within 8 to 12 weeks after beginning therapy)

COMPLICATIONS • Acne conglobata: severe confluent inflammatory acne with systemic symptoms • Facial scarring and psychological distress, including anxiety, depression, and suicidal ideation (3) • Postinflammatory hyperpigmentation, keloids, and scars are more common in skin of color.

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REFERENCES 1. Chien AL, Qi J, Rainer B, et al. Treatment of acne in pregnancy. J Am Board Fam Med. 2016;29(2):254–262. 2. Admani S, Barrio VR. Evaluation and treatment of acne from infancy to preadolescence. Dermatol Ther. 2013;26(6):462–466. 3. Dawson AL, Dellavalle RP. Acne vulgaris. BMJ. 2013;346:f2634. 4. Zaenglein AL, Pathy AL, Schlosser BJ, et al. Guidelines of care for the management of acne vulgaris. J Am Acad Dermatol. 2016;74(5):945.e33– 973.e33. 5. Del Rosso JQ, Kim G. Optimizing use of oral antibiotics in acne vulgaris. Dermatol Clin. 2009;27(1):33–42.

ADDITIONAL READING • Asai Y, Baibergenova A, Dutil M, et al. Management of acne: Canadian clinical practice guideline. CMAJ. 2016;188(2):118–126. • Burris J, Rietkerk W, Woolf K. Acne: the role of medical nutrition therapy. J Acad Nutr Diet. 2013;113(3):416–430. • Fisk WA, Lev-Tov HA, Sivamani RK. Botanical and phytochemical therapy of acne: a systematic review. Phytother Res. 2014;28(8):1137–1152. • Woolery-Lloyd HC, Keri J, Doig S. Retinoids and azelaic acid to treat acne and hyperpigmentation in skin of color. J Drugs Dermatol. 2013;12(4):434– 437.

SEE ALSO • Acne Rosacea • Algorithm: Acne

CODES ICD10 • L70.0 Acne vulgaris • L70.4 Infantile acne

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• L70.1 Acne conglobata

CLINICAL PEARLS • Full results for changes in therapy take 8 to 12 weeks. • Decrease topical frequency to every day or to every other day for irritation. • Use BP every time a topical or oral antibiotic is used.

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ACUTE CORONARY SYNDROMES: NSTE-ACS (UNSTABLE ANGINA AND NSTEMI) Harish C. Devineni, MD • Mahesh Anantha Narayanan, MD • Venkata M. Alla, MD BASICS DESCRIPTION • Unstable angina (UA) and non–ST-segment elevation myocardial infarction (NSTEMI) are acute coronary syndromes (ACS) without ST-segment elevation (NSTE-ACS). • NSTEMI is defined by a rise and fall of cardiac biomarker values (preferably cardiac troponin) with at least one value above the 99th percentile upper reference limit and accompanied by one of the following: symptoms of ischemia, new ST-segment T-wave changes, development of pathologic Q waves on ECG, or imaging evidence of loss of viable myocardium or new regional wall motion abnormality (1). • UA is defined by the presence of clinical symptoms of cardiac ischemia (newonset anginal chest pain, or change in typical anginal pattern, or development of angina at rest, or change in typical anginal equivalent), with negative cardiac biomarkers of injury (troponin). ST-segment depressions or T-wave inversions may be present (1).

EPIDEMIOLOGY • In the United States, median incidence age of ACS presentation is 68 years of age with a male to female ratio of 3:2 (2). • Average age at first MI is 65.1 years for men and 72.0 years for women (3).

Incidence • Based on estimates published in 2016, the incidence of new and recurrent MI in the United States is 550,000 and 200,000 respectively (3). • The annual age-adjusted rates of first MI rates per 1,000 are 5.3 in black men, 3.3 in white men, 3.6 in black women, and 1.9 in white women (3).

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Prevalence The rate of CHD in U.S. adults ≥20 years of age is 7.6% for men and 5.0% for women (3).

ETIOLOGY AND PATHOPHYSIOLOGY • ACS occurs primarily due to a sudden decrease in myocardial blood flow due to acute plaque rupture, thrombus formation, and vascular occlusion. • Dynamic obstruction triggered by intense spasm of a coronary artery, like Prinzmetal angina, coronary spasm, which is drug induced. • Increased myocardial oxygen demand resulting in supply–demand mismatch • Less common causes include coronary arterial inflammation, dissection/rupture, and thromboembolism.

RISK FACTORS • Traditional/classic – Age (strongest risk factor) (1) – Gender – Hypertension – Tobacco use – Diabetes mellitus – Dyslipidemia – Family history of premature coronary artery disease (CAD). (Premature CAD is defined as age of onset prior to 55 years in males and 90%, and tight BP control • Avoid NSAIDs. • Deep vein thrombosis prophylaxis • Smoking cessation

MEDICATION First Line • Antiplatelet therapy: Dual antiplatelet therapy is recommended for all patients with ACS. • Aspirin, nonenteric coated, initial dose of 162 to 325 mg PO or chewed to all patients; decreases mortality and morbidity (1)[A] • P2Y12 Inhibitors – Clopidogrel, loading dose 300 to 600 mg before or at time of PCI followed by 75 mg/day (1)[B], or ticagrelor, loading dose 180 mg followed by 90 mg

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BID (1)[B]. Clopidogrel must be used with caution in thrombocytopenia (24 months of age: for lymphatic filariasis in those with eosinophilia if from endemic countries (sub-Saharan Africa, Egypt, Southern Asia, Western Pacific Islands, the NE coast of Brazil, Guyana, Haiti, and the Dominican Republic) (7)[A] Follow-Up Tests & Special Considerations

ALERT If initially negative, repeat of HIV, Hep B, Hep C, and TB testing are recommended at 6 months; negative tests may represent a “window” period or be falsely negative due to malnutrition in the case of TST (6)[C]. • HIV: If antibody positive in children 12 months: Hep A, measles, mumps, rubella, varicella (8)[C] • Adoptive parents, caretakers, and household members should be up to date on

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Tdap, Hep A, Hep B, and measles (3)[A],(5)[C].

ISSUES FOR REFERRAL • Referrals are often necessary for diagnostic and treatment expertise; however, they should be planned carefully to ensure adjustment to the new home (2)[C]. – Elective surgical procedures should likewise be deferred until the child has grown accustomed to his or her new home (4)[C]. • Individual or family counseling considered for all adoptive families for adjustment support • Internationally adopted children may exhibit self-stimulating behaviors (e.g., rocking, head banging); may be related to prior sensory deprivation. These behaviors typically decrease with time, and no treatment is necessary if otherwise developing normally. If in doubt, refer to developmental pediatrics or occupational therapy. – If a child continues to have disruptive behaviors, or would rather selfsoothe than seek nurturing human interaction, consider a thorough developmental evaluation. – Persistent behavioral issues in the parent–child interactions should be evaluated by a pediatric psychologist or psychiatrist (4)[C]. • Vision (strabismus in 10–25% of previously institutionalized adoptees): Refer to pediatric ophthalmology. • Hearing (higher rates of conductive and sensorineural hearing loss): Refer to audiology and/or ENT for concerns, questionable screening results, or if slow to acquire language skills (4)[C]. • Pediatric dental evaluation by 12 months of age; sooner if signs of dental pathology is present (2)[C]

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Regular well-child visits, particularly within first months of entry into the United States • Close monitoring of developmental milestones, behavior, and individual

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attachment

DIET • Regular diet, with specific attention to known nutritional deficiencies in country of origin (www.adoptionnutrition.org) • Up to 68% fall >2 standard deviations below the mean for one or more growth parameters; most begin to follow a curve 14 drinks a week or >4 per occasion; women: >7 drinks a week or >3 per occasion • System(s) affected: nervous, gastrointestinal (GI) • Synonym(s): alcoholism, alcohol abuse, alcohol dependence

Geriatric Considerations • Common and underdiagnosed in elderly; less likely to report problem; may exacerbate normal age-related cognitive deficits and disabilities • Multiple drug interactions • Signs and symptoms may be different or attributed to chronic medical

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problem or dementia. • Common assessment tools may be inappropriate.

Pediatric Considerations • Children of alcoholics are at increased risk. • In 2004, 28% of persons 12 to 20 years reported use in past month, one in five binge drink; binge drinkers are seven times more likely to report illicit drug use. • Negative effect on maturation and development • Early drinkers are four times more likely to develop a problem than those who begin >21 years. • Depression, suicidal or disorderly behavior, family disruption, violence or destruction of property, poor school or work performance, sexual promiscuity, social immaturity, lack of interests, isolation, moodiness

Pregnancy Considerations • Alcohol is teratogenic, especially during the 1st trimester; women should abstain during conception and throughout pregnancy. • 10–50% of children born to women who are heavy drinkers will have fetal alcohol syndrome. • Women experience harmful effects at lower levels and are less likely to report problems.

EPIDEMIOLOGY • Predominant age: 18 to 25 years, but all ages affected • Predominant sex: male > female (3:1)

Prevalence • Lifetime prevalence: 13.6% • 20% in primary care setting • 48.2% of 21-year-olds in the United States reported binge drinking in 2004.

ETIOLOGY AND PATHOPHYSIOLOGY • Multifactorial: genetic, environment, psychosocial • Alcohol is a CNS depressant, facilitating γ-aminobutyric acid (GABA) inhibition and blocking N-methyl-D-aspartate receptors.

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Genetics 50–60% of risk is genetic.

RISK FACTORS • Family history • Depression (40% with comorbid alcohol abuse) • Anxiety • Other substance abuse • Tobacco • Male gender • Low socioeconomic status • Unemployment • Peer/social approval • Family dysfunction or childhood trauma • Posttraumatic stress disorder • Antisocial personality disorder • Bipolar disorder • Eating disorders • Criminal involvement

GENERAL PREVENTION Counsel with family history and risk factors

COMMONLY ASSOCIATED CONDITIONS • Cardiomyopathy, atrial fibrillation • Hypertension • Peptic ulcer disease/gastritis • Cirrhosis, fatty liver, cholelithiasis • Hepatitis • Diabetes mellitus • Pancreatitis • Malnutrition • Upper GI malignancies • Peripheral neuropathy, seizures • Abuse and violence

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• Trauma (falls, motor vehicle accidents [MVAs]) • Severe psychiatric disorders (depression, bipolar, schizophrenia): >50% of patients with these disorders have a comorbid substance abuse problem.

DIAGNOSIS HISTORY • Behavioral issues – Anxiety, depression, insomnia – Psychological and social dysfunction, marital problems – Social isolation/withdrawal – Domestic violence – Alcohol-related legal problems – Repeated attempts to stop/reduce – Loss of interest in nondrinking activities – Employment problems (tardiness, absenteeism, decreased productivity, interpersonal problems, frequent job loss) – Blackouts – Complaints about alcohol-related behavior – Frequent trauma, MVAs, ED visits • Physical symptoms – Anorexia – Nausea, vomiting, abdominal pain – Palpitations – Headache – Impotence – Menstrual irregularities – Infertility

PHYSICAL EXAM • Physical exam may be completely normal. • General: fever, agitation, diaphoresis • Head/eyes/ears/nose/throat: plethoric face, rhinophyma, poor oral hygiene, oropharyngeal malignancies

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• Cardiovascular: hypertension, dilated cardiomyopathy, tachycardia, arrhythmias • Respiratory: aspiration pneumonia • GI: stigmata of chronic liver disease, peptic ulcer disease, pancreatitis, esophageal malignancies, esophageal varices • Genitourinary: testicular atrophy • Musculoskeletal: poorly healed fractures, myopathy, osteopenia, osteoporosis, bone marrow suppression • Neurologic: tremors, cognitive deficits (e.g., memory impairment), peripheral neuropathy, Wernicke-Korsakoff syndrome • Endocrine/metabolic: hyperlipidemias, cushingoid appearance, gynecomastia • Dermatologic: burns (e.g., cigarettes), bruises, poor hygiene, palmar erythema, spider telangiectasias, caput medusae, jaundice

DIFFERENTIAL DIAGNOSIS • Other substance use disorders • Depression • Dementia • Cerebellar ataxia • Cerebrovascular accident (CVA) • Benign essential tremor • Seizure disorder • Hypoglycemia • Diabetic ketoacidosis • Viral hepatitis

DIAGNOSTIC TESTS & INTERPRETATION Screening: • CAGE Questionnaire: (Cut down, Annoyed, Guilty, and Eye opener): >2 “yes” answers is 74–89% sensitive, 79–95% specific for alcohol use disorder; less sensitive for white women, college students, elderly. Not an appropriate tool for less severe forms of alcohol abuse (1)[A] • Single question for unhealthy use: “How many times in the last year have you had X or more drinks in 1 day?” (X = 5 for men, 4 for women); 81.8% sensitive, 79% specific for alcohol use disorders (2)[C]

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• Alcohol Use Disorders Identification Test (AUDIT): 10 items, if >4: 70–92% sensitive, better in populations with low incidence of alcoholism (3)[A]: http://www.nams.sg/addictions/Alcohol/Pages/Self-Assessment-Tool.aspx

Initial Tests (lab, imaging) • CBC; liver function tests (LFTs); electrolytes; BUN/creatinine; lipid panel; thiamine; folate; hepatitis A, B, and C serology • Amylase, lipase (if GI symptoms present) • Serum levels increased in chronic abuse: – AST/ALT ratio >2.0 – γ-Glutamyl transferase (GGT) – Carbohydrate-deficient transferrin – Elevated mean corpuscular volume (MCV) – ↑ Prothrombin time – Uric acid – ↑ Triglycerides and cholesterol (total) • Often decreased – Calcium, magnesium, potassium, phosphorus – BUN – Hemoglobin, hematocrit – Platelet count – Serum protein, albumin – Thiamine, folate • Blood alcohol concentration – >100 mg/dL in outpatient setting – >150 mg/dL without obvious signs of intoxication – >300 mg/dL at any time • CAT scan or MRI of brain: cortical atrophy, lesions in thalamic nucleus, and basal forebrain • Abdominal ultrasound (US): ascites, periportal fibrosis, fatty infiltration, inflammation

Test Interpretation • Liver: inflammation or fatty infiltration (alcoholic hepatitis), periportal fibrosis (alcoholic cirrhosis occurs in only 10–20% of alcoholics)

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• Gastric mucosa: inflammation, ulceration • Pancreas: inflammation, liquefaction necrosis • Heart: dilated cardiomyopathy • Immune system: decreased granulocytes • Endocrine organs: elevated cortisol levels, testicular atrophy, decreased female hormones • Brain: cortical atrophy, enlarged ventricles

TREATMENT • For management of acute withdrawal, please see “Alcohol Withdrawal.” • For outpatient withdrawal treatment, see “Alcohol Withdrawal, Treatment” or http://www.aafp.org/afp/2005/0201/p495.html.

GENERAL MEASURES • Brief interventions and counseling by clinicians have proven efficacy for problem drinking (4)[B]. • Treat comorbid problems (sleep, anxiety, etc.) but do not prescribe medications with cross tolerance to alcohol (benzodiazepine). • Group programs and/or 12-step programs may have benefit in helping patients accept treatment. • Research shows the benefit of referring patients with alcohol dependence to an addiction specialist or treatment program (3)[A].

MEDICATION First Line • Adjuncts to withdrawal regimens: – Naltrexone: 50 to 100 mg/day PO or 380 mg IM once every 4 weeks; opiate antagonist reduces craving and likelihood of relapse, decreases number of heavy drinking days in recalcitrant alcohol abusers (IM route may enhance compliance and thus efficacy) (3,5)[A]. – Acamprosate (Campral): 666 mg PO TID beginning after completion of withdrawal; reduces relapse risk. If helpful, recommended to use for 1 year (6)[A].

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– Topiramate (Topamax): 25 to 300 mg/day PO or divided BID; enhances abstinence (3,5)[B] (not approved by FDA for use in alcohol dependence; off-label use) • Supplements to all – Thiamine: 100 mg/day (1st dose IV prior to glucose to avoid Wernicke encephalopathy) – Folic acid: 1 mg/day – Multivitamin: daily • Contraindications – Naltrexone: pregnancy, acute hepatitis, hepatic failure – Monitor LFTs. • Precautions: organic pain, organic brain syndromes • Significant possible interactions: alcohol, sedatives, hypnotics, naltrexone, and narcotics

ALERT Treat acute symptoms if in alcohol withdrawal; give thiamine 100 mg/day with 1st dose prior to glucose.

Second Line • Disulfiram: 250 to 500 mg/day PO; unproven efficacy; may provide psychological deterrent. Most effective if used with close supervision (5)[A] • Selective serotonin reuptake inhibitors may be beneficial if comorbid depression exists (5)[A].

ISSUES FOR REFERRAL Addiction specialist, 12-step or long-term program, psychiatrist

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Assess medical and psychiatric condition (CIWA >8). • Correct electrolyte imbalances, acidosis, hypovolemia (treat if in alcohol withdrawal). • Thiamine: 100 mg IM, followed by 100 mg PO; folic acid: 1 mg/day • Benzodiazepines used to lower risk of alcohol withdrawal, seizures

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ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Outpatient detoxification: daily visits (not recommended for heavy alcohol abuse) • Early outpatient rehabilitation: weekly visits • Detoxification alone is not sufficient.

PATIENT EDUCATION • American Council on Alcoholism: (800) 527-5344 or http://www.acausa.com/ (treatment facility locator, educational information) • National Clearinghouse for Alcohol and Drug Information: (800) 729-6686 or http://www.health.org/ • Center for Substance Abuse Treatment: (800) 662-HELP or http://www.samhsa.gov/about-us/who-we-are/offices-centers/csat • Alcoholics Anonymous: http://www.aa.org/ • Rational Recovery: https://rational.org/index.php?id=1 • Secular Organizations for Sobriety: http://www.centerforinquiry.net/sos • http://www.alcoholanswers.org/: an evidence-based website for those seeking credible information on alcohol dependence and online support forums

PROGNOSIS • Chronic relapsing disease; mortality rate more than twice general population, death 10 to 15 years earlier • Abstinence benefits survival, mental health, family, employment • 12-step programs, cognitive behavior, and motivational therapies are often effective during 1st year following treatment.

COMPLICATIONS • Psychosocial complications (family, employment, etc.) • Cirrhosis (women sooner than men) • GI malignancies • Neuropathy, dementia, Wernicke-Korsakoff syndrome • CVA

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• Ketoacidosis • Infection • Adult respiratory distress syndrome • Depression • Suicide • Trauma

REFERENCES 1. Dhalla S, Kopec JA. The CAGE Questionnaire for alcohol misuse: a review of reliability and validity studies. Clin Invest Med. 2007;30(1):33–41. 2. Smith PC, Schmidt SM, Allensworth-Davies D, et al. Primary care validation of a single-question alcohol screening test. J Gen Intern Med. 2009;24(7):783–788. 3. Willenbring ML, Massey SH, Gardner MB. Helping patients who drink too much: an evidence-based guide for primary care clinicians. Am Fam Physician. 2009;80(1):44–50. 4. McQueen J, Howe TE, Allan L, et al. Brief interventions for heavy alcohol users admitted to general hospital wards. Cochrane Database Syst Rev. 2011; (8):CD005191. 5. Miller PM, Book SW, Stewart SH. Medical treatment of alcohol dependence: a systematic review. Int J Psychiatry Med. 2011;42(3):227–266. 6. Rösner S, Hackl-Herrwerth A, Leucht S, et al. Acamprosate for alcohol dependence. Cochrane Database Syst Rev. 2010;(9):CD004332.

ADDITIONAL READING National Institute on Alcohol Abuse and Alcoholism. Helping patients who drink too much: a clinician’s guide. http://www.niaaa.nih.gov/guide. Accessed September 19, 2016.

SEE ALSO Substance Use Disorders; Alcohol Withdrawal

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CODES ICD10 • F10.10 Alcohol abuse, uncomplicated • F10.20 Alcohol dependence, uncomplicated • F10.239 Alcohol dependence with withdrawal, unspecified

CLINICAL PEARLS • CAGE Questionnaire: >2 “yes” answers is 74–89% sensitive, 79–95% specific for alcohol use disorder; less sensitive for white women, college students, elderly. Not an appropriate tool for less severe forms of alcohol abuse • Single question for unhealthy use screening: “How many times in the last year have you had X or more drinks in 1 day?” (X = 5 for men, 4 for women); 81.8% sensitive, 79% specific for alcohol use disorders • National Institute on Alcohol Abuse and Alcoholism criteria for “at-risk” drinking: men >14 drinks a week or >4 per occasion; women: >7 drinks a week or >3 per occasion

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ALCOHOL WITHDRAWAL Robert A. Baldor, MD, FAAFP BASICS DESCRIPTION Alcohol withdrawal syndrome (AWS) is a spectrum of symptoms that results from abrupt cessation of alcohol in a dependent patient. Symptoms can begin within 5 hours of the last drink and persist for 5 to 10 days, ranging in severity.

EPIDEMIOLOGY Annually, over 8 million Americans meet diagnostic criteria for alcohol dependence. Data suggest that 2–9% of patients seen in primary care have alcohol dependence. It is more prevalent among men, whites, Native Americans, younger and unmarried adults, and those with lower socioeconomic status; only 24% of those with dependence are ever treated. Less than 5% will experience withdrawal, but 8% of hospitalized patients exhibit signs and symptoms of withdrawal.

ETIOLOGY AND PATHOPHYSIOLOGY • Consumption of alcohol potentiates the effect of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). With chronic alcohol ingestion, this repeated stimulation downregulates the inhibitory effects of GABA. • Concurrently, alcohol ingestion inhibits the stimulatory effect of glutamate on the CNS, with chronic alcohol use upregulating excitatory NMDA glutamate receptors. • When alcohol is abruptly stopped, the combined effect of a downregulated inhibitory neurotransmitter system (GABA-modulated) and upregulated excitatory neurotransmitter system (glutamate-modulated) results in brain hyperexcitability when no longer suppressed by alcohol; clinically seen as AWS.

Genetics

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There is some evidence for a genetic basis of alcohol dependence.

RISK FACTORS • High tolerance, prolonged use, high quantities • Previous alcohol withdrawal episodes, detoxifications, alcohol withdrawal seizures, and delirium tremens (DTs) • Serious medical problems • Concomitant benzodiazepine (BZD) dependence

Geriatric Considerations Elderly dependent on alcohol are more susceptible to withdrawal, and chronic comorbid conditions place them at higher risk of complications from withdrawal.

Pregnancy Considerations Hospitalization or inpatient detoxification is usually required for treatment of acute alcohol withdrawal.

GENERAL PREVENTION • Routinely screen all adults for alcohol misuse (1)[B]. • Screen with the CAGE or similar questionnaire. – Feeling the need to Cut down – Annoyed by criticism about alcohol use – Guilt about drinking/behaviors while intoxicated – “Eye opener” to quell withdrawal symptoms – Useful to detect problematic alcohol use, positive screen is ≥2 “yes” responses. • 10-question AUDIT screening test is also useful to identify problem drinking. • The “5 A’s” is a screening tool used in primary care settings (Assess, Advise, Agree, Assist, Arrange).

COMMONLY ASSOCIATED CONDITIONS • General: poor nutrition, electrolyte abnormalities (hyponatremia, hypomagnesemia, hypophosphatemia), thiamine deficiency, and dehydration • GI: hepatitis, cirrhosis, varices, GI bleed • Heme: splenomegaly, thrombocytopenia, macrocytic anemia

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• Cardiovascular: cardiomyopathy, hypertension, atrial fibrillation, other arrhythmias • CNS: trauma, seizure disorder, generalized atrophy, Wernicke-Korsakoff syndrome • Peripheral nervous system: neuropathy, myopathy • Pulmonary: aspiration pneumonitis or pneumonia; increased risk of anaerobic infections • Psychiatric: depression, posttraumatic stress disorder, bipolar disease, polysubstance abuse

DIAGNOSIS • Diagnostic and Statistical Manual of Mental Disorders AWS criteria are diagnosed when ≥2 of the following present within a few hours to several days after the cessation or reduction of heavy and prolonged alcohol ingestion (2)[C]: – Autonomic hyperactivity (sweating, tachycardia) – Increased hand tremor – Insomnia – Psychomotor agitation – Anxiety – Nausea – Vomiting – Grand mal seizures – Transient (visual, auditory, or tactile) hallucinations or illusions • Criteria for DTs include ≥2 of the criteria for AWS and disturbances in orientation, memory, attention, awareness, visuospatial ability, or perception • These should cause clinically significant distress or impair functioning and not be secondary to an underlying medical condition or mental disorder. • There are three stages of AWS: – Stage 1 (minor withdrawal; onset 5 to 8 hours after cessation) Mild anxiety, restlessness, and agitation Mild nausea/GI upset and decreased appetite Sleep disturbance

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Sweating Mild tremulousness Fluctuating tachycardia and hypertension – Stage 2 (major withdrawal; onset 24 to 72 hours after cessation) Marked restlessness and agitation Moderate tremulousness with constant eye movements Diaphoresis Nightmares Nausea, vomiting, diarrhea, anorexia Marked tachycardia and hypertension Alcoholic hallucinosis (auditory, tactile, or visual) may have mild confusion but can be reoriented. – Stage 3 (DTs; onset 72 to 96 hours after cessation) Fever Severe hypertension, tachycardia Delirium Drenching sweats Marked tremors Persistent hallucinations – Alcohol withdrawal–associated seizures are often brief, generalized tonic– clonic seizures and typically occur 6 to 48 hours after last drink.

HISTORY Essential historical information should be as follows: • Duration and quantity of alcohol intake, time since last drink • Previous episodes/symptoms of alcohol withdrawal, prior detox admissions • Concurrent substance use • Preexisting medical and psychiatric conditions, prior seizure activity • Social history: living situation, social support, stressors, triggers, and so forth

PHYSICAL EXAM Should include assessment of conditions likely to complicate or that are exacerbated by AWS • Cardiovascular: arrhythmias, heart failure, coronary artery disease • GI: GI bleed, liver disease, pancreatitis

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• Neuro: oculomotor dysfunction, gait ataxia, neuropathy • Psych: orientation, memory (may be complicated by hepatic encephalopathy) • General: hand tremor (6 to 8 cycles per second), infections

DIFFERENTIAL DIAGNOSIS • Cocaine intoxication • Opioid, marijuana, and methamphetamine withdrawal • Anticholinergic drug toxicity • Neuroleptic malignant syndrome • ICU delirium • Liver failure • Sepsis, CNS infection, or hemorrhage • Mania, psychosis • Thyroid crisis

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Blood alcohol level, urine drug screen • CBC; comprehensive metabolic panel • CNS imaging if acute mental status changes

TREATMENT The goal is to prevent and treat withdrawal symptoms (e.g., seizures, DTs, cardiovascular events). This is done primarily with BZDs, which reduce the duration of symptoms and raise the seizure threshold. • Exclude other medical and psychiatric causes. • Provide a quiet, protective environment. • The Clinical Institute Withdrawal Assessment for Alcohol Scale revised (CIWA-Ar) is useful for determining medication dosing and frequency of evaluation for AWS. Severity of symptoms are rated on a scale from 0 to 7, with 0 being without symptoms and 7 being the maximum score (except orientation and clouding of sensorium, scale 0 to 4). – Nausea and vomiting – Tremor

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– Paroxysmal sweats – Anxiety – Agitation – Tactile disturbances – Auditory disturbances – Visual disturbances – Headache or fullness in head – Orientation and clouding of sensorium • The maximum CIWA-Ar score achievable is 67. – Scores >8 are associated with mild withdrawal that will likely resolve without medication. – Scores between 8 and 15 are associated with moderate withdrawal, which often require management with medication. – Scores >15 are considered severe withdrawal and are associated with the highest risk of seizures and development of DTs. • Frequent reevaluation with CIWA-Ar score is crucial.

MEDICATION First Line • BZD monotherapy remains the treatment of choice (3)[A]; it is associated with fewer complications compared with neuroleptics (4)[A]. • BZD should be chosen by the following considerations: – Agents with rapid onset control agitation more quickly (e.g., IV diazepam [Valium]). – Long-acting BZDs (diazepam, chlordiazepoxide [Librium]) are more effective at preventing breakthrough seizures and delirium management. – Short-acting BZDs (lorazepam [Ativan], oxazepam [Serax]) are preferable when prolonged sedation is a concern (e.g., elderly patients or other serious concomitant medical illness) and preferable when severe hepatic insufficiency may impair metabolism (4)[A]. • BZD dosages will vary by patients. Given as symptom-triggered or fixedschedule regimens. Symptom-triggered regimens have been found to require less BZD amounts and reduce hospitalization time (5)[A]. • Symptom-triggered regimen: Start with chlordiazepoxide 50 to 100 mg PO,

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repeat CIWA-Ar hourly, and if score is ≥8, give additional dose of chlordiazepoxide 50 mg PO. Continue to reevaluate with CIWA-Ar hourly until adequate sedation achieved (score chlordiazepoxide with respective doses of diazepam, lorazepam, or oxazepam) (5)[C].

Second Line • Thiamine: 100 mg daily IV or IM for at least 3 days (4)[C] – Note that IV glucose administered before treatment with thiamine may precipitate Wernicke encephalopathy and Korsakoff psychosis. • β-Blockers (e.g., atenolol [Tenormin]) and α2-agonists (e.g., clonidine [Catapres]) help to control hypertension and tachycardia and can be used with BZDs (5)[C]. Not used as monotherapy, due to their inability to prevent DTs and seizures. May worsen underlying delirium • Carbamazepine: Not recommended as first-line therapy; associated with reduced incidence of seizures but more studies are needed. • If the patient exhibits significant agitation and alcoholic hallucinosis, an antipsychotic (3,6)[C] (haloperidol [Haldol]) can be used, but this requires close observation, as it lowers the seizure threshold (5)[C]. • Neuroleptic agents are not recommended as monotherapy due to their association with increased mortality, longer duration of delirium, and complications when compared with sedative agents (7)[A].

ADDITIONAL THERAPIES Peripheral neuropathy and cerebellar dysfunction merit physical therapy evaluation.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • CIWA-Ar score >15, or severe withdrawal • Concurrent acute illness requiring in patient care • Poor ability to follow up or no reliable social support • Pregnancy • Seizure disorder or history of severe alcohol-related seizures • Suicide risk • Concurrent BZD dependence

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• Age >40 years old • Prolonged heavy drinking >8 years • Consumes >1 pint of alcohol or 12 beers per day • Random blood alcohol level >200 mg/dL • Elevated MCV, BUN • Cirrhosis, liver failure • CIWA-Ar scores of 65 years (13%); ~50% at >85 years

Prevalence >5.2 million in United States • 200,000 younger onset (60 years • Predominant sex: male = female

Incidence • 2 to 3 new cases per million per year in Europe and North America • The incidence is 3-fold higher in Thailand and China versus the Western world.

ETIOLOGY AND PATHOPHYSIOLOGY • Idiopathic (~70% of the cases) • Drugs: phenylbutazone, chloramphenicol, sulfonamides, gold, cytotoxic drugs, antiepileptics (felbamate, carbamazepine, valproic acid, phenytoin) • Viral: HIV, Epstein-Barr virus (EBV), nontypeable postinfectious hepatitis (not A, B, or C), parvovirus B19 (mostly in the immunocompromised), atypical mycobacterium • Toxic exposure (benzene, pesticides, arsenic) • Radiation exposure • Immune disorders (systemic lupus erythematosus, eosinophilic fasciitis, graft vs. host disease) • Pregnancy (rare) • Congenital (Fanconi anemia, dyskeratosis congenita, Shwachman-Diamond syndrome, amegakaryocytic thrombocytopenia) • The immune hypothesis: activation of T cells with associated cytokine production leading to destruction or injury of hematopoietic stem cells. This leads to a hypocellular bone marrow without marrow fibrosis (2). • The activation of T cells likely occurs because of both genetic and

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environmental factors. Exposure to specific environmental precipitants, diverse host, genetic risk factors, and individual differences in characteristics of immune response likely account for variations in its clinical manifestations and patterns of responsiveness to treatment. • Telomerase deficiency leads to short telomeres. This leads to impaired regenerative capacity and hence a reduction in marrow progenitors and qualitative deficiency in the repair capacity of hematopoietic tissue. • Reduction of natural killer cells in the bone marrow

Genetics • Telomerase mutations found in a small number of patients with acquired and congenital forms. These mutations render carriers more susceptible to environmental insults. • Mutations in genes called TERC and TERT were found in pedigrees of adults with acquired aplastic anemia who lacked the physical abnormalities or a family history typical of inherited forms of bone marrow failure. These genes encode for the RNA component of telomerase. • HLA-DR2 incidence in aplastic anemia is twice that in the normal population.

RISK FACTORS • Treatment with high-dose radiation or chemotherapy • Exposure to toxic chemicals • Use of certain medications • Certain blood diseases, autoimmune disorders, and serious infections • Tumors of thymus (red cell aplasia) • Pregnancy, rarely

GENERAL PREVENTION • Avoid possible toxic industrial agents. • Use safety measures when working with radiation.

DIAGNOSIS HISTORY • Solvent and radiation history; family, environmental, travel, and infectious

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disease history • Patients are often asymptomatic but may have frequent infections, fatigue, shortness of breath, headache, or bleeding/bruising.

PHYSICAL EXAM • Mucosal hemorrhage, petechiae • Pallor • Fever • Hemorrhage, menorrhagia, occult stool blood, melena, epistaxis • Dyspnea • Palpitations • Progressive weakness • Retinal flame hemorrhages • Systolic ejection murmur • Weight loss • Signs of congenital aplastic anemia – Short stature – Microcephaly – Nail dystrophy – Abnormal thumbs – Oral leukoplakia – Hyperpigmentation (café au lait spots) or hypopigmentation

DIFFERENTIAL DIAGNOSIS Includes other causes of bone marrow failure and pancytopenia • Hypoplastic MDS • Marrow replacement – Acute lymphoblastic leukemia – Lymphoma – Hairy cell leukemia (increased reticulin and infiltration of hairy cells) – Large granular lymphocyte leukemia – Fibrosis • Megaloblastic hematopoiesis – Folate deficiency – Vitamin B12 deficiency

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• Paroxysmal nocturnal hemoglobinuria, hemolytic anemia (dark urine), pancytopenia, and venous thrombosis (classically hepatic veins) • Systemic lupus erythematosus • Prolonged starvation or anorexia nervosa (bone marrow is gelatinous with loss of fat cells and increased ground substance) • Transient erythroblastopenia of childhood • Drug-induced agranulocytosis that may be reversible on withdrawal of drug • Overwhelming infection – HIV with myelodysplasia – Viral hemophagocytic syndrome

DIAGNOSTIC TESTS & INTERPRETATION Screening tests to exclude other etiologies • CBC and absolute reticulocyte count • Blood smear exam • Cytogenetic studies to exclude MDS and of peripheral lymphocytes if 104 • CD 34+ cells decreased in blood and marrow

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• Urinalysis: hematuria • Abnormal liver function tests (hepatitis) • Increased fetal hemoglobin (Fanconi) • Increased chromosomal breaks under specialized conditions (Fanconi) • Molecular determination of abnormal gene (Fanconi) • CT of thymus region if thymoma-associated RBC aplasia suspected • Radiographs of radius and thumbs (if congenital anemia suspected) • Renal ultrasound (to rule out congenital anemia or malignant hematologic disorder) • Chest x-ray to exclude infections such as mycobacterial infection

Diagnostic Procedures/Other Bone marrow aspiration and biopsy

Test Interpretation • Normochromic RBC • Bone marrow – Decreased cellularity ( male, 3:1; onset: early peak, 2 to 4 years; late peak, 6 to 12 years (2) • Oligoarticular: female > male, 5:1; onset: 2 to 4 years (2) • Psoriatic: female > male, 1:0.95 (2); onset: early peak, 2 to 3 years; late peak, 10 to 12 years (1) • Enthesitis: female > male, 1:7; onset: early peak, 2 to 4 years; late peak, 6 to 12 years (2) • Affected patients have an increased risk of developing cancer, although shortterm risk is low.

Incidence 2 to 20/100,000 children female

ETIOLOGY AND PATHOPHYSIOLOGY • Many different pathogens • Nongonococcal: – Staphylococcus aureus (most common in adults) MRSA risk increased in elderly, intravenous drug users (IVDU), postsurgical – Streptococcus spp. (second most common in adults) – Gram-negative rods (GNR): IVDU, trauma, extremes of age, immunosuppressed • Neisseria gonorrhea (most common in young, sexually active adults) • Other: rickettsial (e.g., Lyme), fungal, mycobacterial • Risk by specific age (2): – 40 years: S. aureus • Specific high-risk groups: – Rheumatoid arthritis: S. aureus – IVDU: S. aureus, GNR, opportunistic pathogens – Neonates: GBS – Immunocompromised: gram-negative bacilli, fungi – Trauma patients with open injuries: mixed flora • Pathogenesis: – Hematogenous spread (most common) – Direct inoculation by microorganisms secondary to trauma or iatrogenesis (e.g., joint surgery) – Adjacent spread (e.g., osteomyelitis) • Pathophysiology: – Microorganisms initially enter through synovial membrane and spread to the synovial fluid. – Resulting inflammatory response releases cytokines and destructive proteases leading to systemic symptoms and joint damage.

RISK FACTORS • Age >80 years • Low socioeconomic status; alcoholism • Cellulitis and skin ulcers • Prior violation of joint capsule – Prior orthopedic surgery – Intra-articular steroid injection – Trauma • History of previous joint disease – Inflammatory arthritis (rheumatoid arthritis [RA]: 10-fold increased risk) – Osteoarthritis – Crystal arthritides • Systemic illness – Diabetes mellitus, liver disease, HIV, malignancy, end-stage renal disease/hemodialysis, immunosuppression, sickle cell anemia • Risks for hematogenous spread

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– IVDU, severe sepsis/systemic infection

GENERAL PREVENTION • Prompt treatment of skin and soft tissue infections • Control risk factors. • Immunization (S. pneumoniae; N. meningitidis)

DIAGNOSIS HISTORY • Typically presents with a combination of joint pain, swelling, warmth, and decreased range of motion • Nongonococcal arthritis: predominantly monoarticular (80%) – Typically large joints (knee in 50% of cases) – Most patients report fever. – IV drug users may develop infection in axial joints (e.g., sternoclavicular joint). – Prosthetic joints may show minimal findings and present with draining sinus over the joint. – Patients on chronic immunosuppressive drugs and those receiving steroid joint injections may have atypical presentations (no fever or joint pain). • Pediatric considerations – Infants may refuse to move limb (can be mistaken as neurologic problem). – Hip pain may present as knee or thigh (referred) pain. • Gonococcal arthritis – Bacteremic phase: migratory polyarthritis, tenosynovitis, high fever, chills, pustules (dermatitis–arthritis syndrome) – Localized phase: monoarticular, low-grade fever

PHYSICAL EXAM • Physical exam has poor sensitivity and specificity for septic arthritis. Common findings include: – Limited range of motion – Joint effusion and tenderness – Erythema and warmth over affected joint

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– Pain with passive range of motion • Hip and shoulder involvement may reveal severe pain with range of motion and less obvious swelling. • Infants with septic hip arthritis maintain flexed and externally rotated hip.

DIFFERENTIAL DIAGNOSIS • Crystal arthritis: gout, pseudogout, calcium oxalate, cholesterol • Infectious arthritis: fungi, spirochetes, rheumatic fever, HIV, viral • Inflammatory arthritis: RA, spondyloarthropathy, systemic lupus erythematosus, sarcoidosis • Osteoarthritis • Trauma: meniscal tear, fracture, hemarthrosis • Other: bursitis, cellulitis, tendinitis

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Synovial fluid analysis (gold standard): – Obtain prior to antibiotic therapy if possible – Include Gram stain, culture, cell count/differential, and crystal analysis. – Use blood culture bottles to increase yield. – Obtain Gram stain (positive in 50%) and culture (positive in 50–70%) with understanding of limitations. – >50,000 WBCs/HPF with >90% polymorphonuclear leukocytes is suggestive; synovial WBC (sWBC) count alone is insufficient to rule in or rule out septic arthritis (2)[A]. – The presence of crystals (e.g., urate or calcium pyrophosphate) does not exclude concurrent infectious arthritis (3)[B]. – Prosthetic joint: WBC count is unreliable; a lower number of sWBCs may indicate infection. • Serum tests: – WBC count alone is neither sensitive nor specific. – ESR >15 mm/hr has sensitivity up to 94% but poor specificity (4)[B]. – CRP >20 mg/L has sensitivity of 92% (4)[B]. – Synovial lactate is a potential biomarker (5)[A]. – Blood cultures are positive in 50% of cases.

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• Other tests: – Disseminated gonococcus: culture blood, cervix, urine, urethra, pharynx in addition to joint fluid – Suspected Lyme arthritis: Send serum titers. • Pediatrics: No single lab test distinguishes septic arthritis from transient synovitis. – The combination of fever, non–weight bearing, and elevated ESR and CRP is suspicious; synovial fluid should still be obtained. • Imaging: helpful to identify effusion but does not differentiate septic from other forms of arthritis – Plain films: Nondiagnostic for septic arthritis. Useful for trauma, soft tissue swelling, osteoarthritis, or osteopenia May show nonspecific changes of inflammatory arthritis (i.e., erosions, joint destruction or joint space loss) – Ultrasound: Helps guide arthrocentesis Recommended for aspiration of the hip – MRI: Highly sensitive for effusion; may be helpful to distinguish between transient synovitis and septic arthritis in children – Other imaging techniques: CT is not routinely indicated. Bone scans are not performed unless there is suspicion for osteomyelitis.

Diagnostic Procedures/Other Arthrocentesis in all suspected cases (prior to starting antibiotics). Avoid contaminated tissue (e.g., overlying cellulitis) when performing arthrocentesis.

Test Interpretation Synovial biopsy shows polymorphonuclear leukocytes and possibly the causative organism.

TREATMENT

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GENERAL MEASURES • Admit for parenteral antibiotics and monitoring. Begin antibiotics immediately after arthrocentesis. • Removal of purulent material is required if: – Pediatric: Surgical drainage and irrigation is recommended if hip is involved due to high risk of avascular necrosis. – Prosthetic joint: Antibiotics and consult with orthopedics for consideration of revision arthroplasty, resection arthroplasty, or débridement • Treat for a total of 4 to 6 weeks in most cases. – Exception: gonococcal (2 to 3 weeks) • Intra-articular antibiotics are not recommended.

MEDICATION First Line • Initial antibiotic choice is guided by Gram stain or most likely organism based on age and clinical history. • Nongonococcal (6)[C]: – Gram-positive cocci: Vancomycin 15 to 20 mg/kg 2 to 3 times daily or linezolid 600 mg twice daily – Gram-negative bacilli: Cefepime 2 g twice daily or ceftriaxone 2 g daily or ceftazidime 2 g, 3 times daily or cefotaxime 2 g, 3 times daily For cephalosporin allergy: Consider treatment with ciprofloxacin 400 mg, 3 times daily. – Negative Gram stain: Vancomycin 15 to 20 mg/kg 2 to 3 times daily plus 3rd-generation cephalosporin until cultures and susceptibilities return – Duration of therapy: typically 2 weeks of IV and an additional 2 to 4 weeks PO while monitoring therapeutic response • Gonococcal: – Ceftriaxone 1 g IV/IM daily for 7 to 14 days (and at least 24 to 48 hours after symptoms resolve) – May require concurrent drainage of affected joint

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– Concomitant treatment for Chlamydia (doxycycline 100 mg twice daily or azithromycin 1 g daily) • Other considerations: – Narrow antibiotic therapy based on culture results – Consider Salmonella in pediatric patients with a history of sickle cell disease: 3rd-generation cephalosporin helpful in this instance. – Lyme arthritis: doxycycline 100 mg PO twice daily or amoxicillin 500 mg PO 3 times daily for 28 days if no neurologic involvement, otherwise ceftriaxone 2 g IV daily

ISSUES FOR REFERRAL • Infectious disease and orthopedic consultations • IVDU and immunosuppression warrant infectious disease consultation to guide therapy. Prosthetic joint infection is best managed with orthopedic consultation.

SURGERY/OTHER PROCEDURES • Consider drainage in all cases, particularly shoulder, hip, and prosthetic joints. • Other treatment options include repeat needle aspiration, arthroscopy, or arthrotomy.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Monitor synovial fluid to verify decreasing WBC and sterile fluid after initial treatment. • If no improvement within 24 hours, reevaluate and consider arthroscopy. • Follow up at 1 week and 1 month after stopping antibiotics to ensure no relapse.

PROGNOSIS • Early treatment improves functional outcome. • Delayed recognition/treatment is associated with higher morbidity and mortality.

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• Elderly, concurrent rheumatoid arthritis, S. aureus infections, and infection of hip and shoulder also increase risk of poor outcome.

COMPLICATIONS • Mortality estimated at 11% (1) • Limited joint range of motion, ankylosis • Secondary osteoarthritis • Flail, fused, or dislocated joint • Sepsis, septic necrosis • Sinus formation • Osteomyelitis, postinfectious synovitis • Limb length discrepancy (in children)

REFERENCES 1. Mathews CJ, Weston VC, Jones A, et al. Bacterial septic arthritis in adults. Lancet. 2010;375(9717):846–855. 2. Margaretten ME, Kohlwes J, Moore D, et al. Does this adult patient have septic arthritis? JAMA. 2007;297(13):1478–1488. 3. Shah K, Spear J, Nathanson LA, et al. Does the presence of crystal arthritis rule out septic arthritis? J Emerg Med. 2007;32(1):23–26. 4. Hariharan P, Kabrhel C. Sensitivity of erythrocyte sedimentation rate and Creactive protein for the exclusion of septic arthritis in emergency department patients. J Emerg Med. 2011;40(4):428–431. 5. Carpenter CR, Schuur JD, Everett WW, et al. Evidence-based diagnostics: adult septic arthritis. Acad Emerg Med. 2011;18(8):781–796. 6. Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillinresistant Staphylococcus aureus infections in adults and children. Clin Infect Dis. 2011;52(3):e18–e55.

CODES ICD10 • M00.9 Pyogenic arthritis, unspecified

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• M00.20 Other streptococcal arthritis, unspecified joint • M00.00 Staphylococcal arthritis, unspecified joint

CLINICAL PEARLS • Arthrocentesis and synovial fluid analysis are mandatory in cases of suspected septic arthritis. • Early IV antibiotics and drainage of infected joints are critical to successful management. • Crystalline disease may coexist with septic arthritis. • Initial antibiotic therapy is guided by arthrocentesis results (Gram stain), age, and patient-specific risk factors.

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ARTHROPOD BITES AND STINGS James E. Powers, DO, FACEP, FAAEM BASICS DESCRIPTION Arthropods make up the largest division of the animal kingdom; two classes, insects and arachnids, have the greatest medical impact on humans. Arthropods affect humans by inoculating poison or irritative substances through a bite or sting, by invading tissue, or by contact allergy to their skin, hairs, or secretions. The greatest medical importance is transmission of infectious microorganisms that may occur during insect feeding. Sequelae to arthropod bites, stings, or contact may include the following: • Local redness with itch, pain, and swelling: common, usually immediate and transient • Large local reactions increasing over 24 to 48 hours • Systemic reactions with anaphylaxis, neurotoxicity, organ damage, or other systemic toxin effects • Tissue necrosis or secondary infection • Infectious disease transmission: presentation may be delayed weeks to years

EPIDEMIOLOGY Incidence • Difficult to estimate, as most encounters unreported • ~40 deaths per year in the United States from fatal anaphylactic reaction to insects but likely underreported (1) • Unrecognized anaphylactic reactions to Hymenoptera stings may be cause of 1/4 of sudden and unexpected deaths outdoors (2).

Prevalence Widespread, with regional and seasonal variations

ETIOLOGY AND PATHOPHYSIOLOGY • Arthropods: four medically important classes

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– Insects: Hymenoptera (bees, wasps, hornets, fire ants), mosquitoes, bed bugs, flies, lice, fleas, beetles, caterpillars, and moths – Arachnids: spiders, scorpions, mites, and ticks – Chilopods (centipedes) – Diplopods (millipedes) • Four general categories of pathophysiologic effects: toxic, allergic, infectious, and traumatic – Toxic effects of venom: local (tissue inflammation or destruction) versus systemic (neurotoxic or organ damage) – Allergic: Antigens in saliva may cause local inflammation. Exaggerated immune responses may result in anaphylaxis or serum sickness. – Trauma: Mechanical injury from biting or stinging causes pain, swelling, and portal of entry for bacteria and secondary infection. Retention of arthropod parts can cause a granulomatous reaction. – Infection: Arthropods are vectors and can transmit bacterial, viral, and protozoal diseases.

Genetics Family history of atopy may be a factor in the development of more severe allergic reactions.

RISK FACTORS • Previous sensitization is a key to most severe allergic reactions, but exposure history may not be recalled. • Although most arthropod contact is inadvertent, certain activities, occupations, and travel increase risk. • Greater risk for adverse outcome in young, elderly, immune compromised, or those with unstable cardiac or respiratory status • Increased risk of anaphylaxis following insect sting in patients with mastocytosis (1)

GENERAL PREVENTION • Avoidance of common arthropod habitats • Insect repellents (not effective for bees, spiders, scorpions, caterpillars, bed bugs, fleas, ants)

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– N,N-diethyl-meta-toluamide (DEET) Most effective broad-spectrum repellent against biting arthropods (3) Formulations with higher concentrations (20–50%) are 1st-line choice when visiting areas of endemic arthropod-borne diseases (3). Concentrations >30% give longer duration of effect Safe for children >6 months of age and pregnant and lactating women (3) – Icaridin (formerly known as picaridin) Use of concentrations 20% (3) May be used in children >6 months of age (3) – IR3535: less effective in most studies – Other botanical oils (citronella etc.): less effective than DEET; not for disease-endemic areas • Barrier methods: clothing, bed nets – Use of light-colored pants, long-sleeved shirts, and hats may reduce arthropod impact. – Permethrin: Synthetic insecticide derived from chrysanthemum plant should not be applied to skin, but permethrin-impregnated clothing provides good protection against arthropods. – Mosquito nets: Insecticide-treated nets are advised for all travelers to disease-endemic areas at risk from biting arthropods (3). – WHO-recommended nets are Permanet 2.0 (Vestergaard), Olyset (Sumitomo), and Interceptor (BASF) (3). • Desensitization 75–95% effective for Hymenoptera-specific venom – Skin tests are needed to determine sensitivity. – Refer to allergist/immunologist if candidate • Fire ant control (but not elimination) possible – Baits; sprays, dusts, aerosols; biologic agents • Risk of tick-borne diseases decreased by prompt removal of ticks within 24 hours of attachment.

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DIAGNOSIS HISTORY • Sudden onset of pain or itching with visualization of arthropod • Many cases unknown to patient or asymptomatic initially (bed bugs, lice, scabies, ticks). Consider in patients presenting with localized erythema, urticaria, wheals, papules, pruritus, or bullae. • May identify insect by its habitat or by remnants brought by patient • History of prior exposure useful but not always available or reliable • Travel, occupational, social, and recreational history important

PHYSICAL EXAM • If stinger is still present in skin, remove by flicking or scraping away from skin. • Anaphylaxis is a clinical diagnosis. Essential to examine for signs and symptoms of anaphylaxis (4,5) – Erythema, urticaria, angioedema – Itching/edema of lips, tongue, uvula; drooling – Persistent vomiting – Respiratory distress, wheeze, repetitive cough, stridor, dysphonia – Hypotension, dysrhythmia, syncope, chest pain • If anaphylaxis not present, exam focuses on the sting or bite itself. Common findings include local erythema, swelling, wheals, urticaria, papules, or bullae; excoriations from scratching. • Thorough exam to look for arthropod infestation (lice, scabies) or attached ticks. Body lice usually found in seams of clothing. Skin scraping to identify scabies. • Signs of secondary bacterial infection after 24 to 48 hours: increasing erythema, pain, fever, lymphangitis, or abscess • Delayed manifestations of insect-borne diseases

DIFFERENTIAL DIAGNOSIS • Urticaria and localized dermatologic manifestations: – Contact dermatitis, drug eruption, mastocytosis, bullous diseases, dermatitis herpetiformis, tinea, eczema, vasculitis, pityriasis, erythema multiforme,

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viral exanthem, cellulitis, abscess, impetigo, folliculitis, erysipelas, necrotizing fasciitis • Anaphylactic-type reactions – Cardiac, hemorrhagic, or septic shock; acute respiratory failure, asthma; angioedema, urticarial vasculitis; flushing syndromes (catecholamines, vasoactive peptides); panic attacks, syncope – Differential diagnosis of the acute abdomen should include black widow spider bite.

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) Seldom needed; basic lab parameters usually normal. Some findings may help confirm diagnosis of anaphylaxis: • Plasma histamine levels elevated briefly after mast cell activation • Serum tryptase within 15 minutes to 3 hours after onset of symptoms with second sample 24 hours later (5) Follow-Up Tests & Special Considerations • Severe envenomations may affect organ function and require monitoring of lab values (CBC, comprehensive metabolic panel, prothrombin time/international normalized ratio) • Labs for arthropod-borne diseases, as indicated – Ticks: Lyme disease, Rocky Mountain spotted fever, relapsing fever, anaplasmosis, babesiosis, tularemia – Flies: tularemia, leishmaniasis, African trypanosomiasis, bartonellosis, loiasis – Fleas: plague, tularemia, murine typhus – Chigger mites: scrub typhus – Body lice: epidemic typhus, relapsing fever – Kissing bugs: Chagas disease – Mosquitoes: malaria, yellow fever, dengue fever, West Nile virus, equine encephalitis, chikungunya • Refer to allergist for formal testing with history of anaphylaxis, significant systemic symptoms, progressively severe reactions (4,5)

Diagnostic Procedures/Other

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Various skin tests and immunologic tests available to try to predict anaphylactic risk

TREATMENT ALERT • The more rapidly anaphylaxis develops, the more likely the reaction is to be severe and potentially life-threatening. Most deaths due to anaphylaxis occur within 30 to 60 minutes of sting. • Epinephrine should be given as soon as diagnosis of anaphylaxis is suspected. Delay of epinephrine is associated with fatal anaphylaxis (4,5). • Antihistamines and steroids do not replace epinephrine in anaphylaxis, and no direct outcome data regarding their effectiveness in anaphylaxis are available (4,5). • Airway management critical if angioedema

GENERAL MEASURES Local wound care, ice compress, elevation, analgesics

MEDICATION First Line • For arthropod bites/stings with anaphylaxis – There are no randomized controlled trials on treatments, so the following recommendations are all based on expert opinion consensus (5)[C]. – Epinephrine: most important: IM injection in midanterolateral thigh (vastus lateralis muscle): IM injection: epinephrine 1:1,000 (1 mg/mL): adult: 0.3 to 0.5 mg per dose; pediatric: give 0.01 mg/kg to a maximum dose of 0.5 mg per dose, can repeat every 5 to 15 minutes (5) – Positioning: supine with legs elevated – Oxygen 6 to 8 L/min up to 100%, as needed – IV fluids: Establish 1 to 2 large-bore IV lines. Normal saline rapid bolus 1 to 2 L IV; repeat as needed (pediatrics 20 to 30 mL/kg) – H1 antihistamines: diphenhydramine 25 to 50 mg IV (pediatrics 1 to 2

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mg/kg) – β2 agonists: albuterol for bronchospasm nebulized 2.5 to 5 mg in 3 mL – Emergency treatment of refractory cases: consider epinephrine infusion, dopamine, glucagon, vasopressin, large-volume crystalloids (4,5) • Arthropod bites/stings without anaphylaxis – Tetanus booster, as indicated – Oral antihistamines Diphenhydramine Cetirizine H2 blockers: ranitidine – Oral steroids: consider short course for severe pruritus; prednisone or prednisolone 1 to 2 mg/kg once daily – Topical intermediate-potency steroid cream or ointment × 3 to 5 days Desoximetasone 0.05% Triamcinolone 0.1% Fluocinolone 0.025% – Wound care: antibiotics only if infection – Other specific therapies: Scorpion stings: Treat excess catecholamine release (nitroprusside, prazosin, β-blockers). Diazepam for muscle spasms. Atropine for hypersalivation (6). Only one FDA-approved scorpion antivenom in United States and should be administered in conjunction with toxicologist. Black widow bites: Treat muscle spasms with diazepam and opioid analgesics PO or IV (6). Antivenom: available but should be administered in conjunction with toxicologist. Poison control should be consulted for questions regarding management of envenomation. Poison Control hotline: 1-800-222-1222. – Fire ants: characteristically cause sterile pustules. Leave intact: Do not open or drain. – Brown recluse spider: pain control, supportive treatment; surgical consult if débridement needed – Ticks: early removal. Review guidelines for disease prophylaxis and treatment. – Pediculosis: head, pubic, and body lice

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First line: permethrin 1% (Nix) topical lotion. Apply to affected area, wash off in 10 minutes. Alternatives: pyrethrin or malathion 0.5% lotion, ivermectin (not FDA approved for pediculosis) orally Repeat above treatment in 7 to 10 days. For eyelash infestation: Apply ophthalmic-grade petroleum jelly BID for 10 days. – Sarcoptes scabiei scabies Permethrin 5% cream: Apply to entire body. Wash off after 8 to 14 hours. Repeat in 1 week. Ivermectin: 200 μg/kg PO once; repeat in 2 weeks (not FDA approved for this use) Crotamiton 10% cream or lotion less efficacious; apply daily for 2 days after bathing.

Second Line Second-line options for anaphylaxis: • Ranitidine • Methylprednisolone 1 mg/kg for 3 to 4 days or hydrocortisone 200 mg (5)

ISSUES FOR REFERRAL Refer to allergist with history of anaphylaxis, severe systemic symptoms, or progressively severe reactions

SURGERY/OTHER PROCEDURES Débridement and delayed skin grafting may be needed for brown recluse spider and other bites.

COMPLEMENTARY & ALTERNATIVE MEDICINE • Some stings may be treated with a paste of 3 tsp of baking soda and 1 tsp water. • None well tested

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS Anaphylaxis, vascular instability, neuromuscular events, pain, GI symptoms,

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renal damage/failure

ONGOING CARE FOLLOW-UP RECOMMENDATIONS • Immunotherapy as recommended by allergist/consultant for anaphylaxis or serious reactions; venom immunotherapy cornerstone of treatment for Hymenoptera. • Patient-administered epinephrine must be provided to patients with anaphylaxis. Consider “med-alert” identifiers (4,5).

Patient Monitoring • Monitor for delayed effects, including infectious diseases from arthropod vectors. • Serum sickness reactions, vasculitis (rare)

PATIENT EDUCATION Avoidance and prevention

PROGNOSIS • Excellent for local reactions • For systemic reactions, best response with early intervention to prevent cardiorespiratory collapse

COMPLICATIONS • Scarring • Secondary bacterial infection • Arthropod-associated diseases as mentioned earlier • Psychological effects, phobias

REFERENCES 1. Tanskersley MS, Ledford DK. Stinging insect allergy: state of the art 2015. J Allergy Clin Immunol Pract. 2015;3(3):315–322. 2. Diaz JH. Recognition, management, and prevention of hymenopteran stings and allergic reactions in travelers. J Travel Med. 2009;16(5):357–364.

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3. Moore SJ, Mordue Luntz AJ, Logan JG. Insect bite prevention. Infect Dis Clin North Am. 2012;26(3):655–673. 4. Simons FE, Ardusso LR, Bilò MB, et al. 2012 update: World Allergy Organization guidelines for the assessment and management of anaphylaxis. Curr Opin Allergy Clin Immunol. 2012;12(4):389–399. 5. De Bisschop MB, Bellou A. Anaphylaxis. Curr Opin Crit Care. 2012;18(4):308–317. 6. Quan D. North American poisonous bites and stings. Crit Care Clin. 2012;28(4):633–659.

ADDITIONAL READING • Centers for Disease Control and Prevention. Protection against mosquitoes, ticks, & other insects & arthropods. http://wwwnc.cdc.gov/travel/yellowbook/2014/chapter-2-the-pre-travelconsultation/protection-against-mosquitoes-ticks-and-other-insects-andarthropods. Accessed 2015. • Centers for Disease and Prevention. FAQ. Insect repellent use & safety. http://www.cdc.gov/westnile/faq/repellent.html. Accessed 2015. • Centers for Disease Control and Prevention. Tickborne diseases of the United States: a reference manual for health care providers. Third edition, 2015. Handbook available as a PDF at http://www.cdc.gov/ticks/ • Sicherer SH, Leung DY. Advances in allergic skin disease, anaphylaxis, and hypersensitivity reactions to foods, drugs, and insects in 2012. J Allergy Clin Immunol. 2013;131(1):55–66. • Studdiford JS, Conniff KM, Trayes KP, et al. Bedbug infestation. Am Fam Physician. 2012;86(7):653–658. • Swanson DL, Vetter RS. Bites of brown recluse spiders and suspected necrotic arachnidism. N Engl J Med. 2005;352(7):700–707. • Warrell DA. Venomous bites, stings, and poisoning. Infect Dis Clin North Am. 2012;26(2):207–223. • Juckett G. Arthropod bites. Am Fam Physician. 2013; 88(12):841–847.

CODES

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ICD10 • T63.481A Toxic effect of venom of arthropod, accidental, init • T63.301A Toxic effect of unsp spider venom, accidental, init • T63.484A Toxic effect of venom of oth arthropod, undetermined, init

CLINICAL PEARLS • Urgent administration of epinephrine is a key to anaphylaxis treatment. • Local treatment and symptom management are sufficient in most insect bites and stings.

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ASCITES Daniel J. Stein, MD, MPH • Stephen K. Lane, MD, FAAFP BASICS DESCRIPTION • Accumulation of fluid in the peritoneal cavity; may occur in conditions that cause generalized edema • Men generally have no fluid in peritoneal cavity; women may have up to 20 mL depending on menstrual phase.

EPIDEMIOLOGY • Children: nephrotic syndrome and malignancy most common • Adults: cirrhosis (81%), cancer (10%), heart failure (3%), other (6%)

Incidence ~50–60% of patients with cirrhosis will develop ascites within 10 years (1).

Prevalence 10% of patients with liver cirrhosis have ascites.

ETIOLOGY AND PATHOPHYSIOLOGY • Portal hypertensive versus nonportal hypertensive etiologies – Cannot reliably establish/confirm etiology without paracentesis – Serum-ascites albumin gradient (SAAG): [serum albumin level: ascites albumin level] differentiates causes • High portal pressure (SAAG ≥1.1) – Cirrhosis – Hepatitis (alcoholic, viral, autoimmune, medications) – Acute liver failure – Liver malignancy (primary or metastatic) – Elevated right-sided filling pressures from heart failure or constrictive pericarditis – Hepatic venous thrombosis (Budd-Chiari syndrome)

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– Portal vein thrombosis • Normal portal pressure (SAAG 1500 mL of fluid to detect. • Edema (penile/scrotal, pedal), pleural effusion, rales • Stigmata of cirrhosis (palmar erythema, spider angiomata, dilated abdominal wall collateral veins) • Other signs of advanced liver disease: jaundice, muscle wasting, gynecomastia, leukonychia • Signs of underlying malignancy: cachexia; umbilical (Virchow) node suggests upper abdominal malignancy.

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Diagnostic paracentesis for fluid analysis in all patients with ascites requiring hospital admission and in any new-onset or new-to-treatment patients (1)[C] to determine etiology and rule out infection. – Paracentesis has a complication rate of 1% (despite high prevalence of coexisting coagulation abnormalities). – Routine attempts to correct platelet or coagulation defects are not needed (1)[B]. – Ascitic fluid analysis includes (1)[C]: Cell count and differential: Polymorphonuclear leukocytes ≥250 cells/mm3 suggest infection. Albumin level to calculate SAAG: 1.0 can indicate infection, perforation, or tumor. Carcinoembryonic antigen and alkaline phosphatase (elevated in viscous perforation) • Mycobacterial culture/TB complex PCR for suspicion of tuberculosis • Blood tests: BUN/creatinine, electrolytes (renal function) – Brain natriuretic peptide (heart failure) – Liver function tests and hepatitis serologies (hepatitis) – Albumin (needed for SAAG) • Abdominal ultrasound (US) can confirm ascites; highly sensitive, costeffective, involves no radiation • Portal US Doppler can evaluate for thrombosis or cirrhosis. • CT scan to rule out intra-abdominal pathology (e.g., malignancy) • MRI preferred for evaluation of liver disease or confirmation of portal vein thrombosis.

Diagnostic Procedures/Other Laparoscopy: preferred if imaging and paracentesis are nondiagnostic • Allows for direct visualization and biopsy of peritoneum, liver, and intraabdominal lymph nodes • Preferred for evaluating suspected peritoneal tuberculosis or malignancies

Test Interpretation Cytology may reveal malignant cells: adenocarcinoma (ovary, breast, GI tract) or primary peritoneal carcinoma (most commonly associated with ascites)

TREATMENT For all patients:

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• Daily weight • Restrict dietary sodium to ≤2 g/day if the cause is due to portal hypertension (high SAAG) (1)[A]. • Water restriction (1 to 1.5 L/day) only necessary if serum sodium 2.0 mg/dL: decrease diuretic doses, peritoneal paracentesis • Avoid alcohol and ensure adequate nutrition if liver disease (1)[A]. • Baclofen may be used to reduce alcohol craving/consumption (1)[C] in EtOH cirrhosis.

MEDICATION ALERT • Careful diuresis; aggressive diuresis can induce prerenal acute kidney injury, encephalopathy, and hyponatremia. Monitor creatinine and electrolytes closely. Serum creatinine >2 mg/dL or serum sodium 5,000 cells/mm3) and any two of the following: Ascitic fluid total protein >1 g/dL (often >3 g/dL) Ascitic fluid glucose 80% and FEV1/forced vital capacity (FVC) >80% – Mild persistent: symptoms >2 days/week but not daily, nighttime awakenings 3 to 4 times per month, short-acting β-agonist use >2 days/week but not daily, minor limitations in normal activity, and FEV1 (predicted) >80% and FEV1/FVC >80% – Moderate persistent: daily symptoms, nighttime awakenings ≥1 times per week but not nightly, daily use of short-acting β-agonist, some limitation in normal activity, and FEV1 (predicted) 60–80% and FEV1/FVC 75–80% – Severe persistent: symptoms throughout the day, nighttime awakenings often 7 times per week, short-acting β-agonist use several times a day, extremely limited normal activity, and FEV1 (predicted) 70 kg: 40 mg daily; increase after minimum of 3 days to target dose of 80 mg/day; dose may be increased to maximum of 100 mg/day after additional 2 to 4 weeks. • α2-Agonist – Modest efficacy, high side effects. Consider consultation before use. Clonidine XR (Kapvay): 0.1 mg once daily at bedtime; increase by 0.1

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mg weekly; doses should be taken twice daily with equal or higher split dosage given at HS; maximum of 0.4 mg/day; taper when discontinued. Guanfacine XR (Intuniv): 1 mg daily; increase by 1 mg weekly until 1 to 4 mg daily; taper when discontinued.

ALERT • Atomoxetine carries a “black box” warning regarding potential exacerbation of suicidality (similar to SSRIs). Close follow-up is recommended. • Associated with hepatic injury in a small number of cases; check liver enzymes if symptoms develop. • Interacts with paroxetine (Paxil), fluoxetine (Prozac), and quinidine

ISSUES FOR REFERRAL Should be considered for children 50 and often >100. – Larger number in hereditary AMS versus sporadic atypical nevi (as few as 50), some of which are clinically atypical; and (iii) nevi that have certain histologic features on pathologic examination (8).

HISTORY • Changing lesions: bleeding, scaling, size, texture, nonhealing, hyper- or hypopigmentation • Large number of nevi • Congenital nevi • Sun exposure habits • Prior skin biopsies • Prior melanoma • Immunosuppression (e.g., AIDS, chemotherapy, pancreatic cancer) • First- or second-degree relatives with: – AMS – Melanoma – Pancreatic cancer

PHYSICAL EXAM • Full body skin exams • Goal to distinguish melanoma from AMS • ABCDE mnemonic for skins lesions concerning for melanoma: Asymmetry, Border irregularity, Color variegation, Diameter >6 mm, and Evolving lesion – Atypical mole (AM) is often defined as ≥5 mm + at least two other features. – Melanoma typically with several characteristics of ABCDEs, with increased specificity for melanoma using >6 mm for diameter • “Ugly duckling sign” (9)[B] – Melanoma screening strategy of identifying malignant nevi straying from the predominant nevus pattern when numerous atypical nevi are present. • Most common features of AM on dermoscopy magnification per the pattern

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analysis method include the following (10)[C]: – Atypical pigment network – Irregular/peripheral depigmentation areas – Irregular distribution of brown globules – Pigmentation with central heterogeneity and abrupt termination • Some dermatoscopic features more suggestive of melanoma include the following (11)[C]: – Depigmented areas – Whitish veil – Homogenous areas distributed irregularly, in multiple areas, or >25% of total lesion – ≥4 colors

DIFFERENTIAL DIAGNOSIS • Common nevus: acquired or congenital • Melanoma • Seborrheic keratosis • Dermatofibroma • Lentigo • Pigmented actinic keratosis • Pigmented basal cell carcinoma • Blue rubber bleb nevus syndrome

DIAGNOSTIC TESTS & INTERPRETATION Diagnosis is first suspected with history and physical exam, and then confirmed by biopsy and histopathology.

Initial Tests (lab, imaging) • Dermoscopy can be used for more detailed exam to distinguish between benign and malignant lesions, and for further classification to 1 of 11 subtypes. • Genetic testing is available for CDKN2A mutations, but it is not recommended outside of research studies as results cannot be adequately used for management or surveillance (11)[C]. • When the total nevus count is high and following each nevus is impractical,

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total body photography may aid in the evaluation of evolving nevi as well as in documenting new nevi (12)[C].

Diagnostic Procedures/Other • Biopsy is recommended for any lesion where melanoma cannot be excluded. • Biopsy entails full-thickness biopsy of the entire lesion with a narrow 1- to 3mm margin of normal skin down to fat for adequate depth assessment (12)[C]. – Excisional biopsy, elliptical or punch excision provides the most accurate diagnosis and should be performed when possible. – Scoop shave biopsy can also be used, but care must be taken to not transect the lesion. • Reexcision of mild to moderately dysplastic nevi with positive margins may not change pathologic diagnosis, but for severely dysplastic nevi, consider reexcision, with surgical margins of 2 to 5 mm (13)[C].

Test Interpretation “Dysplastic nevus” is a term more accurately reserved for histological findings. Features may include melanocyte proliferation in the dermoepidermal junction, bridging of rete ridges by melanocytic nests, dermal fibrosis, and interstitial lymphocytic inflammation.

TREATMENT MEDICATION No medications are available to treat AMS.

ISSUES FOR REFERRAL • Consider referral to a dermatologist for routine skin exam in patients at high risk for melanoma. • Ophthalmologic exams for ocular nevi/melanoma screening/papilledema • Oncology or specialized genetics study group involvement if strong family predisposition to pancreatic cancer • Cosmetic surgery consultation for cosmetically poor excision outcomes

ADDITIONAL THERAPIES • Topical chemo- and immunotherapies have been unsuccessfully attempted to

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treat atypical moles. • Laser treatment should be avoided because it is both unsafe and ineffective for melanocytic nevi.

SURGERY/OTHER PROCEDURES Surgical excision of all atypical nevi is not recommended because most melanomas in AMS appear de novo on healthy skin and the procedure leads to both poor cosmetic outcomes and a false sense of security. Lesions suspicious for melanoma should be biopsied or removed surgically.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Close follow-up with a dermatologist or other experienced physician: • Total body skin exam (including nails, scalp, genital area, and oral mucosa) every 6 months initially, starting at puberty; may be reduced to annually once nevi are stable • Dermoscopic evaluation for suspect lesions • Ocular exam for those with familial AMS • Excision of suspect lesions • Total body photography at baseline

Patient Monitoring • Monthly self-exams of skin • Sun avoidance and sun protection

PATIENT EDUCATION For young adults aged 10 to 24 years with fair skin, counsel to minimize exposure to ultraviolet radiation to reduce risk of skin cancer (USPSTF Grade B) [A]. No evidence for adults >24 years (USPSTF Grade I)[A] • Fair skin: light eye, hair, or skin color, freckles • Educate on sun avoidance, proper application of sunscreen, use of protective clothing (e.g., hats), avoidance of tanning booths and sunburns. • Teach “ABCDE” mnemonic + “ugly duckling sign” to assess nevi and identify potential melanomas.

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• Provide instruction on skin self-exam techniques. • A sample listing of patient-centric review sources on this topic are as follows: – American Academy of Dermatology (http://cancer.about.com/od/skincancermelanoma/p/abcdeskincancer.htm) – Skin Cancer Foundation (http://www.skincancer.org/skin-cancerinformation/dysplastic-nevi) – Melanoma Research Foundation (http://www.melanoma.org/understandmelanoma/what-is-melanoma)

PROGNOSIS • Most AM either regress or do not change. • Multiple classification schemes have been developed over the years to delineate risk of melanoma in patients with AMS. Individuals with a family history of melanoma are at greatest risk. A classification system developed by Rigel (14) is simply and readily applied in the clinical setting. Points are assigned based on incidence of melanoma, with 1 point given for a personal history with melanoma and 2 points for each family member with melanoma (modified nuclear family consisting of first-degree relatives plus grandparents and uncles/aunts) and stratified as follows: – Score = 0, Rigel group 0, 6% 25-year accumulated risk for melanoma – Score = 1, Rigel group 1, 10% risk – Score = 2, Rigel group 2, 15% risk – Score ≥3, Rigel group 3, 50% risk • The CDKN2A mutation has also been associated with a 60–90% risk of melanoma by age 80 years and a 17% risk for pancreatic cancer by age 75 years.

COMPLICATIONS • Malignant melanoma • Poor cosmetic outcomes from biopsy

REFERENCES 1. Newton JA, Bataille V, Griffiths K, et al. How common is the atypical mole syndrome phenotype in apparently sporadic melanoma? J Am Acad Dermatol. 1993;29(6):989–996.

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2. Gandini S, Sera F, Cattaruzza MS, et al. Meta-analysis of risk factors for cutaneous melanoma: I. Common and atypical naevi. Eur J Cancer. 2005;41(1):28–44. 3. Silva JH, Sá BC, Avila AL, et al. Atypical mole syndrome and dysplastic nevi: identification of populations at risk for developing melanoma—review article. Clinics (Sao Paulo). 2011;66(3):493–499. 4. Naeyaert JM, Brochez L. Clinical practice. Dysplastic nevi. N Engl J Med. 2003;349(23):2233–2240. 5. Mize DE, Bishop M, Reese E, et al. Familial atypical multiple mole melanoma syndrome. In: Riegert-Johnson DL, Boardman LA, Hefferon T, et al, eds. Cancer Syndromes. Bethesda, MD: National Center for Biotechnology Information; 2009. 6. Csoma Z, Tóth-Molnár E, Balogh K, et al. Neonatal blue light phototherapy and melanocytic nevi: a twin study. Pediatrics. 2011;128(4):e856–e864. 7. Matichard E, Le Hénanff A, Sanders A, et al. Effect of neonatal phototherapy on melanocytic nevus count in children. Arch Dermatol. 2006;142(12):1599–1604. 8. Goldsmith LA, Askin FB, Chang AE, et al. NIH Consensus conference. Diagnosis and treatment of early melanoma. JAMA. 1992;268(10):1314– 1319. 9. Scope A, Dusza SW, Halpern AC, et al. The “ugly duckling” sign: agreement between observers. Arch Dermatol. 2008;144(1):58–64. 10. Salopek TG, Kopf AW, Stefanato CM, et al. Differentiation of atypical moles (dysplastic nevi) from early melanomas by dermoscopy. Dermatol Clin. 2001;19(2):337–345. 11. Kefford R, Bishop JN, Tucker M, et al. Genetic testing for melanoma. Lancet Oncol. 2002;3(11):653–654. 12. Duffy K, Grossman D. The dysplastic nevus: from historical perspective to management in the modern era: part I. Historical, histologic, and clinical aspects. J Am Acad Dermatol. 2012;67(1):1.e1–1.e16. 13. Strazzula L, Vedak P, Hoang MP, et al. The utility of re-excising mildly and moderately dysplastic nevi: a retrospective analysis. J Am Acad Dermatol. 2014;71(6):1071–1076. 14. Rigel DS, Rivers JK, Friedman RJ, et al. Risk gradient for malignant

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melanoma in individuals with dysplastic naevi. Lancet. 1988;1(8581):352– 353.

ADDITIONAL READING • Czajkowski R, Placek W, Drewa G, et al. FAMMM syndrome: pathogenesis and management. Dermatol Surg. 2004;30(2, Pt 2):291–296. • Farber MJ, Heilman ER, Friedman RJ. Dysplastic nevi. Dermatol Clin. 2012;30(3):389–404. • Friedman RJ, Farber MJ, Warycha MA, et al. The “dysplastic” nevus. Clin Dermatol. 2009;27(1):103–115. • Moloney FJ, Guitera P, Coates E, et al. Detection of primary melanoma in individuals at extreme high risk: a prospective 5-year follow-up study. JAMA Dermatol. 2014;150(8):819–827. doi: 10.1001/jamadermatol.2014.514. • Robson ME, Storm CD, Weitzel J, et al. American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility. J Clin Oncol. 2010;28(5):893–901. • Slade J, Marghoob AA, Salopek TG, et al. Atypical mole syndrome: risk factor for cutaneous malignant melanoma and implications for management. J Am Acad Dermatol. 1995;32(3):479–494.

CODES ICD10 • D22.9 Melanocytic nevi, unspecified • D22.4 Melanocytic nevi of scalp and neck • D22.30 Melanocytic nevi of unspecified part of face

CLINICAL PEARLS • Melanoma in AMS tends to arise from healthy skin despite a large number of atypical nevi. • ~20% of individuals with familial AMS will develop pancreatic cancer by age 75 years. • Patients with AMS tend to produce neoplasms in unusual sites such as the

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scalp, eyes, and sun-protected areas (e.g., gluteal folds).

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AUTISM SPECTRUM DISORDERS Derek R. Parkes, MD • Holly L. Baab, MD BASICS DESCRIPTION • Group of neurodevelopmental disorders of early childhood: DSM-5: umbrella term autism spectrum disorders (ASDs) which combines autistic disorder, childhood disintegrative disorder, Asperger disorder, pervasive developmental disorder not otherwise specified (PDD-NOS), early infantile autism, childhood autism, Kanner autism, high-functioning autism, and atypical autism (1)[A]. • Two symptom driven subtypes: impairment of effective social skills and absent or impaired communication skills • Fixed interests/repetitive behaviors • Repetitive and/or stereotyped behaviors and interests, especially in inanimate objects (2)[A] • Severity levels – Level 1: requiring support – Level 2: requiring substantial support – Level 3: requiring very substantial support • Important to distinguish autism disorder from social (pragmatic) communication disorder. Separate DSM-5 criteria for individuals with social communication deficits but do not meet autism-spectrum criteria.

EPIDEMIOLOGY • Predominant age: onset in early childhood • Predominant sex: male > female (4.5:1)

Pediatric Considerations Symptom onset seen in children 60 years.

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• Cases occurring in patients >70 years are more common in those with medical comorbidities.

EPIDEMIOLOGY Babesiosis affects patients of all ages. Most patients present in their 40s or 50s (1).

Incidence • In 2012, there were 911 cases reported to the CDC. • Prevalence is difficult to estimate due to lack of surveillance and asymptomatic infections. • Transfusion-associated babesiosis and transplacental/perinatal transmission have been reported (1). • A 1-year seroconversion study of patients in New York, at high risk for tickborne diseases, showed antibodies to Babesia microti in 7 of 671 individuals (1%) (1).

ETIOLOGY AND PATHOPHYSIOLOGY • B. microti (in the United States) and Babesia divergens and Babesia bovis (in Europe) cause most human infections (1). B. divergens and a new strain Babesia ducani appear to be more virulent. Other species have been identified in case reports. All share morphologic, antigenic, and genetic characteristics (1). • Ixodid (hard-bodied) ticks, particularly Ixodes dammini (Ixodes scapularis: deer tick) and Ixodes ricinus, are the primary vectors. The white-footed mouse is the primary reservoir. • Infection is passed to humans through the saliva of a nymphal-stage tick during a blood meal. Sporozoites introduced at the time of the bite enter red blood cells form merozoites through binary fission (classic morphology on blood smear). Humans are a dead-end host for B. microti.

RISK FACTORS • Residing in endemic areas • Asplenia • Immunocompromised state

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GENERAL PREVENTION • Avoid endemic regions during the peak transmission months of May to September (1). • Appropriate insect repellent is advised during outdoor activities, especially in wooded or grassy areas: – 10–35% N,N-diethyl-meta-toluamide (DEET) provides adequate protection (1). • Early removal of ticks via daily skin checks; the tick must remain attached for at least 24 hours before the transmission of B. microti occurs (1). • Examine pets for ticks.

COMMONLY ASSOCIATED CONDITIONS • Coinfection with Borrelia burgdorferi and B. microti, particularly in endemic areas (1) • Coinfection with Ehrlichia (1).

DIAGNOSIS HISTORY • Travel/exposure history • Comorbidities (immunosuppression, chronic disease) • Fever (68–89%), fatigue, (78–79%), chills (39–68%), sweats (41–56%), headache (32–75%), myalgia (32–37%), anorexia (24–25%), cough (17– 23%), arthralgias (17–32%), nausea (9–22%). Other symptoms reported by case reports include abdominal pain, vomiting, diarrhea, and emotional lability.

PHYSICAL EXAM • High fever (up to 40°C [104°F]) • Hemodynamic instability (shock in extremely ill) • Hepatomegaly and splenomegaly (mild if noted) • Rash (uncommon) • CNS involvement includes headache, photophobia, neck and back stiffness, altered sensorium, and emotional lability. • Jaundice and dark urine may develop later in course of illness.

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DIFFERENTIAL DIAGNOSIS • Bacterial sepsis • Hepatitis • Lyme disease • Ehrlichiosis • Leishmaniasis • Malaria • HIV • EBV

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Requires a high index of clinical suspicion. Nonspecific laboratory clues include evidence of mild to severe hemolytic anemia, normal to slightly depressed leukocyte count (1), elevated LDH or transaminase level, elevated BUN and Cr, proteinuria with hemoglobinuria (1,2). • Definitive diagnosis is made by blood smear – A Wright- or Giemsa-stained peripheral blood smear demonstrates intraerythrocytic parasites (2)[B]. – Dividing “cross-like” tetrads of merozoites (Maltese cross) are pathognomonic (2). – Serial blood smears may be required as low parasite load early in the illness may make identification difficult (2). – Can be confused with Plasmodium falciparum on peripheral smear • If blood smears are negative but suspicion remains, IgM serologies through indirect immunofluorescent antibody testing (IFAT) for B. microti antigen are available: – The cutoff titer for a positive result varies by laboratory protocol. Titers of >1:64 or a 4-fold increase from baseline are consistent with B. microti infection (3). Titers may exceed >1:1,024 in acute infection (2)[B]. Titers often persists for 8 to 12 months and can last for years. – In New England, seroprevalence varies between 0.5% and 16% (3). • Detection of B. microti by polymerase chain reaction (PCR) is more sensitive and equally specific in acute cases. PCR can also be used to monitor disease

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progression (2)[B]. Newer real-time PCR tests have a sensitivity and specificity approaching 100%. • When lab tests are inconclusive and infection is strongly suspected, inoculation of laboratory animals with patient blood reveals B. microti organisms in the blood of the animal within 2 to 4 weeks (2). Follow-Up Tests & Special Considerations Monitoring intraerythrocytic parasitemia helps guide treatment (4)[C].

Diagnostic Procedures/Other Based on blood smear, history, and epidemiologic information (2)

TREATMENT GENERAL MEASURES • In areas endemic for Lyme disease and ehrlichiosis, consider adding doxycycline (Vibramycin) 100 mg BID PO until serologic testing is completed (1)[C]. • Resistance to standard medications has emerged in severely immunocompromised patients (2). • Consider treating asymptomatic patients if parasitemia persists for >3 months; otherwise, do not treat in absence of symptoms (1),(4)[C].

MEDICATION First Line • Mild to moderate infection with B. microti: 7 to 10 days of atovaquone 750 mg PO BID plus azithromycin 500 to 1,000 mg/day PO on day 1, followed by 250 mg/day afterward. Pediatrics: atovaquone 20 mg/kg (max 750 mg) BID and azithromycin 10 mg/kg (max 500 mg) on day 1, then 5 mg/kg (max 250 mg) (4)[B]. For severe B. microti infection: oral quinine 650 mg TID or QID plus oral clindamycin 600 mg TID for 7 to 10 days. Pediatrics: clindamycin 7 to 10 mg/kg (max 600 mg) TID or QID and quinine 8 mg/kg (max 650 mg) TID. IV formulations can be used (4)[C]. • Persistent or relapsing babesiosis: Treat for 6 weeks, including 2 weeks after Babesia is no longer detected on blood smear (5)[B].

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Second Line • Combination of quinine sulfate 650 mg PO TID and clindamycin 600 mg PO TID or 1.2 g parenterally BID for 7 to 10 days is the most commonly used treatment. Pediatric: quinine 8 mg/kg (max 650 mg) every 6 to 8 hours for 7 to 10 days and clindamycin 7 to 10 mg/kg (max 600 mg) PO q6–8h for 7 to 10 days. Some experts prefer this regimen for severe infections (4)[C]. • Other drugs including tetracycline, primaquine, sulfadiazine (Microsulfon), and sulfadoxine/pyrimethamine (Fansidar) have been evaluated. Results vary. Pentamidine (Pentam) is moderately effective in diminishing symptoms and decreasing parasitemia (1)[C].

ALERT Clindamycin can lead to Clostridium difficile–associated diarrhea.

ISSUES FOR REFERRAL Severe disease: Consider consultation with hematology and infectious disease for exchange transfusion in extremely ill patients (blood parasitemia >10%, massive hemolysis, and asplenia) (2)[C].

ONGOING CARE FOLLOW-UP RECOMMENDATIONS • If left untreated, silent babesiosis may persist for months or years (2). • 139 hospitalized cases in New York State between 1982 and 1993: – 9 patients (7%) died. – 25% of the patients were admitted to the ICU. – 25% hospitalized for >14 days. • Alkaline phosphatase levels >125 U/L, WBC counts >5 × 109/L, history of cardiac abnormality, history of splenectomy, presence of heart murmur, and parasitemia of 4% or higher are associated with disease severity (6)[B].

Patient Monitoring The need for clinical and lab monitoring depends on disease severity. Severe infections: Follow hematocrit and parasitemia levels until clinical improvement and parasitemia is 70 years with or without trauma – Age >50 years with minor trauma – History of cancer – Osteoporosis – Immunosuppression, prolonged glucocorticoid use • Yellow flags (predicting poor long-term prognosis): – Lack of social support – Unsupportive work environment – Depression and/or anxiety – Abuse of alcohol or other substances – History of physical or sexual abuse • Pain can be provoked with motion: flexion–extension, side-bending rotation, sitting, standing, and lifting. Pain often relieved with rest. • Radicular pain may radiate to buttocks, thighs, and lower legs.

Pediatric Considerations Back pain is not normal in children and must be carefully evaluated. Patients participating in gymnastics or other high-impact or hyperextension sports (such as skateboarding and cheerleading) frequently land on their feet or buttocks. These can result in a vertebral fracture and/or damage to the intervertebral discs.

PHYSICAL EXAM • Observe gait, positioning, and facial expressions. • Test lumbar spine range of motion. • Evaluate for point tenderness or muscle spasm. • Evaluate for signs of muscle atrophy. – Completely evaluate reflexes, strength, pulses, sensation

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– Straight leg test – FABER test (flexion, abduction, and external rotation) – Stork test: Stand on one leg with opposite hip held in flexion. Extend back. Pain in lumbosacral area is a positive test—consider spondylolisthesis.

DIFFERENTIAL DIAGNOSIS • Localized/nonspecific “mechanical” LBP (87%) (1)[A] • Lumbar strain/sprain (70%) – Disc/facet degeneration (10%) – Osteoporotic compression fracture (4%) – Spondylolisthesis (2%) – Severe scoliosis, kyphosis – Asymmetric transitional vertebrae (16 years of age (1)

ETIOLOGY AND PATHOPHYSIOLOGY • Balanitis: – Allergic reaction (condom latex, contraceptive jelly) – Infections (Candida albicans, Borrelia vincentii, streptococci, Trichomonas, HPV) – Fixed-drug eruption (sulfa, tetracycline) – Plasma cell infiltration (Zoon balanitis) – Autodigestion by activated pancreatic transplant exocrine enzymes • Phimosis: – Physiologic: present at birth; resolves spontaneously during the first 2 to 3 years of life through nocturnal erections, which slowly dilate the phimotic ring – Acquired: recurrent inflammation, trauma, or infections of the foreskin • Paraphimosis: – Often iatrogenically or inadvertently induced by the foreskin not being pulled back over the glans after voiding, cleaning, cystoscopy, or catheter insertion

Geriatric Considerations Condom catheters can predispose to balanitis.

Pediatric Considerations Oral antibiotics predispose male infants to Candida balanitis. Inappropriate care of physiologic phimosis can lead to acquired phimosis by repeated forced reduction of the foreskin.

RISK FACTORS • Balanitis: – Presence of foreskin – Morbid obesity

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– Poor hygiene – Diabetes; probably most common – Nursing home environment – Condom catheters – Chemical irritants – Edematous conditions: CHF, nephrosis • Phimosis: – Poor hygiene – Diabetes by repeated balanitis – Frequent diaper rash in infants – Recurrent posthitis • Paraphimosis: – Presence of foreskin – Inexperienced health care provider (leaving foreskin retracted after catheter placement) – Poor education about care of the foreskin

GENERAL PREVENTION • Balanitis: – Proper hygiene and avoidance of allergens – Circumcision • Phimosis/paraphimosis: – If the patient is uncircumcised, appropriate hygiene and care of the foreskin are necessary to prevent phimosis and paraphimosis.

DIAGNOSIS HISTORY • Balanitis: – Pain – Drainage – Dysuria – Odor – Ballooning of foreskin with voiding

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– Redness • Phimosis: – Painful erections – Recurrent balanitis – Foreskin balloons when voiding – Inability to retract foreskin at appropriate age • Paraphimosis: – Uncircumcised – Pain – Drainage – Voiding difficulty

PHYSICAL EXAM • Balanitis: – Erythema – Tenderness – Edema – Discharge – Ulceration – Plaque • Phimosis: – Foreskin will not retract. – Secondary balanitis – Physiologic phimosis—preputial orifice appears normal and healthy – Pathologic phimosis—preputial orifice has fine white fibrous ring of scar • Paraphimosis: – Edema of prepuce and glans – Drainage – Ulceration

DIFFERENTIAL DIAGNOSIS • Balanitis: – Leukoplakia – Lichen planus – Psoriasis

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– Reiter syndrome – Lichen sclerosus et atrophicus – Erythroplasia of Queyrat – BXO: atrophic changes at end of foreskin; can form band that prevents retraction • Phimosis/paraphimosis: – Penile lymphedema, which can be related to insect bites, trauma, or allergic reactions – Penile tourniquet syndrome: foreign body around penis, most commonly hair – Anasarca

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Microbiology culture • Wet mount • Serology for syphilis • Serum glucose; ESR (if concerns about Reiter syndrome) • STD testing • HIV testing • Gram stain

Diagnostic Procedures/Other Biopsy, if persistent

Pathologic Findings Plasma cells infiltration with Zoon balanitis

TREATMENT GENERAL MEASURES • Consider circumcision for recurrent balanitis and paraphimosis. • Warm compresses or sitz baths • Local hygiene

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MEDICATION • Balanitis: – Antifungal: Clotrimazole (Lotrimin) 1% BID Nystatin (Mycostatin) BID–QID Fluconazole: 150 mg PO single dose • Antibacterial: – Bacitracin QID – Neomycin–polymyxin B–bacitracin (Neosporin) QID – If cellulitis, cephalosporin or sulfa drug PO or parenteral: Dermatitis: topical steroids QID Zoon balanitis: topical steroids QID • Phimosis: – 0.05% fluticasone propionate daily for 4 to 8 weeks with gradual traction placed on foreskin (2)[B] – 1% pimecrolimus BID for 4 to 6 weeks. Not for use in children AC) tests – Transient facial paralysis • All patients with middle ear barotrauma should be evaluated for inner ear barotrauma: – Sensorineural hearing loss with Weber and Rinne tests • Sinus barotrauma – Facial tenderness • Pulmonary barotrauma – Hypoxia, hypotension – Auscultation, percussion – Assessment of respiratory distress

DIFFERENTIAL DIAGNOSIS • Acute and chronic otitis media • Otitis externa • Dental caries • Temporomandibular joint syndrome • Pulmonary: pulmonary embolism; complications of mechanical ventilation

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Otic or sinus – CT to rule out underlying pathology, if suspected Nasopharyngeal tumor (if enlarging facial/neck mass with or without nasal obstruction, recurrent epistaxis) Chronic sinus disease (sinus pain, pressure, fullness, chronic posterior nasal drip/congestion) • Pulmonary

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– Chest radiograph – Chest CT if unclear diagnosis by CXR – Arterial blood gases (ABG) • Other: ultrasound

Diagnostic Procedures/Other • Otic barotrauma – Tympanometry – Audiometry: conductive (middle ear) versus sensorineural (inner ear) hearing loss – Surgical exploration to rule out inner ear involvement, if suspected • Pulmonary barotrauma: chest tube insertion, if clinically indicated, for pneumothorax

Test Interpretation • Tympanic membrane (TM) retraction or bulging – Teed 0: no visible damage – Teed 1: congestion around umbo – Teed 2: congestion of entire TM – Teed 3: hemorrhage into middle ear – Teed 4: extensive middle ear hemorrhage; TM may rupture. – Teed 5: entire middle ear filled with deoxygenated blood • Inner ear involvement with rupture of the round or oval windows, perilymphatic fistula, and leakage of perilymph into the middle ear • Pulmonary barotrauma – Alveolar rupture may progress to interstitial emphysema, pneumoperitoneum, and pneumothorax. • Petechial hemorrhages in area covered by diver’s mask, as well as subconjunctival hemorrhages

TREATMENT GENERAL MEASURES • Prevention/avoidance is best: Avoid flying or diving when risk factors are present.

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• Autoinflate the eustachian tube during pressure changes (3)[B]. – Valsalva during ascent and descent in air travel – Infants: breastfeeding, pacifier use, or bottle feed – ≥4 years: chewing gum – ≥8 years: blowing up a balloon – Adults: chewing gum, swallowing, or yawning • The nasal balloon is effective for prevention (4)[B]. • Pressure-equalizing earplugs are not recommended in air travel and do not prevent ear barotrauma (5)[B]. • For inner ear barotrauma – Bed rest with head elevated to avoid leakage of perilymph – Tympanotomy and repair of round or oval window may be necessary. – Sudden or progressive sensorineural hearing loss accompanied by dizziness following barotrauma should prompt consideration of a perilymph fistula. Early surgical exploration is recommended to improve hearing and vestibular symptoms (6)[C]. • Lung protective settings during mechanical ventilation (1)[A] – Acute lung injury: NNT = 16 – Lung injury: NNT = 11 • Treatment of pneumothorax – Removal of air from pleural space (chest tube; Heimlich valve) • Correct iatrogenic cause (e.g., adjustment of mechanical ventilation).

MEDICATION • Treat predisposing conditions (e.g., upper respiratory congestion prior to air travel): – Oral decongestants – Nasal decongestants – Antihistamines • Antibiotics are not indicated for middle ear effusion secondary to barotrauma. • Analgesics for pain control

ISSUES FOR REFERRAL • Refer to otolaryngology if inner ear is exposed, perilymphatic fistula is present, or sensorineural hearing loss is experienced.

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• Ruptured tympanic membrane not improving after 2 weeks of conservative therapy • Consult with a hyperbaric specialist if recompression is required. • Chest tube placement

SURGERY/OTHER PROCEDURES • If necessary, myringotomy or tympanoplasty • Tympanotomy and repair of round or oval window may be necessary for inner ear barotrauma. • Tube thoracostomy for persistent pneumothorax

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Patients with complicating emergencies (e.g., incapacitating pain requiring myringotomy, large tympanic perforation requiring tympanoplasty) • Inner ear barotrauma with hearing loss • Management of pneumothorax

ONGOING CARE FOLLOW-UP RECOMMENDATIONS • No flying or diving until complete resolution of all signs and symptoms and Valsalva maneuver succeeds in equalizing pressure • Complete bed rest for inner ear barotrauma • No high-risk activities or air travel until pneumothorax is completely resolved

Patient Monitoring • Repeat physical examination until symptoms are clear. • Audiograms and tympanometry if tympanic rupture

PATIENT EDUCATION • Demonstrate proper Valsalva maneuver. • Appropriately treat sinus infections. • American Academy of Pediatrics travel safety tips: https://www.aap.org/enus/about-the-aap/aap-press-room/news-features-and-safety-tips/Pages/travel-

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safety-tips.aspx. • Divers Alert Network of Duke University Medical Center information line: (919) 684-2948

PROGNOSIS • Mild barotitis media may resolve spontaneously. • Tympanic rupture takes weeks to months for healing. • Hearing loss may be permanent in barotitis externa. • Prognosis of pulmonary barotrauma depends on the extent of underlying pathology. • Middle ear barotrauma can lead to permanent hearing loss and vertigo.

COMPLICATIONS • Permanent hearing loss • Ruptured tympanic membrane • Chronic tinnitus, vertigo • Fluid exudate in middle ear • Perilymphatic fistula • Sensorineural hearing loss

REFERENCES 1. Sutherasan Y, Vargas M, Pelosi P. Protective mechanical ventilation in the non-injured lung: review and meta-analysis. Crit Care. 2014;18(2):211. 2. Morgagni F, Autore A, Landolfi A, et al. Predictors of ear barotrauma in aircrews exposed to simulated high altitude. Aviat Space Environ Med. 2012;83(6):594–597. 3. Stangerup SE, Klokker M, Vesterhauge S, et al. Point prevalence of barotitis and its prevention and treatment with nasal balloon inflation: a prospective, controlled study. Otol Neurotol. 2004;25(2):89–94. 4. Landolfi A, Autore A, Torchia F, et al. Ear pain after breathing oxygen at altitude: prevalence and prevention of delayed barotrauma. Aviat Space Environ Med. 2010;81(2):130–132. 5. Klokker M, Vesterhauge S, Jansen EC. Pressure-equalizing earplugs do not prevent barotrauma on descent from 8000 ft cabin altitude. Aviat Space Environ Med. 2005;76(11):1079–1082.

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6. Park GY, Byun H, Moon IJ, et al. Effects of early surgical exploration in suspected barotraumatic perilymph fistulas. Clin Exp Otorhinolaryngol. 2012;5(2):74–80.

SEE ALSO Algorithm: Ear Pain

CODES ICD10 • T70.0XXA Otitic barotrauma, initial encounter • T70.1XXA Sinus barotrauma, initial encounter • T70.29XA Other effects of high altitude, initial encounter

CLINICAL PEARLS • Small children can equalize eustachian tube pressure by breastfeeding or sucking on bottles or pacifiers. Crying also serves as autoinflation. • Pulmonary barotrauma is the second leading cause of death among divers. • Otic barotrauma is common in air travel, especially among flight personnel. • Pulmonary barotrauma is noted in 2–3% of mechanically ventilated patients. • Sudden or progressive sensorineural hearing loss accompanied by dizziness following barotrauma suggests a perilymphatic fistula. Early surgical exploration is recommended to preserve hearing and vestibular functions.

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BARRETT ESOPHAGUS Eric Ji-Yuan Mao, MD • Harlan G. Rich, MD, FACP, AGAF BASICS DESCRIPTION • Metaplasia of the distal esophageal mucosa from native stratified squamous epithelium to abnormal columnar (intestinalized) epithelium, likely as a consequence of chronic GERD • Predisposes to the development of adenocarcinoma of the esophagus

EPIDEMIOLOGY • Predominant age: >50 years • May occur in children (rare 5 years) • Hiatal hernia • Age >50 years • Male gender • White ethnicity—incidence in white males is much higher than white women and African American men. • Smoking history • Intra-abdominal obesity • Family history with at least one first-degree relative with BE or esophageal adenocarcinoma

GENERAL PREVENTION Weight loss, smoking cessation, robust dietary intake of fruits and vegetables, and moderate wine consumption may decrease risk of BE and lower progression to esophageal cancer (1)[C].

COMMONLY ASSOCIATED CONDITIONS GERD, obesity, hiatal hernia

DIAGNOSIS HISTORY • Assess underlying risk factors.

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• Common GERD symptoms: heartburn, regurgitation • Less common symptoms include chest pain, odynophagia, chronic cough, water brash, globus sensation, laryngitis, or wheezing. • Symptoms suggestive of complicated GERD or cancer include weight loss, anorexia, dysphagia, odynophagia, hematemesis, or melena.

ALERT Up to 25% of patients with BE are asymptomatic (1).

PHYSICAL EXAM No abnormal findings on physical exam are specific for BE. A general examination should include vital signs, oral examination, cardiopulmonary examination, abdominal examination, and lymph node examination.

DIFFERENTIAL DIAGNOSIS • Erosive esophagitis • GERD

DIAGNOSTIC TESTS & INTERPRETATION Endoscopy with multiple biopsies demonstrating intestinal metaplasia extending ≥1 cm proximal to the gastroesophageal junction are required to diagnose BE. • Gastric cardia–type epithelium on pathology does not have clear malignant significance and may reflect sampling error. • Specialized intestinal metaplasia at the GEJ: cancer risk difficult to assess with varying definitions of GEJ landmarks

ALERT Endoscopic screening for BE is suggested in men with chronic GERD (>5 years) and/or frequent GERD symptoms with 2 or more risk factors: age >50 years; white ethnicity; central obesity, smoking history, family history of BE or esophageal adenocarcinoma. Screening for BE in the general population with GERD or women with GERD is not recommended, though it can be considered in women with multiple risk factors (2)[C].

Initial Tests (lab, imaging) None: • Helicobacter pylori testing is not indicated. Meta-analyses show an inverse

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relationship between H. pylori infections and BE, which may be related to decreased acid production. • No current biomarkers are effective for diagnosis; some under investigation for risk stratification (1)[B].

Diagnostic Procedures/Other • Endoscopy: visual identification of columnar (reddish, velvety appearance) replacing squamous (pale, glossy appearance) lining of the distal esophagus • White light endoscopy (preferably high resolution) is the standard for diagnosis. Disease extent: long-segment (≥3 cm) versus short-segment (40 years, although incidence increasing in younger populations • Predominant sex: male > female (2:1 ratio)

ETIOLOGY AND PATHOPHYSIOLOGY • UV-induced inflammation and cyclooxygenase activation in skin • In chromosome 9q22, mutation of PTCH1 (patched homolog 1), a tumorsuppressor gene that inhibits the hedgehog signaling pathway

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• UV-induced mutations of the TP53 (tumor protein 53), a tumor-suppressor gene • Activation of BCL2, an antiapoptosis proto-oncogene

Genetics • Several genetic conditions increase the risk of developing BCC: – Albinism (recessive alleles) – Xeroderma pigmentosum (autosomal recessive) – Bazex syndrome (rare, X-linked dominant) – Nevoid BCC syndrome/Gorlin syndrome (rare, autosomal dominant) – Cytochrome P-450 CYP2D6 and glutathione S-transferase detoxifying enzyme gene mutations (especially in truncal BCC, marked by clusters of BCCs and a younger age of onset)

RISK FACTORS • Chronic sun exposure (UV radiation). Most common in the following phenotypes – Light complexion: skin type I (burns but does not tan) and skin type II (usually burns, sometimes tans) – Red or blond hair – Blue or green eyes • Tendency to sunburn • Male sex, although increasing risk in women due to lifestyle changes, such as tanning beds • History of nonmelanoma skin cancer – After initial diagnosis of skin cancer, 35% risk of new nonmelanoma skin cancer at 3 years and 50% at 5 years • Family history of skin cancer • 3 to 4 decades after chronic arsenic exposure • 2 decades after therapeutic radiation • Chronic immunosuppression: transplant recipients (10 times higher incidence), patients with HIV, or lymphomas • No significant association between age and recurrence rate, according to most studies

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GENERAL PREVENTION • Use broad-spectrum sunscreens of at least SPF 30 daily and reapply after swimming or sweating. • Avoid overexposure to the sun by seeking shade between 10 AM and 4 PM and wearing wide-brimmed hats and long-sleeved shirts. • The American Cancer Society recommends cancer-related checkups every 3 years in patients 20 to 40 years old and yearly in patients >40 years.

COMMONLY ASSOCIATED CONDITIONS • Cosmetic disfigurement because head and neck most often affected • Loss of vision with orbital involvement • Loss of nerve function due to perineural spread or extensive and deep invasion • Ulcerating neoplasms are prone to infections.

DIAGNOSIS HISTORY Exposure to risk factors, family history

PHYSICAL EXAM • 80% on face and neck, 20% on trunk and lower limbs (mostly women) • Nodular: most common (60%); presents as pinkish, pearly papule, plaque, or nodule, often with telangiectatic vessels, ulceration, and a rolled periphery usually on face (1) – Pigmented: presents as a translucent papule with “floating pigment”; more commonly seen in darker skin types; may give a blue, brown, or black appearance and be confused with melanoma (1) • Superficial: 30%; light red, scaly plaque resembling eczema or psoriasis but with raised, pearly white borders similar to the nodular subtype, usually on trunk or extremities; least invasive of BCC subtypes • Morpheaform: 5–10%; resembles localized scleroderma; mass is ill-defined and often extends beyond visible lesion.

DIFFERENTIAL DIAGNOSIS • Sebaceous hyperplasia

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• Epidermal inclusion cyst • Intradermal nevi (pigmented and nonpigmented) • Molluscum contagiosum • Squamous cell carcinoma (SCC) • Nummular dermatitis • Psoriasis • Melanoma (pigmented lesions) • Atypical fibroxanthoma • Rare adnexal neoplasms

DIAGNOSTIC TESTS & INTERPRETATION Diagnostic Procedures/Other • Clinical diagnosis and histologic subtype are confirmed through skin biopsy and pathologic examination. • Shave biopsy is typically sufficient; however, punch biopsy is more useful to assess depth of tumor and perineural invasion. • If a genetic disorder is suspected, additional tests may be needed to confirm it.

Test Interpretation • Nodular BCC – Extending from the epidermis are nodular aggregates of basaloid cells. – Tumor cells are uniform; rarely have mitotic figures; large, oval, hyperchromatic nuclei with little cytoplasm, surrounded by a peripheral palisade – Early lesions are usually connected to the epidermis, unlike late lesions. – Increased mucin in dermal stroma Cleft formation (retraction artifact) common between BCC “nests” and stroma due to mucin shrinkage during fixation and staining • Superficial BCC – Appear as buds of basaloid cells attached to undersurface of epidermis – Peripheral palisading • Morpheaform BCC – Thin cords and strands of basaloid cells; embedded in dense, fibrous, scarlike stroma – Less peripheral palisading and retraction, greater subclinical involvement

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• Infiltrating BCC – Like morpheaform BCC but no scar-like stroma and thicker, more spiky, irregular strands – Less peripheral palisading and retraction, greater subclinical involvement • Micronodular BCC – Small, nodular aggregates of tumor cells – Less retraction artifact and higher subclinical involvement than nodular BCC

TREATMENT MEDICATION • May be especially useful in those who cannot tolerate surgical procedures and in those who refuse to have surgery, as well as for low-risk superficial and/or nodular BCC • 5-fluorouracil cream inhibits thymidylate synthetase, interrupting DNA synthesis for superficial lesions in low-risk areas; primary treatment only; 5% applied BID for 3 to 10 weeks • Imiquimod (Aldara) cream approved for treatment of low-risk superficial BCC; daily dosing for 6 to 12 weeks; 90% histologic cure (1,2)[A] • 5-FU is not considered appropriate primary monotherapy for infiltrative or nodular BCC (1)[A]; however, with nodular BCC, imiquimod has been shown to have 5-year clearance rates ranging between 75% and 85% (3)[A]. • Topical treatment failure may yield skip lesions that yield false-negative margins, making Mohs and excisional surgery potentially less effective (1) [A]. • Emerging therapies: – Vismodegib, a sonic hedgehog pathway inhibitor; for patients with advanced BCC when other options are exhausted; not considered appropriate therapy for low-risk tumors (1)[A]. Demonstrated success with this has led to research on other hedgehog inhibitor compounds, including sonidegib (3). – Intralesional IFN-a-2B injection: some efficacy for small (5-year-olds because more covert • Thumb-sucking: decreases with age; most children spontaneously stop between 2 and 4 years.

COMMONLY ASSOCIATED CONDITIONS • Noncompliance: if exceeds what seems normative, rule out depression, compulsive patterns, adjustment disorder, inappropriate discipline • Temper tantrums: difficult child temperament, stress • Sleep problems: often with inconsistent bedtime routine or sleep schedule, stimulating bedtime environment; can be associated with hyperactive behavior, poor impulse control, and poor attention in young children (2). Acute or chronic anxiety is associated with insomnia. • Enuresis: secondary often with medical problems, especially constipation, and frequent behavior problems, especially ADHD • Functional encopresis: enuresis, UTIs, ADHD

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• Normative sexual behaviors: family stressors such as separation or divorce

DIAGNOSIS HISTORY • Noncompliance: complete history from caregivers and teachers, if applicable; direct observation of child or child–caregiver interaction – Criteria are problematic for at least some adults, leading to difficult interactions for at least 6 months. – Reduces child’s ability to take part in structured activities – Creates stressful relationships with compliant children – Disrupts academic progress; places child at risk for physical injury • Temper tantrums: history, with focus on development, family functioning, or violence; may consist of stiffening limbs and arching back, dropping to the floor, shouting, screaming, crying, pushing/pulling, stamping, hitting, kicking, throwing, or running away (1) • Sleep disorders: screening questions about sleep during well-child visit, such as the Bedtime problems, Excessive daytime sleepiness, Awakenings during the night, Regularity and duration of sleep, and Snoring (BEARS) screen; bedtime routine (2)[C] • Nocturnal enuresis: severity, onset, and duration; daytime wetting or any associated genitourinary symptoms; family history of enuresis; medical and psychosocial history; constipation; child and caregiver’s motivation for treatment • Problem eating: review of child’s diet, growth curves, nutritional needs, and caregiver’s response to behavior (5)[C] • Normative sexual behaviors: When was behavior first noticed? Any recent changes or stressors in family? Behavior solitary or with another; if with another, what age? Changes in frequency or nature of behaviors; occurs at home, daycare, school? Is behavior disruptive, intrusive, or coercive? (See “Child Sexual Behavior Inventory” in the following discussion.)

PHYSICAL EXAM • Nocturnal enuresis

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– Physical exam of abdomen for enlarged bladder, kidneys, or fecal masses; rectal exam if history of constipation; back for spinal dysraphism seen in dimpling or hair tufts – Neurologic exam: focus on lower extremities – Genitourinary exam Males: meatal stenosis, hypospadias, epispadias, phimosis Females: vulvitis, vaginitis, labial adhesions, ureterocele at introitus; wide vaginal orifice with scar or healed laceration may be evidence of abuse. • Functional encopresis – Height and weight; abdominal exam for masses or tenderness; rectal exam for tone, size of rectal vault, fecal impaction, masses, fissures, hemorrhoids; back for signs of spinal dysraphism seen in dimpling or hair tufts (4)

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • For nocturnal enuresis: urinalysis (dipstick test OK); if abnormal, consider urine culture. – For secondary enuresis: serum glucose, creatinine, thyrotropin – Urinary tract imaging and urodynamic studies if significant daytime symptoms with history or diagnosis of UTI or history of structural renal abnormalities • For functional encopresis: tests for hypothyroidism or celiac disease if poor growth or family history; urinalysis and culture if enuresis or features of UTI (4) – Spine imaging if evidence of spinal dysraphism or if both encopresis and daytime enuresis; barium enema if suspect Hirschsprung disease Follow-Up Tests & Special Considerations Sleep disorders: Sleep studies may be performed in children if there is a history of snoring and daytime ADHD-type symptoms (2).

Diagnostic Procedures/Other • Pediatric symptom checklist: https://brightfutures.org/mentalhealth/pdf/professionals/ped_sympton_chklst.pdf • National Initiative for Children’s Healthcare Quality (NICHQ) Vanderbilt

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Assessment (ADHD screen): http://www.myadhd.com/vanderbiltparent6175.html • Child Sexual Behavior Inventory: completed by female caregiver to assist with differentiation of normative versus abnormal behaviors particularly those related to sexual abuse: http://www.nctsnet.org/content/child-sexual-behaviorinventory-csbi

TREATMENT • General: Educate caregiver about specific behavioral problem. • Parent management training programs and techniques are effective for many child behavior problems. • Noncompliance: In the case of extreme child disobedience, consider parent training programs. Child may need to be formally screened for ADHD, obsessive-compulsive disorder (OCD), oppositional defiant disorder (ODD), or conduct disorder (CD). • Temper tantrums: Remind caregiver this is a normal aspect of early childhood. – Educate caregiver that tantrums are not attention seeking, although they may reveal that the child needs more attention from caregiver. This attention should be developmentally appropriate and not occur when the child is tantruming but at other times and prior to the tantrum. – If tantrum is set off by external factors, such as hunger or overtiredness, then correct. – Other methods for dealing with a tantrum include one of the following: Ignore the tantrum; remove the child and place him or her in time-out (1 minute for each year of age); hold/restrain child until calmed down; provide child with clear, firm, and consistent instructions as well as enough time to obey. • Sleep problems: Intervention consists largely of education of the caregiver who may need a roadmap for dealing with this difficult and distressing problem. Developmental stages; environmental factors and cues; caregiver emotions and reactions; and child fears, stress, and habits are all important factors in sleep onset and maintenance that should be explored and explained to the caregiver.

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• Specific recommendations may also consist of other interventions including the following (2)[A]: – Graduated extinction: Caregiver ignores cries for specified period; can check at a fixed time or increasing intervals – “Fading”: gradual decrease in direct contact with the child as child falls asleep; goal is for the caregiver to exit the room and allow child to fall asleep independently. – Consider the “5S Intervention” for settling problems in toddlers (used to comfort infants in nurseries): swaddling, sucking, shushing, stomach/side position, and swinging – If fearful, preferred routines or inert sprays or glitter spread by the child (while avoiding the eyes) may help the child feel more secure. • Nocturnal enuresis – Bedwetting alarm: first-line therapy for caregivers who can overcome objection of having their sleep disturbed; about 2/3 of children respond while using the alarm; if enuresis recurs after use, it will often resolve with a second trial. – Decrease fluids an hour before bedtime. – Little evidence from clinical trials but good empirical evidence for behavioral training, including positive reinforcement (small reward for each dry night) or responsibility training (if developmentally able, child is responsible for changing or washing sheets), encouraging daily bowel movements, and frequent bladder emptying during the day • Functional encopresis – First disimpaction: PO with polyethylene glycol solution or mineral oil; if unsuccessful, manual mineral oil enemas – Maintenance therapy Medical: osmotics, such as polyethylene glycol, fiber, lactulose; stimulants, such as senna or bisacodyl Behavior modification: toileting after meals for 10 minutes 2 to 3 times a day, star charts, and rewards (4)[C] • Problem eating – Avoid punishment, prodding, or rewards. Offer a variety of healthy foods at every meal; limit milk to 24 oz/day and decrease juice (5)[C].

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• Normative sexual behavior: No treatment needed; caregivers may need encouragement not to punish or admonish child and to use gentle distraction to redirect behavior when in public setting. • Thumb-sucking: Recommendations to caregivers include praising children when not sucking their thumb, offer alternatives that are soothing (e.g., stuffed toys), provide reminders or negative reinforcement in the form of a bandage around or bitters on the thumb (5)[C].

MEDICATION Most pediatric behavioral issues respond well to nonpharmacologic therapy: • Sleep disorders – Insufficient efficacy data exists to recommend routine psychopharmacology. As in adults, cognitive-behavioral therapy and/or sleep hygiene should be first-line treatment. – For certain delayed sleep-onset disorders, after behavioral methods are exhausted, melatonin 0.5 to 10 mg PO can be tried while behavior modification is continued. Sleep latency is likely to be reduced. However, this is not approved by the FDA for children. Expect rebound insomnia. Daytime exposure to bright or sunlight should be assured before treatment. • Nocturnal enuresis – Desmopressin can decrease urine output to reduce enuresis episodes. Expect fewer episodes, not full cessation. Not before age 6 years; begin with 0.2 mg tablet nightly 1 hour before bedtime; titrate to 0.6 mg. However, use is questionable because its effects do not persist posttreatment. Intranasal formulations can cause severe hyponatremia, resulting in seizures and death in children. Behavioral interventions should be first-line treatment.

ISSUES FOR REFERRAL • A patient who exhibits self-injurious behaviors, slow recovery time from tantrums, more tantrums in the home than outside the home, or more aggressive behaviors toward others may require referral to a psychologist or psychiatrist. • Children with chronic insomnia or anxiety that interferes with sleep should be referred to a psychologist or psychiatrist.

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• A child with loud nightly snoring, with observed apnea spells, daytime excessive sleeping, and neurobehavioral signs such as mood changes, ADHDlike symptoms, or academic problems should be referred for sleep studies (2). • With enuresis and obstructive sleep apnea symptoms, refer for sleep studies because surgical correction of airway obstruction often improves or cures enuresis and daytime wetting. • Must distinguish sexual behavior problems: Developmentally inappropriate behaviors—greater frequency or earlier age than expected— becomes a preoccupation, recurs after adult intervention/corrective efforts. If abuse is not suspected, consider referral to a child psychologist. If abuse is suspected, must report to child protective services. • If disimpaction by either manual or medical methods is unsuccessful, consult gastroenterology or general surgery. Patients who show no improvement after 6 months of maintenance medical therapy should be referred to gastroenterology (4). • Thumb-sucking resistant to behavioral intervention and threatening oral development may be evaluated by a pediatric dentist for use of habit-breaking dental appliances (5)[C].

ONGOING CARE DIET Nutrition is very important in behavioral issues. Avoiding high-sugar foods and caffeine and providing balanced meals has been shown to decrease aggressive and noncompliant behaviors in children.

PATIENT EDUCATION • Yale Parenting Center, Kazdin Method Sessions Webinars, http://yaleparentingcenter.yale.edu/kazdin-method-sessions • See Parent Training Programs: Insight for Practitioners at: http://www.cdc.gov/violenceprevention/pdf/Parent_Training_Brief-a.pdf • The Happiest Baby Guide to Great Sleep: Simple Solutions for Kids from Birth to 5 Years. Harvey Karp, MD New York, HarperCollins Publishers 2012, 384 pp.

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• Products – Nytone Bed Wetting Alarms: by order to: http://www.nytone.com/collections/vendors?q=Nytone

REFERENCES 1. Potegal M, Davidson RJ. Temper tantrums in young children: 1. Behavioral composition. J Dev Behav Pediatr. 2003;24(3):140–147. 2. Bhargava S. Diagnosis and management of common sleep problems in children. Pediatr Rev. 2011;32(3):91–98. 3. Robson WL. Clinical practice. Evaluation and management of enuresis. N Engl J Med. 2009;360(14):1429–1436. 4. Har AF, Croffie JM. Encopresis. Pediatr Rev. 2010;31(9):368–374. 5. Tseng AG, Biagioli FE. Counseling on early childhood concerns: sleep issues, thumb sucking, picky eating, and school readiness. Am Fam Physician. 2009;80(2):139–142.

CODES ICD10 • F91.9 Conduct disorder, unspecified • F91.1 Conduct disorder, childhood-onset type • F91.2 Conduct disorder, adolescent-onset type

CLINICAL PEARLS • Well-child visits provide opportunities for systematic screening for these common conditions. • Noncompliance: In extreme child disobedience, child may need to be screened for ADHD, OCD, ODD, or CD. • Self-injurious behaviors, slow recovery time from tantrums, more tantrums in the home than outside the home, or more aggressive behaviors toward others may require referral to a psychologist or psychiatrist. • Parental education, including a review of age-appropriate discipline, is a key component of treatment.

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BELL PALSY Irina Pechenko, MD BASICS DESCRIPTION A peripheral lower motor neuron facial palsy, usually unilateral, which arises secondary to inflammation and subsequent swelling and compression of cranial nerve VII (facial) and the associated vasa nervorum

EPIDEMIOLOGY • Affects 0.02% of the population annually • Predominant sex: male = female • Median age of onset is 40 years but affects all ages. • Accounts for 60–75% of all cases of unilateral facial paralysis • Occurs with equal frequency on the left and right sides of the face • Most patients recover, but as many as 30% are left with facial disfigurement and pain.

Incidence • 20 to 30 cases per 100,000 people in the United States per year • Lowest in children ≤10 years of age; highest in adults ≥70 years of age • Higher among pregnant women

Prevalence Affects 40,000 Americans every year

ETIOLOGY AND PATHOPHYSIOLOGY • Results from damage to the facial cranial nerve (VII) • Inflammation of cranial nerve VII causes swelling and subsequent compression of both the nerve and the associated vasa nervorum. • May arise secondary to reactivation of latent herpesvirus (herpes simplex virus [HSV] type 1 and herpes zoster virus) in cranial nerve ganglia or due to ischemia from arteriosclerosis associated with diabetes mellitus

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Genetics May be associated with a genetic predisposition, but it remains unclear which factors are inherited

RISK FACTORS • Pregnancy, specially associated with severe preeclampsia • Diabetes mellitus • Age >30 years • Exposure to cold temperatures • Upper respiratory infection (e.g., coryza, influenza) • Chronic HTN • Obesity • Migraine headache • Narrow diameter of facial canal (1)

COMMONLY ASSOCIATED CONDITIONS • HSV • Lyme disease • Diabetes mellitus • Hypertension • Herpes zoster virus • Ramsay-Hunt syndrome • Sjögren syndrome • Sarcoidosis • Eclampsia • Amyloidosis

DIAGNOSIS HISTORY • Time course of the illness (rapid onset) • Predisposing factors: recent viral infection, tick bite, trauma, new medications, hypertension, diabetes mellitus • Presence of hyperacusis or history of recurrent Bell palsy (both associated with poor prognosis)

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• Any associated rash (suggestive of herpes zoster, Lyme disease, or sarcoid) • Weakness on affected side of face, often sudden in onset • Pain in or behind the ear in 50% of cases, which may precede the palsy in 25% of cases • Subjective numbness on the ipsilateral side of the face • Alteration of taste on the ipsilateral anterior 2/3 of the tongue (chorda tympani branch of the facial nerve) • Hyperacusis (nerve to the stapedius muscle) • Decreased tear production

PHYSICAL EXAM • Neurologic – Determine if the weakness is caused by a problem in either the central or peripheral nervous systems. – Flaccid paralysis of muscles on the affected side, including the forehead Impaired ability to raise the ipsilateral eyebrow Impaired closure of the ipsilateral eye Impaired ability to smile, grin, or purse the lips Bell phenomenon: upward diversion of the eye with attempted closure of the lid – Patients may complain of numbness, but no deficit is present on sensory testing. – Examine for involvement of other cranial nerves. • Head, ears, eyes, nose, and throat – Carefully examine to exclude a space-occupying lesion. – Perform pneumatic otoscopic exam. • Skin: Examine for erythema migrans (Lyme disease) and vesicular rash (herpes zoster virus).

DIFFERENTIAL DIAGNOSIS Etiologies include the following: • Infectious – Acute or chronic otitis media – Malignant otitis externa – Osteomyelitis of the skull base

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– Lyme disease (common) • Cerebrovascular – Brainstem stroke involving anteroinferior cerebellar artery – Aneurysm involving carotid, vertebral, or basilar arteries • Neoplastic (Onset of palsy is usually slow and progressive and accompanied by additional cranial nerve deficits and/or headache.) – Tumors of the parotid gland – Cholesteatoma – Skull base tumor – Carcinomatous meningitis – Leukemic meningitis • Traumatic – Temporal bone fracture – Mandibular bone fracture • Other – Multiple sclerosis – Myasthenia gravis (should be considered in cases of recurrent or bilateral facial palsy) – Guillain-Barré syndrome (may also present with bilateral facial palsy) – Sjögren syndrome – Sarcoidosis – Amyloidosis – Melkersson-Rosenthal syndrome – Mononeuritis or polyneuritis

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Blood glucose level (if diabetes a consideration) • Lyme titer, ELISA, and Western blot for immunoglobulin (Ig) M, IgG for Borrelia burgdorferi • Consider CBC, ESR. • Consider rapid plasma reagin test. • Consider HIV test. • In appropriate clinical circumstances, consider titers for varicella-zoster virus,

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cytomegalovirus, rubella, hepatitis A, hepatitis B, and hepatitis C. • Procalcitonin level may predict severity and prognosis of Bell palsy. Follow-Up Tests & Special Considerations • CSF analysis – CSF protein is elevated in 1/3 of cases. – CSF cells show mild elevation in 10% of cases with a mononuclear cell predominance. – Not routinely indicated • Salivary polymerase chain reaction for HSV1 or herpes zoster virus (largely reserved for research purposes) • Facial radiographs – In the setting of trauma, evaluate for fracture. • IV contrast–enhanced head CT – Evaluate for fracture. – Evaluate for stroke, if stroke is in the differential. • IV contrast–enhanced brain MRI – Evaluate for central pontine, temporal bone, and parotid neoplasms. – Not routinely indicated

Diagnostic Procedures/Other • Electromyograph: Nerve conduction on affected and nonaffected sides can be compared to determine the extent of nerve injury, especially if there is dense palsy or no recovery after several weeks. • Electroneurography: Evoked potentials of affected and nonaffected sides can be compared. • MRI-CT combined or 3D modeling: may be used in the future for evaluation of facial canal diameter (1)[B].

Test Interpretation Invasive diagnostic procedures are not indicated because biopsy could further damage cranial nerve XII.

TREATMENT

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GENERAL MEASURES • Artificial tears should be used to lubricate the cornea. • The ipsilateral eye should be patched and taped shut at night to avoid drying and infection.

MEDICATION • Corticosteroids decrease inflammation and limit nerve damage, thereby reducing the number of patients with residual facial weakness. • Routine use of antiviral medication is not recommended. Antiviral agents targeting herpes simplex, when administered concurrently with corticosteroids, may further reduce the risk of unfavorable outcomes in patients with a dense Bell palsy: – Antivirals alone are less likely to produce full recovery than corticosteroids. – A combination of valacyclovir and steroids provides only minimal added benefit over steroid use alone (2)[B]. • Corticosteroids – Prednisolone: total of 500 mg over 10 days, 25 mg PO BID Treatment with prednisolone within 48 hours of palsy onset has shown higher complete recovery rates and less synkinesis compared with no prednisolone. Antivirals in combination with corticosteroids Valacyclovir: 1,000 mg TID for 7 days plus prednisolone 60 mg/day for 5 days; then tapered by 10 mg/day for total treatment length of 10 days (2) [B] Steroids are recommended for all cases of Bell palsy. Controversial whether antiviral treatment is necessary with steroids American Academy of Otolaryngology–Head and Neck Surgery recommends antiviral treatment in all cases of Bell palsy cases (3)[A]. There is a strong recommendation to use corticosteroids for all patients with Bell palsy and strong recommendation against use of antiviral treatment alone (3)[A]. • Contraindications – Documented hypersensitivity – Preexisting infections, including tuberculosis (TB) and systemic mycosis

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• Precautions: Use with discretion in pregnant patients and those with peptic ulcer disease and diabetes. • Significant possible interactions: measles-mumps-rubella, oral polio virus vaccine, and other live vaccines

Pregnancy Considerations Steroids should be used cautiously during pregnancy; consult with an obstetrician.

ISSUES FOR REFERRAL Patients may need to be referred to an ear, nose, and throat specialist or a neurologist.

ADDITIONAL THERAPIES • Physical therapy: strong evidence that physical therapy combined with drug treatment has positive effect on grade and time of recovery compared with drug treatment only (4,5)[A]. • Electrostimulation and mirror biofeedback rehabilitation have limited evidence of effect. • Acupuncture with strong stimulation has shown some therapeutic promise. • Routine use of eye-protective measures for patients with incomplete eye closure is recommended (3)[A].

SURGERY/OTHER PROCEDURES • Surgical treatment of Bell palsy remains controversial and is reserved for intractable cases. • There is insufficient evidence to decide whether surgical intervention is beneficial or harmful in the management of Bell palsy. • In those cases where surgical intervention is performed, cranial nerve XII is surgically decompressed at the entrance to the meatal foramen where the labyrinthine segment and geniculate ganglion reside. • Decompression surgery should not be performed >14 days after the onset of paralysis because severe degeneration of the facial nerve is likely irreversible after 2 to 3 weeks. • A routine surgical decompression is not recommended (2)[B].

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ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Patients should start steroid treatment immediately and be followed for 12 months. • Patients who do not recover complete facial nerve function should be referred to an ophthalmologist for tarsorrhaphy.

PATIENT EDUCATION American Academy of Family Physicians: http://www.aafp.org/afp/2007/1001/p1004.html

PROGNOSIS • Most patients achieve complete spontaneous recovery within 2 weeks. >80% recover within 3 months. • 85% of untreated patients will experience the first signs of recovery within 3 weeks of onset. • 16% are left with a partial palsy, motor synkinesis, and autonomic synkinesis. • 5% experience severe sequelae, and a small number of patients experience permanent facial weakness and dysfunction. • Poor prognostic factors include the following: – Age >60 years – Complete facial weakness – Hypertension – Ramsay-Hunt syndrome • The Sunnybrook and House-Brackmann facial grading systems are clinical prognostic models that identify Bell palsy patients at risk for nonrecovery at 12 months. • Treatment with prednisolone or no prednisolone and the Sunnybrook score are significant factors for predicting nonrecovery at 1 month. • Patients with no improvement or progression of symptoms should be referred to ENT (3)[A] and may require neuroimaging to rule out neoplasms (3)[A].

COMPLICATIONS

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• Corneal abrasion or ulceration • Steroid-induced psychological disturbances; avascular necrosis of the hips, knees, and/or shoulders • Steroid use can unmask subclinical infection (e.g., TB).

REFERENCES 1. Kilicaslan S, Uluyol S, Gur MH, et al. Diagnostic and prognostic value of procalcitonin levels in patients with Bell’s palsy. Eur Arch Otorhinolaryngol. 2016;273(6):1615–1618. 2. Worster A, Keim SM, Sahsi R, et al. Do either corticosteroids or antiviral agents reduce the risk of long-term facial paresis in patients with new-onset Bell’s palsy? J Emerg Med. 2010;38(4):518–523. 3. de Almeida JR, Guyatt GH, Sud S, et al. Management of Bell palsy: clinical practice guideline. CMAJ. 2014;186(12):917–922. 4. Teixeira LJ, Valbuza JS, Prado GF. Physical therapy for Bell’s palsy (idiopathic facial paralysis). Cochrane Database Syst Rev. 2011; (12):CD006283. 5. Ferreira M, Marques EE, Duarte JA, et al. Physical therapy with drug treatment in Bell palsy: a focused review. Am J Phys Med Rehabil. 2015;94(4):331–340.

SEE ALSO Amyloidosis; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Herpes Simplex; Herpes Zoster (Shingles); Lyme Disease; Sarcoidosis; Sjögren Syndrome

CODES ICD10 G51.0 Bell’s palsy

CLINICAL PEARLS

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• Initiate steroids immediately following the onset of symptoms. • Look closely at the voluntary movement on the upper part of the face on the affected side; in Bell palsy, all of the muscles are involved (weak or paralyzed), whereas in a stroke, the upper muscles are spared (because of bilateral innervation). • Protect the affected eye with lubrication and taping. • In areas with endemic Lyme disease, Bell palsy should be considered to be Lyme disease until proven otherwise.

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BIPOLAR I DISORDER Wendy K. Marsh, MD, MSc BASICS DESCRIPTION • Bipolar I (BP-I) is an episodic mood disorder of at least one manic or mixed (mania and depression) episode that causes marked impairment, psychosis, and/or hospitalization; major depressive episodes are not required, but usually occur. • Symptoms are not caused by a substance or general medical condition.

Geriatric Considerations New onset in older patients (>50 years of age) requires a workup for organic or chemically induced pathology.

Pediatric Considerations Diagnosis less well defined. For example, mood elevation symptoms overlap with those of ADD.

Pregnancy Considerations • Pregnancy does not reduce risk of mood episodes • Need to weigh risk of exposure to mood episode to that of medication • Avoid divalproex due to high teratogenicity risk. • Postpartum carries risk of severe acute episode with psychosis and/or infanticidal ideation.

EPIDEMIOLOGY Onset usually between 15 and 30 years of age

Prevalence • 1.0–1.6% lifetime prevalence • Equal among men and women (manic episodes more common in men; depressive episodes more common in women) • Equal among races; however, clinicians tend to diagnose schizoaffective in

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African Americans with BP-I.

ETIOLOGY AND PATHOPHYSIOLOGY Genetic predisposition and major life stressors can trigger initial and subsequent episodes: • Dysregulation of biogenic amines or neurotransmitters (particularly serotonin, norepinephrine, and dopamine) • MRI findings suggest abnormalities in prefrontal cortical areas, striatum, and amygdala that predate illness onset (1)[C].

Genetics • Monozygotic twin concordance 40–70% • Dizygotic twin concordance 5–25% • 50% have at least one parent with a mood disorder. • First-degree relatives are 7 times more likely to develop BP-I than the general population.

RISK FACTORS Genetics, major life stressors, or substance abuse

GENERAL PREVENTION No known way to prevent onset, but treatment adherence and education can help to prevent relapses.

COMMONLY ASSOCIATED CONDITIONS Substance abuse (60%), ADHD, anxiety disorders, and eating disorders

DIAGNOSIS • The diagnosis of BP-I requires at least one manic or mixed episode (simultaneous mania and depression). Although a depressive episode is not necessary for the diagnosis, 80–90% of people with BP-I also experience depression. • Manic episode, DSM-5 criteria (2) – Distinct period of abnormally and persistently elevated, expansive, or irritable mood plus increased activity or energy for at least 1 week (or any

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duration if hospitalization is necessary) – During the period of mood disturbance, three or more of the “DIG FAST” symptoms must persist (four if the mood is only irritable) and must be present to a significant degree. Distractibility Insomnia, decreased need for sleep Grandiosity or inflated self-esteem Flight of ideas or racing thoughts Agitation or increase in goal-directed activity Speech-pressured/more talkative than usual Taking risks: excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g., financial or sexual) – Mixed specifier: when three or more symptoms of opposite mood pole are present during primary mood episode, for example, mania with mixed features (of depression)

HISTORY • Collateral information makes diagnostics more complete and is often necessary for a clear history. • History: safety concerns (e.g., Suicidal/homicidal ideation? Safety plan? Psychosis present?), physical well-being (e.g., Number of hours of sleep? Weight change? Substance abuse?), personal history (e.g., Talkative? Risky driving? Excessive spending? Credit card debt? Promiscuity? Other risktaking behavior? Legal trouble?)

PHYSICAL EXAM • Mental status exam in acute mania – General appearance: bright clothing, excessive makeup, disorganized or discombobulated, psychomotor agitation – Speech: pressured, difficult to interrupt – Mood/affect: euphoria, irritability, expansive, labile – Thought process: flight of ideas (streams of thought occur to patient at rapid rate), easily distracted – Thought content: grandiosity, paranoia, hyperreligious – Perceptual abnormalities: 3/4 of manic patients experience delusions,

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grandiose, or paranoia. – Suicidal/homicidal ideation: aggression toward self or others; suicidal ideation is common with mixed episode. – Insight/judgment: poor/impaired • See “Bipolar II Disorder” for an example of a mental status exam in depression. • With mixed episodes, patients may exhibit a combination of manic and depressive mental states.

DIFFERENTIAL DIAGNOSIS • Other psychiatric considerations: unipolar depression ± psychotic features, schizophrenia, schizoaffective disorder, personality disorders (particularly antisocial, borderline, histrionic, and narcissistic), ADD ± hyperactivity, substance-induced mood disorder • Medical considerations: epilepsy (e.g., temporal lobe), brain tumor, infection (e.g., AIDS, syphilis), stroke, endocrine (e.g., thyroid) disease, multiple sclerosis • In children, consider ADHD and ODD.

DIAGNOSTIC TESTS & INTERPRETATION • BP-I is a clinical diagnosis. • The Mood Disorder Questionnaire is a self-assessment screen for bipolar disorders (sensitivity 73%, specificity 90%) (3). • Patient Health Questionnaire-9 helps to determine the presence and severity of a depressive episode.

Initial Tests (lab, imaging) • TSH, CBC, BMP, LFTs, ANA, RPR, HIV, ESR • Drug/alcohol screen with each presentation • Dementia workup if new onset in elderly • Consider brain imaging (CT, MRI) with initial onset of mania to rule out organic cause (e.g., tumor, infection, or stroke), especially with onset in elderly and if psychosis is present.

Diagnostic Procedures/Other Consider EEG if presentation suggests temporal lobe epilepsy (hyperreligiosity,

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hypergraphia).

TREATMENT • Ensure safety. • Psychotherapy (e.g., cognitive-behavioral therapy, social rhythm therapy, educational) • Stress reduction • Patient and family education

GENERAL MEASURES • Psychotherapy for depression (e.g., cognitive-behavioral therapy, social rhythm, interpersonal) in conjunction with medications • Regular daily schedule, exercise, a healthy diet, and sobriety

MEDICATION (medication details below) • Acute mania – First line Lithium monotherapy (see lithium) Aripiprazole, asenapine, quetiapine, risperidone or ziprasidone monotherapy (see atypicals) Divalproex (see antiseizure) Olanzapine or haloperidol* Lithium or divalproex plus haloperidol or olanzapine* – Second line Lithium plus divalproex Lithium or divalproex plus atypical (non-clozapine) Paliperidone Carbamazepine • Acute bipolar depression – First line Quetiapine monotherapy (see atypicals) Lurasidone monotherapy (see atypicals) Lurasidone or quetiapine adjunctive to lithium or divalproex Olanzapine* (see atypicals) + fluoxetine

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– Second line Lithium Lamotrigine (see antiseizure) Lamotrigine adjunctive to Lithium 2 drug combination of above of different classes (i.e., not two atypicals) • *Side effects concerns: Weight gain, metabolic syndrome and extrapyramidal symptoms (EPS) warrant vigilance and monitoring by the clinician. • Treatment mood stabilizer(s) or other psychotropic medications. When combining, use different classes (e.g., an atypical antipsychotic and/or an antiseizure medication and/or lithium). – Lithium (Lithobid, Eskalith, generic): dosing: 600 to 1,200 mg/day divided BID–QID; start 600 to 900 mg/day divided BID–TID, titrate based on blood levels. Warning: caution in kidney and heart disease; use can lead to diabetes insipidus or thyroid disease. Caution with diuretics or ACE inhibitors; dehydration can lead to toxicity (seizures, encephalopathy, arrhythmias). Pregnancy Category D (Ebstein anomaly). Monitor: Check ECG >40 years, TSH, BUN, creatinine, electrolytes at baseline and every 6 months; check level 5 to 7 days after initiation or dose change, then every 2 weeks × 3 and then every 3 months (goal: 0.8 to 1.2 mmol/L). • Antiseizure medications – Divalproex sodium, valproic acid (Depakote, Depakene, generic): dosing: start 250 to 500 mg BID–TID; maximum 60 mg/kg/day. Black box warnings: hepatotoxicity, pancreatitis, thrombocytopenia, pregnancy Category D. Monitor CBC and LFTs at baseline and every 6 months; check level 5 days after initiation and dose changes (goal: 50 to 125 μg/mL). – Carbamazepine (Equetro, Tegretol, generic): dosing: 800 to 1,200 mg/day PO divided BID–QID; start 100 to 200 mg PO BID and titrate to lowest effective dose. Warning: Do not use with TCA or within 14 days of an MAOI. Caution in kidney/heart disease; risk of aplastic anemia/agranulocytosis, enzyme inducer; pregnancy Category D. Monitor CBC and LFTs at baseline and every 3 to 6 months; check level 4 to 5 days after initiation and dose changes (goal: 4 to 12 μg/mL). – Lamotrigine (Lamictal, generic): dosing: 200 to 400 mg/day; start 25 mg/day for 2 weeks, then 50 mg/day for 2 weeks, then 100 mg/day for 1

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week and then 150 mg/day. (Note: Use different dosing if adjunct to valproate.) Warning: Titrate slowly (risk of Stevens-Johnson syndrome); caution with kidney/liver/heart disease; pregnancy Category C – Oxcarbazepine (Trileptal) dosing: 300 mg PO QD. Titrate to 1,800 to 2,400/day max. • Atypical antipsychotics – Side effects: orthostatic hypotension, metabolic side effects (glucose and lipid dysregulation, weight gain), tardive dyskinesia, neuroleptic malignant syndrome (NMS), prolactinemia (except Abilify), increased risk of death in elderly with dementia-related psychosis, pregnancy Category C – Monitor LFTs, lipids, glucose at baseline, 3 months, and annually; check for EPS with Abnormal Involuntary Movement Scale (AIMS) and assess weight (with abdominal circumference) at baseline, at 4, 8, and 12 weeks and then every 3 to 6 months; monitor for orthostatic hypotension 3 to 5 days after starting or changing dose. – Aripiprazole (Abilify): dosing: 15 to 30 mg/day; less likely to cause metabolic side effects – Asenapine: dosing: 5 to 10 mg sublingual BID – Cariprazine: dosing: 1.5 to 6 mg/day. Start 1.5 mg. – Lurasidone: dosing: 20 to 60 mg/day; FDA-approved for bipolar depression – Olanzapine (Zyprexa, Zydis, generic): dosing: 5–20 mg/day; most likely to cause metabolic side effects (weight gain, diabetes) – Paliperidone dosing: 6 mg/AM; may cause agranulocytosis, cardiac arrythmias – Quetiapine (Seroquel, Seroquel XR, generic): dosing: in mania, 200 to 400 mg BID; in bipolar depression, 50 to 300 mg QHS; XR dosing 50 to 400 mg QHS – Risperidone (Risperdal, Risperdal Consta, generic): dosing: 1 to 6 mg/day divided QD–QID; IM preparation available (q2wk) – Ziprasidone (Geodon): dosing: 40 to 80 mg BID; less likely to cause metabolic side effects. Caution: QTc prolongation (>500 ms) has been associated with use (0.06%). Consider ECG at baseline. • Unipolar antidepressants – There is inadequate information to recommend in bipolar disorder. If used

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(for example for anxiety), antimanic agent is essential. • Avoid – Tricyclic antidepressants (TCAs) and serotonin norepinephrine reuptake inhibitor (SNRI). Increases mood cycling risk.

ISSUES FOR REFERRAL • Refer to psychiatry, depends on knowledge level of the doctor, stability of patient. • Patients benefit from a multidisciplinary team, including a primary care physician, psychiatrist, and therapist.

ADDITIONAL THERAPIES • Electroconvulsive therapy can be helpful in acute or treatment-resistant mania and depression. • Modest evidence supports transcranial magnetic stimulation, vagus nerve stimulation, ketamine infusion, sleep deprivation, and hormone therapy (e.g., thyroid) in bipolar depression.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Admit if dangerous to self or others. • To admit involuntarily, the patient must have a psychiatric diagnosis (e.g., BPI) and present a danger to self or others or the mental disease must be inhibiting the person from obtaining basic needs (e.g., food, clothing). • Nursing: Alert staff to potentially dangerous or agitated patients. Acute suicidal threats need continuous observation. • Discharge criteria determined by safety

ONGOING CARE FOLLOW-UP RECOMMENDATIONS • Regularly scheduled visits support adherence with treatment. • Frequent communication among primary care doctor, psychiatrist, and therapist

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Patient Monitoring Mood charts are helpful to monitor symptoms.

PATIENT EDUCATION • National Alliance on Mental Illness (NAMI): http://www.nami.org/ • National Institutes of Mental Health (NIMH): http://www.nimh.nih.gov/index.shtml • Depression and Bipolar Support Alliance (DBSA): http://www.dbsalliance.org

PROGNOSIS • Frequency and severity of episodes are related to medication adherence, consistency with therapy, quality of sleep, and support systems. • 40–50% of patients experience another manic episode within 2 years of first episode. • 25–50% attempt suicide and 15% die by suicide. • Substance abuse, unemployment, psychosis, depression, and male gender are associated with a worse prognosis.

REFERENCES 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013. 2. Hirshfeld RM. Validation of the mood disorder questionnaire. Bipolar Depression Bulletin. 2004. 3. Ostacher MJ, Tandon R, Suppes T. Florida Best Practice Psychotherapeutic Medication Guidelines for Adults with Bipolar Disorder: a novel, practical patient-centered guide or clinicians. J Clin Psychiatry. 2016;77(7):920–926.

ADDITIONAL READING • American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(4) (Suppl):1–50. • Canadian Network for Mood and Anxiety Treatments: http://www.canmat.org/ • Licht RW. A new BALANCE in bipolar I disorder. Lancet.

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2010;375(9712):350–352.

SEE ALSO Algorithm: Depressive Episode, Major

CODES ICD10 • F31.9 Bipolar disorder, unspecified • F31.10 Bipolar disorder, current episode manic without psychotic features, unspecified • F31.30 Bipolar disord, crnt epsd depress, mild or mod severt, unsp

CLINICAL PEARLS • BP-I is characterized by at least one manic or mixed episode that causes marked impairment, major depressive episodes usually occur but are not necessary. • 25–50% of BP-I patients attempt suicide and 15% die by suicide. • There is no known way to prevent BP-I, but treatment adherence and education helps reduce further episodes. • Goal of treatment is to decrease the intensity, length, and frequency of episodes as well as greater mood stability between episodes.

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BIPOLAR II DISORDER Wendy K. Marsh, MD, MSc BASICS DESCRIPTION Bipolar II (BP-II) is a mood disorder characterized by at least one episode of major depression (with or without psychosis) and at least one episode of hypomania, a nonsevere mood elevation.

Geriatric Considerations New onset in older patients (>50 years) requires a workup for organic or chemically induced pathology.

Pediatric Considerations Diagnosis less well defined

Pregnancy Considerations • Pregnancy does not reduce risk of mood episodes. • Need to weigh risk of exposure to mood episode to that of medication • Avoid divalproex due to high teratogenicity risk. • Postpartum caries risk of severe acute episode with psychosis and/or infanticidal ideation.

EPIDEMIOLOGY Onset usually between 15 and 30 years of age

Prevalence • 0.5–1.1% lifetime prevalence • More common in women

ETIOLOGY AND PATHOPHYSIOLOGY Dysregulation of biogenic amines or neurotransmitters (particularly serotonin, norepinephrine, and dopamine)

Genetics

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Heritability estimate: >77%

RISK FACTORS Genetics, major life stressors, or substance abuse

GENERAL PREVENTION No known way to prevent onset, but treatment adherence and education can help to prevent further episodes.

COMMONLY ASSOCIATED CONDITIONS Substance abuse or dependence, ADHD, anxiety disorders, and eating disorders

DIAGNOSIS • DSM-5 criteria: one hypomanic episode and at least one major depressive episode. The symptoms cause unequivocal change in functioning noticed by others but not severe enough to cause marked impairment (1)[C]. • Hypomania is a distinct period of persistently elevated, expansive, or irritable mood, different from usual euthymic mood, including increase in activity or energy lasting at least 4 days: – The episode must include at least three of the “DIG FAST” symptoms plus increased energy below (four if the mood is only irritable): Distractibility Insomnia, decreased need for sleep Grandiosity or inflated self-esteem Flight of ideas or racing thoughts Agitation or increase in goal-directed activity (socially, at work or school, or sexually) Speech-pressured/more talkative than usual Taking risks: excessive involvement in pleasurable activities that have high potential for painful consequences (e.g., sexual or financial) • Major depression – Depressed mood or diminished interest and four or more of the “SIG E CAPS” symptoms are present during the same 2-week period: Sleep disturbance (e.g., trouble falling asleep, early-morning awakening)

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Interest: loss or anhedonia Guilt (or feelings of worthlessness) Energy, loss of Concentration, loss of Appetite changes, increase or decrease Psychomotor changes (retardation or agitation) Suicidal/homicidal thoughts – Rapid cycling is ≥4 mood episodes in 12 months (major depression or hypomania). – Mixed specifier: when three or more symptoms of opposite mood pole are present during primary mood episode, for example, hypomania with mixed features (of depression) • Note: If symptoms have ever met criteria for a full manic episode or hospitalization was necessary secondary to manic/mixed symptoms or psychosis was present, then the diagnosis is BP-I.

HISTORY • Collateral information makes diagnostics more complete and is often necessary for a clear history. • History: safety concerns (e.g., Suicidal/homicidal ideation? Safety plan? Psychosis present?), physical well-being (e.g., Number of hours of sleep? Substance abuse?), personal history (e.g., Risky driving? Excessive spending? Credit card debt? Promiscuity? Other risk-taking behavior? Legal trouble?)

PHYSICAL EXAM • Mental status exam in hypomania – General appearance: usually appropriately dressed, with psychomotor agitation – Speech: may be pressured, talkative, difficult to interrupt – Mood/affect: euphoria, irritability/congruent, or expansive – Thought process: may be easily distracted, difficulty concentrating on one task – Thought content: usually positive, with “big” plans – Perceptual abnormalities: none – Suicidal/homicidal ideation: low incidence of homicidal or suicidal ideation

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– Insight/judgment: usually stable/may be impaired by their distractibility • Mental status exam in acute depression – General appearance: unkempt, psychomotor retardation, poor eye contact – Speech: low, soft, monotone – Mood/affect: sad, depressed/congruent, flat – Thought process: ruminating thoughts, generalized slowing – Thought content: preoccupied with negative or nihilistic ideas – Perceptual abnormalities: 15% of depressed patients experience hallucinations or delusions. – Suicidal/homicidal ideation: Suicidal ideation is very common. – Insight/judgment: often impaired

DIFFERENTIAL DIAGNOSIS • Other psychiatric considerations – BP-I disorder, unipolar depression, personality disorders (particularly borderline, antisocial, and narcissistic), ADD with hyperactivity, substanceinduced mood disorder • Medical considerations – Epilepsy (e.g., temporal lobe), brain tumor, infection (e.g., AIDS, syphilis), stroke, endocrine (e.g., thyroid disease), multiple sclerosis

DIAGNOSTIC TESTS & INTERPRETATION • BP-II is a clinical diagnosis. • Mood Disorder Questionnaire, self-assessment screen for BP, sensitivity 73%, specificity 90% (2)[B] • Hypomania Checklist-32 distinguishes between BP-II and unipolar depression (sensitivity 80%, specificity 51%) (3)[B]. • Patient Health Questionnaire-9 helps to determine the presence and severity of depression.

Initial Tests (lab, imaging) • Rule out organic causes of mood disorder during initial episode. • Drug/alcohol screen is prudent with each presentation. • Dementia workup if new onset in elderly • With initial presentation: Consider CBC, chem 7, TSH, LFTs, ANA, RPR,

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HIV, and ESR. • Consider brain imaging (CT, MRI) with initial onset of hypomania to rule out organic cause, especially with onset in the elderly.

TREATMENT • Ensure safety. • Medication management • Psychotherapy (e.g., cognitive-behavioral therapy [CBT], social rhythm therapy, educational therapy) • Stress reduction • Patient and family education • Refer to psychiatrist.

GENERAL MEASURES • Psychotherapy (e.g., CBT, social rhythm, interpersonal, family focused) in conjunction with medications • Regular daily schedule, exercise, a healthy diet, and sobriety have been shown to help.

MEDICATION • ACUTE MOOD ELEVATION – First line Atypical: aripiprazole, asenapine, quetiapine, risperidone or ziprasidone monotherapy (see atypicals) Lithium monotherapy (see lithium) Divalproex (see antiseizure) Olanzapine or haloperidol Lithium or divalproex plus haloperidol or olanzapine – Second line Lithium plus divalproex Lithium or divalproex plus atypical (nonclozapine) Paliperidone Carbamazepine • ACUTE BIPOLAR DEPRESSION

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– First line Quetiapine monotherapy (see atypicals) Lurasidone monotherapy (see atypicals) Lurasidone or quetiapine adjunctive to lithium or divalproex Olanzapine (see atypicals) + fluoxetine – Second line Lithium Lamotrigine (see antiseizure) Lamotrigine adjunctive to lithium 2 drug combination of above of different classes (i.e., not two atypicals) • Side effects concerns: Weight gain, metabolic syndrome, and extrapyramidal symptoms warrant vigilance and monitoring by the clinician. • Treatment mood stabilizer(s) or other psychotropic medications. When combining, use different classes (e.g., an atypical antipsychotic and/or an antiseizure medication and/or lithium). • Lithium (Lithobid, Eskalith, generic): dosing: 600 to 1,200 mg/day divided BID–QID; start 600 to 900 mg/day divided BID–TID, titrate based on blood levels. Warning: caution in kidney and heart disease; use can lead to diabetes insipidus or thyroid disease. Caution with diuretics or ACE inhibitors; dehydration can lead to toxicity (seizures, encephalopathy, arrhythmias). Pregnancy Category D (Ebstein anomaly). Monitor: Check ECG >40 years, TSH, BUN, creatine, electrolytes at baseline and every 6 months; check level 5 to 7 days after initiation or dose change, then every 2 weeks × 3, and then every 3 months (goal: 0.8 to 1.2 mmol/L). • Antiseizure medications – Divalproex sodium, valproic acid (Depakote, Depakene, generic): dosing: start 250 to 500 mg BID–TID; maximum 60 mg/kg/day. Black box warnings: hepatotoxicity, pancreatitis, thrombocytopenia, pregnancy Category D. Monitor CBC and LFTs at baseline and every 6 months; check level 5 days after initiation and dose changes (goal: 50 to 125 μg/mL). – Carbamazepine (Equetro, Tegretol, generic): dosing: 800 to 1,200 mg/day PO divided BID–QID; start 100 to 200 mg PO BID and titrate to lowest effective dose. Warning: Do not use with tricyclic antidepressants (TCA) or within 14 days of monoamine oxidase inhibitor (MAOI). Caution in

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kidney/heart disease; risk of aplastic anemia/agranulocytosis, enzyme inducer; pregnancy Category D. Monitor CBC and LFTs at baseline and every 3 to 6 months; check level 4 to 5 days after initiation and dose changes (goal: 4 to 12 μg/mL). – Lamotrigine (Lamictal, generic): dosing: 200 to 400 mg/day; start 25 mg/day for 2 weeks, then 50 mg/day for 2 weeks, then 100 mg/day for 1 week, then 150 mg/day. (Note: Use different dosing if adjunct to valproate). Warning: Titrate slowly (risk of Stevens-Johnson syndrome); caution with kidney/liver/heart disease; pregnancy Category C – Oxcarbazepine (Trileptal) dosing: 300 mg PO QD. Titrate to 1,800 to 2,400/day max. • Atypical antipsychotics – Side effects: orthostatic hypotension, metabolic side effects (glucose and lipid dysregulation, weight gain), tardive dyskinesia, neuroleptic malignant syndrome (NMS), prolactinemia (except Abilify), increased risk of death in elderly with dementia-related psychosis, pregnancy Category C – Monitor LFTs, lipids, glucose at baseline, 3 months, and annually; check for extrapyramidal symptoms (EPS) with Abnormal Involuntary Movement Scale (AIMS) and assess weight (with abdominal circumference) at baseline, at 4, 8, and 12 weeks, and then every 3 to 6 months; monitor for orthostatic hypotension 3 to 5 days after starting or changing dose. – Aripiprazole (Abilify): dosing: 15 to 30 mg/day; less likely to cause metabolic side effects – Asenapine: dosing: 5 to 10 mg sublingual BID – Cariprazine: dosing: 1.5 to 6 mg/day. Start 1.5 mg. – Lurasidone: dosing: 20 to 60 mg/day; FDA-approved for bipolar depression – Olanzapine (Zyprexa, Zydis, generic): dosing: 5 to 20 mg/day; most likely to cause metabolic side effects (weight gain, diabetes) – Paliperidone – Quetiapine (Seroquel, Seroquel XR, generic): dosing: in mania, 200 to 400 mg BID; in bipolar depression, 50 to 300 mg QHS. XR dosing 50 to 400 mg QHS – Risperidone (Risperdal, Risperdal Consta, generic): dosing: 1 to 6 mg/day divided QD–QID; IM preparation available (q2wk)

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– Ziprasidone (Geodon): dosing: 40 to 80 mg BID; less likely to cause metabolic side effects. Caution: QTc prolongation (>500 ms) has been associated with use (0.06%). Consider ECG at baseline. • Unipolar antidepressants – There is inadequate information to recommend in bipolar disorder. If used (e.g., for anxiety), antimanic agent is essential. • Avoid – TCAs and serotonin norepinephrine reuptake inhibitior (SNRI); increases mood cycling risk

ISSUES FOR REFERRAL • Refer to psychiatry, depends on knowledge level of the doctor, stability of patient. • Patients benefit from a multidisciplinary team, including a primary care physician, psychiatrist, and therapist.

ADDITIONAL THERAPIES • Electroconvulsive therapy can be helpful in acute or treatment-resistant mania and depression. • Modest evidence supports transcranial magnetic stimulation, vagus nerve stimulation, ketamine infusion, sleep deprivation, and hormone therapy (e.g., thyroid) in bipolar depression.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Admit if dangerous to self or others. • To admit involuntarily, the patient must have a psychiatric diagnosis (e.g., BPI) and present a danger to self or others or the mental disease must be inhibiting the person from obtaining basic needs (e.g., food, clothing). • Nursing: alert staff to potentially dangerous or agitated patients. Acute suicidal threats need continuous observation. • Discharge criteria determined by safety

ONGOING CARE

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FOLLOW-UP RECOMMENDATIONS • Regularly scheduled visits support adherence with treatment. • Frequent communication among primary care doctor, psychiatrist, and therapist

Patient Monitoring Mood charts are helpful to monitor symptoms.

PATIENT EDUCATION • National Alliance on Mental Illness (NAMI): http://www.nami.org/ • National Institutes of Mental Health (NIMH): http://www.nimh.nih.gov/index.shtml • Depression and Bipolar Support Alliance (DBSA): http://www.dbsalliance.org

PROGNOSIS • Frequency and severity of episodes are related to medication adherence, consistency with therapy, quality of sleep, and support systems. • 40–50% of patients experience another manic episode within 2 years of first episode. • 25–50% attempt suicide and 15% die by suicide. • Substance abuse, unemployment, psychosis, depression, and male gender are associated with a worse prognosis.

REFERENCES 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013. 2. Hirshfeld RM. Validation of the mood disorder questionnaire. Bipolar Depression Bulletin. 2004. 3. Ostacher MJ, Tandon R, Suppes T. Florida best practice psychotherapeutic medication guidelines for adults with bipolar disorder: a novel, practical, patient-centered guide for clinicians. J Clin Psychiatry. 2016;77(7):920–926.

ADDITIONAL READING

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• American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry. 2002;159(4) (Suppl):1–50. • Goodwin FK, Jamison KR. Manic-Depressive Illness: Bipolar Disorders and Recurrent Depression. 2nd ed. New York, NY: Oxford University Press; 2007. • Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013. Bipolar Disord. 2013;15(1):1–44.

SEE ALSO Algorithm: Depressive Episode, Major

CODES ICD10 F31.81 Bipolar II disorder

CLINICAL PEARLS • BP-II is characterized by at least one episode of major depression and one episode of hypomania. • Patients may not recognize symptoms and or decline treatment during a hypomanic episode; they may enjoy the elevated mood and productivity. • Patients with BP-II are at great risk of both attempting and completing suicide.

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BITES, ANIMAL AND HUMAN Kathryn Samai, PharmD, BCPS • Brian J. Kimbrell, MD, FACS BASICS DESCRIPTION • Animal bites to humans from dogs (60–90%), cats (5–20%), rodents (2–3%), humans (2–3%), and rarely other animals, including snakes • System(s) affected: potentially any

Pediatric Considerations Young children are more likely to sustain bites and have bites that include the face, upper extremity, or trunk.

EPIDEMIOLOGY • Predominant age: all ages but children > adults • Predominant gender: dog bites, male > female; cat bites, female > male

Incidence • 3 to 6 million animal bites per year in the United States (1) • Account for 1% of all emergency room visits • 1–2% will require hospital admission, and 20 to 35 victims will die from dog bites annually (1).

ETIOLOGY AND PATHOPHYSIOLOGY • Most dog bite wounds are from a domestic pet known to the victim. • 89% of cat bites are provoked. • Males, pit bull terriers, and German shepherds are most commonly associated with dog bites (2). • Human bites are often the result of one person striking another in the mouth with a clenched fist. • Bites can also occur incidentally in the case of paronychia due to nail biting, or thumb sucking, or “love nips” to the face, breasts, or genital areas. • Animal bites can cause tears, punctures, scratches, avulsions, or crush injuries.

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• Contamination of wound with flora from the mouth of the biting animal or from the broken skin of the victim can lead to infection.

RISK FACTORS • Male dogs and older dogs are more likely to bite. • Clenched-fist human bites are frequently associated with the use of alcohol or drugs. • Patients presenting >8 hours following the bite are at greater risk of infection.

GENERAL PREVENTION • Instruct children and adults about animal hazards and strongly enforce animal control laws. • Educate dog owners.

DIAGNOSIS HISTORY • Obtain detailed history of the incident (provoked or unprovoked). • Type of animal • Vaccine status • Site of the bite • Geographic setting

PHYSICAL EXAM • Dog bites (60–90% of bites) – Hands and face most common site of injury in adults and children, respectively – More likely to have associated crush injury • Cat bites (5–20% of bites) – Predominantly involve the hands, followed by lower extremities, face, and trunk • Human bites (2–3% of bites) – Intentional bite: semicircular or oval area of erythema and bruising, with or without break in skin – Clenched-fist injury: small wounds over the metacarpophalangeal joints

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from striking the fist against another’s teeth • Signs of wound infection include fever, erythema, swelling, tenderness, purulent drainage, and lymphangitis.

ALERT Cat bites (often puncture wounds) are twice as likely to cause infection as dog bites, with higher risks of osteomyelitis, tenosynovitis, and septic arthritis.

Pediatric Considerations If human bite mark on child has intercanine distance >3 cm, bite probably came from an adult and should raise concerns about child abuse.

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Drainage from infected wounds should be Gram-stained and cultured (3)[A]. – If wound fails to heal, perform cultures for atypical pathogens (fungi, Nocardia, and mycobacteria) and ask lab to keep bacterial cultures for 7 to 10 days (some pathogens are slow-growing). • 85% of bite wounds will yield a positive culture, with an average of five pathogens. • Aerobic and anaerobic blood cultures should be obtained before starting antibiotics if bacteremia suspected (e.g., fever or chills). • Previous antibiotic therapy may alter culture results.

ALERT If bite wound is near a bone or joint, a plain radiograph is needed to check for bone injury and to use for comparison later if osteomyelitis is subsequently suspected (3). • Radiographs are needed to check for fractures in clenched-fist injuries. Follow-Up Tests & Special Considerations Subsequent suspicion of osteomyelitis warrants comparison of plain radiograph or MRI. Severe skull bites warrant a CT scan, and ultrasound can be useful for detection of abscess.

Diagnostic Procedures/Other

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Surgical exploration may be needed to ascertain extent of injuries or to drain deep infections (such as tendon sheath infections), especially in serious hand wounds.

Test Interpretation • Dog bites (4,5) – Pasteurella species is present in 50% of bites. – Also found: viridans streptococci, Staphylococcus aureus, Staphylococcus intermedius, Bacteroides, Capnocytophaga canimorsus, Fusobacterium • Cat bites (5) – Pasteurella species is present in 75% of bites. – Also found: Streptococcus spp. (including Streptococcus pyogenes), Staphylococcus spp. (including methicillin-resistant Staphylococcus aureus [MRSA]), Fusobacterium spp., Bacteroides spp., Porphyromonas spp., Moraxella spp. • Human bites – Streptococcus spp., S. aureus, Eikenella corrodens (29%), and various anaerobic bacteria (e.g., Fusobacterium, Peptostreptococcus, Prevotella, and Porphyromonas spp.) – Although rare, case reports have suggested transmission of viruses such as hepatitis, HIV, and herpes simplex. • Reptile bites – If from a venomous snake, use antivenom. Bacteria: Pseudomonas aeruginosa, Proteus spp., Salmonella, Bacteroides fragilis, and Clostridium spp. • Rodent bites – Streptobacillus moniliformis or Spirillum minor, which causes rat-bite fever • Monkey bites – All monkey bites can transmit rabies, and bites of a macaque monkey may transmit herpes B virus, which is potentially fatal.

ALERT Asplenic patients and those with underlying hepatic disease are at risk of bacteremia and fatal sepsis after dog bites infected with Capnocytophaga canimorsus (gram-negative rod).

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TREATMENT GENERAL MEASURES • Elevation of the injured extremity to prevent swelling • Contact the local health department regarding the prevalence of rabies in the species of animal involved (highest in bats). • Snake bite: If venomous, patient needs rapid transport to facility capable of definitive evaluation. If envenomation has occurred, patient should receive antivenom. Be sure patient is stable for transport; consider measuring and/or treating coagulation and renal status along with any anaphylactic reactions before transport. • Monkey bite: Providers should contact CDC and administer an antiviral, such as valacyclovir, active against herpes B virus.

MEDICATION • Consider need for antirabies therapy: rabies immunoglobulin and human diploid cell rabies vaccine for those bitten by wild animals (in the United States, primary vector is bat bite), rabid pets, unvaccinated pets, or if animal cannot be quarantined for 10 days. • Tetanus toxoid (Td) for those previously immunized but >10 years since their last dose (3)[C]; tetanus, diphtheria, and pertussis (Tdap) is preferred over Td (3) • A patient negative for anti-HBs and bitten by an HBsAg-positive individual should receive both hepatitis B immunoglobulin (HBIG) and hepatitis B vaccine. • HIV postexposure prophylaxis is generally not recommended for human bites, given the extremely low risk for transmission, unless blood exposure to broken skin. • Preemptive antibiotics are only recommended for human bites and high-risk wounds (deep puncture, crush injury, venous or lymphatic compromise, hands or near joint, face or genital area, immunocompromised hosts, requiring surgical repair, asplenic, advanced liver, edema). • For preemptive and for empiric treatment of established infection, amoxicillin and clavulanate are first line (3)[B].

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– Adults: amoxicillin 875 mg/clavulanate 125 mg PO BID – Children: female (4:1); but in smokers, risk is 1:1. • 35.3/100,000 men per year (1) • 8.6/100,000 women per year (1) • 20.1/100,000 men and women per year (1)

Prevalence In 2013, 587,426 cases in the United States (1)

ETIOLOGY AND PATHOPHYSIOLOGY Unknown, other than related to risk factors: • 70–80% is nonmuscle invasive (in lamina propria or mucosa): – Usually highly differentiated with long survival – Initial event seems to be the activation of an oncogene on chromosome 9 in superficial cancers. • 20% of tumors are muscle invasive (deeper than lamina propria) at presentation: – Tend to be high grade with worse prognosis – Associated with other chromosome deletions

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Genetics Hereditary transmission is unlikely, although transitional cell carcinoma pathophysiology is related to oncogenes.

RISK FACTORS • Smoking is the single greatest risk factor (increases risk 4-fold) and increases risk equally for men and women (2). • Use of pioglitazone for >1 year may be associated with an increased risk of bladder cancer. The risk seems to increase with duration of therapy and may also be present with other thiazolidinediones. • Other risk factors: – Occupational carcinogens in dye, rubber, paint, plastics, metal, carbon black dust, and automotive exhaust – Schistosomiasis in Mediterranean (squamous cell) cancer – Arsenic in well water – History of pelvic irradiation – Chronic lower UTI – Chronic indwelling urinary catheter – Cyclophosphamide exposure – High-fat diet – Coffee consumption associated with reduced risk (RR 0.83; 95% CI, 0.73– 0.94)

ALERT Any patient who smokes and presents with microscopic or gross hematuria or irritative voiding symptoms such as urgency and frequency not clearly due to UTI should be evaluated by cystoscopy for the presence of a bladder neoplasm.

GENERAL PREVENTION • Avoid smoking and other risk factors. • Counseling of individuals with occupational exposure • The U.S. Preventive Services Task Force has concluded that there is insufficient evidence to determine the balance between risk and harm of screening for bladder cancer (3).

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DIAGNOSIS HISTORY • Painless hematuria is the most common symptom. • Urinary symptoms (frequency, urgency) • Abdominal or pelvic pain in advanced disease • Exposures (see “Risk Factors”)

PHYSICAL EXAM Normal in early cases, pelvic or abdominal mass in advanced disease, wasting in systemic disease

DIFFERENTIAL DIAGNOSIS • Other urinary tract neoplasms • UTI • Prostatism • Bladder instability • Interstitial cystitis • Urolithiasis • Interstitial nephritis • Papillary urothelial hyperplasia

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Urinalysis is the initial test in patients presenting with gross hematuria or urinary symptoms such as frequency, urgency, and dysuria. • Urine cytology (consult your local lab for volume needed and proper fixative/handling) • Cystoscopy with biopsy is the gold standard for at-risk patients with painless hematuria. • Macroscopic hematuria (55% sensitivity, positive predictive value [PPV] 0.22 for urologic cancer) Follow-Up Tests & Special Considerations • Urine cytology: 54% sensitivity overall (lower in less advanced tumors), 94% specific

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• Other urine markers (of little clinical benefit): – Nuclear matrix protein-22 (NMP22): 67% sensitive, 78% specific – Bladder tumor–associated antigen stat: 70% sensitive, 75% specific, may be falsely positive in inflammatory conditions – Fluorescence in situ hybridization (FISH) assay: 69% sensitive, 78% specific (PPV 27.1, negative predictive value 95.3) for all tumors, more sensitive and specific for higher grade – FGFR3 mutation has high specificity (99.9%) but low sensitivity (34.5%); PPV 95.2%. • Bottom line: None of the urine markers is sensitive enough to rule out bladder cancer on its own. • Liver function tests, alkaline phosphatase if metastasis suspected • Done for staging and to evaluate extent of disease but not for diagnosis itself: – CT urogram replacing IVP to image upper tracts if there is a suspicion of disease there – Diffusion-weighted MRI and multidimensional CT scan are undergoing study for use in diagnosis and staging of bladder tumors. – For invasive disease, metastatic workup should include chest x-ray. – Bone scan should be performed if the patient has bone pain or if alkaline phosphatase is elevated. • Urologic CT scan (abdomen, pelvis, with and without contrast) or MRI (40– 98% accurate), with MRI slightly more accurate, is recommended if metastasis is suspected. • Regular cystoscopy (initiated at 3 months postprocedure) is indicated after transurethral resection of bladder tumor (TURBT) and intravesical chemotherapy for superficial bladder cancers.

Diagnostic Procedures/Other • Cystoscopy with biopsy is the gold standard for diagnosis, but one study showed that 33% of patients had residual tumor after TURBT. • Using photodynamic diagnosis (PDD; employing a photosensitizing agent in the bladder that is taken up by tumor cells and visualized using a particular wavelength of light, which is changed to a different wavelength by the photosensitizing agent) has been shown to increase detection and identification of cancerous superficial tumors when compared with plain

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white light cystoscopy. A recent meta-analysis shows that this increases the likelihood of total resection.

Test Interpretation • Characterized as superficial (nonmuscle invasive) or invasive (muscle invasive) • 70–80% present as superficial lesion. • Superficial lesions – Carcinoma in situ: flat lesion, high grade – Ta: noninvasive papillary carcinoma – T1: extends into submucosa, lamina propria • Invasive cancer – T2: invasion into muscle pT2a: invasion into superficial muscle pT2b: invasion into deep muscle – T3: invasion into perivesical fat pT3a: microscopic pT3b: macroscopic – T4: invasion into adjacent organs aT4a: invades prostate, uterus, or vagina aT4b: invades abdominal or pelvic wall • N1–N3: invades lymph nodes • M: metastasis to bone or soft tissue

TREATMENT For nonmuscle-invasive bladder cancer, the treatment is generally removal via cystoscopic surgery (see earlier discussion on PDD). For muscle-invasive cancer, a radical cystectomy with pelvic lymphadenectomy is preferred.

MEDICATION First Line • A recent meta-analysis demonstrated neoadjuvant chemotherapy using platinum-based combination chemotherapy (with ≥1 of doxorubicin/epirubicin, methotrexate, or vinblastine), but not platinum alone,

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confers a significant survival advantage in patients with invasive bladder cancer, with an increase in survival at 5 years from 45% (without neoadjuvant treatment) to 50% (with treatment) (combined hazard ratio 0.86; 95% CI, 0.77–0.95). • Intravesical bacillus Calmette-Guérin (BCG) after TURBT in high-grade lesions has been shown to decrease recurrence in Ta and T1 tumors (4)[A].

Second Line • Chemotherapy is the first-line treatment for metastatic bladder cancer: – Methotrexate-vinblastine-doxorubicin-cisplatin (MVAC) is the preferred regimen. • A recent review showed that gemcitabine plus cisplatin may be better tolerated and result in equivalent survival to MVAC, making it a possible first choice in metastatic bladder cancer.

ISSUES FOR REFERRAL Patients with microscopic or gross hematuria not otherwise explained or resolving should be referred to a urologist for cystoscopy.

ADDITIONAL THERAPIES Radiotherapy: • In the United States, used for patients with muscle-invasive cancer who are not surgical candidates • Preoperative (radical cystectomy) radiotherapy also an option • Treatment of choice for muscle-invasive cancer in some European and Canadian centers: – 65 to 70 Gy over 6 to 7 weeks is standard.

SURGERY/OTHER PROCEDURES • Surgery is definitive therapy for superficial and invasive cancer: – Superficial cancer: TURBT sometimes followed by intravesical therapy • Invasive cancer – Radical cystectomy for invasive disease that is confined to the bladder is more effective than radical radiotherapy. There is insufficient evidence to recommend one form of urinary diversion over another (5). – Currently under trial is a trimodal therapy implementing transurethral

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resection, radiotherapy, and radiosensitizing chemotherapy (6).

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS Need for surgery or intensive therapy

ONGOING CARE FOLLOW-UP RECOMMENDATIONS • Superficial cancers – Urine cytology alone has not been shown to be sufficient for follow-up. – Cystoscopy every 3 months for 18 to 24 months, every 6 months for the next 2 years, then annually • Follow-up for invasive cancers depends on the approach to treatment. • Patients treated with BCG require lifelong follow-up.

DIET Continue adequate fluid intake.

PATIENT EDUCATION Smoking cessation

PROGNOSIS • 5-year relative survival rates (1) – Overall survival: 77.4% In situ 95.9% Localized: 69.9% Regional metastasis: 34.0% Distant metastasis: 5.4% • Superficial bladder cancer – BCG treatment prevents recurrence versus TURBT alone; difference 30%, NNT 3.3. – BCG prevents progression versus TURBT alone, difference 8%. • Invasive cancer – T2 disease: Radical cystectomy results in 60–75% 5-year survival.

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– T3 or T4 disease: Radical cystectomy results in 20–40% 5-year survival. – Neoadjuvant chemotherapy with cystectomy has led to varying degrees of increased survival. – Radiation with chemotherapy has led to varying degrees of increased survival. • Metastatic cancer: – MVAC resulted in mean survival of 12.5 months.

COMPLICATIONS • Superficial bladder cancer – Local symptoms Dysuria, frequency, nocturia, pain, passing debris in urine Bacterial cystitis Perforation – General symptoms Flulike symptoms Systemic infection • Invasive cancer – Symptoms related to definitive treatment, including incontinence, bleeding – Patients with neobladder at risk for azotemia and metabolic acidosis

REFERENCES 1. National Cancer Institute. SEER stat fact sheets: bladder cancer. http://seer.cancer.gov/statfacts/html/urinb.html. Accessed December 6, 2016. 2. Freedman ND, Silverman DT, Hollenbeck AR, et al. Association between smoking and risk of bladder cancer among men and women. JAMA. 2011;306(7):737–745. 3. U.S. Preventive Services Task Force. Recommendation summary. http://www.uspreventiveservicestaskforce.org/Page/Topic/recommendationsummary/bladder-cancer-in-adults-screening. Accessed December 6, 2016. 4. Shelley MD, Court JB, Kynaston H, et al. Intravesical bacillus CalmetteGuerin versus mitomycin C for Ta and T1 bladder cancer. Cochrane Database Syst Rev. 2003;(3):CD003231. 5. Cody JD, Nabi G, Dublin N, et al. Urinary diversion and bladder

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reconstruction/replacement using intestinal segments for intractable incontinence or following cystectomy. Cochrane Database Syst Rev. 2012; (2):CD003306. 6. Kamat AM, Hahn NM, Efstathiou JA, et al. Bladder cancer. Lancet. 2016; 388(10061):2796–2810.

ADDITIONAL READING • Msaouel P, Koutsilieris M. Diagnostic value of circulating tumor cell detection in bladder and urothelial cancer: systematic review and metaanalysis. BMC Cancer. 2011;11:336. • Sharma S, Ksheersagar P, Sharma P. Diagnosis and treatment of bladder cancer. Am Fam Physician. 2009;80(7):717–723. • Zhu Z, Shen Z, Lu Y, et al. Increased risk of bladder cancer with pioglitazone therapy in patients with diabetes: a meta-analysis. Diabetes Res Clin Pract. 2012;98(1):159–163.

SEE ALSO • Hematuria • Algorithm: Hematuria

CODES ICD10 • C67.9 Malignant neoplasm of bladder, unspecified • C67.4 Malignant neoplasm of posterior wall of bladder • C67.3 Malignant neoplasm of anterior wall of bladder

CLINICAL PEARLS • Painless hematuria in smokers should be evaluated with cystoscopy. • Be aware of potential link between pioglitazone treatment and risk for bladder cancer. • The U.S. Preventive Services Task Force recommends against routine

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screening for bladder cancer.

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BORDERLINE PERSONALITY DISORDER William G. Elder, PhD BASICS DESCRIPTION A psychiatric disorder that begins no later than adolescence or early adulthood, borderline personality disorder (BPD) is a consistent and pervasive pattern of unstable and reactive moods and sense of self, impulsivity, and volatile interpersonal relationships (1): • Common behaviors and variations: – Self-mutilation: pinching, scratching, cutting – Suicide: ideation, history of attempts, plans – Splitting: idealizing then devaluing others – Presentation of helplessness or victimization – High utilization of emergency department and resultant inpatient hospitalizations for psychiatric treatment – BPD patients are frequent users of primary care (2). • High rate of associated mental disorders • Typically display little insight into behavior

Geriatric Considerations Illness (both acute and chronic) may exacerbate BPD and may lead to intense feelings of fear and helplessness.

Pediatric Considerations Diagnosis is rarely made in children. Axis I disorders and general medical conditions (GMCs) are more probable.

Pregnancy Considerations Physical, emotional, and social concerns may transiently mimic symptoms of BPD: Consider delay in diagnosis until pregnancy completed. Pregnancy may also induce stress or increased fears, resulting in escalation of borderline behaviors.

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EPIDEMIOLOGY Predominant age: onset no later than adolescence or early adulthood (may go undiagnosed for years)

Prevalence • General population: 0.5–5.9% of U.S. population (2) • Estimated lifetime prevalence: 10–13% (2) • 10% of all psychiatric outpatients and between 15% and 25% of patients in psychiatry inpatient settings have BPD (2).

ETIOLOGY AND PATHOPHYSIOLOGY Undetermined but generally accepted that BPD is due to a combination of the following: • Hereditary temperamental traits • Environment (i.e., history of childhood sexual and/or physical abuse, history of childhood neglect, ongoing conflict in home) • Stress is theorized to exert damaging effects on the brain, specifically the hippocampus (2,3). • Neurobiologic research of BPD continues to increase the understanding of the etiology: – Abnormalities of the frontolimbic circuitry in relation to poor emotional stability (2) – Potential alterations in the sensitivity of opioid receptors and/or deficiencies with endogenous opioids (4) – Heightened activity in brain circuits involved in the experience of negative emotions and reduced activation that normally suppresses negative emotion once it is generated (5).

Genetics First-degree relatives are at greater risk for this disorder (undetermined if due to genetic or psychosocial factors).

RISK FACTORS • Genetic factors contribute; however, no specific genes have yet been identified (2). • Childhood sexual and/or physical abuse and neglect

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• Disrupted family life • Physical illness and external social factors may exacerbate BPD.

GENERAL PREVENTION • Tends to be a multigenerational problem • Children, caregivers, and significant others should have some time and activities away from the borderline individual, which may protect them.

COMMONLY ASSOCIATED CONDITIONS Other psychiatric disorders, including: • Co-occurring personality disorders, frequent • Mood disorders, common • Anxiety disorders, common • Substance-related disorders, common • Eating disorders, common • Posttraumatic stress disorder, common • BPD does not appear to be independently associated with increased risk of violence.

DIAGNOSIS • The comprehensive evaluation should focus on (6)[B]: – Comorbid conditions – Functional impairments – Adaptive/maladaptive coping styles – Psychosocial stressors – Patient strengths; needs/goals • Initial assessment should focus on determining treatment setting (6)[B]: – Establish treatment agreement with patient and outline treatment goals. – Assess suicide ideation and self-harm behavior. – Assess for psychosis. – Hospitalization is necessary if patient presents a threat of harm to self or others.

HISTORY

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• Clinic visits for problems that do not have biologic findings • Conflicts with medical staff members • Idealizing or unexplained anger at physician • History of unrealistic expectations of physician (e.g., “I know you can take care of me.” “You’re the best, unlike my last provider.”) • Obtain collateral information (i.e., from family, partner) about patient behaviors. • History of interpersonal difficulties, affective instability, and impulsivity • History of self-injurious behavior, possibly with suicidal threats or attempts (7)

PHYSICAL EXAM • BPD patients should have a thorough physical examination to help lower suspicion of organic disease (especially thyroid disease) (1,2). • Often physical examination reveals no gross abnormalities other than related to scarring from self-mutilation.

DIFFERENTIAL DIAGNOSIS • Mood disorders: – Look at baseline behaviors when considering BPD versus mood disorder. – BPD symptoms increase the likelihood of misdiagnosing bipolar disorder. – In particular, disruptive mood dysregulation disorder, a new diagnosis appearing in DSM-5 and characterized by severe recurrent temper outbursts manifesting verbally or behaviorally and grossly out of proportion to the situation, may appear quite similar to the acting out and intense emotions seen in BPD. Look for other symptoms characteristic of BPD to differentiate (1). • Psychotic disorder: – With BPD, typically only occurs under intense stress and is characterized as “micropsychotic.” • Other PD: – Thoughts, feelings, and behavior will differentiate BPD from other PDs. • GMC: – Traits may emerge due to the effect of a GMC on the CNS. • Substance use

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DIAGNOSTIC TESTS & INTERPRETATION • Consider age of onset. To meet criteria for BPD, borderline pattern will be present from adolescence or early adulthood. • Formal psychological testing • Rule out personality change due to a GMC (1)[C]: – Traits may emerge due to the effect of a GMC on the CNS. • Rule out symptoms related to substance use. • If symptoms begin later than early adulthood or are related to trauma (e.g., after a head injury), a GMC, or substance use, then consider other diagnoses.

Diagnostic Procedures/Other According to DSM-5 criteria, patient must meet at least five of the following criteria (1)[C]: • Attempt to avoid abandonment • Volatile interpersonal relationships • Identity disturbance • Impulsive behavior: – In ≥2 areas – Impulsive behavior is self-damaging. • Suicidal or self-mutilating behavior • Mood instability • Feeling empty • Is unable to control anger or finds it difficult • Paranoid or dissociative when under stress • With advent of DSM-5, an alternative model is being promulgated that may come to define the diagnosis as impairments in personality functioning AND the presence of pathologic traits. Attention to these features may ultimately enhance provider understanding, diagnosis, and treatment of patients with personality dysfunction. – Criteria regarding personality functioning refer to impairments of selffunctioning (i.e., identity or self-direction) AND interpersonal functioning (i.e., empathy or intimacy). – Pathologic personality traits refer to characteristics in the domains of negative affectivity (i.e., emotional liability, anxiousness, separation

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insecurity, depressivity); disinhibition (i.e., impulsivity, risk taking); OR antagonism (1).

TREATMENT • Outpatient psychotherapy for BPD is the preferred treatment (2,6)[B]: – Dialectical behavior therapy (DBT) combines cognitive-behavioral techniques for emotional regulation and reality-testing with concepts of distress tolerance, acceptance, and self-awareness. Following a dialectal process, therapists are tough-minded allies, who validate feelings and are unconditionally accepting, while also reminding patients to accept their dire level of emotional dysfunction and to apply better alternative behaviors. DBT may be done individually and in groups. • Also consider CBT or transference-focused (psychodynamic) psychotherapy. • Patient may need to be placed on suicide watch. • Brief inpatient hospitalizations are ineffective in changing Axis II disorder behaviors: – Hospitalizations should be limited, and of short duration to adjust medications, implement psychotherapy for crisis intervention, and to stabilize patients from psychosocial stressors. • Extended inpatient hospitalization should be considered for the following reasons (6)[B]: – Persistent/severe suicidal ideation or risk to others – Comorbid substance use and/or nonadherence to outpatient or partial hospitalization treatments – Comorbid Axis I disorders that may increase threat to life for the patient (i.e., eating disorders, mood disorders).

GENERAL MEASURES • Patients with BPD require more medical care and increased “intentionality” by the provider. Therefore, it is important to be aware of which patients in your practice have BPD and to limit this number if demands exceed practice resources.

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• Focus on patient management rather than on “fixing” behaviors: – Schedule consistent appointment follow-ups to relieve patient anxiety. – Meet with and rely on treatment team to avoid splitting of team by patient and to provide opportunity to discuss patient issues. – Treatment is usually most effective when both medications and psychotherapy are used simultaneously.

MEDICATION • Although no specific medications are approved by the FDA to treat BPD, American Psychiatric Association (APA) guidelines recommend pharmacotherapy to manage symptoms (2)[A],(6)[B]. • Treat Axis I disorders (6)[B]. • Consider high rate of self-harm and suicidal behavior when prescribing (2) [A]. • APA guideline recommendations (6)[B]: – Affective dysregulation: mood stabilizers, SSRIs, and monoamine oxidase inhibitors (MAOIs) – Impulsive-behavioral control: SSRIs and mood stabilizers – Cognitive-perceptual symptoms: antipsychotics • With more neurobiologic causes considered in relation to BPD, there is more emphasis on mood stabilizers and atypical antipsychotics, but research is uncertain and inconclusive (8)[B]. • Antipsychotics have short-lived benefit and offer no value other than transient treatment of cognitive perceptual symptoms (9)[B].

ISSUES FOR REFERRAL • If hospitalized, consider for suicide risk, mood or anxiety disorders, or substance-related disorders. • Urgency for scheduled follow-up depends on community resources (e.g., outpatient day programs for suicidal patients; substance abuse programs): – With increased risk for self-harm or self-defeating behaviors and low community resources, the patient can/will have increased need for frequent visits.

ADDITIONAL THERAPIES

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Consider referring patient for specialized mental health behavioral services, including partial hospital therapy.

COMPLEMENTARY & ALTERNATIVE MEDICINE Omega-3 fatty acid dietary supplementation has shown beneficial effects (2)[B].

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS Admit for inpatient services immediately in presence of psychosis or threat of injury to self or others; include police, as necessary, for safety measures. • Assess suicidal ideation. • Consider trial of antipsychotic medications for psychosis. • Nurses can be instrumental in managing and calling patients, potentially relieving patient stress. • Patient should not present risk of harm to self or others and have a safety plan. • Follow-up should be scheduled with a mental health specialist and primary care provider.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS • Schedule visits that are short, more frequent, and focused to relieve patients’ anxiety about relationships with their physician/provider and to help reduce risk of provider burnout. • Maintain open lines of communication with mental health professionals providing psychological support. • Emphasize importance of healthy lifestyle modifications (i.e., exercise, rest, diet).

Patient Monitoring Monitor for suicidal or other self-harm behaviors.

PATIENT EDUCATION Include patients in the diagnosis so they can make sense of their disease process and participate in the treatment strategy (6,9)[C].

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PROGNOSIS • Borderline behaviors may decrease with age and over time. • Patients in treatment improve at a rate of 7 times compared with following natural course (10). • Treatment is complex and takes time. • Medical focus includes patient management and caring for medical and Axis I disorders.

REFERENCES 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Publishing; 2013. 2. Leichsenring F, Leibing E, Kruse J, et al. Borderline personality disorder. Lancet. 2011;377(9759):74–84. 3. Ruocco AC, Amirthavasagam S, Zakzanis KK. Amygdala and hippocampal volume reductions as candidate endophenotypes for borderline personality disorder: a meta-analysis of magnetic resonance imaging studies. Psychiatry Res. 2012;201(3):245–252. 4. Bandelow B, Schmahl C, Falkai P, et al. Borderline personality disorder: a dysregulation of the endogenous opioid system? Psychol Rev. 2010;117(2):623–636. 5. Ruocco A, Amirthavasagam S, Choi-Kain LW, et al. Neural correlates of negative emotionality in borderline personality disorder: an activationlikelihood-estimation meta-analysis. Biol Psychiatry. 2013;73(2):153–160. 6. Oldham JA. Guideline Watch: Practice Guideline for the Treatment of Patients with Borderline Personality Disorder. Arlington, VA: American Psychiatric Association; 2005. 7. Zanarini MC, Laudate CS, Frankenburg FR, et al. Reasons for selfmutilation reported by borderline patients over 16 years of prospective follow-up. J Pers Disord. 2013;27(6):783–794. 8. Feurino L III, Silk KR. State of the art in the pharmacologic treatment of borderline personality disorder. Curr Psychiatry Rep. 2011;13(1):69–75. 9. Sanislow CA, Marcus KL, Reagan EM. Long-term outcomes in borderline

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psychopathology: old assumptions, current findings, and new directions. Curr Psychiatry Rep. 2012;14(1):54–61. 10. Elder W. Personality disorders. In: South-Paul J, Matheny S, Lewis E, eds. Current Diagnosis & Treatment in Family Medicine. 4th ed. New York, NY: McGraw-Hill; 2015: 618–625.

CODES ICD10 F60.3 Borderline personality disorder

CLINICAL PEARLS • BPD may be discerned by the impropriety of reactions to situations others find or minor. • View BPD as a chronic condition with waxing and waning features. It is important to adjust medications/treatments as clinically appropriate when symptoms change. • If there are problems with the patient disrespecting the physician or support staff, clear guidelines should be established with the treatment team and then with the patient. • When considering terminating care, the patient may improve if empathetically confronted about certain behaviors and is given clear guidelines on how to behave in the clinic. It is the patient’s job to follow the guidelines, and it is you and your team’s job to enforce the guidelines. Designate a case management nurse or well-trained support staff person who can be the primary contact person for the patient. • Have an agenda when you visit with BPD patients. Be cordial—they deserve the same professionalism any patient gets. Have and identify one to two issues to be discussed per clinic visit. Frequently scheduled visits can help with this. • Regularly scheduled psychotherapy improves medical care by becoming the “home” for mental health treatment, leaving the physician to focus on the patient’s immediate medical issues.

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BRAIN INJURY, TRAUMATIC Caleb J. Mentzer, DO • James R. Yon, MD BASICS DESCRIPTION • Traumatic brain injury (TBI) is defined as an alteration in brain function or other evidence of brain pathology, caused by an external force. • System(s) affected: neurologic; psychiatric; cardiovascular; endocrine/metabolic; gastrointestinal • Synonym(s): head injury, concussion

EPIDEMIOLOGY Incidence • 2.2 million ED visits and 280,000 hospitalizations/year • 50,000 deaths/year; ~30% of all injury-related deaths • Incidence in males twice that of females with 4-fold risk of fatal trauma

Prevalence • Predominant age: 0 to 4 years, 15 to 19 years, and >65 years • Predominant gender: male > female (2:1)

ETIOLOGY AND PATHOPHYSIOLOGY • Falls (40%) • Motor vehicle accidents (14%) • Assault (10%) • Child abuse (24% of TBI age ≤2 years) • Recreational activities (21% of pediatric TBI, peak seasons spring/summer; peak ages 10 to 14 years) • Primary insult: direct mechanical damage • Secondary insult: actuation of complex cellular and molecular cascades that promote cerebral edema, ischemia, and apoptotic cell death

RISK FACTORS Alcohol and drug use, prior/recurrent head injury, contact sports, seizure

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disorder, ADHD, male sex, luteal phase of female menstrual cycle

Geriatric Considerations Subdural hematomas are common after a fall or blow in elderly; symptoms may be subtle and not present until days after trauma. Many elderly patients are on antiplatelet or anticoagulation therapy.

GENERAL PREVENTION • Safety education • Seat belts; bicycle and motorcycle helmets • Protective headgear for contact sports

Pediatric Considerations Child abuse: Consider if dropped or fell 65 years Follow-Up Tests & Special Considerations Blast-related TBI: much higher rates of postconcussive syndrome, PTSD, depression, and chronic pain. Chronic impairment is strongly correlated with psychological factors. Return to battlefield guidelines similar to return to play in sports (see “General Measures”) (1)[A]

Pediatric Considerations Skull radiographs are not indicated unless abuse is suspected in which case they can detect fractures not seen under CT. No return to activity until they are asymptomatic, and return to school should precede return to sport/physical

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activity (2)[A].

Diagnostic Procedures/Other • CSF rhinorrhea – Contains glucose; nasal mucus does not. – Check for the double-halo sign: If nasal discharge contains CSF and blood, two rings appear when placed on filter paper—a central ring followed by a paler ring.

TREATMENT GENERAL MEASURES • Acute management depends on injury severity. Most patients need no interventions. • Immediate goal: Determine who needs further therapy, imaging studies (CT), and hospitalization to prevent further injury. • For the mildly injured patient – Early education is beneficial for recovery (3)[A]. – Return to play (RTP) Never RTP on same day. Strict guidelines for graduated return to cognitive and physical activity when there are no evident signs or symptoms (physical, cognitive, emotional, or behavioral) on neuropsychological and clinical evaluation (2)[A] • For the moderate to severely injured patient – Avoid hypotension or hypoxia. Head injury causes increased ICP secondary to edema, and cerebral perfusion pressure (CPP) should be maintained between 60 and 70 mm Hg (4)[A]. – 30-degree head elevation decreases ICP and improves CPP. – Hyperventilation (hypocapnia) Use should be limited to patients with impending herniation while preparing for definitive treatment or intraoperatively. Risk of worsening cerebral ischemia and organ damage (4,5)[A] Addition of tromethamine can offset deleterious effects and lead to better

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outcomes (5)[A]. – Mild systematic hypothermia lowers ICP but leads to increased rates of pneumonia. Selective brain cooling may also decrease ICP with improved outcomes at 2 years postinjury (5)[A]. • Seizure prophylaxis – Does not change morbidity or mortality. Consider phenytoin or levetiracetam for 1 week postinjury or longer for patients with early seizures, dural-penetrating injuries, multiple contusions, and/or subdural hematomas requiring evacuation (6)[A].

MEDICATION First Line • Pain – Morphine: 1 to 2 mg IV PRN, with caution, because it can depress mental status, further altering serial neurologic evaluations

ALERT Bolus doses increase ICP and decrease CPP (7)[A]. • Increased ICP – Hypertonic saline: 2 mL/kg IV decreases ICP without adverse hemodynamic status; preferred agent (4,7)[A] – Mannitol: 0.25 to 2 g/kg (0.25 to 1 g/kg in children) given over 30 to 60 minutes in patients with adequate renal function. Prophylactic use is associated with worse outcomes (7)[A]. • Sedation – Propofol: preferred due to short duration of action. Avoid high doses to prevent propofol infusion syndrome. When combined with morphine, it can also effectively decrease ICP and decrease use of other meds (7)[A]. – Midazolam: similar sedating effect to propofol but may cause hypotension (7)[A] • Seizures – Phenytoin (Dilantin): 15 mg/kg IV (1 mg/kg/min IV, not to exceed 50 mg/min). Stop infusion if QT interval increases by >50%.

ALERT

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Avoid corticosteroid use, as it increases mortality rates and risk of developing late seizures (7)[A]. Avoid barbiturates due to risk of hypotension (7)[A].

ISSUES FOR REFERRAL Consult neurosurgery for: • All penetrating head trauma • All abnormal head CTs

ADDITIONAL THERAPIES • Emerging therapies with limited but promising evidence: coma arousal therapy: amantadine, zolpidem, and levodopa/carbidopa; postcoma therapy: bromocriptine • Mixed results for therapeutic hypothermia with defined physiologic parameters (8)[A]

SURGERY/OTHER PROCEDURES • Early evacuation of trauma-related intracranial hematoma decreases mortality especially with GCS 6 (5)[A] • Hyperbaric oxygen temporarily lowers ICP and improves mortality, but evidence is conflicting about outcomes at 6 to 12 months postinjury (5)[A]. The combination of hyperbaric and normobaric hyperoxia reduces ICP and improves overall morbidity/mortality (10)[B]. • CSF drainage reduces ICP but has not been demonstrated to have long-term benefit (5)[A]. • CSF leakage often resolves in 24 hours with bed rest, but if not, may require surgical repair (4)[A].

COMPLEMENTARY & ALTERNATIVE MEDICINE Music therapy in conjunction with multimodal stimulation improves awareness in comatose TBI patients (8)[B].

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS

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• Abnormal GCS or CT • Clinical evidence of basilar skull fracture • Persistent neurologic deficits (e.g., confusion, somnolence) • Patient with no competent adult at home for observation • Possibly admit: LOC, amnesia, patients on anticoagulants with negative CT • ABCs take priority over head injury. • C-spine immobilization should be considered in all head trauma. • Use normal saline for resuscitation fluid. • Discharge criteria: normal CT with return to normal mental status and responsible adult to observe patient at home (see “Patient Monitoring”)

ONGOING CARE FOLLOW-UP RECOMMENDATIONS • Schedule regular follow-up within a week to determine return to activities. • Rehabilitation indicated following a significant acute injury. Set realistic goals. • For patients on anticoagulants, net benefit to restarting therapy after discharge despite increased bleeding risk.

Patient Monitoring Patient should be discharged to the care of a competent adult with clear instructions on signs and symptoms that warrant immediate evaluation (e.g., changing mental status, worsening headache, focal findings, or any signs of distress). Patients should be monitored but not awakened from sleep.

DIET As tolerated, monitor for signs of nausea.

PATIENT EDUCATION Proper counseling, symptomatic management, and gradual return to normal activities are essential.

PROGNOSIS • Gradual improvement may continue for years.

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• 30–50% of severe head injuries may be fatal. • Predicting outcome is difficult; many with even minor to moderate injuries have moderate to severe disability at 1 year, whereas prolonged coma may be followed by satisfactory outcome. • Patients may have new-onset seizures over 2 years following trauma. • Poor prognostic factors: low GCS on admission, nonreactive pupils, old age, comorbidity, midline shift

COMPLICATIONS • Chronic subdural hematoma, which may follow even “mild” head injury, especially in the elderly; often presents with headache and decreased mentation • Delayed hematomas and hydrocephalus • Emotional disturbances and psychiatric disorders resulting from head injury may be refractory to treatment • Seizures: seen in 50% of penetrating head injuries, 20% of severe closed head injuries, and 65 years. • Strict criteria exist for patients to return to normal sport activity following head injury to avoid the second-impact syndrome, which has 50% mortality.

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BREAST ABSCESS Lindsay Petersen, MD • Andrea Madrigrano, MD BASICS DESCRIPTION • Localized collection of pus within the breast parenchyma • Can be associated with lactation or fistulous tracts secondary to squamous epithelial neoplasm or duct occlusion • System(s) affected: skin/exocrine • Synonym(s): mammary abscess; peripheral breast abscess; subareolar abscess; puerperal abscess

Pregnancy Considerations Most commonly associated with postpartum lactation

EPIDEMIOLOGY • Predominant age – Puerperal abscess: lactational – Subareolar abscess: postmenopausal • Predominant sex: female • Higher incidence in African American women

Incidence • 0.1–0.5% of breastfeeding women • Puerperal abscess rare after first 6 weeks of lactation

ETIOLOGY AND PATHOPHYSIOLOGY • Delayed treatment of mastitis • Puerperal abscesses: blocked lactiferous duct • Subareolar abscess: squamous epithelial neoplasm with keratin plugs or ductal extension with associated inflammation • Peripheral abscess: stasis within the duct leading to microbial accumulation and secondary abscess formation • Microbiology

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– Staphylococcus aureus is most common cause. – Less common causes Streptococcus pyogenes; Escherichia coli; Bacteroides Corynebacterium Pseudomonas Proteus • Methicillin-resistant Staphylococcus aureus (MRSA) is increasing. Risk factors for postpartum S. aureus (SA) breast abscess have not changed with rise in community-associated MRSA.

RISK FACTORS • Puerperal mastitis – 5–11% progression to abscess: Most often due to inadequate therapy – Risk factors (stasis): Infrequent or missed feeds Poor latch (1) Damage or irritation of the nipple Use of breast pump (2) Illness in mother or baby Rapid weaning Blocked nipple or duct • General factors – Smoking (3) – Diabetes (3) – Rheumatoid arthritis – Obesity (3) • Medically induced factors – Steroids – Silicone/paraffin implant – Lumpectomy with radiation – Oral antibiotics during breastfeeding (mastitis) (2) – Topical antifungal medication during breastfeeding (mastitis) (2) • Nipple retraction • Nipple piercing (mastitis, subareolar abscess) (3)

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• Higher recurrence rate if polymicrobial abscess

GENERAL PREVENTION Early treatment of mastitis with milk expression, antibiotics, and compresses

COMMONLY ASSOCIATED CONDITIONS Lactation

DIAGNOSIS HISTORY • Tender breast lump, usually unilateral • Breastfeeding • Postmenopausal • Systemic malaise (usually less than with mastitis) • Localized erythema, edema, and pain • Fever, nausea, vomiting, or spontaneous nipple drainage

PHYSICAL EXAM • Fever, tachycardia • Erythema of overlying skin • Tenderness, fluctuance on palpation • Draining pus or skin ulceration • Local edema • Nipple and skin retraction • Regional lymphadenopathy

DIFFERENTIAL DIAGNOSIS • Carcinoma (inflammatory or primary squamous cell) • Engorgement • Galactocele • Tuberculosis (may be associated with HIV infection) • Sarcoid; granulomatous mastitis • Syphilis • Foreign body reactions (e.g., to silicone and paraffin) • Mammary duct ectasia

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DIAGNOSTIC TESTS & INTERPRETATION • CBC (leukocytosis) • Elevated ESR • Ultrasound (US) helps identify fluid collection within breast tissue. • Culture and sensitivity of abscess fluid or expressed breast milk to identify pathogen (usually Staphylococcus or Streptococcus) • MRSA is an increasingly important pathogen in both lactational and nonlactational abscesses. • Other bacteria: – Nonlactational abscess and recurrent abscesses associated with anaerobic bacteria E. coli, Proteus; mixed bacteria less common • Mammogram to rule out carcinoma (generally not in acute phase)

Diagnostic Procedures/Other Aspiration of abscess for culture (not accurate to exclude carcinoma)

Test Interpretation • Squamous metaplasia of the ducts • Intraductal hyperplasia • Epithelial overgrowth • Fat necrosis • Duct ectasia

TREATMENT GENERAL MEASURES • Cold compresses for pain control • Important to continue to breastfeed or express milk to drain the affected breast

MEDICATION Combination of antibiotics and drainage for cure: • Culture midstream sample of milk for mastitis. • Culture abscess fluid for breast abscess. • There is insufficient evidence regarding the effectiveness of antibiotic

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therapies for lactational mastitis alone (4)[A].

First Line • NSAIDs for analgesia and/or antipyresis • Dicloxacillin 500 mg QID for 10 to 14 days (5)[A] • If no response in 24 to 48 hours, switch to cephalexin 500 mg QID for 10 to 14 days. – Or amoxicillin-clavulanate (Augmentin) 250 to 500 mg TID • Clindamycin 300 mg QID if anaerobes are suspected • If MRSA is a concern, TMP-SMZ DS 1 to 2 PO BID for 10 to 14 days. Clindamycin 300 mg PO QID as alternative • Contraindications: antibiotic allergy • In severe infections, vancomycin as an inpatient may be necessary. – Dose (30 mg/kg) IV in 2 divided doses every 24 hours may be necessary until culture results are available. – A 3rd-generation or a combination of a beta-lactam and beta-lactamase agent may need to be added as well.

SURGERY/OTHER PROCEDURES • Aspiration with or without US guidance (6)[A] • Consider US-guided percutaneous catheter placement if abscess >3 cm (6)[A]. • Serial aspirations under US may be necessary (q2–3d) if patients fail to respond (7)[C]. • Needle aspiration alone (without antibiotics) may be effective for small breast abscesses (8)[A]. • Consider incision and drainage if abscess is recurrent, chronic, or >5 cm (6) [A]. • Biopsy nonpuerperal abscesses to rule out carcinoma. • Open all fistulous tracts, especially abscesses in nonlactating patients. • US-guided aspiration with judicious use of antibiotics is superior to incision and drainage (9)[A].

COMPLEMENTARY & ALTERNATIVE MEDICINE • Lecithin supplementation • Acupuncture may help with breast engorgement, and prevention of breast

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abscess (10)[A].

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS Outpatient, unless systemically immunocompromised or septic

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring Ensure resolution to exclude carcinoma.

PATIENT EDUCATION • Wound care • Continue with breastfeeding or pumping (if breastfeeding is not possible due to location of abscess) to prevent engorgement.

PROGNOSIS • Complete healing expected in 8 to 10 days • Subareolar abscesses frequently recur, even after incision and drainage (I&D) and antibiotics; may require surgical removal of ducts

COMPLICATIONS • Fistula: mammary duct or milk fistula • Poor cosmetic outcome

REFERENCES 1. Branch-Elliman W, Golen TH, Gold HS, et al. Risk factors for Staphylococcus aureus postpartum breast abscess. Clin Infect Dis. 2012;54(1):71–77. 2. Mediano P, Fernández L, Rodríguez JM, et al. Case-control study of risk factors for infectious mastitis in Spanish breastfeeding women. BMC Pregnancy Childbirth. 2014;14:195. 3. Gollapalli V, Liao J, Dudakovic A, et al. Risk factors for development and recurrence of primary breast abscesses. J Am Coll Surg. 2010;211(1):41–48.

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4. Jahanfar S, Ng CJ, Teng CL. Antibiotics for mastitis in breastfeeding women. Cochrane Database Syst Rev. 2013;(2):CD005458. 5. Cusack L, Brennan M. Lactational mastitis and breast abscess—diagnosis and management in general practice. Aust Fam Physician. 2011;40(12):976– 979. 6. Lam E, Chan T, Wiseman SM. Breast abscess: evidence based management recommendations. Expert Rev Anti Infect Ther. 2014;12(7):753–762. 7. Elder EE, Brennan M. Nonsurgical management should be first-line therapy for breast abscess. World J Surg. 2010;34(9):2257–2258. 8. Thirumalaikumar S, Kommu S. Best evidence topic reports. Aspiration of breast abscesses. Emerg Med J. 2004;21(3):333–334. 9. Naeem M, Rahimnajjad MK, Rahimnajjad NA, et al. Comparison of incision and drainage against needle aspiration for the treatment of breast abscess. Am Surg. 2012;78(11):1224–1227. 10. Mangesi L, Dowswell T. Treatments for breast engorgement during lactation. Cochrane Database Syst Rev. 2010;(9):CD006946.

ADDITIONAL READING • Berná-Serna JD, Berná-Mestre JD, Galindo PJ, et al. Use of urokinase in percutaneous drainage of large breast abscesses. J Ultrasound Med. 2009;28(4):449–454. • Dabbas N, Chand M, Pallett A, et al. Have the organisms that cause breast abscess changed with time?—implications for appropriate antibiotic usage in primary and secondary care. Breast J. 2010;16(4):412–415. • Rizzo M, Gabram S, Staley C, et al. Management of breast abscesses in nonlactating women. Am Surg. 2010;76(3):292–295. • Trop I, Dugas A, David J, et al. Breast abscesses: evidence-based algorithms for diagnosis, management, and follow-up. Radiographics. 2011;31(6):1683– 1699.

CODES ICD10

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• N61 Inflammatory disorders of breast • O91.13 Abscess of breast associated with lactation • O91.12 Abscess of breast associated with the puerperium

CLINICAL PEARLS • 5–11% of cases of puerperal mastitis go on to abscess (most often due to inadequate therapy for mastitis). Risk factors for mastitis are those that result in milk stasis (infrequent feeds, missing feeds). • Abscesses not associated with lactation should be treated with antibiotics that cover anaerobic bacteria. • The treatment of choice for most breast abscesses is the combination of antibiotics and aspiration. • US-guided aspiration of breast abscess is preferred to incision and drainage in most cases. • Continuing to empty the breast (feeding, pumping or expression of breast milk) is recommended during the presence of lactation-associated breast infection.

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BREAST CANCER Heather A. Dalton, MD • Amy M. Davis, MD BASICS DESCRIPTION • Malignant neoplasm of cells native to the breast—epithelial, glandular, or stroma • Types: DCIS, infiltrating ductal carcinoma, infiltrating lobular carcinoma, Paget disease, phyllodes tumor, inflammatory breast cancer, angiosarcoma • Molecular subtypes: luminal A (HR+/HER2−), triple negative (HR−/HER2−), luminal B (HR+/HER2+), HER2-enriched (HR−/HER2+)

EPIDEMIOLOGY Incidence • Estimated new female breast cancer (BC) cases for in situ 60,290; invasive 231,840 in 2015 • Estimated new male BC cases 2,350 • Estimated deaths 2015 females 40,290; males 440 • Second most common newly diagnosed cancer, leading cause of cancer death for U.S. women

Prevalence Estimated 3.1 million of 162 million U.S. women (1.9%) as of January 1, 2014 (1)

ETIOLOGY AND PATHOPHYSIOLOGY • Genes such as BRCA1 and BRCA2 function as tumor suppressor genes, and mutation leads to cell cycle progression and limitations in DNA repair (2). • Mutations in estrogen/progesterone induce cyclin D1 and c-myc expression, leading to cell cycle progression. • Additional tumors (33%) may cross-talk with estrogen receptors and epidermal growth factors receptors (EGFR), leading to similar abnormal cellular replication.

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Genetics • Criteria for additional risk evaluation/gene testing in affected individual (2) [A] – BC at age ≤50 years – BC at any age and ≥1 family member with BC ≤50 years of age or ovarian/fallopian tube/primary peritoneal CA any age or ≥2 family members with BC or pancreatic CA any age or population at increased risk (e.g., Ashkenazi Jew with BC or ovarian CA at any age) – Triple-negative BC (ER−, PR−, HER2−) – Two BC primaries in single patient – Ovarian/fallopian tube/primary peritoneal CA – 1+ family member with BC and CA of thyroid, adrenal cortex, endometrium, pancreas, CNS, diffuse gastric, aggressive prostate (Gleason >7), leukemia, lymphoma, sarcoma, dermatologic manifestations, and/or macrocephaly, GI hamartomas – Male BC – Known BC susceptibility gene mutation in family • Criteria for additional risk evaluation/gene testing in unaffected BC individual – First- or second-degree relative with BC ≤45 years of age – ≥2 breast primaries in one individual or ≥1 ovarian/fallopian tube/primary peritoneal CA from same side of family or ≥2 w/ breast primaries on same side of family – 1+ family member with BC and CA of thyroid, adrenal cortex, endometrium, pancreas, CNS, diffuse gastric, aggressive prostate (Gleason >7), leukemia, lymphoma, sarcoma, dermatologic manifestations, and/or macrocephaly, GI hamartomas – Ashkenazi Jewish with breast/ovary cancer at any age – Male BC – Known BC susceptibility gene mutation in family • BRCA1 and BRCA2 account for 5–10% of female and 5–20% male cancers; 15–20% familial BCs. – Mutations higher in Ashkenazi Jewish descent (2%) – Mutation in BRCA raises risk to 45–65% from 7% at age 70 years. • Other genes: ATM, BARD1, BRIP, CDH1, PTEN, STK11, CHEK2, p53,

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ERBB2, DIRAS3, NBN, RAD50, RAD51 • Cowden syndrome (PTEN): autosomal dominant, BC, hamartomas of skin, intestine, oral mucosa (trichilemmoma), microencephaly, endometrial CA, nonmedullary thyroid CA, benign thyroid lesions • Li-Fraumeni syndrome (TP53): autosomal dominant, BC and CA in CNS, leukemia, sarcoma, osteosarcoma, adrenal cortex • Ataxia-telangiectasia (ATM): autosomal recessive, ataxia, telangiectasia, lymphoma, leukemia, CA of breast, stomach, ovary • Peutz-Jeghers (STK11): autosomal dominance; hamartomatous polyps of GI tract, mucocutaneous melanin in lips, buccal mucosa, fingers, toes; CA in GI, lung, breast, uterus, ovary

RISK FACTORS • Risk Assessment Tool: http://www.cancer.gov/bcrisktool/ • >4.0 increase in relative risk: age >65 years, atypical hyperplasia, BRCA mutation, DCIS, LCIS, personal history 50%), single first-degree relative • 1.1 to 2.0 RR: EtOH, Ashkenazi Jewish, DES exposure, early menarche, high socioeconomic status, first pregnancy >30 years, fibroadenoma, never breastfed, no full-term pregnancies, obesity, personal history >40 years, personal history of endometrial, ovarian, colon cancer, HRT long term, recent OCP use • 20–25% lifetime risk: BRCA mutation, first-degree relative with BRCA mutation, history of radiation age 10 to 30 years, Li-Fraumeni or Cowden syndrome or first-degree relative with the same • 15–20% lifetime risk: personal history of BC, DCIS, LCIS, atypical ductal hyperplasia, atypical lobular hyperplasia, dense or unevenly dense breasts

GENERAL PREVENTION • Maintain healthy weight—lean, avoid weight gain, limit high calorie foods, drinks • Be physically active—150 minutes of moderate-intensity or 75 minutes vigorous activity weekly

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• Eat healthy diet—limit processed/red meat, 2 1/2 cups of vegetables and fruits daily, limit refined-grain. • Limit EtOH to no more than 1 drink daily for women, 2 for men. • Clinical breast exam (CBE): – ACS: does not recommend in average risk – USPFTF: insufficient evidence to assess clinical benefits and harms (3)[A] • Mammography: – USPSTF: women biennial at age 50 to 74 years (3)[B] – ACS: women 45 to 54 years annually, >55 years until 10 mm) on presentation or no clinical improvement after 24 to 48 hours of antibiotic therapy. • Trauma cases may need débridement or FB removal. • Orbital abscess may need surgical drainage. • Surgical drainage with 4 to 8 weeks of antibiotics is the treatment of choice for brain abscess. • Surgical interventions may include external ethmoidectomy, endoscopic ethmoidectomy, uncinectomy, antrostomy, and subperiosteal drainage.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS Patients with orbital cellulitis should be admitted for IV antibiotics and serial eye exams to evaluate progression of infection or involvement of optic nerve. • Follow temperature, WBC, visual acuity, pupillary reflex, ocular motility, and proptosis. • Repeat CT scan, or surgical intervention, may be required for worsening orbital cellulitis cases.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring Serial visual acuity testing and slit lamp exams

ALERT Bedside exam q4h is indicated, as complications can develop rapidly.

PATIENT EDUCATION • Maintain proper hand washing and good skin hygiene.

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• Avoid skin or lid trauma.

COMPLICATIONS • Vision loss, CNS involvement, and death • Permanent vision loss – Corneal exposure – Optic neuritis – Endophthalmitis – Septic uveitis or retinitis – Exudative retinal detachment – Retinal artery or vein occlusions – Globe rupture – Orbital compartment syndrome • CNS complications – Intracranial abscess, meningitis, cavernous sinus thrombosis (4)[B]

REFERENCES 1. Pasternak A, Irish B. Ophthalmologic infections in primary care. Clin Fam Pract. 2004;6(1):19–33. 2. Seltz LB, Smith J, Durairaj VD, et al. Microbiology and antibiotic management of orbital cellulitis. Pediatrics. 2011;127(3):e566–e572. 3. Chadha NK. An evidence-based staging system for orbital infections from acute rhinosinusitis. Laryngoscope. 2012;122(Suppl 4):S95–S96. 4. Hauser A, Fogarasi S. Periorbital and orbital cellulitis. Pediatr Rev. 2010;31(6):242–249. 5. Carlisle RT, Digiovanni J. Differential diagnosis of the swollen red eyelid. Am Fam Physician. 2015;92(2):106–112. 6. Kloek CE, Rubin PA. Role of inflammation in orbital cellulitis. Int Ophthalmol Clin. 2006;46(2):57–68. 7. Distinguishing periorbital from orbital cellulitis. Am Fam Physician. 2003;67(6):1349–1353. 8. Mahalingam-Dhingra A, Lander L, Preciado DA, et al. Orbital and periorbital infections: a national perspective. Arch Otolaryngol Head Neck Surg. 2011;137(8):769–773.

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9. Rudloe TF, Harper MB, Prabhu SP, et al. Acute periorbital infections: who needs emergent imaging? Pediatrics. 2010;125(4):e719–e726. 10. Bedwell J, Bauman NM. Management of pediatric orbital cellulitis and abscess. Curr Opin Otolaryngol Head Neck Surg. 2011;19(6):467–473. 11. Pushker N, Tejwani LK, Bajaj MS, et al. Role of oral corticosteroids in orbital cellulitis. Am J Ophthalmol. 2013;156(1):178.e1–183.e1.

CODES ICD10 • H05.019 Cellulitis of unspecified orbit • H05.011 Cellulitis of right orbit • H05.012 Cellulitis of left orbit

CLINICAL PEARLS • Most orbital cellulitis cases result from sinusitis. • MRSA orbital cellulitis may present without associated upper respiratory infection. • CT of orbits and sinuses with axial and coronal views with and without contrast is diagnostic modality of choice for suspected cases of orbital cellulitis. • Patients with orbital cellulitis should be admitted for visual monitoring and IV antibiotic therapy. • Older age (>10 years) and diplopia may predict need for surgical intervention in children. • Ophthalmoplegia, mental status changes, contralateral cranial nerve palsy, or bilateral orbital cellulitis raise suspicion for intracranial involvement.

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CELLULITIS, PERIORBITAL Fozia Akhtar Ali, MD • Mohammad Ansar Mughal, MD BASICS DESCRIPTION • An acute bacterial infection of the skin and subcutaneous tissue anterior to the orbital septum; not involving the orbital structures (globe, fat, and ocular muscles) • Synonym(s): preseptal cellulitis

ALERT It is essential to distinguish periorbital cellulitis from orbital cellulitis. Orbital cellulitis is a potentially life-threatening condition. Orbital cellulitis is posterior to the orbital septum; symptoms include restricted eye movement, pain with eye movement, proptosis, and vision changes.

EPIDEMIOLOGY • Occurs more commonly in children; mean age 21 months • 3 times more common than orbital cellulitis (1)[C]

Incidence • Increased incidence in the winter months (due to increased cases of sinusitis) (1)[C]

ETIOLOGY AND PATHOPHYSIOLOGY • The anatomy of the eyelid distinguishes periorbital (preseptal) from orbital cellulitis: – A connective tissue sheet (orbital septum) extends from the orbital bones to the margins of the upper and lower eyelids; it acts as a barrier to infection deep in the orbital structures. – Infection of tissues anterior to the orbital septum is periorbital (preseptal) cellulitis. – Infection deep to the orbital septum is orbital (postseptal) cellulitis. • Periorbital cellulitis classically arises from a contiguous infection of soft

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tissues of the face. – Sinusitis (via lamina papyracea) extension – Local trauma; insect or animal bites – Foreign bodies – Dental abscess extension – Hematogenous seeding • Common organisms (1)[C] – Staphylococcus aureus, typically MSSA (MRSA is increasing) – Staphylococcus epidermidis – Streptococcus pyogenes • Atypical organisms – Acinetobacter sp.; Nocardia brasiliensis – Bacillus anthracis; Pseudomonas aeruginosa – Neisseria gonorrhoeae; Proteus sp. – Pasteurella multocida; Mycobacterium tuberculosis; Trichophyton sp. (ringworm) • Since vaccine introduction, the incidence of Haemophilus influenzae has decreased. This organism should still be suspected in unimmunized or partially immunized patients.

Genetics No known genetic predisposition.

RISK FACTORS • Contiguous spread from upper respiratory infection • Sinusitis • Local skin trauma/puncture wound • Insect bite • Bacteremia

GENERAL PREVENTION • Avoid dermatologic trauma around the eyes. • Avoid swimming in fresh or salt water with facial skin abrasions. • Routine vaccination: particularly H. influenzae type B and Streptococcus pneumoniae

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DIAGNOSIS HISTORY • Induration, erythema, warmth, and/or tenderness of periorbital soft tissue, usually with normal vision and normal eye movements • Chemosis (conjunctival swelling), proptosis; pain with extraocular eye movements can occur in severe cases of periorbital cellulitis, although these symptoms are more common with (and concerning for) orbital cellulitis. • Fever (not always present)

ALERT Pain with eye movement, fever, and conjunctival swelling raise the suspicion for orbital cellulitis.

PHYSICAL EXAM • Vital signs and general appearance. (Patients with orbital cellulitis often appear systemically ill.) • Thorough inspection of the eye and surrounding structures—lids, lashes, conjunctiva, and skin • Erythema, swelling, and tenderness of lids without orbital congestion – Violaceous discoloration of eyelid is more commonly associated with H. influenzae. • Evaluate for any skin break. • Look for vesicles to rule out herpetic infection. • Inspect nasal vaults and palpate sinuses for signs of acute sinusitis. • Examine oral cavity for dental abscesses. • Test ocular motility and visual acuity.

DIFFERENTIAL DIAGNOSIS • Orbital cellulitis – Orbital cellulitis may have the same signs and symptoms as periorbital cellulitis, with more extensive proptosis, chemosis, ophthalmoplegia, decreased visual acuity, or fever. • Abscess • Dacryocystitis

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• Hordeolum (stye) • Allergic inflammation • Orbital or periorbital trauma • Idiopathic inflammation from orbital pseudotumor • Orbital myositis • Rapidly progressive tumors – Rhabdomyosarcoma – Retinoblastoma – Lymphoma • Leukemia

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • CBC with differential • Blood cultures (low yield) (2)[C] • Wound culture of purulent drainage (if present) • Imaging is indicated if there is suspicion for orbital cellulitis (marked eyelid swelling, fever, and leukocytosis or those who fail to improve on appropriate antibiotics in 24 to 48 hours). • CT can evaluate the extent of infection and detect orbital inflammation or abscess (3)[B]: – The classic sign of orbital cellulitis on CT scan is bulging of the medial rectus. – CT should be performed with contrast, thin sections (2 mm); coronal and axial views with bone windows.

Follow-Up Tests & Special Considerations • Children with periorbital or orbital cellulitis often have underlying sinusitis. • If a child is febrile, 1 year of age can be managed on an outpatient basis, if the patient is stable and there are no systemic signs of toxicity. • Consider hospitalization and IV antibiotics: – If patient appears systemically ill – Children upper extremity [UE] involvement) or quadriplegic (UE ≥ LE involvement) Dystonia: hypertonia and reduced movement Choreoathetosis: irregular spasmodic involuntary movements of the limbs or facial muscles Ataxia: loss of orderly muscular coordination – Motor function severity

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The Gross Motor Function Classification System (GMFCS) scores I–IV Score of I: ambulates without limitation Score of II: ambulates without assistive devices but some limitation Score of III: ambulates with assistive mobility devices Score of IV: Self-mobility is limited, but technology can help. Score of V: Self-mobility is severely limited, even with technology. The Manual Ability Classification System (MACS) can be used to assess upper extremity and fine motor function.

DIFFERENTIAL DIAGNOSIS Benign congenital hypotonia, brachial plexus injury, familial spastic paraplegia, dopa-responsive dystonia, transient toe-walking, muscular dystrophy, metabolic disorders (e.g., glutaric aciduria type 1), mitochondrial disorders, genetic disorders (e.g., Rett syndrome)

DIAGNOSTIC TESTS & INTERPRETATION CP is a clinical diagnosis based on history, physical, and risk factors. Laboratory testing is not needed to make diagnosis but can help exclude other etiologies. • Testing for metabolic and genetic syndromes (1)[C] – Not routinely obtained in the evaluation for CP. – Considered if no specific etiology is identified by neuroimaging or there are atypical features in clinical presentation. – Detection of certain brain malformations may warrant genetic or metabolic testing to identify syndromes. • Screening for coagulopathies: Diagnostic testing for coagulopathies should be considered in children with hemiplegic CP with cerebral infarction identified on neuroimaging (1)[C].

Initial Tests (lab, imaging) • Neuroimaging is not essential, but it is recommended in children with CP for whom the etiology has not been established (1)[C]. • MRI is preferred to CT if need to determine etiology and timing of a brain insult (1)[C]. • Abnormalities found in 80–90% of patients: brain malformation, cerebral infarction, intraventricular or other intracranial hemorrhage, periventricular

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leukomalacia, ventricular enlargement, or other CSF space abnormalities

Diagnostic Procedures/Other • The Communication Function Classification System has recently been developed as another means of assessing verbal performance. • International Classification of Functioning, Disability and Health for CP have been newly developed to standardize functional assessments. • Screening for comorbid conditions: developmental delay/intellectual impairment, vision/hearing impairments, speech and language disorders, feeding/swallowing dysfunction, or seizures • EEGs should only be obtained if there is a history of suspected seizures.

Test Interpretation Perinatal brain injury may include the following: • White matter damage – Most common in premature infants – Periventricular leukomalacia: gliosis with or without focal necrosis with resulting cysts and scarring; may be multiple lesions of various ages. Necrosis can lead to cysts/scarring. – Germinal matrix hemorrhage: may lead to intraventricular hemorrhage • Gray matter damage: more common in term infants; cortical infarcts, focal neuronal damage, myelination abnormalities

TREATMENT Focuses on control of symptoms; treatments reduce spasticity to prevent painful contractures, manage comorbid conditions, and optimize functionality and quality of life.

GENERAL MEASURES • Early intervention programs for preterm infants influences motor and cognitive outcomes (2)[A]. • Referral to early intervention for children ages 0 to 3 years is essential. • Various therapy modalities enhance functioning: – Physical therapy to improve posture stability and gait, motor strength and

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control, and prevent contractures – Occupational therapy to increase functional activities of daily living and other fine motor skills – Speech therapy for verbal and nonverbal speech and to aid in feeding • Equipment optimizes participation in activities: – Orthotic splinting (ankle–foot orthosis) maintains functional positioning and prevents contractures. – Spinal bracing (body jacket) may slow down scoliosis. – Augmentative communication with pictures, switches, or computer systems for nonverbal individuals – Therapeutic and functional electrical stimulation decreases activity limitation in gait. – Use of adaptive equipment such as crutches, walkers, gait trainers, and wheelchairs for mobility and standers for weight bearing

MEDICATION First Line • Diazepam (3)[A] – Short-term treatment for generalized spasticity; insufficient evidence on motor function – A γ-aminobutyric acid-A (GABAA) agonist that facilitates CNS inhibition at spinal and supraspinal levels to reduce spasticity – Adverse effects: ataxia and drowsiness – Adult dose: 2 to 12 mg/dose PO q6–12h – Pediatric dose (50% of cases, which may be – Acquired: prior trauma, spondylosis – Congenital: Klippel-Feil syndrome (congenital fusion of any 2 cervical vertebra)

GENERAL PREVENTION Seat belts, use of proper safety equipment, rule changes, and technique-coaching emphasis in sports activities can potentially prevent or minimize injury.

COMMONLY ASSOCIATED CONDITIONS Closed head injuries, whiplash-associated disorders (WAD), SCI, soft tissue trauma

DIAGNOSIS HISTORY Usually acute presentation with mechanism of cervical hyperextension (see “Etiology and Pathophysiology”) and complaints of neck pain, stiffness, or headaches ± neurologic symptoms

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PHYSICAL EXAM • External signs of trauma on the head and neck such as abrasions, lacerations, or contusions are clues to mechanism and associated injuries. • Presence, severity, and location of neck tenderness often helps localize involved structure(s): – Posterior midline, bony tenderness concerning for fracture – Paraspinal or lateral soft tissue tenderness suggests muscular/ligamentous injury. – Anterior tenderness concerning for vascular injury • Carotid bruit suggests carotid dissection. • Neurologic exam: Paresthesias, weakness suggests SCI or stroke secondary to BCVI: – CCS often presents as Distal > proximal symptom distribution, upper extremity > lower extremity Extremity weakness/paralysis predominates. Variable sensory changes below level of lesion (including paresthesias and dysesthesia) Bladder/bowel incontinence may occur.

DIFFERENTIAL DIAGNOSIS • Acute or chronic disc pathology (including herniation or internal disruption) • Osteoarthritis • Cervical radiculopathy • For CCS – Bell cruciate palsy – Bilateral brachial plexus injuries – Carotid or vertebral artery dissection

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Low-risk patients can be cleared clinically (without imaging) using either the Canadian C-spine Rule (CCR) or the National Emergency X-Ray Utilization Study (NEXUS) criteria (3)[B]: – CCR: Clinically clear a stable, adult patient with no history of cervical

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spine disease/surgery if all of the following conditions are met: Glasgow Coma Scale (GCS) ≥15 Nonintoxicated patients without a distracting injury No dangerous mechanism or extremity paresthesias Age 50 years, dens displacement >5 mm, and specific fracture patterns. Type III: Surgical intervention is often reserved for cases of nonunion/malunion after trial of external immobilization. • CCS: Surgical decompression/fixation is indicated in setting of unstable injury, herniated disc, or when neurologic function deteriorates. • BCVI: Surgical and/or angiographic intervention may be required if there is evidence of pseudoaneurysm, total occlusion, or transection of the vessel.

ADMISSION, INPATIENT, AND NURSING

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CONSIDERATIONS • Varies by injury; clinical judgment, imaging findings, concomitant injuries, and need for operative intervention • Advanced Trauma Life Support protocol with backboard and collar

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring Patients with known injuries will often be followed with serial imaging under the care of a specialist.

PATIENT EDUCATION For patient instruction on prevention: ThinkFirst Foundation: http://www.thinkfirst.org

PROGNOSIS • Presenting neurologic status is the most important. • Fractures – Hangman fracture: 93–100% fusion rate after 8 to 14 weeks external immobilization – Odontoid fracture, fusion rate by type: type I ~100% with external immobilization alone; type II nonunion rates of up to 67% with halo immobilization alone, especially with dens displacement >6 mm or age >50 years; type III, 85% with external immobilization, 100% with surgical fixation • BCVI: With early diagnosis and initiation of antithrombotic therapy, patients may have fewer neurologic sequelae. • CCS – Spontaneous recovery of motor function in >50% of cases over several weeks, with younger patients more likely to regain function – Leg, bowel, and bladder functions return first, followed by upper extremities. • WAD: Prognostic factors for development of late whiplash syndrome (>6

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months of symptoms affecting normal activity) include increased initial pain intensity, pain-related disability, and cold hyperalgesia.

COMPLICATIONS • Fractures: instability or malunion/nonunion necessitating second operation, reactions, and infection related to orthosis • BCVI: embolic ischemic events and pseudoaneurysm formation

REFERENCES 1. National Spinal Cord Injury Statistical Center. Spinal Cord Injury: Facts and Figures at a Glance. Birmingham, AL: National Spinal Cord Injury Statistical Center; 2016. 2. Walton DM, MacDermid JC, Giorgianni AA, et al. Risk factors for persistent problems following acute whiplash injury: update of a systematic review and meta-analysis. J Orthop Sports Phys Ther. 2013;43(2):31–43. 3. Stiell IG, Clement CM, McKnight RD, et al. The Canadian C-spine rule versus the NEXUS low-risk criteria in patients with trauma. N Engl J Med. 2003;349(26):2510–2518. 4. Jull G, Kenardy J, Hendrikz J, et al. Management of acute whiplash: a randomized controlled trial of multidisciplinary stratified treatments. Pain. 2013;154(9):1798–1806. 5. Bracken MB. Steroids for acute spinal cord injury. Cochrane Database Syst Rev. 2012;(1):CD001046.

ADDITIONAL READING • Franz RW, Willette PA, Wood MJ, et al. A systematic review and metaanalysis of diagnostic screening criteria for blunt cerebrovascular injuries. J Am Coll Surg. 2012;214(3):313–327. • Liu BC, Ivers R, Norton R, et al. Helmets for preventing injury in motorcycle riders. Cochrane Database Syst Rev. 2008;(1):CD004333. • Shears E, Armitstead CP. Surgical versus conservative management for odontoid fractures. Cochrane Database Syst Rev. 2008;(4):CD005078.

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CODES ICD10 • S13.4XXA Sprain of ligaments of cervical spine, initial encounter • S13.101A Dislocation of unspecified cervical vertebrae, init encntr • S14.109A Unsp injury at unsp level of cervical spinal cord, init

CLINICAL PEARLS • Follow NEXUS or Canadian Cervical Spine rules on every patient with potential neck injury to determine imaging needs, but they do not supercede clinical judgment! • Inquire about preexisting cervical spine conditions, especially in the elderly, as they may increase risk of injury or change radiographic interpretation. • Suspect SCI until exam and imaging suggest otherwise. • Consider BCVI when neurologic deficits are inconsistent with level of known injury or significant mechanism exists.

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CERVICAL MALIGNANCY Benjamin P. Brown, MD • Meaghan Tenney, MD • Jeremy Golding, MD, FAAFP BASICS DESCRIPTION • Invasive cancer of the uterine cervix • Commonly involves the vagina, parametria, and pelvic side walls • Invasion of bladder, rectum, and other pelvic sites in advanced disease

EPIDEMIOLOGY Incidence • In the United States, cervical cancer is the third most common gynecologic malignancy. • It is the second most common cancer among women in the developing world, with these patients representing >80% of reported cases. • The disease has a bimodal distribution, with the highest risk among women aged 40 to 59 years and >70 years.

Prevalence • In 2015, the American Cancer Society (ACS) estimated there were 12,900 new cases in the United States, with 4,100 deaths from the malignancy. • African Americans and women in lower socioeconomic groups have the highest cervical cancer death rates, likely reflecting lower screening as compared with higher socioeconomic groups. • Hispanic and Latina women have the highest incidence of the malignancy.

ETIOLOGY AND PATHOPHYSIOLOGY • Arises from preexisting dysplastic lesions, usually following persistent human papillomavirus (HPV) infection • May be exophytic or endophytic • Lymphatic spread • Local tumor extension involving the bladder, ureters, rectum, and distant

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metastasis from hematogenous spread (Halstedian growth) • Epidemiologic and experimental evidence supports HPV strains 16 and 18 as etiologic agents in ∼70% of cervical cancers. • Association with E6 and E7 oncogenic proteins responsible for malignant cell transformation by inactivation of p53 and Rb tumor suppressor genes • Slow progression from dysplasia to invasive cancer allows time for screening and treatment of preinvasive disease.

Genetics Not an inherited disease, except in very rare cases of Peutz-Jeghers syndrome

RISK FACTORS • Causative agent in the majority of cases is persistent HPV infection. • Other risk factors include the following: – Lack of regular Pap smears – Early coitarche – Multiple sexual partners – Unprotected sex – A history of sexually transmitted diseases (STDs) – Low socioeconomic status – High parity – Cigarette smoking – Immunosuppression – Diethylstilbestrol (DES) exposure in utero

GENERAL PREVENTION • Patient education regarding safer sex • Smoking cessation • HPV vaccines – Gardasil vaccines: quadrivalent and 9-valent options; FDA approved in females and in males (for prevention of genital warts and anal cancer) – Cervarix vaccine: bivalent vaccine against oncogenic HPV strains 16 and 18 – No vaccine yet conclusively shown to prevent cancer – Recommended age of vaccination is 11 to 12 years (prior to coitarche), but

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Gardasil is approved from 9 to 26 years and Cervarix from 10 to 25 years. Vaccine is much more effective prior to initial exposure to HPV. • Regular Pap smears and/or HPV screening at appropriate intervals. In patients with no history of abnormal Paps, current guidelines from the American College of Obstetricians and Gynecologists (ACOG) and the American Society for Colposcopy and Cervical Pathology (ASCCP) are as follows: – Cytology alone every 3 years between 21 and 30 years – Cytology plus HPV testing every 5 years after 30 years (1)[C] • The International Federation of Gynecology and Obstetrics (FIGO) recommends visual inspection with acetic acid (VIA) or Lugol’s iodine (VILI) as alternatives to Pap smears in resource-poor settings (2)[C]. • Despite HPV vaccination, cervical cancer screening will remain the main preventive measure for both vaccinated and nonvaccinated women.

COMMONLY ASSOCIATED CONDITIONS • Condyloma acuminata • Preinvasive/invasive lesions of the vulva and vagina

DIAGNOSIS HISTORY • May be asymptomatic • Most common symptom is vaginal bleeding, often postcoital. • Other gynecologic symptoms include intermenstrual or postmenopausal bleeding and vaginal discharge. • Other less common symptoms include low back pain with radiation down posterior leg, lower extremity edema, vesicovaginal and rectovaginal fistula, and urinary symptoms.

PHYSICAL EXAM • Disease is staged clinically, not surgically. • Thorough pelvic exam is essential: – Many patients have a normal exam, especially with microinvasive disease. – Lesions may be exophytic, endophytic, polypoid, papillary, ulcerative, or necrotic.

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– May have watery, purulent, or bloody discharge • Bimanual and rectovaginal examination for uterine size, vaginal wall, rectovaginal septum, parametrial, uterosacral, and pelvic sidewall involvement • Enlarged supraclavicular or inguinal lymphadenopathy, lower extremity edema, ascites, or decreased breath sounds with lung auscultation may indicate metastases or advanced stage disease.

DIFFERENTIAL DIAGNOSIS • Marked cervicitis and erosion • Glandular hyperplasia • Sexually transmitted infection • Cervical condyloma, leiomyoma, or polyp • Metastasis from endometrial carcinoma or gestational trophoblastic neoplasia

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Biopsy of gross lesions and colposcopically directed biopsies are the definitive means of diagnosis. • CBC may show anemia. • Urinalysis may show hematuria. • In advanced disease, BUN, creatinine, and liver function tests (LFTs) may be helpful. • CT scan of the chest, abdomen, and pelvis and/or a positron emission tomography (PET) scan • Apart from chest x-ray (CXR) and intravenous pyelogram (IVP), imaging does not alter tumor stage. • MRI may be helpful in evaluating parametrial involvement in patients who are surgical candidates or for radiation treatment planning. Follow-Up Tests & Special Considerations Prompt multidisciplinary plan of care • Exam under anesthesia may help in determining clinical stage and disease extent and determine if patient is a surgical candidate. • Endocervical curettage and cervical conization as indicated to determine depth of invasion and presence of lymphovascular involvement • Cystoscopy to evaluate bladder invasion

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• Proctoscopy for invasion into rectum

Test Interpretation • Majority of cases (80%) are invasive squamous cell types usually arising from the ectocervix. • Adenocarcinomas comprise 10–15% of cervical cancer arising from endocervical mucus-producing glandular cells. Often, no exophytic lesion but a “bulky” “barrel-shaped” cervix present on exam. • Other cell types that may be present include rare mixed cell types, neuroendocrine tumors, sarcomas, lymphomas, and melanomas.

TREATMENT GENERAL MEASURES Improve nutritional state, correct any anemia, and treat any vaginal and/or pelvic infections.

MEDICATION • Chemoradiation with cisplatin-containing regimen has superior survival rates over pelvic and extended-field radiation alone (3)[A]. • Neoadjuvant chemotherapy may improve survival for early and locally advanced tumors, but more data are needed (4)[A]. • Adjuvant chemotherapy after chemoradiation may improve progression-free survival in patients who receive primary chemoradiation for stages IIB–IVA tumors. The OUTBACK trial will further investigate these findings (http://www.clinicaltrials.gov). • The addition of bevacizumab to standard combination chemotherapy (cisplatin/topotecan or cisplatin/paclitaxel) for recurrent, persistent, or metastatic disease has been shown to improve overall survival (5)[A].

ISSUES FOR REFERRAL Multidisciplinary management of patients as needed and in a timely fashion

ADDITIONAL THERAPIES • Chemoradiation (without surgery) is the first-line therapy for tumors stage IIB

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and higher (gross lesions with obvious parametrial involvement) and for most bulky stage IB2 tumors (6)[A]. • Combination of external beam pelvic radiation and brachytherapy is usually employed. • If para-aortic lymph node metastases are suspected, extended-field radiation or lymph node dissection prior to radiation therapy may be performed.

SURGERY/OTHER PROCEDURES • Surgical management is an option for patients with early-stage tumors. • Removal of precursor lesions (cervical intraepithelial neoplasia [CIN]) by loop electrosurgical excision procedure (LEEP), cold knife conization, laser ablation, or cryotherapy • Stage IA1 (lesions with 3-mm but 10 colorectal adenomas should get genetic testing for APC and MUTYH (2)[C].

Test Interpretation • Tubular adenoma – Gross: tend to be polypoid – Micro: dysplastic epithelium with a tubular architecture • Villous adenoma: – Gross: tends to be sessile – Micro: dysplastic epithelium with fine fingerlike projections • Tubulovillous adenomas have a combination of tubular and villous architecture. • Hyperplastic polyps are composed of hyperplastic colonic mucosa. • Hamartomatous polyps include muscularis mucosa. • Juvenile polyp – Gross: pedunculated, smooth, red mass, 1 to 3 cm (3)

TREATMENT SURGERY/OTHER PROCEDURES • Colonic polypectomy; diagnostic, therapeutic: – Snare polypectomy with electrocautery for pedunculated polyps – Endoscopic mucosal resection for sessile polyps – Endoscopic submucosal dissection • Colorectal surgery; prophylactic in FAP and MAP and when there are numerous polyps or persistent bleeding (2,3)[C]: – Total colectomy ileorectal anastomosis – Proctocolectomy ileal pouch anal anastomosis • Chemoprevention: NSAIDs and calcium may reduce incidence and recurrence

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of polyps in patients with FAP and MAP (4)[A].

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Follow-up colonoscopy in: • 10 years if no polyps or distal small hyperplastic polyps ( whites

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Incidence • 5 million office visits annually • 100,000 hospitalizations

Prevalence • 16% of adults over 18 years, rising to 33% of adults over 60 years of age • 3% of physician visits in children relate to constipation.

ETIOLOGY AND PATHOPHYSIOLOGY • As food leaves the stomach, the ileocecal valve relaxes (gastroileal reflex) and chyme enters the colon (1 to 2 L/day) from the small intestine. In the colon, sodium is actively absorbed in exchange for potassium and bicarbonate. Water follows the osmotic gradient. Peristaltic contractions move chyme through the colon into the rectum. Chyme is converted into feces (200 to 250 mL). • Normal transit time is 4 hours to reach the cecum and 12 hours to reach the distal colon. • Defecation reflexively follows once stool reaches the rectal vault. This reflex can be inhibited by voluntarily contracting the external sphincter or facilitated by straining to contract the abdominal muscles while voluntarily relaxing the anal sphincter. Rectal distention initiates the defecation reflex. The urge to defecate occurs as rectal pressures increase. Distention of the stomach also initiates rectal contractions and a desire to defecate (gastrocolic reflex). • Primary and secondary defecation disorders result from delay in colonic transit, altered rectal motor activity, and structural or functional problems with pelvic floor muscles (including paradoxical contractions, diminished ability to relax sphincter, and/or poor propulsion).

Genetics Unknown but may be familial

RISK FACTORS • Very young and very old • Polypharmacy • Sedentary lifestyle or condition • Improper diet and inadequate fluid intake

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GENERAL PREVENTION High-fiber diet, adequate fluids, exercise, and training to “obey the urge” to defecate

COMMONLY ASSOCIATED CONDITIONS • General debilitation (disease or aging) • Dehydration • Hypothyroidism • Hypokalemia • Hypercalcemia • Nursing home resident

DIAGNOSIS ALERT Red flags: • New onset after age of 50 years • Hematochezia/melena • Unintentional weight loss • Family history of colon cancer • Anemia • Neurologic defects

HISTORY • Assess onset of symptoms, number of bowel movements per week, straining, completeness of evacuation, use of manual manipulation. • Identify red flags; evaluate diet, lifestyle, prescription and OTC medication use; identify reversible causes; ask about history of sexual abuse. • Bristol stool form scale, which classifies stool form into 7 categories of consistency ranging from separate hard lumps to liquid (2) • Bowel and diet diary helpful in measuring response to treatment. • Rome III criteria (3)[C]: – At least two of the following for 12 weeks in the previous 6 months: 25 mm Hg at rest – Absence of left heart failure (pulmonary capillary wedge pressure 1 in V1 – Right ventricular hypertrophy (R wave in V1 and V2 with S waves in V5 and V6) – Right atrial enlargement as evidenced by P pulmonale (increased amplitude of P wave in lead II) – Incomplete or complete right bundle branch block – S1S2S3 pattern or S1Q3T3 inverted pattern • Chest x-ray – Cardiomegaly

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– Enlargement of the central pulmonary arteries and reduced size of peripheral vessels (oligemia) – Reduced retrosternal space due to right ventricular enlargement on lateral views – Enlargement of the right atrium resulting in prominence of the right heart border – Evidence of COPD, ILD, and structural disease (i.e., kyphosis) – Evidence of PE (Westermark sign and Hampton hump) • Spiral CT scan of chest – Diagnosis of acute PE – Diagnosis of COPD and ILD • Ventilation/perfusion scan (V/Q) – High specificity and sensitivity for acute and chronic thromboembolic disease – May be used for diagnosis of acute thromboembolic disease if contraindication to chest spiral CT – May be preferred to chest spiral CT for diagnosis of chronic thromboembolic pulmonary disease, given higher sensitivity (can detect peripheral pulmonary emboli otherwise missed by spiral CT) – Diagnosis of chronic thromboembolic disease may warrant confirmation by pulmonary angiography. • Pulmonary angiography – Gold standard in diagnosis of chronic thromboembolic pulmonary disease • Polysomnography – Gold standard for diagnosis of OSA • Pulmonary function tests (PFTs) – Impaired diffusion capacity – Obstructive or restrictive ventilatory defects (ILD, structural abnormalities, and COPD)

TREATMENT Reduce symptoms and improve quality of life and survival. Reduce disease burden via oxygenation, preservation of cardiac function, and attenuation of

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pulmonary hypertension.

GENERAL MEASURES • Treat underlying disease (2)[A]. – For underlying pulmonary disease, bronchodilators and/or steroids may be beneficial. – For underlying chronic thromboembolic disease, anticoagulation may be indicated. • Supportive therapy as necessary – Continuous positive airway pressure/bilevel positive airway pressure may be used for hypoxia/sleep disorders. – Ventilation using positive-pressure masks, negative-pressure body suits, or mechanical ventilation is suggested for patients with neuromuscular disease. – Phlebotomy may be indicated for severe polycythemia (hematocrit >55%).

MEDICATION • Oxygen (3)[A] – Long-term continuous oxygen therapy improves the survival of hypoxemic patients with COPD and cor pulmonale. – All patients with pulmonary hypertension whose PaO2 is consistently 92 mm Hg. • Preservation of cardiac function (4)[B] – Inotropes: Dobutamine and milrinone may improve cardiac output; should be reserved for hemodynamically unstable patients – Diuretics: decrease RV filling pressures; also reduces peripheral edema secondary to RHF Excessive volume depletion should be avoided. Monitor closely for metabolic alkalosis, as this may suppress ventilatory drive and contribute to hypoxia. • Ameliorate pulmonary hypertension (1,4)[C] – Treatment of underlying disease is hallmark of management. – When refractory to traditional medical treatment, advanced therapies may be beneficial, although evidence is lacking.

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– For chronic thromboembolic associated pulmonary hypertension (WHO Group IV), riociguat and macitentan may be used.

ISSUES FOR REFERRAL Patients with cor pulmonale should be referred to a specialized center for expert consultation.

SURGERY/OTHER PROCEDURES • Endarterectomy for chronic thromboembolic disease (WHO Group IV) • Moderate to severe disease refractory to medication may require lung and/or heart transplantation.

ONGOING CARE DIET Salt and fluid restriction

PATIENT EDUCATION • Smoking cessation and avoidance of exposure to secondary smoke is strongly recommended. • Level of physical activity should be discussed with physician. • Pregnancy should be avoided.

PROGNOSIS • Patients with cor pulmonale resulting from COPD have a greater likelihood of dying than do similar patients with COPD alone. • Pulmonary arterial pressure is a reliable indicator of prognosis; higher pressure is associated with a worse prognosis. • In patients with COPD and mild disease (PAP 20 to 35 mm Hg), 5-year survival is 50%.

REFERENCES 1. Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology

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(ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2009:30(20):2493–2537. 2. McLaughlin VV, Archer SL, Badesch DB, et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension a report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents and the American Heart Association developed in collaboration with the American College of Chest Physicians; American Thoracic Society, Inc.; and the Pulmonary Hypertension Association. J Am Coll Cardiol. 2009;53(17):1573–1619. 3. Naeije R. Pulmonary hypertension and right heart failure in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2005;2(1):20–22. 4. Price LC, Wort SJ, Finney SJ, et al. Pulmonary vascular and right ventricular dysfunction in adult critical care: current and emerging options for management: a systematic literature review. Crit Care. 2010;14(5):R169.

SEE ALSO Chronic Obstructive Pulmonary Disease and Emphysema; Congestive Heart Failure: Differential Diagnosis; Pulmonary Arterial Hypertension; Pulmonary Embolism

CODES ICD10 • I27.81 Cor pulmonale (chronic) • I26.09 Other pulmonary embolism with acute cor pulmonale

CLINICAL PEARLS • Treatment of cor pulmonale requires treatment of the underlying disease. • Continuous, long-term oxygen therapy improves life expectancy and quality of life in cor pulmonale. • Referral of patients with cor pulmonale to a specialized center is strongly

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recommended.

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CORNEAL ABRASION AND ULCERATION Christie Racine, MD • Christine S. Persaud, MD BASICS DESCRIPTION • Corneal abrasions: result from cutting, scratching, or abrading the thin, protective, clear coat of the exposed anterior portion of the ocular epithelium. These injuries cause pain, tearing, photophobia, foreign body sensation, and a gritty feeling (1). • Corneal ulceration: break in the epithelial layer of the cornea leading to exposure of the underlying corneal stroma, which results in a corneal ulcer. The superficial ulcers limited to loss of the corneal epithelium are the most common form of ulceration (2). • Corneal abrasion and ulceration can both lead to impaired vision from scarring.

EPIDEMIOLOGY Incidence • Corneal abrasions commonly seen in primary care. Eye-related diagnoses make up 8% of total ER visits. Of those eye-related visits, 45% are corneal abrasions. Abrasions are the third leading cause of red eye, following conjunctivitis and subconjunctival hemorrhage (3). • Associated with significant morbidity and loss of productivity

ETIOLOGY AND PATHOPHYSIOLOGY • Corneal abrasions are most often caused by mechanical trauma but may also result from foreign bodies, contact lenses wear, or chemical and flash burns. • Corneal ulceration: Contact lenses use, HIV, trauma, ocular surface disease, and ocular surgery increase the incidence. Edema plays a major role in epithelial defect. Edema can lead trauma, ischemia, and increased intraocular pressure. Excessive fluid disrupts the normal architecture of the epithelial layer (4). • Causes of ulcerations include the following:

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– Infection with gram-positive organisms ~29–53% (Staphylococcus aureus and coagulase-negative Streptococcus are common ones) – Infection with gram-negative organisms ~47–50% (Pseudomonas being most common, followed by Serratia marcescens, Proteus mirabilis, and gram-negative enteric bacilli) • Increased risk of corneal ulceration in HIV and diabetes mellitus (DM) patients and immunocompromised

RISK FACTORS • History of trauma (direct blunt trauma, chemical burn, radiation exposure, etc.) • Contact lenses wear • Male gender • Age: 20 to 34 years old • Job (construction, manufacturing) • Lack of eye protection

GENERAL PREVENTION Protective eyewear during work (automechanics, metal workers, miners, etc.) and during sports

COMMONLY ASSOCIATED CONDITIONS • Vitamin A deficiency is associated with corneal ulcers. • Neuropathy of cranial nerve (CN) V • DM, thyroid dysfunction, immunocompromised disorders, connective tissue disease

DIAGNOSIS HISTORY Corneal abrasion is a clinical diagnosis. It includes a history of recent ocular trauma and acute pain. Other symptoms include photophobia, pain with extraocular muscle movement, excessive tearing, blepharospasm, foreign body sensation, gritty feeling, blurred vision, and headache.

PHYSICAL EXAM

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• Gross examination of the anatomy: eyelids, surface of the eye, pupils, and extraocular muscles • Snellen chart • Tonometry • Penlight • Blepharospasm: fluorescein stain • Wood lamp (5)

DIFFERENTIAL DIAGNOSIS • Corneal abrasion – Acute angle-closure glaucoma Conjunctivitis – Infective keratitis Uveitis Keratoconjunctivitis (5,6) • Corneal ulceration – Herpes zoster Herpes zoster ophthalmicus

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Ulcer culture • Pretreatment with topical antibiotics may alter culture results.

Diagnostic Procedures/Other • Slit lamp and fluorescein dye to identify and evaluate corneal abrasions • Document visual acuity

Test Interpretation Scraping culture/staining identifies bacteria, yeast, or intranuclear inclusions to help narrow diagnosis.

TREATMENT GENERAL MEASURES

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• Most complicated corneal abrasions heal in 24 to 48 hours • May not require follow up if lesion is >4 mm, uncomplicated abrasion, normal vision, and resolving symptoms • Patching not recommended – Does not reduce pay – Delays healing (4)[A]

MEDICATION • Treatment guidelines: pain control, infection prevention and daily symptom monitoring • Oral analgesic: narcotics, acetaminophen, NSAIDs • Topical anesthetics include proparacaine hydrochloride 0.1–0.5%, tetracaine hydrochloride 1% – Proparacaine may be less cytotoxic than tetracaine (4)[B]

First Line • Ophthalmic NSAIDs: Diclofenac 0.1% QID helps relieve moderate pain: – Alternatives include ketorolac 0.5% and bromfenac 0.09%. – Caution: Ophthalmic NSAIDs may rarely cause corneal melting and perforation. • Ophthalmic antibiotics may help prevent further infection and ulceration of corneal abrasions (7)[C]. • Some ophthalmic antibiotics include ciprofloxacin 0.3%, ofloxacin 0.3%, gentamicin 0.3%, erythromycin 0.5%, polymyxin B/trimethoprim (Polytrim), and tobramycin 0.3%. • Large corneal abrasions (>4 mm) or very painful abrasions should be treated with a combination of topical antibiotic and topical NSAID. • Fungal keratitis is treated with a protracted course of topical antifungal agents (by ophthalmologist). • A combination of cryotherapy and antifungal agents for treatment of fungal corneal ulcer could help facilitate the practice of fungal keratitis treatment in the future (8)[C]. • Herpetic keratitis should be referred promptly to ophthalmologist and treated initially with trifluridine: – Vidarabine and acyclovir are alternatives.

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ISSUES FOR REFERRAL • Indications for referral include: – Chemical burn – Evidence of corneal ulcer or infiltrate – Failure to heal after 3 to 4 days – Inability to remove a foreign body – Increase size of abrasion after 24 hours – Penetrating injury – Presence of hyphema (blood) or hypopyon (pus) – Rust ring – Vision loss of more than 20/40 • Worsening symptoms or improvement after 24 hours (5) – Immediate ophthalmology consultation for corneal ulceration for culture and initiation of treatment

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Most uncomplicated corneal abrasions heal in 24 to 48 hours. • Follow-up not necessary for small (4 mm, decreased vision, and abrasions due to contact lenses need follow-up within 24 hours (6)[C].

PATIENT EDUCATION Prevention of abrasions and proper handling of contact lenses can prevent recurrence of corneal ulcers.

PROGNOSIS • Corneal abrasions heal within 24 to 48 hours. • Ophthalmology consult with penetrating eye injury

COMPLICATIONS • Recurrence

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• Scarring of the cornea • Loss of vision

REFERENCES 1. Wilson SA, Last A. Management of corneal abrasion. Am Fam Physician. 2004;70(1):123–128. 2. Belknap EB. Corneal emergencies. Top Companion Anim Med. 2015;30(3):74–80. 3. Ahmed F, House RJ, Feldman BH. Corneal abrasions and corneal foreign bodies. Prim Care. 2015;42(3):363–375. 4. Malafa MM, Coleman JE, Bowman RW, et al. Perioperative corneal abrasion: updated guidelines for prevention and management. Plast Reconstr Surg. 2016;137(5):790e–798e. 5. Pflipsen M, Massaquoi M, Wolf S. Evaluation of the painful eye. Am Fam Physician. 2016;93(12):991–998. 6. Wipperman JL, Dorsch JN. Evaluation and management of corneal abrasions. Am Fam Physician. 2013;87(2):114–120. 7. Fraser S. Corneal abrasion. Clin Ophthalmol. 2010;4:387–390. 8. Chen Y, Yang W, Gao M, et al. Experimental study on cryotherapy for fungal corneal ulcer. BMC Ophthalmol. 2015;15:29.

CODES ICD10 • S05.00XA Inj conjunctiva and corneal abrasion w/o fb, unsp eye, init • H16.009 Unspecified corneal ulcer, unspecified eye • H16.049 Marginal corneal ulcer, unspecified eye

CLINICAL PEARLS • Contact lenses use should be discontinued until corneal abrasion or ulcer is healed and pain is fully resolved. • Eye patching is not recommended. • Prescribe topical and/or oral analgesic medication for symptom relief and

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consider ophthalmic antibiotics. • Prompt referral to an ophthalmologist should be made with suspicion of an ulcer, recurrence of abrasion, retained foreign body, viral keratitis, significant visual loss, or lack of improvement despite therapy.

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CORNS AND CALLUSES Neil J. Feldman, DPM, FACFAS BASICS DESCRIPTION • A callus (tyloma) is a diffuse area of hyperkeratosis, usually without a distinct border. – Typically, the result of exposure to repetitive forces, including friction and mechanical pressure; tend to occur on the palms of hands and soles of feet (1). • A corn (heloma) is a circumscribed hyperkeratotic lesion with a central conical core of keratin that causes pain and inflammation. The conical core in a corn is a thickening of the stratum corneum. • Hard corn or heloma durum (more common): more often on toe surfaces, especially 5th toe (proximal interphalangeal [PIP]) joint • Soft corn (heloma molle): commonly in the interdigital space (1) • Digital corns are also known as clavi. • Intractable plantar keratosis is usually located under a metatarsal head (1st and 5th most common), is typically more difficult to resolve, and often is resistant to usual conservative treatments.

EPIDEMIOLOGY Corns and calluses have the largest prevalence of all foot disorders.

Incidence Incidence of corns and calluses increases with age. Less common in pediatric patients. Women affected more often than men. Blacks report corns and calluses 30% more often than whites.

Prevalence • 9.2 million Americans • ~38/1,000 people affected

ETIOLOGY AND PATHOPHYSIOLOGY

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Increased activity of keratinocytes in superficial layer of skin leading to hyperkeratosis. This is a normal response to excess friction, pressure, or stress. • Calluses typically arise from repetitive friction, motion, or pressure to skin. • Soft corns arise from increased moisture from perspiration leading to skin maceration, along with mechanical irritation, especially between toes. • Hard corns are an extreme form of callus with a keratin-based core. Often found on the digital surfaces and commonly linked to bony protrusions, causing skin to rub against shoe surfaces.

Genetics No true genetic basis was identified because most corns and calluses are due to mechanical stressors on the foot/hands.

RISK FACTORS • Extrinsic factors producing pressure, friction, and local stress – Ill-fitting shoes – Not using socks, gloves – Manual labor – Walking barefoot – Activities that increase stress applied to skin of hands or feet (running, walking, sports) • Intrinsic factors – Bony prominences: bunions, hammertoes • Enlarged bursa or abnormal foot function/structure: hammertoe, claw toe, or mallet toe deformity

GENERAL PREVENTION External irritation is by far the most common cause of calluses and corns. General measures to reduce friction on the skin are recommended to reduce incidence of callus formation. Examples include wearing shoes that fit well and using socks and gloves.

Geriatric Considerations In elderly patients, especially those with neurologic or vascular compromise, skin breakdown from calluses/corns may lead to increased risk of infection/ulceration. 30% of foot ulcers in the elderly arise from eroded

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hyperkeratosis. Regular foot exams are emphasized for these patients as well as diabetic patients (2).

COMMONLY ASSOCIATED CONDITIONS • Foot ulcers, especially in diabetic patients or patients with neuropathy or vascular compromise • Infection: look for warning signs of: – Increasing size or redness – Puslike drainage – Increased pain/swelling – Fever – Change in color of fingers or toes • Signs of gangrene

DIAGNOSIS • Most commonly a clinical diagnosis based on visualization of the lesion • Examination of footwear may also provide clues.

HISTORY • Careful history can usually pinpoint cause. • Ask about neurologic and vascular history and diabetes. These may be risk factors for progression of corns/calluses to frank ulcerations and infection.

PHYSICAL EXAM • Calluses – Thickening of skin without distinct borders – Often on feet, hands; especially over palms of hands, soles of feet – Colors from white to gray-yellow, brown, red – May be painless or tender – May throb or burn • Corns – Hard corns: commonly on dorsum of toes or dorsum of 5th PIP joint Varied texture: dry, waxy, and transparent to a hornlike mass Distinct borders

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More common on feet Often painful – Soft corns Often between toes, especially between 4th and 5th digits at the base of the webspace Often yellowed, macerated appearance Often extremely painful

DIFFERENTIAL DIAGNOSIS • Plantar warts (typically a loss of skin lines within the wart), which are viral in nature • Porokeratoses (blocked sweat gland) • Underlying ulceration of skin, with or without infection (rule out especially with diabetic patients)

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Radiographs may be warranted if no external cause is found. Look for abnormalities in foot structure, bone spurs. • Use of metallic radiographic marker and weight-bearing films often highlight the relationship between the callus and bony prominence.

Diagnostic Procedures/Other Biopsy with microscopic evaluation in rare cases

Test Interpretation Abnormal accumulation of keratin in epidermis, stratum corneum

TREATMENT GENERAL MEASURES • Débridement of affected tissue and use of protective padding • Low-heeled shoes; soft upper with deep and wide toebox • Extra-width shoes for 5th-toe corns • Avoidance of activities that contribute to painful lesions

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• Prefabricated or custom orthotics

MEDICATION • Most therapy for corns and calluses can be done as self-care in the home (1). • Use bandages, soft foam padding, or silicone sleeve over the affected area to decrease friction on the skin and promote healing with digital clavi. • Use socks or gloves regularly. • Use lotion/moisturizers for dry calluses and corns. • Keratolytic agents, such as urea or ammonium lactate, can be applied safely. • Use sandpaper discs or pumice stones over hard, thickened areas of skin.

Geriatric Considerations Use of salicylic acid corn plasters can cause skin breakdown and ulceration in patients with thin, atrophic skin; diabetes; and those with vascular compromise. The skin surrounding the callus will often turn white and can become quite painful. Aggressive use of pumice stones can also lead to skin breakdown, especially surrounding the callus.

ISSUES FOR REFERRAL • May benefit from referral to podiatrist if use of topical agents and shoe changes are ineffective • Abnormalities in foot structure may require surgical treatment. • Diabetic, vascular, and neuropathic patients may benefit from referral to podiatrist for regular foot exams to prevent infection or ulceration.

SURGERY/OTHER PROCEDURES • Surgical treatment to areas of protruding bone where corns and calluses form • Rebalancing of foot pressure through functional foot orthotics • Shaving or cutting off hardened area of skin using a chisel or 15-blade scalpel. For corns, remove keratin core and place pad over area during healing.

COMPLEMENTARY & ALTERNATIVE MEDICINE • Many over-the-counter topical creams, ointments, and lotions are available for calluses (Kera brand, CalleX, Urea, Lac-Hydrin). Do not use on broken skin. • Warm water/Epsom salt soaks.

ADMISSION, INPATIENT, AND NURSING

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CONSIDERATIONS • Admission usually not necessary, unless progression to ulcerated lesion with signs of severe infection, gangrene • May require aggressive débridement in operating room should an abscess or deep space infection be suspected. Deep-space infections can develop where an abscess can penetrate into tendon sheaths and/or deep compartments within the foot or hand, potentially leading to rapid sepsis. Vascular status must be assessed and vascular referral considered. • Nursing: wound care, dressing changes for infected lesions

ONGOING CARE PATIENT EDUCATION • General information: http://www.mayoclinic.org/diseases-conditions/cornsand-calluses/basics/definition/con-20014462 • American Podiatric Medical Association: http://www.apma.org

PROGNOSIS Complete cure is possible once factors causing pressure or injury are eliminated.

COMPLICATIONS Ulceration, infection

REFERENCES 1. Freeman DB. Corns and calluses resulting from mechanical hyperkeratosis. Am Fam Physician. 2002;65(11):2277–2280. 2. Pinzur MS, Slovenkai MP, Trepman E, et al. Guidelines for diabetic foot care: recommendations endorsed by the Diabetes Committee of the American Orthopaedic Foot and Ankle Society. Foot Ankle Int. 2005;26(1):113–119.

ADDITIONAL READING Theodosat A. Skin diseases of the lower extremities in the elderly. Dermatol Clin. 2004;22(1):13–21.

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CODES ICD10 L84 Corns and callosities

CLINICAL PEARLS Most therapy for corns and calluses can be done as self-care in the home using padding over the affected area to decrease friction or pressure. However, if simple home care is not helpful, then removal of the lesions is often immediately curative.

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CORONARY ARTERY DISEASE AND STABLE ANGINA Melody L. Strattan, DO • Merrill Krolick, DO, FACC, FACP, FSCAI BASICS DESCRIPTION • Coronary artery disease (CAD) refers to the atherosclerotic narrowing of the epicardial coronary arteries. It may manifest insidiously as angina pectoris or as an acute coronary syndrome (ACS). • Stable angina is a chest discomfort due to myocardial ischemia that occurs predictably at a certain level of exertion or emotional stress. • The spectrum of ACS includes unstable angina (UA), non–ST elevation myocardial infarction (NSTEMI), and ST elevation myocardial infarction (STEMI). See separate chapters on these ACS. • Definitions – Typical angina: exhibits three classical characteristics: (i) substernal chest tightness, pressure, or heaviness that frequently radiates to the jaw, back, or arms and generally lasts from 2 to 15 minutes; (ii) occurs in a consistent pattern at a certain level of myocardial oxygen demand from exertion, emotional stress, or increased sympathetic tone; and (iii) relieved with rest or sublingual nitroglycerin – Atypical angina: exhibits two of the above typical characteristics – Noncardiac chest pain: exhibits ≤1 of the above typical characteristics – Anginal equivalent: Patients may present without chest discomfort but with nonspecific symptoms such as dyspnea, diaphoresis, fatigue, belching, nausea, light-headedness, or indigestion that occur with exertion or stress. – UA: anginal symptoms that are new or changed in character to become more frequent, more severe, or both; it is considered an ACS but does not present with cardiac biomarker elevation. – NSTEMI: presents with cardiac biomarker elevation. Ischemic ECG

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changes may be present, but there is no ST segment elevation. – STEMI: defined by ST elevations on ECG and elevated cardiac biomarkers; generally caused by acute plaque rupture and complete obstruction of the culprit vessel • Canadian Cardiovascular Society grading scale: – Class I: Angina does not limit ordinary physical activity, occurring only with strenuous or prolonged exertion (7 to 8 metabolic equivalents [METs]). – Class II: Angina causes slight limitation of ordinary activity. It occurs when walking rapidly, uphill, or >2 blocks; climbing >1 flight of stairs; or with emotional stress (5 to 6 METs). – Class III: Angina causes marked limitation of ordinary physical activity. It occurs when walking one to two blocks or climbing one flight of stairs (3 to 4 METs). – Class IV: Angina occurs with any physical activity and may occur at rest (1 to 2 METs).

Geriatric Considerations • Elderly may present with atypical symptoms. • Other physical limitations may delay recognition of angina until it occurs with minimal exertion or at rest. • Maintain a high degree of suspicion during evaluation of dyspnea and other nonspecific complaints. • Geriatric patients may be very sensitive to the side effects of medications used to treat angina.

EPIDEMIOLOGY • CAD is the leading cause of death for adults both in the United States and worldwide. • CAD is responsible for about 30% of all deaths, averaging 1 death every 40 seconds in the United States alone. • Global cost of CAD in 2010 was $863 billion. • ~80% of CAD is preventable with a healthy lifestyle.

Incidence

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In the United States, the lifetime risk of a 40-year-old developing CAD is 49% for men and 32% for women.

Prevalence In the United States, 17.6 million people carry a diagnosis of CAD, while 10.2 million have angina pectoris (1).

ETIOLOGY AND PATHOPHYSIOLOGY • Anginal symptoms occur during times of myocardial ischemia caused by a mismatch between coronary perfusion and myocardial oxygen demand. • Atherosclerotic narrowing of the coronary arteries is the most common etiology of angina, but it may also occur in those with significant aortic stenosis, pulmonary hypertension, hypertrophic cardiomyopathy, coronary spasm, or volume overload. • Sensory nerves from the heart enter the spinal cord at levels C7–T4, causing diffuse referred pain/discomfort in the associated dermatomes.

RISK FACTORS • Traditional risk factors: hypertension, ↓ HDL, ↑ low- LDL, smoking, diabetes, premature CAD in first-degree relatives (men 55 for women). • Nontraditional risk factors: obesity, sedentary lifestyle, chronic inflammation, abnormal ankle-brachial indices, renal disease

GENERAL PREVENTION • Smoking cessation • Regular aerobic exercise program • Weight loss for obese patients (goal BMI male • No correlation between development of adverse reaction and patient’s age, diagnosis, or survival. • Special consideration in the geriatric population who are on multiple medications: increased likelihood of severe cutaneous and systemic reactions; also consider in the pediatric group: difficult to distinguish from viral exanthems

Incidence In the United States, prevalence of 2–3% in hospitalized patients; estimated 1/1,000 hospitalized patients has had a severe cutaneous reaction.

ETIOLOGY AND PATHOPHYSIOLOGY • Predictable adverse reactions are due to overdose, side effect, or drug interaction. • Unpredictable reactions include intolerance, drug idiosyncrasy secondary to

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abnormality in metabolism, or immune reaction. >700 drugs are known to cause a dermatologic reaction: – Immunologically mediated reaction: immunoglobulin (Ig) E–mediated reaction (type I hypersensitivity), cytotoxic/IgG/IgM induced (type II), immune complex reactions (type III), and delayed-type hypersensitivity (type IV) with T cells, eosinophils, neutrophils, and monocytes – Acneiform: OCPs, corticosteroids, iodinated compounds, hydantoins, lithium – Erythema multiforme/Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN): >100 drugs reported. Most common include sulfonamides, cephalosporins NSAIDs, barbiturates, hydantoins, anticonvulsants tetracycline, terbinafine. – Fixed drug eruptions: NSAIDS, sulfonamides, tetracycline, barbiturates, salicylates, OCPs – Lichenoid: thiazides, NSAIDs, gold, ACE inhibitors, proton pump inhibitors, antimalarials, sildenafil – Photosensitivity: doxycycline, thiazides, sulfonylureas, quinolones, sulfonamides, NSAIDs – Hypersensitivity vasculitis: hydralazine, penicillins, cephalosporins, thiazides, gold, sulfonamides, NSAIDs, propylthiouracil – Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome: anticonvulsants, sulfonamides, dapsone, minocycline, allopurinol – Acute generalized exanthematous pustulosis (AGEP): penicillins, cephalosporins, macrolides, calcium channel blockers, antimalarials, carbamazepine, acetaminophen, terbinafine, nystatin, vancomycin – Sweet syndrome (acute febrile neutrophilic dermatosis): sulfa drugs, granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), diazepam, minocycline, nitrofurantoin, captopril, penicillamine – Serum sickness-like reaction: cephalosporins, penicillins, TMP-SMX, propranolol, bupropion, minocycline – Morbilliform/urticarial/exfoliative erythroderma: numerous medications, including penicillins, cephalosporins, sulfonamides, tetracyclines, ibuprofen, naproxen, allopurinol, acetylsalicylic acid, radiocontrast media

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(1)[A]

Genetics Genetics may play a role, as certain HLA antigens have been associated with increased predisposition to specific drug eruptions: • HLA-B*5801 , HLA-B*5701, and HLA-B*1502 have been linked to allopurinol-induced and carbamazepine- induced SJS/TEN, respectively. • HLA class I antigens, such as HLA-A2, HLA-B12 , and HLA-B22 , have been linked to TEN and fixed drug eruptions, respectively.

RISK FACTORS Previous drug reaction, multiple medications, concurrent infections, immunocompromised, disorders of metabolism, and certain genetic HLA haplotypes

GENERAL PREVENTION Always ask patients about prior adverse drug events. Be aware of medications with higher incidence of reactions as well as drug cross-reactions.

DIAGNOSIS HISTORY • New medications within the preceding 6 weeks, most commonly within preceding 2 weeks: all oral, parenteral, and topical agents, including over the counter drugs, vitamins, and herbal remedies • Consider other etiologies: bacterial infections, viral exanthems, or underlying skin disease including cutaneous lymphoma

PHYSICAL EXAM May present as a number of different eruption types, including, but not limited to the following: • Morbilliform eruptions (exanthems) – Most frequent cutaneous reaction (75–95%); difficult to distinguish from viral exanthem; often secondary to antibiotic – Starts on trunk as pruritic red macules and papules and extends to extremities in confluent fashion, sparing face, palms, soles, and mucous

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membranes – Onset 7 to 21 days after drug initiation (2)[C]. • Urticaria – Pruritic erythematous wheals distributed anywhere on the body, including mucous membranes; may progress to angioedema, appears as nonpitting edema without erythema or margins – Individual lesions fade within 24 hours, but new lesions may develop (2). • Acneiform eruptions – Folliculocentric, monomorphous pustules typically involving the face, chest, and back distinguished from acne vulgaris by absence of gross and/or microscopic comedones – Often may become secondarily infected (2)[C] • Fixed drug eruptions – Single/multiple, round, sharply demarcated, violaceous plaques with gray center that may leave postinflammatory hyperpigmentation; occur on skin or mucous membrane – Appear shortly after drug exposure and recur in identical location after reexposure; some patients have a refractory period during which the drug fails to activate lesions. – Onset usually is 48 hours after ingestion of drug (2). • AGEP – Multiple nonfollicular sterile pustules on erythematous background with desquamation after 7 to 10 days – Involves intertriginous areas but can be generalized and involve the face – Appears similar to pustular psoriasis, but AGEP has fever and marked leukocytosis with neutrophilia and/or eosinophilia (2)[C] • DRESS syndrome – Classic triad of fever, exanthem, and internal organ involvement with possible pharyngitis and lymphadenopathy – Can lead to exfoliative dermatitis, often accompanied by facial edema – Internal organ involvement: 80% hepatic, 40% renal, 33% pulmonary, and cardiac lab tests show elevated liver transaminases and eosinophilia. – Onset 2 to 8 weeks after drug exposure; may develop 3 months or later into therapy (3)[B].

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• Erythema multiforme – Relatively common, acute, often recurrent – Most commonly associated with herpes simplex virus and other viral/bacterial etiologies (i.e., mycoplasma); less likely secondary to drug exposure. 50% with unknown etiology – Three-zone target lesions and raised atypical two-zone targets with localized erythema – Lesions predominant on distal extremities including on acral surface with limited mucosal involvement; 1,500 mutations exist that can cause varying severity of phenotypic CF, all of which are recessively inherited. Most common is loss of the phenylalanine residue at 508th position (deltaF508), which accounts for 8.7% of affected alleles in the CF population in the United States. G551D mutation accounts for 4.3% of affected alleles.

RISK FACTORS • CF is a single-gene disorder. The severity of the phenotype can be affected by the specific CFTR mutation (most predictive of pancreatic disease), other modifier genes (CFTM1 for meconium ileus), gastroesophageal reflux disease (GERD), severe respiratory virus infection, and environmental factors such as tobacco smoke exposure. • Preconception counseling – American Congress of Obstetricians and Gynecologists (ACOG) recommends preconception or early (1st/2nd trimester) genetic analysis for all North American couples planning a pregnancy, with appropriate counseling to identified carriers and genetic analysis of siblings of known CF patients. – Universal newborn screening (NBS) has been integral in early diagnosis (64% of new CF diagnosis in 2014 were found by NBS). Patients diagnosed prior to onset of symptoms have better lung function and nutritional outcomes and should receive referral and early intervention services by an accredited regional CF center.

Pregnancy Considerations • Pulmonary disease may worsen during pregnancy. • CF may cause increased incidence of preterm delivery, IUGR, and cesarean

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section (2)[A]. • Advances in fertility treatments now allow men with CF to father children (1) [A].

DIAGNOSIS HISTORY • Suspect with failure to thrive, steatorrhea, and recurrent respiratory problems. – Chronic/recurrent respiratory symptoms, including airway obstruction and infections – Persistent infiltrates on chest x-rays (CXRs) – Hypochloremic metabolic acidosis • Hx during neonatal period – Meconium ileus (20%) (generally considered pathognomonic for CF) – Prolonged jaundice • Hx during infancy – Failure to thrive – Chronic diarrhea – Anasarca/hypoproteinemia – Pseudotumor cerebri (vitamin A deficiency) – Hemolytic anemia (vitamin E deficiency) • Hx during childhood – Recurrent endobronchial infection – Bronchiectasis – Chronic pansinusitis – Steatorrhea – Poor growth – Distal intestinal obstruction syndrome (DIOS) – Allergic bronchopulmonary aspergillosis (ABPA) • Hx for adolescence and adulthood (7% diagnosed >18 years old) (3)[A] – Recurrent endobronchial infection – Bronchiectasis – ABPA – Chronic sinusitis

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– Hemoptysis – Pancreatitis – Portal hypertension – Azoospermia – Delayed puberty

PHYSICAL EXAM • Respiratory – Rhonchi and/or crackles – Hyperresonance on percussion – Nasal polyps • GI: hepatosplenomegaly when cirrhosis present • Other: digital clubbing, growth retardation, and pubertal delay

COMMONLY ASSOCIATED CONDITIONS • CF-related diabetes (CFRD) – May present as steady decline in weight, lung function, or increased frequency of exacerbation – Leading comorbid complication (20.7%) – Result of progressive insulin deficiency – Early screening and treatment may improve reduced survival found in CFRD (4)[A]. • Upper respiratory – Rhinosinusitis is seen in up to 100% of patients with CF. – Nasal polyps are seen in up to 86% of patients. • The GI tract – Pancreatic exocrine insufficiency (85–90%) (5)[A] – Malabsorption of fat, protein, and fat-soluble vitamins (A, D, E, and K) – Hepatobiliary disease (12.6%) – Focal biliary cirrhosis – Cholelithiasis – Meconium ileus at birth (10–15%) (5)[A] – DIOS: intestinal blockage that typically occurs in older children and adults (5.3%) (1)[A] – GERD (32.7%) (1)[A]

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• Endocrine – Bone mineral disease (16.6%) (1)[A] – Joint disease (3.0%) (1)[A] – Hypogonadism – Frequent low testosterone levels in men – Menstrual irregularities are common. • Reproductive organs – Congenital bilateral absence of the vas deferens: obstructive azoospermia in 98% of males • Depression (12.8%) (1)[A]

DIFFERENTIAL DIAGNOSIS • Immunologic – Severe combined immunodeficiency • Pulmonary – Difficult-to-manage asthma – COPD – Recurrent pneumonia – Chronic/recurrent sinusitis – Primary ciliary dyskinesia • Gastrointestinal – Celiac disease – Protein-losing enteropathy – Pancreatitis of unknown etiology – Shwachman-Diamond syndrome

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • NBS tests blood levels of immunoreactive trypsin (IRT) (1)[A]. • Patients must have clinical symptoms of CF involving at least one organ system. • Sweat test (gold standard) – Sweat chloride >60 mmol/L (on 2 occasions) is (+) for CF. 90% of mutations; finite chance of false-negative finding. Fullsequence testing is more costly and time-consuming. – Nasal potential difference (when sweat test and DNA testing inconclusive) – CXR Follow-Up Tests & Special Considerations To further investigate the presence of CF-related complications, these tests are generally ordered: • Sputum culture (common CF organisms) • Pulmonary function tests (PFTs) • 72-hour fecal fat, stool elastase • Oral glucose tolerance test (OGTT) annually after age 10 years • Head CT: Abnormal sinus CT findings are nearly universal in CF and may include mucosal thickening, intraluminal sinus polyps, and sinus effusions. • Chest CT (not routine): useful when unusual findings noted on CXR

Diagnostic Procedures/Other • Flexible bronchoscopy • Bronchoalveolar lavage

TREATMENT GENERAL MEASURES • CF Foundation Guidelines call for yearly evaluation: – 4 office visits, 4 respiratory cultures, PFTs q6mo, and at least 1 evaluation by a multidisciplinary team including dietitian, GI, and social worker – PFT goals: >75% predicted for adults, >100% predicted for children 6 years with total serum IgE concentration – Annual influenza vaccination for all CF patients age >6 months – Screen all adults for osteoporosis with a DXA scan. – Annual measurement of fat soluble vitamins to r/o vitamin deficiencies

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– Annual LFTs – Decrease exposure to tobacco smoke. • All patients should be followed in a CF center (accredited sites are listed at www.cff.org). • Infant care: – Monthly visits for first 6 months of life and then every 2 months until 1 year of life – Fecal elastase testing and salt supplementation after diagnosis – Consider palivizumab for RSV prophylaxis in infants with CF 50%) (1)[A]. • Inhaled steroids are not recommended for chronic use in the absence of asthma or ABPA. • Insufficient evidence to recommend for or against chronic use: inhaled βagonist, inhaled anticholinergics, leukotriene modifiers, inhaled colistin – Pancreatic enzymes (87.3%) (1)[A] Often combined with H2 blocker or PPI to increase effectiveness – Fat-soluble vitamin supplementation (A, D, E, and K) – Liver disease (cholestasis) Ursodeoxycholic acid has not been proven effective.

ADDITIONAL THERAPIES • High-frequency chest wall oscillation vest is the most widely used airway clearance technique. • Aerobic exercise is used as an adjunct therapy for airway clearance (8)[A]. – CF-related bone disease: Consider bisphosphonate therapy.

SURGERY/OTHER PROCEDURES • Timing for lung transplantation (bilateral) is polyfactorial (9)[A]. • 5-year posttransplant survival is up to 62%. • Liver transplantation is reserved for progressive liver failure ± portal hypertension with GI bleeding. • Nasal polypectomy in 4.5% of CF patients (1)[A]

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • CF exacerbations should always be admitted on contact precautions and private rooms.

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• Pulmonary exacerbation (most common reason for admission) • Bowel obstruction (due to DIOS, previously known as meconium ileus equivalent [MIE]) • Pancreatitis (in pancreatic-sufficient patients) • Nasal cannula oxygen when the patient is hypoxemic (SaO2 40 years, the incidence is 1.4/1,000 person-years compared with 0.6/1,000 person-years for those younger than 20 years. • Women have an incidence rate ratio of 2.8/1,000 person-years compared with 0.6/1,000 person-years in men. • The incidence ratio rate of de Quervain tenosynovitis is 1.3/1,000 personyears in blacks and 0.8/1,000 person-years in whites.

ETIOLOGY AND PATHOPHYSIOLOGY • Repetitive motions of the wrist and/or thumb result in microtrauma and thickening of the tendons (EPB, APL) and surrounding tendon sheath • EPB and APL movement is resisted as they glide over the radial styloid causing pain with movements of the thumb and wrist.

RISK FACTORS • Women age 30 to 50 years

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• Pregnancy (primarily 3rd trimester and postpartum) • African American • Systemic diseases (e.g., rheumatoid arthritis) • Participation in activities that include repetitive motion or forceful grasping with thumb and wrist deviation such as golf, fly fishing, racquet sports, rowing, or bicycling • Repetitive movements with the hand/thumb requiring forceful grasping with wrist involving ulnar/radial deviation; dental hygienists, musicians, carpenters, assembly workers, and machine operators

GENERAL PREVENTION Avoid overuse or repetitive movements of the wrist and/or thumb associated with forceful grasping and ulnar/radial deviation.

DIAGNOSIS HISTORY • Repetitive motion activity; overuse of wrist or thumb • Gradually worsening pain along the radial aspect of the thumb and wrist with certain movements, particularly ulnar deviation of the wrist • Pregnancy • Sports, leisure, and occupational history • Trauma (rare)

PHYSICAL EXAM • Pain over the radial styloid exacerbated when patients move the thumb or make a fist. • Crepitus with movement of the thumb • Swelling over the radial styloid and base of the thumb • Decreased range of motion of the thumb • Pain over the 1st dorsal compartment on resisted thumb abduction or extension • Tenderness may extend proximally or distally along the tendons with palpation or stress. • Finkelstein test: The examiner grasps the affected thumb and deviates the

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hand sharply in the ulnar direction. A positive test occurs when there is pain along the distal radius. • Eickhoff test: Patient grasps a flexed thumb and the examiner deviates the wrist in an ulnar direction. • Finkelstein test is more sensitive for determining tenosynovitis of the APL and EPB tendons (2)[A].

DIFFERENTIAL DIAGNOSIS • Scaphoid fracture • Scapholunate ligament tear • Dorsal wrist ganglion • Osteoarthritis of the 1st carpometacarpal joint • Flexor carpi radialis tendonitis • Infectious tenosynovitis • Tendonitis of the wrist extensors • Intersection syndrome • Trigger thumb

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Primarily a clinical diagnosis. Radiographs of the wrist to rule out other pathology, such as carpometacarpal (CMC) arthritis, if the diagnosis is in question. • MRI is the imaging test of choice to rule out coexisting soft tissue injury or wrist joint pathology. Follow-Up Tests & Special Considerations Ultrasound can help to detect anatomic variations in the 1st dorsal extensor compartment of the wrist and target corticosteroid injections (3),(4)[C],(5)[B].

Test Interpretation Inflamed and thickened retinacular sheath of the tendon

TREATMENT • Most cases of de Quervain syndrome are self-limited.

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• Rest and NSAIDs (2)[A] • Ice (15 to 20 minutes 5 to 6 times a day) • Immobilization with a thumb spica splint (2)[A] • Occupational therapy (6)[A] • Corticosteroid injection (ultrasound guided) (7)[A] • Consider surgery if conservative measures fail >6 months.

GENERAL MEASURES • If full relief is not achieved, a corticosteroid injection of the tendon sheath can improve symptoms. • Anatomic variation, including two tendon sheaths in the 1st compartment or the EPB tendon traveling in a separate compartment may complicate treatment. Ultrasound can distinguish these variants and improve anatomic accuracy of injections (3),(8)[B],(9,10). • Surgical release may be indicated after 3 to 6 months of conservative treatment if symptoms persist. Surgery is highly effective and has a relatively low rate of complications.

MEDICATION First Line Splinting, rest, and NSAIDs

Second Line • Corticosteroid injection of the tendon sheath has shown significant cure rates. An 83% success rate after single injection has been reported. Additional injections are sometimes required (7)[A]. • Corticosteroid injection plus immobilization is more effective than immobilization alone (5)[B]. • Addition of hyaluronic acid to the corticosteroid injection improves outcome and reduces recurrence (11)[B]. • A 4-point injection technique may be preferred to 1- and 2-point injection techniques in high-resistance training athletes (12)[B]. • Percutaneous tenotomy and/or injection of platelet-rich plasma are newer techniques that show promise for treatment of de Quervain tenosynovitis.

ISSUES FOR REFERRAL

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Referral to a hand surgeon is indicated if there is no improvement with conservative therapy.

ADDITIONAL THERAPIES • Hand therapy, along with iontophoresis/phonophoresis, may help improve outcomes in persistent cases. • Patients may use thumb-stretching exercises as part of their rehabilitation.

SURGERY/OTHER PROCEDURES • Indicated for patients who have failed conservative treatment • Endoscopic release may provide earlier relief, fewer superficial radial nerve complications, and greater patient satisfaction with resultant scar compared to open release (5)[B].

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS Hospitalization for care associated with surgical treatment

ONGOING CARE FOLLOW-UP RECOMMENDATIONS • Additional corticosteroid injection may be performed at 4 to 6 weeks if symptoms persist. Caution with repeat steroid injections. • Avoid repetitive motions and activities that cause pain.

DIET As tolerated

PATIENT EDUCATION Activity modification: Avoid repetitive movement of the wrist/thumb and forceful grasping.

PROGNOSIS Extremely good with conservative treatment. Complete resolution can take up to 1 year. 95% success rates have been shown with conservative therapy over 1 year. Up to 1/3 of patients will have recurrence (7)[A].

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COMPLICATIONS • Most complications are secondary to treatment. This includes GI, renal, and hepatic injury secondary to NSAID use. • Nerve damage may occur during surgery (13)[B]. • Hypopigmentation, fat atrophy, bleeding, infection, and tendon rupture have been reported as potential adverse events from corticosteroid injection. Ultrasound guidance reduces the rate of complications (14)[B]. • If not appropriately treated, thumb flexibility may be lost due to fibrosis.

REFERENCES 1. Wolf JM, Sturdivant RX, Owens BD. Incidence of de Quervain’s tenosynovitis in a young, active population. J Hand Surg Am. 2009;34(1):112–115. 2. Huisstede BM, Coert JH, Fridén J, et al. Consensus on a multidisciplinary treatment guideline for de Quervain disease: results from the European HANDGUIDE study. Phys Ther. 2014;94(8):1095–1110. 3. Lee KH, Kang CN, Lee BG, et al. Ultrasonographic evaluation of the first extensor compartment of the wrist in de Quervain’s disease. J Orthop Sci. 2014;19(1):49–54. 4. Di Sante L, Martino M, Manganiello I, et al. Ultrasound-guided corticosteroid injection for the treatment of de Quervain’s tenosynovitis. Am J Phys Med Rehabil. 2013;92(7):637–638. 5. Kang HJ, Koh IH, Jang JW, et al. Endoscopic versus open release in patients with de Quervain’s tenosynovitis: a randomised trial. Bone Joint J. 2013;95B(7):947–951. 6. Goel R, Abzug JM. de Quervain’s tenosynovitis: a review of the rehabilitative options. Hand (N Y). 2015;10(1):1–5. 7. Ashraf MO, Devadoss VG. Systematic review and meta-analysis on steroid injection therapy for de Quervain’s tenosynovitis in adults. Eur J Orthop Surg Traumatol. 2014;24(2):149–157. 8. Kume K, Amano K, Yamada S, et al. In de Quervain’s with a separate EPB compartment, ultrasound-guided steroid injection is more effective than a clinical injection technique: a prospective open-label study. J Hand Surg Eur

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Vol. 2012;37(6):523–527. 9. Kwon BC, Choi SJ, Koh SH, et al. Sonographic identification of the intracompartmental septum in de Quervain’s disease. Clin Orthop Relat Res. 2010;468(8):2129–2134. 10. Rousset P, Vuillemin-Bodaghi V, Laredo JD, et al. Anatomic variations in the first extensor compartment of the wrist: accuracy of US. Radiology. 2010;257(2):427–433. 11. Orlandi D, Corazza A, Fabbro E, et al. Ultrasound-guided percutaneous injection to treat de Quervain’s disease using three different techniques: a randomized controlled trial. Eur Radiol. 2015;25(5):1512–1519. 12. Pagonis T, Ditsios K, Toli P, et al. Improved corticosteroid treatment of recalcitrant de Quervain tenosynovitis with a novel 4-point injection technique. Am J Sports Med. 2011;39(2):398–403. 13. Scheller A, Schuh R, Hönle W, et al. Long-term results of surgical release of de Quervain’s stenosing tenosynovitis. Int Orthop. 2009;33(5):1301–1303. 14. Jeyapalan K, Choudhary S. Ultrasound-guided injection of triamcinolone and bupivacaine in the management of de Quervain’s disease. Skeletal Radiol. 2009;38(11):1099–1103.

ADDITIONAL READING • Choi SJ, Ahn JH, Lee YJ, et al. De Quervain disease: US identification of anatomic variations in the first extensor compartment with an emphasis on subcompartmentalization. Radiology. 2011;260(2):480–486. • Peters-Veluthamaningal C, van der Windt DA, Winters JC, et al. Corticosteroid injection for de Quervain’s tenosynovitis. Cochrane Database Syst Rev. 2009;(3):CD005616.

SEE ALSO Algorithm: Pain in Upper Extremity

CODES

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ICD10 M65.4 Radial styloid tenosynovitis [de Quervain]

CLINICAL PEARLS • Repetitive movements of the wrist and thumb, and activities that require forceful grasping are the most common causes of de Quervain tenosynovitis. • Initial treatment is typically conservative. • Corticosteroid injections are helpful and have lower complication rates if done under ultrasound guidance. • Surgery is helpful for recalcitrant cases.

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DEEP VEIN THROMBOPHLEBITIS Patricia Martinez Quinones, MD • Keith O’Malley, MD, FACS BASICS DESCRIPTION • Development of blood clot within the deep veins, usually accompanied by inflammation of the vessel wall. Symptoms may be nonspecific or absent. • Major clinical consequences are embolization (usually to the lung), recurrent thrombosis, and postphlebitic syndrome. • System(s) affected: cardiovascular

EPIDEMIOLOGY • Age- and gender-adjusted incidence of venous thromboembolism (VTE) is 100 times higher in the hospital than in the community. Almost half of all VTEs occur either during or soon after discharge from a hospital stay or surgery. • Of patients with VTE, 20% complicated with pulmonary embolism (PE). The 28-day deep venous thrombosis (DVT) fatality rate is 5.4%; at 1 year, 20%; at 3 years, 29%.

Incidence • In the United States, VTE occurs for the first time in 80/100,000 persons/year. • Higher incidence with increasing age and in Caucasian and African American populations • Lower extremity DVT is most common thrombosis. • Complicates ~1/1,000 pregnancies

Prevalence Variable; depends on medical condition or procedure • At time of DVT diagnosis, as many as 40% of patients also have silent PE; conversely, 30% of patients diagnosed with PE do not have demonstrable source.

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• 25% of patients with superficial venous thrombosis (1)[B] • Present in 11% of patients with acquired brain injury entering to neurorehabilitation

ETIOLOGY AND PATHOPHYSIOLOGY Factors involved may include venous stasis, endothelial injury, and abnormalities of coagulation (Virchow triad).

Genetics • Factor V Leiden is found in 5% of the population and in 10–65% of all VTE events. It is the most common thrombophilia; increases VTE risk 3- to 6-fold • Prothrombin 20210A is found in 3% of Caucasians; increases the risk of thrombosis ∼3-fold

RISK FACTORS • Acquired: previous DVT, age >75, cancer, immobilization, obesity, major surgery, orthopedic surgery, medications (oral contraceptives, estrogens), antiphospholipid syndrome, cerebrovascular accident, acute infectious process, thrombocytosis, pregnancy/puerperium, central venous catheters • Inherited: deficiencies of protein C, protein S, or antithrombin III; factor V Leiden R506Q, prothrombin G20210A, dysfibrinogenemia • Mixed/unknown: hyperhomocysteinemia, high levels of factor VIII, high levels of thrombin activatable fibrinolysis inhibitor (TAFI), high levels of factor XI

GENERAL PREVENTION • Mechanical thromboprophylaxis is recommended in patients with high bleeding risk and as adjunct to anticoagulant-based thromboprophylaxis. • Compression stocking use not recommended for postthrombotic syndrome (PTS) prevention (2)[B]. • Risk stratification of hospitalized patients using standardized scores is recommended (i.e., Caprini score). • For acutely ill and for critically ill hospitalized patients at increased risk of thrombosis, low-molecular-weight heparin [LMWH], low-dose unfractionated heparin [LDUH], or fondaparinux are recommended (3)[C]. • Rivaroxaban and apixaban are approved in United States for surgical DVT

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prevention. • For most patients, prolonged secondary prophylaxis is not recommended.

DIAGNOSIS Modified Wells criteria (validated clinical prediction rules) • Active cancer (+1 point). Calf swelling >3 (+1 point). Collateral superficial veins (+1 point). Pitting edema (+1 point). Previous documented DVT (+1 point). Swelling of entire leg (+1 point). Localized tenderness along deep venous system (+1 point). Paralysis, paresis, or recent cast immobilization of lower extremities (+1 point). Recently bedridden >3 days or major surgery in past 4 weeks (+1 point). Alternative diagnosis at least as likely (−2 points) – Interpretation: Score 0 to 1 DVT unlikely. Score ≥2: moderate to high probability

HISTORY • Establish pretest probability based on Wells criteria. • Classify as “provoked” or “idiopathic” based on underlying risk factors. • Clinical assessment of bleeding risk: bleeding with previous history of anticoagulation, history of liver disease, recent interventions, history of GI bleed

PHYSICAL EXAM • Physical exam is only 30% accurate for DVT. • Resistance to dorsiflexion of the foot (Homan sign) is unreliable, nonspecific. • Edema is most specific symptom. Swelling of collateral veins • Massive edema with cyanosis is a medical emergency (phlegmasia cerulea dolens, rare). • Skin discoloration of extremity • Thoracic outlet maneuvers in upper extremity DVT • Attention to signs of possible malignancy

DIFFERENTIAL DIAGNOSIS Cellulitis, fracture, ruptured synovial cyst (Baker cyst), lymphedema, muscle strain/tear, extrinsic compression of vein (e.g., by tumor/enlarged lymph nodes),

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compartment syndrome, localized allergic reaction

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • D-dimer (sensitive but not specific; has a high negative predictive value [NPV], useful in patients with low test probability of DVT or PE) • Patients with a prior DVT and those with malignancy have a high rate of VTE, which decreases the NPV of Wells prediction rule (4). • CBC, platelet count, activated partial thromboplastin time (aPTT), prothrombin time (PT)/INR • In young patients, those of concern or with idiopathic/recurrent VTE, consider thrombophilia testing (factor V Leiden mutation, prothrombin G20210A genetic assay, ATIII functional assay, protein C functional assay, protein S antigen and functional assay and free S, phospholipid-dependent tests and anticardiolipin antibodies, lupus anticoagulant (drawn before heparin). • Diagnostic imaging required in patients with high pretest probability (Wells criteria). • Compression ultrasound (CUS): first-line imaging for DVT due to noninvasive nature and ease of use; sensitive and specific for popliteal, femoral thrombi if experienced user; recommended in patients with intermediate or high pretest probability • Contrast venography: gold standard, technically difficult requiring pedal vein cannulation, risk of morbidity • Impedance plethysmography: sensitive and specific for proximal vein thrombosis but not for calf vein thrombi • MR venography: as accurate as contrast venography; may be useful for patients with contraindications to IV contrast • 125I-fibrinogen scan: detects only active clot formation; very good at detecting ongoing calf thrombi; takes 4 hours for results • In patients with suspected DVT, the choice of diagnostic test process should be guided by the assessment of the pretest probability. – Low pretest probability: high-sensitivity D-dimer assay sufficient to exclude DVT if negative. If positive, follow with CUS. – Moderate to high pretest probability: CUS initial test; if positive, CUS then

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treat DVT. If negative, DVT is excluded but consider repeat CUS in 1 week. Follow-Up Tests & Special Considerations Risk of an underlying malignancy is more likely if recurrent VTE, risk 3.2 (95% CI 2.0–4.8). Unprovoked VTE, 4.6 times higher (vs. secondary); upper extremity DVT, not catheter associated; odds ratio (OR) 1.8, abdominal DVT; OR 2.2, (5) bilateral lower extremity DVT, OR 2.1 (5)

TREATMENT MEDICATION Consider starting therapy even before confirmation in patients with high pretest probability. • Anticoagulation is mainstay of therapy. Patients with PE or proximal DVT, long-term therapy (3 months) is recommended.

First Line • Unfractionated heparin (UFH) prevents extension of the thrombus; used for admitted patients – IV drip: initial dose of 80 U/kg followed by continuous infusion of 18 U/kg/hr. Target an aPTT ratio >1.5× control. Monitor aPTT every 6 hours and adjust infusion rate accordingly, until 2 successive values are within therapeutic range. • LMWH: Enoxaparin (Lovenox): 1 mg/kg/dose SC q12h or 1.5 mg/kg/dose OD • Dalteparin (Fragmin): 200 U/kg SC q24h • Fondaparinux (Arixtra): 5 mg (body weight 100 kg) SC once daily • Rivaroxaban (Xarelto): 15 mg PO twice daily with food for the first 3 weeks. • Apixaban (Eliquis): 10 mg PO twice daily for 1 week followed by 2.5 to 5 mg PO twice daily • 2016 CHEST guidelines recommend using dabigatran, rivaroxaban, apixaban, or edoxaban instead of vitamin K antagonists for the first 3 months’ treatment in patients with lower extremity or PE and no cancer.

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• Maintenance therapy – Warfarin (Coumadin): 5 mg/day for 3 days and then adjust to a target INR of 2 to 3; overlap with parenteral anticoagulant for minimum of 5 days until therapeutic INR sustained ≥24 hours. – Rivaroxaban (Xarelto): 20 mg PO once daily with food after the first 3 weeks – Apixaban (Eliquis): 2.5 to 5 mg PO twice daily after the first 1 week – Dabigatran (Pradaxa): 150 mg PO twice daily (CrCl >30 mL/min) after 5 to 10 days of parenteral anticoagulant – Edoxaban (Savaysa): 60 mg PO once daily following 5 to 10 days of initial therapy with a parenteral anticoagulant (30 mg if CrCl 15 to 50 mL/min or ≤60 kg) • Adverse effects – Heparin or LMWH: bleeding, edema, injection site irritation, skin eruptions, hematoma, thrombocytopenia – Fondaparinux: bleeding, injection site irritation, rash, fever, anemia – Warfarin: bleeding, skin necrosis, teratogenicity – Rivaroxaban: bleeding, anemia, rash, increase in transaminases – Dabigatran: bleeding, rash, edema – Edoxaban: bleeding, rash, anemia • Contraindications – Heparin or LMWH: bleeding, heparin hypersensitivity, heparin-induced thrombocytopenia (HIT), idiopathic thrombocytopenic purpura (ITP) – Fondaparinux: bleeding, thrombocytopenia – Warfarin: current bleeding, alcoholism, preeclampsia, pregnancy, surgery

Second Line Heparin can be given by intermittent SC self-injection.

Pregnancy Considerations • Warfarin (Coumadin) is a teratogen; treat with full-dose heparin initially, followed by SC heparin starting at 15,000 U q12h. • Warfarin is safe with breastfeeding. • LMWH, dalteparin, fondaparinux, apixaban are pregnancy Category B. • Dabigatran, edoxaban are pregnancy Category C.

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ADDITIONAL THERAPIES Edoxaban (recently FDA approved) after initial treatment with heparin is as effective as warfarin in preventing recurrences in patients with acute VTE and has less bleeding complications (6)[B].

SURGERY/OTHER PROCEDURES • In selected patients with proximal DVT (acute iliofemoral DVT, good functional status, >1 year of life expectancy), may consider catheter-directed thrombolysis/open thrombectomy • IVC filter use is discouraged in anticoagulated patients.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Admission for respiratory distress, proximal VTE, candidate for thrombolysis, active bleeding, renal failure, phlegmasia cerulea dolens, history of HIT • Limb elevation and multilayered compression • Medically stable and properly anticoagulated; overlap of anticoagulation and warfarin monitoring may be done as an outpatient.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS • Gradual resumption of normal activity, with avoidance of prolonged immobility • Duration of warfarin treatment after DVT – 3 months for treatment of a DVT secondary to a reversible risk factor – Patients with unprovoked DVT can be considered for prolonged secondary prophylaxis. In patients who have completed 3 months of anticoagulation after an unprovoked VTE, a positive D-dimer 1 month after discontinuation of therapy correlates with the risk of VTE recurrence (7)[A].

Patient Monitoring • Monitor platelet count while on heparin, LMWH, fondaparinux for HIT. • An anti-Xa activity level may help guide LMWH titration of therapy but is not

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usually needed. • Investigate significant bleeding (e.g., hematuria or GI hemorrhage) because anticoagulant therapy may unmask a preexisting lesion (e.g., cancer, peptic ulcer disease, or arteriovenous malformation).

PATIENT EDUCATION • A trial of compression stockings post-DVT may be recommended if symptoms of PTS. • Dietary habits should be discussed when warfarin is initiated to ensure that intake of vitamin K–rich foods is monitored.

PROGNOSIS • 20% of untreated proximal (e.g., above the calf) DVTs progress to pulmonary emboli, and 10–20% of those are fatal; with anticoagulant therapy, mortality is decreased 5- to 10-fold. • DVT confined to the infrapopliteal veins has a small risk of embolization but can propagate into the proximal system. • Up to 75% of patients with symptomatic DVT present with PTS after 5 to 10 years.

COMPLICATIONS PE (fatal in 10–20%), arterial embolism (paradoxical embolization) with arteriovenous (AV) shunting, chronic venous insufficiency, postphlebitic syndrome (pain and swelling in affected limb without new clot formation), treatment-induced hemorrhage, soft tissue ischemia associated with massive clot and high venous pressures; phlegmasia cerulea dolens (rare but a surgical emergency)

REFERENCES 1. Decousus H, Quéré I, Presles E, et al. Superficial venous thrombosis and venous thromboembolism: a large, prospective epidemiologic study. Ann Intern Med. 2010;152(4):218–224. 2. Kahn S, Shapiro S, Wells P, et al. Compression stockings to prevent postthrombotic syndrome: a randomized placebo-controlled trial. Lancet. 2014;383(9920):880–888.

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3. Holbrook A, Schulman S, Witt DM, et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(Suppl 2):e152S–e184S. 4. Geersing GJ, Zuithoff NP, Kearon C, et al. Exclusion of deep vein thrombosis using the Wells rule in clinically important subgroups: individual patient data meta-analysis. BMJ. 2014;348:g1340. 5. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest. 2016; 149(2):315–352. 6. Büller HR, Décousus H, Grosso MA, et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013:369(15):1406–1415. 7. Palareti G, Cosmi B, Legnani C, et al. D-dimer testing to determine the duration of anticoagulation therapy. N Engl J Med. 2006;355(17):1780–1789.

ADDITIONAL READING • Agnelli G, Büller HR, Cohen A, et al. Oral apixaban for the treatment of acute venous thromboembolism. N Eng J Med. 2013;369(9):799–808. • Bauersachs R, Berkowitz SD, Brenner B, et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Eng J Med. 2010;363(26):2499– 2510. • Kyrle PA, Rosendaal FR, Eichinger S. Risk assessment for recurrent venous thrombosis. Lancet. 2010;376(9757):2032–2039. • Lyman GH, Khorana A, Kuderer N, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013;31(17):2189–2204. • Prins MH, Lensing AW, Bauersachs R, et al. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J. 2013;11(1):21. • Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342–2352.

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SEE ALSO Antithrombin Deficiency; Factor V Leiden; Protein C Deficiency; Protein S Deficiency; Prothrombin 20210 (Mutation); Pulmonary Embolism

CODES ICD10 • I80.209 Phlbts and thombophlb of unsp deep vessels of unsp low extrm • I80.299 Phlebitis and thombophlb of deep vessels of unsp low extrm • I80.10 Phlebitis and thrombophlebitis of unspecified femoral vein

CLINICAL PEARLS • Many cases are asymptomatic and are diagnosed after pulmonary embolization. • Of the patients with superficial thrombophlebitis, 25% will have DVT at presentation. • Parenteral anticoagulant and warfarin should overlap for a minimum of 5 days until target INR is achieved and then discontinue parenteral therapy. • The current American Society of Clinical Oncology guidelines acknowledge the value of primary prophylaxis in selected patients with active cancer receiving outpatient chemotherapy.

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DEHYDRATION Jerin Mathew, MD • Mony Fraer, MD, FACP, FASN BASICS DESCRIPTION • Dehydration is a state of negative fluid balance; strictly defined as free water deficiency • The two types of dehydration: – Water loss – Salt and water loss (combination of dehydration and hypovolemia)

EPIDEMIOLOGY • Cause of 10% of all pediatric hospitalizations in the United States • Gastroenteritis, one of its leading causes, accounts to 13/1,000 children 12 hours in a child, diarrhea has lasted >2 days in an adult/child, or an infant/child is much less active than usual or is very irritable.

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• Patient information on dehydration: http://www.mayoclinic.org/diseasesconditions/dehydration/basics/definition/con-20030056

PROGNOSIS Self-limited if treated early; potentially fatal

COMPLICATIONS • Seizures • Renal failure • Cardiovascular arrest

REFERENCES 1. Thomas DR, Cote TR, Lawhorne L, et al. Understanding clinical dehydration and its treatment. J Am Med Dir Assoc. 2008;9(5):292–301. 2. Gorelick MH, Shaw KN, Murphy KO. Validity and reliability of clinical signs in the diagnosis of dehydration in children. Pediatrics. 1997;99(5):E6. 3. Steiner MJ, DeWalt DA, Byerley JS. Is this child dehydrated? JAMA. 2004;291(22):2746–2754. 4. Lanier JB, Mote MB, Clay EC. Evaluation and management of orthostatic hypotension. Am Fam Physician. 2011;84(5):527–536. 5. Rouhani S, Meloney L, Ahn R, et al. Alternative rehydration methods: a systematic review and lessons for resource-limited care. Pediatrics. 2011;127(3):e748–e757. 6. Colletti JE, Brown KM, Sharieff GQ, et al. The management of children with gastroenteritis and dehydration in the emergency department. J Emerg Med. 2010;38(5):686–698. 7. Carter B, Fedorowicz Z. Antiemetic treatment for acute gastroenteritis in children: an updated Cochrane systematic review with meta-analysis and mixed treatment comparison in a Bayesian framework. BMJ Open. 2012;2(4):e000622. 8. Lopez JH, Reyes-Ortiz CA. Subcutaneous hydration by hypodermoclysis. Rev Clin Gerontol. 2010;20(2):105–113.

SEE ALSO

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Oral Rehydration

CODES ICD10 • E86.0 Dehydration • E87.1 Hypo-osmolality and hyponatremia • E86.1 Hypovolemia

CLINICAL PEARLS • Dehydration is the result of a negative fluid balance and is a common cause of hospitalization in both children and the elderly. • Begin by assessing the level of dehydration and determining the underlying cause. • Treatment is directed at restoring fluid balance via oral rehydration (first-line) therapy or IV fluids and treating underlying causes.

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DELAYED SLEEP-WAKE PHASE DISORDER (DSWPD) Adam J. Sorscher, MD BASICS DESCRIPTION • Circadian rhythm sleep disorders (CRSDs) are a family of conditions that occur when an individual’s preferred timing of sleep is not synchronized to commitments to job, school, family, or social engagements. In CRSDs, intrinsic sleep is normal (i.e., there is no sleep fragmenting condition such as obstructive sleep apnea or periodic limb movement disorder). However, when forced by obligations to attempt sleep at nonpreferred times, individuals with CRSDs may complain of both sleep-initiation insomnia and excessive sleepiness in their wake time. These symptoms resolve entirely if the individual is allowed to sleep at his or her preferred time. • Delayed sleep-wake phase disorder (DSWPD) is marked by a stable but persistent inability to initiate sleep at a desired time. Individuals are typically unable to initiate sleep until 2 to 6 hours later than societal norms (typically after 2 AM), and this frequently results in insufficient sleep/sleepiness in the day that follows.

EPIDEMIOLOGY DSWPD is the most common circadian rhythm disorder seen by referral in sleep medicine clinics.

Prevalence DSWPD has an estimated prevalence of 0.1–0.2% in the general population. It is most common in adolescents, with a prevalence of 7–16%.

ETIOLOGY AND PATHOPHYSIOLOGY In all mammals, an oscillating signal from the suprachiasmatic nucleus (SCN) in the anterior hypothalamus establishes circadian rhythms, including the propensity to be awake or asleep. The average period of this signal in humans is

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24.2 hours, slightly longer than the environmental day. Certain factors, most significantly morning light, shift the timing of the circadian rhythm and thereby synchronize it to the shorter environmental cycle day by day. DSWPD occurs when the circadian rhythm is not adequately synchronized to the shorter 24-hour environmental cycle, creating a mismatch between them. Some theories to account for inadequate synchronization are that it occurs in individuals who have an abnormally long circadian period (>25 hours) or whose circadian clock does not properly respond to synchronizing agents such as light (1). • Release of melatonin from the pineal gland in the evening initiates a cascade of events that usually triggers sleep behavior several hours later. Studies suggest that the timing of melatonin release within the circadian cycle is delayed by 40 to 120 minutes in late adolescence compared with prepuberty. This suggests that the tendency for teenagers to delay sleep onset is largely a genetically programmed developmental phenomenon. • DSWPD is the result of biologic, behavioral, and psychosocial factors. The relative contributions of genetically predetermined endogenous factors (the shifting of the circadian phase just described) versus voluntary behaviors that delay bedtime are not fully delineated.

Genetics Emerging evidence indicates a genetic component to DSWPD—a positive family history is reported in approximately 40% of individuals. In one familial case report, DSWPD was shown to occur in an autosomal dominant inheritance pattern. Polymorphisms in circadian rhythm genes such as hPer3 and clock among individuals with DSWPD constitute evidence of a genetic component to the disorder (2).

RISK FACTORS DSWPD primarily affects adolescents and young adults—a cohort who have a biologic tendency to delay the onset of sleep yet often need to be up early for school/work responsibilities. Children with autism spectrum disorders also frequently have disturbed circadian rhythm cycles.

GENERAL PREVENTION In DSWPD (and all CRSDs), careful attention to sleep hygiene is necessary to

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establish and maintain a desired sleep schedule. The most important behavioral practices needed to prevent an undesirably late fall-asleep time are as follows: • Maintain a regular sleep/wake schedule 7 days/week. • Avoid daytime napping. • Minimize caffeine and stimulants. • Avoid stimulating activities in the late evening, such as computer, TV, and social interactions. A 30-minute “wind-down” time prior to bedtime in which homework, socializing, and electronic devices are off-limits is helpful. • If computer screens are to be used in the evening, consider “apps” that filter out blue and green wavelengths because these frequencies are especially potent at further delaying the onset of sleep. • Attempt to arise at a similar time on weekends as on school/work mornings— adolescents who sleep ad lib on the weekends (sometimes into the afternoon) often find that they have especially great difficulty initiating sleep on Sunday night and, thus, get the week off to a bad start.

DIAGNOSIS HISTORY • People with DSWPD report both sleep initiation insomnia and excessive sleepiness in the daytime. They do not initiate sleep until 2 to 6 hours later than normative sleep times and they struggle to awaken for school/work in the morning. • Careful questioning should explore for competing/comorbid causes of insomnia (poor sleep hygiene, significant mental health disorders, restless legs syndrome, medical conditions/medication side effects, and substance abuse disorders) and for competing/comorbid causes of hypersomnolence (symptoms of narcolepsy and obstructive sleep apnea, voluntary insufficient sleep, medical conditions/medication side effects, and substance abuse disorders). • In contrast to DSWPD, individuals with psychophysiologic insomnia (psychologically conditioned arousal when attempting to initiate sleep) do not usually experience genuine hypersomnolence in the daytime despite short sleep times overnight, but instead complain of fatigue.

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• People with DSWPD will have no complaint about sleep/wakefulness and their sleep will be of normal duration when they are able to sleep at their preferred time (e.g., their sleep/wakefulness complaints resolve when on summer vacation from school, when they can choose their own preferred sleep-wake schedule).

PHYSICAL EXAM Explore for features of sleep apnea, a competing cause of hypersomnolence: obesity/large neck circumference; hypertension; crowded oropharynx

DIFFERENTIAL DIAGNOSIS DSWPD and other CRSDs are unique in that they are often marked by the twin complaints of insomnia when attempting to sleep and hypersomnolence in the wake period. Other sleep disorders usually cause either insomnia or hypersomnolence but not both. DSWPD and other CRSDs resolve entirely if the individual is allowed to sleep at his or her preferred time.

DIAGNOSTIC TESTS & INTERPRETATION • Diagnosis of DSWPD is made primarily by thorough history taking. • Sleep logs completed over 3 weeks time graphically reveal fall-asleep times that are consistently 2 to 6 hours later than societal norms and much later wake-up times (not infrequently in the afternoon) on days off from school/work (3)[B]. • Wrist actigraphy (using a wristwatch-like device with an accelerometer), undertaken for 3 weeks, also provides an accurate display of sleep and wake timing but is usually not reimbursable by insurance and is not needed if the individual can complete sleep logs (3)[B]. • Testing in the sleep lab is not indicated unless a suspicion exists of comorbid intrinsic disorders of sleep, such as sleep apnea, narcolepsy, or parasomnias (unusual behaviors arising out of sleep) (3)[A].

TREATMENT • The goal of treatment in DSWPD is to help the individual consistently initiate sleep at an earlier time. The principal therapies that advance sleep onset are

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light and melatonin (factors that shift the circadian rhythm are called zeitgebers). Comparatively, light is much more potent than melatonin in its phase-shifting ability. The phase-shifting effects of light and melatonin depend on the timing at which they are provided as depicted in the phaseresponse curve (see online version). Key points: Light will advance sleep onset to an earlier time if provided after the body’s temperature nadir that occurs ~2/3 through the habitual sleep phase and for several hours thereafter. Proper timing is critical because exposure to light in the evening or before the temperature nadir (i.e., in the initial 2/3 of the sleep period) will have the opposite effect—it will further delay sleep onset. For melatonin, the most potent phase-advancing effect occurs if it is provided in the evening, 4 to 6 hours before an individual’s usual sleep onset time. • Use the following rules to guide prescribing of light in order to advance sleep phase (3)[B]: – No single rule exists for intensity, duration, or wavelength for light therapy. Most protocols employ a 2,500 to 10,000 lux full-spectrum light box, set 2 to 3 feet from the individual for 30 to 120 minutes. A common prescription is 10,000 lux box for 30 minutes upon awakening in the morning. Retailers of full-spectrum light boxes abound on the Internet. Sunlight, when present in the morning in warm-weather seasons, is equally effective. – Prescribe exposure to full-spectrum light immediately upon awakening. (Note: Although the phase-advancing effect of light is actually greatest if it is provided immediately after the body temperature nadir that occurs ~2/3 through the sleep period, the strategy of waiting until the habitual waking time is preferred for these reasons: [i] it acknowledges that it is onerous for the individual to wake up artificially early for light therapy and [ii] it minimizes the risk of unintentionally providing light before the temperature nadir, which further delays the sleep phase.) – Light exposure in the evening has the effect of delaying sleep phase and worsening DSWPD. Instruct individuals to limit light exposure in the evening (consider using sunglasses or curtailing outdoors activities in warm-weather months). – Contraindications to phototherapy include retinopathy, photosensitivity, and bipolar disorder.

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MEDICATION • Prescribe melatonin to be taken 4 to 6 hours before the habitual (usual) fallasleep time, not at bedtime. Melatonin in minute doses is as effective as higher doses in producing phase-shift; therefore, use the lowest dose available —usually 1 or 3 mg (3)[B]. • Once earlier sleep onset and wake-up occurs, adjust the timing of therapies every 3 to 5 days—continue to use light directly upon awakening; provide melatonin earlier and earlier in the evening corresponding to 4 to 6 hours before the newly observed fall-asleep time.

ALERT Melatonin has a weak sedating effect, and individuals should be counseled not to drive/operate dangerous machines after taking the medication. Other side effects include headache and unusual taste in mouth.

ISSUES FOR REFERRAL • Referral for evaluation and testing at a sleep clinic is not necessary in most cases of DSWPD. The chief indications for referral are suspicion of the following comorbid disorders: – Obstructive sleep apnea: indicated by loud snoring, obesity/large neck, witnessed apneas, and history of hypertension – Narcolepsy: indicated by severe levels of daytime sleepiness, despite adequate sleep quantity, and sometimes accompanied by cataplexy (bouts of sudden muscular weakness triggered by strong emotions) – Parasomnias: undesirable experiential/behavioral phenomena that arise out of sleep, such as dangerous sleepwalking or dream-enactment behavior • In addition, many individuals with the complaint of insomnia/sleepiness have comorbid mental health disorders, primarily depression and possibly substance abuse. Referral for mental health disorders/substance abuse treatment is indicated if these are present.

ADDITIONAL THERAPIES • Chronotherapy is an older strategy in which the individual is instructed to delay sleep and wake times by 2 to 3 hours every 2 to 3 days, shifting the sleep cycle across the 24-hour day, until the individual reaches a desired

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bedtime. Carried out over several weeks, this protocol is extremely disruptive to daytime schedules and also has not been demonstrated to be effective. It is seldom used (4)[C]. • Some early reports suggest that vitamin B12 has circadian phase-shifting properties. This finding has not been confirmed in subsequent investigations, and presently, no evidence of benefit to the use of this supplement in CRSDs (3)[B]. • Use of sedative-hypnotic medications to treat the insomnia component and stimulant medications to treat daytime sleepiness has not been shown to be effective in the context of DSWPD (3)[C]. • In terms of public policy, systematic reviews have shown that high schools that shift their start times to 8:30 AM or later witness significantly increased overnight total sleep times obtained by students, improved academic performance, decreased tardiness, and few car crashes in teen drivers. Therefore, arrangements to begin work or school later in the morning is another potential therapy for DSWPD (5)[A].

ONGOING CARE Remind patients to practice healthy sleep behaviors (see “General Prevention”) if they wish to maintain an earlier sleep/wake pattern.

PATIENT EDUCATION American Academy of Family Physicians: http://www.aafp.org/afp/1999/0401/p1918.html

REFERENCES 1. Wyatt JK, Stepanski EJ, Kirkby J. Circadian phase in delayed sleep phase syndrome: predictors and temporal stability across multiple assessments. Sleep. 2006;29(8):1075–1080. 2. Ebisawa T, Uchiyama M, Kajimura N, et al. Association of structural polymorphisms in the human period3 gene with delayed sleep phase syndrome. EMBO Rep. 2001;2(4):342–346.

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3. Morgenthaler TI, Lee-Chiong T, Alessi C, et al. Practice parameters for the clinical evaluation and treatment of circadian rhythm sleep disorders. An American Academy of Sleep Medicine report. Sleep. 2007;30(11):1445– 1459. 4. Sack RL, Auckley D, Auger RR, et al. Circadian rhythm sleep disorders: part II, advanced sleep phase disorder, delayed sleep phase disorder, free-running disorder, and irregular sleep-wake rhythm. An American Academy of Sleep Medicine review. Sleep. 2007;30(11):1484–1501. 5. Wahlstrom K, Dretzke B, Gordon M, et al. Examining the Impact of Later School Start Times on the Health and Academic Performance of High School Students: A Multi-Site Study. St Paul, MN: Center for Applied Research and Educational Improvement; 2014.

ADDITIONAL READING • Barion A, Zee PC. A clinical approach to circadian rhythm sleep disorders. Sleep Med. 2007;8(6):566–577. • Kanathur N, Harrington J, Lee-Chiong T Jr. Circadian rhythm sleep disorders. Clin Chest Med. 2010;31(2):319–325. • Kripke DF, Rex KM, Ancoli-Israel S, et al. Delayed sleep phase cases and controls. J Circadian Rhythms. 2008;6:6. • Wilson SJ, Nutt DJ, Alford C, et al. British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders. J Psychopharmacol. 2010;24(11):1577–1601.

CODES ICD10 G47.21 Circadian rhythm sleep disorder, delayed sleep phase type

CLINICAL PEARLS • The tendency to become “night-owlish” with adolescence is, to a large extent, a biologically programmed phenomenon, not strictly a behavioral choice.

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Enlightened public policy would recognize this and allow for later start times for high schools. • DSWPD can be diagnosed with careful history taking and sleep logs; referral for formal sleep studies is usually not indicated. • Use of light and melatonin can shift habitual sleep onset and offset time by their action on the human circadian rhythm. • To maintain a desirable sleep phase, individuals with DSWPD usually need to maintain meticulous attention to sleep hygiene, including a regular sleep/wake schedule 7 days/week, to avoid lapsing into a delayed phase pattern.

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DELIRIUM Whitney A. Gray, CRNP, MSN • Katrina A. Booth, MD BASICS DESCRIPTION • A neurologic complication of illness and/or medication(s), especially common in older patients, manifested by new confusion and impaired attention • A medical emergency requiring immediate evaluation to decrease morbidity and mortality • System(s) affected: neurologic • Synonym(s): acute confusional state, altered mental status, organic brain syndrome, acute mental status change, encephalopathy

EPIDEMIOLOGY • Predominant age: older persons • Predominant sex: male = female

Incidence • >50% in older ICU patients • 11–51% in postoperative patients • 10–40% in hospitalized older patients

Prevalence • 8–17% in older ED patients • 14% in older postacute care patients

ETIOLOGY AND PATHOPHYSIOLOGY • Multifactorial: believed to result from a decline in physiologic reserves with aging, resulting in a vulnerability to new stressors • Neuropathophysiology is not clearly defined; cholinergic deficiency, dopamine excess, and neuroinflammation are leading hypotheses. • Often interaction between predisposing and precipitating risk factors • With more predisposing factors (i.e., frail patients), fewer precipitating factors needed to cause delirium.

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• If few predisposing factors (e.g., very robust patients), more precipitating factors needed to cause delirium. • Multicomponent approach addressing contributing factors can reduce incidence and complications.

RISK FACTORS • Predisposing risk factors (1) – Advanced age, >70 years – Preexisting cognitive impairment – Functional impairment – Dehydration; high BUN:creatinine ratio – History of alcohol abuse – Malnutrition – Hearing or vision impairment • Precipitating risk factors – Severe illness in any organ system(s) – Environmental irritants (urinary catheter, restraints) – Polypharmacy (≥5 medications) – Specific medications, especially benzodiazepines, opioids (meperidine), and anticholinergics (diphenhydramine) – Pain – Any iatrogenic event – Surgery – Sleep deprivation

GENERAL PREVENTION Follow treatment approach.

COMMONLY ASSOCIATED CONDITIONS Multiple but most common are the following: • New medicine or medicine changes • Infections (especially lung, urine, and blood stream, but consider meningitis as well) • Toxic-metabolic (especially low sodium, elevated calcium, renal failure, and hepatic failure)

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• Heart attack or stroke • Alcohol or drug withdrawal • Preexisting cognitive impairment increases risk

DIAGNOSIS Diagnosis is made using a careful history, behavioral observation, and cognitive assessment. • DSM-5 is the current standard; diagnostic criteria include (2): – Disturbance in attention and awareness – Change in cognition not due to dementia – Onset over short (hours to days) period and fluctuates during course of day – Evidence from history, exam, or lab that disturbance is caused by physiologic consequence of medical condition, intoxicating substance, medication use, or more than one cause. • The Confusion Assessment Method (CAM) is the most well validated and tested clinical tool and has been adapted for ICU setting in adults (CAM-ICU) and children (pediatric CAM-ICU [pCAM-ICU]) (3)[B].

ALERT • Key diagnostic features of the CAM – Acute change in mental status that fluctuates – Abnormal attention and either disorganized thinking or altered level of consciousness • Several nondiagnostic symptoms may be present: – Short- and long-term memory problems – Sleep–wake cycle disturbances – Hallucinations and/or delusions – Emotional lability – Tremors and asterixis • Subtypes based on level of consciousness – Hyperactive delirium (15%): Patients are loud, agitated, and disruptive. – Hypoactive delirium (20%): quietly confused; sleepy; may sit and not eat, drink, or move

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– Mixed delirium (50%): features of both hyperactive and hypoactive delirium – Normal consciousness delirium (15%): still displays disorganized thinking, along with acute onset, inattention, and fluctuating mental status

HISTORY • Time course of mental status changes • Recent medication changes • Symptoms of infection • New neurologic signs • Abrupt change in functional ability

PHYSICAL EXAM • Comprehensive cardiorespiratory exam is essential. • Focal neurologic signs are usually absent. • Mini mental state exam (MMSE) is the most well known and studied cognitive screen, but it may not be the most appropriate in an acute care setting; shorter cognitive screens have been studied in delirious patients (i.e., short blessed test [SBT], Brief Alzheimer Screen [BAS], and Ottawa 3DY) and may be helpful if performed serially over time. Most patients will perform poorly if delirium is present; dementia cannot be diagnosed when delirium is present. • GI/GU exam for constipation/urinary retention

DIFFERENTIAL DIAGNOSIS • Depression (disturbance of mood, normal level of consciousness, fluctuates weeks to months) • Dementia (insidious onset, memory problems, normal level of consciousness, fluctuates days to weeks) • Psychosis (rarely sudden onset in older adults)

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Guided by history and physical exam – CBC with differential – Comprehensive metabolic panel (CMP)

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– Urinalysis, urine culture, blood culture – Medication levels (digoxin, theophylline, antiepileptics where applicable) • Chest radiograph for most • ECG as necessary • Others, if indicated by history and exam Follow-Up Tests & Special Considerations • If lab tests listed above do not indicate a precipitator of delirium, consider – Arterial blood gases – Troponin – Toxicology screen – Ammonia – Thyroid-stimulating hormone – Thiamine • Noncontrast-enhanced head CT scan if – Unclear diagnosis – Recent fall – Receiving anticoagulants – New focal neurologic signs – Need to rule out intracranial mass before lumbar puncture

Diagnostic Procedures/Other • Lumbar puncture (rarely necessary) – Perform if clinical suspicion of a CNS bleed or infection is high. • EEG (rarely necessary) – Consider after above evaluation if cause remains unclear or suspicion of seizure activity.

TREATMENT • The best treatment is prevention (4)[A]. • Addressing six risk factors (i.e., cognitive impairment, sleep deprivation, dehydration, immobility, vision impairment, and hearing impairment) in atrisk hospitalized patients can reduce the incidence of delirium by 33%. • Principles: Maintain safety, identify causes, and manage symptoms.

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• Stabilize vital signs and ensure immediate evaluation.

GENERAL MEASURES • Postoperative patients should be monitored and treated for – Myocardial infarction/ischemia – Infection (i.e., pneumonia, UTI) – Pulmonary embolism – Urinary or stool retention (attempt catheter removal by postoperative day 2) • Anesthesia route (general vs. epidural) does not affect the risk of delirium. • ICU sedation-avoidance of benzodiazepines may reduce risk (5)[B]. • Multifactorial treatment: Identify contributing factors and provide preemptive care to avoid iatrogenic problems, with special attention to – CNS oxygen delivery (attempt to attain): SaO2 >90% with goal of SaO2 >95% Systolic BP 90 mm Hg Hematocrit >30% • Fluid/electrolyte balance – Sodium, potassium, and glucose normal (glucose 65 years – Vascular dementia (VaD) Usually correlated with a cerebrovascular event and/or cerebrovascular disease Stepwise deterioration with periods of clinical plateaus – Lewy body dementia Fluctuating cognition associated with parkinsonism, hallucinations and delusions, gait difficulties, and falls – Frontotemporal dementia Language difficulties, personality changes, and behavioral disturbances – Creutzfeldt-Jakob disease (CJD) Very rare; rapid onset – HIV dementia – Substance-/medication-induced neurocognitive disorder

EPIDEMIOLOGY Prevalence • In patients age ≥71 years – AD: 5–10% up to 25% after 7th decade of life

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– VaD: 17% – Other: 13% • Estimated 5.4 million Americans had AD in 2010. – 5 million >65 years of age; 200,000 65 years) • Progressive cognitive decline of insidious onset • No disturbances of consciousness • Deficits in areas of cognition • No other explainable cause of symptoms • Specifically rule out thyroid disease, vitamin deficiency (B12), grief reaction, and depression • Supportive factors: family history of dementia

PHYSICAL EXAM • Often normal physical • Clues on examination may define cause of dementia – Tremors: Dementia with Lewy bodies Parkinson disease dementia – Myoclonus:

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Creutzfeldt-Jakob disease HIV dementia – Rigidity: Dementia with Lewy bodies Wilson disease Parkinson disease dementia – Pseudobulbar palsy: Multiinfarct dementia – Vital signs: Bradycardia or hypotension–hypothyroidism Hypertension–multiinfarct dementia Hypothermia–hypothyroidism – Gait apraxia: Normal pressure hydrocephalus – Polyneuropathy: Neurosyphilis Vitamin B12 deficiency HIV dementia • Cognitive decline demonstrated by standardized instruments, including the following: – Mini–mental state exam – Montreal Cognitive Assessment Test (MoCA) – ADAS-Cog – Clock draw test

DIFFERENTIAL DIAGNOSIS • Major depression • Medication side effect • Chronic alcohol use • Normal pressure hydrocephalus • Brain tumor • Thyroid disease • Parkinson disease • Vitamin B12 deficiency

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• Toxins (aromatic hydrocarbons, solvents, heavy metals, marijuana, opiates, sedative-hypnotics)

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Used to rule out causes – CBC, CMP, lipid profile – Thyroid-stimulating hormone – Vitamin B12 level • Select patients – HIV, rapid plasma regain (RPR) – Erythrocyte sedimentation rate (ESR) – Folate – Heavy metal and toxicology screen • Research studies with cerebrospinal fluid (CSF) biomarkers in patient with confirmed AD have shown decreased A beta (1 to 42) and increased tau and p-tau levels, which are specific features of AD, and CSF tau proteins are increased in CJD (3)[A]. • Neuroimaging (CT/MRI of brain): – Important findings AD: diffuse cerebral atrophy starting in association areas, hippocampus, amygdala VaD: old infarcts, including lacunar

Diagnostic Procedures/Other PET scan not routinely recommended; has been approved to differentiate between Alzheimer disease and frontotemporal dementia

Test Interpretation AD • Neurofibrillary tangles: abnormally phosphorylated tau protein • Senile plaques: amyloid precursor protein derivatives • Microvascular amyloid

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TREATMENT GENERAL MEASURES • Identification and treatment of risk factors (stroke, cardiovascular disease) for dementia may serve to reduce progression of cognitive decline. • Daily schedules and written directions • Emphasis on nutrition, personal hygiene, accident-proofing the home, safety issues, sleep hygiene, and supervision • Socialization (adult daycare) • Sensory stimulation (display of clocks and calendars) in the early to middle stages • Discussion with the family concerning support and advance directives

MEDICATION • Medications for AD show a small improvement in some cognitive measures, but it remains unclear if the improvement is clinically significant (4)[A]. • Cognitive dysfunction, mild – Cholinesterase inhibitors: donepezil (Aricept), 5 to 10 mg/day; rivastigmine (Exelon), 1.5 to 6 mg BID, transdermal system 4.6 mg/24 hours and 9.5 mg/24 hours; galantamine (Razadyne), 4 to 12 mg BID, extended release 8 to 24 mg/day Adverse events: nausea, vomiting, diarrhea, anorexia, nightmares, bradycardia/syncope Galantamine warning: associated with mortality in patients with mild cognitive impairment in clinical trial Start drug with lowest acquisition cost; also consider adverse event profile, adherence, medical comorbidity, drug interactions, and dosing profiles. • Cognitive dysfunction, moderate to severe – Cholinesterase inhibitors OR – Memantine (Namenda), 5 to 20 mg/day Adverse events: dizziness, confusion, headache, constipation OR combination cholinesterase inhibitor and memantine • Commonly associated conditions

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– Psychosis and agitation/aggressive behavior Look for precipitating factors (infection, pain, depression, medications). Nonpharmacologic therapies (behavioral interventions, music therapy, etc.) are preferred as first-line treatment. For moderate/severe symptoms; antipsychotics: Initiate low doses, risperidone 0.25 to 1 mg/day; olanzapine 1.25 to 5 mg/day; quetiapine 12.5 to 50 mg/day; aripiprazole 5 mg/day; ziprasidone 20 mg/day Atypical antipsychotics associated with a better side effect profile: quetiapine and aripiprazole often first line due to decreased extrapyramidal side effect

ALERT Black box warning on antipsychotics due to increased mortality in elderly with dementia • Depression and insomnia – Depression Selective serotonin reuptake inhibitors (SSRIs): Initiate low doses, citalopram (Celexa) 10 mg/day; escitalopram (Lexapro) 5 mg/day; sertraline (Zoloft) 25 mg/day Adverse events: nausea, vomiting, agitation, parkinsonian effects, sexual dysfunction, hyponatremia Venlafaxine, mirtazapine, and bupropion are also useful. – Sleep disturbances Low-dose antidepressants (e.g., Remeron) have significant sedative properties at 7.5 or 15 mg. Trazodone 25 to 100 mg is frequently used because of better side effect profile. – Psychosis and agitation/aggressive behavior Some data for SSRIs Benzodiazepines if agitation with anxiety; in elderly, use PRN.

Geriatric Considerations Initiate pharmacotherapy at low doses and titrate slowly up if necessary.

ALERT

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Benzodiazepine use is associated with increased fall risk (5)[B]. • Watch decreased renal function and hepatic metabolism.

ISSUES FOR REFERRAL Neuropsychiatric evaluation particularly helpful in early stages or mild cognitive impairment

ADDITIONAL THERAPIES Behavioral modification • Socialization, such as adult daycare, to prevent isolation and depression • Sleep hygiene program as alternative to pharmaceuticals for sleep disturbance • Scheduled toileting to prevent incontinence

COMPLEMENTARY & ALTERNATIVE MEDICINE • Vitamin E is no longer recommended due to lack of evidence. • Ginkgo biloba is not recommended due to lack of evidence. • NSAIDs, selegiline, and estrogen lack efficacy and safety data.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Worsening physical health issues • Psychiatry admission may be required because of safety concerns (selfharm/harm to others), self-neglect, aggressive behaviors, or other behavioral issues.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Progression of cognitive impairment by use of standardized tool (e.g., MMSE, ADAS-Cog) • Development of behavioral problems: sleep, depression, psychosis • Adverse events of pharmacotherapy • Nutritional status • Caregiver evaluation of stress

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• Evaluate issues that may affect quality of life.

PATIENT EDUCATION • Safety concerns • Long-term issues: management of finances, medical decision making, possible placement when appropriate; legal guardianship, if necessary, to avoid capacity and competency issues • Advance directives • National Institute on Aging. About Alzheimer’s disease: other dementias. http://www.nia.nih.gov/alzheimers/topics/other-dementias

PROGNOSIS • AD: usually steady progression leading to profound cognitive impairment – Average survival of AD is about 8 years. • VaD: incrementally worsening dementia, but cognitive improvement is unlikely • Secondary dementias: Treatment of the underlying condition may lead to improvement. Commonly seen with normal pressure hydrocephalus, hypothyroidism, and brain tumors

COMPLICATIONS • Wandering • Delirium • Sundowner syndrome: It is frequently common in older people (who are sedated) and also in people who have dementia (adverse reaction to small dose of psychoactive substances). • Falls with injury – Falls, hip fracture – Head trauma/ hematomas – Pressure ulcers • Neglect and abuse • Caregiver burnout

REFERENCES 1. McGuinness B, Craig D, Bullock R, et al. Statins for the prevention of

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dementia. Cochrane Database Syst Rev. 2009;(2):CD003160. 2. Blass DM, Rabins PV. In the clinic. Dementia. Ann Intern Med. 2008;148(7):ITC4-1–ITC4-16. 3. van Harten AC, Kester MI, Visser PJ, et al. Tau and p-tau as CSF biomarkers in dementia: a meta-analysis. Clin Chem Lab Med. 2011;49(3):353–366. 4. Birks J. Cholinesterase inhibitors for Alzheimer’s disease. Cochrane Database Syst Rev. 2006;(1):CD005593. 5. Softic A, Beganlic A, Pranjic N, et al. The influence of the use of benzodiazepines in the frequency falls in the elderly. Med Arch. 2013;67(4):256–259.

ADDITIONAL READING • Lyketsos CG, Colenda CC, Beck C. Position statement of the American Association for Geriatric Psychiatry regarding principles of care for patients with dementia resulting from Alzheimer disease. Am J Geriatr Psychiatry. 2006;14(7):561–572. • National Collaborating Centre for Mental Health. Dementia: The NICE-SCIE Guideline on Supporting People with Dementia and Their Carers in Health and Social Care. London, United Kingdom: British Psychological Society, Royal College of Psychiatrists; 2007. https://www.nice.org.uk/guidance/cg42. Accessed September 21, 2016. • Rabins PV, Blacker D, Rovner BW, et al; for the American Psychiatric Association Work Group on Alzheimer’s Disease and Other Dementias. American Psychiatric Association practice guideline for the treatment of patients with Alzheimer’s disease and other dementias. Second edition. Am J Psychiatry. 2007;164(12 Suppl):5–56.

SEE ALSO Algorithm: Dementia

CODES

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ICD10 • F03 Unspecified dementia • G30.9 Alzheimer’s disease, unspecified • F01.50 Vascular dementia without behavioral disturbance

CLINICAL PEARLS • Medications for AD show a small improvement in some cognitive measures. • Do not forget the role of adult protective services in case of elderly abuse. • A particular concern in nursing homes relates to the use of physical restraints and antipsychotic medication, which are regulated in the United States by the Omnibus Reconciliation Act of 1987.

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DEMENTIA, VASCULAR Birju B. Patel, MD, FACP, AGSF • N. Wilson Holland, MD, FACP, AGSF BASICS Vascular dementia is a heterogeneous disorder caused by the sequel of cerebrovascular disease that manifests in cognitive impairment affecting memory, thinking, language, behavior, and judgment.

DESCRIPTION • Vascular dementia (previously known as multi-infarct dementia) was first mentioned by Thomas Willis in 1672. Later, it was further described in the late 19th century by Binswanger and Alzheimer as a separate entity from dementia paralytica caused by neurosyphilis. This concept has evolved tremendously since the advent of neuroimaging modalities. • Synonym(s): vascular cognitive impairment (VCI); vascular cognitive disorder (VCD); arteriosclerotic dementia; poststroke dementia; senile dementia due to hardening of the arteries; Binswanger disease. Diagnostic and Statistical Manual of Mental Disorders (DSM-5) categorizes vascular dementia as mild or major VCD.

EPIDEMIOLOGY Second most common cause of dementia after Alzheimer dementia in the elderly

Incidence About 6 to 12 cases/1,000/person age >70 years • Incidence of vascular dementia is declining in high-income countries in the past several decades likely due to better management of vascular risks.

Prevalence • ~1.2–4.2% in those age >65 years • 14–32% prevalence of dementia after a stroke

ETIOLOGY AND PATHOPHYSIOLOGY

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Upon autopsy of those with dementia, many have significant vascular pathology that are present, but this is not necessarily correlated clinically with vascular dementia. No set pathologic criteria exist for the diagnosis of vascular dementia such as those that exist for Alzheimer dementia. Pathology includes the following: • Large vessel disease: cognitive impairment that follows a stroke • Small vessel disease: includes white matter changes (leukoaraiosis), subcortical infarcts, and incomplete infarction. This is usually the most common cause of multi-infarct dementia. • Subcortical ischemic vascular disease: due to small vessel involvement within cerebral white matter, brain stem, and basal ganglia. Lacunar infarcts and deep white matter changes are typically included in this category. • Noninfarct ischemic changes and atrophy • Transient ischemic attack (TIA)/stroke • Vascular, demographic, genetic factors • Vascular disease (i.e., hypertension [HTN], peripheral vascular disease [PVD], atrial fibrillation, hyperlipidemia, diabetes)

Genetics • Cerebral autosomal dominant arteriopathy with subcortical infarcts (CADASIL) is caused by a mutation in the NOTCH3 gene on chromosome 19 that results in leukoencephalopathy and subcortical infarcts. This is clinically manifested in recurrent strokes, migraine with aura, and vascular dementia. • Apolipoprotein E gene type: Those with ApoE4 subtypes are at higher risk of developing both vascular and Alzheimer dementia. • Amyloid precursor protein (APP) gene: leads to a form of vascular dementia called heritable cerebral hemorrhage with amyloidosis

RISK FACTORS • Age • Previous stroke • Smoking • Diabetes (especially with frequent hypoglycemia) • HTN • Atrial fibrillation

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• PVD • Hyperlipidemia • Metabolic syndrome • Coronary atherosclerotic heart disease (1)

GENERAL PREVENTION • Optimization and aggressive treatment of vascular risk factors, such as HTN, diabetes, and hyperlipidemia (2)[C] • HTN is the single most modifiable risk factor and treatment for it must be optimized. • Smoking is associated with white matter changes on imaging which may be associated with small vessel disease and vascular dementia progression (3) [B]. • Lifestyle modification: weight loss, physical activity, smoking cessation • Medication management for vascular risk reduction: aspirin usage, statin therapy for hyperlipidemia, antihypertensive therapy (4)[B]

COMMONLY ASSOCIATED CONDITIONS • CADASIL • Cerebral amyloid angiopathy (CAA) causes ischemic white matter damage due to amyloid deposition in penetrating cortical vessels.

DIAGNOSIS Differentiation between Alzheimer dementia and vascular dementia can be difficult, and significant overlap is seen in the clinical presentation of these two dementias. The diagnosis of vascular dementia is a clinical diagnosis.

HISTORY • Gradual, stepwise progression is typical. • Ask about onset and progression of cognitive impairment and the specific cognitive domains involved. • Ask about vascular risk factors and previous attempts to control these risk factors. • Ask about medication compliance.

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• Ask about urinary incontinence and gait disturbances. Abnormal gait and falls are strong predictors of development of vascular dementia, particularly unsteady, frontal, and hemiparetic types of gait. • Look for early symptoms, including difficulty performing cognitive tasks, memory, mood, and assessment of instrumental activities of daily living (IADLs). • Past history may include TIAs, cerebrovascular accidents (CVAs), coronary atherosclerotic heart disease, atrial fibrillation, hyperlipidemia, and/or PVD.

PHYSICAL EXAM • Screen for HTN. Average daily BP and not office BP is associated with progression of cerebrovascular disease and cognitive decline in the elderly. • Focal neurologic deficits may be present. • Gait assessment is important, especially looking at gait initiation, gait speed, and balance (5)[C],(6)[B]. • Check for carotid bruits as well as abdominal bruits and assess for presence of PVD. • Check body mass index and waist circumference. • Do a thorough cardiac evaluation that includes looking for arrhythmias (i.e., atrial fibrillation).

DIFFERENTIAL DIAGNOSIS • Alzheimer dementia • Depression • Drug intoxication • CNS tumors • Hypothyroidism • Vitamin B12 deficiency

DIAGNOSTIC TESTS & INTERPRETATION • Cognitive testing, such as Mini-Mental Status Examination (MMSE), Saint Louis University Mental Status (SLUMS), and Montreal Cognitive Assessment (MOCA), provides more definitive information in terms of cognitive deficits, especially executive function, which may be lost earlier in vascular dementia.

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• Neuropsychological testing may also be beneficial, especially in evaluating multiple cognitive domains and their specific involvements and deficits.

Initial Tests (lab, imaging) As appropriate, consider CBC, comprehensive metabolic profile, lipid panel, thyroid function, hemoglobin A1C, and vitamin B12. • Imaging is used in conjunction with history and physical examination to support a clinical diagnosis of vascular dementia. • Cognitive deficits observed clinically do not always have to correlate with findings found on neuroimaging studies. • MRI is best in terms of evaluation of subtle subcortical deficits. • White matter changes and specific location of these changes can be associated with executive dysfunction and episodic memory impairment (7)[C].

TREATMENT Prevention is the real key to treatment: • Control of risk factors, including HTN, hyperlipidemia, and diabetes • Avoidance of tobacco and smoking cessation • Healthy, low-cholesterol diet

MEDICATION • Acetylcholinesterase inhibitors may be used but are of limited benefit in vascular dementia (8)[A]. • Clinical evidence for use of memantine is limited with the clinical benefit likely modest. • Controlling BP with any antihypertensive medications, treatment of dyslipidemia (e.g., statins), and treatment of diabetes are very important. • Nicardipine has been studied and has been found to have some neuroprotective effects for vascular dementia (9)[B]. • Selective serotonin receptor inhibitors (SSRIs) may be of benefit for agitation and psychosis in vascular dementia (10)[A].

ADDITIONAL THERAPIES • Limit alcohol drink intake to ≤1/day in women and 2/day in men.

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• Heavy sustained alcohol use contributes to HTN. • Aspirin and/or clopidogrel may be useful in some cases.

SURGERY/OTHER PROCEDURES Carotid endarterectomy/stenting should be considered if evidence of significant internal carotid artery stenosis (i.e., >70–80%).

COMPLEMENTARY & ALTERNATIVE MEDICINE Ginkgo biloba should be avoided due to increased risk of bleeding, especially in CAA.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Remain sensitive to functional assessment and avoidance of pressure ulcers after CVAs. • Avoid Foley catheter usage unless absolutely necessary due to increased risk of infection. • Nonpharmacologic approaches to behavior management should be attempted prior to medication usage. • Providing optimal sensory input to patients with cognitive impairment is important during hospitalizations to avoid delirium and confusion. Patients should be given frequent cues to keep them oriented to place and time. They should be informed of any changes in the daily schedule of activities and evaluations. Family and caregivers should be encouraged to be with patients with dementia as much as possible to further help them from becoming confused during hospitalization. Recreational, physical, occupational, and music therapy can be beneficial during hospitalization in avoiding delirium and preventing functional decline. • Particular emphasis has to be placed on screening for, and optimizing, the mood of the patient. Depression is very common in older patients, especially those who have had strokes and have become hospitalized. Depression in itself can present as “pseudodementia” with worsening confusion during hospitalization and is a treatable condition.

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ONGOING CARE Vascular dementia is a condition that should be followed with multiple visits in the office setting with goals of optimizing cardiovascular risk profiles for patients. Future planning and advanced directives should be addressed early. Family and caregiver evaluation and burden should also be evaluated.

FOLLOW-UP RECOMMENDATIONS Perform regular follow-up with a primary care provider or geriatrician for risk factor modification and education on importance of regular physical and mental exercises as tolerated.

Patient Monitoring Appropriate evaluation and diagnosis of this condition, need for future planning, optimizing vascular risk factors, lifestyle modification counseling, therapeutic interventions

DIET • The American Heart Association diet and dietary approaches to stop hypertension (DASH) diet is recommended for optimal BP and cardiovascular risk factor control. • Low-fat, decreased concentrated sweets and carbohydrates, especially in those with metabolic syndrome

PATIENT EDUCATION • Lifestyle modification is important in vascular risk reduction (smoking cessation, exercise counseling, dietary counseling, weight-loss counseling). • Optimizing vascular risk factors via medications (i.e., HTN, diabetes, atrial fibrillation, PVD, heart disease) • Avoiding smoking, including secondhand smoke • Home BP monitoring and glucometer testing of blood sugars if HTN, impaired glucose tolerance, and/or diabetes is present

PROGNOSIS • Lost cognitive abilities that persist after initial recovery of deficits from stroke do not usually return. Some individuals can have intermittent periods of self-

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reported improvement in cognitive function. • Risk factors for progression of cognitive and functional impairment poststroke include age, prestroke cognitive abilities, depression, polypharmacy, and decreased cerebral perfusion during acute stroke.

COMPLICATIONS • Physical disability from stroke • Severe cognitive impairment • Death

REFERENCES 1. Gorelick PB, Scuteri A, Black SE, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42(9):2672–2713. 2. Hasnain M, Vieweg WV. Possible role of vascular risk factors in Alzheimer’s disease and vascular dementia. Curr Pharm Des. 2014;20(38):6007–6013. 3. Power MC, Deal JA, Sharrett AR, et al. Smoking and white matter hyperintensity progression: the ARIC-MRI Study. Neurology. 2015;84(8):841–848. 4. White WB, Wolfson L, Wakefield DB, et al. Average daily blood pressure, not office blood pressure, is associated with progression of cerebrovascular disease and cognitive decline in older people. Circulation. 2011;124(21):2312–2319. 5. Montero-Odasso M, Verghese J, Beauchet O, et al. Gait and cognition: a complementary approach to understanding brain function and the risk of falling. J Am Geriatr Soc. 2012;60(11):2127–2136. 6. Verghese J, Lipton RB, Hall CB, et al. Abnormality of gait as a predictor of non-Alzheimer’s dementia. N Engl J Med. 2002;347(22):1761–1768. 7. Smith EE, Salat DH, Jeng J, et al. Correlations between MRI white matter lesion location and executive function and episodic memory. Neurology. 2011;76(17):1492–1499. 8. Kavirajan H, Schneider LS. Efficacy and adverse effects of cholinesterase

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inhibitors and memantine in vascular dementia: a meta-analysis of randomised controlled trials. Lancet Neurol. 2007;6(9):782–792. 9. Amenta F, Lanari A, Mignini F, et al. Nicardipine use in cerebrovascular disease: a review of controlled clinical studies. J Neurol Sci. 2009;283(1– 2):219–223. 10. Seitz DP, Adunuri N, Gill SS, et al. Antidepressants for agitation and psychosis in dementia. Cochrane Database Syst Rev. 2011;(2):CD008191.

SEE ALSO Alzheimer Disease; Depression; Mild Cognitive Impairment

CODES ICD10 • F01.50 Vascular dementia without behavioral disturbance • F01.51 Vascular dementia with behavioral disturbance

CLINICAL PEARLS • Executive dysfunction and gait abnormalities are often seen early and are more pronounced in vascular dementia as opposed to Alzheimer dementia. • Memory is relatively preserved in vascular dementia when compared with Alzheimer dementia in the early stages of this disease. • Stepwise progression, as opposed to progressive decline in Alzheimer dementia, is typical. • Considerable overlap exists between vascular dementia and Alzheimer dementia in clinical practice, and classification into one of these categories is often difficult.

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DENTAL INFECTION Sheila O. Stille, DMD • Hugh Silk, MD, MPH, FAAFP BASICS DESCRIPTION • Very painful area ± swelling in the head and neck region arising from infection in the teeth and supporting structures; if left untreated, can lead to serious and potentially life-threatening illnesses • Assume any head and neck infection or swelling to be odontogenic in origin until proven otherwise. • System(s) affected: oropharynx, throat, dental, gastrointestinal • Synonym(s): odontogenic infections, dental abscess

EPIDEMIOLOGY • 17.5% of 5- to 19-year-olds have untreated dental caries (1). • 24.7% of 20- to 44-year-olds have untreated dental caries (1). • Rates are higher in Hispanic (22.2%) and black (23.2%) children (1)[A]. • 92% of adults 20 to 64 years have had dental caries (1). • 25% of children 5 to 17 years account for 80% of caries in the United States. • 5% of adults age 20 to 64 years are edentulous.

ETIOLOGY AND PATHOPHYSIOLOGY Caries or trauma can lead to pulpal death, which in turn leads to infection of pulp and/or abscess of adjacent tissues via direct or hematogenous bacterial colonization. • Caries (a.k.a. tooth decay or cavity) is a contagious bacterial infection that causes demineralization and destruction of the hard tissues of the teeth (enamel, dentin, and cementum). • Streptococcus mutans vertically transmitted to newly dentate infants from caregivers • Acidic secretions from S. mutans are implicated in early caries. • Often polymicrobial mix of strict anaerobes and facultative anaerobes in dental abscess, such as viridans streptococci and streptococcus anginosus

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• Anaerobes, including peptostreptococci, Bacteroides, Prevotella, and Fusobacterium, have been implicated. Lactobacilli not seen in healthy subjects but seen in those with rampant caries (2). • Completely preventable disease with good oral hygiene and diet The introduction of fluoride has dramatically decreased dental caries.

RISK FACTORS • Low socioeconomic status • Parent and/or sibling with history of caries or existing untreated dental caries (especially in past 12 months) • Previous dental caries • Poor access to dental and health care • Fear of dentist • Poor oral hygiene • Poor nutrition, including diet containing high level of sugary foods and drinks • Trauma to the teeth or jaws • Inadequate access to and use of fluoride • Gingival recession (increased risk of root caries) • Physical and mental disabilities • Decreased salivary flow (e.g., use of anticholinergic medications, immunologic diseases, radiation therapy to head and neck)

GENERAL PREVENTION • Prevent caries and contagious bacterial infection (S. mutans). • Majority of dental problems can be avoided through flossing/use of interdental brushes; brushing with fluoride toothpaste, systemic fluoride (fluoridated bottled water; fluoride supplements for high-risk patients in nonfluoridated areas), and fluoride varnish for moderate- to high-risk patients; and regular dental cleanings (1). • Prevention of transmission of S. mutans from mother/caregiver to infant by improving mother’s dentition and decreasing mother’s bacterial load through proper dental care, chlorhexidine gluconate rinses, and use of xylitol products for mother especially during first 2 years of a child’s life. Avoid smoking, which is linked to severe periodontal disease (2). • Good control of systemic diseases (e.g., diabetes)

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• Fluoride varnish provided by dental or medical primary care providers twice per year (2)

COMMONLY ASSOCIATED CONDITIONS • Rampant caries throughout dentition, faulty restorations, extractions, crowding, and multiple missing teeth • Periapical abscesses associated with necrotic teeth • Periodontal abscess • Soft tissue cellulitis • Periodontitis (deep inflammation ± infection of gingiva, alveolar bone support, and ligaments)

DIAGNOSIS HISTORY • Pain at infected site or referred pain to ears, jaw, cheek, neck, or sinuses; unexplained headaches • Sensitivity to hot or cold stimuli • Unprovoked, intermittent, or constant throb along nerve pathway • Pain on biting or chewing • Trismus (inability to open mouth) • Bleeding or purulent drainage from gingival tissues • When severe infection (systemic) – Fever – Difficulty breathing or swallowing – Raspy voice – Mental status changes • Children males (2:1)

ETIOLOGY AND PATHOPHYSIOLOGY Complex etiology with two major models in the literature • Monoamine-deficiency hypothesis: symptoms related to decreased levels of norepinephrine (dullness and lethargy) and serotonin (irritability, hostility, and suicidal ideation) in multiple regions of the brain; other neurotransmitters involved include dopamine, acetylcholine, γ-aminobutyric acid (GABA),

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glutamate. • Stress/hypothalamic–pituitary–adrenal axis: Abnormalities in cortisol response lead to depression; elevated cortisol levels can be associated with depression, but cortisol tests are not indicated for diagnosis. • Other areas of research interest: inflammatory processes and abnormal circadian rhythms; impaired synthesis/metabolism of neurotransmitters • Environmental factors and learned behavior may affect neurotransmitters and/or have an independent influence on depression.

Genetics Multiple gene loci place a person at increased risk when faced with environmental stressor; twin studies suggest 37% concordance (1).

RISK FACTORS • Female > male (2:1) • Severity of first episode • Persistent sleep disturbances • Presence of chronic disease(s), recent myocardial infarction (MI), cardiovascular accident (CVA) • Strong family history (depression, bipolar, suicide, substance abuse), spouse with depression • Childhood trauma/maltreatment • Substance abuse and dependence, domestic abuse/violence • Losses, stressors, unemployment • Single, divorced, or unhappily married

COMMONLY ASSOCIATED CONDITIONS • Bipolar disorder, cyclothymic disorder, grief reaction, anxiety disorders, somatoform disorders, schizophrenia/schizoaffective disorders • Medical comorbidity • Substance abuse

DIAGNOSIS HISTORY

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DSM-5 requires all of the following criteria for MDD: • Criterion A: ≥5 of the following symptoms present nearly every day during the same 2-week period, with at least one of the five being either depressed mood or loss of interest or pleasure: – Depressed mood most of the day by subjective report or observation from other people – Diminished interest or pleasure in all activities most of the day by subjective report or observation from other people – Decreased or increased appetite or significant weight loss without dieting – Insomnia or hypersomnia – Fatigue or energy loss – Restlessness, irritability, or withdrawal observable by others – Worthlessness, excessive/inappropriate guilty feelings – Diminished thinking/concentration, poor memory, indecisiveness – Recurrent thoughts of death, suicidal ideations, and may or may not have a specific plan • Criterion B: Symptoms cause significant social, occupational, or functional distress or impairment. • Criterion C: symptoms not attributable to substance effects or other medical conditions

Geriatric Considerations • Difficult to diagnose due to medical comorbidity • Can present with memory difficulties as chief complaint; treatment reverses memory difficulty. • Can be the initial presentation of irreversible dementia • Geriatric Depression Scale (GDS 15) improves rate of diagnosis in primary care setting (2,3)[A].

Pediatric Considerations • Can present as irritable or angry rather than sad or dejected • Failure to make expected weight gains can substitute weight loss symptom above. • A sudden and remarkable drop in grades can indicate difficulty concentrating. • Can present with separation anxiety

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PHYSICAL EXAM Complete physical with focus on endocrine, cardiac, neurologic, and psychiatric (affect, attention, cognition, memory); look for evidence of contributing medical or neurologic disorder.

DIFFERENTIAL DIAGNOSIS • Psychiatric: depressed phase of bipolar disorder—inquire if prior mania, family or personal history of bipolar disorder, prior agitation or excitement with antidepressant medication. If positive, monitor carefully for mood elevation or destabilization, adjustment disorder, and bereavement. • Neurologic or degenerative CNS diseases, dementias • Medical comorbidity: adrenal disease, thyroid disorders, diabetes, metabolic abnormalities (hypercalcemia), liver/renal failure, malignancy, chronic fatigue syndrome, fibromyalgia, lupus • Nutritional: pernicious anemia, pellagra • Medications/substances: abuse, side effects, overdose, intoxication, dependence, withdrawal

DIAGNOSTIC TESTS & INTERPRETATION • A clinical diagnosis made by eliciting personal, family, social, and psychosocial factors • The Patient Health Questionnaire-9 (PHQ-9) is a brief screening test valid for diagnosis of MDD in primary care settings (3)[A]. • Other validated standard rating scales include the following: Beck Depression Inventory, Zung, GDS 15, and so forth. Rating scales are also useful to track response to treatment over time (3)[A]. • Rule out hypothyroidism, anemia, and metabolic disorders with TSH, CBC, and comprehensive metabolic panel (CMP). • Order urine drug screen if symptoms suggest intoxication.

TREATMENT American Psychiatric Association (APA) 2010 guidelines recommend phasic approach: acute phase (first 3 months), continuation phase (4 to 9 months), and

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maintenance (9 months until discontinuation) (4)[A]. • Acute phase – Full evaluation, including risk to self and others, with selection of appropriate treatment setting (hospitalization for those at risk of harm to self or others, or so incapacitated as to be unable to take care of themselves and/or who have no support system to assist with treatment) – Goal should be symptom remission, with intervention based on clinical picture, including patient’s preference, availability of services. – For mild to moderate depression, psychotherapies (individual, interpersonal, or cognitive-behavioral therapy [CBT]) and/or medication are recommended. – For refractory/severe depression, medication is indicated. – For patients not responding to medication alone, CBT should be initiated. – Continue to increase dosage q3–4wk until symptoms in remission. Full medication effect is complete in 4 to 6 weeks. Augmentation with second medication may be necessary. – See within 2 to 4 weeks of starting medication and q2wk until improvement and then monthly to monitor medication changes. – ≥6 visits recommended for monitoring (younger patients, those at high suicide risk, see within 1st week, and follow frequently) • Continuation/maintenance phase – Regular visits to monitor for signs of relapse, q3–6mo if stable; depression rating scales should be used. – Once remission achieved, dosage should be continued for at least 6 to 9 months to reduce relapse; CBT is also effective in reducing relapse (visits typically q2wk). – If/when drug discontinuation is considered, medications should be tapered gradually (weeks to months).

ISSUES FOR REFERRAL • Refer immediately for active suicidal ideations, psychosis, severe agitation, severe self-neglect, and significant risk of self-harm. • Refer to psychiatry for failed response to medication trials, suspected bipolar disorder, more persistent suicidal thoughts, and self-neglect.

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MEDICATION • Effectiveness of medications is comparable between/within classes; selection should be based on provider familiarity and patient characteristics/preferences (5)[A]. • Selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) are effective, but TCAs are second line due to side effects and lethality in overdose. Tolerability is much poorer than newer antidepressants. • First-line SSRIs* (starting dose; usual dose) – Fluoxetine (Prozac): 20 mg/day; 20 to 60 mg/day – Sertraline (Zoloft): 50 mg/day; 50 to 200 mg/day – Paroxetine (Paxil): 10 mg/day; 20 to 50 mg/day – Paroxetine CR (Paxil CR): 12.5 mg/day; 25 to 62.5 mg/day – Citalopram (Celexa): 20 mg/day; 20 to 40 mg/day (higher doses not advised; ECG monitoring for doses >40 mg/day due to increased risk of QTc prolongation) – Escitalopram (Lexapro): 10 mg/day; 10 to 20 mg/day – Precautions: Abrupt discontinuation may result in withdrawal symptoms (i.e., dizziness, nausea, headache, paresthesia). – Fluoxetine, paroxetine may raise serum levels of other drugs; escitalopram, sertraline have minimal to no drug interactions. – Common side effects: sexual dysfunction (20%), nausea, GI upset, dizziness, insomnia, headache; typically resolve in the 1st week – Less common side effects: drowsiness, weight gain, emotional blunting, dry mouth – *Lower starting doses for elderly, adolescents, those with comorbid conditions, panic disorder, significant anxiety, or hepatic conditions • Others (starting dose; usual dose) – Venlafaxine (Effexor, Effexor XR): 37.5 mg/day; 300 mg/day – Bupropion XL (Wellbutrin XL): 150 mg/day; 300 to 450 mg/day (precautions: powers seizure threshold at doses >450 mg/day) – Duloxetine (Cymbalta): 30 mg/day; 60 to 120 mg/day – Desvenlafaxine (Pristiq): 50 to 100 mg/day – Vilazodone: start 10 mg/day; usual target 40 mg/day – Vortioxetine: start 5 mg/day; target dose 20 mg/day

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– Levomilnacipran: start 20 mg/day; target dose 40 to 120 mg/day

Second Line • TCAs (starting dose; usual dose) – Amitriptyline (Elavil): 25 to 50 mg/day; 100 to 300 mg/day – Nortriptyline (Pamelor): 25 mg/day; 50 to 150 mg/day – Doxepin (Sinequan): 25 to 50 mg/day; 100 to 300 mg/day – Imipramine (Tofranil, Tofranil-PM): 25 to 50 mg/day; 100 to 300 mg/day – Desipramine (Norpramin): 25 to 50 mg/day; 100 to 300 mg/day – Precautions: advanced age, glaucoma, benign prostate hyperplasia, hyperthyroidism, cardiovascular disease, liver disease, monamine oxidase inhibitor (MAOI) treatment, potential for fatal overdose, arrhythmia, worsening glycemic control, SSRIs recommended for patients with diabetes (4)[A] – Common side effects: dry mouth, blurred vision, constipation, urinary retention, tachycardia, confusion/delirium; elderly particularly susceptible • α2-Antagonists (sedating) (starting dose; usual dose) – Mirtazapine (Remeron): 15 mg/day; 15 to 45 mg/day • Atypical antipsychotics – Adjunctive treatment: aripiprazole or quetiapine – Treatment-resistant depression (TRD): olanzapine – Significant side effects: dyslipidemia, hypertriglyceridemia, glucose dysregulation, diabetes mellitus, hyperprolactinemia, tardive dyskinesia, neuroleptic malignant syndrome, QTc prolongation (6)[A] – Recommended for depression with psychotic features; consult with psychiatry and consider carefully before starting (4)[A]. • Significant potential interactions – TCAs: amphetamines, barbiturates, clonidine, epinephrine, ethanol, norepinephrine – ALL ANTIDEPRESSANTS: Allow 14-day washout period before starting MAOIs. – MAOIs: not recommended in primary care. Significant drug and food interactions limit use.

ALERT

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• Black box warning: increased risk of suicidality in children, adolescents, and young adults up to age 25 years who are treated with antidepressants. Although this has not been extended to adults, suicide risk assessments are warranted for all patients. • Serotonin syndrome—a rare but potentially lethal complication from rapid increase in dose or new addition of medication with serotonergic effects • Caution with personal or family history of bipolar disorder: Antidepressants can precipitate mania.

Pregnancy Considerations SSRIs: Fluoxetine, sertraline, and bupropion considered safe in pregnancy (paroxetine, Category D; other SSRIs, Category C).

ADDITIONAL THERAPIES • Electroconvulsive therapy (ECT) for refractory cases • Repetitive transcranial magnetic stimulation (rTMS) may be helpful for TRD (6)[A].

COMPLEMENTARY & ALTERNATIVE MEDICINE Used in mild depression but not regulated by FDA nor recommended by APA • Hypericum perforatum (St. John’s wort): multiple drug interactions; not safe in pregnancy • Data do not support S-adenosyl methionine (SAM-e) or acupuncture.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Inpatient care is indicated for severe depression, patients at risk of suicide/homicide, and for comorbid conditions. • Discharge criteria: depressive symptoms abating, no longer suicidal, appropriate outpatient follow-up in place

ONGOING CARE PATIENT EDUCATION • Depression is a common medical illness, not a character defect.

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• Emphasize the need for long-term treatment and follow-up, which includes lifestyle changes. • Exercise, good sleep hygiene, good nutrition, and decreased use of tobacco and alcohol are recommended. The optimal regimen is one the patient prefers and will adhere to.

PROGNOSIS • 70% show significant improvement • Of patients with a single depressive episode, 50% will relapse over their lifetime.

COMPLICATIONS • Suicide • Substance misuse • Anxiety • Weight gain • Lower quality of life

REFERENCES 1. Flint J, Kendler KS. The genetics of major depression. Neuron. 2014;81(3):484–503. 2. Mitchell AJ, Bird V, Rizzo M, et al. Diagnostic validity and added value of the Geriatric Depression Scale for depression in primary care: a meta-analysis of GDS30 and GDS15. J Affect Disord. 2010;125(1–3):10–17. 3. Deneke DE, Schultz H, Fluent TE. Screening for depression in the primary care population. Prim Care. 2014;41(2):399–420. 4. American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder. http://www.psychiatryonline.com/pracGuide/pracGuideTopic_7.aspx. Accessed September 21, 2016. 5. Arroll B, Elley CR, Fishman T, et al. Antidepressants versus placebo for depression in primary care. Cochrane Database Syst Rev. 2009; (3):CD007954. 6. McIntyre RS, Filteau MJ, Martin L, et al. Treatment-resistant depression: definitions, review of the evidence, and algorithmic approach. J Affect

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Disord. 2014;156:1–7.

ADDITIONAL READING • American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013. • Patient Health Questionnaire (PHQ) Screeners: http://www.phqscreeners.com/overview.aspx?Screener=03_GAD-7

SEE ALSO Algorithms: Depressed Mood Associated with Medical Illness; Depressive Episode, Major

CODES ICD10 • F32.9 Major depressive disorder, single episode, unspecified • F33.9 Major depressive disorder, recurrent, unspecified • F34.1 Dysthymic disorder

CLINICAL PEARLS • Therapeutic alliance is important to treatment success. • Given the high recurrence rates, long-term treatment is often necessary.

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DEPRESSION, ADOLESCENT Nanette Lacuesta, MS, MD • Joseph B. Gladwell, MD BASICS DESCRIPTION • DSM-5 depressive disorders include disruptive mood dysregulations disorder (DMDD), major depressive disorder (MDD), dysthymia, premenstrual dysphoric disorder, substance-/medication-induced depressive disorder, and other nonspecific depression. This chapter focuses on MDD. • MDD is a primary mood disorder characterized by sadness and/or irritable mood with impairment of functioning; abnormal psychological development; and a loss of self-worth, energy, and interest in typically pleasurable activities. • DMDD is characterized by a chronic, severe persistent irritability with frequent temper outbursts in response to frustration. • Dysthymic disorder is differentiated from major depression by less intense symptoms that are more persistent, lasting at least 1 year. • Adolescents with depression are likely to suffer broad functional impairment across social, academic, family, and occupational domains, along with a high incidence of relapse and a high risk for substance abuse and other psychiatric comorbidity.

EPIDEMIOLOGY Incidence During adolescence, the cumulative probability of depression ranges from 5% to 20% (1).

Prevalence • MDD: 6–12% of adolescents; twice as common in females • DMDD: 2–5%; more prominent in males (2)

ETIOLOGY AND PATHOPHYSIOLOGY • Unclear; low levels of neurotransmitters (serotonin, norepinephrine) may produce symptoms; decreased functioning of the dopamine system also

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contributes. • External factors may affect neurotransmitters independently.

Genetics • Offspring of parents with depression have three to four times increased rates of depression compared with offspring of parents without mood disorder (1). • Family studies indicate that anxiety in childhood tends to precede adolescent depression (1).

RISK FACTORS • Increased three to six times if first-degree relative has a major affective disorder; three to four times in offspring of parents with depression • Prior depressive episodes • History of low self-esteem, anxiety disorders, attention deficit hyperactivity disorder (ADHD), and/or learning disabilities • Hormonal changes during puberty • Female gender • Low socioeconomic status • General stressors: adverse life events, difficulties with peers, loss of a loved one, academic difficulties, abuse, chronic illness, and tobacco abuse

GENERAL PREVENTION Insufficient evidence for universal depression prevention programs (psychological and social) • Some evidence indicates that child and adolescent mental health can be improved by successfully treating maternal depression (1)[A]. • Agency for Healthcare Research and Quality (AHRQ) recommends the screening of adolescents (12 to 18 years of age) for MDD when systems are in place to ensure accurate diagnosis, appropriate treatment, and follow-up.

COMMONLY ASSOCIATED CONDITIONS • 2/3 of adolescents with depression have at least one comorbid psychiatric disorder. • 20% meet the criteria for generalized anxiety disorder. • Also associated with behavioral disorders, substance abuse, eating disorders

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DIAGNOSIS HISTORY • Adolescents may present with medically unexplained somatic complaints (fatigue, irritability, headache). • Based on DSM-5 criteria, ≥5 of the following symptoms have been present during the same 2-week period and represent a change from previous functioning: At least one of the symptoms is either depressed mood or loss of interest or pleasure (2): – Criterion A Depressed mood most of the day, nearly every day by either subjective report or observation by others (feelings of sadness, emptiness, hopelessness; in children, can be irritability) Markedly diminished interest or pleasure in all activities most of the day, nearly every day Significant weight loss when not dieting or weight gain (>5% body weight in 1 month) Insomnia or hypersomnia Psychomotor agitation or retardation nearly every day Fatigue or loss of energy Feelings of worthlessness or excessive or inappropriate feelings of guilt nearly every day Diminished ability to think or concentrate, or indecisiveness, nearly every day Recurrent thoughts of death, recurrent suicidal ideation, or attempt – Criterion B. Symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. – Criterion C. Episode is not attributable to substances’ effects or other medical conditions. – Criterion D. Episode is not better explained by a schizoaffective, schizophreniform, or delusional disorder. – Criterion E. There has never been a manic or hypomanic episode.

PHYSICAL EXAM

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• Psychomotor retardation/agitation may be present. • Clinicians should carefully assess patients for signs of self-injury (wrist lacerations) or abuse.

DIFFERENTIAL DIAGNOSIS • Normal bereavement • Substance-induced mood disorder • Bipolar disorder • Mood disorder secondary to a medical condition (thyroid, anemia, vitamin deficiency, diabetes) • Organic CNS diseases • Malignancy • Infectious mononucleosis or other viral diseases • ADHD, posttraumatic stress disorder (PTSD), eating disorders, and anxiety disorders • Sleep disorder

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) May be used to rule out other diagnoses (i.e., CBC, TSH, glucose, mono spot, and urine drug) Follow-Up Tests & Special Considerations None with sufficient sensitivity/specificity for diagnosis

Diagnostic Procedures/Other • Depression is primarily diagnosed after a formal interview, with supporting information from caregivers and teachers. • Standardized tests are useful as screening tools and to monitor response to treatment but should not be used as the sole basis for diagnosis: – Beck Depression Inventory (BDI): ages 12 to 18 years (1)[A] – Child Depression Inventory (CDI): ages 7 to 17 years – Reynolds Adolescent Depression Scale (RADS): teenagers in grades 7 to 12 – Mood and Feelings Questionnaire (MFQ) (3)[A] – Patient Health Questionnaire-9 (PHQ-9): ages 13 to 17 years with ideal cut point of 11 or higher (instead of 10 used for adults) (4)[B]

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• The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for suicide risk in adolescents in a primary care setting (5)[C].

TREATMENT GENERAL MEASURES • Active support and monitoring with short validated scales should be used in mild cases for 6 to 8 weeks. • Psychotherapy and/or medication should be considered if active support and monitoring do to improve symptoms (6)[A]. • Treatment should include psychoeducation, supportive management, and family and school involvement (7)[C]. • Initial management should include treatment planning and ensuring that the patient and family is comfortable with the plan (7)[C]. • A Cochrane review showed that there was no significant difference between remission rates for adolescents treated with cognitive-behavioral therapy (CBT) versus medication or combination therapy immediately postintervention (8)[A]. • A multitreatment meta-analysis showed that combined fluoxetine/CBT had higher efficacy than monotherapies, but other selective serotonin reuptake inhibitors (SSRIs) such as sertraline and escitalopram were better tolerated (6) [A].

MEDICATION First Line • Fluoxetine: for depression in age >8 years. Starting dose 10 mg/day; effective dose 10 to 60 mg/day. The most studied SSRI and with the most favorable effectiveness and safety data has the longest half-life of the SSRIs and is not generally associated with withdrawal symptoms between doses or upon discontinuation (9)[A]. • Escitalopram: for depression in age >12 years. Starting dose of 5 mg/day; effective dose of 10 to 20 mg/day (9)[A] • Citalopram: for depression in age >12 years. Starting dose of 10 mg/day;

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effective dose of 10 to 40 mg/day (10)[A] • Sertraline: for depression in age >12 years. Starting dose of 25 mg/day; effective dose of 50 to 200 mg/day (10)[A] • Can titrate dose every 1 to 2 weeks if no significant adverse effects emerge (headaches, GI upset, insomnia, agitation, behavior activation, suicidal thoughts) (10)[A] • SSRI black box warning to monitor for worsening condition, behavior changes, and suicidal thoughts (10)[A] • Antidepressant treatment should be continued for 6 to 12 months at full therapeutic dose after the resolution of symptoms at the same dosage (7)[C]. • Given their rates of increased drug metabolism, adolescents may be at higher risk for withdrawal symptoms from SSRIs than adults; if these are present, twice-daily dosing may be considered (6)[A]. • All other SSRIs except fluoxetine should be slowly tapered when discontinued (6)[A].

Pediatric Considerations • Tricyclic antidepressants (TCAs) have not been proven to be effective in adolescents and should not be used (6)[A]. • Paroxetine (SSRI): Avoid use due to short half-life, associated withdrawal symptoms, and higher association with suicidal ideation.

ISSUES FOR REFERRAL • Collaborative care interventions between mental health and primary care have a greater improvement in depressive symptoms after 12 months (10)[B]. • Primary care providers should provide initial treatment of pediatric depression. Refer to a child psychiatrist for severe, recurrent, or treatmentresistant depression or if the patient has comorbidities (9)[A].

COMPLEMENTARY & ALTERNATIVE MEDICINE • Physical exercise and light therapy may have a mild to moderate effect (11) [B]. • St. John’s wort, acupuncture, S-adenosylmethionine, and 5hydroxytryptophan have not been shown to have an effect or have inadequate studies to support use in adolescent depression (11)[B].

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ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS If severely depressed, psychotic, suicidal, or homicidal, one-on-one supervision may be needed.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Systematic and regular tracking of goals and outcomes from treatment should be performed, including assessment of depressive symptoms and functioning in home, school, and peer settings (9)[A]. • Diagnosis and initial treatment should be reassessed if no improvement is noted after 6 to 8 weeks of treatment (9)[A]. • The goal of treatment should be sustained symptom remission and restoration of full function (12)[C]. • Educate patients and family members about the causes, symptoms, course and treatments of depression, risks of treatments, and risk of no treatment.

PROGNOSIS • 60–90% of episodes remit within 1 year. • 50–70% of remissions develop subsequent depressive episodes within 5 years. • Depression in adolescence predicts mental health disorders in adult life, psychosocial difficulties, and ill health (2)[A]. • Baseline symptom severity and comorbid anxiety may impact treatment response (13)[A]. • Parental depression at baseline significantly affects intervention effects.

COMPLICATIONS • Treatment-induced mania, aggression, or lack of improvement in symptoms • School failure/refusal • One-third of adolescents with suicidal ideation go on to make an attempt (14) [C].

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REFERENCES 1. Thapar A, Collishaw S, Pine DS, et al. Depression in adolescence. Lancet. 2012;379(9820):1056–1067. 2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013. 3. Thapar A, Collishaw S, Potter R, et al. Managing and preventing depression in adolescents. BMJ. 2010;340:c209. 4. Larun L, Nordheim LV, Ekeland E, et al. Exercise in prevention and treatment of anxiety and depression among children and young people. Cochrane Database Syst Rev. 2006;(3):CD004691. 5. Richardson LP, McCauley E, Grossman DC, et al. Evaluation of the Patient Health Questionnaire-9 item for detecting major depression among adolescents. Pediatrics. 2010;126(6):1117–1123. 6. Ma D, Zhang Z, Zhang X, et al. Comparative efficacy, acceptability, and safety of medicinal, cognitive-behavioral therapy, and placebo treatments for acute major depressive disorder in children and adolescents: a multipletreatments meta-analysis. Curr Med Res Opin. 2014;30(6):971–995. 7. Cheung AH, Kozloff N, Sacks D. Pediatric depression: an evidence-based update on treatment interventions. Curr Psychiatry Rep. 2013;15:381–389. 8. Cox GR, Callahan P, Churchill R, et al. Psychological therapies versus antidepressant medication, alone and in combination for depression in children and adolescents. Cochrane Database Syst Rev. 2014; (11):CD008324. 9. Cheung AH, Kozloff N, Sacks D. Pediatric depression: an evidence-based update on treatment interventions. Curr Psychiatry Rep. 2013;15(8):381. 10. Reeves GM, Riddle MA. A practical and effective primary care intervention for treating adolescent depression. JAMA. 2014;312(8):797–798. 11. Popper CW. Mood disorders in youth: exercise, light therapy, and pharmacologic complementary and integrative approaches. Child Adolesc Psychiatr Clin N Am. 2013;22(3):403–441. 12. Lewandowski RE, Acri MC, Hoagwood KE, et al. Evidence for the management of adolescent depression. Pediatrics. 2013;132(4):e996–e1009. 13. Nilsen TS, Eisemann M, Kvernmo S. Predictors and moderators of outcome

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in child and adolescent anxiety and depression: a systematic review of psychological treatment studies. Eur Child Adolesc Psychiatry. 2013;22(2):69–87. 14. Nock MK, Green JG, Hwang I, et al. Prevalence, correlates, and treatment of lifetime suicidal behavior among adolescents. JAMA Psychiatry. 2013;7(3):300–310.

ADDITIONAL READING LeFevre ML. Screening for suicide risk in adolescents, adults, and older adults in primary care: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2014;160(10):719–726.

CODES ICD10 • F32.9 Major depressive disorder, single episode, unspecified • F33.9 Major depressive disorder, recurrent, unspecified • F33.8 Other recurrent depressive disorders

CLINICAL PEARLS • Adolescent depression is underdiagnosed and often presents with irritability and anhedonia. • Fluoxetine is the most studied FDA-approved for treatment of adolescent depression. • Escitalopram, citalopram, and sertraline are also FDA-approved antidepressants. • CBT combined with fluoxetine is efficacious for adolescents with major depression. • Paroxetine and TCAs should not be used to treat adolescent depression. • Referral to a child psychiatrist is appropriate for complex cases or treatmentresistant depression. • Monitor all adolescents with depression for suicidality, especially during the 1st month of treatment with an antidepressant.

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DEPRESSION, GERIATRIC Fozia Akhtar Ali, MD • Nneka I. Okafor, MD, MPH BASICS DESCRIPTION • Depression is a primary mood disorder characterized by a depressed mood and/or a markedly decreased interest or pleasure in normally enjoyable activities most of the day, almost every day for at least 2 weeks, and causing significant distress or impairment in daily functioning with at least four other symptoms of depression. • Depression is not a normal result of aging.

EPIDEMIOLOGY Prevalence rates among the elderly vary largely depending on the specific diagnostic instruments used and their current health and/or home environment: • 2–10% of community-dwelling elderly • 5–10% seen in primary care clinics • 10–37% of hospitalized elderly patients • 12–27% of nursing home residents

ETIOLOGY AND PATHOPHYSIOLOGY • Significant gaps exist in the understanding of the underlying pathophysiology. • Ongoing research has identified several possible mechanisms, including the following: – Monoamine transmission and associated transcriptional and translational activity • Epigenetic mechanisms and resilience factors • Neurotrophins, neurogenesis, neuroimmune systems, and neuroendocrine systems • Depression appears to be a complex interaction between heritable and environmental factors.

RISK FACTORS

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• General – Female sex – Lower socioeconomic status – Widowed, divorced, or separated marital status – Chronic physical health condition(s) – History of mental health problems – Family history of depression – Death of a loved one – Caregiving – Social isolation – Functional/cognitive impairment – Lack/loss of social support – Significant loss of independence – Uncontrolled or chronic pain – Insomnia/sleep disturbance • Prevalence of depression in medical illness – Stroke (22–50%) – Cancer (18–50%) – Myocardial infarction (15–45%) – Parkinson disease (10–39%) – Rheumatoid arthritis (13%) – Diabetes mellitus (5–11%) – Alzheimer dementia (5–15%) • Suicide – Suicide is the 11th leading cause of death in the United States for all ages. – Elderly account for 24% of all completed suicides. – Suicide rates are highest for males aged >85 years (rate 55/100,000).

DIAGNOSIS HISTORY • Depressed mood most of the day, nearly every day, and/or loss of interest/pleasure in life for at least 2 weeks • Other common symptoms include the following:

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– Feeling hopeless, helpless, or worthless – Insomnia and loss of appetite/weight (alternatively, hypersomnia with increased appetite/weight in atypical depression) – Fatigue and loss of energy – Somatic symptoms (headaches, chronic pain) – Neglect of personal responsibility or care – Psychomotor retardation or agitation – Diminished concentration, indecisiveness – Thoughts of death or suicide • Screening with “SIGECAPS” – Sleep: changes in sleep habits from baseline, including excessive sleep, early waking, or inability to fall asleep – Interest: loss of interest in previously enjoyable activities (anhedonia) – Guilt: excessive or inappropriate guilt that may or may not focus on a specific problem or circumstance – Energy: perceived lack of energy – Concentration: inability to concentrate on specific tasks – Appetite: increase/decrease in appetite – Psychomotor: restlessness and agitation or the perception that everyday activities are too strenuous to manage – Suicidality: desire to end life or hurt oneself, harmful thoughts directed internally, recurrent thoughts of death or thoughts of homicidality

PHYSICAL EXAM Mental status exam, thorough neurologic exam, and general physical exam to rule out other conditions

DIFFERENTIAL DIAGNOSIS Concurrent medical conditions, cognitive disorders, and medications may cause symptoms that mimic depression: • Medical conditions: hypothyroidism, vitamin B12 or folate deficiency, liver or renal failure, cancers, stroke, sleep disorders, electrolyte imbalances, Cushing disease, chronic fatigue syndrome • Dementia and neurodegenerative disorders • Delirium

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• Medication-induced: interferon-α, β2-blockers, isotretinoin, benzodiazepines, glucocorticoids, levodopa, clonidine, H2 blockers, baclofen, varenicline, metoclopramide, reserpine • Psychiatric disorders: adjustment disorder with depressed mood, grief reaction, bipolar disorder, dysthymic disorder, anxiety disorders, substance abuse–related mood disorders, psychotic disorders

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) Initial laboratory evaluation is done primarily to rule out potential medical factors that could be causing symptoms. • Thyroid-stimulating hormone (hypothyroidism) • CBC with differential (anemia, infection) • Vitamin B12, folic acid (deficiencies) • Urinalysis (urinary tract infection, glucosuria) • Comprehensive metabolic panel (uremia, hypo- or hyperglycemia, hypo- or hypernatremia, hypercalcemia, liver failure) • Urine drug screen • 24-hour urine-free cortisol (Cushing disease) Follow-Up Tests & Special Considerations Additional testing for possible confounding medical and cognitive disorders, as warranted. May consider a sleep study for patients with decreased energy, sleep disturbances, changes in concentration, or psychomotor activity

Diagnostic Procedures/Other Validated screening tools and rating scales: • Geriatric Depression Scale: 15- or 30-point scales • Patient Health Questionnaire (PHQ-2 or PHQ-9) • Hamilton Depression Rating Scale • Beck Depression Inventory • Cornell Scale for Depression in Dementia (1)[A]

TREATMENT

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Although response alone, usually interpreted as a 50% reduction in symptoms, can be clinically meaningful, the goal is to treat patients to the point of remission (i.e., essentially the absence of depressive symptoms).

GENERAL MEASURES • Lifestyle modifications: – Increase physical activity. – Improve nutrition. – Encourage social interactions – Exercise: may be beneficial for depression in the elderly population (2)[A] • Psychotherapy: Studies do show some benefit in depressed elderly patients (3) [B]: – Cognitive-behavioral therapy – Problem-solving therapy – Interpersonal therapy – Psychodynamic psychotherapy

MEDICATION • Typically more conservative initial dosing and titration of antidepressants in the elderly, starting with 1/2 of the usual initiation dose and increasing within 2 to 4 weeks, as tolerated • Continue titrating dose every 2 to 4 weeks, as appropriate, to reach an adequate treatment dose.

First Line • SSRIs have been found to be effective in treating depression in the elderly and are considered first line in pharmacotherapy for depression (4)[A]. • No single SSRI clearly outperforms others in the class; choice of medication often reflects side effect profile or practitioner familiarity (5)[A]: – Citalopram: Start at 10 mg/day. Treatment range 10 to 20 mg/day – Sertraline: Start at 25 to 50 mg/day. Treatment range 50 to 200 mg/day – Escitalopram: Start at 10 mg/day. Treatment range 10 to 20 mg/day – Fluoxetine: Start at 10 mg/day. Treatment range 20 to 60 mg/day – Paroxetine: Start at 10 mg/day. Treatment range 20 to 40 mg/day • SSRIs should not be used concomitantly with monoamine oxidase inhibitors

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(MAOIs). • Common side effects—increased risk of falls, nausea, diarrhea, sexual dysfunction

Second Line • Atypical antidepressants: more effective than placebo in treatment of depression in the elderly, although additional studies are needed to better delineate patient factors that determine response: – Bupropion (sustained/twice a day and extended/once daily available): Start at 150 mg/day. Increase dose in 3 to 4 days. Treatment range 300 to 450 mg/day. Avoid in patients with elevated seizure risk, tremors, or anxiety (5) [B]. – Venlafaxine (immediate- and extended-release available): Start at 37.5 mg/day extended-release and titrate weekly. Treatment range 150 to 225 mg/day. May be associated with elevated BP at higher doses (5)[C] – Duloxetine: Start at 20 to 30 mg/day. Treatment range 60 to 120 mg/day. Also may be associated with elevated BP (5)[A] – Mirtazapine: Start at 7.5 to 15 mg nightly. Treatment range 30 to 45 mg/day; can produce problems with dry mouth, weight gain, sedation, and cognitive dysfunction (5)[B] – Desvenlafaxine: 50 mg/day in AM; higher doses do not confer additional benefit; 50 mg every other day if CrCl 60 mg have not been demonstrated to be more effective) – Desvenlafaxine (Pristiq): 50 mg/day PO. • Bipolar disorder requires treatment with mood stabilizer. • Among breastfeeding mothers – Breastfeeding should generally not preclude treatment with antidepressants. – SSRIs and some other antidepressants are considered a reasonable option during breastfeeding. – All antidepressants are excreted in breast milk but are generally compatible with lactation. – Paroxetine and sertraline have lower translactal passage. – SSRIs and nortriptyline have a better safety profile. – Translactal passage is greater with fluoxetine and citalopram (4)[B]. – Start with low doses and increase slowly. Monitor infant for adverse side effects. – Continuing an efficacious medication is preferred over switching antidepressants to avoid exposing the mother and infant to the risks of untreated PPD (4)[B]. – Breastfeeding women need additional education and support regarding the risks and benefits of use of antidepressants during breastfeeding. – Consider negative effects of untreated PPD on infant and child development. – Discussions of the treatment options with the patient and her partner when possible. Take into account the patient’s personal psychiatric history and previous response to treatment, the risks of no treatment or undertreatment,

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available data about the safety of medications during breastfeeding, and her individual expectations and treatment preferences (6)[B]. – For further information: http://toxnet.nlm.nih.gov/

Second Line Consider switching to a different antidepressant or augmentation if patient has a lack of response. Electroconvulsive therapy (ECT) is an option for depressed postpartum women who do not respond to antidepressant medications, have severe or psychotic symptoms, cannot tolerate antidepressant medications, are actively engaged in suicidal self-destructive behaviors, or have a previous history of response to ECT (7)[B].

ISSUES FOR REFERRAL • Obtain psychiatric consultation for patients with psychotic symptoms. • Strongly consider immediate hospitalization if delusions or hallucinations are present. • Hospitalization is indicated if mother’s ability to care for self and/or infant is significantly compromised.

ADDITIONAL THERAPIES • Psychoeducation, including providing reading material for the patient and family • Psychotherapy: Interpersonal psychotherapy, cognitive behavioral therapy, and psychodynamic psychotherapy have shown to be effective (5)[B].

COMPLEMENTARY & ALTERNATIVE MEDICINE • Breastfeeding has been associated with reduced stress and improved maternal mood. • Infant massage, infant sleep intervention, exercise, and bright light therapy may be beneficial (7)[B].

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS ALERT Obtain psychiatric consultation for patients with psychotic symptoms. If

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delusions or hallucinations are present, strongly consider immediate hospitalization. The psychotic mother should not be left alone with the baby. • Admission criteria/initial stabilization: presence of suicidal or homicidal ideation and/or psychotic symptoms and/or thoughts of harming baby and/or inability to care for self or infant, severe weight loss • Discharge criteria – Absence of suicidal or homicidal ideation and/or psychotic symptoms and/or thoughts of harming the baby – Mother must be able to care for self and infant.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Collaborative care approach, including primary care visits and case manager follow-ups • Consultation with the infant’s doctor, particularly if the mother is breastfeeding while taking psychotropic medications

DIET • Good nutrition and hydration, especially when breastfeeding • Mixed evidence to support the addition of multivitamin with minerals and omega-3 fatty acids

PATIENT EDUCATION • This Isn’t What I Expected: Overcoming Postpartum Depression, by Karen R. Kleinman and Valerie Davis Raskin • Down Came the Rain: My Journey Through Postpartum Depression, by Brooke Shields, 2005 • Behind the Smile: My Journey Out of Postpartum Depression, by Marie Osmond, Marcia Wilkie, and Judith Moore, 2001 • Web resources – Postpartum Support International: http://www.postpartum.net/ – La Leche League: http://www.llli.org/

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– http://toxnet.nlm.nih.gov/ – http://www.mededppd.org/ – http://www.womensmentalhealth.org/ – http://www.motherrisk.org/ – http://www.step-ppd.com/

PROGNOSIS • Treatment of maternal depression to remission has been shown to have a positive impact on children’s mental health. • Some patients, particularly those with undertreated or undiagnosed depression, may develop chronic depression requiring long-term treatment. • Untreated maternal depression is linked to impaired mother–infant bonding and cognitive and language development delay in infants and children (8). • Postpartum psychosis is associated with tragic outcomes such as maternal suicide and infanticide.

COMPLICATIONS • Suicide • Self-injurious behavior • Psychosis • Neglect of baby • Harm to the baby

REFERENCES 1. Stuart-Parrigon K, Stuart S. Perinatal depression: an update and overview. Curr Psychiatry Rep. 2014;16(9):468. 2. Wisner KL, Sit DK, McShea MC, et al. Onset timing, thoughts of self-harm, and diagnoses in postpartum women with screen-positive depression findings. JAMA Psychiatry. 2013;70(5):490–498. 3. Bobo WV, Yawn PB. Concise review for physicians and other clinicians: postpartum depression. Mayo Clin Proc. 2014;89(6):835–844. 4. Gavin NI, Gaynes BN, Lohr KN, et al. Perinatal depression: a systematic review of prevalence and incidence. Obstet Gynecol. 2005;106(5 Pt 1): 1071– 1083. 5. Cerulli C, Talbot NL, Tang W, et al. Co-occurring intimate partner violence

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and mental health diagnoses in perinatal women. J Womens Health (Larchmt). 2011;20(12):1797–1803. 6. Nicholson WK, Robinson KA, Smallridge RC, et al. Prevalence of postpartum thyroid dysfunction: a quantitative review. Thyroid. 2006;16(6):573–582. 7. Pearlstein T, Howard M, Salisbury A, et al. Postpartum depression. Am J Obstet Gynecol. 2009;200(4):357–364. 8. Fitelson E, Kim S, Baker AS, et al. Treatment of postpartum depression: clinical, psychological and pharmacological options. Int J Womens Health. 2010;3:1–14.

ADDITIONAL READING • Edinburgh Postnatal Depression Scale. http://www.fresno.ucsf.edu/pediatrics/downloads/edinburghscale.pdf. • Gjerdingen D, Katon W, Rich DE. Stepped care treatment of postpartum depression: a primary care-based management model. Womens Health Issues. 2008;18(1):44–52. • Harrington AR, Greene-Harrington CC. Healthy Start screens for depression among urban pregnant, postpartum and interconceptional women. J Natl Med Assoc. 2007;99(3):226–231. • Hirst KP, Moutier CY. Postpartum major depression. Am Fam Physician. 2010;82(8):926–933. • Howard LM, Boath E, Henshaw C. Antidepressant prevention of postnatal depression. PLoS Med. 2006;3(10):e389. • Kendall-Tackett K. A new paradigm for depression in new mothers: the central role of inflammation and how breastfeeding and anti-inflammatory treatments protect maternal mental health. Int Breastfeed J. 2007;2:6. • Musters C, McDonald E, Jones I. Management of postnatal depression. BMJ. 2008;337:a736. • Ng RC, Hirata CK, Yeung W, et al. Pharmacologic treatment for postpartum depression: a systematic review. Pharmacotherapy. 2010;30(9):928–941. • Sit DK, Wisner KL. Identification of postpartum depression. Clin Obstet Gynecol. 2009;52(3):456–468. • Tammentie T, Tarkka MT, Astedt-Kurki P, et al. Family dynamics and

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postnatal depression. J Psychiatr Ment Health Nurs. 2004;11(2):141–149.

CODES ICD10 • F53 Puerperal psychosis • O90.6 Postpartum mood disturbance

CLINICAL PEARLS • PPD is a common, debilitating medical condition that impairs a mother’s ability to function and interact with her infant and family. • Universal screening for depression is recommended during the 1st and 3rd trimester and at regular intervals during the postpartum period. • Early diagnosis and treatment are vital, as untreated PPD can lead to developmental difficulties for the infant and prolonged disability and suffering for the mother. • Breastfeeding is recommended for maternal and child health. Several medication options for treating depression in mothers are safe for breastfeeding infants. • Treatment with antidepressants should be individualized for breastfeeding mothers (4)[B].

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DEPRESSION, TREATMENT RESISTANT Michelle Magid, MD • Roger L. McRoberts, III, MD BASICS DESCRIPTION • Major depressive disorder (MDD) that has failed to respond to ≥2 adequate trials of antidepressant therapy in ≥2 different classes (1) • Antidepressant therapy must be given for 6 weeks at standard doses before being considered a failure.

EPIDEMIOLOGY • Depression affects >18 million people in the United States and >340 million people worldwide. • 16% lifetime risk of MDD • Approximately 1/3 of patients with MDD will develop treatment-resistant depression (2).

ETIOLOGY AND PATHOPHYSIOLOGY • Unclear. Low levels of neurotransmitters (serotonin, norepinephrine, dopamine) have been indicated. • Serotonin has been linked to irritability, hostility, and suicidal ideation. • Norepinephrine has been linked to low energy. • Dopamine may play a role in low motivation and depression with psychotic features. • Environmental stressors such as abuse and neglect may affect neurotransmission. • Inflammation and oxidative stress in the brain can contribute to treatmentresistant depression.

Genetics A genetic abnormality in the serotonin transporter gene (5-HTTLPR) may increase risk for treatment-resistant depression.

RISK FACTORS

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• Severity of disease • Mislabeling patients with depression who are bipolar • Comorbid medical disease (including chronic pain) • Comorbid personality disorder • Comorbid anxiety disorder • Comorbid substance abuse • Familial predisposition to poor response to antidepressants

GENERAL PREVENTION • Medication adherence in combination with psychotherapy • Maintenance electroconvulsive therapy (ECT) may prevent relapse.

COMMONLY ASSOCIATED CONDITIONS • Suicide • Bipolar disorder • Substance use disorders • Anxiety disorders • Dysthymia • Eating disorders • Somatic symptom disorders

DIAGNOSIS HISTORY • Symptoms are the same as in MDD. However, patients do not respond to standard form of treatment. Severity and duration are extreme. • Especially important to screen for suicidality in treatment-resistant depression • Screening with SIGECAPS – Sleep: too much or too little – Interest: failure to enjoy activities – Guilt: excessive and uncontrollable – Energy: poor energy – Concentration: inability to focus on tasks – Appetite: too much or too little – Psychomotor changes: restlessness/agitation or slowing/lethargy

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– Suicidality: desire to end life

PHYSICAL EXAM Mental status exam may reveal poor hygiene, poor eye contact, blunted affect, tearfulness, weight loss or gain, psychomotor retardation, or agitation.

DIFFERENTIAL DIAGNOSIS • Bipolar disorder • Dysthymia • Dementia • Early-stage Parkinson disease • Personality disorder • Medical illness such as malignancy, thyroid disease, HIV • Substance use disorders

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Used to rule out medical factors that could be causing/contributing to treatment resistance – CBC – Complete metabolic profile, including liver tests, calcium, and glucose – Urine drug screen – Thyroid-stimulating hormone (TSH) – Vitamin D level (25-OH vitamin D) – Testosterone, if applicable • CT or MRI of the brain if neurologic disease, tumor, or dementia is suspected. Follow-Up Tests & Special Considerations Delirium and dementia may often look like depression.

Diagnostic Procedures/Other • Depression is a clinical diagnosis. • Validated depression rating scales to assist – Beck Depression Inventory – Hamilton Rating Scale for Depression – Patient Health Questionnaire 9 (PHQ-9)

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TREATMENT MEDICATION First Line • Please see “Depression” topic. When those fail, augmentation and combination strategies are as follows: – Antidepressants in combination Citalopram (start 20 mg/day; max dose 40 mg/day) + bupropion (start 100 mg BID; max dose 450 mg total) (2,3)[B] Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) may be used in combination. Proceed with caution due to risk of serotonin syndrome. Citalopram (start 20 mg/day; max dose 40 mg/day) + nortriptyline (start 50 mg at bedtime; max dose 150 mg at bedtime) – Antidepressants + antipsychotics Citalopram (start 20 mg/day; max dose 40 mg/day) + aripiprazole (2 to 5 mg/day, different mechanism of action at higher doses) OR + risperidone (start 0.5 to 1 mg at bedtime; max dose 6 mg/day) OR + quetiapine (start 25 mg at bedtime; titrate to 100 to 300 mg at bedtime; max dose 600 mg/day) (4,5)[A] – Antidepressant + lithium TCA: nortriptyline (start 50 mg at bedtime; max dose 150 mg at bedtime) + lithium (start 300 mg at bedtime; max dose 900 mg BID) (1,4,6)[A] SSRI: citalopram (start 20 mg/day; max dose 40 mg QD) + lithium (start 300 mg at bedtime; max dose 900 mg BID) (1,2,4)[B] – Antidepressant + thyroid supplementation Citalopram (start 20 mg/day; max dose 40 mg/day) + triiodothyronine (T3) (12.5 to 50 μg/day) (2,7)[B] • In all above combinations, citalopram (Celexa) can be replaced with other SSRIs such as fluoxetine (Prozac) 20 to 80 mg/day, sertraline (Zoloft) 50 to 200 mg/day, and escitalopram (Lexapro) 10 to 20 mg/day or with serotoninnorepinephrine reuptake inhibitors (SNRIs) duloxetine (Cymbalta) 30 to 120 mg/day, venlafaxine XR (Effexor XR) 75 to 225 mg/day, or desvenlafaxine

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(Pristiq) 50 to 100 mg/day. • Maximum doses for medication in treatment-resistant cases may be higher than in treatment-responsive cases.

Second Line • Antidepressant in combination with therapy—in particular cognitivebehavioral therapy (CBT) (8)[B] • Monamine oxidase inhibitor (MAOI) • Tranylcypromine (Parnate): start 10 mg BID, increase 10 mg/day every 1 to 3 weeks; max dose 60 mg/day • Selegiline transdermal (Emsam patch): apply 6-mg patch daily, increase 3 mg/day; max dose 12 mg/day • Side-effect profile (e.g., hypertensive crisis), drug–drug interactions, and dietary restrictions make MAOIs less appealing. Patch version does not require dietary restrictions at lower doses. • High risk of serotonin syndrome, if combined with another antidepressant; 2week washout period is advised.

ISSUES FOR REFERRAL Treatment-resistant depression should be managed in consultation with a psychiatrist.

ADDITIONAL THERAPIES • First line – ECT: safe and effective treatment for treatment-resistant and lifethreatening depression, with a 60–90% success rate (9,10)[A]: Known to rapidly relieve suicidality, psychotic depression, and catatonia Controversy due to cognitive side effects during the treatment 3 types of lead placements Bitemporal: rapid and effective. Usually need 6 to 10 treatments at 1.5× seizure threshold Right unilateral: may be slightly less rapid but fewer cognitive side effects. Usually need 8 to 12 treatments at 6× seizure threshold Bifrontal: newer technique that may offer similar speed to bitemporal, with slightly improved side-effect profile

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• Second line – Deep brain stimulation (DBS): surgical implantation of intracranial electrodes, connected to an impulse generator implanted in the chest wall (11,12)[C]: Reserved for those who have failed medications, psychotherapy, and ECT Preliminary data are promising, showing 40–70% response rate and 35% remission rate, but further trials are warranted. – Repetitive transcranial magnetic stimulation (rTCMS): noninvasive brain stimulation technique that is generally safe. A few case reports on efficacy in treatment-resistant depression but thus far is only FDA approved for less severe forms of the illness (6,12)[C]. – Vagus nerve stimulation (VNS): Surgical implantation of electrodes onto left vagus nerve. Its use in treatment-resistant depression has become limited in recent years (11)[C]. – Ketamine—not FDA approved, but evidence of rapid improvement in mood and suicidal thinking, although the literature is limited. In addition, the effects of ketamine appear temporary, disappearing after days to weeks (6,13)[C].

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Inpatient care is indicated for severely depressed, psychotic, catatonic, or suicidal patients. • Discharge criteria: symptoms improving, no longer suicidal, psychosocial stressors addressed

ONGOING CARE FOLLOW-UP RECOMMENDATIONS • Frequent visits (i.e., every month) • During follow-up, evaluate side effects, dosage, and effectiveness of medication as well as need for referral to ECT. • Patients who have responded to ECT may need maintenance treatments (q3– 12wk) to prevent relapse.

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• Combination of lithium/nortriptyline after ECT appears to be as effective as maintenance ECT in reducing relapse.

DIET Patients on MAOIs need dietary restriction.

PATIENT EDUCATION Educate patients that depression is a medical illness, not a character defect. • Review signs and symptoms of worsening depression and when patient needs to come in for further evaluation. • Discuss safety plan to address suicidal thoughts.

PROGNOSIS With medication adherence, close follow-up, improved social support, and psychotherapy, prognosis improves.

COMPLICATIONS • Suicide • Disability • Poor quality of life

REFERENCES 1. Keller MB. Issues in treatment-resistant depression. J Clin Psychiatry. 2005;66(Suppl 8):5–12. 2. Rush AJ, Trivedi MH, Wisniewski SR, et al. Acute and longer-term outcomes in depressed outpatients requiring one or several treatment steps: a STAR*D report. Am J Psychiatry. 2006;163(11):1905–1917. 3. Trivedi MH, Fava M, Wisniewski SR, et al. Medication augmentation after the failure of SSRIs for depression. N Engl J Med. 2006;354(12):1243– 1252. 4. Hicks P, Hicks XP, Meyer H, et al. How best to manage treatment-resistant depression? J Fam Pract. 2010;59(9);490–497. 5. Maglione M, Maher AR, Hu JH, et al. Off-Label Use of Atypical Antipsychotics: An Update. Rockville, MD: Agency for Healthcare Research and Quality; 2011.

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6. Holtzheimer PE. Advances in the management of treatment-resistant depression. Focus (Am Psychiatr Publ). 2010;8(4):488–500. 7. Nierenberg AA, Fava M, Trivedi MH, et al. A comparison of lithium and T(3) augmentation following two failed medication treatments for depression: a STAR*D report. Am J Psychiatry. 2006;163(9):1519–1530. 8. Wiles NJ, Thomas L, Turner N, et al. Long-term effectiveness and costeffectiveness of cognitive behavioral therapy as an adjunct to pharmacotherapy for treatment-resistant depression in primary care: followup of the CoBalT randomised controlled trial. Lancet Psychiatry. 2016;3(2);137–144. 9. Gelenberg AJ, Freeman MP, Markowitz JC, et al; for the American Psychiatric Association Work Group on Major Depressive Disorder. Practice guideline for the treatment of patients with major depressive disorder, third edition. Am J Psychiatry. 2010;167(Suppl):1–118. 10. Weiner RD. The Practice of Electroconvulsive Therapy: Recommendations for Treatment, Training, and Privileging: A Task Force Report of the American Psychiatric Association. 2nd ed. Washington, DC: American Psychiatric Association; 2001:5–25. 11. Morishita T, Fayad SM, Higuchi MA, et al. Deep brain stimulation for treatment-resistant depression: systematic review of clinical outcomes. Neurotherapeutics. 2014;11(3):475–484. 12. Holtzheimer PE III, Mayberg HS. Deep brain stimulation for treatmentresistant depression. Am J Psychiatry. 2010;167(12):1437–1444. 13. Caddy C, Giaroli G, White TP, et al. Ketamine as the prototype glutamatergic antidepressant: pharmacodynamic actions, and a systematic review and meta-analysis of efficacy. Ther Adv Psychopharmacol. 2014;4(2):75–99.

CODES ICD10 • F32.9 Major depressive disorder, single episode, unspecified • F33.9 Major depressive disorder, recurrent, unspecified

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CLINICAL PEARLS • Treatment-resistant depression is common, affecting 1/3 of those with MDD. • Combination and augmentation strategies with antidepressants, antipsychotics, therapy, and mood stabilizers can be helpful. • ECT should be considered in severe and life-threatening cases.

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DERMATITIS HERPETIFORMIS Geoffrey Strider Farnsworth, MD BASICS DESCRIPTION • Dermatitis herpetiformis (DH) presents as a chronic, relapsing, polymorphous, intensely pruritic, erythematous papulovesicular eruption with symmetrical distribution primarily involving extensor skin surfaces of the elbows, knees, buttocks, back, and scalp. • DH is an autoimmune disease associated with gluten sensitivity with genetic, environmental, and immunologic influences. • DH is distinguished from other bullous diseases by characteristic histologic and immunologic findings, as well as associated gluten-sensitive enteropathy (GSE). • System(s) affected: skin • Synonym(s): Duhring disease, Duhring-Brocq disease

EPIDEMIOLOGY • Occurs most frequently in those of Northern European origin • Rare in persons of Asian or African American origin • Predominant age: most common in 4th and 5th decades but may present at any age • Childhood DH is rare in most countries, although an Italian study showed 27% of patients were younger than the age of 10 and 36% younger than the age of 20. • Predominant gender: Adults: male > female (1.5:1 in the United States, 2:1 worldwide) Children: female > male

Incidence 1/100,000 persons per year in the United States

Prevalence 11/100,000 persons in the U.S. population; as high as 39/100,000 persons

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worldwide

ETIOLOGY AND PATHOPHYSIOLOGY • Evidence suggests that epidermal transglutaminase (eTG) 3, a keratinocyte enzyme involved in cell envelope formation and maintenance, is the autoantigen in DH. • eTG is highly homologous with tissue transglutaminase (tTG), which is the antigenic target in celiac disease and GSE. • The initiating event for DH is presumed to be the interaction of wheat peptides with tTGs, which results in the formation of an autoantigen with high affinity for particular class II major histocompatibility complex (MHC) molecules. • Presentation of the autoantigen leads to activation of T cells and the humoral immune system. • IgA antibodies against tTG cross-react with eTG and result in IgA-eTG immune complexes that are deposited in the papillary dermis. Subsequent activation of complement and recruitment of neutrophils to the area result in inflammation and microabscesses. • Skin eruption may be delayed up to 5 to 6 weeks after exposure to gluten. • Gluten applied directly to the skin does not result in the eruption, whereas gluten taken by mouth or rectum does. This implies necessary processing by the GI system. • Thought to be immune complex–mediated disease

Genetics • High association with human leukocyte antigen DQ2 (95%), with remaining patients being positive for DQ8, DR4, or DR3 • Strong association with combination of alleles DQA1*0501 and DQB1*0201/0202, DRB1*03 and DRB1*05/07, or DQA1*0301 and DQB1*0302

RISK FACTORS • GSE: >90% of those with DH will have GSE, which may be asymptomatic. • Family history of DH or celiac disease

GENERAL PREVENTION

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Gluten-free diet (GFD) results in improvement of DH and reduces dependence on medical therapy. GFD also may reduce the risk of lymphomas associated with DH.

COMMONLY ASSOCIATED CONDITIONS • Hypothyroidism is the most common autoimmune condition associated with DH. • GSE, gluten ataxia • Gastric atrophy, hypochlorhydria, pernicious anemia • GI lymphoma, non-Hodgkin lymphoma • Hyperthyroidism, thyroid nodules, thyroid cancer • IgA nephropathy • Autoimmune disorders, including systemic lupus erythematosus, dermatomyositis, Sjögren syndrome, rheumatoid arthritis, sarcoidosis, Raynaud phenomenon, insulin-dependent diabetes mellitus, myasthenia gravis, Addison disease, vitiligo, alopecia areata, primary biliary cirrhosis, and psoriasis

DIAGNOSIS Diagnosis of DH involves a clinicopathologic correlation among clinical presentation, histologic and direct immunofluorescence evaluation, serology, and response to therapy or dietary restriction.

HISTORY • Waxing and waning, intensely pruritic eruption with papules and tiny vesicles • Eruption may worsen with gluten intake. • GI symptoms may be absent or may not be reported until prompted.

PHYSICAL EXAM • Classic lesions described as symmetric, grouped, erythematous papules and vesicles • More commonly presents with erosions, excoriations, lichenification, hypopigmentation, and/or hyperpigmentation secondary to scratching and healing of old lesions

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• Areas involved include extensor surfaces of elbows (90%), knees (30%), shoulders, buttocks, and sacrum. The scalp is also frequently affected. Oral lesions are rare. • In children, purpura may be visible on digits and palmoplantar surfaces. • Adults with associated enteropathy are most often asymptomatic, with about 20% experiencing steatorrhea and 90% specific for DH in patients on unrestricted diets (1,2) [A]. • Serum IgA eTG antibodies: Antibodies to eTG, the primary autoantigen in DH, were shown to be more sensitive than antibodies to tTG in the diagnosis of patients with DH on unrestricted diets (95% vs. 79%) but is not widely available in all labs (1,2)[A]. • Serum IgA endomysial antibodies: have a sensitivity between 50% and 100%

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and a specificity close to 100% in patients on unrestricted diets but is more expensive, time-consuming, and operator-dependent than tTG (2) Follow-Up Tests & Special Considerations Serologic assessment of anti-tTG and anti-eTG correlate with intestinal involvement of disease and in conjunction with antiendomysial antibodies (EMA) may be useful in monitoring major deviations from GFD (1,2).

Diagnostic Procedures/Other The “gold standard” for diagnosing DH is a skin biopsy of perilesional skin evaluated via direct immunofluorescence, which demonstrates granular IgA deposited in dermal papillae and/or basement membrane (1,2)[A],(3)[C].

Test Interpretation • Direct immunofluorescence of perilesional skin reveals a granular pattern of IgA deposition in the dermal papillae (1,2). • Histopathology of lesion with routine staining reveals neutrophilic microabscesses in the tips of the dermal papillae and may show subepidermal blistering (1,2).

TREATMENT GENERAL MEASURES • GFD is the mainstay of treatment and can lead to complete resolution of symptoms (1,2)[A]. • Typically requires 18 to 24 months of strict adherence to GFD prior to resolution of skin lesions without other treatment. • Lesions can recur within 12 weeks of reintroduction of gluten.

MEDICATION Medication is useful for immediate symptom management but should be used as an adjunct to dietary modification (2).

First Line • Dapsone is approved by the FDA for use in DH and is the most widely used medication (2,4)[A]. Initial dosing of 50 mg/day typically results in

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improvement of symptoms within 24 to 48 hours; can increase dose to 200 mg to obtain control (1)[C]. Use minimum effective dose with slow titration based on patient response and tolerability. Average maintenance dose is 1 mg/kg/day (50 to 150 mg/day). Minor outbreaks on the face and scalp are common even with treatment. Not ideal for long-term use in DH. • Dapsone works by inhibiting neutrophil recruitment and IL-8 release, inhibiting the respiratory burst of neutrophils, and protecting cells from neutrophil-mediated injury, thereby suppressing the skin reaction. It has no role in preventing IgA deposition or mitigating the immune reaction in the gut (2,4). • Precautions – Common side effects include nausea, vomiting, headache, dizziness, weakness, and hemolysis. – A drop in hemoglobin of 1 to 2 g is characteristic with dapsone 100 mg/day. – G6PD deficiency increases severity of hemolytic stress. Dapsone should be avoided, if possible, in those who are G6PD-deficient. – Dose-related methemoglobinemia may occur with doses >100 mg/day. Cimetidine may reduce the severity of this side effect. – Risk of distal motor neuropathy

ALERT • Monitor for potentially fatal dapsone-induced sulfone syndrome: fever, jaundice and hepatic necrosis, exfoliative dermatitis, lymphadenopathy, methemoglobinemia, and hemolytic anemia. • Can occur 48 hours or 6 months after treatment, most often 5 weeks after initiation

Pediatric Considerations • 2 years: 0.5 to 1.0 mg/kg/day

Pregnancy Considerations • Category C: Safety during pregnancy is not established. • Secreted in breast milk and will produce hemolytic anemia in infants • Adherence to a strict GFD 6 to 12 months before conception should be

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considered with the hope of eliminating need for dapsone during pregnancy.

Second Line • High-potency topical steroids can be used acutely to control symptoms until dapsone becomes effective (1)[C]. • Sulfapyridine (1 to 2 g/day) is FDA approved for use in DH and is thought to be the active metabolite in sulfasalazine (2 to 4 g/day) (2,5)[B]. Common side effects include nausea, vomiting, and anorexia. Enteric-coated form may reduce side effects. Other side effects include agranulocytosis, hypersensitivity reactions, hemolytic anemia, proteinuria, and crystalluria (2,5).

ISSUES FOR REFERRAL Over time, interdisciplinary treatment may involve a dermatologist, gastroenterologist, and registered dietician. Genetic counseling and testing should be considered on diagnosis (1,2).

ADDITIONAL THERAPIES A single case report describes topical dapsone therapy as potential alternative treatment or as an adjunct to oral dapsone to decrease systemic exposure and risk of severe side effects. However, it has not been studied extensively (6)[C].

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Every 6 to 12 months by physician and dietician to evaluate GFD adherence and recurrence of symptoms • Adherence to GFD can be monitored with serologic levels of anti-tTG, anti eTG, and EMA levels (1). • Patients on dapsone require lab monitoring weekly for the 1st month, biweekly for 2 months, then every 3 months for the duration of medication use (1,4).

DIET

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GFD • Grains that should be avoided: wheat (includes spelt, kamut, semolina, and triticale), rye, and barley (including malt) • Safe grains (gluten-free): rice, amaranth, buckwheat, corn, millet, quinoa, sorghum, teff (an Ethiopian cereal grain), and oats • Care should be taken to avoid gluten-free grains that are contaminated with sources of gluten during processing such as oats. • Sources of gluten-free starches that can be used as flour alternatives – Cereal grains: amaranth, buckwheat, corn, millet, quinoa, sorghum, teff, rice (white, brown, wild, basmati, jasmine), and montina – Tubers: arrowroot, jicama, taro, potato, and tapioca – Legumes: chickpeas, lentils, kidney beans, navy beans, pea beans, peanuts, and soybeans – Nuts: almonds, walnuts, chestnuts, hazelnuts, and cashews – Seeds: sunflower, flax, and pumpkin

PATIENT EDUCATION • Patients on dapsone should be made aware of potential hemolytic anemia and the signs associated with methemoglobinemia. • American Academy of Dermatology, 930 N. Meacham Road, P.O. Box 4014, Schaumberg, IL 60168-4014; (708) 330-0230 • The University of Chicago Celiac Disease Center, 5841 S. Maryland Ave., Mail Code 4069, Chicago, IL 60637; (773) 702-7593; www.celiacdisease.net or http://www.cureceliacdisease.org/ • Gluten Intolerance Group of North America, 31214-124 Ave. SE, Auburn, WA 98092; (206) 246-6652; fax (206) 246-6531; https://www.gluten.org/ • The Celiac Disease Foundation, 13251 Ventura Blvd., #1, Studio City, CA 9160; (818) 990-2354; fax (818) 990-2379

PROGNOSIS • Lifelong disease with favorable prognosis • 10- to 15-year survival rates do not seem to differ from general population. • Remission in 10–15% • Skin disease responds readily to dapsone. Occasional new lesions (2 to 3 per week) are to be expected and are not an indication for altering daily dosage.

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• Strict adherence to a GFD improves clinical symptoms and decreases dapsone requirement. GFD is the only sustainable method of eliminating cutaneous and GI disease. • Risk of lymphoma may be decreased in those who maintain a GFD.

COMPLICATIONS • Majority of complications are associated with GSE. • Malnutrition, weight loss, nutritional deficiencies (folate, B12, iron) • Abdominal pain, dyspepsia • Osteoporosis, dental abnormalities • Autoimmune diseases • Lymphomas

REFERENCES 1. Antiga E, Caproni M. The diagnosis and treatment of dermatitis herpetiformis. Clin Cosmet Investig Dermatol. 2015;8:257–265. 2. Bolotin D, Petronic-Rosic V. Dermatitis herpetiformis. Part II. Diagnosis, management, and prognosis. J Am Acad Dermatol. 2011;64(6):1027–1033. 3. Junkins-Hopkins JM. Dermatitis herpetiformis: pearls and pitfalls in diagnosis and management. J Am Acad Dermatol. 2010;63(3):526–528. 4. Wozel G, Blasum C. Dapsone in dermatology and beyond. Arch Dermatol Res. 2014;306(2):103–124. 5. Willsteed E, Lee M, Wong LC, et al. Sulfasalazine and dermatitis herpetiformis. Australas J Dermatol. 2005;46(2):101–103. 6. Handler MZ, Chacon AH, Shiman MI, et al. Letter to the editor: application of dapsone 5% gel in a patient with dermatitis herpetiformis. J Dermatol Case Rep. 2012;6(4):132–133.

ADDITIONAL READING • Bolotin D, Petronic-Rosic V. Dermatitis herpetiformis. Part I. Epidemiology, pathogenesis, and clinical presentation. J Am Acad Dermatol. 2011;64(6):1017–1024. • Cardones AR, Hall RP III. Management of dermatitis herpetiformis. Immunol

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Allergy Clin North Am. 2012;32(2):275–281. • Cardones AR, Hall RP III. Pathophysiology of dermatitis herpetiformis: a model for cutaneous manifestations of gastrointestinal inflammation. Immunol Allergy Clin North Am. 2012;32(2):263–274. • Kárpáti S. An exception within the group of autoimmune blistering diseases: dermatitis herpetiformis, the gluten-sensitive dermopathy. Immunol Allergy Clin North Am. 2012;32(2):255–262. • Paek SY, Steinberg SM, Katz SI. Remission in dermatitis herpetiformis: a cohort study. Arch Dermatol. 2011;147(3):301–305.

SEE ALSO • Celiac Disease • Algorithm: Rash, Focal

CODES ICD10 L13.0 Dermatitis herpetiformis

CLINICAL PEARLS • DH is a chronic, relapsing, intensely pruritic rash that often presents with erosions, excoriations, lichenification, and pigmentary changes secondary to scratching and healing of old papulovesicular lesions. • Strong association with gluten-sensitive enteropathy • Diagnosis established with perilesional skin biopsy showing direct immunofluorescence demonstrating granular IgA deposits in the dermal papillae. • Serologic levels of IgA transglutaminase aid in diagnosis and monitoring of deviations from GFD. • Mainstay of treatment is a GFD with dapsone used primarily for short-term symptom relief.

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DERMATITIS, ATOPIC Dennis E. Hughes, DO, FAAFP, FACEP BASICS DESCRIPTION • A chronic, relapsing, pruritic eczematous condition affecting characteristic sites • Early onset cases have coexisting allergen sensitization more often than late onset. • Clinical phenotypical presentation is highly variable, suggesting multifactorial pathophysiology. • May have significant effect on quality of life for patient and family

EPIDEMIOLOGY • 45% of all cases begin in the first 6 months of life with 95% onset prior to age 5 years. • 70% of affected children will have a spontaneous remission before adolescence. • Incidence on the rise for the past 3 decades in industrialized countries; overall, affects ~15% of children at some time (United States) • Also, may have late-onset dermatitis in adults or relapse of childhood condition—primarily hand eczema • Asians and blacks are affected more often than whites. • 60% if one parent is affected; rises to 80% if both parents are affected

ETIOLOGY • Two main hypothesis: immunologic with unbalanced immune response and/or skin barrier dysfunction (1) • Alteration in stratum corneum results in transepidermal water loss and defect in barrier function. • Epidermal adhesion is reduced either as a result of (i) genetic mutation resulting in altered epidermal proteins or (ii) defect in immune regulation causing an altered inflammatory response.

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• Interleukin-31 (IL-31) upregulation is thought to be a major factor in pruritus mediated by cytokines and neuropeptides rather than histamine excess.

Genetics • Recent discovery of association between atopic dermatitis (AD) and mutation in the filaggrin gene (on chromosome 1), which codes for a skin barrier protein (2) • Both epidermal and immune coding likely involved

RISK FACTORS • “Itch–scratch cycle” (stimulates histamine release) • Skin infections • Emotional stress • Irritating clothes and chemicals • Excessively hot or cold climate • Food allergy in children (in some cases) • Exposure to tobacco smoke • Family history of atopy – Asthma – Allergic rhinitis

COMMONLY ASSOCIATED CONDITIONS • Food sensitivity/allergy in many cases • Asthma • Allergic rhinitis • Hyper-IgE syndrome (Job syndrome) – AD – Elevated IgE – Recurrent pyodermas – Decreased chemotaxis of mononuclear cells

DIAGNOSIS HISTORY Presence of major symptoms, including relapsing of condition, family history,

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typical distribution, and morphology necessary to make diagnosis of AD

PHYSICAL EXAM Primarily skin manifestations • Distribution of lesions – Infants: trunk, face, and flexural surfaces; diaper-sparing – Children: antecubital and popliteal fossae – Adults: hands, feet, face, neck, upper chest, and genital areas • Morphology of lesions – Infants: erythema and papules; may develop oozing, crusting vesicles – Children and adults: Lichenification and scaling are typical with chronic eczema as a result of persistent scratching and rubbing (lichenification rare in infants). • Associated signs – Facial erythema, mild to moderate – Perioral pallor – Infraorbital fold (Dennie sign/Morgan line)-atopic pleat – Dry skin progressing to ichthyosis – Increased palmar linear markings – Pityriasis alba (hypopigmented asymptomatic areas on face and shoulders) – Keratosis pilaris

DIFFERENTIAL DIAGNOSIS • Photosensitivity rashes • Contact dermatitis (especially if only the face is involved) • Scabies • Seborrheic dermatitis (especially in infants) • Psoriasis or lichen simplex chronicus if only localized disease is present in adults • Rare conditions of infancy – Histiocytosis X – Wiskott-Aldrich syndrome – Ataxia-telangiectasia syndrome • Ichthyosis vulgaris

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DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • No test is diagnostic. • Serum IgE levels are elevated in as many as 80% of affected individuals, but test is not routinely ordered. • Eosinophilia tends to correlate with disease severity. • Scoring atopic dermatitis (SCORAD) is scoring system for AD comprising scores for area, intensity, and subjective symptoms.

TREATMENT GENERAL MEASURES • Minimize flare-ups and control the duration and intensity of flare-up. • Avoid agents that may cause irritation (e.g., wool, perfumes). • Minimize sweating. • Lukewarm (not hot) bathing • Minimize use of soap (superfatted soaps best). • Sun exposure may be helpful. • Humidify the house. • Avoid excessive contact with water. • Avoid lotions that contain alcohol. • If very resistant to treatment, search for a coexisting contact dermatitis.

Pediatric Considerations Chronic potent fluorinated corticosteroid use may cause striae, hypopigmentation, or atrophy, especially in children.

MEDICATION First Line • Frequent systemic lubrication with thick emollient creams (e.g., Eucerin, Vaseline) over moist skin is the mainstay of treatment before any other intervention is considered (1)[A]. • Infants and children: 0.5–1% topical hydrocortisone creams or ointments (use the “fingertip unit [FTU]” dosing) (1)[C]

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• Adults: higher potency topical corticosteroids in areas other than face and skin folds • Short-course, higher potency corticosteroids for flares; then return to the lowest potency (creams preferred) that will control dermatitis. • Antihistamines for pruritus (e.g., hydroxyzine 10 to 25 mg at bedtime and as needed)

Second Line • Topical immunomodulators (tacrolimus or pimecrolimus) for episodic use for children >2 years. There is a black box warning from the FDA regarding potential cancer risk. • Plastic occlusion in combination with topical medication to promote absorption • For severe AD, consider systemic steroids for 1 to 2 weeks (e.g., prednisone 2 mg/kg/day PO [max 80 mg/day] initially, tapered over 7 to 14 days). • Topical tricyclic doxepin, as a 5% cream, may decrease pruritus. • Modified Goeckerman regimen (tar and ultraviolet light) • Low-dose methotrexate was established as effective treatment in adults, and recent review suggests it is safe for children and adolescents (3)[B].

ISSUES FOR REFERRAL • Ophthalmology evaluation for persistent vernal conjunctivitis • If using topical steroids around eyes for extended periods, ophthalmology follow-up for cataract evaluation

ADDITIONAL THERAPIES • Methods to reduce house mite allergens (micropore filters on heating, ventilation, and air-conditioning systems; impermeable mattress covers) • Behavioral relaxation therapy to reduce scratching • Bleach baths may reduce staph colonization, but definitive evidence for benefit in the condition is lacking. Recommend 1/2 cup of standard 6% household bleach for a full tub of water and soak for 5 to 10 minutes, blotting skin dry upon leaving the bath.

COMPLEMENTARY & ALTERNATIVE MEDICINE • Evening primrose oil (includes high content of fatty acids)

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– May decrease prostaglandin synthesis – May promote conversion of linoleic acid to omega-6 fatty acid • Probiotics may reduce the severity of the condition, thus reducing medication use.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring Evaluate to ensure that secondary bacterial or fungal infection does not develop as a result of disruption of the skin barrier. Most patients with AD are colonized by Staphylococcus. There is a little evidence for the routine use of antimicrobial interventions to reduce skin bacteria, but treatment of clinical infection with coverage for Staphylococcus is recommended.

DIET • Trials of elimination may find certain “triggers” in some patients. • Breastfeeding in conjunction with maternal hypoallergenic diets may decrease the severity in some infants.

PATIENT EDUCATION • http://www.aad.org/skin-conditions/dermatology-a-to-z/atopic-dermatitis • National Eczema Association: www.nationaleczema.org

PROGNOSIS • Chronic disease • Declines with increasing age • 90% of patients have spontaneous resolution by puberty. • Localized eczema (e.g., chronic hand or foot dermatitis, eyelid dermatitis, or lichen simplex chronicus) may continue in some adults.

COMPLICATIONS • Cataracts are more common in patients with AD. • Skin infections (usually Staphylococcus aureus); sometimes subclinical • Eczema herpeticum

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– Generalized vesiculopustular eruption caused by infection with herpes simplex or vaccinia virus – Causes acute illness requiring hospitalization • Atrophy and/or striae if fluorinated corticosteroids are used on face or skin folds • Systemic absorption may occur if large areas of skin are treated, particularly if high-potency medications and occlusion are combined.

REFERENCES 1. Thomsen SF. Atopic dermatitis: natural history, diagnosis, and treatment. ISRN Allergy. 2014;2014:354250. 2. Wollenberg A, Seba A, Antal AS. Immunological and molecular targets of atopic dermatitis treatment. Br J Dermatol. 2014;170(Suppl 1):7–11. 3. Deo M, Yung A, Hill S, et al. Methotrexate for treatment of atopic dermatitis in children and adolescents. Int J Dermatol. 2014;53(8):1037–1041.

ADDITIONAL READING • Boguniewicz M, Leung DY. Recent insights into atopic dermatitis and implications for management of infectious complications. J Allergy Clin Immunol. 2010;125(1):4–13. • Catherine Mack Correa M, Nebus J. Management of patients with atopic dermatitis: the role of emollient therapy. Dermatol Res Pract. 2012;2012:836931. • Lifschitz C. The impact of atopic dermatitis on quality of life. Ann Nutr Metab. 2015;66(Suppl 1):34–40.

SEE ALSO Algorithm: Rash, Focal

CODES ICD10

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• L20.9 Atopic dermatitis, unspecified • L20.89 Other atopic dermatitis • L20.83 Infantile (acute) (chronic) eczema

CLINICAL PEARLS • Institute early and proactive treatment to reduce inflammation. Use the lowest potency topical steroid that controls symptoms. • Monitor for secondary bacterial infection. • Frequent systemic lubrication with thick emollient creams (e.g., Eucerin, Vaseline) over moist skin is the mainstay of treatment before any other intervention is considered.

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DERMATITIS, CONTACT Aamir Siddiqi, MD BASICS DESCRIPTION • A cutaneous reaction to an external substance • Primary irritant dermatitis is due to direct injury of the skin. It affects individuals exposed to specific irritants and generally produces discomfort immediately after exposure (1). • Allergic contact dermatitis (ACD) affects only individuals previously sensitized to a substance. It represents a delayed hypersensitivity reaction, requiring several hours for the cascade of cellular immunity to be completed to manifest itself (2). • System(s) affected: skin/exocrine • Synonym(s): dermatitis venenata

EPIDEMIOLOGY Common

Incidence Occupational contact dermatitis: 20.5/100,000 workers/year in one Australian study

Prevalence • Contact dermatitis represents >90% of all occupational skin disorders. • Predominant sex: male = female – Variations due to differences in exposure to offending agents, as well as normal cutaneous variations between males and females (eccrine and sebaceous gland function and hair distribution)

Geriatric Considerations Increased incidence of irritant dermatitis secondary to skin dryness

Pediatric Considerations

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Increased incidence of positive patch testing due to better delayed hypersensitivity reactions (3)

ETIOLOGY AND PATHOPHYSIOLOGY Hypersensitivity reaction to a substance generating cellular immunity response (4) • Plants – Urushiol (allergen): poison ivy, poison oak, poison sumac – Primary contact: plant (roots/stems/leaves) – Secondary contact: clothes/fingernails (not blister fluid) • Chemicals – Nickel: jewelry, zippers, hooks, and watches (5) – Potassium dichromate: tanning agent in leather – Paraphenylenediamine: hair dyes, fur dyes, and industrial chemicals – Turpentine: cleaning agents, polishes, and waxes – Soaps and detergents • Topical medicines – Neomycin: topical antibiotics – Thimerosal (Merthiolate): preservative in topical medications – Anesthetics: benzocaine – Parabens: preservative in topical medications – Formalin: cosmetics, shampoos, and nail enamel

Genetics Increased frequency of ACD in families with allergies

RISK FACTORS • Occupation • Hobbies • Travel • Cosmetics • Jewelry

GENERAL PREVENTION • Avoid causative agents. • Use of protective gloves (with cotton lining) may be helpful.

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DIAGNOSIS HISTORY • Itchy rash • Assess for prior exposure to irritating substance.

PHYSICAL EXAM • Acute – Papules, vesicles, bullae with surrounding erythema – Crusting and oozing – Pruritus • Chronic – Erythematous base – Thickening with lichenification – Scaling – Fissuring • Distribution – Where epidermis is thinner (eyelids, genitalia) – Areas of contact with offending agent (e.g., nail polish) – Palms and soles relatively more resistant, although hand dermatitis is common. – Deeper skin folds spared – Linear arrays of lesions – Lesions with sharp borders and sharp angles are pathognomonic. • Well-demarcated area with a papulovesicular rash

DIFFERENTIAL DIAGNOSIS • Based on clinical impression – Appearance, periodicity, and localization • Groups of vesicles – Herpes simplex • Diffuse bullous or vesicular lesions – Bullous pemphigoid • Photodistribution – Phototoxic/allergic reaction to systemic allergen

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• Eyelids – Seborrheic dermatitis • Scaly eczematous lesions – Atopic dermatitis – Nummular eczema – Lichen simplex chronicus – Stasis dermatitis – Xerosis

DIAGNOSTIC TESTS & INTERPRETATION Diagnostic Procedures/Other Consider patch tests for suspected allergic trigger (systemic corticosteroids or recent, aggressive use of topical steroids may alter results).

Test Interpretation • Intercellular edema • Bullae

TREATMENT GENERAL MEASURES • Remove offending agent: – Avoidance – Work modification – Protective clothing – Barrier creams, especially high-lipid content moisturizing creams (e.g., Keri lotion, petrolatum, coconut oil) • Topical soaks with cool tap water, Burow solution (1:40 dilution), saline (1 tsp/pt water), or silver nitrate solution • Lukewarm water baths • Aveeno oatmeal baths • Emollients (white petrolatum, Eucerin)

MEDICATION First Line

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• Topical medications (6)[A] – Lotion of zinc oxide, talc, menthol 0.15% (Gold Bond), phenol 0.5% – Corticosteroids for ACD as well as irritant dermatitis High-potency steroids: fluocinonide (Lidex) 0.05% gel, cream, or ointment TID–QID Use high-potency steroids only for a short time, then switch to low- or medium-potency steroid cream or ointment Caution regarding face/skin folds: use lower potency steroids, and avoid prolonged usage. Switch to lower potency topical steroid once the acute phase is resolved. • Calamine lotion for symptomatic relief • Topical antibiotics for secondary infection (bacitracin, erythromycin) • Systemic – Antihistamine Hydroxyzine: 25 to 50 mg PO QID, especially useful for itching Diphenhydramine: 25 to 50 mg PO QID Cetirizine 10 mg PO BID–TID • Corticosteroids – Prednisone: taper starting at 60 to 80 mg/day PO, over 10 to 14 days – Used for moderate to severe cases – May use burst dose of steroids for up to 5 days • Antibiotics for secondary skin infections – Dicloxacillin: 250 to 500 mg PO QID for 7 to 10 days – Amoxicillin-clavulanate (Augmentin): 500 mg PO BID for 7 to 10 days – Erythromycin: 250 mg PO QID in penicillin-allergic patients – Trimethoprim-sulfamethoxazole (Bactrim DS): 160 mg/800 mg (1 tablet) PO BID for 7 to 10 days (suspected resistant Staphylococcus aureus) • Precautions – Antihistamines may cause drowsiness. – Prolonged use of potent topical steroids may cause local skin effects (atrophy, stria, telangiectasia). – Use tapering dose of oral steroids if using >5 days.

Second Line

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Other topical or systemic antibiotics, depending on organisms and sensitivity

Pregnancy Considerations Usual caution with medications.

ISSUES FOR REFERRAL May need referral to a dermatologist or allergist if refractory to conventional treatment

COMPLEMENTARY & ALTERNATIVE MEDICINE The use of complementary and alternative treatment is a supplement and not an alternative to conventional treatment.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS Rarely needs hospital admission

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Stay active, but avoid overheating.

Patient Monitoring • As necessary for recurrence • Patch testing for etiology after resolved

DIET No special diet

PATIENT EDUCATION • Avoidance of irritating substance • Cleaning of secondary sources (nails, clothes) • Fallacy of blister fluid spreading disease

PROGNOSIS • Self-limited • Benign

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COMPLICATIONS • Generalized eruption secondary to autosensitization • Secondary bacterial infection

REFERENCES 1. Ale IS, Maibacht HA. Diagnostic approach in allergic and irritant contact dermatitis. Expert Rev Clin Immunol. 2010;6(2):291–310. 2. Tan CH, Rasool S, Johnston GA. Contact dermatitis: allergic and irritant. Clin Dermatol. 2014;32(1):116–124. 3. Admani S, Jacob SE. Allergic contact dermatitis in children: review of the past decade. Curr Allergy Asthma Rep. 2014;14(4):421. 4. Martin SF. Contact dermatitis: from pathomechanisms to immunotoxicology. Exp Dermatol. 2012;21(5):382–389. 5. Tuchman M, Silverberg JI, Jacob SE, et al. Nickel contact dermatitis in children. Clin Dermatol. 2015;33(3):320–326. 6. Usatine RP, Riojas M. Diagnosis and management of contact dermatitis. Am Fam Physician. 2010;82(3):249–255.

ADDITIONAL READING SEE ALSO Algorithm: Rash, Focal

CODES ICD10 • L25.9 Unspecified contact dermatitis, unspecified cause • L23.9 Allergic contact dermatitis, unspecified cause • L25.5 Unspecified contact dermatitis due to plants, except food

CLINICAL PEARLS

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• Anyone exposed to irritants or allergic substances is predisposed to contact dermatitis, especially in occupations that have high exposure to chemicals. • The most common allergens causing contact dermatitis are plants of the Toxicodendron genus (poison ivy, poison oak, poison sumac). • Poison-ivy dermatitis typically requires 10 to 14 days of topical or oral steroid therapy to prevent recurrent eruption. • The usual treatment for contact dermatitis is avoidance of the allergen or irritating substance and temporary use of topical steroids. • A contact dermatitis eruption presents in a nondermatomal geographic fashion due to the skin being in contact with an external source.

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DERMATITIS, DIAPER Dennis E. Hughes, DO, FAAFP, FACEP BASICS DESCRIPTION • Diaper dermatitis is a rash occurring under the covered area of a diaper. It is usually initially a contact dermatitis. • System(s) affected: skin/exocrine • Synonym(s): diaper rash; nappy rash; napkin dermatitis

Geriatric Considerations Incontinence is a significant cofactor.

EPIDEMIOLOGY Incidence • The most common dermatitis found in infancy • Peak incidence: 7 to 12 months of age, then decreases • Lower incidence reported in breastfed babies due to lower pH, urease, protease, and lipase activity.

Prevalence Prevalence has been variably reported from 4–35% in the first 2 years of life.

ETIOLOGY AND PATHOPHYSIOLOGY • Immature infant skin with histologic, biochemical, functional differences compared to mature skin (1) • Wet skin is central in the development of diaper dermatitis, as prolonged contact with urine or feces results in susceptibility to chemical, enzymatic, and physical injury; wet skin is also penetrated more easily. • Fecal proteases and lipases are irritants. • Superhydrase urease enzyme found in the stratum corneum liberates ammonia from cutaneous bacteria. • Fecal lipase and protease activity is increased by acceleration of GI transit; thus, a higher incidence of irritant diaper dermatitis is observed in babies who

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have had diarrhea in the previous 48 hours. • Once the skin is compromised, secondary infection by Candida albicans is common. 40–75% of diaper rashes that last >3 days are colonized with C. albicans. • Bacteria may play a role in diaper dermatitis through reduction of fecal pH and resulting activation of enzymes. • Allergy is exceedingly rare as a cause in infants.

RISK FACTORS • Infrequent diaper changes • Improper laundering (cloth diapers) • Family history of dermatitis • Hot, humid weather • Recent treatment with oral antibiotics • Diarrhea (>3 stools per day increases risk) • Dye allergy • Eczema may increase risk.

GENERAL PREVENTION Attention to hygiene during bouts of diarrhea

COMMONLY ASSOCIATED CONDITIONS • Contact (allergic or irritant) dermatitis • Seborrheic dermatitis • Psoriasis • Candidiasis • Atopic dermatitis

DIAGNOSIS HISTORY • Onset, duration, and change in the nature of the rash • Presence of rashes outside the diaper area • Associated scratching or crying • Contact with infants with a similar rash

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• Recent illness, diarrhea, or antibiotic use • Fever • Pustular drainage • Lymphangitis

PHYSICAL EXAM • Mild forms consist of shiny erythema ± scale. • Margins are not always evident. • Moderate cases have areas of papules, vesicles, and small superficial erosions. • It can progress to well-demarcated ulcerated nodules that measure ≥1 cm in diameter. • It is found on the prominent parts of the buttocks, medial thighs, mons pubis, and scrotum. • Skin folds are spared or involved last. • Tidemark dermatitis refers to the bandlike form of erythema of irritated diaper margins. • Diaper dermatitis can cause an id reaction (autoeczematous) outside the diaper area.

DIFFERENTIAL DIAGNOSIS • Contact dermatitis • Seborrheic dermatitis • Candidiasis • Atopic dermatitis • Scabies • Acrodermatitis enteropathica • Letterer-Siwe disease • Congenital syphilis • Child abuse • Streptococcal infection • Kawasaki disease • Biotin deficiency • Psoriasis • HIV infection

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DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) Rarely needed Follow-Up Tests & Special Considerations • Consider a culture of lesions or a potassium hydroxide (KOH) preparation. • The finding of anemia in association with hepatosplenomegaly and the appropriate rash may suggest a diagnosis of Langerhans cell histiocytosis or congenital syphilis. • Finding mites, ova, or feces on a mineral oil preparation of a burrow scraping can confirm the diagnosis of scabies.

Test Interpretation • Biopsy is rare. • Histology may reveal acute, subacute, or chronic spongiotic dermatitis.

TREATMENT Prevention is the key to treatment of this condition.

GENERAL MEASURES • Expose the buttocks to air as much as possible. • Use mild, slightly acidic cleanser with water; no rubbing and pat dry. • Avoid impermeable waterproof pants during treatment (day or night); they keep the skin wet and subject to rash or infection. • Change diapers frequently, even at night, if the rash is extensive. • Superabsorbable diapers are beneficial, as they wick urine away from skin and still allow air to permeate (2)[C]. • Discontinue using baby lotion, powder, ointment, or baby oil (except zinc oxide). • Use of appropriately formulated baby wipes (fragrance-free) is safe and as effective as water (3)[B]. • Apply zinc oxide ointment or other barrier cream to the rash at the earliest sign and BID or TID (e.g., Desitin or Balmex). Thereafter, apply to clean, thoroughly dried skin (4)[C].

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• Cornstarch can reduce friction. Talc powders that do not enhance the growth of yeast can provide protection against frictional injury in diaper dermatitis, but do not form a continuous lipid barrier layer over the skin and obstruct the skin pores. These treatments are not recommended.

MEDICATION First Line • For a pure contact dermatitis, a low-potency topical steroid (hydrocortisone 0.5–1% TID for 3 to 5 days) and removal of the offending agent (urine, feces) should suffice. • If candidiasis is suspected or diaper rash persists, use an antifungal such as miconazole nitrate 2% cream, miconazole powder, econazole (Spectazole), clotrimazole (Lotrimin), or ketoconazole (Nizoral) cream at each diaper change. • If inflammation is prominent, consider a very low-potency steroid cream such as hydrocortisone 0.5–1% TID along with an antifungal cream ± a combination product such as clioquinol–hydrocortisone (Vioform– Hydrocortisone) cream. • If a secondary bacterial infection is suspected, use an antistaphylococcal oral antibiotic or mupirocin (Bactroban) ointment topically. • Precautions: Avoid high- or moderate-potency steroids often found in combination of steroid antifungal mixtures—these should never be used in the diaper area.

Second Line Sucralfate paste for resistant cases

ISSUES FOR REFERRAL Consider if a systemic disease such as Langerhans cell histiocytosis, acrodermatitis enteropathica, or HIV infection is suspected

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Admission criteria/initial stabilization – Febrile neonates – Recalcitrant rash suggestive of immunodeficiency

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– Toxic-appearing infants • Assist first-time parents with hygiene education.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring Recheck weekly until clear; then at times of recurrence.

PATIENT EDUCATION Patient education is vital to the treatment and prevention of recurrent cases.

PROGNOSIS • Quick, complete clearing with appropriate treatment • Secondary candidal infections may last a few weeks after treatment has begun.

COMPLICATIONS • Secondary bacterial infection (consider community-acquired methicillinresistant Staphylococcus aureus [MRSA] in pustular dermatitis that does not respond to normal therapy) • Rare complication is inoculation with group A β-hemolytic Streptococcus resulting in necrotizing fasciitis. • Secondary yeast infection

REFERENCES 1. Stamatas GN, Tierney NK. Diaper dermatitis: etiology, manifestations, prevention, and management. Pediatr Dermatol. 2014;31(1):1–7. 2. Erasala GN, Romain C, Merlay I. Diaper area and disposable diapers. Curr Probl Dermatol. 2011;40:83–89. 3. Lavender T, Furber C, Campbell M, et al. Effect on skin hydration of using baby wipes to clean the napkin area of newborn babies: assessor-blinded randomised controlled equivalence trial. BMC Pediatr. 2012;12:59. 4. Humphrey S, Bergman JN, Au S. Practical management strategies for diaper dermatitis. Skin Therapy Lett. 2006;11(7):1–6.

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ADDITIONAL READING Serdaroğlu S, Üstünbaş TK. Diaper dermatitis (napkin dermatitis, nappy rash). J Turk Acad Dermatol. 2010;4(4):04401r.

SEE ALSO Algorithm: Rash, Focal

CODES ICD10 • L22 Diaper dermatitis • B37.2 Candidiasis of skin and nail

CLINICAL PEARLS • Hygiene is the main preventative measure. • Look for secondary infection in persistent cases.

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DERMATITIS, SEBORRHEIC Juan Qiu, MD, PhD BASICS DESCRIPTION Chronic, superficial, recurrent inflammatory rash affecting sebum-rich, hairy regions of the body, especially the scalp, eyebrows, and face

EPIDEMIOLOGY Incidence • Predominant age: infancy, adolescence, and adulthood • Predominant sex: male > female

Prevalence Seborrheic dermatitis: 3–5%

ETIOLOGY AND PATHOPHYSIOLOGY • Skin surface yeasts Malassezia (formerly Plasmodium ovale) may be a contributing factor (1,2). • The mite Demodex folliculorum may have a direct/indirect role (3). • Genetic and environmental factors: Flares are common with stress/illness. • Parallels increased sebaceous gland activity in infancy and adolescence or as a result of some acnegenic drugs. • Seborrheic dermatitis is more common in immunosuppressed patients, suggesting that immune mechanisms are implicated in the pathogenesis of the disease, although the mechanisms are not well defined (1).

Genetics Positive family history; no genetic marker is identified to date.

RISK FACTORS • Parkinson disease • AIDS (disease severity correlated with progression of immune deficiency) • Emotional stress

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• Medications may flare/induce seborrheic dermatitis: auranofin, aurothioglucose, buspirone, chlorpromazine, cimetidine, ethionamide, gold, griseofulvin, haloperidol, interferon-α, lithium, methoxsalen, methyldopa, phenothiazine, psoralen, stanozolol, thiothixene, trioxsalen (2)

GENERAL PREVENTION Seborrheic skin should be washed more often than usual.

COMMONLY ASSOCIATED CONDITIONS • Parkinson disease • AIDS

DIAGNOSIS Diagnosis of seborrheic dermatitis usually can be made by history and physical exam.

HISTORY • Intermittent active phases manifest with burning, scaling, and itching, alternating with inactive periods; activity is increased in winter and early spring, with remissions commonly occurring in summer. • Infants – Cradle cap: greasy scaling of scalp, sometimes with associated mild erythema – Diaper and/or axillary rash – Age at onset typically ~1 month – Usually resolves by 8 to 12 months • Adults – Red, greasy, scaling rash in most locations consisting of patches and plaques with indistinct margins – Red, smooth, glazed appearance in skin folds – Minimal pruritus – Chronic waxing and waning course – Bilateral and symmetric – Most commonly located in hairy skin areas: scalp and scalp margins,

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eyebrows and eyelid margins, nasolabial folds, ears and retroauricular folds, presternal area, middle to upper back, buttock crease, inguinal area, genitals, and armpits

PHYSICAL EXAM • Scalp appearance varies from mild, patchy scaling to widespread, thick, adherent crusts. Plaques are rare. • Seborrheic dermatitis can spread onto the forehead, the posterior part of the neck, and the postauricular skin, as in psoriasis. • Skin lesions manifest as brawny or greasy scaling over red, inflamed skin. • Hypopigmentation is seen in African Americans. • Infectious eczematoid dermatitis, with oozing and crusting, suggests secondary infection. • Seborrheic blepharitis may occur independently.

DIFFERENTIAL DIAGNOSIS • Atopic dermatitis: Distinction may be difficult in infants. • Psoriasis – Usually knees, elbows, and nails are involved. – Scalp psoriasis will be more sharply demarcated than seborrhea, with crusted, infiltrated plaques rather than mild scaling and erythema. • Candida • Tinea cruris/capitis: Suspect these when usual medications fail/hair loss occurs. • Eczema of auricle/otitis externa • Rosacea • Discoid lupus erythematosus: Skin biopsy will be beneficial. • Histiocytosis X: may appear as seborrheic-type eruption • Dandruff: scalp only, noninflammatory

DIAGNOSTIC TESTS & INTERPRETATION Diagnostic Procedures/Other Consider biopsy if • Usual therapies fail • Petechiae is noted.

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• Histiocytosis X is suspected. • Fungal cultures in refractory cases or when pustules and alopecia are present.

Test Interpretation Nonspecific changes • Hyperkeratosis, acanthosis, accentuated rete ridges, focal spongiosis, and parakeratosis are characteristic. • Parakeratotic scale around hair follicles and mild superficial inflammatory lymphocytic infiltrate

TREATMENT GENERAL MEASURES • Increase frequency of shampooing. • Sunlight in moderate doses may be helpful. • Cradle cap – Frequent shampooing with a mild, nonmedicated shampoo – Remove thick scale by applying warm mineral oil, then wash off 1 hour later with a mild soap and a soft-bristle toothbrush or terrycloth washcloth. • Adults: Wash all affected areas with antiseborrheic shampoos. Start with overthe-counter products (selenium sulfide) and increase to more potent preparations (containing coal tar, sulfur, or salicylic acid) if no improvement is noted. • For dense scalp scaling, 10% liquor carbonic detergens in Nivea oil may be used at bedtime, covering the head with a shower cap. This should be done nightly for 1 to 3 weeks.

MEDICATION First Line • Cradle cap: Use a coal tar shampoo or ketoconazole (Nizoral) shampoo if the nonmedicated shampoo is ineffective. • Adults – Topical antifungal agents Ketoconazole or miconazole 2% shampoo twice a week for clearance,

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then once a week or every other week for maintenance (1,4–6)[A] Ketoconazole (Nizoral) and sertaconazole 2% cream may be used to clear scales in other areas (1,4–6)[A]. Ciclopirox 1% shampoo twice weekly (1)[A] – Topical corticosteroids Begin with 1% hydrocortisone and advance to more potent (fluorinated) steroid preparations, as needed (1,4–6)[A]. Avoid continuous use of the more potent steroids to reduce the risk of skin atrophy, hypopigmentation, or systemic absorption (especially in infants and children). Precautions: Fluorinated corticosteroids and higher concentrations of hydrocortisone (e.g., 2.5%) may cause atrophy or striae if used on the face or on skin folds. – Other topical agents Coal tar 1% shampoo twice a week Selenium sulfide 2.5% shampoo twice a week (1,4–6)[A] Zinc pyrithione shampoo twice a week Lithium succinate ointment twice a week • Once controlled, washing with zinc soaps or selenium lotion with periodic use of steroid cream may help to maintain remission.

Second Line • Calcineurin inhibitors – Pimecrolimus 1% cream BID (7)[B] – Tacrolimus 0.1% ointment BID (1,4–6)[A] • Systemic antifungal therapy – Data are limited. – For moderate to severe seborrheic dermatitis Ketoconazole: 200 mg/day (8)[A] Itraconazole: 200 mg/day (8)[A] Daily regimen for 1 to 2 months followed by twice-weekly dosing for chronic treatment Monitor potential hepatotoxic effects. • Low-molecular-weight hyaluronic acid

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– Hyaluronic acid sodium salt gel 0.2% BID (9)[B]

ISSUES FOR REFERRAL No response to first-line therapy and concerns regarding systemic illness (e.g., HIV)

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring Every 2 to 12 weeks, as necessary, depending on disease severity and degree of patient sophistication

PATIENT EDUCATION http://familydoctor.org/familydoctor/en/diseases-conditions/seborrheicdermatitis.html

PROGNOSIS • In infants, seborrheic dermatitis usually remits after 6 to 8 months. • In adults, seborrheic dermatitis is usually chronic and unpredictable, with exacerbations and remissions. Disease is usually easily controlled with shampoos and topical steroids.

COMPLICATIONS • Skin atrophy/striae is possible from fluorinated corticosteroids, especially if used on the face. • Glaucoma can result from use of fluorinated steroids around the eyes. • Photosensitivity is caused occasionally by tars. • Herpes keratitis is a rare complication of herpes simplex: Instruct patient to stop eyelid steroids if herpes simplex develops.

REFERENCES 1. Dessinioti C, Katsambas A. Seborrheic dermatitis: etiology, risk factors, and treatment: facts and controversies. Clin Dermatol. 2013:31(4):343–351. 2. Hay RJ. Malassezia, dandruff and seborrhoeic dermatitis: an overview. Br J

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Dermatol. 2011;165(Suppl 2):2–8. 3. Karincaoglu Y, Tepe B, Kalayci B, et al. Is Demodex folliculorum an aetiological factor in seborrhoeic dermatitis? Clin Exp Dermatol. 2009;34(8):e516–e520. 4. Clark GW, Pope SM, Jaboori KA. Diagnosis and treatment of seborrheic dermatitis. Am Fam Physician. 2015;91(3):185–190. 5. Stefanaki I, Katsambas A. Therapeutic update on seborrheic dermatitis. Skin Therapy Lett. 2010;15(5):1–4. 6. Kastarinen H, Oksanen T, Okokon EO, et al. Topical anti-inflammatory agents for seborrheic dermatitis of the face or scalp. Cochrane Database Syst Rev. 2014;(5):CD009446. 7. Kim GK, Rosso JD. Topical pimecrolimus 1% cream in the treatment of seborrheic dermatitis. J Clin Aesthet Dermatol. 2013;6(2):29–35. 8. Gupta AK, Richarson M, Paquet M. Systematic review of oral treatments for seborrheic dermatitis. J Eur Acad Dermatol Venereol. 2014:28(1):16–26. 9. Schlesinger T, Rowland Powell C. Efficacy and safety of a low molecular weight hyaluronic acid topical gel in the treatment of facial seborrheic dermatitis final report. J Clin Aesthet Dermatol. 2014:7(5):15–18.

ADDITIONAL READING • Bikowski J. Facial seborrheic dermatitis: a report on current status and therapeutic horizons. J Drugs Dermatol. 2009;8(2):125–133. • Darabi K, Hostetler SG, Bechtel MA, et al. The role of Malassezia in atopic dermatitis affecting the head and neck of adults. J Am Acad Dermatol. 2009;60(1):125–136. • Johnson BA, Nunley JR. Treatment of seborrheic dermatitis. Am Fam Physician. 2000;61(9):2703–2710, 2713–2714. • Naldi L, Rebora A. Clinical practice. Seborrheic dermatitis. N Engl J Med. 2009;360(4):387–396. • Shemer A, Kaplan B, Nathansohn N, et al. Treatment of moderate to severe facial seborrheic dermatitis with itraconazole: an open non-comparative study. Isr Med Assoc J. 2008;10(6):417–418.

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SEE ALSO Algorithm: Rash, Focal

CODES ICD10 • L21.9 Seborrheic dermatitis, unspecified • L21.1 Seborrheic infantile dermatitis • L21.0 Seborrhea capitis

CLINICAL PEARLS • Search for an underlying systemic disease in a patient who is unresponsive to usual therapy. • In adults, seborrheic dermatitis is usually chronic and unpredictable, with exacerbations and remissions. Disease is usually easily controlled with shampoos and topical steroids.

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DERMATITIS, STASIS Joseph A. Florence, MD • Fereshteh Gerayli, MD, FAAFP BASICS DESCRIPTION • Chronic, eczematous, erythema, scaling, and noninflammatory edema of the lower extremities accompanied by cycle of scratching, excoriations, weeping, crusting, and inflammation in patients with chronic venous insufficiency, due to impaired circulation and other factors (nutritional edema) • Clinical skin manifestation of chronic venous insufficiency usually appears late in the disease. • May present as a solitary lesion • System(s) affected: skin/exocrine • Synonym(s): gravitational eczema; varicose eczema; venous dermatitis

EPIDEMIOLOGY Incidence In the United States: common in patients age >50 years; annual incidence of varicose vein 2–2.6%

Prevalence • Prevalence of varicose vein is 7% (5–30%) and symptomatic chronic venous insufficiency is 0.86% • Predominant age: adult, geriatric • Predominant sex: female > male

Geriatric Considerations Prevalence • Common in this age group: – Estimated to affect 15 to 20 million patients age >50 years in the United States

ETIOLOGY AND PATHOPHYSIOLOGY

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• Incompetence of perforating veins causing blood to backflow to the superficial venous system leading to venous hypertension (HTN) and cutaneous inflammation • Deposition of fibrin around capillaries • Microvascular abnormalities • Ischemia • Continuous presence of edema in ankles, usually present because of venous valve incompetency (varicose veins) • Weakness of venous walls in lower extremities • Trauma to edematous, ischemic skin • Itch may be caused by inflammatory mediators (from mast cells, monocytes, macrophages, or neutrophils) liberated in the microcirculation and endothelium. • Abnormal leukocyte–endothelium interaction is proposed to be a major factor. • A cascade of biochemical events leads to ulceration.

Genetics Familial link probable

RISK FACTORS • Previous deep venous thrombosis • Chronic edema (due to CHF, pulmonary HTN, obstructive sleep apnea; cirrhosis, nephrotic syndrome, or medication) • Previous pregnancy • Obesity • Atopy • Superimposed itch scratch cycle • Trauma • Genetic propensity • Prolonged medical illness • Secondary infection • Low-protein diet • Old age • Tight garments that constrict the thigh • Vein stripping

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• Vein harvesting for coronary artery bypass graft surgery • Previous cellulitis

GENERAL PREVENTION • Use compression stockings to avoid recurrence of edema and to mobilize the interstitial lymphatic fluid from the region of stasis dermatitis and also following DVT. • Topical lubricants twice a day to prevent fissuring and itching

COMMONLY ASSOCIATED CONDITIONS • Varicose veins • Venous insufficiency • Other eczematous disease • Hyperhomocysteinemia • Venous HTN • Most diseases that worsen peripheral edema (e.g. CHF, diastolic dysfunction)

DIAGNOSIS HISTORY • Older than 50 years with exception of acquired venous insufficiency due to surgery, trauma, or thrombosis (1) • Pruritus, pain, and burning may precede skin signs, which are aggravated during evening hours. • Insidious onset (2) • Usually bilateral (3) • Reddish-brown skin discoloration (3) • Edema—initially develops around the ankle (3) • Trauma is more indicative of cellulitis (3).

PHYSICAL EXAM • Evaluation of the lower extremities characteristically reveals: – Bilateral, pitting edema (4,5) – Typically with erythema, hyperpigmentation—more common in the lower 1/3 of the extremity and medially (4,5)

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• Violaceous (sometimes brown), erythematous-colored lesions due to deoxygenation of venous blood (postinflammatory hyperpigmentation and hemosiderin deposition within the cutaneous tissue) – Serous drainage, weeping, crusting, inflammation of the skin – Superficial desquamation (4) – May present as a solitary lesion mimicking a neoplasm (6)

DIFFERENTIAL DIAGNOSIS • Cellulitis or erysipelas • Trauma-related inflammation • Deep vein thrombosis • Nonspecific dermatitis • Thrombophlebitis • Contact dermatitis • Vasculitis • Basal cell or squamous cell carcinoma • Lipodermatosclerosis • Lymphedema • Eosinophilic cellulitis • Other eczematous diseases

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Blood tests usually not indicated unless cellulitis and/or sepsis are suspected. Leukocytosis is more likely with true cellulitis (3). • If stasis dermatitis is secondary to venous thrombosis, a thorough hematologic workup may be indicated to rule out hypercoagulability states. • Duplex ultrasound imaging may diagnose deep venous thrombosis or severe valve damage secondary to past thrombosis. • Potentially more accurate gold standards (e.g., skin biopsy) would introduce considerable risk to study patients and would not be acceptable from an ethical standpoint (3)

Diagnostic Procedures/Other • Rule out arterial insufficiency (check peripheral pulses); ankle brachial

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pressure index (ABPI or ABI). • Check for diabetes.

Test Interpretation • ABPI female (3:1) • Nocturnal > day (3:1)

Geriatric Considerations Infrequent; often associated with daytime incontinence (formerly referred to as diurnal enuresis)

ETIOLOGY AND PATHOPHYSIOLOGY • A disorder of sleep arousal, a low nocturnal bladder capacity, and nocturnal polyuria are the three factors that interrelate to cause NE. • Both functional and organic causes (below); many theories, none absolutely confirmed • Detrusor instability • Deficiency of arginine vasopressin (AVP); decreased nocturnal AVP or decreased AVP stimulation secondary to an empty bladder (bladder distension stimulates AVP) • Maturational delay of CNS • Severe NE with some evidence of interaction between bladder overactivity and brain arousability: association with children with severe NE and frequent cortical arousals in sleep • Organic urologic causes in 1–4% of enuresis in children: UTI, occult spina bifida, ectopic ureter, lazy bladder syndrome, irritable bladder with wide bladder neck, posterior urethral valves, neurologic bladder dysfunction • Organic nonurologic causes: epilepsy, diabetes mellitus, food allergies, obstructive sleep apnea, chronic renal failure, hyperthyroidism, pinworm infection, sickle cell disease • NE occurs in all stages of sleep.

Genetics Most commonly, NE is an autosomal-dominant inheritance pattern with high penetrance (90%). • 1/3 of all cases are sporadic.

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• 75% of children with enuresis have a first-degree relative with the condition. • Higher rates in monozygotic versus dizygotic twins (68% vs. 36%) • If both parents had NE, risk in child is 77%; 44% if one parent is affected. Parental age of resolution often predicts when child’s enuresis should resolve.

RISK FACTORS • Family history • Stressors (emotional, environmental) common in secondary enuresis (e.g., divorce, death) • Constipation • Encopresis • Organic disease: 1% of monosymptomatic NE (e.g., urologic and nonurologic causes) • Psychological disorders – Comorbid disorders are highest with secondary NE: depression, anxiety, social phobias, conduct disorder, hyperkinetic syndrome, internalizing disorders – Association with ADHD; more pronounced in ages 9 to 12 years • Altered mental status or impaired mobility

GENERAL PREVENTION No known measures

COMMONLY ASSOCIATED CONDITIONS • Obstructive sleep apnea syndrome: atrial natriuretic factor inhibits reninangiotensin-aldosterone pathway leading to diuresis • Constipation (1/3 of patients with NE) • Behavioral problems (specifically ADHD)

DIAGNOSIS HISTORY • Age of onset, duration, severity • LUT tract symptoms • Constipation and encopresis (15% with comorbid encopresis)

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• Daily intake patterns • Voiding and elimination patterns (voiding diary) • Psychosocial history • Family history of enuresis • Investigation and previous treatment history

PHYSICAL EXAM • ENT: evaluation for adenotonsillar hypertrophy • Abdomen: enlarged bladder, kidneys, fecal masses, or impaction • Back: Look for dimpling or tufts of hair on sacrum. • Genital urinary exam – Males: meatal stenosis, hypospadias, epispadias, phimosis – Females: vulvitis, vaginitis, labial adhesions, ureterocele at introitus; evidence of abuse • Rectal exam: tone and constipation • Neurologic exam, especially lower extremities

DIFFERENTIAL DIAGNOSIS • Primary NE – Delayed physiologic urinary control – UTI (both) – Spina bifida occulta – Obstructive sleep apnea (both) – Idiopathic detrusor instability – Previously unrecognized myelopathy or neuropathy (e.g., multiple sclerosis, tethered cord, epilepsy) – Anatomic urinary tract abnormality (e.g., ectopic ureter) • Secondary NE – Bladder outlet obstruction – Neurologic disease, neurogenic bladder (e.g., spinal cord injury)

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Only obligatory test in children is urinalysis. • Urinalysis and urine culture: UTI, pyuria, hematuria, proteinuria, glycosuria,

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and poor concentrating ability (low specific gravity) may suggest organic etiology, especially in adults. • Urinary tract imaging is usually not necessary. • If abnormal clinical findings or adult onset: renal and bladder US • IV pyelogram, voiding cystourethrogram (VCUG), or retrograde pyelogram as indicated • Spine radiographs for spina bifida occulta Follow-Up Tests & Special Considerations • Secondary enuresis: serum glucose, BUN, creatinine, thyroid-stimulating hormone (TSH), urine culture • In children, imaging and urodynamic studies are helpful for significant daytime symptoms, history of UTIs, suspected structural abnormalities, and in refractory cases.

Diagnostic Procedures/Other Urodynamic studies may be beneficial in adults and nonmonosymptomatic NE.

Test Interpretation • Dysfunctional voiding • Detrusor instability and/or reduced bladder capacity most common findings

TREATMENT GENERAL MEASURES • Use nonpharmacologic approaches as first line before prescribing medications (1)[A]. • Simple behavioral interventions (e.g., scheduled wakening, positive reinforcement, bladder training, diet changes) are effective though less so than alarms or medications (2)[B]. – Explain the three pathophysiologic factors. – Encourage normal drinking patterns during daytime hours and reduction of intake in the hours prior to sleep. – Emphasize regular bedtime with full night’s sleep. – Scheduled voiding before bed

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– Nightlights to light the way to the bathroom – Reward system for dry nights – Use pull up over regular underwear or cloth underwear with built in waterproof barrier. • Do not shame or punish bedwetting but have the child participate in removing and laundering soiled bedding and garments. • If behavioral interventions alone have no success, combined therapy (e.g., enuresis alarm, bladder training, motivational therapy, and pelvic floor muscle training) is more effective than each component alone or than pharmacotherapy (1)[A]. • Enuresis alarms (bells or buzzers) – 66–70% success rate; must be used nightly for 3 to 4 months; offers cure; significant parental involvement; disruption of sleep for entire family – In children, number needed to treat (NNT) = 2 (3)[A]. – If successful, it should be used until 14 consecutive dry nights achieved (4) [B]. • See “Patient Education” for options.

MEDICATION First Line • Desmopressin (DDAVP): synthetic analogue of vasopressin that decreases nocturnal urine output (5)[A] – Adults only: 20 mg (2 sprays) intranasally at bedtime – FDA recommends against use in children due to reports of severe hyponatremia resulting in seizures and deaths in children using intranasal formulations of desmopressin. – Oral DDAVP: dose-dependent: begin at 0.2 mg tablet taken at bedtime on empty stomach; may titrate to 0.6 mg Maximally effective in 1 hour; cleared within 9 hours Trial nightly for 6 months, then stop for 2 weeks for test of dryness Suspend dose in children who experience acute condition affecting fluid/electrolyte balances (fever, vomiting, diarrhea, vigorous exercise). – 10–70% success; safe even when used for >12 months; high relapse rate after discontinuation without a structured withdrawal program

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– In children, NNT = 6 (6)[A]. • Anticholinergics – Oxybutynin (Ditropan, Ditropan XL, Oxytrol patch): anticholinergic; smooth muscle relaxant, antispasmodic; may increase functional bladder capacity and aids in timed voiding (6)[B] Ditropan: adults and children >5 years of age: 5 mg PO TID to QID; children 1 to 5 years of age: 0.02 mg/kg/dose BID to QID (syrup 5 mg/5 mL) Ditropan XL: adults: 5 mg/day PO; increase to 30 mg/day PO (5-, 10-mg tabs) Oxytrol patch: 1 patch every 3 to 4 days (3.9 mg/patch) (periodic trials off the medication, that is, weekends or weeks at a time, will help determine efficacy and resolution of primary disturbance) Ditropan: 5 to 10 mg at night; 30–50% success; 50% relapse after stopped – Tolterodine (Detrol, Detrol LA): anticholinergic; fewer side effects than Ditropan (7)[B] Detrol: 1 to 2 mg PO BID Detrol LA: 2 to 4 mg/day

Pediatric Considerations FDA recommends against using intranasal formulations of desmopressin in children due to reports of severe hyponatremia resulting in seizures and deaths (8)[A].

Second Line • Imipramine (Tofranil): tricyclic antidepressant, anticholinergic effects; increases bladder capacity, antispasmodic properties – Primarily in adults; use in children is reserved for resistant cases. – Dose: adults, 25 to 75 mg and children >6 years, 10 to 25 mg PO at bedtime; increase by 10 to 25 mg at 1- to 2-week intervals; treat for 2 to 3 months; then taper – 25–30% success when used 40 years • Predominant sex: male = female

Incidence • Common overuse injury • Lateral > medial • Estimated between 1% and 3%

Prevalence • Lateral epicondylitis: 1.3% • Medial epicondylitis: 0.4%

ETIOLOGY AND PATHOPHYSIOLOGY

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• Acute (tendonitis) – Inflammatory response to injury • Chronic (tendinosis) – Overuse injury – Tendon degeneration, fibroblast proliferation, microvascular proliferation, lack of inflammatory response • Repetitive wrist flexion or extension places strain across enthesis of flexor/extensor group • Tool/racquet gripping • Shaking hands • Sudden maximal muscle contraction • Direct blow

RISK FACTORS • Repetitive wrist motions – Flexion/pronation: medial – Extension/supination: lateral • Smoking • Obesity • Upper extremity forceful activities

GENERAL PREVENTION • Limit overuse of the wrist flexors, extensors, pronators, and supinators. • Use proper techniques when working with hand tools or playing racquet sports. • Use lighter tools and smaller grips.

DIAGNOSIS HISTORY • Pain typically localized to lateral or medial elbow. • Occupational activities • Sports participation • Direct trauma • Duration and location of symptoms

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• Prior treatments or medication use • Pain with gripping • Sensation of mild forearm weakness

PHYSICAL EXAM • Localized pain just distal to the affected epicondyle • Increased pain with wrist flexion/pronation (medial) • Increased pain with wrist extension/supination (lateral) • Medial epicondylitis – Tenderness at origin of wrist flexor tendons – Increased pain with resisted wrist flexion and pronation – Normal elbow range of motion – Increased pain with gripping • Lateral epicondylitis – Tenderness at origin of wrist extensors – Increased pain with resisted wrist extension/supination – Normal elbow range of motion – Increased pain with gripping

DIFFERENTIAL DIAGNOSIS • Elbow osteoarthritis • Epicondylar fractures • Posterior interosseous nerve entrapment (lateral) • Ulnar neuropathy (medial) • Synovitis • Medial collateral ligament injury • Referred pain from shoulder or neck

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) No imaging is required for initial evaluation and treatment of a classic overuse injury. Follow-Up Tests & Special Considerations • Anterior-posterior/lateral radiographs if decreased range of motion, trauma, or no improvement with initial conservative therapy. Assess for fractures or signs

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of arthritis. • For recalcitrant cases – Musculoskeletal ultrasound (US) reveals abnormal tendon appearance (e.g., tendon thickening, partial tear at tendon origin, calcifications). US can also guide injections of steroid and/or anesthetic. – MRI can show intermediate or high T2 signal intensity within the common flexor or extensor tendon or the presence of peritendinous soft tissue edema.

Diagnostic Procedures/Other Infiltration of local anesthetic with subsequent resolution of symptoms supports the diagnosis if clinically in doubt.

TREATMENT GENERAL MEASURES Initial treatment consists of activity modification, counterforce bracing, oral or topical NSAIDs, ice, and physical therapy: • Observation: If left untreated, symptoms typically last between 6 months and 2 years. For patients with good function and minimal pain, consider conservative management using a “wait and see” approach based on patient preference. • Modify activity, encourage relative rest, and correct faulty biomechanics • Counterforce bracing with a forearm strap is easy and inexpensive. Systematic reviews are inconclusive about overall efficacy, but initial bracing may improve the ability to perform daily activities in the first 6 weeks. • Consider nighttime wrist splinting for repetitive daily activities if counterforce bracing fails. • Ice frequently after activities • Physical therapy – Begin once acute pain is resolved. Infiltration of local anesthetic can reduce pain and allow for physical therapy – Eccentric strength training and stretching program – US therapy

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– Corticosteroid iontophoresis – Dry needling

MEDICATION First Line • Topical NSAIDs: Low-quality evidence suggests topical NSAIDS are significantly more effective than placebo with respect to pain and number needed to treat to benefit (NNT = 7) in the short term (up to 4 weeks) with minimal adverse effects (1)[A]. • Oral NSAIDs: Unclear efficacy with respect to pain and function, but may offer short-term pain relief. Associated with adverse GI effects (1)[A].

Second Line Corticosteroid injections: Short-term (≤8 weeks) reduction in pain. No benefits found for intermediate or long-term outcomes (2)[A].

ISSUES FOR REFERRAL Failure of conservative therapy

ADDITIONAL THERAPIES • Platelet-rich plasma (PRP) injections – Injection of concentrated autologous PRP leads to a local inflammatory response. Platelets degranulate, release growth factors, and stimulate the physiologic healing cascade – PRP treatment of chronic lateral epicondylitis significantly reduces pain and increases function. The benefit exceeds that of corticosteroid injection even after a follow-up of 2 years (3)[B]. • Autologous blood injections – Stimulates the inflammatory cascade within the degenerated tendon by providing cellular and humoral mediators for regeneration. – More effective at 3 months then corticosteroid injection for improving pain, function and grip strength (4)[B] • US-guided percutaneous needle tenotomy – Injection of a local anesthetic followed by US-guided tendon fenestration, aspiration, and abrasion of the underlying bone. Thought to break apart scar tissue and stimulate inflammation and healing.

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• Prolotherapy – Injection of a dextrose solution into and around the tendon attachment stimulates a localized inflammatory response, leading to increased blood flow to stimulate healing. • Glyceryl trinitrate (GTN) transdermal patch – Nitric oxide (NO) is a small free radical generated by nitric oxide synthases. NO is expressed by fibroblasts and is postulated to aid in collagen synthesis. Topical application of GTN theoretically improves healing by this mechanism. 1/4 of a 5-mg/24-hour GTN transdermal patch is applied once daily for up to 24 weeks. – Significant decrease in pain are seen at 3 weeks and 6 months compared to placebo patch (5)[B]. • Botulinum toxin A for chronic lateral epicondylitis – Injections into the forearm extensor muscles (60 units) can be performed in the outpatient setting.

SURGERY/OTHER PROCEDURES • Elbow surgery may be indicated in refractory cases: – Fair evidence for treatment (6)[B] – Involves débridement and tendon release – Can be performed open or arthroscopically • Denervation of the lateral humeral epicondyle – Transection of the posterior cutaneous nerve of the forearm with implantation into the triceps may help with chronic symptoms and pain.

COMPLEMENTARY & ALTERNATIVE MEDICINE Acupuncture: effective for short-term pain relief for lateral epicondyle pain

ONGOING CARE PROGNOSIS Good: Majority resolve with conservative care.

REFERENCES

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1. Pattanittum P, Turner T, Green S, et al. Non-steroidal anti-inflammatory drugs (NSAIDs) for treating lateral elbow pain in adults. Cochrane Database Syst Rev. 2013;(5):CD003686. 2. Krogh TP, Bartels EM, Ellingsen T, et al. Comparative effectiveness of injection therapies in lateral epicondylitis: a systematic review and network meta-analysis of randomized controlled trials. Am J Sports Med. 2013;41(6):1435–1446. 3. Gosens T, Peerbooms JC, van Laar W, et al. Ongoing positive effect of platelet-rich plasma versus corticosteroid injection in lateral epicondylitis: a double-blind randomized controlled trial with 2-year follow-up. Am J Sports Med. 2011;39(6):1200–1208. 4. Arik HO, Kose O, Guler F, et al. Injection of autologous blood versus corticosteroid for lateral epicondylitis: a randomised controlled study. J Orthop Surg (Hong Kong). 2014;22(3):333–337. 5. Ozden R, Uruç V, Doğramaci Y, et al. Management of tennis elbow with topical glyceryl trinitrate. Acta Orthop Traumatol Turc. 2014;48(2):175–180. 6. Yeoh KM, King GJ, Faber KJ, et al. Evidence-based indications for elbow arthroscopy. Arthroscopy. 2012;28(2):272–282.

ADDITIONAL READING • Cullinane FL, Boocock MG, Trevelyan FC. Is eccentric exercise an effective treatment for lateral epicondylitis? A systematic review. Clin Rehabil. 2014;28(1):3–19. • Dingemanse R, Randsdorp M, Koes BW, et al. Evidence for the effectiveness of electrophysical modalities for treatment of medial and lateral epicondylitis: a systematic review. Br J Sports Med. 2014;48(12):957–965. • Green S, Buchbinder R, Barnsley L, et al. Acupuncture for lateral elbow pain. Cochrane Database Syst Rev. 2002;(1):CD003527. • Kalichman L, Bannuru RR, Severin M, et al. Injection of botulinum toxin for treatment of chronic lateral epicondylitis: systematic review and metaanalysis. Semin Arthritis Rheum. 2011;40(6):532–538. • McShane JM, Shah VN, Nazarian LN. Sonographically guided percutaneous needle tenotomy for treatment of common extensor tendinosis in the elbow: is a corticosteroid necessary? J Ultrasound Med. 2008;27(8):1137–1144.

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• Rose NE, Forman SK, Dellon AL. Denervation of the lateral humeral epicondyle for treatment of chronic lateral epicondylitis. J Hand Surg Am. 2013;38(2):344–349.

SEE ALSO Algorithm: Pain in Upper Extremity

CODES ICD10 • M77.00 Medial epicondylitis, unspecified elbow • M77.10 Lateral epicondylitis, unspecified elbow • M77.01 Medial epicondylitis, right elbow

CLINICAL PEARLS • Medial epicondylitis (golfer’s elbow) is characterized by pain and tenderness at the tendinous origins of the wrist flexors at the medial epicondyle. • Lateral epicondylitis (tennis elbow) is characterized by pain and tenderness at the tendinous origins of the wrist extensors at the lateral epicondyle. • Left untreated, symptoms typically last between 6 months and 2 years. • Most patients improve using conservative treatment with bracing, activity modification, and physical therapy.

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EPIDIDYMITIS Thomas M. Savage, MD • Holly L. Baab, MD BASICS • Acute epididymitis: pain for 13 years, must rule out testicular torsion • History not helpful in distinguishing epididymitis from testicular torsion

Geriatric Considerations Diabetics with sensory neuropathy may have no pain despite severe infection/abscess.

PHYSICAL EXAM • The tail of the epididymis is larger in comparison with the contralateral side. • Epididymis is markedly tender to palpation. • Absence of a cremasteric reflex should raise suspicion for testicular torsion.

DIFFERENTIAL DIAGNOSIS • Epididymal congestion following vasectomy • Testicular torsion • Torsion of testicular appendages • Orchitis • Testicular malignancy • Testicular trauma • Epididymal cyst • Inguinal hernia • Urethritis • Spermatocele • Hydrocele • Hematocele • Varicocele • Epididymal adenomatoid tumor • Epididymal rhabdomyosarcoma • Vasculitis (Henoch-Schönlein purpura)

DIAGNOSTIC TESTS & INTERPRETATION

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Initial Tests (lab, imaging) • All suspected cases should be evaluated for objective evidence of inflammation by one of the following: – Urinalysis preferably on first-void urine to evaluate for positive leukocyte esterase – Gram stain urethral discharge; ≥2 WBC per oil immersion field; also for evaluation of presence or absence of gonococcal infection – Microscopic examination of sediment from a spun first-void urine with ≥10 WBC per high power field. • Urine culture, preferably first-void • Urine GC/chlamydia testing by NAAT for all suspected cases (2)[A] • CRP >24 mg/L suggestive of epididymitis (4)[C] • Urinalysis clear and culture-negative suggest sterile epididymitis. • If testicular torsion cannot be excluded (especially in children), Doppler ultrasound is test of choice (1). • In adult men, Doppler ultrasound: sensitivity and specificity of 100% in evaluation of acute scrotum (5)

Pediatric Considerations Further radiographic imaging in children should be done to rule out anatomic abnormalities.

Diagnostic Procedures/Other This is a clinical diagnosis.

TREATMENT GENERAL MEASURES • Bed rest or restriction on activity • Athletic scrotal supporter • Scrotal elevation • Ice pack wrapped in towel • Avoid constipation. • Spermatic cord block with local anesthesia in severe cases

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• If chemical epididymitis – No strenuous physical activity and avoidance of any Valsalva maneuvers for several weeks – Empty bladder prior to strenuous exercises.

MEDICATION First Line • 60 days (2)[A]. • If chemical epididymitis, then educate on noninfectious etiology and proper lifestyle changes.

PROGNOSIS • Pain improves within 1 to 3 days, but induration may take several weeks/months to completely resolve. • If bilateral involvement, sterility may result. • In chemical epididymitis, symptoms usually resolve in 50 years, particularly ages 70 to 79 years • Most common in males 3 times a week or more than once in 24 hours. – Alprostadil may also be combined with papaverine (Bimix) plus phentolamine (Tri-Mix).

ALERT • Initial trial dose of second-line agents should be administered under supervision of a specialist or primary care physician with expertise in these therapies. • Patient should notify physician if erection lasts >4 hours for immediate attention.

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• Vacuum pump devices are a noninvasive second-line option and are available over the counter. Do not use vacuum devices in men with sickle cell anemia or blood dyscrasias. • Testosterone supplementation in men with hypogonadism improves ED and libido (3)[B]. Available formulations include injectable depots, transdermal patches and gels, SC pellets, and oral therapy. • Contraindications: – Nitroglycerin (or other nitrates) and phosphodiesterase inhibitors: potential for severe, fatal hypotension – Precautions/side effects: Testosterone: precautions: Exogenous testosterone reduces sperm count and thus do not use in patients wishing to keep fertility; side effects: acne, sodium retention Intraurethral suppository: local penile pain, urethral bleeding, dizziness, and dysuria Intracavernosal injection: penile pain, edema and hematoma, palpable nodules or plaques, and priapism Sildenafil: hypotension (caution for patients on nitrates) PDE-5 inhibitors: Use caution with congenital prolonged QT syndrome, class Ia or II antiarrhythmics, nitroglycerin, α-blockers (e.g., terazosin, tamsulosin), retinal disease, unstable cardiac disease, liver and renal failure. Significant possible interactions PDE-5 inhibitor concentration is affected by CYP3A4 inhibitors (e.g., erythromycin, indinavir, ketoconazole, ritonavir, amiodarone, cimetidine, clarithromycin, delavirdine, diltiazem, fluoxetine, fluvoxamine, grapefruit juice, itraconazole, nefazodone, nevirapine, saquinavir, and verapamil). Serum concentrations and/or toxicity may be increased. Lower starting doses should be used in these patients. PDE-5 inhibitor concentration may be reduced by rifampin and phenytoin.

ADDITIONAL THERAPIES Relationship difficulties found that men who received this therapy plus sildenafil

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had more successful intercourse than those who received only sildenafil (6)[A].

SURGERY/OTHER PROCEDURES Penile prosthesis should be reserved for patients who have failed or are ineligible first- or second-line therapies.

COMPLEMENTARY & ALTERNATIVE MEDICINE Trazodone, yohimbine, and herbal therapies are not recommended for the treatment of ED, as they have not proven to be efficacious.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring Treatment should be assessed at baseline and after the patient has completed at least 1 to 3 weeks of a specific treatment: Monitor the quality and quantity of penile erections and monitor the level of satisfaction patient achieves.

DIET Diet and exercise recommended to achieve a normal body mass index; limit alcohol.

PROGNOSIS • All commercially available PDE-5 inhibitors are equally effective. In the presence of sexual stimulation, they are 55–80% effective. – Lower success rates with diabetes mellitus and radical prostatectomy patients who suffer from ED. • Overall effectiveness is 70–90% for intracavernosal alprostadil and 43–60% for intraurethral alprostadil (4)[B]. • Penile prostheses are associated with an 85–90% patient satisfaction rate (4) [C].

REFERENCES 1. Lindau ST, Schumm LP, Laumann EO, et al. A study of sexuality and health among older adults in the United States. N Engl J Med. 2007;357(8):762–

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774. 2. Inman BA, Sauver JL, Jacobson DJ, et al. A population-based, longitudinal study of erectile dysfunction and future coronary artery disease. Mayo Clin Proc. 2009;84(2):108–113. 3. Heidelbaugh JJ. Management of erectile dysfunction. Am Fam Physician. 2010;81(3):305–312. 4. McVary KT. Clinical practice. Erectile dysfunction. N Engl J Med. 2007;357(24):2472–2481. 5. American Urological Association. Guideline on the management of erectile dysfunction: diagnosis and treatment recommendations. http://www.auanet.org/education/guidelines/erectile-dysfunction.cfm. Accessed January 13, 2017. 6. Melnik T, Soares BG, Nasselo AG. Psychosocial interventions for erectile dysfunction. Cochrane Database Syst Rev. 2007;(3):CD004825.

CODES ICD10 • N52.9 Male erectile dysfunction, unspecified • N52.1 Erectile dysfunction due to diseases classified elsewhere • F52.21 Male erectile disorder

CLINICAL PEARLS • Nitrates should be withheld for 24 hours after sildenafil or vardenafil administration and for 48 hours after use of tadalafil. PDE-5 inhibitors are contraindicated in patients taking concurrent nitrates of any form (regular or intermittent nitrate therapy), as it can lead to severe hypotension and syncope. • Reserve surgical treatment for patients who do not respond to drug treatment. • The use of PDE-5 inhibitors with α-adrenergic antagonists may increase the risk of hypotension. Tamsulosin is the least likely to cause orthostatic hypotension. • Avanafil should not be used with strong CYP3A4 inhibitors and max dose should be 50 mg with moderate CYP3A4 inhibitors.

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• ED may be a marker for subclinical cardiovascular disease. Thoroughly assess patients with nonpsychogenic ED for CV risks.

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ERYSIPELAS Fozia Akhtar Ali, MD • Barbara M. Kiersz, DO BASICS DESCRIPTION • Distinct form of cellulitis notable for acute, well-demarcated, superficial bacterial skin infection with lymphatic involvement almost always caused by Streptococcus pyogenes • Usually acute, but a chronic recurrent form also exists (1) • Nonpurulent • System(s) affected: skin, exocrine • Synonym(s): St. Anthony’s Fire

EPIDEMIOLOGY • Predominant age: infants, children, and adults >40 years • Greatest in elderly (>75 years) • No gender/racial predilection • Affects all races

Incidence • Erysipelas occurs in ~1/1,000 persons/year (2). • Incidence on the rise since the 1980s (3)

Prevalence Unknown

ETIOLOGY AND PATHOPHYSIOLOGY • Group A streptococci induce inflammation and activation of the contact system, a proinflammatory pathway with antithrombotic activity, releasing proteinases and proinflammatory cytokines. • The generation of antibacterial peptides and the release of bradykinin, a proinflammatory peptide, increase vascular permeability and induce fever and pain. • The M proteins from the group A streptococcal cell wall interact with

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neutrophils, leading to the secretion of heparin-binding protein, an inflammatory mediator that also induces vascular leakage. • This cascade of reactions leads to the symptoms seen in erysipelas: fever, pain, erythema, and edema. • Group A β-hemolytic streptococci primarily; commonly S. pyogenes, occasionally, other Streptococcus groups C/G • Rarely, group B streptococci/Staphylococcus aureus may be involved.

RISK FACTORS • Disruption in the skin barrier (surgical incisions, insect bites, eczematous lesions, local trauma, abrasions, dermatophytic infections, intravenous drug user [IVDU]) • Chronic diseases (diabetes, malnutrition, nephrotic syndrome, heart failure) • Immunocompromised (HIV)/debilitated • Fissured skin (especially at the nose and ears) • Toe-web intertrigo and lymphedema (2) • Leg ulcers/stasis dermatitis • Venous/lymphatic insufficiency (saphenectomy, varicose veins of leg, phlebitis, radiotherapy, mastectomy, lymphadenectomy) • Alcohol abuse • Morbid obesity • Recent streptococcal pharyngitis • Varicella

GENERAL PREVENTION • Good skin hygiene • It is recommended that predisposing medical conditions, such as tinea pedis and stasis dermatitis, be appropriately managed first. • Men who shave within 5 days of facial erysipelas are more likely to have a recurrence. • With recurrences, search for other possible sources of streptococcal infection (e.g., tonsils, sinuses). • Compression stockings should be encouraged for patients with lower extremity edema. • Consider suppressive prophylactic antibiotic therapy, such as penicillin, in

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patients with >2 episodes in a 12-month period.

Pediatric Considerations Group B Streptococcus may be a cause of erysipelas in neonates/infants.

DIAGNOSIS Prodromal symptoms before the skin eruption of erysipelas may include: • Moderate- to high-grade fever • Chills • Headache • Malaise • Anorexia, usually in the first 48 hours (4)[B] • Vomiting • Arthralgias

ALERT It is important to differentiate erysipelas from a methicillin-resistant Staphylococcus aureus (MRSA) infection, which usually presents with an indurated center, significant pain, and later evidence of abscess formation.

PHYSICAL EXAM • Vital signs: moderate- to high-grade fever with resultant tachycardia. Hypotension may occur. • The presence of a fever in erysipelas can be considered a differentiating factor from other skin infections. • Headache and vomiting may be prominent. • Acute onset of intense erythema; well-demarcated painful plaque (5) • Peau d’orange appearance • Milian ear sign (erythema involves skin of ear as well as face implies erysipelas) • Vesicles and bullae may form but are not uniformly present. • Desquamation may occur later. • Lymphangitis • Location

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– Lower extremity 70–80% of cases – Face involvement is less common (5–20%), especially nose and ears. – Chronic form usually recurs at site of the previous infection and may recur years after initial episode. • Patients on systemic steroids may be more difficult to diagnose because signs and symptoms of the infection may be masked by anti-inflammatory action of the steroids. • Systemic toxicity resolves rapidly with treatment; skin lesions desquamate on days 5 to 10 but usually heal without scarring. • In geriatric patients, facial involvement presents in a butterfly pattern. Pustules characteristically absent and regional lymphadenopathy with lymphangitic streaking is seen.

Pediatric Considerations • Abdominal involvement is more common in infants, especially around umbilical stump. • Face, scalp, and leg involvement are common in older children due to the excoriations of anterior rhinitis sicca allowing an easy port of entry.

Geriatric Considerations • Fever may not be as prominent. • Face and lower extremity are the most common areas. • High-output cardiac failure may occur in debilitated patients with underlying cardiac disease. • More susceptible to complications

DIFFERENTIAL DIAGNOSIS • Cellulitis (margins are less clear and does not involve ear) • Necrotizing fasciitis (systemic illness and more pain) • Skin abscess (feel for area of fluctuance) • DVT (need to rule out if clinically suspected) • Acute gout (check patient history) • Insect bite (check patient history) • Dermatophytes • Impetigo (blistered/crusted appearance; superficial)

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• Ecthyma (ulcerative impetigo) • Herpes zoster (dermatomal distribution) • Erythema annulare centrifugum (raised pink-red ring/bull’s-eye marks) • Contact dermatitis (no fever, pruritic, not painful) • Giant cell urticaria (transient, wheal appearance, severe itching) • Angioneurotic edema (no fever) • Scarlet fever (widespread rash with indistinct borders and without edema; rash is most common early in skin folds; develops generalized “sandpaper” feeling as it progresses) • Toxic shock syndrome (diffuse erythema with evidence of multiorgan involvement) • Lupus (of the face; less fever, positive antinuclear antibodies) • Polychondritis (common site is the ear) • Other bacterial infections to consider: – Meat, shellfish, fish, and poultry workers: Erysipelothrix rhusiopathiae (known as erysipeloid) – Human bite: Eikenella corrodens – Cat/dog bite: Pasteurella multocida/Capnocytophaga canimorsus – Salt water exposure: Vibrio vulnificus – Fresh/brackish water exposure: Aeromonas hydrophila

DIAGNOSTIC TESTS & INTERPRETATION Reserve diagnostic tests for severely ill, toxic patients, or those who are immunosuppressed.

Initial Tests (lab, imaging) • Leukocytosis • Blood culture (28 days = 50,000 U/kg per day – Cefazolin 0 to 7 days, 2,000 g = 25 mg/kg q8h >28 days = 25 mg/kg q8h • No reported group A streptococci resistance to β-lactam antibiotics • In chronic recurrent infections, prophylactic treatment after the acute infection resolves: – Penicillin G benzathine: 1.2 million U IM q4wk or penicillin VK 500 mg PO BID or azithromycin 250 mg PO QD • If staphylococcal infection is suspected or if patient is acutely ill, consider a β–lactamase-stable antibiotic. • Consider community-acquired MRSA, and depending on regional sensitivity, may treat MRSA with TMP-SMX DS 1 tab PO BID or vancomycin 1 g IV

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q12h or doxycycline 100 mg PO BID

ISSUES FOR REFERRAL Recurrent infection, treatment failure

ADDITIONAL THERAPIES Some patients may notice a deepening of erythema after initiating antimicrobial therapy. This may be due to the destruction of pathogens that release enzymes, increasing local inflammation. In this case, treatment with corticosteroids, in addition to antimicrobials, can mildly reduce healing time and antibiotic duration in patients with erysipelas. Consider prednisolone 30 mg/day with taper over 8 days (7).

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Admission criteria/initial stabilization – Patient with systemic toxicity – Patient with high-risk factors (e.g., elderly, lymphedema, postsplenectomy, diabetes) – Failed outpatient care • IV therapy if systemic toxicity/unable to tolerate PO • Discharge criteria: no evidence of systemic toxicity with resolution of erythema and swelling

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Bed rest with elevation of extremity during acute infection, then activity as tolerated

Patient Monitoring Patients should be treated until all symptoms and skin manifestations have resolved.

PATIENT EDUCATION Stress importance of completing prescribed medication regimen.

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PROGNOSIS • Patients should recover fully if adequately treated. • May experience deepening of erythema after initiation of antibiotics • Most respond to therapy after 24 to 48 hours. • Mortality is 3 attacks but has a mean number of 6 attacks (range 2 to 24) per year and a mean duration of 6 to 9.5 years (range 2 to 36) (1).

EPIDEMIOLOGY Incidence • Annual U.S. incidence is estimated at 0.01–1% (1).

Prevalence

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• Peak incidence in 20s and 40s; rare 50 years of age (4) • Male > female (3:2 to 2:1)

ETIOLOGY AND PATHOPHYSIOLOGY • The exact pathophysiology of EM is incompletely understood but appears to be the result of a TH1-mediated immune reponse to an inciting event such as infection or drug exposure. • Genetic susceptibility can be a predisposing factor in some patients with EM. Different HLA alleles have been found to be consistent in patients with EM. • HSV containing a certain HSV pol, a polymerase associated with the HSVtriggered EM seems to involve autoimmune activation (1) • With electron microscopy, there is evidence of lichenoid inflammatory infiltrate and epidermal necrosis including circulating immune complexes, deposition of C3, IgM, and fibrin around the upper dermal blood vessels. • SJS and TEN have an increased granulysin and perforin expression within T cells than in EM (5,6). • Previous viral infections, particularly; also Epstein-Barr, coxsackie, echovirus, varicella, mumps, poliovirus, hepatitis C, cytomegalovirus, HIV, molluscum contagiosum virus (1) • Bacterial infections, particularly M. pneumoniae; other reported bacterial infections include Treponema pallidum and Gardnerella vaginalis (1) • Medications, including NSAIDs, antibiotics, sulfonamides, and antiepileptics (1,3) • Vaccines: stronger association with HPV, MMR, and small pox vaccines, but also associated with hepatitis B, meningococcal, pneumococcal, varicella, influenza, diphtheria-pertussis-tetanus, and H. influenzae (2,7) • Occupational exposures: herbicides (alachlor and butachlor), iodoacetonitrile • Radiation therapy • Premenstrual hormone changes (3) • Malignancy (3)

Genetics Strong association with HLA-DQB10301, particularly in herpes-related cases (1); possible association in recurrent cases with HLA-B35, -B62, -DR53

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RISK FACTORS Previous history of EM

GENERAL PREVENTION • Known or suspected etiologic agents should be avoided. • Acyclovir or valacyclovir may help prevent herpes-related recurrent EM.

COMMONLY ASSOCIATED CONDITIONS See “Etiology and Pathophysiology” earlier.

DIAGNOSIS Clinical

HISTORY • Absent or mild prodromal symptoms • Acute, self-limiting, episodic course • History of new medication • Preceding HSV infection 10 to 15 days before the skin eruptions • Rash involving the skin and sometimes the mucous membrane, most commonly the mouth. • Symptoms of any of the infections associated with EM, most commonly HSV and Mycoplasma pneumoniae

PHYSICAL EXAM • Acral extremities • Symmetric cutaneous eruptions composed of targetoid lesions with concentric color variation. • Mucosal involvement – Oral involvement manifest as erythema, erosions, bullae, and ulcerations on both nonkeratinized and keratinized mucosal surfaces and on the vermilion of the lips. Minimal involvement in EMm, if present, most commonly involves the mouth. – Can include any mucosal tissue including genital, ocular, oral, and so forth – At least two mucosal sites involved in EMM, including eyes (conjunctivitis, keratitis); mouth (stomatitis, cheilitis, characteristic blood-stained crusted

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erosions on lips); and probable trachea, bronchi, GI tract, or genital tract (balanitis and vulvitis) (6)

DIFFERENTIAL DIAGNOSIS • SJS – Generalized distribution of lesions; concentrated on the trunk – Macular atypical targetoid lesions – Flat target lesions or macules with coalescence of lesions – Blisters and skin detachment 38.5°C) more likely with SJS than EM – More likely to have mucosal involvement at ≥2 sites, lymphadenopathy, high C-reactive protein levels (>10 mg/dL), and hepatic dysfunction, and >90% have severe mucosal involvement at least at one site (1) • TEN – Similar to SJS but has full-thickness skin necrosis and skin detachment >30% of the total body surface area (6,8) – 34–40% mortality rate (4) • Urticaria • Fixed drug eruption • Bullous pemphigoid • Paraneoplastic pemphigoid • Sweet syndrome • Rowell syndrome • Polymorphus light eruption • Cutaneous small-vessel vasculitis • Mucocutaneous lymph node syndrome • Erythema annulare centrifugum • Acute hemorrhagic edema of infancy • Subacute cutaneous lupus erythematosus • Contact dermatitis • Pityriasis rosea • HSV • Secondary syphilis

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• Tinea corporis • Dermatitis herpetiformis • Herpes gestationis • Septicemia • Serum sickness • Viral exanthem • Rocky Mountain spotted fever • Meningococcemia • Lichen planus • Behçet syndrome • Recurrent aphthous ulcers • Herpetic gingivostomatitis • Granuloma annulare

DIAGNOSTIC TESTS & INTERPRETATION • No lab test is indicated to make the diagnosis of EM (1,4,9). • Skin biopsy of lesional and perilesional tissue in equivocal conditions • Direct and indirect immunofluorescence (DIF and IIF) to differentiate EM from other vesiculobullous diseases. DIF is detected on a biopsy of perilesional skin, and IIF is detected from a blood sample (1). • HSV tests in recurrent EM (serologic tests, swab culture, or tests using skin biopsy sample to check HSV antigens or DNA in keratinocytes by DIF or direct fluorescent antibody [DFA] or polymerase chain reaction [PCR]) • Antibody staining to IFN-γ and TNF-α to differentiate HSV from drugassociated EM • As the second most common cause of EM, M. pneumoniae should be worked up with CXR, swabs, and serologic test. • In persistent EM, check complement levels (1).

Initial Tests (lab, imaging) No imaging studies are indicated in most cases unless there is suspicion for M. pneumoniae. Follow-Up Tests & Special Considerations Chest x-ray may be necessary if an underlying pulmonary infection (M. pneumoniae) is suspected.

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Test Interpretation • Vacuolar interface dermatitis with CD4+ T lymphocytes and histiocytes in papillary dermis and the dermal–epidermal junction • Superficial perivascular lymphocytic inflammation • Satellite cell necrosis • Necrotic keratinocytes mainly in the basal layer • Papillary dermal edema

TREATMENT GENERAL MEASURES • Step 1 DISCONTINUE OR TREAT INCITING FACTOR (1,4,9) • Wound care for severe cases with epidermal detachment. • Oral lesions should be addressed to insure maintenance of PO intake. This can include oral anesthetic solutions and antiseptic rinses.

MEDICATION • Acute EM – Discontinuation of inciting factors and treatment of underlying disease (1,4,9)[B] – Symptomatic treatment with oral antihistamines and topical (1)[B] – HSV-induced EM: Most recent sources report no proven effect on the course of EM using antivirals with acute mild EM (1,9)[B] – M. pneumoniae-associated EM may require antibiotics. • Mucosal membrane EM – Consider high-potency topical corticosteroid gel, oral antiseptic, and oral anesthetic solutions if mild. – If more severe, consider prednisone 40 to 60 mg/day with dosage tapered over 2 to 4 weeks (1)[B]. – Ophthalmology consultation is imperative for ocular involvement (4)[A]. • Recurrent EM – First-line treatment for HSV-associated and idiopathic recurrent EM is antiviral prophylaxis; 12 to 24 months of prophylaxis is most effective (1,10)[B].

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– Therapy includes acyclovir 400 mg BID, valacyclovir 500 mg BID, famciclovir 250 mg BID (1)[B] – Second-line therapy includes dapsone (100 to 150 mg/day), azathioprine (Imuran, 100 to 150 mg/day), thalidomide (100 to 200 mg/day), tacrolimus (0.1% ointment daily), mycophenolate mofetil (CellCept 1,000 to 1,500 mg BID), hydroxychloroquine (400 mg/day) (1)[B]

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Care at home • Hospitalization needed for fluid and electrolyte management in patient with severe mucous membrane involvement, impaired oral intake, and dehydration • IV antibiotics if secondary infection develops

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • The disease is self-limiting. • Complications are rare, with no mortality.

DIET As tolerated, with increased fluid intake

PATIENT EDUCATION • The disease is self-limiting. However, the recurrence risk may be 30%. • Avoid any identified etiologic agents.

PROGNOSIS • Rash evolves over 1 to 2 weeks and subsequently resolves within 2 to 6 weeks, generally without scarring or sequelae. • Following resolution, there may be some postinflammatory hyper- or hypopigmentation.

COMPLICATIONS Secondary infection

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REFERENCES 1. Sokumbi O, Wetter DA. Clinical features, diagnosis, and treatment of erythema multiforme: a review for the practicing dermatologist. Int J Dermatol. 2012;51(8):889–902. 2. Rosenblatt AE, Stein SL. Cutaneous reactions to vaccinations. Clinical Dermatology. 2015;33(3):327–332. 3. Levin J, Hofstra T. Recurrent erythema multiforme. JAMA. 2014;312(4):426–427. 4. Habif TP. Erythema multiforme. Clinical Dermatology. 5th ed. St. Louis, MO: Mosby-Elsevier; 2010:710–714. 5. Iwai S, Sueki H, Watanabe H, et al. Distinguishing between erythema multiforme major and Stevens-Johnson syndrome/toxic epidermal necrolysis immunopathologically. J Dermatol. 2012;39(9):781–786. 6. Scwartz RA, McDonough PH, Lee BW. Toxic epidermal necrolysis: part I. Introduction, history, classification, clinical features, systemic manifestations, etiology, and immunopathogenesis. J Am Acad Dermatol. 2013;69(2):173.e1–173.e13. 7. Storie EB, Perry A. Erythema multiforme following smallpox vaccination. Mil Med. 2014;179(1):e113–e115. 8. Scwartz RA, McDonough PH, Lee BW. Toxic epidermal necrolysis: part II. Prognosis, sequelae, diagnosis, differential diagnosis, prevention, and treatment. J Am Acad Dermatol. 2013;69(2):187.e1–187.e16. 9. Sola CA, Beute TC. Erythema multiforme. J Spec Oper Med. 2014;14(3):90–92. 10. Wetter DA, Davis MD. Recurrent erythema multiforme: clinical characteristics, etiologic associations, and treatment in a series of 48 patients at Mayo Clinic, 2000 to 2007. J Am Acad Dermatol. 2010;62(1):45–53.

SEE ALSO Cutaneous Drug Reactions; Dermatitis Herpetiformis; Pemphigoid Gestationis; Stevens-Johnson Syndrome; Toxic Epidermal Necrolysis; Urticaria

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CODES ICD10 • L51.9 Erythema multiforme, unspecified • L51.8 Other erythema multiforme • L51.0 Nonbullous erythema multiforme

CLINICAL PEARLS • EM is diagnosed clinically by careful review of the history, thorough detailed physical exam, and by excluding other similar disorders. No lab tests are required for the diagnosis. • Typical lesions are characteristic targetoid or “iris” lesions but can include raised targetoids. • Lesions are symmetrically distributed on palms, soles, dorsum of the hands, and extensor surfaces of extremities and face. The oral mucosa is the most affected mucosal region in EM. • Management of EM involves determining the etiology when possible. The first step is to treat the suspected infection or discontinue the causative drug. • Complications are rare. Most cases are self-limited. However, the recurrence risk may be as high as 30%. • Recurrent cases often are secondary to HSV infection. Antiviral therapy may be beneficial.

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ERYTHEMA NODOSUM Faruq Pradhan, MBBCh • Fredric D. Gordon, MD, AGAF BASICS DESCRIPTION • A delayed-type hypersensitivity reaction to various antigens, or an autoimmune reaction presenting as a panniculitis that affects subcutaneous fat • Clinical pattern of multiple, bilateral, erythematous, tender nodules in a typically pretibial distribution that undergo a characteristic pattern of color changes, similar to that seen in bruises. Unlike erythema induratum, the lesions of erythema nodosum (EN) do not typically ulcerate. • Occurs most commonly on the shins; less commonly on the thighs, forearms, trunk, head, or neck • Often associated with nonspecific prodrome including fever, weight loss, and arthralgia • Often idiopathic but may be associated with a number of clinical entities • Usually remits spontaneously in weeks to months without scarring, atrophy, or ulceration • Uncommon to have recurrences after initial presentation

Pregnancy Considerations May have repeat outbreaks during pregnancy

Pediatric Considerations Rare pediatric variant has lesions only on palms or soles, often unilateral. Typically has a shorter duration in children than adults.

EPIDEMIOLOGY Incidence • 1 to 5/100,000/year • Predominant age: 20 to 30 years • Predominant sex: female > male (6:1) in adults

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Prevalence Varies geographically depending on the prevalence of disorders associated with EN

ETIOLOGY AND PATHOPHYSIOLOGY • Idiopathic: up to 55% • Infectious: 44%. Streptococcal pharyngitis (most common), mycobacteria, mycoplasma, chlamydia, mycoplasma, coccidiodomycosis, rarely can be caused by Campylobacter spp., ricketssiae, Salmonella spp., psittacosis, syphilis • Sarcoidosis: 11–25% • Drugs: 3–10%. Sulfonamides, amoxicillin, oral contraceptives, bromides, azathioprine, vemurafenib • Pregnancy: 2–5%, • Enteropathies: 1–4%. Ulcerative colitis, Crohn disease, Behçet disease, celiac disease, diverticulitis • Rare causes: 12 weeks, or absence of nodules overlying lower limbs (3)[C]

Test Interpretation • Septal panniculitis without vasculitis • Neutrophilic infiltrate in septa of fat tissue early in course • Actinic radial (Miescher) granulomas, consisting of collections of histocytes around a central stellate cleft, may be seen. • Fibrosis, paraseptal granulation tissue, lymphocytes, and multinucleated giant cells predominate late in course (4).

TREATMENT • Condition usually self-limited within 1 to 2 months • All medications listed as treatment for EN are off-label uses of the medications. There are no specific FDA-approved medications.

GENERAL MEASURES • Mild compression bandages and leg elevation may reduce pain. (Wet dressings, hot soaks, and topical medications are not useful.) • Discontinue potentially causative drugs. • Treat underlying disease. • Indication for treatment is poorly defined in literature; hence, therapy specifically for EN is directed towards symptom management.

MEDICATION First Line • NSAIDs: – Ibuprofen 400 mg PO q4–6h (not to exceed 3,200 mg/day)

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– Indomethacin 25 to 50 mg PO TID – Naproxen 250 to 500 mg PO BID • Precautions – GI upset/bleeding (avoid in Crohn or ulcerative colitis) – Fluid retention – Renal insufficiency – Dose reduction in elderly, especially those with renal disease, diabetes, or heart failure – May mask fever – NSAIDs can increase cardiovascular (CV) risk. • Significant possible interactions – May blunt antihypertensive effects of diuretics and β-blockers – NSAIDs can elevate plasma lithium levels. – NSAIDs can cause significant elevation and prolongation of methotrexate levels.

Second Line • Potassium iodide 400 to 900 mg/day divided BID or TID for 3 to 4 weeks (for persistent lesions); need to monitor for hyperthyroidism with prolonged use; pregnancy class D (5)[B] • Corticosteroids for severe, refractory, or recurrent cases in which an infectious workup is negative. Prednisone 1 mg/kg/day for 1 to 2 weeks is the recommended dose/duration. Potential side effects include hyperglycemia, hypertension, weight gain, worsening gastroesophageal reflux disease, mood changes, bone loss, osteonecrosis, and proximal myopathy (1) • For EN related to Behçet disease, one can also consider colchicine 0.6 to 1.2 mg BID. Potential side effects include GI upset and diarrhea (6)[B].

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS Occasionally, admission may be needed for the antecedent illness (e.g., tuberculosis).

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ONGOING CARE FOLLOW-UP RECOMMENDATIONS • Keep legs elevated • Elastic wraps or support stockings may be helpful when patients are ambulating.

Patient Monitoring Monthly follow-up or as dictated by underlying disorder

DIET No restrictions

PATIENT EDUCATION • Lesions will resolve over a few weeks to months • Scarring is unlikely. • Joint aches and pains may persist. • female

ETIOLOGY AND PATHOPHYSIOLOGY • Portal hypertension causes portacaval anastomosis to develop to decompress portal circulation. This leads to a congested submucosal venous plexus with tortuous dilated veins in the distal esophagus. Variceal rupture results in

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hemorrhage. • Pathophysiology of portal hypertension: – Increased resistance to portal flow at the level of hepatic sinusoids caused by Intrahepatic vasoconstriction due to decreased nitric oxide production, and increased release of endothelin-1 (ET-1), angiotensinogen, and eicosanoids Sinusoidal remodeling causing disruption of blood flow – Increased portal flow caused by hyperdynamic circulation due to splanchnic arterial vasodilation through mediators such as nitric oxide, prostacyclin, and TNF. • Causes of portal hypertension: – Prehepatic: Extrahepatic portal vein obstruction (EHPVO) or Massive splenomegaly with increased splenic vein blood flow – Posthepatic: Severe right-sided heart failure, constrictive pericarditis, and hepatic vein obstruction (Budd-Chiari syndrome) – Intrahepatic: Cirrhosis accounts for most cases of portal hypertension. – Less frequent causes are schistosomiasis, massive fatty change, diseases affecting portal microcirculation as nodular regenerative hyperplasia and diffuse fibrosing granulomatous disease as sarcoidosis.

Genetics Cirrhosis is rarely hereditary.

RISK FACTORS • Cirrhosis due to any cause • In cirrhotic patients, thrombocytopenia and splenomegaly are independent predictors of esophageal varices. • Noncirrhotic portal hypertension • Increased bleeding risk for known varices is associated with varix size; endoscopic signs (red wale marks, cherry-red spots); vessel wall thickness; abrupt increase in variceal pressure (i.e., Valsalva maneuver)

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• MELD/Child-Pugh score; presence of portal vein thrombosis; high hepatic venous pressure gradient (HVPG)

GENERAL PREVENTION • Prevent underlying causes: alcoholism, hepatitis B vaccine, needle hygiene, detox in IV drug use (IVDU) to avoid HCV exposure; specific screening and therapy for hepatitis B and C, hemochromatosis

COMMONLY ASSOCIATED CONDITIONS • Portal hypertensive gastropathy; varices in stomach, duodenum, colon, rectum (causes massive bleeding, unlike hemorrhoids); rarely at umbilicus (caput medusa) or ostomy sites • Isolated gastric varices can occur due to splenic vein thrombosis/stenosis from hypercoagulability/contiguous inflammation (most commonly, chronic pancreatitis). • Other complications of cirrhosis: hepatic encephalopathy, ascites, hepatorenal syndrome, spontaneous bacterial peritonitis, hepatocellular carcinoma

DIAGNOSIS • First indication of varices is often the presence of a GI bleeding episode: hematemesis, hematochezia, and/or melena. • Occult bleeding (anemia): uncommon

HISTORY • Underlying history of cirrhosis/liver disease. Variceal bleed can be initial presentation of previously undiagnosed cirrhosis. • Alcoholism, exposure to blood-borne viruses • Hematemesis, melena, or hematochezia • Rapid upper GI bleed can present as rectal bleeding.

PHYSICAL EXAM • Assess hemodynamic stability: hypotension, tachycardia (active bleeding). • Abdominal exam—liver palpation/percussion (often small and firm with cirrhosis) • Splenomegaly, ascites (shifting dullness; puddle splash)

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• Visible abdominal periumbilical collateral circulation (caput medusae) • Peripheral stigmata of alcohol abuse: spider angiomata on chest/back, palmar erythema, testicular atrophy, gynecomastia • Anal varices • Hepatic encephalopathy; asterixis • Blood on rectal exam

DIFFERENTIAL DIAGNOSIS • Upper GI bleeding: 10–30% are due to varices. – In patients with known varices, as many as 50% bleed from nonvariceal sources. – Peptic ulcer; gastritis – Gastric/esophageal malignancy – Congestive gastropathy of portal hypertension – Arteriovenous malformation – Mallory-Weiss tears – Aortoenteric fistula – Hemoptysis; nosebleed • Lower GI bleeding – Rectal varices; hemorrhoids – Colonic neoplasia – Diverticulosis/arteriovenous malformation – Rapidly bleeding upper GI site • Continued/recurrent bleeding risk: actively bleeding/large varix, high ChildsPugh severity score, infection, renal failure

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Anemia: Hemoglobin may be normal in active bleeding; may require 6 to 24 hours to equilibrate; other causes of anemia are common in cirrhotics. • Thrombocytopenia: most sensitive and specific lab parameter, correlates with portal hypertension, large esophageal varices • Abnormal aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, bilirubin; prolonged PT, low albumin suggest cirrhosis. • BUN, creatinine (BUN often elevated in GI bleed)

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• Sodium level; may drop in patients treated with terlipressin (1)[A] • Esophagogastroduodenoscopy (1)[A] – Can identify actively bleeding varices as well as large varices and stigmata of recent bleeding – Can be used to treat bleeding with esophageal band ligation (preferred to sclerotherapy); prevent rebleeding; detect gastric varices, portal hypertensive gastropathy; diagnose alternative bleeding sites – Can identify and treat nonbleeding varices (protruding submucosal veins in the distal third of the esophagus)

Diagnostic Procedures/Other • Transient elastography (TE) for identifying CLD patients at risk of developing clinically significant portal hypertension (CSPH) (1)[A] • Hepatic vein pressure gradient (HVPG) >10 mm Hg: gold standard to diagnose CSPH (normal: 1 to 5 mm Hg) (1)[A] • HVPG response of ≥10% or to ≤12 mm Hg to intravenous propranolol may identify responders to nonselective β-blocker (NSBB) and is linked to a significant decrease in risk of variceal bleeding (1,2)[A]. • Video capsule endoscopy screening may be an alternative to traditional endoscopy. • Doppler sonography (second line): demonstrates patency, diameter, and flow in portal and splenic veins, and collaterals; sensitive for gastric varices; documents patency after ligation or transjugular intrahepatic portosystemic shunt (TIPS) • CT- or MRI-angiography (second line, not routine): demonstrates large vascular channels in abdomen, mediastinum; demonstrates patency of intrahepatic portal and splenic vein – Venous-phase celiac arteriography: demonstrates portal vein and collaterals; diagnoses hepatic vein occlusion – Portal pressure measurement using retrograde catheter in hepatic vein

TREATMENT GENERAL MEASURES

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• Treat underlying cirrhotic comorbidities. • Variceal bleeding is often complicated by hepatic encephalopathy and infection. • Active bleeding (3)[A] – IV access, hemodynamic resuscitation – Type and crossmatch packed RBCs. Overtransfusion increases portal pressure and increases rebleeding risk. – Treat coagulopathy as necessary. Fresh frozen plasma may increase blood volume and increase rebleeding risk. – Avoid sedation, monitor mental status, avoid nephrotoxic drugs and βblockers acutely. – IV octreotide to lower portal venous pressure as adjuvant to endoscopic management. IV bolus of 50 μg followed by drip of 50 μg/hr. – Terlipressin (alternative): 2 mg q4h IV for 24 to 48 hours, then 1 mg q4h – Erythromycin 250 mg IV 30 to 120 minutes before endoscopy (1)[A] – Urgent upper GI endoscopy for diagnosis and treatment Variceal band ligation preferred to sclerotherapy for bleeding varices. Also for nonbleeding medium-to-large varices to decrease bleeding risk Ligation: lower rates of rebleeding, fewer complications, more rapid cessation of bleeding, higher rate of variceal eradication. • Repeat ligation/sclerosant for rebleeding. • If endoscopic treatment fails, consider self-expanding esophageal metal stents or per oral placement of Sengstaken-Blakemore-type tube up to 24 hours to stabilize patient for TIPS (1)[C]. • As many as 2/3 of patients with variceal bleeding develop an infection, most commonly spontaneous bacterial peritonitis, UTI, or pneumonia. Antibiotic prophylaxis with oral norfloxacin 400 mg or IV ceftriaxone 1 g q24h for up to a week. • In active bleeding, avoid β-blockers, which decrease BP and blunt the physiologic increase in heart rate during acute hemorrhage. • Prevent recurrence of acute bleeding – Vasoconstrictors: terlipressin, octreotide (reduce portal pressure) – Endoscopic band ligation (EBL): if bleeding recurs/portal pressure measurement shows portal pressure remains >12 mm Hg

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– TIPS: Second-line therapy if above methods fail; TIPS decreases portal pressure by creating communication between hepatic vein and an intrahepatic portal vein branch.

MEDICATION Primary prevention of variceal bleeding (4)[A] • Endoscopy: assesses variceal size, presence of red wale sign (longitudinal variceal reddish streak that suggests either a recent bleed or a pending bleed) to determine risk stratification – Endoscopy every 2 to 3 years if cirrhosis but no varices; every 1 to 2 years if small varices and not receiving β-blockers (2)[A]

First Line • (Not actively bleeding). NSBB reduce portal pressure and decrease risk of first bleed from 25% to 15% in primary prophylaxis. Used in cirrhosis with small varices and increased hemorrhage risk as well as cirrhosis + medium-tolarge varices (2,4)[A] • Carvedilol: 6.25 mg daily (2)[A] is more effective than NSBB in dropping HVPG (1)[A]. – Propranolol: 20 mg BID increase until heart rate decreased by 25% from baseline – Nadolol 80 mg daily; increase as above – Contraindications: severe asthma • Chronic prevention of rebleeding (secondary prevention): NSBBs and EBL reduce rate of rebleeding to a similar extent, but β-blockers reduce mortality, whereas ligation does not (5)[A].

Second Line Obliterate varices with esophageal banding for not tolerant of medication prophylaxis. • During ligation: proton pump inhibitors, such as lansoprazole 30 mg/day, until varices obliterated • Management of Budd-Chiari syndrome: anticoagulation, angioplasty/thrombolysis, TIPS, and orthotopic liver transplantation (1)[C] • Management of extrahepatic portal vein obstruction: anticoagulation (1)[B];

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mesenteric-left portal vein bypass (Meso-Rex procedure) (1)[C]

ISSUES FOR REFERRAL Refer for endoscopy, liver transplant, and interventional radiology for TIPS.

ADDITIONAL THERAPIES Pneumococcal and hepatitis A/B (HAV/HBV) vaccine

SURGERY/OTHER PROCEDURES • Esophageal transection: in rare cases of uncontrollable, exsanguinating bleeding • Liver transplantation

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Inpatient to stabilize acute bleeding and hemodynamic status, therapeutic endoscopy. ICU is typically the most appropriate initial setting. • Discharge criteria: bleeding cessation; hemodynamic stability and appropriate plan for treating comorbidities

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Close monitoring of vital signs. • Endoscopic variceal ligation, every 1 to 4 weeks, until varices eradicated • If TIPS, repeat endoscopy to assess rebleeding. • Endoscopic screening in patients with known cirrhosis every 2 to 3 years; yearly in patients with decompensated cirrhosis (1)[C] • Patients with a liver stiffness 150,000 can avoid endoscopic screening (1)[A] and may follow up by annual TE and platelet count (1)[C].

PATIENT EDUCATION National Digestive Information Clearinghouse (http://www.niddk.nih.gov/healthinformation/health-topics/digestive-diseases/Pages/default.aspx) or American

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Liver Foundation (http://www.liverfoundation.org/)

PROGNOSIS • Depends on underlying comorbidities • In cirrhosis, 1-year survival is 50% for those surviving 2 weeks following a variceal bleed. • In-hospital mortality remains high related to severity of underlying cirrhosis, ranging from 0% in Child A to 32% in Child C disease (3). • Prognosis in noncirrhotic portal fibrosis is better than for cirrhotics.

COMPLICATIONS • Formation of gastric varices after eradication of esophageal varices • Esophageal varices can recur. • Hepatic encephalopathy, renal dysfunction, hepatorenal syndrome • Infections after banding/ligation of varices

REFERENCES 1. de Franchis R; and the Baveno VI Faculty. Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension. J Hepatol. 2015;63(3):743. 2. Tripathi D, Stanley AJ, Hayes PC, et al. U.K. guidelines on the management of variceal haemorrhage in cirrhotic patients. Gut. 2015;64(11):1680. 3. Herrera JL. Management of acute variceal bleeding. Clin Liver Dis. 2014;18(2):347–357. 4. Simonetto DA, Shah VH, Kamath PS. Primary prophylaxis of variceal bleeding. Clin Liver Dis. 2014;18(2):335–345. 5. Albillos A, Tejedor M. Secondary prophylaxis for esophageal variceal bleeding. Clin Liver Dis. 2014;18(2):359–370.

ADDITIONAL READING • Kochhar GS, Navaneethan U, Hartman J, et al. Comparative study of endoscopy vs. transjugular intrahepatic portosystemic shunt in management of gastric variceal bleeding. Gastroenterol Rep (Oxf). 2015;3(1):75–82. • Zanetto A, Senzolo M, Ferrarese A, et al. Assessment of bleeding risk in

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patients with cirrhosis. Curr Hepatol Rep. 2015;14(1):9–18.

SEE ALSO Cirrhosis of the Liver; Portal Hypertension

CODES ICD10 • I85.00 Esophageal varices without bleeding • I85.01 Esophageal varices with bleeding • I85.10 Secondary esophageal varices without bleeding

CLINICAL PEARLS • Thrombocytopenia is the most sensitive marker of increased portal pressure and large esophageal varices. • In acute bleeding, avoid β-blockers. • In acute bleeding, overtransfusion can elevate portal pressure and increase bleeding risk.

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ESSENTIAL TREMOR SYNDROME Jonathon M. Firnhaber, MD BASICS DESCRIPTION • A postural (occurring with voluntary maintenance of a position against gravity) or kinetic (occurring during voluntary movement) flexion–extension tremor that is slow and rhythmic and primarily affects the hands and forearms, head, and voice with a frequency of 4 to 12 Hz • Older patients tend to have lower frequency tremors, whereas younger patients exhibit frequencies in the higher range. • May be familial, sporadic, or associated with other movement disorders • Can begin at any age but the incidence and prevalence increase with age • The tremor can be exacerbated by emotional or physical stresses, fatigue, and caffeine. • System(s) affected: neurologic, musculoskeletal, ear/nose/throat (ENT) (voice)

EPIDEMIOLOGY Essential tremor is the most common pathologic tremor in humans.

Incidence • Can occur at any age but bimodal peaks exist in the 2nd and 6th decades • Incidence rises significantly after age 49 years.

Prevalence The overall prevalence for essential tremor has been estimated between 0.4% and 0.9% but is increased in older (65 years) patients to 4.6% and in advanced age (95 years) up to 22% (1)[B].

ETIOLOGY AND PATHOPHYSIOLOGY • Suspected to originate from an abnormal oscillation within thalamocortical and cerebello-olivary loops, as lesions in these areas tend to reduce essential tremor

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• Essential tremor is not a homogenous disorder; many patients have other motor manifestations and nonmotor features, including cognitive and psychiatric symptoms.

Genetics • Positive family history in 50–70% of patients; autosomal dominant inheritance is demonstrated in many families, but twin studies suggest that environmental factors are also involved. • A link to genetic loci exists on chromosomes 2p22–2p25, 3q13, and 6p23. In addition, a Ser9Gly variant in the dopamine D3 receptor gene on 3q13 has been suggested as a risk factor.

COMMONLY ASSOCIATED CONDITIONS • Can be present in 10% of patients with Parkinson disease (PD); characteristics of PD that distinguish it from essential tremor include 3- to 5-Hz resting tremor; accompanying rigidity, bradykinesia, or postural instability; and no change with alcohol consumption. • Patients with essential tremor have a 4% risk of developing PD. Although action tremors may precede PD, they will be diagnosed as essential tremor as long as the bradykinesia and rigidity of PD are not yet present (1)[B]. • Resting tremor, typically of the arm, may be seen in up to 20–30% of patients with essential tremor. Although action tremor is the hallmark feature of essential tremor, it is commonly found in patients with PD as well.

DIAGNOSIS HISTORY • Core criteria for diagnosis – Bilateral (less likely unilateral) action (postural or kinetic) tremor of the hands and forearms that is most commonly asymmetric – Absence of other neurologic signs, with the exception of cogwheel phenomenon – May have isolated head tremor with no signs of dystonia • Secondary criteria include long duration (>3 years), positive family history,

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and beneficial response to alcohol (2)[C].

PHYSICAL EXAM • Tremor can affect upper limbs (~95% of patients). • Less commonly, the tremor affects head (~34%), lower limbs (~30%), voice (~12%), tongue (~7%), face (~5%), and trunk (~5%).

DIFFERENTIAL DIAGNOSIS • PD • Wilson disease • Hyperthyroidism • Multiple sclerosis • Dystonic tremor • Cerebellar tremor • Asterixis • Psychogenic tremor • Orthostatic tremor • Drug-induced or enhanced physiologic tremor (amiodarone, cimetidine, lamotrigine, itraconazole, valproic acid, SSRIs, steroids, lithium, cyclosporine, β-adrenergic agonists, ephedrine, theophylline, tricyclic antidepressants [TCAs], antipsychotics) (3)[B].

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • No specific biologic marker or diagnostic test is available. • Ceruloplasmin and serum copper to rule out Wilson disease • Thyroid-stimulating hormone to rule out thyroid dysfunction • Serum electrolytes, BUN, creatinine • Brain MRI usually is not necessary or indicated unless Wilson disease is found or exam findings imply central lesion.

Diagnostic Procedures/Other • Accelerometry evaluates tremor frequency and amplitude; >95% of PD cases exhibit frequencies in the 4- to 6-Hz range, and 95% of essential tremor cases exhibit frequencies in the 5- to 8-Hz range. • Surface electromyography is less helpful in distinguishing essential tremor

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from PD.

Test Interpretation Posture-related tremor

TREATMENT MEDICATION Pharmacologic treatment should be considered when tremor interferes with activities of daily living (ADLs) or causes psychological distress.

First Line • Propranolol 60 to 320 mg/day in divided doses or in long-acting formulation reduces limb tremor magnitude by ~50%, and almost 70% of patients experience improvement in clinical rating scales. There is insufficient evidence to recommend propranolol for vocal tremor. Single doses of propranolol, taken before social situations that are likely to exacerbate tremor, are useful for some patients. • Primidone 25 mg at bedtime, gradually titrated to 150 to 300 mg at bedtime, improves tremor amplitude by 40–50%. Maximum dose is 750 mg/day, with doses >250 mg/day typically divided to BID or TID. Low-dose therapy (14.5 categorizes patient as having diagnosis of ETD (1,2)[B]. Data is limited but promising. Questions: – Pressure in ears in past 1 month? – Pain in ears in past 1 month?

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– A feeling that ears are clogged or “under water”? – Ear symptoms when you have cold or sinusitis? – Crackling or popping sounds in the ears? – Ringing in ears? – A feeling that your hearing is muffled?

PHYSICAL EXAM • Pneumatic otoscopy: retracted tympanic membrane, effusion, decreased drum movement • Toynbee maneuver: view changes of the drum while patient autoinsufflates against closed lips and pinched nostrils; may show various degrees of retraction – Entire drum may be retracted and “lateralize” with insufflation. – Posterosuperior quadrant (pars flaccida) may form a retraction pocket. • Tuning fork tests: 512-Hz fork placed on the forehead lateralizes to affected ear (Weber test); the fork will be louder behind the ear on the mastoid than in front of the ear (bone conduction > air conduction, Rinne test) in conductive hearing loss. • Nasopharyngoscopy: adenoid hypertrophy or nasopharyngeal mass • Anterior rhinoscopy: deviated nasal septum, polyps, mucosal hypertrophy, turbinate hypertrophy

DIFFERENTIAL DIAGNOSIS • SSNHL (a medical emergency) • Tympanic membrane perforation • Barotrauma • Temporomandibular joint disorder • Ménière disease • Superior semicircular canal dehiscence

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Radiologic studies are not performed routinely if clinical signs/symptoms suggest ETD. • CT scan (not necessary) may show changes related to OM or middle

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ear/mastoid opacification. • Functional MRI might determine cause of ETD (in recalcitrant cases), as the ET opening can be visualized during Valsalva.

Diagnostic Procedures/Other • Audiogram may show conductive hearing loss. • Tympanometry: type B or C tympanograms indicate fluid or retraction, respectively. Negative middle ear peak pressures seen even with normal (type A) tympanograms.

TREATMENT • Due to limited high-quality evidence, it is difficult to recommend any one treatment option/intervention as superior (3)[C]. • Use of a “nasal balloon” shown effective for clearing OM with effusion; unclear of benefit for ETD • Generally, principle of treatment is to remove or fix the underlying cause (e.g., infection, tumor, perforation of TM, restore tensor palitini muscle, etc.) and hopefully end or at least reduce cycle of infection/inflammation. • Although no evidence exists, some consider antibiotics for AOM; decongestants, nasal steroids, antihistamines (if allergic rhinitis is present), and surgery/procedures for recalcitrant cases • Tympanostomy tubes ± adenoidectomy when indicated for recurrent ear infections or severe progressive retractions

MEDICATION • Only when infection such as AOM is suspected as driving cause of ETD should antibiotics be given; large study giving antibiotics to children with OM with effusion showed no benefit (4)[A]. • Few data support pharmacologic treatments such as decongestants, nasal steroids, or antihistamines for ETD. • Medication options are for treatment of comorbid conditions. • Decongestants, topical, oral – Avoid prolonged use (>3 days); can cause rhinitis medicamentosa. – Decongestants are most useful for acute ETD related to a resolving URI.

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– Decongestants are not typically used for relief of chronic ETD in children. Phenylephrine: adults and children ≥12 years of age, 1 tablet (10 mg) q4h PRN; children 6 to 11 years of age, 5 mg q4h PRN; children 4 to 5 years of age, 2.5 mg q4h PRN Pseudoephedrine: adults, 60 mg q4–6h PRN; children 6 to 12 years of age, 30 mg q4–6h PRN; children 4 to 5 years of age, 15 mg q4–6h PRN Oxymetazoline: adults and children ≥6 years of age, 1 to 2 sprays each nostril q12h PRN. Limit use to ≤3 days. Phenylephrine: adults, 1 to 2 sprays each nostril q4h PRN. Limit use to ≤3 days. • Nasal steroids (may be beneficial for those with allergic rhinitis) (5)[A] – Beclomethasone (Beconase, Vancenase): adults and children ≥12 years of age, 1 to 2 sprays each nostril BID; children 6 to 11 years of age, 1 spray each nostril BID. Not recommended for children 2 for 2 consecutive days, at which time enoxaparin can be stopped. – Fondaparinux (Arixtra): 5 mg (body weight 100 kg) SC daily – Tinzaparin (Innohep): 175 anti-Xa IU/kg SC daily for minimum of 5 days and patient is adequately anticoagulated with warfarin (INR of at least 2 for 2 consecutive days) – Dalteparin (Fragmin): 200 IU/kg SC daily • Oral anticoagulant – Warfarin (Coumadin) PO with dose adjusted to an INR of 2 to 3 (3)[A]. • Contraindications – Active bleeding precludes anticoagulation. – Risk of bleeding is a relative contraindication to long-term anticoagulation. – Warfarin is contraindicated in patients with history of warfarin skin necrosis (6)[A]. – Warfarin is contraindicated in pregnancy. • Precautions – Observe patient for signs of embolization, further thrombosis, or bleeding. – Avoid IM injections. Periodically check stool and urine for occult blood; monitor CBCs, including platelets. – Heparin: thrombocytopenia and/or paradoxic thrombosis with thrombocytopenia – Warfarin: necrotic skin lesions (typically breasts, thighs, or buttocks) – LMWH: Adjust dosage in renal insufficiency. May also need dose adjustment in pregnancy • Significant possible interactions – Agents that intensify the response to oral anticoagulants: alcohol,

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allopurinol, amiodarone, anabolic steroids, androgens, many antimicrobials, cimetidine, chloral hydrate, disulfiram, all NSAIDs, sulfinpyrazone, tamoxifen, thyroid hormone, vitamin E, ranitidine, salicylates, acetaminophen – Agents that diminish the response to anticoagulants: aminoglutethimide, antacids, barbiturates, carbamazepine, cholestyramine, diuretics, griseofulvin, rifampin, oral contraceptives

Second Line • Heparin 80 mg/kg IV bolus followed by 18 g/kg/h continuous infusion • Adjust dose depending on aPTT. • In patients requiring large daily doses of heparin, measure an anti-Xa level for dose guidance. • Alternatively, for outpatients, weight-adjusted subcutaneous unfractionated heparin with 333 U/kg first, then 250 U/kg, without monitoring (6)[A] • Consider deficiency of antithrombin as a comutation in patients with significant elevated heparin requirements.

ISSUES FOR REFERRAL • Recurrent thrombosis on anticoagulation • Difficulty anticoagulating • Genetic counseling • Homozygous state in pregnancy

SURGERY/OTHER PROCEDURES • Anticoagulation must be held for surgical interventions. • For most patients with DVT, recommendations are against routine use of vena cava filter in addition to anticoagulation except when there is contraindication for anticoagulation (6)[A]. • Thrombectomy may be necessary in some cases.

ADMISSION, NURSING, AND INPATIENT CONSIDERATIONS • Admission criteria/initial stabilization: complicated thrombosis, such as PE • Nursing – Teach LMWH and warfarin use.

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– See earlier for drug interactions. • Discharge criteria: stable on anticoagulation

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring Warfarin use requires periodic (~monthly after initial stabilization) INR measurements, with a goal of 2 to 3 (6)[A].

DIET • No restrictions • Large amounts of foods rich in vitamin K may interfere with anticoagulation with warfarin.

PATIENT EDUCATION • Patients should be educated about the following: – Use of oral anticoagulant therapy – Avoidance of NSAIDs while on warfarin • The role of family screening is unclear, as most patients with this mutation do not have thrombosis. In a patient with a family history of factor V Leiden, consider screening during pregnancy or if considering oral contraceptive use.

PROGNOSIS • Most patients heterozygous for factor V Leiden do not have thrombosis. • Homozygotes have about a 50% lifetime incidence of thrombosis. • Recurrence rates after a first thrombosis are not clear, with some investigators finding rates as high as 5% and others finding rates similar to the general population. • Despite the increased risk for thrombosis, factor V Leiden does not increase overall mortality.

COMPLICATIONS • Recurrent thrombosis • Bleeding on anticoagulation

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REFERENCES 1. Rosendaal FR, Koster T, Vandenbroucke JP, et al. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood. 1995;85(6):1504–1508. 2. Lijfering WM, Middeldorp S, Veeger NJ, et al. Risk of recurrent venous thrombosis in homozygous carriers and double heterozygous carriers of factor V Leiden and prothrombin G20210A. Circulation. 2010;121(15):1706–1712. 3. Eichinger S, Welterman A, Mannhalter C, et al. The risk of recurrent venous thromboembolism in heterozygous carriers of factor V Leiden and a first spontaneous venous thromboembolism. Arch Intern Med. 2002;162(20):2357–2360. 4. Ye Z, Liu EH, Higgins JP, et al. Seven haemostatic gene polymorphisms in coronary disease: meta-analysis of 66,155 cases and 91,307 controls. Lancet. 2006;367(9511):651–658. 5. Prüller F, Weiss EC, Raggam RB, et al. Activated protein C resistance assay and factor V Leiden. N Engl J Med. 2014;371(7):685–686. 6. Guyatt GH, Akl EA, Crowther M, et al. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest. 2012;141(Suppl 2):7S–47S.

ADDITIONAL READING Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis. N Engl J Med. 2001;344(16):1222–1231.

SEE ALSO Deep Vein Thrombophlebitis

CODES ICD10 D68.51 Activated protein C resistance

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CLINICAL PEARLS • Extremely rare in Asian and African populations • Asymptomatic patients with factor V Leiden do not need anticoagulation. • For pregnant women homozygous for factor V Leiden but no prior history of VTE, postpartum prophylaxis with prophylactic or intermediate-dose LMWH or vitamin K antagonists with target INR 2 to 3 for 6 weeks is recommended. Antepartum prophylaxis is added if there is positive family of VTE.

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FAILURE TO THRIVE Durr-e-Shahwaar Sayed, DO BASICS DESCRIPTION • Failure to thrive (FTT) is not a diagnosis but a sign of inadequate nutrition in young children manifested by a failure of physical growth, usually affecting weight. In severe cases, decreased length and/or head circumference may develop. • Various parameters are used to define FTT, but in clinical practice, it is commonly defined as either weight for age that falls below the 5th percentile on more than one occasion or weight that drops two or more major percentile lines on standard growth charts. • A combination of anthropometric criteria rather than one criterion should be used to identify children at risk of FTT (1)[C].

Pediatric Considerations • Children with genetic syndromes, intrauterine growth restriction (IUGR), or prematurity follow different growth curves. • 25% of children will decrease their weight or height crossing ≥2 major percentile lines in the first 2 years of life. These children are failing to reach their genetic potential or demonstrating constitutional growth delay (slow growth with a bone age < chronologic age). After shifting down, these infants grow at a normal rate along their new percentile and do not have FTT.

EPIDEMIOLOGY Incidence • Predominant age: 6 to 12 months; 80% bone growth), increased periods of sleep, fidgetiness, and mild hyperactivity. – There may also be an initial period of malabsorption with resultant diarrhea. • Catch-up growth should be seen in 2 to 7 days. If this is not seen, reevaluation of causes is needed.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS • If specific disease is identified, follow up as indicated. • Close long-term follow-up with frequent visits is important to create and maintain a healthy, supportive environment (3)[B],(4). • Children with history of FTT are at increased risk of recurrent FTT, and longterm sequelae and growth should be monitored closely (1,2),(3)[B]. • If the family fails to comply, child protection authorities must be notified.

DIET Nutritional requirements for a “normal” child: • Infant – 120 kcal/kg/day, decreased to 95 kcal/kg/day at 6 months; if breastfed, ensure appropriate frequency and duration of feeding. – Between 6 and 12 months, continue breast milk and/or formula, but pureed foods should be consumed several times a day during this period. • Toddler – Three meals plus two nutritional snacks, 16 to 32 oz of milk/day; avoid juice and soda and feed in a social environment. – Do not restrict fat and cholesterol in children 35 days), and primary and secondary hypothalamic amenorrhea. – Primary amenorrhea, although less common, can occur in young athletes. Secondary amenorrhea is defined as the absence of menstrual cycles for >3 months after menarche established. – Although hypothalamic suppression is the most common cause of secondary amenorrhea in these athletes, other causes must be ruled out. • BMD – Ranges from optimal bone health to osteoporosis – Bone health encompasses bone strength as well as bone quality. The current practice standard (dual-energy x-ray absorptiometry) measures bone density not bone quality. However, newer research using peripheral quantitative CT scans have shown that amenorrheic female athletes have a lower proportion of cortical bone, which is thought to be related to deficient mineralization and may be responsible for the increased fracture risk (2). This research may help providers better understand why two athletes with the same BMD may have very different bone fracture histories. ACSM Position Stand recommends using the International Society of Clinical Densitometry (ISCD) guidelines for BMD Z-scores 16 years and 6 months, hypoestrogenism, amenorrhea, oligomenorrhea, and/or in patients with a history of stress fractures or fractures from minimal impact.

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FEVER OF UNKNOWN ORIGIN (FUO) Scott T. Henderson, MD BASICS DESCRIPTION • Classic definition – Repeated fever >38.3°C – Fever duration at least 3 weeks – Uncertain diagnosis after 1 week of study in the hospital • The definition of fever of unknown origin (FUO) has evolved and is based on patient characteristics and presentation. The need for in-hospital evaluation has been eliminated in previously healthy people. • Some expand the definition to include nosocomial, neutropenic (immunodeficient), and HIV-associated fevers.

EPIDEMIOLOGY Incidence Incidence unclear

ETIOLOGY AND PATHOPHYSIOLOGY • >200 causes; each with prevalence of ≤5% • Most commonly, FUO is an atypical presentation of a common condition. • Spectrum of causes varies geographically and temporally – Noninfectious inflammatory diseases are the most frequent causes in highincome countries. Common causes include temporal arteritis, polymyalgia rheumatica, or rheumatoid arthritis. • Infection – Abdominal or pelvic abscesses – Amebic hepatitis – Catheter infections – Cytomegalovirus – Dental abscesses – Endocarditis/pericarditis

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– HIV (advanced stage) – Mycobacterial infection (often with advanced HIV) – Osteomyelitis – Renal – Sinusitis – Wound infections – Other miscellaneous infections • Neoplasms – Atrial myxoma – Colorectal cancer and other GI malignancies – Hepatoma – Lymphoma – Leukemia – Solid tumors (renal cell carcinoma) • Noninfectious inflammatory disease – Connective tissue diseases Adult Still disease Rheumatoid arthritis Systemic lupus erythematosus – Granulomatous disease Crohn disease Sarcoidosis – Vasculitis syndromes Giant cell arteritis Polymyalgia rheumatica • Other causes – Alcoholic hepatitis – Cerebrovascular accident – Cirrhosis – Medications Allopurinol, captopril, carbamazepine, cephalosporins, cimetidine, clofibrate, erythromycin, heparin, hydralazine, hydrochlorothiazide, isoniazid, meperidine, methyldopa, nifedipine, nitrofurantoin, penicillin, phenytoin, procainamide, quinidine, sulfonamides

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– Endocrine disease – Factitious/fraudulent fever – Occupational causes – Periodic fever – Pulmonary emboli/deep vein thrombosis – Thermoregulatory disorders • In up to 20–30% of cases, the cause of the fever will not be identified despite thorough workup.

RISK FACTORS • Recent travel (malaria, enteric fevers) • Exposure to biologic or chemical agents • HIV infection (particularly in acute infection and advanced stages) • Elderly • Drug abuse • Immigrants • Young female health care workers (consider factitious fever)

Geriatric Considerations Common causes of geriatric infections include intra-abdominal abscess, urinary tract infection, tuberculosis, and endocarditis. Other common causes of FUO in patients >65 years include malignancies (particularly hematologic cancers) and drug-induced fever.

Pediatric Considerations • ~50% of FUO in pediatric cases are infectious. Collagen vascular disease, malignancy are common (1)[A]. • Inflammatory bowel disease is a common cause of FUO in older children and adolescents.

DIAGNOSIS HISTORY • Onset and pattern of fever • Constitutional symptoms:

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– Chills, night sweats, myalgias, weight loss with an intact appetite (infectious etiology) – Arthralgias, myalgias, fatigue (inflammatory etiology) – Fatigue, night sweats, weight loss with loss of appetite (neoplastic etiology) • Past medical history: chronic infections, abdominal diseases, transfusion history, malignancy, psychiatric illness, and recent hospitalization • Past surgical history: type of surgery performed, postoperative complications, and any indwelling foreign material • Comprehensive medication history, including over-the-counter and herbal products • Family history, such as periodic fever syndromes and recent febrile illnesses in close contacts • Social history: travel, exposures, living environment, sexual activity, recreational drug use

ALERT Obtain a thorough travel, psychosocial, occupational, sexual, and drug use history.

PHYSICAL EXAM • Physical findings with high diagnostic yield – Funduscopic exam for choroid tubercles or Roth spots – Temporal artery tenderness – Oral-mucosal lesions – Cardiac auscultation for bruits and murmurs – Pulmonary exam: Assess for consolidation or effusion. – Abdominal palpation for organomegaly and tenderness – Rectal examination – Testicular examination – Lymph node examination – Skin and nail bed exam for clubbing, nodules, lesions, and erosions – Focal neurologic signs – Musculoskeletal exam for tenderness or effusion – Serial exams help identify evolving physical signs (e.g., findings associated with endocarditis).

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DIFFERENTIAL DIAGNOSIS See “Etiology and Pathophysiology.”

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • CBC; C-reactive protein; ESR • Peripheral blood smear • Electrolytes, BUN and creatinine; LFT; calcium • Lactate dehydrogenase • HIV testing • Blood cultures (not to exceed six sets) • Urinalysis and urine culture • Chest x-ray • CT or MRI of abdomen and pelvis (with directed biopsy, if indicated) (2)[C] Follow-Up Tests & Special Considerations • Rheumatoid factor and antinuclear antibody test • Serologies: Epstein-Barr, hepatitis, syphilis, Lyme disease, Q fever, cytomegalovirus, brucellosis, amebiasis, coccidioidomycosis • Serum ferritin • Serum procalcitonin • Serum protein electrophoresis • Sputum and urine cultures for TB • Tuberculin skin test – May not be helpful if anergic or acute infection – If test negative, repeat in 2 weeks. – If indicated, consider an interferon gamma release assay (IGRA) test. • Thyroid function tests • Technetium-based scan (infection tumor) (2)[B] • FDG-PET/CT scan if infectious process, inflammatory process, or tumor suspected; PET scans have a high negative predictive value and good sensitivity (but may have false positives) (3)[A]. • Ultrasound of abdomen and pelvis (with directed biopsy, if indicated) if renal obstruction or biliary pathology suspected • Echocardiogram if endocarditis, atrial myxomas, or pericardial effusion is

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suspected • Lower extremity Doppler if deep vein thrombosis/pulmonary embolism suspected • CT scan of chest if pulmonary embolism suspected • Indium-labeled leukocyte scanning if inflammatory process or occult abscess suspected • Bone scan if osteomyelitis or metastatic disease suspected

Diagnostic Procedures/Other • Liver biopsy if granulomatous disease suspected (2)[C] • Temporal artery biopsy, particularly in the elderly • Lymph node, muscle, or skin biopsy, if clinically indicated • Bone marrow aspiration biopsy with smear, culture, histologic examination, and flow cytometry • Spinal tap, if clinically indicated

TREATMENT GENERAL MEASURES • Treatment depends on the specific etiology. • Therapeutic trials are a last resort and should be as specific as possible based on available clinical evidence. Avoid “shotgun” approaches as they obscure the clinical picture, have untoward effects, and do not provide a diagnostic solution (2)[C].

MEDICATION First Line • First-line drugs depend on the diagnosis. • Evidence does not support isolated treatment of fever (4)[C].

Second Line Consider a therapeutic trial only if the patient has localizing symptoms associated with the fever or continues to decline. Consultation with appropriate specialists (infectious disease, rheumatology) is recommended in this case. • Antibiotic trial based on patient’s history and suspected culture negative

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endocarditis • Antituberculous therapy if there is a high risk for TB pending definitive culture results • Corticosteroid trial based on patient’s history (once occult malignancy is ruled out) if temporal arteritis is suspected

ALERT If a steroid trial is initiated, patient may have a relapse after treatment or if certain conditions (e.g., TB) have been undiagnosed.

ADDITIONAL THERAPIES Febrile patients have increased caloric and fluid demands.

SURGERY/OTHER PROCEDURES The need for exploratory laparotomy has been largely eliminated with the advent of more sophisticated tests and imaging modalities.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Reserved for the ill and debilitated • Consider if factitious fever has been ruled out or an invasive procedure is indicated.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring If the etiology of the fever remains unknown, repeat the history, physical exam, and screening lab studies.

DIET No specific dietary recommendations have been shown to ameliorate undiagnosed fever.

PATIENT EDUCATION Maintain an open line of communication between physician and patient/family

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as the workup progresses: • The extended time required in establishing a diagnosis can be frustrating.

PROGNOSIS • Depends on etiology and age – Patients with HIV have the highest mortality. • 1-year survival rates (reflecting deaths due to all causes) Age < 35 years 35–64 years > 64 years

Survival 91% 82% 67%

COMPLICATIONS Depends on etiology

Pregnancy Considerations Fever increases the risk of neural tube defects in pregnancy and can also trigger preterm labor.

REFERENCES 1. Chow A, Robinson JL. Fever of unknown origin in children: a systematic review. World J Pediatr. 2011;7(1):5–10. 2. Mourad O, Palda V, Detsky AS. A comprehensive evidence-based approach to fever of unknown origin. Arch Intern Med. 2003;163(5):545–551. 3. Takeuchi M, Dahabreh IJ, Nihashi T, et al. Nuclear imaging for classic fever of unknown origin: meta-analysis [published online ahead of print June 23, 2016]. J Nucl Med. 4. Hersch EC, Oh RC. Prolonged febrile illness and fever of unknown origin in adults. Am Fam Physician. 2014;90(2):91–96.

ADDITIONAL READING • Ben-Baruch S, Canaani J, Braunstein R, et al. Predictive parameters for a diagnostic bone marrow biopsy specimen in the work-up of fever of unknown origin. Mayo Clin Proc. 2012;87(2):136–142.

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• Hayakawa K, Ramasamy B, Chandrasekar PH. Fever of unknown origin: an evidence-based review. Am J Med Sci. 2012;344(4):307–316. • Mulders-Manders C, Simon A, Bleeker-Rovers C Fever of unknown origin. Clin Med (Lond). 2015;15(3):280–284.

SEE ALSO • Arthritis, Juvenile Idiopathic; Colorectal Cancer; Cytomegalovirus (CMV) Inclusion Disease; Endocarditis, Infective; Hepatoma; HIV/AIDS; Lupus Erythematosus, Discoid; Osteomyelitis; Polyarteritis Nodosa; Polymyalgia Rheumatica; Pulmonary Embolism; Rheumatic Fever; Sinusitis; Stroke, Acute; Arteritis, Temporal • Algorithms: Fever in the First 3 Months of Life; Fever of Unknown Origin

CODES ICD10 R50.9 Fever, unspecified

CLINICAL PEARLS • A sequential approach to FUO based on a careful history, physical examination, with targeted testing and imaging typically yields an appropriate diagnosis. • Use empiric therapy only in carefully defined circumstances. • FUO cases that defy precise diagnosis after intensive investigation and prolonged observation generally carry a favorable prognosis. • FUO in older persons may represent an atypical presentation of a common disease. • The most common causes of FUO in high-income countries are noninfectous inflammatory diseases and other idiopathic causes.

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FIBROCYSTIC CHANGES OF THE BREAST Alain Michael P. Abellada, MD BASICS DESCRIPTION • Fibrocystic changes (FCC) is not a disease but refers to a constellation of benign histologic findings. It is the most frequent female benign clinical breast finding. • The most common symptoms are cyclic pain and tenderness, swelling, and fullness. • The breast tissue may feel dense with areas of thicker tissue having an irregular, nodular, or ridge-like surface. • Women may experience sensitivity to touch with a burning sensation. For some women, the pain is so severe that it limits exercise or the ability to lie prone. • Usually affects both breasts, most often in the upper outer quadrant where most of the milk-producing glands are located. • Histologically, in addition to macrocysts and microcysts, FCC may contain solid elements including adenosis, sclerosis, apocrine metaplasia, stromal fibrosis, and epithelial metaplasia and hyperplasia. – Depending on the presence of epithelial hyperplasia, fibrocystic change is classified as nonproliferative, proliferative without atypia, or proliferative with atypia. • System(s) affected: endocrine/metabolic, reproductive • Synonym(s): diffuse cystic mastopathy; fibrocystic disease; chronic cystic mastitis; or mammary dysplasia

EPIDEMIOLOGY FCC occurs with great frequency in the general population. It affects women between the ages of 25 and 50 years and it is rare below the age of 20.

Incidence Unknown but very frequent

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Prevalence Up to 1/3 of women aged 30 to 50 years have cysts in their breasts. It most commonly presents in the 3rd decade, peaks in the 4th decade when hormonal function is at its peak, and sharply diminishes after menopause. • With hormone replacement therapy, FCC may extend into menopause • Less common in East Asian races

ETIOLOGY AND PATHOPHYSIOLOGY • FCC originates from an exaggerated response of breast stroma and epithelium to a variety of circulating and locally produced hormones (mainly estrogen and progesterone) and growth factors. • Cysts may form due to dilatation of the lobular acini possibly due to imbalance of fluid secretion and resorption, or due to obstruction of the duct leading to the lobule.

RISK FACTORS • In many women, methylxanthine-containing substances (e.g., coffee, tea, cola, and chocolate) can potentiate symptoms of FCC, though a direct causality has not been established. • Diet high in saturated fats may increase risk of FCC.

COMMONLY ASSOCIATED CONDITIONS FCC categorized as proliferative with atypia confers a higher risk of breast cancer.

DIAGNOSIS HISTORY • Obtain personal history of breast biopsy and family history of breast disease (benign or malignant). It is important to ascertain if the patient has a known family history of BRCA1 or BRCA2-related cancer. • Inquire regarding pertinent signs/symptoms, such as breast pain, engorgement, nipple discharge, palpable lumps, tenderness. – Symptomatically, the condition is manifested as premenstrual cyclic mastalgia, with pain and tenderness to touch.

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PHYSICAL EXAM • The patient should be examined in the following positions while disrobed down to the waist (1): – With the patient standing with arms at sides, observe for elevation of the level of a nipple, dimpling, bulging, and peau d’orange. – With the patient’s arms raised above her head, observe for dimpling and elevation of the nipple (may accentuate a mass fixed to the pectoral fascia). If so, have the patient push her hands down against her hips to flex and tense the pectoralis major muscles, move the mass to determine fixation to the underlying fascia. – If the patient has large and pendulous breasts, ask her to lean forward, so that her breasts hang free from the chest wall (retraction and masses may become more evident). – With the patient lying supine, palpate with the pads of the three middle fingers (with varying pressures from light, to medium, to deep), rotating the fingers in small circular motions and moving in vertical overlapping passes from rostral to caudal and then back caudal to rostral in the next pass. The lateral half of the breast is best palpated with the patient rolled onto the contralateral hip and the medial half with the patient supine, both with the ipsilateral hand behind the head. The entire breast from the second to sixth rib and from the left sternal border to the midaxillary line must be palpated against the chest wall. • Be certain to examine the creases under and between the breasts. If the patient has noted a lump, ask her to point it out; always palpate the opposite breast first. • Patients with fibrocystic changes have clinical breast findings that range from mild alterations in texture to dense, firm breast tissue with palpable masses.

DIFFERENTIAL DIAGNOSIS • Pain – Mastitis – Costochondritis – Pectoralis muscle strain – Neuralgia

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– Breast cancer – Angina pectoris – Gastroesophageal reflux (GERD) – Superficial phlebitis of the thoracoepigastric vein (Mondor disease) • Masses – Breast cancer – Sebaceous cyst – Fibroadenoma – Lipoma – Fat necrosis • Skin changes – Breast cancer (peau d’orange: thickened skin similar to peel of an orange) – Eczema

DIAGNOSTIC TESTS & INTERPRETATION • Evaluation should focus on excluding breast cancer. • Testing may be conducted based on a level of clinical suspicion. • FCC can be evaluated with mammogram, though dense breast tissue may appear normal in women 35 years: Diagnostic mammography ± US, then refer to surgeon.

SURGERY • Breast cyst aspiration can be both diagnostic and therapeutic. • Core-needle biopsies performed under stereotactic guidance with vacuum assistance has similar accuracy in distinguishing between malignant and benign lesions compared to open surgical biopsy (6)[A].

COMPLEMENTARY & ALTERNATIVE MEDICINE • The use of vitamin E has shown effectiveness in treating breast pain due to FCC (3)[B]. • Evening primrose oil and pyridoxine have not been shown to reduce mastalgia (4)[A],(7)[B].

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Condition is benign, chronic, and recurrent.

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Patient Monitoring • Follow-up times are variable, depending on the clinical situation and pertinent family history. • US is useful to differentiate cysts from solid lesions and in evaluating women male (70–90% are females) (1) • Predominant age range: 20 to 65 years

Prevalence 2–5% of adult U.S. population (2); 8% of primary care patients

ETIOLOGY AND PATHOPHYSIOLOGY • Idiopathic but appears to be a primary disorder of central pain processing, termed central sensitization with afferent augmentation of peripheral nociceptive stimuli • Alterations in neuroendocrine, neuromodulation, neurotransmitter, neurotransporter, biochemical, and neuroreceptor function/physiology • Sleep abnormalities—α-wave intrusion • Inflammation is not a feature of fibromyalgia.

Genetics • Genetics – High familial aggregation – Inheritance is unknown but likely polygenic. – Odds ratio may be as high as 8.5 for a first-degree relative of a familial

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proband. • Environmental—several triggers have been described: – Physical trauma or severe illness – Stressors (e.g., work, family, life events, and physical or sexual abuse) – Viral and bacterial infections

RISK FACTORS • Female gender • Poor functional status • Negative/stressful life events • Low socioeconomic status

GENERAL PREVENTION No known strategies for prevention.

COMMONLY ASSOCIATED CONDITIONS • Often a comorbid condition with other rheumatologic or neurologic disorders • Obesity is frequently present and is associated with increased severity of symptoms.

DIAGNOSIS • Original 1990 ACR criteria, still widely used: (i) pain in all four quadrants, (ii) axial (neck/spine) involvement, (iii) tender points (TPs) ≥11, (iv) no other explanation for symptoms (2) • Per the 2010 revised ACR criteria (2) – Based on Widespread Pain Index (WPI) and Symptom Score (SS) Must have (WPI ≥7 + SS ≥5) or (WPI ≥3 and SS ≥9); and Symptoms for >3 months; and No other explanation for these symptoms • A questionnaire tool to facilitate WPI/SS patient scoring and diagnosis may be found at: https://www.umassmed.edu/uploadedFiles/cme/CME_Members_Area/C1Handout-Fibromyalgia.pdf • The Visual Analogue Scale Fibromyalgia Impact Questionnaire (VASFIQ) is

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recommended for initial and serial assessment of patient’s functional status. It may be found at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3383533/figure/fig11759720X11416863/ • Enhancements to the 2010 criteria, termed 2011modCr and 2013altCr (2), have been proposed but are not yet widely accepted.

HISTORY • Universal symptoms include – Chronic widespread pain ≥3 months: bilateral limbs and in the axial skeleton – Fatigue and sleep disturbances • Often present: – Mood disorders, including depression, anxiety, and panic symptoms – Cognitive impairment: qualitatively different from that seen in isolated mood disorders (“fibro fog”) – Headaches: typically, tension and migraine types – Other regional pain syndromes, such as irritable bowel syndrome, chronic pelvic pain, vulvodynia, and interstitial cystitis – Paresthesias, often “nonanatomic” – Exercise intolerance, dyspnea, and palpitations – Sexual dysfunction – Ocular dryness – “Multiple chemical sensitivity” and an increased tendency to report drug reactions – Impaired social/occupational functioning – Symptoms can wax and wane on a day-to-day basis, varying in quality, intensity, and location.

PHYSICAL EXAM • Classic fibromyalgia tender point (TPs): 9 symmetric pairs (5 anterior, 4 posterior). A detailed diagram may be found at https://www.nfra.net/Diagnost.htm. • The presence of ≥11 TPs carries a sensitivity of 88.4% and specificity 81.1% for the disease (2).

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• These are distinct from the “trigger points” found in myofascial pain syndromes and cannot be injected. • Joints should be examined for swelling, tenderness, erythema, decreased range of motion, crepitus, and cystic or mass lesions—all typically absent in isolated fibromyalgia. • Document absence of inflammatory musculoskeletal disease features (e.g., no synovitis, enthesopathy, dermatologic or ocular findings). • Neurologic exam: may demonstrate generalized or “nonanatomic” dysesthesia, hyper- or hypesthesia

DIFFERENTIAL DIAGNOSIS • RA, SLE, sarcoidosis, and other inflammatory connective tissue disorders • Diffuse/advanced OA • Seronegative spondyloarthropathies (AS, psoriatic arthritis, etc.) • Polymyalgia rheumatica • Inherited myopathies • Drug-induced and endocrine myopathies • Viral/postviral polyarthralgia • Anemia and iron deficiency • Electrolyte disturbances: Mg, Na, K, Ca • Obstructive sleep apnea • Osteomalacia/vitamin D deficiency • Opioid-induced hyperalgesia • Hypothyroidism • Multiple sclerosis • Lyme disease • Hepatitis B and C (chronic) • Inclusion-body myositis • Spinal stenosis/neuropathies • Peripheral vascular disease • Somatoform disorder • Overlap syndromes – Chronic fatigue syndrome/chronic fatigue immune dysfunction syndrome (CFIDS) – Myofascial pain syndrome (more anatomically localized than fibromyalgia,

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but they may co-occur)

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • CBC with differential, ESR or CRP, CPK, TSH, comprehensive metabolic profile; consider 25-OH vitamin D, Mg, B12, folate, and urine drug screen • ANA, RF, and other rheumatologic labs generally unnecessary, unless there is evidence of an inflammatory connective tissue disorder. • Imaging is not indicated, except to exclude other diagnoses.

Diagnostic Procedures/Other • Sleep studies may be indicated to rule out obstructive sleep apnea or narcolepsy. • Consider psychiatric or neuropsychiatric evaluation for mood disorders and cognitive disturbances.

TREATMENT According to the HHS National Guideline Summary (3) and other sources, evidence-based interventions include the following: • Nonpharmacologic treatment critical to successful outcomes. It is vital to encourage the patient to be an active participant in his or her care, especially with regard to exercise and healthy lifestyle. • Regular exercise and sleep management foundation of improved outcomes • Nonpharmacologic – Educate the patient about the diagnosis, signs, symptoms, and treatment options. – Provide Internet education resources. www.fmaware.org www.nfra.net – Use the VASFIQ for initial assessment and interval evaluation during treatment. – Cognitive-behavioral therapy improves mood, energy, pain, and functional status.

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– Aerobic exercise: moderately intense, with gradual progression to avoid symptom exacerbation – Weight loss may augment the benefits of exercise. – Strength/resistance training—mild to moderate – Aquatic exercise training – Sleep hygiene – Address tobacco, alcohol, and other substances • Pharmacologic – The three FDA-approved drugs are duloxetine, milnacipran, and pregabalin; many others are used off-label. – Caution: Although fibromyalgia patients are frequently treated with multidrug therapy, care must be taken to monitor for drug interactions and overall sedative and anticholinergic burden.

MEDICATION First Line • Amitriptyline 10 to 50 mg PO at bedtime to treat pain, fatigue, and sleep disturbances (4)[A] • Duloxetine initially 30 mg/day for 1 week and then increase to 60 mg/day as tolerated. Taper if discontinued (4)[A]. • Milnacipran day 1: 12.5 mg/day; days 2 to 3, begin dividing doses: 12.5 mg BID; days 4 to 7: 25 mg BID; after day 7: 50 mg BID; max dose 100 to 200 mg BID. Taper if discontinued (4)[A]. • Pregabalin: Start with 75 mg BID, titrate over 1 week to 150 mg BID; max dose 450 mg/day divided BID–TID • Cyclobenzaprine 5 mg qHS; titrate to 10 mg BID-TID as tolerated.

Second Line • Gabapentin: Start at 300 mg HS, titrate to 1,200 to 2,400 mg/day divided BID–TID; max dose 3,600 mg daily • Tramadol 50 to 100 mg q6h; likely more effective in combination with acetaminophen • Quetiapine 25–100 mg qHS • Several investigational agents show some promise of benefit, including pramipexole, naltrexone, sodium oxybate, and pirlindole

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• Cholecalciferol may be beneficial in patients with low 25-OH vitamin D levels • Medications likely to be ineffective for pain, fatigue, or sleep disturbance include NSAIDs, full-agonist opioids, benzodiazepines, SSRIs, magnesium, guaifenesin, thyroxine, corticosteroids, DHEA, melatonin, calcitonin, and antiepileptic agents (other than pregabalin and gabapentin) (5)[A] • Note that, given the frequent copresentation of fibromyalgia with other pain syndromes, it may be reasonable to treat these latter with NSAIDs, corticosteroids, opioids, and other such agents in conjunction with evidencebased fibromyalgia therapies.

COMPLEMENTARY & ALTERNATIVE MEDICINE • Acupuncture and electroacupuncture, biofeedback, hypnotherapy • Balneotherapy (mineral-rich baths) • Yoga, tai chi, and qi gong—improve sleep, fatigue, and quality of life but may not decrease pain • Limited double-blind trials have shown effectiveness of supplementation with S-adenosyl methionine and acetyl-L-carnitine. • Some evidence for transcranial direct current or magnetic stimulation and repetitive transcranial magnetic stimulation • Likely to be ineffective: chiropractic treatment, massage, electrotherapy, ultrasound, trigger-point injections

ISSUES FOR REFERRAL In the case of unclear diagnosis or poor response to therapy, may refer to rheumatology, neurology, and/or pain management

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • For efficacy of initial therapy: at 2- to 4-week intervals; then every 1 to 6 months, tailored to patient’s needs • Advance exercise gradually to maintain tolerability.

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DIET No specific diet is recommended, but patient should be urged to make healthy choices and address negative dietary habits. Caloric or carbohydrate restriction may be helpful in obese patients.

PROGNOSIS • 50% with partial remission after 2 to 3 years of therapy; complete remission possible but rare. • Typically has fluctuating, chronic course • Poorer outcome tied to greater duration and severity of symptoms, depression, advanced age, lack of social support

REFERENCES

1. Wolfe F, Häuser W. Fibromyalgia diagnosis and diagnostic criteria. Ann Med. 2011;43(7):495–502. 2. Bennett RM, Friend R, Marcus D, et al. Criteria for the diagnosis of fibromyalgia: validation of the modified 2010 preliminary American College of Rheumatology criteria and the development of alternative criteria. Arthritis Care Res (Hoboken). 2014;66(9):1364–1373. 3. National Guideline Clearinghouse. Guideline summary NGC-7367: management of fibromyalgia syndrome in adults. http://f.imd.com/medinfo/material/8d0/4eb2854244ae46d1d13648d0/4eb2855d44ae46d1d13648d3 Accessed November 10, 2016. 4. Häuser W, Petzke F, Üçeyler N, et al. Comparative efficacy and acceptability of amitriptyline, duloxetine and milnacipran in fibromyalgia syndrome: a systematic review with meta-analysis. Rheumatology (Oxford). 2011;50(3):532–543. 5. Häuser W, Walitt B, Fitzcharles MA, et al. Review of pharmacological therapies in fibromyalgia syndrome. Arthritis Res Ther. 2014;16(1):201.

ADDITIONAL READING Theadom A, Cropley M, Smith HE, et al. Mind and body therapy for fibromyalgia. Cochrane Database Syst Rev. 2015;(4):CD001980.

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SEE ALSO Algorithm: Fatigue

CODES ICD10 M79.7 Fibromyalgia

CLINICAL PEARLS • Use rigorous ACR criteria to make the diagnosis. • Fibromyalgia is not a somatoform disorder and is not merely a manifestation of depression or anxiety, although as with all chronic pain syndromes, it is frequently associated with mood disturbances. • Best outcomes occur in patients who understand their illness and are willing to actively engage in a multimodal treatment plan, including exercise, sleep hygiene, medication, CBT, and lifestyle modifications.

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FOLLICULITIS David L. Anderson, MD • Thomas P. Garigan, MD, MA BASICS DESCRIPTION • Superficial inflammation of a follicle, usually a hair follicle, caused by infection, local trauma, or chemical irritation (1) • Can occur anywhere on the body that hair is found • Most frequent symptom is pruritus. • Painless or tender pustules, vesicles, or pink/red papulopustules up to 5 mm in size. • Most commonly infectious in etiology: – Staphylococcus aureus bacteria (most common) – Pseudomonas aeruginosa infects areas of the body exposed to poorly chlorinated hot tubs, pools, or contaminated water. – Aeromonas hydrophila with recreational water exposure – Fungal (dermatophytic, Pityrosporum, Candida) – Viral (VZV, herpes simplex virus [HSV]) – Parasitic (Demodex spp. mites, schistosomes) • Noninfectious types – Acneiform folliculitis – Actinic superficial folliculitis – Acne vulgaris – Keloidal folliculitis – Folliculitis decalvans – Perioral dermatitis – Rosacea – Fox-Fordyce disease – Pruritus folliculitis of pregnancy – Eosinophilic pustular folliculitis (three variants: Ofuji disease in patients of Asian descent, HIV-positive/immunocompromised, infantile) – Toxic erythema of the newborn

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– Eosinophilic folliculitis (seen in HIV-positive/immunocompromised) – Follicular mucinosis • Skin disorders may produce a follicular eruption that includes the following: – Pseudofolliculitis: similar in appearance; occurs after shaving; affects the face, scalp, pubis, and legs. Pseudofolliculitis barbae, or razor bumps, occurs frequently in black men. – Atopic dermatitis – Follicular psoriasis

EPIDEMIOLOGY Affects persons of all ages, gender, and race

ETIOLOGY AND PATHOPHYSIOLOGY Predisposing factors to folliculitis • Chronic staphylococcal carrier • Diabetes mellitus • Malnutrition • Pruritic skin disease (e.g., scabies, eczema, etc.) • Exposure to poorly chlorinated swimming pools/hot tubs or water contaminated with P. aeruginosa, A. hydrophila, or schistosomes • Occlusive corticosteroid use (for multiple hours) • Bacteria – Superficial or deep – Most frequently due to S. aureus (increasing number of MRSA cases) – Also due to Streptococcus species, Pseudomonas (following exposure to water contaminated with the species), or Proteus. – May progress to furunculosis (painful pustular nodule with central necrosis that leaves a permanent scar after healing) • Fungal – Dermatophytic (tinea capitis, corporis, pedis) – Pityrosporum (Pityrosporum orbiculare) commonly affecting teenagers and men, predominantly on upper chest and back – Candida albicans, although rare, has been reported with broad spectrum antibiotic use, glucocorticoid use, immunosuppression, and in those who abuse heroin, resulting in candidemia that leads to pustules and nodules in

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hair-bearing areas. • Viral – HSV – May be due to molluscum contagiosum, usually a sign of immunosuppression • Parasitic – Demodex spp. mites (most commonly Demodex folliculorum) – Schistosomes (swimmer’s itch) • Acneiform type commonly drug-induced (systemic and topical corticosteroids, lithium, isoniazid, rifampin), EGFR inhibitors • Severe vitamin C deficiency • Actinic superficial type occurs within 24 to 48 hours of exposure to the sun, resulting in multiple follicular pustules on the shoulders, trunk, and arms. • Acne vulgaris • Keloidal folliculitis is a chronic condition affecting mostly black patients; involves the neck and occipital scalp, resulting in hypertrophic scars and hair loss; usually secondary to folliculitis barbae from shaving • Folliculitis decalvans is a chronic folliculitis that leads to progressive scarring and alopecia of the scalp. • Rosacea consists of papules, pustules, and/or telangiectasias of the face; individuals are genetically predisposed. Helicobacter pylori and D. folliculorum have also been implicated. • Perioral dermatitis seen most commonly in children and young women; restricted to the perioral region as well as the lower eyelids. May be due to cosmetics, hyperandrogenemia, or use of fluorinated topical corticosteroids – Typically spares vermillion border • Fox-Fordyce disease affects the skin containing apocrine sweat glands (i.e., axillae), resulting in chronic pruritic, annular, follicular papules. • Eosinophilic pustular folliculitis (EPF) has three variants: classic (Ofuji disease), associated with HIV infection, and infantile • Toxic erythema of the newborn is a self-limiting pustular eruption usually appearing during the first 3 to 4 days of life and subsequently fading in the following 2 weeks. • Malassezia infections in adult males with lesions on trunk (2)

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RISK FACTORS • Hair removal (shaving, plucking, waxing, epilating agents) • Other pruritic skin conditions: eczema, scabies • Occlusive dressing or clothing • Personal carrier or contact with methicillin-resistant S. aureus (MRSA)– infected persons • Diabetes mellitus • Immunosuppression (medications, chemotherapy, HIV) • Use of hot tubs or saunas • Use of EGFR inhibitors • Chronic antibiotic use (gram-negative folliculitis)

GENERAL PREVENTION • Good hygiene practices – Wash hands frequently. – Antimicrobial soap – Wash towels, clothes, and linens frequently with hot water to avoid reinfection. • Good hair removal practices – Exfoliate beforehand. – Use witch hazel, alcohol, or Tend Skin afterward. – Shave in direction of hair growth; use moisturizer/warm water. – Decrease frequency of shaving – Use clippers primarily or single-blade razors if straight shaving is desired.

COMMONLY ASSOCIATED CONDITIONS • Impetigo • Furunculosis • Scabies • Acne • Follicular psoriasis • Eczema

DIAGNOSIS

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HISTORY • Recent use of hot tubs, swimming pools, topical corticosteroids, certain hair styling and shaving practices, antibiotics or systemic steroids • HIV status • History of STDs (specifically syphilis) • MRSA exposures/carrier status • Ask about home and work environment (risk/exposure potential). • Pityrosporum folliculitis occurs more often in warm, moist climates. • Inquire about the timeline in which the lesions have occurred, including previous similar episodes.

PHYSICAL EXAM • Characteristic lesions are 1- to 5-mm–wide vesicles, pustules, or papulopustules with surrounding erythema. • Rash occurs on hair-bearing skin, especially the face (beard), proximal limbs, scalp, and pubis. • Pseudomonal folliculitis appears as a widespread rash, mainly on the trunk and limbs. • In pseudofolliculitis, the growing hair curls around and penetrates the skin at shaved areas.

DIFFERENTIAL DIAGNOSIS • Acne vulgaris/acneiform eruptions • Arthropod bite • Contact dermatitis • Cutaneous candidiasis • Milia • Atopic dermatitis • Follicular psoriasis • Hidradenitis suppurativa

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Diagnosis is usually made clinically, taking risk factors, history, and location of lesion into account.

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• Culture and Gram stain of the pustule by scraping the pustule with a no. 15 blade and not directly swabbing the skin to identify infectious agent and sensitivities to antibiotics • KOH preparation as well as Wood lamp fluorescence to identify Candida or yeast • Tzanck smear where suspicion of herpetic simplex viral folliculitis is high Follow-Up Tests & Special Considerations • If risk factors or clinical suspicion exist, consider serologies for HIV or syphilis. • If recurrent, consider HIV testing and A1C/fasting blood sugar testing to evaluate for diabetes. • Punch biopsy may be considered if lesions persist despite treatment (3)[C].

Test Interpretation • Treat positive bacterial culture according to sensitivities. • Positive HIV serology: Follow up with CD4 count and punch biopsy to rule out eosinophilic folliculitis. • Eosinophilic folliculitis: Collect eosinophils within superficial follicle (4).

TREATMENT GENERAL MEASURES • Lesions usually resolve spontaneously. • Avoid shaving and waxing affected areas (5)[C]. • Warm compresses may be applied TID. • Systemic antibiotics are typically unnecessary. • Topical mupirocin may be used in presumed S. aureus infection. • Topical antifungals for fungal folliculitis (2)[B] • Preventive measures are keys to avoidance of recurrence: – Antibacterial soaps (Dial soap, chlorhexidine, or benzyl peroxide wash when showering/bathing) – Bleach baths (1/2 cup of 6% bleach per standard bathtub, and soak for 5 to 15 minutes followed by water rinse 1 to 2 times a week) – Keep skin intact; daily skin care with noncomedogenic moisturizers; avoid

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scratching. – Clean shaving instruments daily or use disposable razor, disposing after 1 use. – Change washcloths, towels, and sheets daily.

MEDICATION Antiseptic and supportive care is usually enough. Systemic antibiotics may be used with questionable efficacy.

First Line • Staphylococcal folliculitis – Mupirocin ointment applied TID for 10 days – Cephalosporin (cephalexin): 250 to 500 mg PO QID for 7 to 10 days – Dicloxacillin: 250 to 500 mg PO QID for 7 to 10 days • For MRSA – Bactrim DS: 1 to 2 tablets (160 mg/800 mg) BID PO for 5 to 10 days – Clindamycin: 300 mg PO TID for 10 to 14 days – Minocycline: 200 mg PO initially then 100 mg BID for 5 to 10 days – Doxycycline: 50 to 100 mg PO BID for 5 to 10 days • Pseudomonal folliculitis – Topical dilute acetic acid baths – Ciprofloxacin: 500 to 750 mg PO BID for 7 to 14 days only if patient is immunocompromised or lesions are persistent • Eosinophilic folliculitis/eosinophilic pustular folliculitis – HAART treatment for HIV-positive–related causes – Topical corticosteroids: betamethasone 0.1% BID for 3 to 24 weeks or – Antihistamines (hydroxyzine, cetirizine) or – Tacrolimus topically BID for 3 to 24 weeks or – Isotretinoin 0.5 mg/kg/day PO for 4 to 8 weeks or – Itraconazole or metronidazole • Fungal folliculitis – Topical antifungals: ketoconazole 2% cream or shampoo or selenium sulfide shampoo daily or – Econazole cream applied to affected area BID for 2 to 3 weeks Systemic antifungals for relapses fluconazole (100 to 200 mg/day for 3

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weeks) or itraconazole (200 mg/day for 1 to 3 weeks) Griseofulvin (tinea capitis in children; 10 to 20 mg/kg/day for 6 weeks minimum) • Parasitic folliculitis – 5% permethrin: Apply to affected area, leave on for 8 hours, and wash off. – Ivermectin: 200 μg/kg × 1 followed by topical permethrin • Herpetic folliculitis – Valacyclovir: 500 mg PO TID for 5 to 10 days or – Famciclovir: 500 mg PO TID for 5 to 10 days or – Acyclovir: 200 mg PO 5 times daily for 5 to 10 days

ISSUES FOR REFERRAL Unusual or persistent cases should be biopsied and then referred to dermatology.

ADDITIONAL THERAPIES Public Health Measures • Outbreaks of culture-positive Pseudomonas hot tub folliculitis should be reported so that source identification can be determined and superchlorination (14 parts/million) can occur.

SURGERY/OTHER PROCEDURES Incision and drainage is unlikely to be necessary and typically not preferred due to potential for scar formation.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Resistant cases should be followed every 2 weeks until cleared. • One return visit in 2 weeks if symptoms abate

DIET For obese patients, weight reduction will decrease skin-on-skin friction.

PATIENT EDUCATION Avoid shaving in involved areas.

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PROGNOSIS • Usually resolves with treatment; however, S. aureus carriers may experience recurrences. • Mupirocin nasal treatment for carrier status and for family/household members might be helpful. • Resistant or severe cases may warrant testing for diabetes mellitus or immunodeficiency (HIV) (3)[C].

COMPLICATIONS • Primary complication is recurrent folliculitis. • Extensive scarring with hyperpigmentation • Progression to furunculosis or abscesses

REFERENCES 1. Breitkopf T, Leung G, Yu M, et al. The basic science of hair biology: what are the causal mechanisms for the disordered hair follicle? Dermatol Clin. 2013;31(1):1–19. 2. Song HS, Kim SK, Kim YC. Comparison between Malassezia folliculitis and non-Malassezia folliculitis. Ann Dermatol. 2014;26(5):598–602. 3. Tilley DH, Satter EK, Kakimoto CV, et al. Disseminated verrucous varicella zoster with exclusive follicular involvement. Arch Dermatol. 2012;148(3):405–407. 4. Annam V, Yelikar BR, Inamadar AC, et al. Clinicopatholigical study of itchy folliculitis in HIV-infected patients. Indian J Dermatol Venereol Leprol. 2010;76(3):259–262. 5. Khanna N, Chandramohan K, Khaitan BK, et al. Post waxing folliculitis: a clinicopathological evaluation. Int J Dermatol. 2014;53(7):849–854.

ADDITIONAL READING • Bachet JB, Peuvrel L, Bachmeyer C, et al. Folliculitis induced by EGFR inhibitors, preventive and curative efficacy of tetracyclines in the management and incidence rates according to the type of EGFR inhibitor administered: a systematic literature review. Oncologist. 2012;17(4):555–568.

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• Böer A, Herder N, Winter K, et al. Herpes folliculitis: clinical, histopathological, and molecular pathologic observations. Br J Dermatol. 2006;154(4):743–746. • Brooke RCC, Griffiths CEM. Folliculitis decalvans. Clin Exp Dermatol. 2001;26(1):120–122. • Ellis E, Scheinfeld N. Eosinophilic pustular folliculitis: a comprehensive review of treatment options. Am J Clin Dermatol. 2004;5(3):189–197. • Fiorillo L, Zucker M, Sawyer D, et al. The Pseudomonas hot-foot syndrome. N Engl J Med. 2001;345(5):335–338. • Fridkin SK, Hageman JC, Morrison M, et al. Methicillin-resistant Staphylococcus aureus disease in three communities. N Engl J Med. 2005;352(14):1436–1444. • James WD. Clinical practice. Acne. N Engl J Med. 2005;352(14):1463–1472. • Luelmo-Aguilar J, Santandreu MS. Folliculitis: recognition and management. Am J Clin Dermatol. 2004;5(5):301–310. • Nervi SJ, Schwartz RA, Dmochowski M. Eosinophilic pustular folliculitis: a 40 year retrospect. J Am Acad Dermatol. 2006;55(2):285–289.

SEE ALSO Algorithm: Rash, Focal

CODES ICD10 • L73.9 Follicular disorder, unspecified • L66.2 Folliculitis decalvans • L73.8 Other specified follicular disorders

CLINICAL PEARLS • Folliculitis lesions are typically 1 to 5 mm clusters of pruritic erythematous papules and pustules. • Most commonly due to S. aureus. If community has increased incidence of

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MRSA, consider anti-MRSA treatment. – It is extremely important to educate patients on proper hygiene and skin care techniques in order to prevent chronic or recurrent cases.

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FOOD ALLERGY Stanley Fineman, MD BASICS DESCRIPTION • Hypersensitivity reaction caused by certain foods • System(s) affected: gastrointestinal, hemic/lymphatic/immunologic, pulmonary, skin/exocrine • Synonym(s): allergic bowel disease; dietary protein sensitivity syndrome

EPIDEMIOLOGY • Predominant age: all ages but more common in infants and children • Predominant sex: male > female (2:1)

Incidence Prospective studies indicate ~2.5% of infants experience hypersensitivity reactions to cow’s milk in their 1st year of life (1)[B].

Prevalence • The true prevalence of IgE-mediated food allergy when assessed by doubleblind, placebo-controlled food challenge is 3% (2)[B]. • The self-reported prevalence of food allergy is 12% in children and 13% in adults (2)[B]. • In young children, the most common food allergies are cow’s milk (2.5%), egg (1.3%), peanut (0.8%), and wheat (0.4%) (3)[B]. • Adults tend to have allergies to shellfish (2%), peanut (0.6%), tree nuts (0.5%), and fish (0.4%). • In general, only 3–4% of children >4 years of age have persisting food allergy; food allergy is frequently a transient phenomenon (4)[B]. • 20% of children with peanut protein allergy may outgrow their sensitivity by school age.

ETIOLOGY AND PATHOPHYSIOLOGY Allergic response triggered by immunologic mechanisms, such as the classic

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IgE-allergic response or nonimmunologic-mediated mechanisms • Any food or ingested substance can cause allergic reactions: – Most commonly implicated foods include cow’s milk, egg whites, wheat, soy, peanuts, fish, tree nuts (walnut and pecan), and shellfish. • Several food dyes and additives may elicit non–IgE-mediated allergic-like reactions.

Genetics In family members with a history of food hypersensitivity, the probability of food allergy in subsequent siblings may be as high as 50%.

RISK FACTORS • Persons with allergic or atopic predisposition have increased risk of hypersensitivity reaction to food. • Family history of food hypersensitivity

GENERAL PREVENTION • Avoidance of offending food • In patients at risk for anaphylaxis, epinephrine autoinjectors should be readily available.

DIAGNOSIS PHYSICAL EXAM • GI (system usually affected) – More common: nausea, vomiting, diarrhea, abdominal pain, occult bleeding, flatulence, and bloating – Less common: malabsorption, protein-losing enteropathy, eosinophilic enteritis, colitis • Dermatologic – More common: urticaria/angioedema, atopic dermatitis, pallor, or flushing – Less common: contact rashes • Respiratory – More common: allergic rhinitis, asthma and bronchospasm, cough, serous otitis media

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– Less common: pulmonary infiltrates (Heiner syndrome), pulmonary hemosiderosis • Neurologic – Less common: migraine headaches • Other symptoms – Systemic anaphylaxis, vasculitis

DIFFERENTIAL DIAGNOSIS • A careful history is necessary to document a temporal relationship with the manifestations of suspected food hypersensitivity. • True food allergy or hypersensitivity should be differentiated from food intolerance which may present with similar symptoms. • GI (irritable bowel syndrome, celiac sprue, dumping syndrome, inflammatory bowel diseases, etc.), dermatologic, respiratory, neurologic, psychiatric (generalized anxiety disorder, personality disorders, etc.), or other systemic manifestations may mimic a variety of clinical entities.

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • CBC with differential: Eosinophilia in blood or tissue suggests atopy. • Serum IgA antitissue transglutaminase (IgA-anti-TTG) • Epicutaneous (prick or puncture) allergy skin tests are used to document IgEmediated immunologic hypersensitivity and can be done using commercially available extracts (variable sensitivities) or fresh food skin testing. • Skin testing using the suspect food is helpful. If negative on skin test, an oral challenge may aid in diagnosis. The overall correlation between commercially available allergy skin testing and oral food challenge is 60% but increases to 90% when fresh food skin testing is done (i.e., a positive skin test correlates with a positive challenge to a particular food). – Skin testing has a high sensitivity (low false-negative rate) but a low specificity (high false-positive rate) so only skin test against antigens found on history (5)[C]. • Food-specific IgE assays (radioallergosorbent [RAST] and fluorescent enzyme immunoassay [FEI]) detect specific IgE antibodies to offending foods and are less sensitive to skin testing.

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– In certain laboratories, the ImmunoCAP food-specific IgE was almost as accurate as a skin test in predicting positive oral challenges. – Using a serum assay alone to diagnose food allergy has been shown to result in misdiagnosis of true clinical food allergic sensitivity, particularly in children with atopic dermatitis. Do not test using a panel but rather for specific IgE to foods based on patient history. • Periodic monitoring of the peanut-specific IgE levels every 2 years may be helpful. If the level of peanut-specific IgE falls to 15 to 20 eosinophils per high-power field on esophageal biopsy (9)[C].

TREATMENT GENERAL MEASURES • Avoiding the offending food is the most effective mode of treatment for patients with food allergies. • Those patients with exquisite and severe allergy hypersensitivity to a food should be more cautious in their avoidance of that food. They should carry epinephrine for self-administration in the event that the offending food is ingested unknowingly and a subsequent immediate reaction develops. • There have been recent reports of efficacy using oral immunotherapy (OIT) for certain food allergies. This technique should still be considered experimental and is not recommended for patients who are not participating in

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appropriately controlled and monitored clinical trials (10)[C]. • Immunotherapy or hyposensitization with food extracts by various routes, including SC immunotherapy or sublingual neutralization, are not recommended. Research studies are in progress, but immunotherapy is considered experimental at this time.

MEDICATION • Patients with significant type 1, IgE-mediated hypersensitivity should have epinephrine for autoinjection available in case of accidental ingestion and resulting severe anaphylactic reaction. • After receiving epinephrine for a systemic anaphylactic reaction to a food, the patient should be monitored in a medical facility because 15–25% of patients may require >1 dose of epinephrine. • Symptomatic treatment for milder reactions (e.g., antihistamine) • The use of cromolyn has been suggested but is not recommended for use in most patients with food allergy.

COMPLEMENTARY & ALTERNATIVE MEDICINE There are reports of benefit using various Chinese herbal medicines in laboratory animals with induced food allergy. Benefits have not been reported in humans at this time.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring As needed

DIET • As determined by tests and clinical evaluation • Strict avoidance of offending food

PATIENT EDUCATION • Patients should be counseled by a dietitian to maintain a nutritionally sound diet despite avoiding those foods to which the patient is sensitive.

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• Patient support: Food Allergy Research & Education, Inc.: 7925 Jones Branch Drive Suite 1100 McLean, VA 22102 Toll-Free: 800-929-4040; Web site www.foodallergy.org • Other information available at: www.allergyasthmanetwork.org, www.acaai.org, and www.aaaai.org

PROGNOSIS • Most infants will outgrow their food hypersensitivity by 2 to 4 years: – It may be possible to reintroduce the offending food cautiously into the diet (particularly helpful when the food is one that is difficult to avoid). It is critical that a specific IgE to the offending food is checked, optimally by fresh food allergy skin test, and is negative prior to an oral challenge. – 20% of young children with peanut allergy experience resolution by the age of 5 years. – 42% of children with egg allergy and 48% of children with milk allergy develop clinical tolerance and lose their sensitivity over time (1)[C]. • Adults with food hypersensitivity (particularly to milk, fish, shellfish, or nuts) tend to maintain their allergy for many years (3)[B].

COMPLICATIONS • Anaphylaxis • Angioedema • Bronchial asthma • Enterocolitis • Eosinophilic esophagitis • Eczematoid lesions

REFERENCES 1. Sicherer SH, Sampson HA. Food allergy: epidemiology, pathogenesis, diagnosis, and treatment. J Allergy Clin Immunol. 2014;133(2):291–307. 2. Rona RJ, Keil T, Summers C, et al. The prevalence of food allergy: a metaanalysis. J Allergy Clin Immunol. 2007;120(3):638–646. 3. Boyce JA, Assa’ad A, Burks AW, et al. Guidelines for the diagnosis and management of food allergy in the United States: summary of the NIAID-

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sponsored expert panel report. J Allergy Clin Immunol. 2010;126(6):1105– 1118. 4. Burks AW, Tang M, Sicherer S, et al. ICON: food allergy. J Allergy Clin Immunol. 2012;129(4):906–920. 5. Sicherer SH, Wood RA. Advances in diagnosing peanut allergy. J Allergy Clin Immunol Pract. 2013;1(1):1–13. 6. Fleischer DM, Bock SA, Spears GC, et al. Oral food challenges in children with a diagnosis of food allergy. J Pediatr. 2011;158(4):578–583.e1. 7. Lieberman J, Glaumann S, Batelson S, et al. The utility of peanut components in the diagnosis of IgE-mediated peanut allergy among distinct populations. J Allergy Clin Immunol Pract. 2013;1(1):75–82. 8. Spergel JM, Brown-Whitehorn T, Beausoleil JL, et al. Predictive values for skin prick test and atopy patch test for eosinophilic esophagitis. J Allergy Clin Immunol. 2007;119(2):509–511. 9. Spergel JM, Brown-Whitehorn TF, Cianferoni A, et al. Identification of causative foods in children with eosinophilic esophagitis treated with an elimination diet. J Allergy Clin Immunol. 2012;130(2):461.e5–467.e5. 10. Sampson H. Peanut oral immunotherapy: is it ready for clinical practice? J Allergy Clin Immunol Pract 2013;1(1):15–21. 11. Greer FR, Sicherer SH, Burks AW, et al. Effects of early nutritional interventions on the development of atopic disease in infants and children: the role of maternal dietary restriction, breastfeeding, timing of introduction of complementary foods, and hydrolyzed formulas. Pediatrics. 2008;121(1):183–191. 12. Du Toit G, Roberts G, Sayre PH, et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. N Engl J Med. 2015;372(9):803–813.

ADDITIONAL READING • American College of Allergy, Asthma, & Immunology. Food allergy: a practice parameter. Ann Allergy Asthma Immunol. 2006;96(3)(Suppl 2):S1– S68. • Høst A, Halken S. A prospective study of cow milk allergy in Danish infants during the first 3 years of life. Clinical course in relation to clinical and

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immunological type of hypersensitivity reaction. Allergy. 1990;45(8):587– 596. • Maloney JM, Rudengren M, Ahlstedt S, et al. The use of serum-specific IgE measurements for the diagnosis of peanut, tree nut, and seed allergy. J Allergy Clin Immunol. 2008;122(1):145–151.

SEE ALSO Anaphylaxis; Celiac Disease; Irritable Bowel Syndrome

CODES ICD10 • T78.1XXA Oth adverse food reactions, not elsewhere classified, init • T78.00XA Anaphylactic reaction due to unspecified food, init encntr • L27.2 Dermatitis due to ingested food

CLINICAL PEARLS • Recent studies suggest that up to 20% of children with peanut allergy may outgrow their sensitivity: – Periodic monitoring of the peanut-specific IgE levels every 2 years may be helpful. If the level of peanut-specific IgE falls to 50% of cases of foodborne illness (4). • The bacterial pathogens most commonly contributing to foodborne illness are Salmonella (nontyphoidal), Campylobacter, Clostridium perfringens, Staphylococcus aureus, Listeria monocytogenes, and Escherichia coli (1,3).

ETIOLOGY AND PATHOPHYSIOLOGY • Short incubation period (1 to 6 hours) – Bacillus cereus toxin Food sources: improperly cooked rice/fried rice and red meats Causes sudden onset of severe nausea and vomiting. Diarrhea may be present. – S. aureus Food sources: nonrefrigerated or improperly refrigerated meats and potato and egg salads Causes sudden onset of severe nausea and vomiting. Abdominal cramps and fever may be present.

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• Medium incubation period (8 to 16 hours) – Bacillus cereus Food sources: meat, stews, gravy, vanilla sauce Causes watery diarrhea, abdominal cramps, nausea – C. perfringens Food sources: dry/precooked meats and poultry Causes watery diarrhea, nausea, abdominal cramps • Long incubation period (>16 hours) Toxin-producing organisms: – Clostridium botulinum Food source: commercially canned or improperly home-canned foods Causes vomiting, diarrhea, slurred speech, diplopia, dysphagia, and descending muscle weakness/flaccid paralysis – Enterohemorrhagic E. coli (e.g., 0157:H7) Food sources: undercooked beef, especially hamburger; unpasteurized milk; raw fruits and vegetables; and contaminated water Causes severe diarrhea that often becomes bloody, abdominal pain, vomiting – Enterotoxigenic E. coli Food sources: food or water contaminated by human feces Causes watery diarrhea, abdominal cramps, and vomiting – Vibrio cholera Food sources: contaminated water, fish, and shellfish, especially food sold by street vendors Causes profuse watery diarrhea and vomiting, which can lead to severe dehydration and death within hours Invasive organisms – Salmonella Food sources: contaminated eggs, poultry, unpasteurized milk or juice, cheese, contaminated raw fruit and vegetables, and contaminated peanut butter Causes watery diarrhea, fever, abdominal cramps, vomiting – Campylobacter jejuni Food sources: raw and undercooked poultry, unpasteurized milk, and

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contaminated meats Causes diarrhea (may be bloody), cramps, vomiting, fever – Shigella: Food sources: food or water contaminated by human fecal material Causes abdominal cramps, fever, diarrhea – Vibrio parahaemolyticus: Food source: raw shellfish Causes nausea, vomiting, diarrhea, abdominal pain – Vibrio vulnificus: Food source: undercooked and raw seafood; wounds exposed to sea water Causes vomiting, diarrhea, abdominal pain, bacteremia, wound infections; can be fatal in patients with liver disease or those who are immunocompromised – Yersinia enterocolitica and Yersinia pseudotuberculosis: Food sources: undercooked pork, unpasteurized milk, tofu, contaminated water Causes abdominal pain, fever, diarrhea, vomiting – Listeria: Food sources: unpasteurized/contaminated milk, soft cheese, and processed/delicatessen meats Causes nausea, vomiting, fever, watery diarrhea

RISK FACTORS • Recent travel to a developing country (4) • Food handlers, daycare attendees, nursing home residents, and recently hospitalized patients (2) • Altered immunity due to underlying disease or medications, including antacids, H2 blockers, and proton pump inhibitors (4) • Cross-contamination and subsequent ingestion of improperly prepared and stored foods

GENERAL PREVENTION • When preparing food at home: – Wash hands, cutting boards, and surfaces before food preparation and after preparing each food item.

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– Wash fresh produce thoroughly before eating. – Keep raw meat, poultry, fish, and their juices away from other food that will not be cooked (e.g., salad). – Do not put cooked protein or washed produce back into containers or on surfaces where unwashed or raw food was stored. – Thoroughly cook meat to the following internal temperature: Fresh beef, veal, pork, and lamb: 145°F Ground meats and egg dishes: 160°F Poultry: 165°F Cook chicken eggs thoroughly until the yolk is firm. Seafood: 145°F – Refrigerate leftovers within 2 to 3 hours in clean, shallow, and covered containers. If the temperature is >90°F, refrigerate within 1 hour. • When traveling to underdeveloped countries: – Eat only freshly prepared foods. – Avoid beverages and foods prepared with nonpotable water. – Other risky foods include raw or undercooked meat and seafood, unpeeled raw fruits, and vegetables. – Bottled, carbonated, and boiled beverages are generally safe to drink. • Concerning prevention, improved hygiene and sanitation reduces the risk of traveler’s diarrhea, but the prevention strategy “Boil it, Cook it, Peel it, or Forget it” has inconsistent and limited evidence (5). • Chemoprophylaxis for traveler’s diarrhea is only recommended for patients with risk factors that would lead to complicated illness (5).

DIAGNOSIS HISTORY • Onset, duration, frequency, severity, and character (i.e., watery, bloody, mucus-filled, etc.) of diarrhea should be noted (2). • The definition of diarrhea is >3 or more unformed stools daily or the passage of >250 g of unformed stool per day (4). • Suspect bacterial food poisoning when multiple persons have rapid onset of symptoms after eating the same meal; have high fever, blood, or mucus in

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stool; severe abdominal pain; signs of dehydration; or recent travel to a foreign country (2,4). • Any of the following should prompt further evaluation and possible supportive treatment: high fever (≥101.3°F), ≥6 stools/day, blood in the stools, elevated white blood cell count, signs of dehydration, and diarrheal illness that lasts >2 to 3 days (4).

PHYSICAL EXAM • Focus on signs of dehydration: delayed capillary refills, increased skin turgor, dry mucous membranes, and orthostatic changes (2) • Fever may be suggestive of a more invasive or toxin-producing bacteria (2). • Abdominal exam: important to assess for pain and to differentiate between other acute abdominal processes (2) • Rectal exam may be useful to assess for blood, rectal pain, or consistency of stool (2).

DIFFERENTIAL DIAGNOSIS • Infectious gastrointestinal illness of any kind (i.e., viral or parasitic) • C. difficile colitis • Inflammatory bowel disease • Appendicitis and other acute abdominal processes • Hepatitis • Malabsorption

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • For most cases of mild, self-limiting food poisoning, a stool culture is not necessary and will not change management (1)[C]. • Testing for fecal leukocytes and fecal occult blood is not mandatory. Presence of fecal WBC or RBC increases the likelihood of inflammatory diarrhea (2). • Consider ova and parasites if dehydration, history of foreign travel, or symptoms lasting >2 weeks (4). • CBC, BMP for severe cases with dehydration, inpatient, and nursing home exposure (4) • Flexible sigmoidoscopy and colonoscopy are reserved for severe cases or

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when pathogen is suspected in setting of negative stool cultures (4). • Abdominal CT may be helpful when intra-abdominal pathology or bowel disease is in the differential (4). Follow-Up Tests & Special Considerations Epidemiologic investigation may be warranted. Reporting requirements vary by state and organism (1).

TREATMENT Most cases of food poisoning are self-limited and do not require medication.

MEDICATION First Line • Oral rehydration is the first-line therapy in treating acute diarrheal or gastroenteritis episodes (2). • Use of a formal oral rehydration solution (ORS) with balanced electrolytes is recommended for elderly or pediatric patients with severe diarrhea, or for travelers with severe, cholera-like watery diarrhea (6)[B]. • Most patients with mild illness do not need formal ORS and can rehydrate with a balance of fluids, carbohydrates, and salt found in a typical bland diet, including water, sports drinks, juices, soups, and crackers (6). • Empiric antibiotic therapy is not recommended for most cases of acute diarrhea, other than in traveler’s diarrhea (6)[A].

Second Line Antibiotics for food poisoning should only be considered for patients with severe illness possibly requiring hospitalization and those with fever and hematochezia or when diagnostic testing confirms a bacterial source (1). Pathogen-specific therapy is noted below. • Bacillus cereus (2) – Supportive care only • Campylobacter jejuni (2,4) – Mild: supportive care only—antibiotics may induce resistance. – Severe: azithromycin 500 mg/day for 3 to 5 days. Fluoroquinolones are no

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longer recommended due to resistance (1). • C. botulinum – Supportive care only. Antitoxin can be helpful early during illness. • C. perfringens – Supportive care only • Enterohemorrhagic E. coli (e.g., 0157:H7) (4) – Supportive care only. Closely monitor renal function, hemoglobin, and platelets. Infection associated with hemolytic uremic syndrome (HUS). Antibiotics may increase this risk. • Enterotoxigenic E. coli (common cause of traveler’s diarrhea) (2,4,5) – Generally self-limited. Antibiotics shorten course of illness (5)[A]. – Ciprofloxacin 500 mg BID or 750 mg daily for 1 to 3 days; azithromycin 1 g × single dose or daily for 3 days; or rifaximin 200 mg TID for 3 days • Salmonella, nontyphoidal (2,4,5) – No therapy in mild disease – Moderate: ciprofloxacin 500 mg BID for 5 to 7 days, levofloxacin 500 mg daily for 7 to 10 days, or TMP/SMX DS 160/800 mg twice per day for 5 to 7 days – Severe diarrhea, immunocompromised, systemic signs, positive blood cultures: IV ceftriaxone 1 to 2 g daily for 7 to 10 days • Shigella (2,4) – Ciprofloxacin 500 mg BID or 750 mg daily for 3 days, or 2-g single dose; alternative options: azithromycin 500 mg twice per day for 3 days, TMP/SMX DS 160/800 mg twice per day for 5 days, or ceftriaxone 2 to 4 g single dose • Staphylococcus aureus (4) – Supportive care only • Noncholeraic Vibrio (4) – Ciprofloxacin 750 mg daily for 3 days or azithromycin 500 mg daily for 3 days • Vibrio cholerae (4) – Doxycycline 300 mg one-time dose in most cases or tetracycline 500 mg QID for 3 days or erythromycin 250 mg TID for 3 days or azithromycin 500 mg/day for 3 days

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• Yersinia (2) – Usually supportive care only – Severe: doxycycline combine with aminoglycoside; TMP/SMX DS 160/800 mg BID for 5 days; or ciprofloxacin 500 mg BID for 7 to 10 days

ADDITIONAL THERAPIES • For severe nausea and vomiting, promethazine is effective in adults. Ondansetron is effective in children (5). • Loperamide 4 mg initially and then 2 mg after each loose stool to a maximum of 8 mg in a 24-hour period may be used unless high fever, bloody diarrhea, and/or severe abdominal pain present (signs of enteroinvasion) (5) • Bismuth subsalicylate (Pepto-Bismol) 525 mg QID is moderately effective in traveler’s diarrhea (5). • Evidence for the effectiveness of probiotics and prebiotics is limited and inconsistent, and currently their use is not recommended (6). • Diligent hand washing throughout the course of illness will decrease spread (2).

ONGOING CARE DIET • Avoid food while nausea is present but drink plenty of fluids in frequent sips. • As the nausea subsides, drink adequate fluids; add in bland, low-fat meals; and rest. Avoid alcohol, coffee, nicotine, and spicy foods. • Nursing infants should continue to be breastfed on demand, and infants and older children should be offered their usual food. • For diarrhea, consider a bland diet (BRAT: Bananas, Rice, Apples, Toast-dry). • Limiting dairy to 24 hours after last diarrhea episode may assist in symptom reduction.

PROGNOSIS Most infections are self-limited and will resolve over the course of 4 to 5 days. If antibiotics are given in moderate to severe traveler’s diarrhea, the duration may shorten to a day and a half (5).

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COMPLICATIONS • Dehydration (2) • Hemolytic uremic syndrome (HUS following E. coli 0157:H7 infection) (4) • Guillain-Barré syndrome after Campylobacter enteritis (4) • Reactive arthritis after salmonella, shigella, or yersinia infections (4) • Postinfectious irritable bowel (4)

REFERENCES 1. Switaj T, Winter K, Christensen S. Diagnosis and management of foodborne illness. Am Fam Physician. 2015;92(5):258–365. 2. Barr W, Smith A. Acute diarrhea. Am Fam Physician. 2014;89(3):180–189. 3. Centers for Disease Control and Prevention. Trends in Foodborne Illness in the United States, 2013. Atlanta, GA: Centers for Disease Control and Prevention; 2014. http://www.cdc.gov/foodborneburden/ 4. DuPont HL. Acute infectious diarrhea in immunocompetent adults. N Engl J Med. 2014;370(16):1532–1540. 5. Steffen R, Hill DR, DuPont HL. Traveler’s diarrhea: a clinical review. JAMA. 2015;313(1):71–80. 6. Riddle M, DuPont H, Connor B. ACG clinical guideline: diagnosis, treatment, and prevention of acute diarrheal infections in adults. Am J Gastroenterol. 2016;111(5):602–622.

ADDITIONAL READING • Kalyoussef S, Feja KN. Foodborne illnesses. Adv Pediatr. 2014;61(1):287– 312. • U.S. Food & Drug Administration: Foodborne Illness & Contaminants: http://www.fda.gov/Food/FoodborneIllnessContaminants/

SEE ALSO Appendicitis, Acute; Botulism; Brucellosis; Dehydration; Diarrhea, Acute; Guillain-Barré Syndrome; Hypokalemia; Intestinal Parasites; Salmonella Infection; Typhoid Fever

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CODES ICD10 • A05.9 Bacterial foodborne intoxication, unspecified • A02.0 Salmonella enteritis • A04.5 Campylobacter enteritis

CLINICAL PEARLS • Consider bacterial food poisoning when multiple people present after ingesting the same food with fevers and blood/mucus in stool or have recently returned from a developing nation. • Consider culture and antibiotics in a prolonged febrile state with blood/mucus in stool, septicemic states, and/or symptoms lasting >7 days (6). • With signs of enteroinvasion (high prolonged fever, bloody diarrhea, severe pain, septicemia), consider withholding antispasmodics (e.g., loperamide). • Empiric antibiotic therapy for traveler’s diarrhea should be considered in cases of moderate to severe disease (5,6)[A].

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FROSTBITE Donald Morando, DO • Lina N. Qazi, DO • Courtney Maiden, DO BASICS DESCRIPTION • A localized complication of exposure to cold, causing tissue to freeze, resulting in diminished blood flow to the affected part (especially hands, face, or feet). • System(s) affected: endocrine/metabolic, skin/exocrine • Synonym(s): dermatitis congelationis; frostnip; environmental injuries

EPIDEMIOLOGY • Predominant age: all ages • Predominant sex: male = female

ETIOLOGY AND PATHOPHYSIOLOGY • Prolonged exposure to cold • Refreezing thawed extremities • Ice crystals form intracellularly, damaging capillaries • Vasoconstriction reduces blood flow and microclotting leads to ischemia. • Cellular dehydration, abnormal electrolyte concentrations due to the above and ultimately cell death • In severe cases, deep tissue freezing may occur with damage to underlying blood vessels, muscles, and nerve tissue. • With rewarming, the ice crystals melt and injured endothelium promotes edema resulting in the formation of epidermal blisters. • Inflammatory mediators, prostaglandins, and thromboxane A2 induce vasoconstriction and platelet aggregation, worsening ischemia.

RISK FACTORS • Environmental: lack of proper clothing or shelter resulting in prolonged exposure to below freezing temperatures

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• Substance abuse, especially alcohol • Age: infants and elderly • Previous cold-related injury • Decreased caloric intake (7,500 meters)

COMMONLY ASSOCIATED CONDITIONS • Alcohol and/or drug abuse • Hypothermia

DIAGNOSIS HISTORY • Throbbing pain • Paresthesia • Excessive sweating • Joint pain • Determine duration and severity of cold exposure.

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PHYSICAL EXAM • Feet, hands, and face are the most commonly affected. • Classified as superficial or deep injuries • Superficial: Only the skin and subcutaneous tissues are involved. Tissue is pliable. White mottled appearance with minimal capillary refill. Erythematous and edematous on rewarming, blisters are usually clear and neurovascular compromise is reversible. • Deep: Injury extends into the bone. Tissue remains mottled and pulseless after rewarming, loss of sensation persists. Infrequent hemorrhagic blister formation. Tissue loss is common. High risk of infection

DIFFERENTIAL DIAGNOSIS • Frostnip: a superficial cold injury that does not cause permanent damage • Chilblains (pernio): an inflammatory reaction to short-term cold, wet exposure without tissue freezing • Immersion syndrome (trench foot): inflammatory reaction to prolonged cold, wet exposure, typically socks or footwear

DIAGNOSTIC TESTS & INTERPRETATION ECG in hypothermia may show bradycardia, atrial fibrillation, atrial flutter, ventricular fibrillation, diffuse T-wave inversion, Osborn waves (upward-going “hump” following S wave in the RST segment).

Initial Tests (lab, imaging) • Baseline labs: CBC, CMP, UA for myoglobinuria, culture wound if suspected infection • Triple-phase bone scan can identify tissue viability at early stage and facilitate early débridement. • Other imaging techniques sometimes used include MRI/MRA, infrared thermography, angiography, digital plethysmography, and laser Doppler studies.

Test Interpretation • Ice crystallization in the intravascular extracellular space • Atrophy • Fibroblastic proliferation

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• Skin necrosis

TREATMENT Geriatric Considerations • Associated disease states increase mortality. • Periarticular osteoporosis complicates • More prone to hypothermia

Pediatric Considerations Loss of epithelial growth centers

ALERT Acidosis

GENERAL MEASURES • Admit patient to a burn center for deep injuries. • Increase patient’s body temperature to 34°C. • Only warm areas of injury if possibility of refreezing can be excluded. Warm affected parts of body in 37–39°C water with antiseptics (iodine, polyhexanide) for 15 to 60 minutes or until skin color changes to red/violet (1) [C]. • Apply topical aloe vera gel before dressing. • Débride open blisters only, débridement of tense, cloudy, or clear blisters at discretion of provider • Splint and elevate affected extremity. • Tetanus prophylaxis • Analgesia and hydration, oral hydration if patient is alert and has no GI symptoms, otherwise IV hydration with warm normal saline in small boluses. • Ibuprofen 400 mg BID • Daily bathing in warm water containing antiseptics with active and passive mobilization • Dry, loose bulky dressings, including in between fingers/toes (2)[C] • Prohibit smoking • Regular monitoring for reperfusion, consider experimental vasodilatation,

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thrombolytics, or sympathectomy for failed reperfusion (1)[C].

MEDICATION First Line • tPA administered within 24 hours of injury may prevent damage from thrombosis and may reduce amputation rate (3),(4)[B]. • Low-molecular-weight dextran to decrease blood viscosity should be considered in patients not given other systemic treatments (e.g., thrombolysis) (2)[C]. • Aspirin 250 mg plus buflomedil 400 mg IV followed by 8 days of iloprost 0.5 to 2 mg/kg/min for 6 hr/day may prevent amputation in patients with frostbite extending to the proximal phalanx (5)[B]. • Tetanus toxoid • Ibuprofen 400 mg q12h to inhibit prostaglandins (6)[C] • NSAIDs for mild to moderate pain; for severe pain, narcotic analgesia • Systemic antibiotics should be used for proven infection, trauma, or cellulitis. Prophylactic antibiotics are not recommended (7)[C]. • Precautions: tPA should not be used with history of recent bleeding, stroke, ulcer, and so forth.

Second Line Pentoxifylline has been tried with some success (6)[C].

ADDITIONAL THERAPIES • Heated oxygen • Warm IV fluids via central venous pressure line • Avoid rubbing the affected area, as this can lead to further tissue destruction and worse outcomes.

SURGERY/OTHER PROCEDURES • Urgent surgery is rarely needed, except fasciotomy for compartment syndrome. • Suspect compartment syndrome if tissue swollen and compartment pressures >37 to 40 mm Hg. • Fasciotomy is indicated if elevated compartment pressures (2)[B] • Surgical débridement, as needed, to remove necrotic tissue

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• Amputation should not be considered until tissues are definitively dead: may take ~3 weeks to know whether the tissue is permanently injured. • Imaging with 99 mTc bone scan and/or MRA should be considered in severe cases to help determine extent of injury and assess viability of surrounding tissue. Imaging can help determine need for surgery (8).

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Hospitalization is generally recommended unless no blisters are present after rewarming (4,8). – Institute emergency measures for hypothermic patient without pulse or respiration. Such measures may include CPR and internal warming with warm IV fluids and warm oxygen (see topic “Hypothermia”). – Prevent refreezing. – It may be necessary to keep the frostbitten part frozen until the patient can be transported to a care facility. Prolonged freezing is preferable to warming and refreezing (9)[C]. – Remove nonadherent wet clothing and shoes. – Treat for hypothermia. – Treat for pain. – NSAIDs and/or narcotics, if needed. – Do not rub areas to warm them; increased tissue damage may occur (3)[C]. – Avoid pressure on frostbitten body parts except when the life of the patient or rescuer is in danger (10)[C]. • If patient cannot tolerate oral fluids or has altered mental status, give warmed normal saline in small boluses (2)[C].

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Outpatient or inpatient, depending on severity • As tolerated; protect injured body parts. • Initiate physical therapy once healing progresses sufficiently. • Avoid nicotine.

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• Avoid recurrent cold exposure. • Properly fitting attire; consider custom footwear if feet were affected (7).

Patient Monitoring • Preferably, electronic probe for temperature monitoring (rectal or vascular) • Follow-up for physical therapy progress, infection, other complications

DIET • As tolerated • Warm oral fluids

PATIENT EDUCATION • Refer to local library for information. • Provide education on – Exposure protection – Risk factors for frostbite injuries – Early signs and symptoms of frostbite

PROGNOSIS • Anesthesia and bullae may occur. • The affected areas will heal or mummify without surgery; the process may take 6 to 12 months for healing. • Patient may be sensitive to cold and experience burning and tingling. • Cyanotic nonblanching skin and blisters with dark fluid suggest worse prognosis (9)[C]. • Loss of sensation after rewarming indicates poor prognosis.

COMPLICATIONS • Hyperglycemia • Acidosis • Refractory arrhythmias • Tissue loss: Distal parts of an extremity may undergo spontaneous amputation. • Gangrene • Hyperhidrosis due to nerve injury • Decreased hair and nail growth

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• Raynaud phenomenon • Chronic regional pain • Localized osteoporosis • Death

REFERENCES 1. Sachs C, Lehnhardt M, Daigeler A, et al. The triaging and treatment of coldinduced injuries. Dtsch Arztebl Int. 2015;112(44):741–747. 2. McIntosh SE, Hamonko M, Freer L, et al. Wilderness Medical Society practice guidelines for the prevention and treatment of frostbite. Wilderness Environ Med. 2011;22(2):156–166. 3. Bruen KJ, Ballard JR, Morris SE, et al. Reduction of the incidence of amputation in frostbite injury with thrombolytic therapy. Arch Surg. 2007;142(6):546–551. 4. Jurkovich GJ. Environmental cold-induced injury. Surg Clin North Am. 2007;87:247–267. 5. Cauchy E, Cheguillaume B, Chetaille E. A controlled trial of a prostacyclin and rt-PA in the treatment of severe frostbite. N Engl J Med. 2011;364(2):189–190. 6. Imray C, Grieve A, Dhillon S. Cold damage to the extremities: frostbite and non-freezing cold injuries. Postgrad Med J. 2009;85(1007):481–488. 7. Handford C, Buxton P, Russell K, et al. Frostbite: a practical approach to hospital management. Extrem Physiol Med. 2014;3:7. 8. Ingram BJ, Raymond TJ. Recognition and treatment of freezing and nonfreezing cold injuries. Curr Sports Med Rep. 2013;12(2):125–130. 9. Biem J, Koehncke N, Classen D, et al. Out of the cold: management of hypothermia and frostbite. CMAJ. 2003;168(3):305–311. 10. State of Alaska Department of Health and Social Services. Cold injuries guidelines: Alaska Multi-level 2003 version. http://www.hypothermia.org/Hypothermia_Ed_pdf/Alaska-ColdInjuries.pdf.

ADDITIONAL READING

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• Cappaert TA, Stone JA, Castellani JW, et al. National Athletic Trainers’ Association position statement: environmental cold injuries. J Athl Train. 2008;43(6):640–658. • Murphy JV, Banwell PE, Roberts AH, et al. Frostbite: pathogenesis and treatment. J Trauma. 2000;48(1):171–178. • Twomey JA, Peltier GL, Zera RT. An open-label study to evaluate the safety and efficacy of tissue plasminogen activator in treatment of severe frostbite. J Trauma. 2005;59(6):1350–1354.

SEE ALSO • Hypothermia • Algorithm: Hypothermia

CODES ICD10 • T33.90XA Superficial frostbite of unspecified sites, init encntr • T34.90XA Frostbite with tissue necrosis of unsp sites, init encntr • T33.829A Superficial frostbite of unspecified foot, initial encounter

CLINICAL PEARLS • Frostbite is considered a tetanus-prone injury. Treat as any injury involving tissue destruction. • Avoid rewarming en route to the hospital if there is a chance of refreezing. Avoid burns to affected areas, which may be numb and insensitive to heat. • It is difficult to assess degree of tissue involvement early on. Delay surgery until definite tissue destruction is present.

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FURUNCULOSIS Zoltan Trizna, MD, PhD BASICS DESCRIPTION • Acute bacterial abscess of a hair follicle (often Staphylococcus aureus) • System(s) affected: skin/exocrine • Synonym(s): boils

EPIDEMIOLOGY Incidence • Predominant age – Adolescents and young adults – Clusters have been reported in teenagers living in crowded quarters, within families, or in high school athletes. • Predominant sex: male = female

Prevalence Exact data are not available.

ETIOLOGY AND PATHOPHYSIOLOGY • Infection spreads away from hair follicle into surrounding dermis. • Pathogenic strain of S. aureus (usually); most cases in United States are now due to community-acquired methicillin-resistant S. aureus (CA-MRSA) whereas methicillin-sensitive S. aureus (MSSA) is most common elsewhere (1).

Genetics Unknown

RISK FACTORS • Carriage of pathogenic strain of Staphylococcus sp. in nares, skin, axilla, and perineum • Rarely, polymorphonuclear leukocyte defect or hyperimmunoglobulin

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E–Staphylococcus sp. abscess syndrome • Diabetes mellitus, malnutrition, alcoholism, obesity, atopic dermatitis • Primary immunodeficiency disease and AIDS (common variable immunodeficiency, chronic granulomatous disease, Chediak-Higashi syndrome, C3 deficiency, C3 hypercatabolism, transient hypogammaglobulinemia of infancy, immunodeficiency with thymoma, Wiskott-Aldrich syndrome) • Secondary immunodeficiency (e.g., leukemia, leukopenia, neutropenia, therapeutic immunosuppression) • Medication impairing neutrophil function (e.g., omeprazole) • The most important independent predictor of recurrence is a positive family history.

GENERAL PREVENTION Patient education regarding self-care (see “General Measures”); treatment and prevention are interrelated.

COMMONLY ASSOCIATED CONDITIONS • Usually normal immune system • Diabetes mellitus • Polymorphonuclear leukocyte defect (rare) • Hyperimmunoglobulin E–Staphylococcus sp. abscess syndrome (rare) • See “Risk Factors.”

DIAGNOSIS HISTORY • Located on hair-bearing sites, especially areas prone to friction or repeated minor traumas (e.g., underneath belt, anterior aspects of thighs, nape, buttocks) • No initial fever or systemic symptoms • The folliculocentric nodule may enlarge, become painful, and develop into an abscess (frequently with spontaneous drainage).

PHYSICAL EXAM

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• Painful erythematous papules/nodules (1 to 5 cm) with central pustules • Tender, red, perifollicular swelling, terminating in discharge of pus and necrotic plug • Lesions may be solitary or clustered.

DIFFERENTIAL DIAGNOSIS • Folliculitis • Pseudofolliculitis • Carbuncles • Ruptured epidermal cyst • Myiasis (larva of botfly/tumbu fly) • Hidradenitis suppurativa • Atypical bacterial or fungal infections

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) Obtain culture if with multiple abscesses marked by surrounding inflammation, cellulitis, systemic symptoms such as fever, or if immunocompromised. Follow-Up Tests & Special Considerations • Immunoglobulin levels in rare (e.g., recurrent or otherwise inexplicable) cases • If culture grows gram-negative bacteria or fungus, consider polymorphonuclear neutrophil leukocyte functional defect.

Test Interpretation Histopathology (although a biopsy is rarely needed) • Perifollicular necrosis containing fibrinoid material and neutrophils • At deep end of necrotic plug, in SC tissue, is a large abscess with a Gram stain positive for small collections of S. aureus.

TREATMENT GENERAL MEASURES • Moist, warm compresses (provide comfort, encourage localization/pointing/drainage) 30 minutes QID • If pointing or large, incise and drain: consider packing if large or incompletely

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drained. • Routine culture is not necessary for localized abscess in nondiabetic patients with normal immune system. • Sanitary practices: Change towels, washcloths, and sheets daily; clean shaving instruments; avoid nose picking; change wound dressings frequently; do not share items of personal hygiene (2)[B].

MEDICATION First Line • Systemic antibiotics usually unnecessary, unless extensive surrounding cellulitis or fever • If suspecting MRSA, see “Second Line.” • If multiple abscesses, lesions with marked surrounding inflammation, cellulitis, systemic symptoms such as fever, or if immunocompromised: place on antibiotics therapy directed at S. aureus for 10 to 14 days. – Dicloxacillin (Dynapen, Pathocil) 500 mg PO QID or cephalexin 500 mg PO QID or clindamycin 300 mg TID, if penicillin-allergic

Second Line • Resistant strains of S. aureus (MRSA): clindamycin 300 mg q6h or doxycycline 100 mg q12h or trimethoprim-sulfamethoxazole (TMP-SMX DS) 1 tab q8–12h or minocycline 100 mg q12h • If known or suspected impaired neutrophil function (e.g., impaired chemotaxis, phagocytosis, superoxide generation), add vitamin C 1,000 mg/day for 4 to 6 weeks (prevents oxidation of neutrophils). • If antibiotic regimens fail: – May try PO pentoxifylline 400 mg TID for 2 to 6 months – Contraindications: recent cerebral and/or retinal hemorrhage; intolerance to methylxanthines (e.g., caffeine, theophylline); allergy to the particular drug selected – Precautions: prolonged prothrombin time (PT) and/or bleeding; if on warfarin, frequent monitoring of PT

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ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring Instruct patient to see physician if compresses are unsuccessful.

DIET Unrestricted

PROGNOSIS • Self-limited: usually drains pus spontaneously and will heal with or without scarring within several days. • Recurrent/chronic: may last for months or years • If recurrent, usually related to chronic skin carriage of staphylococci (nares or on skin). Treatment goals are to decrease or eliminate pathogenic strain or suppress pathogenic strain. – Culture nares, skin, axilla, and perineum (culture nares of family members). – Mupirocin 2%: Apply to both nares BID for 5 days each month. – Culture anterior nares every 3 months; if failure, retreat with mupirocin or consider clindamycin 150 mg/day for 3 months. • Especially in recurrent cases, wash entire body and fingernails (with nailbrush) daily for 1 to 3 weeks with povidone-iodine (Betadine), chlorhexidine (Hibiclens), or hexachlorophene (pHisoHex soap), although all can cause dry skin.

COMPLICATIONS • Scarring • Bacteremia • Seeding (e.g., septal/valve defect, arthritic joint)

REFERENCES 1. Demos M, McLeod MP, Nouri K. Recurrent furunculosis: a review of the literature. Br J Dermatol. 2012;167(4):725–732. 2. Fritz SA, Camins BC, Eisenstein KA, et al. Effectiveness of measures to

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eradicate Staphylococcus aureus carriage in patients with communityassociated skin and soft-tissue infections: a randomized trial. Infect Control Hosp Epidemiol. 2011;32(9):872–880.

ADDITIONAL READING • El-Gilany AH, Fathy H. Risk factors of recurrent furunculosis. Dermatol Online J. 2009;15(1):16. • Ibler KS, Kromann CB. Recurrent furunculosis–challenges and management: a review. Clin Cosmet Investig Dermatol. 2014;7:59–64. • McConeghy KW, Mikolich DJ, LaPlante KL. Agents for the decolonization of methicillin-resistant Staphylococcus aureus. Pharmacotherapy. 2009;29(3):263–280. • Rivera AM, Boucher HW. Current concepts in antimicrobial therapy against select gram-positive organisms: methicillin-resistant Staphylococcus aureus, penicillin-resistant pneumococci, and vancomycin-resistant enterococci. Mayo Clin Proc. 2011;86(12):1230–1243. • Wahba-Yahav AV. Intractable chronic furunculosis: prevention of recurrences with pentoxifylline. Acta Derm Venereol. 1992;72(6):461–462. • Winthrop KL, Abrams M, Yakrus M, et al. An outbreak of mycobacterial furunculosis associated with footbaths at a nail salon. N Engl J Med. 2002;346(18):1366–1371.

SEE ALSO Folliculitis; Hidradenitis Suppurativa

CODES ICD10 • L02.92 Furuncle, unspecified • L02.12 Furuncle of neck • L02.429 Furuncle of limb, unspecified

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CLINICAL PEARLS • Pathogens may be different in different localities. Keep up-to-date with the locality-specific epidemiology. • If few, furuncles/furunculosis do not need antibiotic treatment. If systemic symptoms (e.g., fever), cellulitis, or multiple lesions occur, oral antibiotic therapy is used. • Other treatments for MRSA include linezolid PO or IV and IV vancomycin. • Folliculitis, furunculosis, and carbuncles are parts of a spectrum of pyodermas. • Other causative organisms include aerobic (e.g., Escherichia coli, Pseudomonas aeruginosa, and Streptococcus faecalis), anaerobic (e.g., Bacteroides, Lactobacillus, Peptobacillius, and Peptostreptococcus), and Mycobacteria. • Decolonization (treatment of the nares with topical antibiotic) is only recommended if the colonization was confirmed by cultures because resistance is common and treatment is of uncertain efficacy.

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GALACTORRHEA Christine K. Jacobs, MD BASICS DESCRIPTION • Milky nipple discharge not associated with gestation or present >1 year after weaning. Galactorrhea does not include serous, purulent, or bloody nipple discharge. • System(s) affected: endocrine/metabolic, nervous, reproductive

Pregnancy Considerations Most cases of galactorrhea during pregnancy are physiologic.

EPIDEMIOLOGY • Predominant age: 15 to 50 years (reproductive age) • Predominant sex: female > male (rare, e.g., in patients with multiple endocrine neoplasia type 1 [MEN1], the most common anterior pituitary tumors are prolactinomas)

Prevalence 6.8% of women referred to physicians with a breast complaint have nipple discharge.

ETIOLOGY AND PATHOPHYSIOLOGY Lactation is stimulated by prolactin, which is secreted in pulses by the anterior pituitary, inhibited by dopamine produced in the hypothalamus. Galactorrhea results either from prolactin overproduction or loss of inhibitory regulation by dopamine. • Afferent neural stimulation – Nipple stimulation – Chest wall trauma – Spinal cord injury – Herpes zoster • Organic hyperprolactinemia

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– Prolactinoma – Craniopharyngiomas – Meningiomas or other tumors – Sarcoid – Irradiation – Vascular malformations (aneurysms) – Pituitary stalk compression – Multiple sclerosis (MS) (with hypothalamic lesion) – Traumatic injury • Functional hyperprolactinemia – Hypothyroidism – Adrenal insufficiency – Cirrhosis – Chronic kidney disease – Lung cancer – Renal cell cancer • Medications that suppress dopamine: – Typical and atypical antipsychotics – SSRIs (prolactin not always elevated) – Tricyclic antidepressants – H2 blockers – Reserpine – α-Methyldopa – Verapamil – Estrogens – Isoniazid – Opioids – Stimulants – Neuroleptics – Metoclopramide – Domperidone – Protease inhibitors • Postoperative condition, especially oophorectomy • Idiopathic

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– Normal prolactin levels

GENERAL PREVENTION • Frequent nipple stimulation can cause galactorrhea. • Avoid medications that can suppress dopamine.

COMMONLY ASSOCIATED CONDITIONS See “Etiology and Pathophysiology.”

DIAGNOSIS • Findings vary with causes. • Look for signs/symptoms of associated conditions: – Adrenal insufficiency – Acromegaly – Hypothyroidism – Polycystic ovarian syndrome – Chest wall conditions

HISTORY • Usually bilateral milky nipple discharge; may be spontaneous or induced by stimulation • Determine possibility of pregnancy or recent discontinuation of lactation. • Signs of hypogonadism from hyperprolactinemia – Oligomenorrhea, amenorrhea – Inadequate luteal phase, anovulation, infertility – Decreased libido (especially in affected males) • Mass effects from pituitary enlargement – Headache, cranial neuropathies – Bitemporal hemianopsia, amaurosis, scotomata

PHYSICAL EXAM Breast examination should be performed with attention to the presence of spontaneous or induced nipple discharge.

DIFFERENTIAL DIAGNOSIS

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• Pregnancy-induced lactation or recent weaning • Nonmilky nipple discharge – Intraductal papilloma – Fibrocystic disease • Purulent breast discharge – Mastitis – Breast abscess – Impetigo – Eczema • Bloody breast discharge: Consider malignancy (Paget disease, breast cancer).

DIAGNOSTIC TESTS & INTERPRETATION Perform formal visual field testing if pituitary adenoma suspected.

Initial Tests (lab, imaging) • Prolactin level, thyroid-stimulating hormone, pregnancy test, liver, and renal functions • Situations that may alter lab results: – Lab evaluation of prolactin may be falsely elevated by a recent breast examination. – Vigorous exercise – Sexual activity – High-carbohydrate diet – Consider repeating the test under different circumstances if the value is borderline (30 to 40) elevated. • Prolactin levels may fluctuate. Elevated prolactin levels should be confirmed with at least one additional level drawn in a fasting, nonexercised state, with no breast stimulation (1)[C]. • Prolactin levels >250 ng/mL are highly suggestive of a pituitary adenoma (2) [C]. • If a breast mass is palpated in the setting of nipple discharge, evaluation of that mass is indicated with mammogram and/or ultrasound. • Pituitary MRI with gadolinium enhancement if the serum prolactin level is significantly elevated (>200 ng/mL) or if a pituitary tumor is otherwise suspected

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Follow-Up Tests & Special Considerations • Consider evaluation of follicle-stimulating hormone and luteinizing hormone if amenorrheic. • Consider evaluation of growth hormone levels if acromegaly suspected. • Measure adrenal steroids if signs of Cushing disease present.

Diagnostic Procedures/Other If diagnosis is in question, confirm by microscopic evaluation that nipple secretions are lipoid.

TREATMENT • Avoid excess nipple stimulation. • Idiopathic galactorrhea (normal prolactin levels) does not require treatment. • Discontinue causative medications, if possible. • If SSRI is implicated, trial of mirtazapine • Medication is preferred therapy, with surgery or radiotherapy for patients not responding to medication (3)[C]. • Medical treatment is preferred except for tumors >10 mm (even if asymptomatic) which should be removed to reduce pituitary tumor size or prevent progression to avoid neurologic sequelae. • If microadenoma, watchful waiting can be appropriate because 95% do not enlarge.

MEDICATION • Dopamine agonists work to reduce prolactin levels and shrink tumor size. Therapy is suppressive, not curative (4)[C]. • Treatment is discontinued when tumor size has reduced or regressed completely or after pregnancy has been achieved. • Cabergoline (Dostinex) – Start at 0.25 mg PO twice weekly and increase by 0.25 mg monthly until prolactin levels normalize. Usual dose ranges from 0.25 to 1 mg PO once or twice weekly. – More effective and better tolerated than bromocriptine (5)[A] – Check ESR and creatinine at baseline and then periodically.

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– ECG at baseline and every 6 to 12 months – DC after prolactin level normal for 6 months. • Bromocriptine – Start at 1.25 mg qhs PO with food and increase every 3 to 7 days by 2.5 mg/day until therapeutic response achieved (usually 2.5 to 15 mg/day). – More expensive and more frequent dosing; however, most providers have experience with this effective drug. – Long-term treatment can cause woody fibrosis of the pituitary gland. – Check creatinine, CBC, LFTs, cardiovascular evaluation. Pregnancy test every 4 weeks during amenorrhea and after menses restored if period is >3 days late. • Contraindications are similar for all and include the following: – Uncontrolled hypertension – Sensitivity to ergot alkaloids • Precautions – Dopamine antagonists may cause nausea, vomiting, psychosis, or dyskinesia. • Significant possible interactions – H2 blockers, CYP3A4; weak serotonin effect; hypotensive effect

SURGERY/OTHER PROCEDURES • Surgery – Macroadenomas need surgery if (i) medical management does not halt growth, (ii) neurologic symptoms persist, (iii) size >10 mm, or (iv) patient cannot tolerate medications; also considered in young patients with microadenomas to avoid long-term medical therapy – Transsphenoidal pituitary resection – 50% recurrence after surgery • Radiotherapy – Radiation is an alternative tumor therapy for macroprolactinomas not responsive to other modes of treatment: 20–30% success rate 50% risk of panhypopituitarism after radiation Risk of optic nerve damage, hypopituitarism, neurologic dysfunction, and

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increased risk for stroke and secondary brain tumors

ONGOING CARE FOLLOW-UP RECOMMENDATIONS • Outpatient care unless pituitary resection required • Bromocriptine patients need adequate hydration. • Dopamine agonist therapy should be discontinued in pregnancy.

Patient Monitoring • Varies with cause • Check prolactin levels every 6 weeks until normalized and then every 6 to 12 months. • Monitor visual fields and/or MRI at least yearly until stable for prolactinoma.

DIET No restrictions

PATIENT EDUCATION

• Warn about symptoms of mass enlargement in pituitary. • Discuss treatment rationale, risks of treating, and expectant management. • Patient education material available from American Family Physician: www.aafp.org/afp/20040801/553ph.html • Patient education material from American Society for Reproductive Medicine: https://www.asrm.org/uploadedFiles/ASRM_Content/Resources/Patient_Resources/Fact_Sh

PROGNOSIS • Depends on underlying cause • Symptoms can recur after discontinuation of a dopamine agonist. • Surgery can have 50% recurrence. • Prolactinomas 200 ng/mL (or signs suspicion for a pituitary macroadenoma) with a gadolinium-enhanced MRI.

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GASTRITIS Anna Worley, MD • Naureen Rafiq, MD BASICS DESCRIPTION • Inflammation of the mucosa of the stomach • Patchy erythema of gastric mucosa – Common on endoscopy; usually insignificant • Erosive gastritis or reactive gastropathy – A reaction to mucosal injury by a noxious agent (especially NSAIDs or alcohol) – Damage to the surface epithelium caused by mucosal hypoxia or the direct action of NSAIDs • Reflux gastritis – A reaction to protracted reflux exposure to biliary and pancreatic fluid – Typically limited to the prepyloric antrum • Hemorrhagic gastritis (stress ulceration) – A reaction to hemodynamic disorder (e.g., hypovolemia or hypoxia [shock]) – Common in ICU patients, particularly after severe burns and trauma – Seen rarely with dabigatran (oral thrombin inhibitor) • Infectious gastritis – Commonly associated with acute and/or chronic Helicobacter pylori infection – Viral infection, usually as a component of systemic infection, is common. • Atrophic gastritis – Autoimmune versus environmental – Frequent in the elderly – Primarily from long-standing H. pylori infections – May be caused by prolonged proton pump inhibitor (PPI) use – Major risk factor for gastric cancer – Associated with primary (pernicious) anemia

Geriatric Considerations

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Persons age >60 years often harbor H. pylori infection.

Pediatric Considerations Gastritis rarely occurs in infants or children; increasing prevalence with age

EPIDEMIOLOGY • Predominant age: all ages (more common with older age) • Predominant sex: male = female

ETIOLOGY AND PATHOPHYSIOLOGY • Noxious agents cause a breakdown in the gastric mucosal barrier, leaving the epithelial cells unprotected. • Infection: H. pylori (most common cause), Staphylococcus aureus exotoxins, and viral infection • Alcohol • Aspirin and other NSAIDs • Bile reflux • Pancreatic enzyme reflux • Portal hypertensive (HTN) gastropathy • Emotional stress

Genetics Unknown, but observational studies show that 10% of a given population is never colonized with H. pylori, regardless of exposure. Genetic variations in TLR1 may help explain some of this observed variation in individual risk for H. pylori infection.

RISK FACTORS • Age >60 years—prevalence of 50–60% by age 60 years • Exposure to potentially noxious drugs or chemicals (e.g., alcohol or NSAIDs) • Hypovolemia, hypoxia (shock), burns, head injury, complicated postoperative course • Autoimmune diseases (thyroid disease and diabetes) • Family history of H. pylori and/or gastric cancer • Stress (hypovolemia or hypoxia) • Tobacco use

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• Radiation • Ischemia • Pernicious anemia • Gastric mucosal atrophy

GENERAL PREVENTION • Avoid injurious drugs or chemical agents. • Patients with hypovolemia or hypoxia (especially ICU patients) should receive prophylactic therapy. H2 receptor antagonists, prostaglandins, or sucralfate are commonly used for gastric mucosal protection. • Consider testing for H. pylori (and eradicating if present) in patients on longterm NSAID therapy.

COMMONLY ASSOCIATED CONDITIONS • Gastric or duodenal peptic ulcer • Primary (pernicious) anemia—atrophic gastritis • Portal HTN, hepatic failure • Gastric lymphoma linked to lymphoid follicles

DIAGNOSIS HISTORY • Nondescript (sometimes severe) epigastric discomfort, often aggravated by eating • Burning epigastric pain • Anorexia • Nausea, with or without vomiting • Significant bleeding is unusual except in hemorrhagic gastritis. • Rectal bleeding/melena • Hiccups • Bloating or abdominal fullness

PHYSICAL EXAM • Assess vital signs. Abdominal exam often normal • Mild epigastric tenderness

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• May have heme-positive stool • Examine for stigmata of chronic alcohol abuse.

DIFFERENTIAL DIAGNOSIS • Functional abdominal pain (dyspepsia) • Peptic ulcer disease • Viral gastroenteritis • Gastric cancer (elderly) • Cholecystitis • Pancreatic disease (inflammation vs. tumor)

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Usually normal • CBC to evaluate for blood loss/anemia • 13C-urea breath test for H. pylori – 95% specificity and sensitivity • H. pylori, serology serum IgG – Inexpensive; 85% sensitivity, 79% specificity – Positive in history of colonization or prior infections; cannot be used to assess eradication • Stool analysis for fecal H. pylori antigen – 95% specificity and sensitivity • Gastric acid analysis may be abnormal but is not a reliable indicator of gastritis. • Low serum pepsinogen I (PG I) relative to PG II is associated with fundal intestinal metaplasia. • Drugs that may alter lab results: Antibiotics or PPIs may affect urea breath test for H. pylori. – Hold PPIs for 2 weeks, H2 receptor antagonists for 24 hours, and antibiotics for 4 weeks prior to stool or breath tests (1)[C]. Follow-Up Tests & Special Considerations Endoscopy for H. pylori • Culture; polymerase chain reaction (PCR); histology; rapid urease testing

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Diagnostic Procedures/Other • Gastroscopy with biopsy allows for a precise diagnosis and is a first-line diagnostic tool in: – Age >55 years with new-onset signs and symptoms – Weight loss, persistent vomiting, or GI bleed (1)[C] • Gastric biopsies (multiple) in both body and antrum recommended if there is a poor response to initial treatment. Patients must discontinue PPIs for 2 weeks prior to endoscopy to improve accuracy of result.

Test Interpretation Acute or chronic inflammatory infiltrate in gastric mucosa, often with distortion or erosion of adjacent epithelium. Presence of H. pylori often confirmed

TREATMENT GENERAL MEASURES • Treatment of H. pylori is required to relieve symptoms. • Parenteral fluid and electrolyte supplements if oral intake is compromised • Consider discontinuing NSAIDs. • Encourage abstinence from alcohol and smoking cessation. • Endoscopy in patients not responsive to treatment

MEDICATION First Line • Antacids: best given in liquid form, 30 mL 1 hour after meals and at bedtime; useful mainly as an emollient • H2 receptor antagonists (e.g., cimetidine [Tagamet]): oral cimetidine 300 mg q6h (or ranitidine [Zantac] 150 mg BID or famotidine [Pepcid] 20 mg BID or nizatidine [Axid]); 150 mg BID not shown to be clearly superior to antacids • Sucralfate (Carafate): 1 g q4–6h on an empty stomach; rationale uncertain but empirically helpful • Prostaglandins (misoprostol [Cytotec]): can help allay gastric mucosal injury; suggested dosage 100 to 200 μg QID • PPIs can be used if there is no response to antacids or H2 receptor blockers

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(e.g., omeprazole 20 mg daily or BID or esomeprazole 20 mg daily or BID) • H. pylori eradication – Clarithromycin triple therapy (CTT) A short-course therapy (10 to 14 days) of amoxicillin 1 g BID, standard dose PPI BID (omeprazole 20 mg BID, etc.), and clarithromycin 500 mg BID (2)[A] 70–85% eradication Optimal treatment still undefined. IF PCN ALLERGIC: Substitute amoxicillin with metronidazole 500 mg BID. – Bismuth quadruple therapy (BQT) PPI (omeprazole 20 mg) BID plus bismuth (Pepto-Bismol) 30 mL liquid or 2 tablets QID plus metronidazole 250 mg QID plus tetracycline 500 mg QID for 10 to 14 days (2,3)[A] 75–90% eradication Use as initial therapy in areas of high clarithromycin resistance (>15%). Consider in penicillin-allergic patients. • H. pylori alternative treatment: Consider sequential antibiotic therapy with standard dose PPI (i.e., omeprazole 20 mg) and amoxicillin 1 g BID for 5 days followed by clarithromycin 500 mg and tinidazole mg BID with standard-dose PPI (omeprazole 20 mg) BID for 5 days. Some studies show it works just as well or better than triple therapy (1)[B],(2)[A]. • H. pylori treatment failure: Use a different regimen, avoiding clarithromycin (unless resistance testing confirms susceptibility): – BQT for 7 to 14 days (1,2)[A]. – Consider levofloxacin 250 mg BID, amoxicillin 1 g BID, and standard-dose PPI BID for 14 days in those who fail two attempts (1,2)[A]. • Consider probiotics in known symptomatic H. pylori to decrease the density of H. pylori in the gastric antrum and body; decrease severity of gastritis, peptic ulcers; and possibly slow the progression toward atrophic gastritis and gastric adenocarcinoma (4)[A],(5)[C],(6)[A]. – Probiotics alone likely do not eradicate H. pylori. • Contraindications: hypersensitivity • Precautions:

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– If bismuth is prescribed, warn the patient about the side effect of stool becoming black. – Refer to the manufacturer’s profile of each drug. • Significant possible interactions: Refer to the manufacturer’s profile of each drug.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Gastritis prophylaxis in ICU patients • Outpatient management, except for severe hemorrhagic gastritis

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Usually no restrictions • Confirm H. pylori eradication in patients with: – Gastric ulcer – Persistent dyspepsia despite treatment – H. pylori–associated mucosa-associated lymphoid tissue (MALT) lymphoma – History of resection of gastric cancer

Patient Monitoring • Repeat gastroscopy after 6 weeks if gastritis was severe or if patient has a poor treatment response. • Surveillance gastroscopy every 3 to 5 years in patients with atrophic gastritis in both the antrum and body; within 1 year for patients with low-grade dysplasia, (with extensive biopsy sampling); 6 and 12 months in patients with high-grade dysplasia

DIET Restrictions, if any, depend on symptom severity (e.g., bland, light, soft foods); avoid caffeine and spicy foods and alcohol.

PATIENT EDUCATION

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• Smoking cessation; limit alcohol. • Dietary changes • Relaxation therapy • Avoid NSAIDs as possible.

PROGNOSIS • Most cases clear spontaneously when the cause has been identified and treated. • Recurrence of H. pylori infection requires a repeated course of treatment.

COMPLICATIONS • Bleeding from extensive mucosal erosion or ulceration • Clearing H. pylori before chronic gastritis develops may prevent development of gastric cancer.

REFERENCES 1. McColl KE. Clinical practice. Helicobacter pylori infection. N Engl J Med. 2010;362(17):1597–1604. 2. Malfertheiner P, Megraud F, O’Morain CA, et al. Management of Helicobacter pylori infection—the Maastricht IV/Florence Consensus report. Gut. 2012;61(5):646–664. 3. Venerito M, Krieger T, Ecker T, et al. Meta-analysis of bismuth quadruple therapy versus clarithromycin triple therapy for empiric primary treatment of Helicobacter pylori infection. Digestion. 2013;88(1):33–45. 4. Patel A, Shah N, Prajapati JB. Clinical applications of probiotics in the treatment of Helicobacter pylori infection—a brief review. J Microbiol Immunol Infect. 2014;47(5):429–437. 5. Emara MH, Elhawari SA, Yousef S, et al. Emerging role of probiotics in the management of Helicobacter pylori infection: histopathologic perspectives. Helicobacter. 2016;21(1):3–10. 6. Ruggiero P. Use of probiotics in the fight against Helicobacter pylori. World J Gastrointest Pathophysiol. 2014;5(4):384–391.

ADDITIONAL READING

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• El-Zimaity H, Serra S, Szentgyorgyi E, et al. Gastric biopsies: the gap between evidence-based medicine and daily practice in the management of gastric Helicobacter pylori infection. Can J Gastroenterol. 2013;27(10):e25– e30. • Eslami L, Nasseri-Moghaddam S. Meta-analyses: does long-term PPI use increase the risk of gastric premalignant lesions? Arch Iran Med. 2013;16(8):449–458.

CODES ICD10 • K29.70 Gastritis, unspecified, without bleeding • K29.71 Gastritis, unspecified, with bleeding • K29.00 Acute gastritis without bleeding

CLINICAL PEARLS • H. pylori is the most common cause of gastritis. • >50% of adult patients are colonized with H. pylori. • H. pylori antibodies decline in the year after treatment and should not be used to determine eradication. H. pylori antibody titers rise significantly with reinfection. • H. pylori stool antigen tests can be used before and after therapy to assess for eradication and reinfection. • Several courses of rescue therapy may be necessary to eradicate H. pylori. • Discontinue PPIs 2 weeks prior to endoscopy to improve diagnostic accuracy in cases of suspected gastritis. • Consider probiotics as adjunct treatment in symptomatic H. pylori gastritis.

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GASTROESOPHAGEAL REFLUX DISEASE Anna Cecilia S. Tenorio, MD • Fozia Akhtar Ali, MD BASICS DESCRIPTION • Often described as “heartburn,” “acid indigestion,” and “acid reflux” • Changes of the esophageal mucosa resulting from reflux of gastric contents into the esophagus

EPIDEMIOLOGY Incidence Incidence: 5 per 1,000 person-years

Prevalence • 10–20% in the United States • 40% of adults in the United States have reflux symptoms. • 50–85% of gastroesophageal reflux disease (GERD) patients have nonerosive reflux disease. • Chronic GERD is a risk factor for Barrett esophagus. • 10% of patients with chronic GERD have Barrett esophagus. • Risk of adenocarcinoma without Barrett esophagus and no dysplasia: 0.1– 0.5% per patient-year • Risk of adenocarcinoma with Barrett esophagus and high-grade dysplasia: 6– 19% per patient-year • Pediatric population: Regurgitation occurs at least once a day in 2/3 of 4month-old infants, decreasing to 21% at age 6 to 7 months, and 5% at 10 to 12 months.

ETIOLOGY AND PATHOPHYSIOLOGY • The pattern and mechanism of reflux varies depends on the severity of disease. • GERD begins when acidic stomach contents contact the squamous mucosal lining of the esophagus, at the esophagogastric junction (EGJ).

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• Usually affected by inappropriate transient lower esophageal sphincter (LES) relaxation. Foods that are spicy; acidic; and high in fat, caffeine, alcohol, tobacco, anticholinergic medications, nitrates, smooth muscle relaxants affect LES relaxation. • Patients with severe GERD often have evidence of an associated hiatal hernia, which affects GERD by (1): – Trapping acid in the hernia sac – Impairing acid emptying – Increasing retrograde acid flow rate – Reducing the EGJ sphincter pressure – Increased frequency of transient LES relaxations

Genetics Genetic heterogeneity has been associated with GERD.

RISK FACTORS • Obesity • Hiatal hernia • Scleroderma • Alcohol use • Tobacco use • Pregnancy

GENERAL PREVENTION • Decrease consumption of food and beverage triggers such as spicy, fatty foods, alcohol, and caffeine • Weight loss • Avoid lying down after eating a meal. • Tobacco and alcohol cessation • Elevate head of bed at night • Avoid meals close to bedtime. • Infants: Use car seat for 2 to 3 hours after meals; thickened feedings

COMMONLY ASSOCIATED CONDITIONS • Nonerosive esophagitis • Erosive esophagitis

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• Irritable bowel syndrome • Peptic ulcer disease • Extraesophageal reflux: aspiration, chronic cough, laryngitis, vocal cord granuloma, sinusitis, otitis media • Halitosis • Hiatal hernia: acid pocket (zone of high acidity in the proximal stomach above the diaphragm) (2)[B] • Peptic stricture: 10% of patients with GERD • Barrett esophagus • Esophageal adenocarcinoma

DIAGNOSIS HISTORY • Typical symptoms: acid regurgitation, heartburn, dysphagia (mostly postprandial) • Atypical symptoms: epigastric fullness/pressure/pain, dyspepsia, nausea, bloating, belching, chest pain, lump in throat • Extraesophageal signs and symptoms: chronic cough, bronchospasm, wheezing, hoarseness, sore throat, hoarseness • Heartburn: retrosternal burning sensation • Regurgitation; sour or acid taste in mouth (“water brash”) • Symptoms worse with bending or lying down • Diet, alcohol and tobacco use

PHYSICAL EXAM Often unremarkable. Make note of: • BMI • Epigastric tenderness or palpable epigastric mass • Stigmata of chronic systemic disease or alcohol use • Dental erosions

DIFFERENTIAL DIAGNOSIS • Infectious esophagitis (Candida, herpes, HIV, cytomegalovirus) • Chemical esophagitis; pill-induced esophagitis

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• Eosinophilic esophagitis • Nonulcer dyspepsia • Biliary tract disease • Radiation injury • Crohn disease • Angina/coronary artery disease • Esophageal stricture or anatomic defect (ring, sling) • Esophageal adenocarcinoma • Achalasia; scleroderma • Peptic ulcer disease

DIAGNOSTIC TESTS & INTERPRETATION Diagnosis often solely based on history and clinical symptoms. Initially treat patients with typical symptoms of GERD and without alarm symptoms (dysphagia odynophagia, weight loss, early satiety, anemia, new onset, male >50 years) empirically with antisecretory agents without any further diagnostic testing.

Initial Tests (lab, imaging) • Indication for blood work depends on clinical presentation. Check for anemia (history of bleeding; or possible poor vitamin B12 absorption due to chronic proton pump inhibitor [PPI] use). • Patients with GERD who present with symptoms suspicious for cardiac disease should undergo the appropriate evaluation.

Diagnostic Procedures/Other • Upper endoscopy – First-line diagnostic test for those with alarm signs and uncontrolled symptoms (2)[B] – Indications for UGI endoscopy Alarm symptoms such as dysphagia, bleeding, anemia, weight loss, recurrent vomiting Persistent typical GERD symptoms despite treatment with twice-daily PPI for 4 to 8 weeks Men >50 with chronic GERD (>5 years) and other risk factors: hiatal

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hernia, high BMI, tobacco use, high abdominal fat distribution History of severe erosive esophagitis (assess healing and check for UGI pathology including Barrett esophagus) Surveillance (history of Barrett esophagus) – ~50–70% of patients with heartburn have negative endoscopic findings. – Savary-Miller classification (grades esophagitis based on endoscopy) Grade I: ≥1 nonconfluent reddish spots, with or without exudate Grade II: erosive and exudative lesions in the distal esophagus; may be confluent but not circumferential Grade III: circumferential erosions in the distal esophagus Grade IV: chronic complications such as deep ulcers, stenosis, or scarring with Barrett metaplasia • Esophageal manometry – Not recommended for primary GERD diagnosis; a second option for those with GERD and normal endoscopy (2)[B] – Diagnose motility disorders: functional heartburn, achalasia, and distal esophageal spasm. – Used to evaluate peristaltic function preoperatively and to record LES pressure • Ambulatory reflux (pH) monitoring – Evaluate excessive acid exposure in those with GERD symptoms, normal endoscopy, and no response to PPI (2)[B]. – Used to document frequency of reflux – Discontinue PPI for 7 days prior to procedure. • Barium swallow: not used for GERD diagnosis; used to evaluate complaints of dysphagia or to outline anatomic abnormalities (hiatal hernia)

Test Interpretation • Acute inflammation (especially eosinophils) • Epithelial basal zone hyperplasia seen in 85% • Barrett epithelial change: Gastric columnar epithelium replaces squamous epithelium in distal esophagus (metaplasia).

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TREATMENT GENERAL MEASURES Lifestyle changes are first-line intervention: • Elevate head of bed (2)[B]. • Avoid meals 2 to 3 hours before bedtime (2)[B]. • Avoid stooping, bending, and tight-fitting garments. • Avoid medications that relax LES (anticholinergic drugs; calcium channel blockers). • Weight loss (2)[B] • Tobacco cessation and alcohol avoidance • Limit consumption of patient-specific food triggers (global elimination of all reflux-causing foods is not necessary, practical, or beneficial). • Stepped therapy – Phase I: lifestyle and diet modifications, antacids plus H2 blockers or PPIs – Phase II: If symptoms persist, consider endoscopy. – Phase III: If symptoms still persist, consider surgery.

MEDICATION First Line • H2 blockers in equipotent oral doses (e.g., cimetidine 800 mg BID or 400 mg QID, ranitidine 150 mg BID, famotidine 20 mg BID, or nizatidine 150 mg BID) – Renally dosed • PPIs: irreversibly bind proton pump (H+/K+ ATPase), effective onset within 4 days; omeprazole 20 to 40 mg/day, lansoprazole 15 to 30 mg/day, dexlansoprazole 30 mg/day, pantoprazole 40 mg/day, rabeprazole 20 mg/day, esomeprazole 40 mg/day – No major differences in efficacy among PPIs (3)[A] – Dose 30 to 60 minutes before meals with the exception of dexlansoprazole (2)[A]. – PPIs may increase risk of hypomagnesemia, hip fracture, Clostridium difficile infection, vitamin B12 deficiency, and community acquired pneumonia.

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• PPI more effective than H2 blocker and prokinetics for healing erosive and nonerosive esophagitis (4)[A]. • Erosive esophagitis: 8 weeks of PPI effective in 90%

Pediatric Considerations Antacids or liquid H2 blockers and PPIs are available. Prokinetics have a minimal role due to safety concerns and limited efficacy.

Second Line • Antacids or barrier agents (sucralfate 1 g PO QID 1 hour before meals and at bedtime for 4 to 8 weeks) may relieve breakthrough symptoms. • Prokinetics: metoclopramide 5 to 10 mg before meals • Baclofen as add-on therapy with a PPI • Precautions – Blood dyscrasias and anemia with PPIs and H2 blockers – Metoclopramide is a dopamine blocker; risk of dystonia and tardive dyskinesia – Tachyphylaxis may occur with H2 blockers. • Significant possible interactions – PPIs and H2 blockers: multiple cytochrome P450 drug interactions; that is, warfarin, phenytoin, antifungals, digoxin

SURGERY/OTHER PROCEDURES • Laparoscopic fundoplication (wrapping gastric fundus around distal esophagus) increases pressure gradient between stomach and esophagus. • Bariatric surgery – Surgery indicated if patient desires to discontinue medical therapy, has side effects with medical therapy, has a large hiatal hernia, has esophagitis refractory to medical therapy, or has refractory symptoms (4)[A]. – Preop ambulatory pH monitor mandatory in patients with no evidence of erosive esophagitis (4)[A]. – Manometry to rule out esophageal dysmotility, achalasia, or scleroderma prior to surgery (4)[A]. – Best surgical response in patients with typical symptoms who respond well to PPI therapy.

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– If patient is expected to require >10 years of PPI treatment, surgery may be more cost-effective. – Consider bariatric surgery for morbidly obese patients. Gastric bypass is preferred (4)[A].

Pediatric Considerations Surgery for severe symptoms (apnea, choking, persistent vomiting)

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Track symptoms over time. • Repeat endoscopy in 4 to 8 weeks if there is a poor symptomatic response to medical therapy, especially in older patients. • In patients with Barret esophagus who would opt for treatment if cancer is detected; perform endoscopic surveillance every 2 to 3 years.

DIET Avoid foods that can trigger or make symptoms worse.

PATIENT EDUCATION Lifestyle and dietary modifications: Eat small meals; avoid lying down after meals; elevate head of bed; weight loss; smoking cessation; avoid alcohol and caffeine.

PROGNOSIS • Symptoms and esophageal inflammation often return promptly when treatment is withdrawn. To prevent relapse of symptoms, continue antisecretory therapy (in addition to lifestyle and dietary modifications). – PPI maintenance therapy likely improves quality of life more than H2 blockers. – Full-dose PPIs are more effective than half-dose for maintenance (4)[A]. – In erosive esophagitis, daily maintenance therapy with PPI prevents relapse; intermittent PPI therapy not as effective (2)[A]

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• Medical and surgical therapy are equally effective for symptom reduction (4) [A]. • Antireflux surgery – 90–94% symptom response. Patients with persistent symptoms should have repeat anatomic evaluation (endoscopy or esophagram). – Some surgically treated patients eventually require medical therapy. • Regression of Barrett epithelium does not routinely occur despite aggressive medical or surgical therapy.

COMPLICATIONS • Peptic stricture: 10–15% • Barrett esophagus: 10% – Adenocarcinoma cancer develops at an annual rate of 0.5%. – Primary treatment for Barrett esophagus with high-grade dysplasia is endoscopic radiofrequency ablation. • Extraesophageal symptoms: hoarseness, aspiration, (including pneumonia) • Bleeding due to mucosal injury • Noncardiac chest pain

Geriatric Considerations Complications more likely (e.g., aspiration pneumonia)

REFERENCES 1. Lee YY, McColl KE. Pathophysiology of gastroesophageal reflux disease. Best Pract Res Clin Gastroenterol. 2013;27(3):339–351. 2. Kahrilas PJ, Shaheen NJ, Vaezi MF, et al. American Gastroenterological Association Medical Position Statement on the management of gastroesophageal reflux disease. Gastroenterology. 2008;135(4):1383.e5– 1391.e5. 3. Agency for Healthcare Research and Quality. Comparing effectiveness of management strategies for gastroesophageal reflux disease. An update to the 2005 report. http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guidesreviews-and-reports/?productid=781&pageaction=displayproduct/. Accessed October 11, 2016.

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4. Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and management of gastroesophageal reflux disease. Am J Gastroenterol. 2013;108(10):308– 328.

ADDITIONAL READING • Anderson WD III, Strayer SM, Mull SR. Common questions about the management of gastroesophageal reflux disease. Am Fam Physician. 2015;91(10):692–697. • El-Serag HB, Sweet S, Winchester CC, et al. Update on the epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut. 2014;63(6):871– 880.

SEE ALSO Algorithms: Dyspepsia; Epigastric Pain

CODES ICD10 • K21.9 Gastro-esophageal reflux disease without esophagitis • K21.0 Gastro-esophageal reflux disease with esophagitis

CLINICAL PEARLS • GERD is primarily a historical diagnosis. • Consider GERD in nonsmokers who have a chronic cough (persisting >3 weeks). • Empiric treatment with H2 blockers or PPI leads to symptomatic relief in most cases. Persistent symptoms should be evaluated with endoscopy.

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GENITO-PELVIC PAIN/PENETRATION DISORDER (VAGINISMUS) Jeffrey D. Quinlan, MD, FAAFP BASICS Genito-pelvic pain/penetration disorder is the name of the conditions formally known as vaginismus and dyspareunia. Vaginismus results from involuntary contraction of the vaginal musculature. Primary vaginismus occurs in women who have never been able to have penetrative intercourse. Women with secondary vaginismus were previously able to have penetrative intercourse but are no longer able to do so.

DESCRIPTION • Persistent or recurrent difficulties for 6 months or more with at least one of the following: – Inability to have vaginal intercourse/penetration on at least 50% of attempts – Marked genito-pelvic pain during at least 50% of vaginal intercourse/penetration attempts – Marked fear of vaginal intercourse/penetration or of genito-pelvic pain during intercourse/penetration on at least 50% of vaginal intercourse/penetration attempts – Marked tensing or tightening of the pelvic floor muscles during attempted vaginal intercourse/penetration on at least 50% of occasions • The disturbance causes marked distress or interpersonal difficulty. • Dysfunction is not as a result of: – Nonsexual mental disorder – Severe relationship stress – Other significant stress – Substance or medication effect • Specify if with a general medical condition (e.g., lichen sclerosis, endometriosis) (1).

Pregnancy Considerations

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• May first present during evaluation for infertility • Pregnancy can occur in patients with genito-pelvic pain/penetration disorder when ejaculation occurs on the perineum. • Vaginismus may be an independent risk factor for cesarean delivery.

EPIDEMIOLOGY Incidence The incidence of vaginismus is thought to be about 1–17% per year worldwide. In North America, 12–21% of women have genito-pelvic pain of varying etiologies (2).

Prevalence • True prevalence is unknown due to limited data/reporting. • Population-based studies report prevalence rates of 0.5–30%. • Affects women in all age groups. • Approximately 15% of women in North America report recurrent pain during intercourse.

ETIOLOGY AND PATHOPHYSIOLOGY Most often multifactorial in both primary and secondary vaginismus • Primary – Psychological and psychosocial issues Negative messages about sex and sexual relations in upbringing may cause phobic reaction. Poor body image and limited understanding of genital area History of sexual trauma – Abnormalities of the hymen – History of difficult gynecologic examination • Secondary – Often situational – Often associated with dyspareunia secondary to: Vaginal infection Inflammatory dermatitis Surgical or postdelivery scarring Endometriosis

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Inadequate vaginal lubrication Pelvic radiation Estrogen deficiency – Conditioned response to pain from physical issues previously listed

RISK FACTORS • Most often idiopathic • Although the exact role in the condition is unclear, many women report a history of abuse or sexual trauma. • Often associated with other sexual dysfunctions

COMMONLY ASSOCIATED CONDITIONS • Marital stress, family dysfunction • Anxiety • Vulvodynia/vestibulodynia

DIAGNOSIS DSM-5 has combined vaginismus and dyspareunia in a condition called genitopelvic pain/penetration disorder.

HISTORY • Complete medical history • Full psychosocial and sexual history, including the following: – Onset of symptoms (primary or secondary) – If secondary, precipitating events, if any – Relationship difficulty/partner violence – Inability to allow vaginal entry for different purposes Sexual (penis, digit, object) Hygiene (tampon use) Health care (pelvic examination) – Infertility – Traumatic experiences (exam, sexual, etc.) – Religious beliefs – Views on sexuality

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PHYSICAL EXAM • Pelvic examination is necessary to exclude structural abnormalities or organic pathology. • Educating the patient about the examination and giving her control over the progression of the examination is essential, as genital/pelvic examination may induce varying degrees of anxiety in patients. • Referral to a gynecologist, family physician, or other provider specializing in the treatment of sexual disorders may be appropriate. • Contraction of pelvic floor musculature in anticipation of examination may be seen. • Lamont classification system aids in the assessment of severity – First degree: Perineal and levator spasm relieved with reassurance. – Second degree: Perineal spasm maintained throughout the pelvic exam. – Third degree: levator spasm and elevation of buttocks – Fourth degree: levator and perineal spasm and elevation with adduction and retreat

DIFFERENTIAL DIAGNOSIS • Vaginal infection • Vulvodynia/vestibulodynia • Vulvovaginal atrophy • Urogenital structural abnormalities • Interstitial cystitis • Endometriosis

DIAGNOSTIC TESTS & INTERPRETATION No laboratory tests indicated unless signs of vaginal infection are noted on examination. When diagnosing of this disorder has been conducted, five factors should be considered. • Partner factors • Relationship factors • Individual vulnerability factors • Cultural/religious factors • Medical factors

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Test Interpretation Not available; may be needed to check for secondary causes

TREATMENT • Genito-pelvic pain penetration disorder may be successfully treated (2)[B]. • Outpatient care is appropriate. • Treatment of physical conditions, if present, is first line (see “Secondary” under “Etiology and Pathophysiology”). • Role for pelvic floor physical therapy and myofascial release • Some evidence suggests that cognitive-behavioral therapy may be effective, including desensitization techniques, such as gradual exposure, aimed at decreasing avoidance behavior and fear of vaginal penetration (3)[A]. • Based on a Cochrane review, a clinically relevant effect of systematic desensitization cannot be ruled out (4)[A]. • Evidence suggests that Masters and Johnson sex therapy may be effective (5) [B]. – Involves Kegel exercises to increase control over perineal muscles – Stepwise vaginal desensitization exercises With vaginal dilators that the patient inserts and controls With woman’s own finger(s) to promote sexual self-awareness Advancement to partner’s fingers with patient’s control Coitus after achieving largest vaginal dilator or three fingers; important to begin with sensate-focused exercises/sensual caressing without necessarily a demand for coitus Female superior at first; passive (nonthrusting); female-directed Later, thrusting may be allowed. • Topical anesthetic or anxiolytic with desensitization exercises may be considered. • Patient education is an essential component of treatment (see “Patient Education” section).

MEDICATION • Antidepressants and anticonvulsants have been used with limited success.

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Low-dose tricyclic antidepressant (amitriptyline 10 mg) may be initiated and titrated as tolerated (6)[B]. • Topical anesthetics or anxiolytics may be utilized in combination with either cognitive-behavioral therapy or desensitization exercises as noted above (4) [B]. • Botulinum neurotoxin type A injections may improve vaginismus in patients who do not respond to standard cognitive-behavioral and medical treatment for vaginismus. – Dosage: 20, 50, and 100 to 400 U of botulinum toxin type A injected in the levator ani muscle have been shown to improve vaginismus (4)[B]. • Intravaginal botulinum neurotoxin type A injection (100 to 150 U) followed by bupivacaine 0.25% with epinephrine 1:400,000 intravaginal injection (20 to 30 mL) while the patient is anesthetized may facilitate progressive placement of dilators and ultimately resolution of symptoms (7)[B].

ISSUES FOR REFERRAL For diagnosis and treatment recommendations, the following resources may be consulted: • Obstetrics/gynecology • Pelvic floor physical therapy • Psychiatry • Sex therapy • Hypnotherapy

SURGERY/OTHER PROCEDURES Contraindicated

COMPLEMENTARY & ALTERNATIVE MEDICINE • Biofeedback • Functional electrical stimulation

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Desensitization techniques of gentle, progressive, patient-controlled vaginal

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dilation

Patient Monitoring General preventive health care

DIET No special diet

PATIENT EDUCATION • Education about pelvic anatomy, nature of vaginal spasms, normal adult sexual function • Handheld mirror can help the woman to learn visually to tighten and loosen perineal muscles. • Important to teach the partner that spasms are not under conscious control and are not a reflection on the relationship or a woman’s feelings about her partner • Instruction in techniques for vaginal dilation • Resources – American College of Obstetricians & Gynecologists (ACOG), 409 12th St., SW, Washington, DC 20024-2188; 800-762-ACOG. http://www.acog.org/ – Valins L. When a Woman’s Body Says No to Sex: Understanding and Overcoming Vaginismus. New York, NY: Penguin; 1992.

PROGNOSIS Favorable, with early recognition of the condition and initiation of treatment

REFERENCES 1. American Psychiatric Association. Diagnostic Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013. 2. Landry T, Bergeron S. How young does vulvo-vaginal pain begin? Prevalence and characteristics of dyspareunia in adolescents. J Sex Med. 2009;6(4):927–935. 3. ter Kuile MM, Both S, van Lankveld JJ. Cognitive behavioral therapy for sexual dysfunctions in women. Psychiatr Clin North Am. 2010;33(3):595– 610. 4. Melnik T, Hawton K, McGuire H. Interventions for vaginismus. Cochrane

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Database Syst Rev. 2012;(12):CD001760. 5. Pereira VM, Arias-Carrión O, Machado S, et al. Sex therapy for female sex dysfunction. Int Arc Med. 2013;6(1):37. 6. Crowley T, Goldmeier D, Hiller J. Diagnosing and managing vaginismus. BMJ. 2009;338:b2284. 7. Pacik PT. Vaginismus: review of current concepts and treatment using botox injections, bupivacaine injections, and progressive dilation with the patient under anesthesia. Aesthetic Plast Surg. 2011;35(6):1160–1164.

ADDITIONAL READING • Basson R, Wierman ME, van Lankveld J, et al. Summary of the recommendations on sexual dysfunctions in women. J Sex Med. 2010;7(1, Pt 2):314–326. • Jeng CJ, Wang LR, Chou CS, et al. Management and outcome of primary vaginismus. J Sex Marital Ther. 2006;32(5):379–387. • Pacik PT. Understanding and treating vaginismus: a multimodal approach. Int Urogynecol J. 2014;25(12):1613–1620. • Reissing ED, Binik YM, Khalifé S, et al. Etiological correlates of vaginismus: sexual and physical abuse, sexual knowledge, sexual self-schema, and relationship adjustment. J Sex Marital Ther. 2003;29(1):47–59. • Simons JS, Carey MP. Prevalence of sexual dysfunctions: results from a decade of research. Arch Sex Behav. 2001;30(2):177–219. • ter Kuile MM, van Lankveld JJ, de Groot E, et al. Cognitive-behavioral therapy for women with lifelong vaginismus: process and prognostic factors. Behav Res Ther. 2007;45(2):359–373.

SEE ALSO Dyspareunia; Sexual Dysfunction in Women

CODES ICD10

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• N94.2 Vaginismus • N94.1 Dyspareunia

CLINICAL PEARLS • In a patient with suspected genito-pelvic pain penetration disorder, a complete medical history, including a comprehensive psychosocial and sexual history and a patient-centric, patient-controlled educational pelvic exam should be conducted. • This condition can be treated effectively. • Cognitive-behavioral therapy may be effective for the treatment of this condition. • Botox injection therapy is in the experimental stages but looks promising for the treatment of vaginismus. Bupivacaine and dilation under general anesthesia has also been tried as a treatment for vaginismus.

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GIARDIASIS Iryna Matkovska, DO • Deborah Pierce, DO • Chaiya Laoteppitaks, MD, FAAEM, FACEP BASICS DESCRIPTION • Intestinal infection caused by the protozoan parasite Giardia lamblia: – G. lamblia is also called Giardia duodenalis and Giardia intestinalis. • Infection results from ingestion of cysts, which transform into trophozoites and colonize the small intestine to cause symptoms. – Infectious cycle is continued when the trophozoites encyst in the small intestine and are subsequently transmitted through water, food, or hands contaminated by feces of infected person. • Most infections result from fecal–oral transmission or ingestion of contaminated water (e.g., swimming). • Less commonly acquired through contaminated food

EPIDEMIOLOGY • Predominant age: – All ages but most common in early childhood ages 1 to 9 years and adults 35 to 44 years • Predominant gender: – Male > female (slightly) • Minimal seasonal variability; slight summer increase

Pediatric Considerations Most common in early childhood

Prevalence • 5% of patients with stools submitted for ova and parasite exams • >19,000 cases/year in reportable U.S. states: – Giardia is not reportable in Indiana, Kentucky, Mississippi, North Carolina, and Texas.

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ETIOLOGY AND PATHOPHYSIOLOGY Giardia trophozoites colonize the surface of the proximal small intestine: The mechanism of diarrhea is unknown.

Genetics No known genetic risk factors

RISK FACTORS • Daycare centers • Anal intercourse • Wilderness camping • Travel to developing countries • Children adopted from developing countries • Public swimming pools • Pets with Giardia infection/diarrhea

GENERAL PREVENTION • Hand hygiene • Water purification when camping and when traveling to developing countries • Properly cook all foods.

COMMONLY ASSOCIATED CONDITIONS Hypogammaglobulinemia, IgA deficiency, and immunosuppression are associated with prolonged course of the disease and treatment failures (1)[B].

DIAGNOSIS HISTORY • 25–50% of infected persons are symptomatic. • Symptoms usually appear 1 to 2 weeks after exposure. • Chronic diarrhea (can last for weeks) • Abdominal bloating • Flatulence • Loose, greasy, foul-smelling stools that tend to float • Weight loss

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• Nausea • Lactose intolerance

PHYSICAL EXAM • Typically normal vital signs • Nonspecific; abdominal exam; may have bloating tenderness or increased bowel sounds

DIFFERENTIAL DIAGNOSIS • Cryptosporidiosis, isosporiasis, cyclosporiasis • Other causes of malabsorption include celiac sprue, tropical sprue, bacterial overgrowth syndromes, and Crohn ileitis. • Irritable bowel (diarrhea without weight loss)

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Stool for ova and parasites: – Repeat 3 times on separate days – Cysts in fixed or fresh stools, and occasionally, trophozoites are found in fresh diarrheal stools. • Test limitations: experienced operator, intermittent shedding of ova may not be present in stool sample, labor intensive – ELISA: sensitivity and specificity of 100% and 91.5%, respectively (compared to 50–70% sensitivity using microscopy) (2)[B] • Polymerase chain reaction (PCR) techniques are more sensitive than microscopy but have not been widely adopted due to high cost. • Rapid detection tests have been studied showing high detection rates not widely available (3)[B]. Follow-Up Tests & Special Considerations String test (Entero-test): • A gelatin capsule on a string is swallowed and left in the duodenum for several hours or overnight. The string is removed and visualized microscopically.

Diagnostic Procedures/Other

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Esophagogastroduodenoscopy (EGD) with biopsy and sample of small intestinal fluid

Test Interpretation Intestinal biopsy shows flattened, mild lymphocytic infiltration and trophozoites on the surface.

TREATMENT Outpatient for mild cases; inpatient if symptoms are severe enough to cause dehydration warranting parenteral fluid replacement.

GENERAL MEASURES • No treatment required in asymptomatic patients • Prophylactic therapy indicated for asymptomatic patients in close contact with pregnant or immunocompromised individuals • Fluid replacement if dehydrated

MEDICATION First Line • Metronidazole (Flagyl): 250 mg PO TID for 5 to 7 days • Tinidazole: 2 g PO single dose (50 mg/kg up to 2 g for children) • Albendazole: 400 mg/day PO for 5 days: – Albendazole has comparable effectiveness to metronidazole with fewer side effects. • Precautions: – Theoretical risk of carcinogenesis with metronidazole • Significant possible interactions: occasional disulfiram reaction with metronidazole or tinidazole • Paromomycin (Humatin): A nonaminoglycoside commonly recommended in pregnancy due to lower risk of teratogenicity.

Pregnancy Considerations Medications to treat giardiasis are relatively contraindicated during pregnancy.

Pediatric Considerations

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Limited evidence to suggest vitamin A reduces prevalence of G. lamblia (4)[A].

Second Line • Nitazoxanide suspension was approved by the FDA in 2003 for treatment of giardiasis in children 1 to 11 years. Children aged 1 to 4 years: 100 mg BID and age 5 to 11 years 200 mg BID for 3 days. • Several other medications effective against Gardia are not available in the United States. • Treatment failures may be treated with longer course of original agent or change to a different agent class. • Combination therapies are still being investigated with multiple reported successful combinations; however, there are no definitive guidelines (1)[B], (5)[C].

ADDITIONAL THERAPIES • There have been anecdotal reports of herbal products containing Mentha crispa for the treatment of Giardia (efficacy is unclear).

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring Symptoms, weight, stool exams if patients fail to improve

DIET Low lactose/lactose free, low fat

PATIENT EDUCATION • Hand washing may be more important than water purification to prevent transmission in outdoor enthusiasts. • Lactose intolerance may follow Giardia infection and cause of persistent diarrhea posttreatment. Recommend low-lactose/lactose free diet. • CDC Facts about Giardia and Swimming Pools: http://www.cdc.gov/healthywater/pdf/swimming/resources/giardiafactsheet.pdf

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– Don’t swim if you have diarrhea. – Wash hands with soap after changing diapers before returning to the pool. – Do not ingest pool, lake, or river water. – Use chlorine to kill Giardia in water used for recreational activities.

PROGNOSIS • Untreated giardiasis lasts for weeks. • Most (90%) patients respond to treatment within a few days: – Most nonresponders or relapses respond to a second course with the same or a different agent.

COMPLICATIONS Malabsorption, reactive arthritis, and weight loss, lactose intolerance

ALERT Reportable disease to the CDC

REFERENCES 1. Escobedo AA, Lalle M, Hrastnik NI, et al. Combination therapy in the management of Giardiasis: what laboratory and clinical studies tell us, so far. Acta Trop. 2016;162:196–205. 2. Jahan N, Khatoon R, Ahmad S. A comparison of microscopy and enzyme linked immunosorbent assay for diagnosis of Giardia lamblia in human faecal specimens. J Clin Diagn Res. 2014;8(11):DC04–DC06. 3. Van den Bossche D, Cnops L, Verschueren J, et al. Comparison of four rapid diagnostic tests, ELISA, microscopy and PCR for the detection of Giardia lamblia, Cryptosporidium spp. and Entamoeba histolytica in feces. J Microbiol Methods. 2015;110:78–84. 4. Lima AA, Soares AM, Lima NL, et al. Effects of vitamin A supplementation on intestinal barrier function, growth, total parasitic, and specific Giardia spp infections in Brazilian children: a prospective randomized, double-blind, placebo-controlled trial. J Pediatr Gastroenterol Nutr. 2010;50(3):309–315. 5. Yadav P, Tak V, Mirdha B, et al. Refractory giardiasis: a molecular appraisal from a tertiary care centre in India. Indian J Med Microbiol. 2014;32(4):378– 382.

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ADDITIONAL READING • Cañete R, Rodríguez P, Mesa L, et al. Albendazole versus metronidazole in the treatment of adult giardiasis: a randomized, double-blind, clinical trial. Curr Med Res Opin. 2012;28(1):149–154. • Eissa MM, Amer EI. Giardia lamblia: a new target for miltefosine. Int J Parasitol. 2012;42(5):443–452. • Hahn J, Seeber F, Kolodziej H, et al. High sensitivity of Giardia duodenalis to tetrahydolipstatin (orlistat) in vitro. PLoS One. 2013;8(8):e71597. • Mukku KK, Raju S, Yelanati R. Refractory giardiasis in renal transplantation: a case report. Nephrology (Carlton). 2015;20(1):44. • Tejman-Yarden N, Miyamoto Y, Leitsch D, et al. A reprofiled drug, auranofin, is effective against metronidazole-resistant Giardia lamblia. Antimicrob Agents Chemother. 2013;57(5):2029–2035. • Teles NS, Fechine FV, Viana FA, et al. Evaluation of the therapeutic efficacy of Mentha crispa in the treatment of giardiasis. Contemp Clin Trials. 2011;32(6):809–813.

SEE ALSO Algorithm: Diarrhea, Chronic

CODES ICD10 A07.1 Giardiasis [lambliasis]

CLINICAL PEARLS • Daycare facilities and public swimming pools are common sources of Giardia transmission (don’t assume camping or travel is required). • Commonly presents with abdominal bloating and loose, foul-smelling stool • Metronidazole has high cure rates (but is often poorly tolerated). • Most treatment failures respond to a second course of antibiotics (with same or other drugs).

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• A single FA or ELISA is as sensitive as three stool samples for ova and parasites for detecting Giardia.

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GILBERT DISEASE Robert A. Marlow, MD, MA BASICS DESCRIPTION Mild, chronic, or intermittent unconjugated hyperbilirubinemia (not due to hemolysis) with otherwise normal liver function (1)

Pediatric Considerations Rare for the disorder to be diagnosed before puberty (2)

Pregnancy Considerations The relative fasting that may occur with morning sickness can elevate bilirubin level.

EPIDEMIOLOGY • Predominant age: present from birth but most often presents in the 2nd or 3rd decade of life; heterozygous for single abnormal gene (3) • Predominant sex: male > female (2 to 7:1)

Prevalence Prevalence in the United States: ~7% of the population (4); ~1 in 3 of those affected are not aware that they have the disorder.

ETIOLOGY AND PATHOPHYSIOLOGY The hyperbilirubinemia results from impaired hepatic bilirubin clearance (~30% of normal). Hepatic bilirubin conjugation (glucuronidation) is reduced, although this is likely not the only defect (3).

Genetics A gene defect resulting in reduced bilirubin uridine diphosphate– glucuronosyltransferase-1 appears to be necessary but not sufficient for Gilbert syndrome (5).

RISK FACTORS

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Male gender

COMMONLY ASSOCIATED CONDITIONS Gilbert disease may be part of a spectrum of hereditary disorders that includes types I and II Crigler-Najjar syndrome.

DIAGNOSIS HISTORY No significant symptoms, although a variety of nonspecific symptoms have been described. An episode of nonpruritic jaundice can be triggered by stressors such as fasting, dehydration, infections, physical exertion, lack of sleep, and surgery. Some medications may also trigger episodes of jaundice, such as drugs that inhibit glucuronyl transferase, such as gemfibrozil and the protease inhibitors atazanavir and indinavir. Any symptoms present during an episode of jaundice, including fatigue, are caused by the triggering factor and are not directly a result of the Gilbert disease (6).

PHYSICAL EXAM No abnormal physical findings other than occasional mild jaundice that can be precipitated by the above-mentioned triggers (fasting, dehydration, infections, physical exertion, lack of sleep, and surgery).

DIFFERENTIAL DIAGNOSIS • Hemolysis • Ineffective erythropoiesis (megaloblastic anemias, certain porphyrias, thalassemia major, sideroblastic anemia, severe lead poisoning, congenital dyserythropoietic anemias) • Cirrhosis • Chronic persistent hepatitis • Pancreatitis • Biliary tract disease

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Bilirubin: Elevated but 50 years • Shallow anterior chamber • Female gender • Family history of angle closure • Asian, Chinese, or Inuit descent • Short axial length • Thick crystalline lens • Anterior positioned lens • Plateau iris • Drugs that can induce angle closure: – Adrenergic agonists (albuterol, phenylephrine), anticholinergics (oxybutynin, atropine, botulinum toxin A), antihistamines, antidepressants including selective serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs), sulfa-based drugs, topiramate, cocaine, ecstasy

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GENERAL PREVENTION • Routine eye exam with gonioscopy for high-risk populations • U.S. Preventive Services Task Force: insufficient evidence to recommend for or against screening adults for glaucoma without visual symptoms (3)[A] • Prophylactic laser iridotomy may be considered in patient with PACS for preventing PACG.

COMMONLY ASSOCIATED CONDITIONS • Cataract • Hyperopia • Microphthalmos • Systemic hypertension

DIAGNOSIS HISTORY • Patient may be asymptomatic as in PACS or may have acute symptoms as in AACC. • Acute symptoms include – Severe eye pain – Blurred vision – Eye redness – Halos around lights/objects – Frontal headache – Nausea and vomiting, which may lead to erroneous abdominal exploration • Patients with PACG can have subacute symptoms (intermittent subacute attacks), compromised peripheral vision, or be asymptomatic. • Family history of acute angle-closure glaucoma • Obtain history of prescription, over-the-counter, and herbal medications. • Precipitating factors (dim light, medicines) • Review of symptoms

PHYSICAL EXAM Includes, but is not limited to, the following in the undilated eye • Visual acuity with refractive error (hyperopic eyes especially in older phakic

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patients) • Visual field testing and ocular motility • Pupil size and reactivity (mid-dilated, asymmetric or oval, minimally reactive, and may have relative afferent papillary pupillary defect) • Slit-lamp biomicroscopy–conjunctival hyperemia (in acute cases),central and peripheral anterior chamber depth narrowing, corneal swelling, iris abnormalities (diffuse and focal iris atrophy, posterior synechiae), lens changes (cataract and glaukomflecken-patchy localized anterior subcapsular lens opacities) • Intraocular pressure as measured by applanation tonometry • Gonioscopy: visualization of anatomy of the angle of both eyes and to look for ITC and peripheral anterior synechiae • Anterior segment imaging with ultrasound (US) biomicroscopy and anterior segment optical coherence tomography (AS-OCT) to understand the angle anatomy • Undilated fundus exam (congestion, cupping, atrophy of optic nerve)

DIFFERENTIAL DIAGNOSIS • Acute orbital compartment syndrome • Traumatic hyphema • Conjunctivitis, episcleritis • Corneal abrasion • Glaucoma, malignant, or neovascular • Herpes zoster ophthalmicus • Iritis and uveitis • Orbital/periorbital infection • Vitreous or subconjunctival hemorrhage • Tight necktie, causing increased IOP • Lens-induced angle closure

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) US biomicroscopy AS-OCT (1)[C]

Diagnostic Procedures/Other

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Careful ophthalmic examination including possible evaluation of fundus and optic nerve head, slit lamp biomicroscopy, gonioscopy, and tonometry (1)[C]

Test Interpretation • Narrow or closed anterior angle • Corneal stromal and epithelial edema • Endothelial cell loss (guttata) • Iris stromal necrosis • Anterior subcapsular cataract (glaukomflecken) • Optic disc congestion, cupping, excavation • Optic nerve atrophy

TREATMENT GENERAL MEASURES • Goals of treatment (1)[C]: – Reverse or prevent angle-closure process. – Control IOP. – Prevent damage to the optic nerve. • PACS – Majority will not develop PAC or PACG. – They may be either observed for development of PAC or be treated with iridotomy (1)[C]. • PAC and PACG – Iridotomy performed using thermal or neodymium-doped yttrium aluminium garnet (Nd:YAG) laser (1)[A] – Complications of iridotomy: increased IOP, laser burn to the cornea, lens, or retina; late-onset corneal edema; development of posterior synechiae; hyphema; iritis; and ocular dysphotopsia • AACC – Initial treatment of AACC is to lower the IOP with medications to relieve the acute symptoms followed by iridotomy as soon as possible (1)[A]. For acute attack: ocular emergency Manage nausea and pain.

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Immediate ophthalmology consultation

MEDICATION • During acute attack, medical therapy lowers IOP to relieve symptoms and clear corneal edema so that iridotomy can be performed as soon as possible. • Medical therapy aims at – Reduction of aqueous production and reduction of inflammation with Carbonic anhydrase inhibitors (CAI): acetazolamide 10 mg/kg IV or orally. May repeat 250 mg in 4 hours to a maximum of 1 g/day. CAI are contraindicated in sulfa allergy and hepatic insufficiency. Topical carbonic anhydrase inhibitors are not potent enough to break the papillary block. Topical β-blockers: timolol 0.5%, levobunolol 0.5%, betaxolol 0.5%, or carteolol 1% Topical α2-agonists: brimonidine 0.2% or apraclonidine 0.5% – Withdrawing aqueous from vitreous body and posterior chamber using hyperosmotic agents Glycerol 1.0 to 1.5 g/kg orally Mannitol 1.0 to 1.5g/kg IV Hyperosmotic agent should be used with caution in patient with heart and kidney disease. Glycerol can increase blood sugar level and should not be given to diabetic patients. – Pupillary constriction to open the chamber angle: topical pilocarpine 1% or 2% or aceclidine 2%. Miotic therapy is ineffective when IOP is markedly elevated due to sphincter ischemia .They may cause forward rotation of ciliary muscle, increasing the papillary block and worsening the IOP. • During acute attack, acetazolamide 500 mg IV is given followed by 500 mg PO. Topical therapy is initiated with 0.5% timolol maleate and 1% apraclonidine drops 1 minute apart. Reduction of inflammation is accomplished with topical steroids 1 to 2 doses. In addition, systemic therapy with mannitol 20% 1.5 to 2 g/kg infused over 30 to 60 minutes or oral glycerol (Osmoglyn) (50%) 6 oz PO may be needed. Also treat pain and nausea with analgesic and antiemetics. About an hour after initiating treatment, two doses of pilocarpine drops administered 15 minutes apart to

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cause miosis in an attempt to open the angle (2)[C]. • After corneal edema clears, a peripheral iridotomy is done.

ADDITIONAL THERAPIES Keep patient supine.

SURGERY/OTHER PROCEDURES • Definitive therapy for PAC, PACG, and AACC is Nd:YAG laser iridotomy (1,2)[B]. • Surgical iridectomy may be performed if cornea is cloudy and laser iridotomy cannot be performed. • Corneal indentation with four-mirror gonioscopic lens, cotton-tipped applicator, or muscle hook may be used to break a pupillary block in AACC (1)[C]. • Effectiveness of phacoemulsification with IOL implantation in PACG is unclear (1), (2)[B]. Other procedures to reduce IOP that have been studied include argon laser peripheral iridoplasty (especially for plateau iris configuration/syndrome), anterior chamber paracentesis, goniosynechialysis, and trabeculectomy.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Patient requires metabolic ± electrolyte and volume status monitoring (with osmotic agents). • Facilitate close ophthalmology monitoring.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Schedule an immediate ophthalmologic follow-up.

Patient Monitoring • Postsurgical follow-up and routine monitoring after acute attack as per ophthalmologist • Half of the fellow eye of patients with AACC will develop AACC within 5

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years. Hence, prophylactic LPI should be performed in the fellow eye as soon as possible (1)[B].

PATIENT EDUCATION • Advise patient to seek emergency medical attention if experiencing a change in visual acuity, blurred vision, eye pain, or headache. • Patients with PACS and no iridotomy, avoid use of decongestants, motion sickness medications, adrenergic agents, antipsychotics, antidepressants, and anticholinergic agents. • Correct eyedrop administration technique, including the following: – Remove contact lenses before administration and wait 15 minutes before reinserting. – Allow at least 5 minutes between administration of multiple ophthalmic products. • Patient education materials: – Glaucoma Research Foundation: http://www.glaucoma.org – National Eye Institute: http://www.nei.nih.gov

PROGNOSIS • With timely treatment, most patients do not have permanent vision loss. • Prognosis depends on ethnicity, underlying eye disease, and time to treatment.

COMPLICATIONS • Chronic corneal edema, corneal fibrosis, and vascularization • Iris atrophy • Cataract • Optic atrophy • Malignant glaucoma • Central retinal artery/vein occlusion • Permanent decrease in visual acuity • Repeat episode • Fellow (contralateral) eye attack

REFERENCES 1. American Academy of Ophthalmology. Primary Angle Closure Preferred

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Practice Pattern. San Francisco, CA: American Academy of Ophthalmology; 2015. http://www.aao.org. Accessed October 27, 2016. 2. European Glaucoma Society. Terminology and guidelines for glaucoma. 4th ed. Savona, Italy: Dogma; 2014. http://www.eugs.org/eng/EGS_guidelines4.asp. Accessed October 27, 2016. 3. Moyer VA. Screening for glaucoma: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2013;159(7):484–489.

ADDITIONAL READING • Gupta D, Chen PP. Glaucoma. Am Fam Physician. 2016;93(8):668–674. • Kolko M. Present and new treatment strategies in the management of glaucoma. Open Ophthalmol J. 2015;9:89–100.

SEE ALSO Glaucoma, Primary Open-Angle

CODES ICD10 • H40.20X0 Unsp primary angle-closure glaucoma, stage unspecified • H40.219 Acute angle-closure glaucoma, unspecified eye • H40.2290 Chronic angle-closure glaucoma, unsp eye, stage unspecified

CLINICAL PEARLS • Examiner can determine if patient is hyperopic by observing the magnification of the patient’s face through his or her glasses (myopic lenses minify). • A careful history may reveal similar episodes of angle closure that resolved spontaneously. Miotics, such as pilocarpine, can be effective during mild attacks but ineffective in the setting of high IOP (due to pressure-induced iris sphincter ischemia). • In patient with AACC, the fellow eye should undergo prophylactic laser iridotomy.

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GLAUCOMA, PRIMARY OPEN-ANGLE Richard W. Allinson, MD BASICS DESCRIPTION • Primary open-angle glaucoma (POAG) is an optic neuropathy resulting in visual field loss frequently associated with increased intraocular pressure (IOP). • Normal IOP is 10 to 22 mm Hg. However, glaucomatous optic nerve damage also can occur with normal IOP and as a secondary manifestation of other disorders such as corticosteroid-induced glaucoma. • System(s) affected: nervous • Synonym(s): chronic open-angle glaucoma

Pregnancy Considerations Prostaglandins should be avoided during pregnancy in the treatment of POAG.

EPIDEMIOLOGY Incidence • Predominant age: usually >40 years • Increases with age • Predominant gender: male = female

Prevalence Prevalence in persons >40 years of age is ~1.8%.

Geriatric Considerations Increasing prevalence with increasing age

ETIOLOGY AND PATHOPHYSIOLOGY • Abnormal aqueous outflow resulting in increased IOP • Normally, aqueous is produced by the ciliary epithelium of the ciliary body and is secreted into the posterior chamber of the eye. • Aqueous then flows through the pupil and enters the anterior chamber to be

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drained by the trabecular meshwork (TM) in the iridocorneal angle of the eye into Schlemm canal and into the venous system of the episclera. • 5–10% of the total aqueous outflow leaves via the uveoscleral pathway. • Impaired aqueous outflow through the TM – Increased resistance within the aqueous drainage system

Genetics A family history of glaucoma increases the risk for developing glaucoma.

RISK FACTORS • Increased IOP • Myopia • Diabetes mellitus (DM) • African American • Elderly • Hypothyroidism • Positive family history • Central corneal thickness 0.5: Normal eyes show a characteristic configuration for disc rim thickness of inferior ≥ superior ≥ nasal ≥ temporal (ISNT rule). • Earliest visual field defects are paracentral scotomas and peripheral nasal steps.

DIFFERENTIAL DIAGNOSIS • Normal-tension glaucoma • Optic nerve pits • Anterior ischemic optic neuropathy • Compressive lesions of the optic nerve or chiasm • Posthemorrhagic (shock optic neuropathy)

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) Optical coherence tomography (OCT) can be useful in the detection of glaucoma by measuring the thickness of the retinal nerve fiber layer (RNFL).

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• RNFL is thinner in patients with glaucoma. • RNFL tends to be thinner with older age, in Caucasians, greater axial length, and smaller optic disc area.

Diagnostic Procedures/Other • Visual field testing: perimetry – A multifocal intraocular lens may reduce visual sensitivity on standard automated perimetry. • Tonometry to measure IOP

Test Interpretation • Atrophy and cupping of optic nerve • Loss of retinal ganglion cells (RGCs) and their axons produces defects and thinning in the RNFL. • Significant RGC loss may occur at specific location before corresponding visual field loss is detected. • Assessment of RNFL thickness with OCT can detect glaucomatous damage before the appearance of visual field defects on standard automated perimetry (2)[B].

TREATMENT GENERAL MEASURES • Early Manifest Glaucoma Trial – Early treatment delays progression. – The magnitude of initial IOP reduction influences disease progression (3) [A]. • Ocular Hypertension Treatment Study – Patients who only had increased IOP in the range of 24 to 32 mm Hg were treated with topical ocular hypotensive medication. – Treatment produced ~20% reduction in IOP. – At 5 years, treatment reduced the incidence of POAG by >50%: 9.5% in the observation group versus 4.4% in the medication-treated group (4)[A]. • The Advanced Glaucoma Intervention Study

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– Eyes were randomized to laser trabeculoplasty or filtering surgery when medical therapy failed. – In follow-up, if IOP was always 17 mm Hg, more than 1/2 the time, patients tended to have worsening of visual fields (5)[A]. – Whites did better with trabeculectomy (ALT) first, whereas African Americans did better with argon laser trabeculoplasty as the initial procedure. • Collaborative Initial Glaucoma Treatment Study – Both initial medical and surgical (trabeculectomy) treatment achieved significant IOP reduction, and both had little visual field loss over time (6) [A]. – There was a 5-year risk of endophthalmitis of 1.1% after trabeculectomy.

MEDICATION • >1 medication, with different mechanisms of action, may be needed. • When ≥3 medications are required, compliance is difficult, and surgery may be needed; ocular hypotensive agent categories – Prostaglandin analogues: generally used as first-line treatment. Enhance uveoscleral outflow and increase aqueous outflow through the TM: latanoprost 0.005% one drop at bedtime; travoprost 0.004% one drop at bedtime; bimatoprost 0.01% one drop at bedtime – β-Adrenergic antagonists (nonselective and selective): decrease aqueous formation; best when used as an add-on therapy: timolol 0.25% (initial) to 0.5% one drop in affected eye q12h; gel-forming solution (0.35% or 0.5%) one drop in affected eye once daily; betaxolol 0.5% one drop affected eye twice daily – Parasympathomimetics (miotic), including cholinergic (direct-acting) and anticholinesterase agents (indirect-acting parasympathomimetic): increase aqueous outflow Pilocarpine 1–4%: one drop in affected eye BID to QID (cholinergic) – Carbonic anhydrase inhibitors (oral, topical): decrease aqueous formation Acetazolamide: 250 mg PO 1 to 4 times per day Dorzolamide 2%: one drop TID

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Brinzolamide 1%: one drop TID – Adrenergic agonists (nonselective and selective α2-adrenergic agonists) Epinephrine 0.5–2%: One drop BID and Propine (dipivefrin) 0.1% one drop BID are both nonselective agents that increase aqueous outflow through the TM and increase uveoscleral outflow. Brimonidine tartrate 0.1%: One drop TID (α2-adrenergic agonist) decreases aqueous formation and increases uveoscleral outflow. – Hyperosmotic agents: increase blood osmolality, drawing water from the vitreous cavity Mannitol 20% solution: administered IV at 2 g/kg of body weight Glycerin 50% solution: administered PO; dosage is usually 4 to 7 oz. • Contraindications/precautions – Prostaglandin analogues may cause increased pigmentation of the iris and periorbital tissue. Increased pigmentation and growth of eyelashes Should be used with caution in active intraocular inflammation (iritis/uveitis) Caution is also advised in eyes with risk factors for herpes simplex, iritis, and cystoid macular edema. Macular edema may be a complication associated with treatment. Prostaglandin analogues: Caution with uveitis and avoid during pregnancy. – Nonselective β-adrenergic antagonists: Avoid in asthma, chronic obstructive pulmonary disease (COPD), 2nd- and 3rd-degree atrioventricular (A-V) block, and decompensated heart failure. Betaxolol is a selective βadrenergic antagonist and is safer in pulmonary disease. – Significant possible interactions: β-adrenergic antagonists: caution in patients taking calcium antagonists because of possible A-V conduction disturbances, left ventricular failure, or hypotension – Carbonic anhydrase inhibitors Do not use with sulfa drug allergies. Do not use with cirrhosis because of the risk of hepatic encephalopathy. – Adrenergic agonists: Caution is recommended when using brimonidine and monoamine oxidase (MAO) inhibitor or tricyclic antidepressant (TCA) and

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in patients with vascular insufficiency. Brimonidine can cause excessive sleepiness and lethargy in children. Parasympathomimetics (miotic): cause pupillary constriction and may cause decreased vision in patients with a cataract; may cause eye pain or myopia due to increased accommodation. All miotics break down the blood–aqueous barrier and may induce chronic iridocyclitis. Parasympathomimetics (miotic): Indirect-acting parasympathomimetic agents increase risk of ocular and systemic side effects and are used rarely. Parasympathomimetics (miotic): Indirect-acting parasympathomimetic agents, anticholinesterase eye drops, can reduce serum pseudocholinesterase levels. If succinylcholine is used for induction of general anesthesia, prolonged apnea may result. – Hyperosmotic agents Glycerin can produce hyperglycemia or ketoacidosis in diabetic patients. Can cause congestive heart failure Do not use in patients with anuria. Hyperosmotic agents: caution in diabetics; dehydrated patients; and those with cardiac, renal, and hepatic disease – Contact lenses wearers: Many products contain benzalkonium chloride; remove contact lenses prior to administration and wait 15 minutes before reinsertion.

SURGERY/OTHER PROCEDURES • ALT – Can be applied up to 180 degrees of the TM – Improves aqueous outflow – The Glaucoma Laser Trial Research Group showed in newly diagnosed, previously untreated patients with POAG that ALT was as effective as topical glaucoma medication within the first 2 years of follow-up. – Usually reserved for patients needing better IOP control while taking topical glaucoma drops • Selective laser trabeculoplasty (SLT) – 532-nm Nd:YAG laser – Appears to be as effective as ALT in lowering IOP

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• Trabeculectomy (glaucoma filtering surgery) – Usually reserved for patients needing better IOP control after maximal medical therapy and who may have previously undergone an ALT – Mitomycin C can be applied at the time of surgery to increase the chances of a surgical success. – Subconjunctival bevacizumab may be a beneficial adjunctive therapy for reducing late surgical failure after trabeculectomy. • Shunt (tube) surgery – For example, Molteno and Ahmed devices – Generally reserved for difficult glaucoma cases in which conventional filtering surgery has failed or is likely to fail • Tube Versus Trabeculectomy (TVT) Study – After 5 years of follow-up, both procedures were associated with similar IOP reduction and the number of glaucoma medications needed. • Ciliary body ablation: indicated to lower IOP in patients with poor visual potential or those who are poor candidates for filtering or shunt procedures. • Minimally invasive glaucoma surgery (MIGS) is frequently combined with cataract surgery. Currently targeted at patients with mild-to-moderate glaucoma (7)[C] – Schlemm canal stents iStent, Hydrus – Suprachoroidal stents CyPass, iStent supra – Subconjunctival stents Xen, Innfocus – The Trabectome system performs a trabeculotomy via an internal approach, removing both a strip of TM and the inner wall of Schlemm canal. • Cataract extraction can decrease IOP in patients with ocular hypertension.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Monitor vision and IOP every 3 to 6 months.

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• Visual field testing every 6 to 18 months • Optic nerve evaluation every 3 to 18 months, depending on POAG control • A worsening of the mean deviation by 2 dB on the Humphrey field analyzer and confirmed by a single test after 6 months had a 72% probability of progression. • The IOP response to ocular hypotensive agents tends to be reduced in persons with thicker corneas.

PATIENT EDUCATION POAG is a silent robber of vision, and patients may not appreciate the significance of their disease until much of their visual field is lost.

PROGNOSIS • With standard glaucoma therapy, the rate of visual field loss in POAG is slow. • Patients still may lose vision and develop blindness, even when treated appropriately. • The rate of legal blindness from POAG over a follow-up of 22 years is 19%. • The rate of progression of visual field loss increases with older age.

COMPLICATIONS Blindness

REFERENCES 1. Kang JH, Willett WC, Rosner BA, et al. Association of dietary nitrate intake with primary open-angle glaucoma: a prospective analysis from the Nurses’ Health Study and Health Professionals Follow-up Study. JAMA Ophthalmol. 2016;134(3):294–303. 2. Kuang TM, Zhang C, Zangwill LM, et al. Estimating lead time gained by optical coherence tomography in detecting glaucoma before development of visual field defects. Ophthalmology. 2015;122(10):2002–2009. 3. Heijl A, Leske MC, Bengtsson B, et al. Reduction of intraocular pressure and glaucoma progression: results from the Early Manifest Glaucoma Trial. Arch Ophthalmol. 2002;120(10):1268–1279. 4. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular

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hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120(6):701–713. 5. The Advanced Glaucoma Intervention Study (AGIS): 7. The relationship between control of intraocular pressure and visual field deterioration. Am J Ophthalmol. 2000;130(4):429–440. 6. Lichter PR, Musch DC, Gillespie BW, et al. Interim clinical outcomes in the Collaborative Initial Glaucoma Treatment Study comparing initial treatment randomized to medications or surgery. Ophthalmology. 2001;108(11):1943– 1953. 7. Richter GM, Coleman AL. Minimally invasive glaucoma surgery: current status and future prospects. Clin Ophthalmol. 2016;10:189–206.

CODES ICD10 • H40.11X0 Primary open-angle glaucoma, stage unspecified • H40.11X1 Primary open-angle glaucoma, mild stage • H40.11X2 Primary open-angle glaucoma, moderate stage

CLINICAL PEARLS • Topical or systemic steroids can cause the IOP to increase. • Pain is not a frequent symptom of POAG. • Painless, slowly progressive visual loss; patients generally are unaware of the visual loss until late in the disease. Central visual acuity remains unaffected until late in the disease. • Patients still may lose vision and develop blindness, even when treated appropriately.

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GLOMERULONEPHRITIS, ACUTE Jonathan T. Lin, MD • Michael J. Ross, MD BASICS DESCRIPTION • Acute glomerulonephritis (GN) is an inflammatory process involving the glomerulus of the kidney, resulting in a clinical syndrome consisting of hematuria, proteinuria, and renal insufficiency, often in association with hypertension and edema. • Acute GN may be caused by primary glomerular disease or secondary to systemic disease. – Infection-related GN (also called postinfectious GN) – IgA nephropathy/Henoch-Schönlein purpura (HSP) – Antiglomerular basement membrane disease (anti-GBM disease) – Antineutrophil cytoplasmic antibody (ANCA)–associated GN – Membranoproliferative GN (MPGN) – Lupus nephritis – Cryoglobulin-associated GN • Clinical severity ranges from asymptomatic microscopic or gross hematuria to a rapid loss of kidney function over days to weeks, termed rapidly progressive GN (RPGN). Kidney biopsy often demonstrates crescentic GN in patients with RPGN, and these findings usually require urgent and aggressive treatment.

ALERT Urgent investigation and treatment are required to avoid irreversible loss of kidney function.

EPIDEMIOLOGY • Infection-related GN – Most commonly follows group A β-hemolytic Streptococcus infection (poststreptococcal) but can occur as a result of other bacterial infections, such as infective endocarditis, or less commonly in the setting of viral or

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parasitic infections – Accounts for 80% of acute GN in children • IgA nephropathy – Most common primary GN in the world – Occurs mainly in the 2nd and 3rd decades – Male > female (2:1) – Incidence differs geographically: Asia > United States – HSP, the form with extrarenal manifestations, typically occurs in children female (2:1) (1)

ETIOLOGY AND PATHOPHYSIOLOGY • Glomerular immune complex disease induced by specific nephritogenic strains of bacteria: – Group A β-hemolytic Streptococcus (GAS)

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– Staphylococcus (predominantly Staphylococcus aureus; more commonly methicillin-resistant S. aureus [MRSA], occasionally coagulase-negative Staphylococcus) – Gram-negative bacteria including Escherichia coli, Yersinia, Pseudomonas, and Haemophilus (1) • Proposed mechanisms for the glomerular injury (2): – Deposition of circulating immune complexes with streptococcal or staphylococcal antigens—these complexes can be detected in patients with streptococcal- or staphylococcal-related GN but do not correlate to disease activity (3). – In situ immune complex formation from deposition of antigens within the glomerular basement membrane (GBM) and subsequent antibody binding – In situ glomerular immune complex formation promoted by antibodies to streptococcal or staphylococcal antigens – Alteration of normal renal antigen leading to molecular mimicry that elicits an autoimmune response • Glomerular immune complex causing complement activation and inflammation: – Nephritis-associated plasmin receptor (NAPlr): activates plasmin, contributes to activation of the alternative complement pathway – Streptococcal pyrogenic exotoxin B (SPE B): binds plasmin and acts as a protease; promotes the release of inflammatory mediators • Activation of the alternative complement pathway causes initial glomerular injury as evidenced by C3 deposition and decreased levels of serum C3. The lectin pathway of complement activation has also been recently implicated in glomerular injury (4).

RISK FACTORS • Children 5 to 12 years of age • Older patients (>65 years of age) (1): – Patients with immunocompromising comorbid conditions – Diabetes – Alcohol abuse

GENERAL PREVENTION

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• Early antibiotic treatment for streptococcal and staphylococcal infections, when indicated, although efficacy in preventing GN is uncertain • Improved hygiene • Prophylactic penicillin treatment to be used in closed communities and household contacts of index cases in areas where PIGN is prevalent

COMMONLY ASSOCIATED CONDITIONS Streptococcal infection, staphylococcal infection

DIAGNOSIS HISTORY • Patients present with acute nephritic syndrome, characterized by sudden onset of hematuria associated with edema and HTN 1 to 2 weeks after an infection • A triad of edema, hematuria, and HTN is classic. • Urine described as “tea-colored” or “cola-colored.” • PIGN in children usually follows GAS skin/throat infection. • The latent period between GAS infection and PIGN depends on the site of infection: 1 to 3 weeks following GAS pharyngitis and 3 to 6 weeks following GAS skin infection. • Adult PIGN most commonly follows staphylococcal infections (3 times more common than streptococcal infections) of the upper respiratory tract, skin, heart, lung, bone, or urinary tract. Studies show 7–16% of cases of adult PIGN have no preceding evidence of infection and, in 24–59% the offending microorganism cannot be identified (5)[A].

PHYSICAL EXAM • Edema: present in ~2 of 3 adult patients due to sodium and water retention; less common in pediatric patients • Gross hematuria: present in 25–60% of patients • HTN: present in 80–90% of patients and varies from mild to severe; secondary to fluid retention Hypertensive encephalopathy is an uncommon but serious complication • Microscopic hematuria: subclinical cases of PIGN • Respiratory distress: due to pulmonary edema (rare)

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DIFFERENTIAL DIAGNOSIS The diagnosis of PIGN is generally by history once the diagnosis of acute nephritis is made, with documentation of a recent infection and nephritis beginning to resolve 1 to 2 weeks after presentation. However, with progressive disease >2 weeks, persistent hematuria/HTN >4 to 6 weeks, or no adequate documentation of a GAS or other infection, the differential diagnosis of GN needs to be considered and renal biopsy ordered: • Membranoproliferative glomerulonephritis (MPGN): The presentation of MPGN may be indistinguishable initially with hematuria, HTN, proteinuria, and hypocomplementemia after an upper respiratory infection. However, patients with MPGN continue to have persistent nephritis and hypocomplementemia beyond 4 to 6 weeks and possibly also have a further elevation in serum creatinine. Patients with PIGN tend to have resolution of their disease and a return of normal C3 and CH50 levels within 2 to 4 weeks. • Secondary causes of GN: Lupus nephritis and Henoch-Schönlein purpura nephritis have features similar to PIGN. Extrarenal manifestations and laboratory tests for these underlying systemic diseases help differentiate them from PIGN. Hypocomplementemia is not characteristic of Henoch-Schönlein purpura and the hypocomplementemia that occurs in lupus nephritis is with reductions in both C3 and C4, whereas C4 levels are normal in PIGN. • IgA nephropathy often presents after an upper respiratory infection. It can be distinguished from PIGN based on a shorter time frame between the upper respiratory illness and hematuria, as well as history of gross hematuria, as PIGN recurrence is rare. IgA nephropathy is a chronic illness and will recur. Patients with IgA nephropathy have normal C3/C4 levels. – Note: IgA-dominant PIGN is a newly recognized form of PIGN occurring in poststaphylococcal GN. This differs from primary IgA nephropathy in that these patients do not have a history of renal disease (1)[A]. • Pauci-immune crescentic GN: In elderly patients with severe renal failure and active urine sediment, this is much more common, so antineutrophil cytoplasmic antibody (ANCA) testing should be done (1)[A].

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (labs, imaging)

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Urinalysis shows hematuria; can be with/without RBC casts and pyuria. Proteinuria is present, but nephrotic range proteinuria is uncommon in children (more likely in adults).

Follow-Up Tests & Special Considerations • Culture: PSGN usually presents weeks after a GAS infection; only ~25% of patients will have either a positive throat or skin culture. • Complement: 90% of pediatric patients (slightly fewer adult patients) will have depressed C3 and CH50 levels in the first 2 weeks of the disease, whereas C2 and C4 levels remain normal. C3 and CH50 levels return to normal within 4 to 8 weeks after presentation. • Creatinine: elevated to the point of renal insufficiency in 25–83% of cases, more commonly in adults (83%) (4)[A]. • Serology: Elevated titers of antibodies support evidence of a recent GAS infection. Streptozyme test measuring antistreptolysin O (ASO), antihyaluronidase (AHase), antistreptokinase (ASKase), anti–nicotinamideadenine dinucleotidase (anti-NAD), and anti-DNAse B antibodies: positive in >95% of patients with PSGN due to pharyngitis and 80% with skin infections. In pharyngeal infection, ASO, anti-DNAse B, anti-NAD, and AHase titers are elevated. In skin infections, only the anti-DNAse and AHase titers are typically elevated.

Diagnostic Procedures/Other Renal biopsy is rarely done in children; recommended in most adults to confirm the diagnosis and rule out other glomerulopathies with similar clinical presentations that require immunosuppressive treatment.

Test Interpretation • Light microscopy: diffuse proliferative glomerulonephritis with prominent endocapillary proliferation and numerous neutrophils within the capillary lumen. Deposits may also be found in the mesangium (“starry sky”). Severity of involvement varies and correlates with clinical findings. Crescent formation is uncommon and is associated with a poor prognosis. • Immunofluorescence microscopy: Deposits of C3 and IgG distributed in a diffuse granular pattern.

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• Electron microscopy: dome-shaped subepithelial electron-dense deposits that are referred to as “humps.” These deposits are immune complexes, and they correspond to the deposits of IgG and C3 found on immunofluorescence. Rate of clearance of these deposits affects recovery time. • Renal biopsy: usually not performed in most patients to confirm the diagnosis of PIGN as clinical history is highly suggestive and resolution of PIGN typically begins within 1 week of presentation. A biopsy is done when other glomerular disorders are being considered, such as in the case of persistently low C3 levels beyond 6 weeks for possible diagnosis of MPGN, recurrent episodes of hematuria suggestive of IgA nephropathy, or a progressive increase in serum creatinine not characteristic of PIGN.

TREATMENT MEDICATION • No specific therapy exists for PIGN, and no randomized controlled trials indicate that aggressive immunosuppressive therapy has a beneficial effect in patients with rapidly progressive crescentic disease. Despite this, patients with >30% crescents on renal biopsy are often treated with steroids (4)[A]. • Older patients often require hospitalization to prevent and treat complications of heart failure (HF) from volume overload (1). • Management is supportive, with focus on treating the clinical manifestations of PIGN. These include HTN and pulmonary edema: – General measures include salt and water restriction and loop diuretics. – Calcium channel blockers/angiotensin-converting enzyme (ACE) inhibitors may be used in cases of severe HTN (4)[A]. • Patients with evidence of persistent bacterial infection should be given a course of antibiotic therapy.

SURGERY/OTHER PROCEDURES Acute dialysis is required in approximately 50% of elderly patients (1).

ONGOING CARE

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FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Repeat urinalysis to check for clearance of hematuria and/or proteinuria. • Consider other diagnosis if no improvement within 2 weeks. • Recurrence is rare.

DIET Renal diet if requiring instances of dialysis

PROGNOSIS • Most children with PIGN have an excellent outcome, with >90% of cases achieving full recovery of renal function. • Elderly patients, especially adults, develop HTN, recurrent proteinuria, and renal insufficiency long after the initial illness. Adults with multiple comorbid factors have the worst prognosis and highest incidence of chronic renal injury following PIGN (1). • Complete remission in adult PIGN is only 26–56%. This has declined since the 1990s, suggesting prognosis is worsening (5). • The presence of diabetes, higher creatinine levels, and more severe glomerular disease (e.g., crescents) on biopsy are all risk factors for developing end-stage renal disease (1).

REFERENCES 1. Nasr SH, Radhakrishnan J, D’Agati VD. Bacterial infection-related glomerulonephritis in adults. Kidney Int. 2013;83(5):792–803. 2. Nadasdy T, Hebert LA. Infection-related glomerulonephritis: understanding mechanisms. Semin Nephrol. 2011;31(4):369–375. 3. Uchida T, Oda T, Watanabe A, et al. Clinical and histologic resolution of poststreptococcal glomerulonephritis with large subendothelial deposits and kidney failure. Am J Kidney Dis. 2011;58(1):113–117. 4. Ramdani B, Zamd M, Hachim K, et al. Acute postinfectious glomerulonephritis. Nephrol Ther. 2012;8(4):247–258. 5. Wen YK. Clinicopathological study of infection-associated glomerulonephritis in adults. Int Urol Nephrol. 2010;42(2):477–485.

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ADDITIONAL READING • Eison TM, Ault BH, Jones DP, et al. Post-streptococcal acute glomerulonephritis in children: clinical features and pathogenesis. Pediatr Nephrol. 2011;26(2):165–180. • Nasr SH, Fidler ME, Valeri AM, et al. Postinfectious glomerulonephritis in the elderly. J Am Soc Nephrol. 2011;22(1):187–195. • Nast CC. Infection-related glomerulonephritis: changing demographics and outcomes. Adv Chronic Kidney Dis. 2012;19(2):68–75. • Rodriguez-Iturbe B, Musser JM. The current state of poststreptococcal glomerulonephritis. J Am Soc Nephrol. 2008;19(10):1855–1864. • Singh GR. Glomerulonephritis and managing the risks of chronic renal disease. Pediatr Clin North Am. 2009;56(6):1363–1382.

CODES ICD10 • N05.9 Unsp nephritic syndrome with unspecified morphologic changes • N00.9 Acute nephritic syndrome with unsp morphologic changes

CLINICAL PEARLS • PIGN is an immune complex disease occurring after infection with certain strains of bacteria, most commonly group A Streptococcus pyogenes. • The clinical presentation varies from asymptomatic to the acute nephritic syndrome, characterized by gross hematuria, proteinuria, edema, HTN, and acute kidney injury. • Treatment is primarily supportive and includes treating HTN and edema, along with antibiotics for any ongoing bacterial infection. • Persistent nephritis and low C3 levels for >2 weeks should prompt evaluation for other causes of GN, such as MPGN or systemic lupus erythematosus nephritis.

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GLUCOSE INTOLERANCE Carl A. Cassel, DO, FAAFP • Amy M. Davis, MD BASICS DESCRIPTION • Glucose intolerance is a chronic condition defined as blood glucose higher than considered normal, yet does not meet criteria levels for diabetes. • Individuals with impaired fasting glucose (IFG) and/or impaired glucose intolerance (IGT) have been referred to as having prediabetes: – IFG: 100 to 125 mg/dL – IGT: 140 to 199 mg/dL 2 hours after ingestion of 75 g oral glucose load – Hemoglobin A1c 5.7–6.4% (1)

EPIDEMIOLOGY • As of 2010, it is estimated that one of every three U.S. adults ≥20 years of age have prediabetes (2). • An estimated 86 million people in the United States are living with prediabetes. • Only 11% of people with prediabetes are aware of their condition (3). • Prediabetes has a 37% prevalence among adults >20 years old and 51% of adults ≥65 years in the United States (4).

Incidence • Systematic review indicates a 5-year cumulative incidence of developing diabetes of 9–25% for people with an A1c of 5.5–6.0% and 25–50% with an A1c of 6.0–6.5% (1). • Highest incidence in American Indians/Alaska Natives, non-Hispanic blacks, and Hispanics (2)

ETIOLOGY AND PATHOPHYSIOLOGY Progressive loss of insulin secretion on the background of insulin resistance (1)

RISK FACTORS • Body mass index (BMI) ≥25: overweight

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• Obesity and metabolic syndrome • History of gestational diabetes (GDM) • Sedentary lifestyle • Medications (see “Differential Diagnosis”)

GENERAL PREVENTION • Lifestyle modification with weight reduction and increased physical activity • A decrease in excess body fat provides the greatest risk reduction.

Pregnancy Considerations • Screening for diabetes in pregnancy is based on risk factor analysis: – High risk: first prenatal visit – Average risk: 24 to 28 weeks’ gestation • Women with GDM should be screened for diabetes 6 to 12 weeks’ postpartum with 75g OGTT, then every 1 to 3 years via any method (5).

COMMONLY ASSOCIATED CONDITIONS • Obesity (abdominal and visceral obesity) • Dyslipidemia with high triglycerides (TG) • Metabolic syndrome • PCOS • GDM • Low HDL • HTN • Congenital diseases (Down, Turner, Klinefelter, and Wolfram syndromes)

DIAGNOSIS Who to screen • BMI ≥25 • Age >45 years • First-degree relative with diabetes • High TG >250 mg/dL • HTN: BP >140/90 mm Hg or on treatment • Hx of GDM

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• Physical inactivity • Hx of cardiovascular disease • Ethnic group at increased risk (non-Hispanic black, Native American, Hispanics, Asian American, Pacific Islander) • HgbA1c ≥5.7%, IGT, or IFG on previous testing • PCOS • Conditions associated with insulin resistance such as severe obesity or acanthosis nigricans

HISTORY • No clear symptoms • Polyuria • Polydipsia • Weight loss • Blurred vision • Polyphagia

PHYSICAL EXAM • General physical exam • BMI assessment

DIFFERENTIAL DIAGNOSIS • Type A insulin resistance • Leprechaunism • Rabson-Mendenhall syndrome • Lipoatrophic diabetes • Pancreatitis • Cystic fibrosis • Hemochromatosis • Acromegaly • Cushing syndrome • Glucagonoma • Pheochromocytoma • Hyperthyroidism • Somatostatinoma

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• Aldosteronoma • Drug-induced hyperglycemia – Thiazide diuretics (high doses) – β-blockers – Corticosteroids (including inhaled corticosteroids) – Thyroid hormone – α-Interferon – Pentamidine – Protease inhibitors – Atypical antipsychotics – Selective serotonin reuptake inhibitors

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Fasting glucose • 2-Hour OGTT • HbA1c • Repeat screen at 3-year intervals with normal results, sooner depending on risk status, and yearly in patients with prediabetes (1). Follow-Up Tests & Special Considerations • Fasting lipid profile • Creatinine and GFR • Urinalysis • Microalbumin-to-creatinine ratio • Thyroid-stimulating hormone with free T4

TREATMENT • Therapeutic lifestyle modification to include physical activity focused on weight loss and medical nutrition therapy (preferably via a registered dietitian). • Lifestyle intervention reduced 3-year diabetes incidence by 58% compared to 31% with metformin alone (6). • Mediterranean diet and diets high in fiber-rich foods such as vegetables, fruits,

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whole grains, seeds, and nuts plus white meat sources are protective against type 2 diabetes (7). • Patients with prediabetes should be referred to an intensive diet and physical activity behavioral counseling program adhering to the tenets of the Diabetes Prevention Program targeting a loss of 7% of body weight and should increase their moderate-intensity physical activity (such as brisk walking to at least 150 min/week) (7)[A]. • Resistance training and endurance exercise both reduce diabetes risk • Follow-up counseling (7)[B] • Diabetes prevention programs are cost-effective and should be covered by third-party payers (7)[B]. • Screening and treating for modifiable risk factors for cardiovascular disease is suggested (7)[B]. • Diabetes self-management education and support systems are appropriate venues for people with prediabetes to receive education and support to develop and maintain behaviors that can prevent or delay the onset of diabetes (7)[B]. • Technology-assisted tools including internet-based social networks, distance learning, DVD-based content, and mobile applications can be useful elements of effective lifestyle modification to prevent diabetes (7)[B].

MEDICATION Metformin therapy for prevention of type 2 diabetes should be considered in those with prediabetes, especially in those with BMI >35, those aged 45 kg: same dosing as adults (1,2,3)[A] • Children 6.8 mg/dL) (1). • Acute gouty arthritis can affect ≥1 joints; the first metatarsophalangeal joint is most commonly involved at presentation (podagra). • Although hyperuricemia is necessary for the development of gout, it is not the only determining factor. • Characterized by deposition of monosodium urate (MSU) crystals that accumulate in joints and soft tissues, resulting in acute and chronic arthritis, soft-tissue masses called tophi, urate nephropathy, and uric acid nephrolithiasis • After an initial flare, a second flare occurs in ~60% of patients within 1 year and 78% within 2 years of the initial attack (2). • Management involves treating acute attacks and preventing recurrent disease by long-term reduction of SUA levels through pharmacology and lifestyle adjustments.

EPIDEMIOLOGY Incidence Annual incidence of gout (3): • Uric acid 7 to 8.9 mg/dL is 0.5%. • Uric acid >9 mg/dL is 4.5%.

Prevalence • Increasing prevalence over the past decades (3) • Overall prevalence of 3.9% (8.3 million) in the United States in 2008 (3) – Men 5.8% (6.1 million) – Women 2.0% (2.2 million) • 2008 prevalence of hyperuricemia in the United States (3):

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– Men 21.2% (SUA >7.0 mg/dL) – Women 21.6% (SUA >5.7 mg/dL)

ETIOLOGY AND PATHOPHYSIOLOGY • Hyperuricemia results from urate overproduction, underexcretion, or often a combination of the two. • Gout occurs when MSU, a product of purine metabolism, precipitates out of solution and accumulates in joints and soft tissues. • Transient changes in urate solubility caused by local temperature decrease, trauma, or acidosis may lead to an acute gouty attack. • Urate crystals that precipitate trigger an immune response. • Left untreated, this crystal deposition leads to permanent joint damage and tophus formation.

Genetics • Phosphoribosyl pyrophosphate (PRPP) deficiency and hypoxanthine-guaninephosphoribosyltransferase (HGPRT) deficiency (Lesch-Nyhan syndrome) are inherited enzyme defects associated with overproduction of uric acid. • Polymorphisms in the URAT1 and SLC 2A9 (GLUT9) renal transporters are hereditary enzyme defects resulting in primary underexcretion of uric acid.

RISK FACTORS • Age >40 years • Male gender • Increased purine uptake (meats and seafood) • Alcohol intake (especially beer) • High fructose intake • Obesity • Congestive heart failure • Coronary artery disease • Dyslipidemia • Renal disease • Organ transplant • Hypertension • Smoking

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• Diabetes mellitus • Urate-elevating medications: – Thiazide diuretics: ethambutol – Loop diuretics (less of a risk vs. thiazides) – Niacin – Calcineurin inhibitors (cyclosporine and tacrolimus)

GENERAL PREVENTION • Maintain optimal weight. • Regular exercise • Diet modification purine-rich foods) • Reduce alcohol consumption (beer and liquor). • Smoking cessation • Maintain fluid intake and avoid dehydration.

COMMONLY ASSOCIATED CONDITIONS • Hypertension • Dyslipidemia • Nontraumatic joint disorders • Heart disease • Diabetes mellitus • Metabolic syndrome • Obesity • Renal disease

DIAGNOSIS HISTORY • Classic presentation of acute gouty arthritis: – Intense pain and tenderness in the first metatarsophalangeal joint (podagra) – Can occur in the midtarsal, ankle, or knee joints – Joint may be swollen, warm, and red. – Often awakes patients from sleep due to an intolerance to contact with clothing or bed sheets – There is a rapid onset of intense pain, often beginning in the early morning

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and progressing rapidly over 12 to 24 hours. – In the absence of treatment, flares can last up to 10 days. • Fever can be present. • Subcutaneous or intraosseous nodules, referred to as tophi, can be seen. • Pain with urination secondary to uric acid renal stones

PHYSICAL EXAM • Examine suspected joint(s) for tenderness, swelling, and range of motion (ROM). • Assess for presence of firm nodules known as tophi. • In patients with chronic gout, tophi can frequently be found in the helix of the ear, over the olecranon process, or on the Achilles tendon. • Patients with untreated chronic gout can have evidence of joint inflammation and deformity.

DIFFERENTIAL DIAGNOSIS Acute bursitis, tendonitis, septic arthritis, pseudogout (calcium pyrophosphate deposition disease), cellulitis, osteoarthritis

DIAGNOSTIC TESTS & INTERPRETATION • SUA (may be normal during an acute flare) • CBC (can see elevation of WBC during gout flare) • Synovial fluid analysis: urate crystals (negatively birefringent under polarizing microscopy), cell count (WBC usually 2,000 to 5,000 cells/mm3); culture to rule out infection. • Screen for uric acid overproduction using 24-hour urinary uric acid in those patients with gout onset before the age of 25 years or with a history of urolithiasis (1)[C]. • Radiograph’s are normal early in disease but can reveal – Swelling in acute gout – Periarticular erosions with periosteum overgrowth in chronic gout • Urate kidney stones are radiolucent and thus invisible on radiograph. • Ultrasound evidence of urate deposition—hyperechoic enhancement over surface of hyaline cartilage (4). • Dual-energy CT (DECT) imaging can show urate deposition at articular or

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periarticular sites (4). • ACR-EULAR Gout Classification calculator: (goutclassificationcalculator.aukland.ac.nz) validated classification criteria with sensitivity 92%, specificity 89% [with clinical criteria only sensitivity of 85% and specificity of 78%] (4).

TREATMENT GENERAL MEASURES Topical ice as needed (5)[B]

MEDICATION • Acute treatment – General principles: Acute gouty arthritis attacks should be treated with pharmacologic therapy (5)[C]. Pharmacologic treatment should be initiated within 24 hours of acute gout attack (5)[C]. Ongoing pharmacologic urate-lowering therapy should not be interrupted during an acute gout attack (5)[C]. Choice of agent is based on severity of pain and the number of joints involved (5). – Mild/moderate gout severity (≤6 of 10 on visual analog pain scale, particularly for an attack involving only one or a few small joints or one to two large joints) NSAIDs: Naproxen (Naprosyn, Anaprox, Aleve): 750 mg followed by 250 mg q8h for 5–8 days (5)[A] Indomethacin (Indocin): 50–150 mg/day for 2–7 days (5)[A] Sulindac (Clinoril): 200 mg BID for 7–10 days (5)[A] Celecoxib (Celebrex) Not FDA approved but can be considered in selected patients with contraindications or intolerance to NSAIDs (5)[B]. Dose: 800 mg once, then 400 mg on day 1, then 400 mg BID for 1

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week (5)[B] Corticosteroids Those with an acute flare involving one to two large joints can consider intra-articular corticosteroids; can consider using oral corticosteroids in combination. Corticosteroids are useful in patients with acute gout flare who cannot tolerate NSAIDs or have contraindications to NSAIDs such as chronic kidney disease (CKD) For other acute flares, use oral corticosteroids: Prednisone (Sterapred): 0.5 mg/kg/day for 5 to 10 days followed by discontinuation (5)[A] or alternately 2 to 5 days at full dose followed by tapering for 7 to 10 days and then discontinuing (5)[C] Methylprednisolone (Medrol) dose pack (5)[C] Triamcinolone acetonide (Trivaris): 60 mg IM single dose followed by oral corticosteroids (5)[C] Colchicine (Colcrys) Used for gout attacks where the onset was 1 region, or involving three separate large joints) Initial combination therapy is an option and includes the use of full doses of the following (5)[C]: Colchicine and NSAIDs PO corticosteroids and colchicine Intra-articular steroids – For patients not responding to initial pharmacologic monotherapy, add a second agent (5)[C]. • Chronic treatment

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– Indications for pharmacologic urate-lowering therapy include any patient with Tophus or tophi by clinical exam or imaging study (1)[A] Frequent attacks of acute gouty arthritis (≥2 attacks/year) (1)[A] CKD stage 2 or worse (1)[C] Past urolithiasis (1)[C] – Treat to the serum urate: Minimum serum urate target is 1 serving per day for women) (1)[A] – Any alcohol use in gout during periods of frequent gout attacks or advanced gout under poor control • Limit – Serving sizes of beef, lamb, pork, and seafood with high purine content such as sardines and shellfish (1)[B] – Servings of naturally sweetened fruit juices – Table sugar, sweetened beverages and desserts – Table salt, including in sauces and gravies – Alcohol (particularly beer) in all patients (1)[B] • Encourage – Low-fat or nonfat dairy products – Vegetables

PATIENT EDUCATION • Dietary and lifestyle modifications (1)[B]

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• Instructions on initiating treatment on signs and symptoms of an acute gout attack without the need to consult health care provider for each attack (1)[B] • Discussion that gout is caused by excess uric acid and that effective uratelowering therapy is essential treatment (1)[B]

PROGNOSIS Gout can usually be successfully managed with proper treatment.

COMPLICATIONS • AHS • Increased susceptibility to infection • Urate nephropathy • Renal stones

REFERENCES 1. Khanna D, Fitzgerald JD, Khanna PP, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 1: systematic nonpharmacologic and pharmacologic therapeutic approaches to hyperuricemia. Arthritis Care Res. 2012;64(10):1431–1446. 2. Doghramji PP. Managing your patient with gout: a review of treatment options. Postgrad Med. 2011;123(3):56–71. 3. Zhu Y, Pandya BJ, Choi HK. Prevalence of gout and hyperuricemia in the US general population: the National Health and Nutrition Examination Survey 2007–2008. Arthritis Rheum. 2011;63(10):3136–3141. 4. Neogi T, Jansen T, Dalbeth N, et al. 2015 Gout Classification Criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheumatol. 2015;67(10):2557–2568. 5. Khanna D, Khanna PP, Fitzgerald JD, et al. 2012 American College of Rheumatology guidelines for management of gout. Part 2: therapy and antiinflammatory prophylaxis of acute gouty arthritis. Arthritis Care Res. 2012;64(10):1447–1461.

CODES

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ICD10 • M10.9 Gout, unspecified • M10.00 Idiopathic gout, unspecified site • M10.30 Gout due to renal impairment, unspecified site

CLINICAL PEARLS • MSU crystals found in synovial fluid aspirate are pathognomonic for gout. • Pharmacologic treatment should begin within 24 hours of acute gout flare. • Asymptomatic hyperuricemia does not require treatment.

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GRANULOMA ANNULARE Mary Iaculli, DO • Joanne Wilkinson, MD, MSc BASICS DESCRIPTION A benign skin condition characterized by grouped, flesh-colored, or erythematous papules, which typically occur in an annular (ring-like) pattern. Five variants have been described; the most common of which is localized granuloma annulare (GA). The other types are generalized, patch type, subcutaneous (SC) (deep dermal), and perforating.

EPIDEMIOLOGY Incidence • GA is not common, although exact prevalence in the general population is unknown. • Predominant sex: female > male (2.5:1) • Most lesions resolve in 2 to 24 months but may last up to 5 to 10 years. 2/3 of patients are 80% of attacks, often associated with nausea, vomiting, photophobia, and/or phonophobia – With aura (classic migraine): visual or other types of fully reversible neurologic phenomenon lasting 5 to 60 minutes – Chronic (transformed) migraine: chronic headache pattern evolving from episodic migraine. Migraine-like attacks are superimposed on a daily or near-daily headache pattern (e.g., tension headaches) >15 headache days/month for at least 3 months. – Menstrual-related (molimina) migraine: associated with onset of menstrual period • Rare but important subtypes (1): – Status migrainosus: debilitating migraine lasting >72 hours – With brainstem aura (basilar migraine): brainstem symptoms—dysarthria, vertigo, tinnitus, or ataxia, which are fully reversible and lasting 5 to 60 minutes. – Hemiplegic migraine: aura consisting of fully reversible hemiplegia and/or hemiparesis – Recurrent painful ophthalmoplegic neuropathy (ophthalmoplegic migraine): neuralgia accompanied by paresis of an ocular cranial nerve with ipsilateral headache – Retinal: repeated attacks of monocular visual disturbance, including scintillations, scotomata, or blindness, associated with migraine headache

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EPIDEMIOLOGY Female > male (3:1)

Prevalence • Affects >28 million Americans • Adults: women 18%; men 6%

ETIOLOGY AND PATHOPHYSIOLOGY • No longer believed to be primarily vascular in etiology; rather, cortical spreading depolarization/depression • Trigeminovascular hypothesis: Hyperexcitable trigeminal sensory neurons in brainstem are stimulated and release neuropeptides, such as substance P and calcitonin gene-related peptide (CGRP),leading to vasodilation and neurogenic inflammation.

Genetics • >80% of patients have a positive family history. • Familial hemiplegic migraine has been shown to be linked to chromosomes 1, 2, and 19 (1).

RISK FACTORS • Family history of migraine • Female gender • Stress • Menstrual cycle, hormones • Sleep pattern disruption • Diet: skipped meals (40–56%), alcohol (29–35%), chocolate (19–22%), cheese (9–18%), caffeine overuse (14%), monosodium glutamate (MSG) (12%), and artificial sweeteners (e.g., aspartame, sucralose) • Medications: estrogens, vasodilators

GENERAL PREVENTION • Avoid precipitants of attacks. • Biofeedback, education, and psychological intervention • Lifestyle modifications are the cornerstone of prevention: sleep hygiene, stress management, healthy diet, and regular exercise.

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• Prophylactic medication if attacks are frequent, severely debilitating, or not controlled by acute interventions

COMMONLY ASSOCIATED CONDITIONS • Depression, psychiatric disorders • Sleep disturbance (e.g., sleep apnea) • Cerebral vascular disease • Peripheral vascular disease • Seizure disorders • Irritable bowel syndrome • Obesity • Patent foramen ovale (PFO) • Medication overuse headache (MOH)

DIAGNOSIS Migraine is a clinical diagnosis; thorough history and neuro examination are usually all that are necessary.

HISTORY • Screening mnemonic “POUND”: Pulsating, duration of to 72 hOurs, Unilateral, Nausea, Disabling – + Likelihood ratio (LR) = 24 for migraine diagnosis if 4 of 5 criteria present – + LR = 0.41 for migraine diagnosis if ≤2 criteria present (2) • Headache usually begins with mild pain escalating into unilateral (30–40% bilateral) throbbing (40% nonthrobbing) pain lasting 4 to 72 hours. • Intensified by movement and associated with systemic manifestations: nausea (87%), vomiting (56%), diarrhea (16%), photophobia (82%), phonophobia (78%), muscle tenderness (65%), light-headedness (72%), and vertigo (33%) • May be preceded by aura – Visual disruptions are most common—scotoma, hemianopsia, fortification spectra, geometric visual patterns, and occasionally hallucinations. – Somatosensory disruption in face or arms – Speech difficulties • Obtain headache profile: number of headaches per month, number of days per

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month headaches limit daily activities, and frequency and amount of all headache medications used. • Migraine disability assessment (MiDAS) is a useful tool to assess level of disability and correlates well with headache diaries. • Identify possible triggers (e.g., stress, sleep disturbance, food, caffeine, alcohol).

PHYSICAL EXAM Neurologic exam should be performed including funduscopy; abnormalities consistent with other causes to severe headaches MIGHT include the following: • Gait abnormalities and other new cerebellar findings • Loss of gross and/or fine motor function • Altered mental status including possible hallucinations (visual, auditory, olfactory) • Short-term memory loss

DIFFERENTIAL DIAGNOSIS • Other primary headache syndromes • If focal neurologic signs/symptoms are present, consider transient ischemic attack (TIA) or stroke. • Secondary headaches: tumor, infection, vascular pathology, prescription, or illicit drug use (MOH). • Psychiatric disease • Rarely, atypical forms of epilepsy

DIAGNOSTIC TESTS & INTERPRETATION Neuroimaging is appropriate ONLY with suspicious symptomatology and/or an abnormality on physical examination (3). Other red flags include the following: • New onset in patient >50 years of age • Change in established headache pattern • Atypical pattern or unremitting/progressive neurologic symptoms • Prolonged or bizarre aura • Type of imaging: Data are insufficient to make evidence-based recommendations regarding relative sensitivity of MRI compared with CT in the evaluation of migraine or other nonacute headache.

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• EEG is NOT indicated unless evaluating loss of consciousness or altered mental status.

Pediatric Considerations NSAIDs and triptans appear to be effective for the acute treatment of children and adolescents with migraine. Triptans may have better efficacy than NSAIDs but also have higher rates of side effects. Not all triptans are approved for use in children (4).

Pregnancy Considerations • Frequency may decrease in 2nd and 3rd trimesters. • Nonpharmacologic methods are preferred. • No treatment drug has FDA approval in pregnancy – Acetaminophen (category C) triptans, antiemetics, and short-acting opioids can be considered for acute headaches during pregnancy. – Ergotamines are contraindicated (category X). – Avoid herbal remedies. – Sumatriptan, naratriptan, and opiates are pregnancy category C—risk cannot be ruled out, but early data suggest no increase in birth defects. – Sumatriptan by injection is ideal for breastfeeding women with disabling migraines. – Propranolol (category C) is effective for prophylaxis during pregnancy and lactation.

TREATMENT GENERAL MEASURES • Most patients manage attacks with self-care. • Cold compresses to area of pain • Withdrawal from stressful surroundings • Sleep is desirable. • See also “General Prevention.”

MEDICATION • First-line abortive treatments

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– Mild to moderate attacks: Acetaminophen is effective for mild to moderate attacks and when combined with metoclopramide has relief rates similar to triptans (5)[A]. NSAIDs are inexpensive and effective in up to 60% of cases (5)[B]. Aspirin-acetaminophen–caffeine (Excedrin Migraine) is an inexpensive, OTC treatment with efficacy higher than its components (5)[B]. – Moderate to severe attacks: Triptans when OTC agents fail for moderate attacks OR first line for severe attacks (6)[B] All triptans have similar efficacy/tolerability, but patients often respond better to one triptan over another (5)[C]. – Suggested initial doses (6)[B]: Sumatriptan 100 mg PO; 6 mg SQ; 20 mg intranasal. SQ is most rapid. Eletriptan 40 mg PO Rizatriptan 10 mg PO Zolmitriptan 2.5 mg PO; 5 mg intranasal Naratriptan 2.5 mg PO Frovatriptan 2.5 mg PO 44–77% of patients taking triptans report complete pain relief within 2 hours. Frovatriptan and naratriptan have slow onset but long half-lives—best for people with long migraine duration/recurrence. – Combination triptan and NSAID: Sumatriptan 85 mg/naproxen 500 mg PO at onset of headache show improved efficacy over either alone. – Antiemetics: Dopamine antagonists are excellent adjunctive medications (5,6)[B]. • Contraindications to treatments – Avoid triptans and ergots in coronary artery or peripheral vascular disease, uncontrolled hypertension, and complicated migraine (e.g., brainstem or hemiplegic migraine). – Do not combine triptans or use with ergots or MAOIs. – Avoid opioids or butalbital in patients with frequent migraines. • Precautions – Frequent use of acute-treatment drugs can result in MOH.

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– Triptan adverse reactions are common and include chest pressure, flushing, weakness, dizziness, feeling of warmth, and paresthesias. • Second-line abortive treatment – Ergotamines (e.g., dihydroergotamine SC, Migranal intranasal): drug of choice in status migrainosus but limited use due to side effects and replaced by triptans – Opiate use is controversial and can contribute to medication overuse or chronic daily headache with use as few as 8 days per month (7). • First-line preventative treatment – Should not be limited to pharmacologic agents; trigger reduction, biofeedback, relaxation techniques, and CBT have evidence of efficacy. – Lifestyle modifications should be recommended for all migraine sufferers. – ~38% of migraineurs need preventative therapy, but only 3–13% use it. Trial and error is needed to determine optimal therapy. • The American Migraine Prevalence and Prevention Study suggests prophylactic treatment when: – Quality of life is severely impaired. – ≥6 headache days/month, ≥4 headache days/month of moderate severity, or ≥2 headache days/month of severe impairment – Migraines do not respond to abortive treatment. – Frequent, very long, or uncomfortable auras occur. • Prevention of episodic migraine, divalproex, valproate, topiramate, metoprolol, and timolol are effective in reducing frequency/severity (6)[A]. – NSAIDs are probably effective for prevention in people with predictable triggers (menses, etc.) but pose a risk for MOH (8)[B]. – For treatment/prevention of chronic migraine, botulinum toxin A (Botox) significantly reduces frequency of headache days.

ISSUES FOR REFERRAL • Obscure diagnosis, concomitant medical conditions, significant psychopathology • Unresponsive to usual treatment • Analgesic-dependent headache patterns

COMPLEMENTARY & ALTERNATIVE MEDICINE

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• Butterbur (Petasites hybridus; Petadolex): 50 to 75 mg BID (8)[A]—Use caution with CYP3A4 meds. • Riboflavin (vitamin B2): 400 mg/day (8)[B] • Magnesium: 400 mg/day (8)[B] • MIG-99 (Feverfew): 6.25 mg TID (8)[B] • Histamine SC: 1 to 10 ng twice weekly (8)[B] • Acupuncture is at least as effective as, or possibly more effective than, prophylactic drug treatment and has fewer adverse effects (9)[B].

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Consider if diagnosis not clear; status migrainosus; may need to exclude intracranial bleeds; TIA; stroke; monitor vital signs and patient comfort. • Fluids are a necessary part of inpatient management. Keeping patients hydrated and on antiemetics around the clock may be helpful. • Discharge criteria judgment based on patient’s overall clinical status and patient’s ability to tolerate PO medications

ONGOING CARE FOLLOW-UP RECOMMENDATIONS • Early intervention is key at the onset of an attack. • Preventative treatment to decrease frequency and severity of attacks, make acute treatments more efficacious, and minimize adverse drug reactions.

Patient Monitoring • Monitor frequency of attacks, pain behaviors, and medication usage via headache diary. • Encourage lifestyle modifications. Counsel patients and manage expectations.

PATIENT EDUCATION Educate patients about migraine triggers.

PROGNOSIS • With increasing age, there may be a reduction in severity, frequency, and

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disability of attacks. • Most attacks subside within 72 hours.

COMPLICATIONS • Status migrainosus (>72 hours) • Cerebral ischemic events (rare) • MOH: headache occurring 10 or more days/month for >3 months as a consequence of regular overuse of an acute or symptomatic headache medication. Likelihood with butalbital > opiates > triptans > NSAIDs.

REFERENCES 1. Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013;33(9):629–808. 2. Detsky ME, McDonald DR, Baerlocher MO, et al. Does this patient with headache have a migraine or need neuroimaging? JAMA. 2006;296(10):1274–1283. 3. Loder E, Weizenbaum E, Frishberg B, et al. Choosing wisely in headache medicine: the American Headache Society’s list of five things physicians and patients should question. Headache. 2013;53(10):1651–1659. 4. Richer L, Billinghurst L, Linsdell MA, et al. Drugs for the acute treatment of migraine in children and adolescents. Cochrane Database of Syst Rev. 2016; (4):CD005220. 5. Becker WJ. Acute migraine treatment in adults. Headache. 2015;55:778–793. 6. Gilmore B, Michael M. Treatment of acute migraine headache. Am Fam Physician. 2011;83(3):271–280. 7. Taylor FR, Kaniecki RG. Symptomatic treatment of migraine: when to use NSAIDs, triptans, or opiates. Curr Treat Options Neurol. 2011;13(1):15–27. 8. Holland S, Silberstein SD, Freitag F, et al. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology. 2012;78(17):1346–1353. 9. Linde K, Allais G, Brinkhaus B, et al. Acupuncture for the prevention of

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episodic migraine. Cochrane Database Syst Rev. 2009;(6):CD001218.

SEE ALSO Algorithm: Headache, Chronic

CODES ICD10 • G43.909 Migraine, unsp, not intractable, without status migrainosus • G43.109 Migraine with aura, not intractable, w/o status migrainosus • G43.409 Hemiplegic migraine, not intractable, w/o status migrainosus

CLINICAL PEARLS • Migraine is a chronic headache disorder of unclear etiology often characterized by unilateral, throbbing headaches that may be associated with additional neurologic symptoms. • Accurate diagnosis of migraine is crucial. • Consider nonspecific analgesics for mild attacks; migraine-specific treatments for more severe attacks • Avoid opiates and barbiturates as well as frequent (>8/month) use of triptans or NSAIDs to avoid creating an MOH. • All patients should be counseled on lifestyle modifications and trigger identification. • In those with frequent or highly debilitating migraines, prophylactic treatment should be encouraged.

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HEADACHE, TENSION Kaelen C. Dunican, PharmD • Brandi Hoag, DO BASICS DESCRIPTION • Typically characterized by bilateral mild to moderate pain and pressure; may be associated with pericranial tenderness at the base of the occiput • Two types – Episodic tension–type headache (ETTH) divided into Infrequent: 2 days/week may lead to medication-overuse headaches; must withdraw acute treatment to diagnose

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Pediatric Considerations ASA and antidepressants are contraindicated.

ADDITIONAL THERAPIES • The combination of stress management therapy and a TCA (amitriptyline) may be most effective for CTTH. • Maprotiline: 75 mg/day (not FDA approved for CTTH) (2)[C] • Topiramate: 100 mg/day (limited clinical evidence for prevention of CTTH; not FDA approved for CTTH) • Alternative TCAs (although limited evidence of benefit, all are widely used for prophylaxis) (3)[B] – Desipramine (Norpramin): 50 to 100 mg/day – Imipramine (Tofranil): 50 to 100 mg/day – Nortriptyline (Pamelor): 25 to 50 mg/day – Protriptyline (Vivactil): 25 mg/day • Drugs with conflicting clinical evidence for CTTH (not FDA approved for CTTH): – Tizanidine: 2 to 6 mg TID – Memantine: 20 to 40 mg/day • Botulinum toxin type A is not likely to be effective for ETTH or CTTH.

COMPLEMENTARY & ALTERNATIVE MEDICINE • Electromyographic (EMG) biofeedback may be effective and is enhanced when combined with relaxation therapy (2,4)[C]. • Cognitive-behavioral therapy may be helpful (2,4)[C]. • Physical therapy, including positioning, ergonomic instruction, massage, transcutaneous electrical nerve simulation, and application of heat/cold may help. • Alternative agents (not FDA approved for TTH) – Tiger Balm or peppermint oil applied topically to the forehead may be effective for ETTH. – Limited evidence for use of acupuncture and physical therapy (4)[B] • Chiropractic spinal manipulation cannot be recommended for the management of ETTH; recommendations cannot be made for CTTH (5)[B].

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ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS Outpatient treatment

ONGOING CARE FOLLOW-UP RECOMMENDATIONS • Regulate sleep schedule. • Regular exercise

DIET • Identify and avoid dietary triggers. • Regulate meal schedule.

PATIENT EDUCATION For additional information, contact: • National Headache Foundation: http://www.headaches.org

PROGNOSIS • Usually follows a chronic course when life stressors are not changed • Most cases are intermittent.

COMPLICATIONS • Lost days of work and productivity (more with CTTH) • Cost to health system • Dependence/addiction to narcotic analgesics • GI bleeding from NSAID use

REFERENCES 1. Ferrante T, Manzoni GC, Russo M, et al. Prevalence of tension-type headache in adult general population: the PACE study and review of the literature. Neurol Sci. 2013;34(Suppl 1):S137–S138. 2. Bendtsen L, Jensen R. Treating tension-type headache—an expert opinion. Expert Opin Pharmacother. 2011;12(7):1099–1109. 3. Verhagen AP, Damen L, Berger MY, et al. Lack of benefit for prophylactic

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drugs of tension-type headache in adults: a systematic review. Fam Pract. 2010;27(2):151–165. 4. Sun-Edelstein C, Mauskop A. Complementary and alternative approaches to the treatment of tension-type headache. Curr Pain Headache Rep. 2012;16(6):539–544. 5. Bryans R, Descarreaux M, Duranleau M, et al. Evidence-based guidelines for the chiropractic treatment of adults with headache. J Manipulative Physiol Ther. 2011;34(5):274–289.

SEE ALSO Algorithm: Headache, Chronic

CODES ICD10 • G44.209 Tension-type headache, unspecified, not intractable • G44.219 Episodic tension-type headache, not intractable • G44.229 Chronic tension-type headache, not intractable

CLINICAL PEARLS • Tension-type headache may be difficult to distinguish from migraine without aura. A tension-type headache is typically described as bilateral, mild to moderate, and dull pain, whereas a migraine is typically pulsating, unilateral, and associated with nausea, vomiting, and photophobia or phonophobia. • Evidence suggests that NSAIDs may be more effective than APAP for ETTH. Consider APAP for patients who cannot tolerate, or have a contraindication, to NSAIDs. Initial dose of APAP should be 1,000 mg (500 mg may not be as effective). • CTTH is difficult to treat, and these patients are more likely to develop medication-overuse headache. Clinical evidence supports the use of amitriptyline plus stress management therapy for CTTH. • Medication-overuse headaches must be avoided by limiting use of abortive

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agents to no more than 2 days/week. • A headache diary may be useful to identify triggers, response to treatment, and medication-overuse headaches.

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HEARING LOSS Susan L. Steffans, DO BASICS DESCRIPTION • Decrease in the ability to perceive and comprehend sound. It can be partial, complete, unilateral, or bilateral. • Types of hearing loss include conductive hearing loss (CHL or air–bone gap), sensorineural hearing loss (SNHL), or mixed hearing loss. • System(s) affected: auditory; outer and middle ear (CHL) or inner ear, auditory nerve, and/or brainstem (SNHL)

EPIDEMIOLOGY • All ages affected; common in children (CHL) and elderly (SNHL) • Usually more severe at an earlier age in men

Incidence • Increases with age • Sudden sensorineural hearing loss (SSHL) occurs in 5 to 20 per 100,000 persons/year.

Prevalence WHO estimates that 538 million people affected worldwide.

Geriatric Considerations • ~80% of people aged >85 years have hearing loss. • Hearing aids are underused. • Loss of communication is a source of emotional stress and a physical risk for the elderly.

Pediatric Considerations • Congenital hearing loss – 1 to 6/1,000 infants have hearing loss. – Mandatory screening in >97% of newborns with otoacoustic emission

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(OAE) and auditory brainstem response (ABR) testing • Audiologic testing after major intracranial infection (meningitis) • Significant hearing loss at birth and infancy can lead to speech, language, and cognitive delays. Early diagnosis and treatment improves outcome.

Pregnancy Considerations • Otosclerosis can worsen during pregnancy. • Maternal infections cause permanent pediatric hearing loss.

ETIOLOGY AND PATHOPHYSIOLOGY • CHL: Hearing loss can result from middle ear effusion, obstruction of canal (cerumen/foreign body, osteomas/exostoses, cholesteatoma, tumor), loss of continuity (ossicular discontinuity), stiffening of the components (myringosclerosis, tympanosclerosis, and otosclerosis), and loss of the pressure differential across the tympanic membrane (TM) (perforation). • SNHL: damage along the pathway from oval window, cochlea, auditory nerve, and brainstem. Examples include vascular/metabolic insult, mass effect, infection and inflammation, and acoustic trauma. – Noise-induced hearing loss is caused by acoustic insult that affects outer hair cells in the organ of Corti, causing them to be less stiff. Over time, severe damage occurs with fusion and loss of stereocilia; eventually may progress to inner hair cells and auditory nerve as well. • Large vestibular aqueduct or superior canal dehiscence: Third mobile window shunts acoustic energy away from cochlea.

Genetics • Connexin 26 (13q11–13q12): most common cause of nonsyndromic genetic hearing loss • Mitochondrial disorders (may predispose to aminoglycoside ototoxicity) • Otosclerosis: familial • Most common congenital syndromes – Hemifacial microsomia – Stickler syndrome – Congenital cytomegalovirus – Usher syndrome

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– Branchio-oto-renal syndrome – Pendred syndrome – CHARGE association – Neurofibromatosis type 2 – Waardenburg syndrome

RISK FACTORS • Conductive – Eustachian tube dysfunction Chronic sinusitis; allergy Adenoid hypertrophy; nasopharyngeal mass Cigarette smoking – Sleep apnea with continuous positive airway pressure (CPAP) use – Neuromuscular disease – Family history/heredity – Prematurity and low birth weight – Craniofacial abnormalities (e.g., cleft palate, Down syndrome) – Third mobile window (superior canal dehiscence or large vestibular aqueduct) • Sensorineural – Aging/older age – Loud noise/acoustic trauma – Dizziness/vertigo: especially Ménière disease or history of labyrinthitis – Medications (aminoglycosides, loop diuretics, aspirin, quinine, chemotherapeutic agents, especially cisplatin) – Bacterial meningitis – Head trauma – Atherosclerosis – Vestibular schwannoma/skull base neoplasm – Previous ear surgery • Sensorineural, pediatric specific – Perinatal asphyxia – Mechanical ventilation lasting ≥5 days – Congenital infections (toxoplasmosis, other agents, rubella, cytomegalovirus, herpes simplex [TORCH] syndrome)

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– Toxemia of pregnancy – Maternal diabetes – Rh incompatibility – Prematurity or birth weight 55,000 deaths each year and a contributing factor in >280,000 deaths. • >1 million hospital discharges/year, unchanged from 2000 to 2010, and about half of people who have HF die within 5 years of diagnosis. One in 9 deaths has HF mentioned on the death certificate.

Prevalence • ~5.7 million people over the age of 20 years in the United States carry an HF diagnosis; prevalence is expected to increase 46% from 2012 to 2030 resulting in more than 8 million cases in patients >18 years of age. • HF is primarily a disease of the elderly; 75% of hospital admissions for HF are in persons >65 years of age. • African Americans have the highest risk of developing HF, followed by Hispanics, Whites, and Chinese Americans. A higher risk reflects differences in prevalence of hypertension (HTN), DM, and socioeconomic status.

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ETIOLOGY AND PATHOPHYSIOLOGY • Two potential pathophysiologic conditions lead to the clinical findings of ADHF, namely systolic and/or diastolic heart dysfunction. – Systolic dysfunction: an inotropic abnormality, often due to myocardial infarction (MI) or dilated or ischemic cardiomyopathy, resulting in diminished systolic emptying (ejection fraction 45%). – In order to adopt a more pragmatic approach, one that has already been accepted by both the European and American HF guidelines, the terms HF with reduced or preserved LVEF (HFREF and HFPEF, respectively) have been adopted recently. • ADHF can be caused by the following conditions: – Myocardial disease: Exacerbation of chronic HF heralded by noncompliance, infection; any of the following as cause of new HF or exacerbation: coronary artery disease (CAD), MI (especially new-onset ADHF), toxic damage, immune-mediated and inflammatory damage, infiltrative diseases, metabolic derangements, and genetic abnormalities – Abnormal loading conditions HTN, valvular and myocardial structural defects, pericardial and endomyocardial pathologies, high output states, volume overload – Arrhythmias Arrhythmia: atrial fibrillation, tachyarrhythmias, high-grade heart block, bradyarrhythmias

Genetics Familial cardiomyopathy is a predisposition to development of HF (rare).

RISK FACTORS • CAD and MI: RR 8.1 • Diabetes mellitus: RR 1.9 • Cigarette smoking: RR 1.6 • Valvular heart disease: RR: 1.5

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• HTN, systemic or pulmonary: RR 1.4 • Dietary sodium intake: RR 1.4 • Obesity: RR 1.3

GENERAL PREVENTION Mortality declines have been attributed to treating HF risk factors above (see above), and implementation of ACE inhibitors, β-blockers, coronary revascularization, implantable cardioverter-defibrillators, and cardiac resynchronization strategies in patients.

COMMONLY ASSOCIATED CONDITIONS • Dysrhythmia followed by pump failure is the leading cause of death in ADHF. Most patients have >5 comorbidities (especially CAD, chronic kidney disease, and diabetes) and take >5 medications. • Cardiogenic shock

DIAGNOSIS Clinical diagnosis, no gold standard: No single historical, PE, ECG, or radiographic finding that can rule out HF.

HISTORY • Patients typically have a history of HF, MI, uncontrolled HTN, and other risk factors. • Dyspnea on exertion and orthopnea are the only symptoms with high sensitivity but suffer from low specificity. • Other symptoms include deteriorating exercise capacity, fatigue, general weakness, chest pain/discomfort if acute coronary syndrome (ACS) is present, paroxysmal nocturnal dyspnea, nocturnal nonproductive cough, wheezing (especially nocturnal) in absence of history of asthma or infection (cardiac asthma). • Edema, abdominal bloating (ascites), anasarca, cyanosis, weight gain (>2 kg/week)

PHYSICAL EXAM • S3 was the physical exam (PE) finding with highest likelihood ratio (LR) with

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positive LR ranging from 1.6 to 13.0. No PE finding has sensitivity >70%. • Peripheral pitting edema, cool extremities, cyanosis, hepatomegaly, hepatojugular reflux, cardiac murmur, hypotension, laterally displaced apical impulse • Lung exam: rales (crackles) and sometimes wheezing, Cheyne-Stokes respirations

DIFFERENTIAL DIAGNOSIS Rule out life-threatening diagnoses first! Pulmonary embolism, MI, tamponade, pneumothorax, ARDS, sepsis, chronic obstructive pulmonary disease (COPD), pneumonia, constrictive pericarditis, high-output states (anemia, hyperthyroidism)

DIAGNOSTIC TESTS & INTERPRETATION Laboratory data are adjunctive and indicative of complications.

Initial Tests (lab, imaging) • First, assess BP and other vital signs and rule out hemodynamic instability and cardiogenic shock state. • Cardiac troponins, ECG to evaluate for ACS. Note that elevated troponins are detected in the majority of HF patients, often without obvious myocardial ischemia (1)[C]. • BUN, creatinine, electrolytes, liver function tests, TSH, glucose, and CBC (1) [C] • Routine ABG is not needed (1)[C]. • Transthoracic echocardiogram: recommended immediately in hemodynamically unstable ADHF patients and within 48 hours when cardiac structure and function are either not known or may have changed since previous studies (1)[C] • B-type natriuretic peptide (BNP) and/or N-type pro-BNP (BT-BNP): Measurement of BNP or NT-proBNP is recommended in all patients with acute dyspnea and suspected ADHF to help in the differentiation of ADHF from noncardiac causes (1)[A]. – BNP 500 have specificity of 89.8% (2)[A].

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BNP 100 to 400 may indicated HF or may be due to a variety of cardiac and noncardiac conditions (1)[A]. – BNP has a relative increase in women, is lower with obesity, and higher with renal dysfunction (1)[A]. • NT-proBNP values >450 pg/mL for people below age 50 years, >900 pg/mL ages 50 to 75 years, and >1,800 pg/mL for people older than 75 years are highly suggestive of HF (sensitivity 90%, specificity of 84%) (3)[B]. • Chest x-ray: to look for pulmonary congestion and to detect other cardiac or noncardiac diseases that may cause or contribute to the patient’s symptoms: increased heart size, vascular redistribution (cephalization) with “butterfly” pattern of pulmonary edema, interstitial and alveolar edema, Kerley B lines, pleural effusions (1)[C] • Lung ultrasound (LUS): emerging as a diagnostic tool for ADHF with a positive LUS defined by presence of >3 B lines in two bilateral lung zones yielding a specificity of 92.7% and LR of 7.4 (2)[A] Follow-Up Tests & Special Considerations Please see “Heart Failure, Chronic” topic.

Diagnostic Procedures/Other Cardiac catheterization may be considered when CAD is suspected. Pulmonary artery catheterization may be performed to guide therapy in severe cases with cardiogenic shock.

Test Interpretation Cardiac pathology depends on the etiology of HF. Please refer to “Heart Failure, Chronic” topic.

TREATMENT Goal of treatment is to improve hemodynamics and organ perfusion, alleviate symptoms, limit cardiac and renal damage, restore oxygenation, and minimize hospital length of stay as well as identify the etiology or precipitating factors. See “Heart Failure, Chronic” chapter as well.

MEDICATION

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ALERT Contemporary therapies for ADHF remain suboptimal and many therapies do not favorably impact morbidity or mortality. Diuretics are used initially in fluid overload ADHF, with nitrates added if needed. Once ADHF is stabilized, an ACE inhibitor and β-blocker should be started in patients with reduced systolic function (4)[A]. Avoid NSAIDS and COX-2 inhibitors. There are no class IA drug recommendations for ADHF.

First Line • IV loop diuretics recommended for all patients with ADHF and symptoms of fluid overload in hemodynamically stable patients (contraindicated if SBP 90 mm Hg and patients with hypertensive ADHF should get IV vasodilators as initial therapy to reduce congestion (1)[B]. – IV nitroglycerin may be of short-term benefit to decrease preload, afterload, and systemic resistance (IV 10 to 20 μg/min, increase up to 200 μg/min) (1) [B]. – IV nitroprusside: Administer with caution, start with 0.3 μg/kg/min and increase up to 5 μg/kg/min (1)[B].

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Second Line • Tolvaptan (an oral vasopressin antagonist) for treatment of severe hypervolemic hyponatremia refractory to water restriction and maximum medical therapy (4)[B] • Inotropes: reserved for patients with severe systolic dysfunction occurring most often in hypotensive ADHF. Withdraw as hemodynamics improve due to increased short- and medium-term mortality. ECG monitoring is required as they can induce ischemia and arrhythmias. – Phosphodiesterase inhibitors (milrinone, enoximone) decrease pulmonary resistance; may be used for patients on β-blockers but may increase medium-term mortality in CAD patients – Dobutamine infusion 2 to 20 μg/kg/min requires close BP monitoring; avoid in cardiogenic shock or with tachyarrhythmias. – Low-dose dopamine infusion may be considered (3 to 5 μg/kg/min). – Levosimendan (calcium sensitizer) improves hemodynamic parameters but not survival compared to placebo while improving hemodynamic parameters and survival compared to dobutamine. • Vasopressors: Consider in patients with cardiogenic shock despite treatment with another inotrope (1)[B]. – Norepinephrine 0.2 to 1.0 μg/kg/min compared with dopamine has fewer side effects and lower mortality (1)[C]. – Epinephrine restricted to patients with persistent hypotension despite other agents (1)[C]. • Nesiritide, a BNP analog, is not recommended secondary to higher rates of hypotension, no benefit on death, or rehospitalization rates. • Ultrafiltration renal replacement therapy: Routine use of ultrafiltration is not recommended and should be used only in patients with refractory volume overload (1)[C].

ADDITIONAL THERAPIES • Oxygen: Begin treatment early; ideally, arterial oxygen saturation >92% (90% if COPD). For ADHF, noninvasive positive pressure ventilation decreases early mortality (6)[A]. • Cochrane review shows that 1 death can be avoided for every 14 ADHF

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patient treated with NPPV. Similarly, 1 death can be prevented for every 9 ADHF patients treated with CPAP (6)[A]. Avoid mechanical ventilation for patients with right HF (6)[A]. • Treat anemia with transfusion: conservative trigger Hgb 120 mm Hg, RR 50 years, male gender, and smoking. • American Urological Association (AUA) suggests upper urinary tract imaging in all adults with unexplained hematuria (1)[C].

Initial Tests (lab, imaging) • Urine dipstick (sensitivity 91–100%; specificity 65–99%) – False negatives are rare but can be caused by high-dose vitamin C. – False positives: oxidizers (povidone, bacterial peroxidases, bleach), myoglobin, alkaline urine (>9), semen, food coloring, food (beets, blackberries) – Phenazopyridine may discolor the dipstick, making interpretation difficult. • Microscopic urinalysis should always be done to confirm dipstick findings and quantify RBCs. – AUA defines clinically significant microscopic hematuria as ≥3 RBCs/HPF on a properly collected urinary specimen when there is not an obvious benign cause (1)[C]. – Positive dipstick but a negative microscopic exam should be followed by three repeat tests. If any one is positive, proceed with a workup (1)[C]. – Exclude factitious or nonurinary causes, such as menstruation, mild trauma,

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exercise, poor collection technique, or chemical/drug causes, through cessation of activity/cause and a repeat urinalysis in 48 hours. – RBC casts are pathognomonic for glomerular origin; dysmorphic cells are also suggestive. • Voided urine cytology (sensitivity 26–90%; specificity >95%) – No longer recommended by AUA for routine evaluation of hematuria (1) [C] – May be considered in those with risk factors for urinary malignancy • Renal function tests (eGFR, BUN, creatinine) to differentiate intrinsic renal disease and to evaluate for risks for imaging contrast dye or certain medications – Indicators of renal disease are: significant (>500 mg/day) proteinuria, red cell casts, dysmorphic RBCs, increased creatinine, and albumin:creatinine ratio ≥30 mg/mmol (1)[C] • Urine culture if suspected infection/pyuria • PT/INR for patients on warfarin or suspected of abusing warfarin • Multidetector CT urography (MDCTU); sensitivity 95%, specificity 92% (2) [C] – The initial imaging of choice in nonpregnant adults with unexplained hematuria (2)[C] – Highly specific and relatively sensitive for the diagnosis of upper urinary tract neoplasms, especially when >1 cm (2)[C] – Higher radiation dose; weigh risk of disease versus risk of radiation exposure. – Does not obviate the need for cystoscopy, particularly in high-risk patients (2)[C] – Presence of calculi on noncontrast does not exclude another diagnosis or need for contrast phase. – Visualization of ureters is discontinuous. – Less cost-efficient • CT – Perform unenhanced helical CT for suspected stone disease in children if US is negative (3)[C]. – Perform CT abdomen and pelvis with contrast in children with traumatic

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hematuria (3)[C]. • Renal ultrasound – Best for differentiating cystic from solid masses – Sensitive for hydronephrosis – No radiation or iodinated contrast exposure – Cost-efficient – Poor sensitivity for renal masses 15 years is 5.1%; risk increases with age and male gender.

Pregnancy Considerations Renal US is initial imaging choice for pregnant patients (2)[C]. MRU or RPG combined with either MRI or US are alternatives (1)[C].

Pediatric Considerations

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• Consider GN, Wilms tumor, child abuse, and hypercalciuria. • Isolated asymptomatic microscopic hematuria may not need full workup; these patients rarely need cystoscopy; observe for development of hypertension, gross hematuria, or proteinuria (5)[C]. • Gross or symptomatic hematuria needs a full workup. – If eumorphic RBCs, consider US (rule out stones, congenital abnormalities) and urinary Ca:Cr ratio. Urine Ca:Cr ratio >0.2 is suggestive of hypercalciuria in children >6 years of age (5)[C]. • If dysmorphic RBCs, consider renal consult. • Renal US identifies most congenital and malignant conditions; CT is reserved for cases of suspected trauma (with contrast) or stones (without contrast) (3,5) [C].

TREATMENT MEDICATION None indicated for undiagnosed hematuria

ISSUES FOR REFERRAL Prompt nephrology referral for proteinuria, red cell casts, elevated serum creatinine, and albumin: creatinine ratio ≥30 mg/mmol (1)[C]

SURGERY/OTHER PROCEDURES Gross hematuria: Clots may require continuous bladder irrigation with a largebore Foley catheter (two- or three-way catheter may be helpful) to prevent clot retention.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring Some experts still recommend periodic urinalysis; recent literature suggests that, after thorough initial negative investigations (imaging, cystoscopy), no followup is indicated for the asymptomatic patient with microscopic hematuria unless

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symptoms or frank hematuria develop. AUA recommends annual urinalyses in these patients, until two consecutive are negative and the consideration for a repeat workup at 3 to 5 years if hematuria is persistent (1)[C].

DIET Increased fluids for stones or clots

PROGNOSIS • Generally excellent for common causes of hematuria • Poorer for malignant tumors and certain types of nephritis • Persistent asymptomatic microscopic hematuria is associated with an increased risk of end-stage renal disease in patients aged 16 to 25 years.

REFERENCES 1. Davis R, Jones JS, Barocas DA, et al. Diagnosis, evaluation and follow-up of asymptomatic microhematuria (AMH) in adults: AUA guideline. J Urol. 2012;188(6 Suppl):2473–2481. 2. Shen L, Raman SS, Beland MD, et al; for the Expert Panel on Urologic Imaging. ACR Appropriateness Criteria® Hematuria. Reston, VA: American College of Radiology; 2014. 3. Dillman JR, Coley BD, Karmazyn B, et al; for the Expert Panel on Pediatric Imaging. ACR Appropriateness Criteria® Hematuria—Child. Reston, VA: American College of Radiology; 2012. http://www.guideline.gov/content.aspx?id=43874. Accessed September 12, 2016. 4. Smith-Bindman R, Aubin C, Bailitz J, et al. Ultrasonography versus computed tomography for suspected nephrolithiasis. N Engl J Med. 2014;371(12):1100–1110. 5. Massengill SF. Hematuria. Pediatr Rev. 2008;29(10):342–348.

SEE ALSO Algorithm: Hematuria

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CODES ICD10 • R31.9 Hematuria, unspecified • R31.1 Benign essential microscopic hematuria • R31.0 Gross hematuria

CLINICAL PEARLS • Screening asymptomatic patients for microscopic hematuria is an “I” recommendation from the USPSTF. • Asymptomatic hematuria and hematuria persisting after treatment of UTIs must be evaluated. • Patients with bladder cancer can have intermittent microscopic hematuria; a thorough evaluation in high-risk patients is needed after just one episode. • Routine use of anticoagulants should not cause hematuria unless there is an underlying urologic abnormality. • Signs of underlying renal disease indicate the need for a nephrologic workup, but a urologic evaluation is still needed in the presence of persistent hematuria (1)[C].

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HEMOCHROMATOSIS Robert A. Marlow, MD, MA BASICS DESCRIPTION Hemochromatosis is a hereditary disorder in which the small intestine absorbs excessive iron (1,2). • Early clinical features include fatigue, arthralgia, and decreased libido. • Late effects include cirrhosis of the liver, diabetes, hypermelanotic pigmentation of the skin, and heart failure. • Because there is no mechanism to excrete excess iron, the excess is stored in muscle and in organs, including the liver, pancreas, and heart, eventually resulting in severe damage to the affected organs. • Liver damage (cirrhosis) ultimately may result in hepatocellular carcinoma. • System(s) affected: endocrine/metabolic • Synonym(s): bronze diabetes; Troisier-Hanot-Chauffard syndrome

EPIDEMIOLOGY Incidence • Predominant age: Metabolic abnormality is congenital, but symptoms usually present in the 5th and 6th decades. • Predominant sex: gene frequency: male = female, although clinical signs are more frequent in men (3)

Prevalence • 3/1,000 people (heterozygote frequency, 1/10) (4) • The most common genetic abnormality in the United States

Pediatric Considerations Rarely, iron overload may occur as early as 2 years of age. The disorder can be diagnosed before iron overload is clinically apparent.

ETIOLOGY AND PATHOPHYSIOLOGY • Type 1 hemochromatosis is caused by mutations in the HFE gene, type 2 by

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mutations in either the HFE2 gene or HAMP gene, type 3 by mutations in the TFR2 gene, and type 4 by mutations in the SLC40A1 gene. The cause of neonatal hemochromatosis is unknown. • The mechanism for increased iron absorption in the face of excessive iron stores is not clear. Iron metabolism appears normal in this disease except for a higher level of circulating iron. • Iron overload may be caused by thalassemia, sideroblastic anemia, liver disease, excess iron intake, or chronic transfusion.

Genetics • Genetically heterogeneous disorder of iron overload; types 1, 2, and 3 are autosomal recessive; type 4 is autosomal dominant. Neonatal hemochromatosis is rare. • Penetrance is incomplete; expressivity is variable. • Factors contributing to variable expressivity include different mutations in the same gene, mitigating or exacerbating genes, and environmental factors.

RISK FACTORS • The disease is a genetic disorder. • Affected individuals should not ingest iron supplements; eat raw shellfish; or eat large quantities of iron-rich food, such as red meat. • Alcohol increases the absorption of iron. (As many as 41% of patients with symptomatic disease are alcoholic.) • Loss of blood, such as that which occurs during menstruation and pregnancy, delays the onset of symptoms.

GENERAL PREVENTION • Family members of affected individuals should be screened. • Pregnant women with the disorder should avoid iron supplements.

ALERT Screening of the general population is not recommended because the vast majority of those with homozygous hemochromatosis will remain asymptomatic and have a normal life span (5,6)[A].

COMMONLY ASSOCIATED CONDITIONS

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See “Complications.”

DIAGNOSIS HISTORY • Weakness • Arthralgia • Abdominal pain • Loss of libido or potency • Amenorrhea • Dyspnea on exertion • Neurologic symptoms • Symptoms of diabetes

PHYSICAL EXAM • Hepatomegaly • Increased skin pigmentation • Loss of body hair • Splenomegaly • Peripheral edema • Jaundice • Gynecomastia • Ascites • Testicular atrophy • Hepatic tenderness

DIFFERENTIAL DIAGNOSIS • Repeated transfusions • Hereditary anemias with ineffective erythropoiesis • Alcoholic cirrhosis • Porphyria cutanea tarda • Atransferrinemia • Excessive ingestion of iron (rare)

DIAGNOSTIC TESTS & INTERPRETATION

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• Transferrin saturation (serum iron concentration ÷ total iron-binding capacity × 100): >70% is virtually diagnostic of iron overload; ≥45% warrants further evaluation. Iron supplements and transfusions may elevate serum iron. • Serum ferritin: >300 μg/L for men and postmenopausal women and 200 μg/L for premenopausal women (7); may be elevated by inflammatory reactions, other forms of liver disease, certain tumors (e.g., acute granulocytic leukemia), and rheumatoid arthritis • After the diagnosis is established – Obtain an oral glucose tolerance test or hemoglobin A1C to rule out diabetes; consider echocardiogram to rule out cardiomyopathy if clinical or biochemical abnormalities. – Consider abdominal US to assess for cirrhosis. – Decreased FSH – Decreased LH – Decreased testosterone – Increased serum aspartate transaminase (AST) – Hypoalbuminemia • If the diagnosis is uncertain after laboratory testing, MRI may be helpful to assess hepatic iron (1).

Diagnostic Procedures/Other • Liver biopsy for stainable iron is the standard for diagnosis. Presence or absence of cirrhosis also can be ascertained. However, with the availability of genetic testing, liver biopsy is not frequently necessary to confirm the diagnosis (7)[C]. • DNA PCR testing for HFE gene mutations C282Y and H63D: present in 85– 90% of patients • Homozygosity for the C282Y mutation or compound heterozygosity for C282Y and H63D with biochemical evidence for iron overload can confirm the diagnosis (8).

Test Interpretation • Increased hepatic parenchymal iron stores • Hepatic fibrosis and cirrhosis with hepatomegaly • Pancreatic enlargement

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• Excess hemosiderin in liver, pancreas, myocardium, thyroid, parathyroid, joints, skin • Cardiomegaly • Joint deposition of iron

TREATMENT MEDICATION • None. Only when phlebotomy is not feasible or in the presence of severe heart disease should the iron-chelating agent deferoxamine (Desferal) be considered. • Hepatitis A and hepatitis B immunizations should be done if there is no evidence of previous exposure (9).

GENERAL MEASURES • Remove excess iron by repeated phlebotomy once or twice weekly to establish and maintain a mild anemia (hematocrit of 35–39%) (7)[C]. • When the patient finally becomes iron deficient, a lifelong maintenance program of 2 to 6 phlebotomies a year to keep storage iron normal; maintain serum ferritin 50 to 100 μg/L.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS Outpatient treatment

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Full activity unless there is significant heart disease

Patient Monitoring • Measure hematocrit before each phlebotomy; skip phlebotomy if hematocrit is 40%.

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• When anemia becomes refractory, repeat transferrin saturation and serum ferritin to confirm depletion of iron stores. • When iron stores are depleted, 2 to 6 phlebotomies a year should keep iron stores normal; maintain serum ferritin 50 to 100 μg/L. • During maintenance therapy, measure transferrin saturation and serum ferritin yearly.

DIET • An iron-poor diet is not of significant benefit. • Avoid alcohol, iron-fortified foods, iron-containing supplements, and uncooked shellfish (increased susceptibility to Vibrio sp.). • Restrict vitamin C to small doses between meals. • Tea chelates iron and may be drank with meals.

PATIENT EDUCATION • Iron Disorders Institute, PO Box 675, Taylors, SC 29687 • American Hemochromatosis Society, Inc., PO Box 950871, Lake Mary, FL 32795-0871

PROGNOSIS • Patients diagnosed before cirrhosis develops and treated with phlebotomy have a normal life expectancy. • Life expectancy is reduced in patients with cirrhosis and DM and in those who require >18 months of phlebotomy therapy to return iron stores to normal. • Patients with ferritin levels AST • Alkaline phosphatase: mildly elevated • Bilirubin: conjugated and unconjugated fractions usually increased. Bilirubin rises typically follow rise in ALT/AST, consistent with hepatocellular injury pattern. • Prothrombin time and partial thromboplastin time usually remain normal or near normal. – Significant rises should raise concern for acute hepatic failure or coexisting chronic liver disease. • CBC: mild leukocytosis; aplasia and pancytopenia – Thrombocytopenia may predict illness severity. – Autoimmune hemolytic anemia (rare) • Albumin, electrolytes, and glucose to evaluate for hepatic and renal function (rare renal failure) • Urinalysis (not clinically necessary): bilirubinuria • Consider ultrasound (US) to rule out biliary obstruction only if lab pattern is cholestatic. Follow-Up Tests & Special Considerations Illness usually resolves within 4 weeks of symptom onset. Repeat labs are not

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indicated unless symptoms persist or new symptoms develop.

Diagnostic Procedures/Other Liver biopsy is usually not necessary. US can evaluate other causes (e.g., thrombosis or concurrent cirrhosis).

Test Interpretation • Positive serum markers in hepatitis A – Acute disease: anti-HAV IgM only – Recent disease (last 6 months): anti-HAV IgM and IgG positive – Previous disease: anti-HAV IgM negative and IgG positive • If liver biopsy obtained, shows portal inflammation; immunofluorescent stains for HAV antigen positive

TREATMENT GENERAL MEASURES • Maintain appropriate nutrition/hydration. • Avoid alcohol. • Universal precautions to prevent spread • Monitor coagulation defects, fluid, electrolytes, acid–base imbalance, hypoglycemia, and renal function. • Report cases to local public health department. • Laboratory evaluation including coagulation factors is important to rule out fulminant hepatic failure. • Referral to liver transplant center for fulminant failure (rare)

MEDICATION • Preexposure vaccination should be given according to recommended guidelines. Both hepatitis A vaccines the US (Havrix, Vaqta) require two doses. • For travelers, the ACIP recommends administering the first dose as soon as possible with any planned travel to endemic areas (1)[C]. – For healthy individuals 40 years or younger, vaccination is sufficient up to the day or departure (1)[C].

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– Immunoglobulin (0.02 mL/kg) should also be given to anyone >40 years or with chronic medical conditions if less than 2 weeks from planned departure (1)[C]. • Give postexposure prophylaxis to persons who have not previously received HAV vaccine within 2 weeks of exposure to HAV (3)[A],(4)[C]. – Administer hepatitis A vaccine to healthy persons between the ages of 1 and 40 years at age-appropriate dose (5)[A]. – Administer immunoglobulin (0.02 mL/kg) to persons 40 years of age or to patients with significant comorbidities (immunosuppression, liver disease) who are at risk for poor immune response (3)[A],(4)[C]. • Use immunoglobulin for passive preexposure prophylaxis in those not eligible for the vaccine (3)[A],(4)[C]. – 0.02 mL/kg provides 1 to 2 months of coverage; 0.06 mL/kg provides 3 to 5 months of coverage – Long-term prophylaxis should be with 0.06 mL/kg every 5 months for sustained risk (e.g., travelers). – Use immunoglobulin alone in children 50 years)

COMPLICATIONS • Coagulopathy, encephalopathy, and renal failure • Relapsing HAV: usually milder than the initial case • Positive anti-HAV IgM. Total duration is usually 3 months), resolves without intervention (supportive care only) • Autoimmune hepatitis: can be seen after HAV infection; good response to steroids • Hepatic failure: rare (1–2%) • Postviral encephalitis, Guillain-Barré syndrome, pancreatitis, aplastic or hemolytic anemia, agranulocytosis, thrombocytopenic purpura, pancytopenia, arthritis, vasculitis, and cryoglobulinemia (all rare)

REFERENCES 1. Centers for Disease Control and Prevention. Hepatitis A questions and answers for health professionals. http://www.cdc.gov/hepatitis/hav/havfaq.htm. Accessed August 8, 2016. 2. Irving GJ, Holden J, Yang R, et al. Hepatitis A immunisation in persons not previously exposed to hepatitis A. Cochrane Database Syst Rev. 2012; (7):CD009051. 3. Liu JP, Nikolova D, Fei Y. Immunoglobulins for preventing hepatitis A. Cochrane Database Syst Rev. 2009;(2):CD004181. 4. Fiore AE, Wasley A, Bell BP. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006;55(RR-7):1–23. 5. Victor JC, Monto AS, Surdina TY, et al. Hepatitis A vaccine versus immune globulin for postexposure prophylaxis. N Engl J Med. 2007;357(17):1685– 1694.

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SEE ALSO • Hepatitis B; Hepatitis C • Algorithm: Hyperbilirubinemia, Cirrhosis, and Jaundice

CODES ICD10 B15.9 Hepatitis A without hepatic coma

CLINICAL PEARLS • HAV vaccine is indicated for all children, travelers, those at elevated risk of disease, and anyone with liver impairment. • Check HAV IgG in all HIV-positive patients; provide HAV vaccine to those who are negative. • HAV disease severity directly correlates with age; children are often asymptomatic. • Treatment of acute disease is supportive. • Give postexposure prophylaxis to eligible patients within 14 days of exposure.

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HEPATITIS B Jason Chao, MD, MS • Navpreet K. Singh, MD BASICS DESCRIPTION Systemic viral infection associated with acute and chronic liver disease and hepatocellular carcinoma (HCC)

EPIDEMIOLOGY Incidence • Predominant age: can infect patients of all ages • Predominant sex: fulminant hepatitis B virus (HBV): male > female (2:1) • In the United States, ~3,000 cases of acute HBV reported in 2014 • African Americans have the highest rate of acute HBV infection in the United States. • Overall rate of new infections is down 82% since 1991 (due to national immunization strategy). • U.S. vaccine coverage for the birth dose of HBV increased from 69% in 2011 to 72% in 2012.

Prevalence • In the United States, 800,000 to 1.4 million people have chronic HBV. • Asia and the Pacific Islands have the largest populations at risk for HBV. • Chronic HBV worldwide: 350 to 400 million persons – 1 million deaths annually Second most important carcinogen (behind tobacco) Of chronic carriers with active disease, 25% die due to complications of cirrhosis or HCC. Of chronic carriers, 75% are Asian.

ETIOLOGY AND PATHOPHYSIOLOGY HBV is a DNA virus of the Hepadnaviridae family. Highly infectious via blood and secretions

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Genetics Family history of HBV and/or HCC

RISK FACTORS • Screen the following high-risk groups for HBV with HBsAg/sAb. Vaccinate if seronegative (1)[A]: – Persons born in endemic areas (45% of world) – Hemodialysis patients – IV drug users (IVDUs), past or present – Men who have sex with men (MSM) – HIV- and HCV-positive patients – Household members of HBsAg carriers – Sexual contacts of HBsAg carriers – Inmates of correctional facilities – Patients with chronically elevated aspartate aminotransferase/alanine aminotransferase (AST/ALT) levels • Additional risk factors: – Needle stick/occupational exposure – Recipients of blood/products; organ transplant recipients – Intranasal drug use – Body piercing/tattoos – Survivors of sexual assault

Pediatric Considerations • Shorter acute course; fewer complications • 90% of vertical/perinatal infections become chronic

Pregnancy Considerations • Screen all prenatal patients for HBsAg (1)[A]. • Consider treating patients with high viral load at 28 weeks or hx of previous HBV (+) infant with oral nucleos(t)ide medicines beginning at 32 weeks to reduce perinatal transmission (2)[C]. • Infants born to HBV-infected mothers require HB immune globulin (HBIg) (0.5 mL) and HBV vaccine within 12 hours of birth. • Breastfeeding is safe if HBIg and HBV vaccines are administered and the

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areolar complex is without fissures or open sores. Oral nucleos(t)ide medications are not recommended during lactation. • HIV coinfection increases risk of vertical transmission. • Continue medications if pregnancy occurs while on an oral antiviral therapy to prevent acute flare.

GENERAL PREVENTION Most effective: HBV vaccination series (three doses) • Vaccinate – All infants at birth and during well-child care visits – All at-risk patients (see “Risk Factors”) – Health care and public safety workers – Sexual contacts of HBsAg carriers – Household contacts of HBsAg carriers • Proper hygiene/sanitation by health care workers, IVDU, and tattoo/piercing artists – Barrier precautions, needle disposal, sterilize equipment, cover open cuts • Do not share personal items exposed to blood (e.g., nail clipper, razor, toothbrush). • Safe sexual practices (condoms) • HBsAg carriers cannot donate blood or tissue. • Postexposure (e.g., needle stick): HBIg 0.06 mL/kg in 6 months defines chronic HBV: • Measure HBV DNA level and ALT every 3 to 6 months. • If age >40 years and ALT borderline or mildly elevated, consider liver biopsy. • Measure baseline AFP. • Follow HBeAg for elimination (every 6 to 12 months). • Lifetime monitoring for progression, need for treatment, and screening for HCC

Diagnostic Procedures/Other • Liver biopsy • Noninvasive tests (Hepascore, Fibrotest) or measurement of elastography (Fibroscan) to assess for hepatic fibrosis

Test Interpretation Liver biopsy in chronic HBV may show interface hepatitis and inflammation, necrosis, cholestasis, fibrosis, cirrhosis, or chronic active hepatitis.

TREATMENT

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GENERAL MEASURES • Vaccinate for HAV if seronegative. • Monitor CBC, coagulation, electrolytes, glucose, renal function, and phosphate. • Monitor ALT and HBV DNA; increased ALT and reduced DNA implies response to therapy. • Screen for HCC if HBsAg+.

MEDICATION First Line • Acute HBV – Supportive care; spontaneously resolves in 95% of immunocompetent adults – Antiviral therapy not indicated except for fulminant liver failure or immunosuppressed • Chronic HBV: Treatment is based on HBeAg status: – FDA-approved drugs: lamivudine 100 mg, adefovir 10 mg, entecavir 0.5 to 1 mg, telbivudine 600 mg, or tenofovir 300 mg, all given PO every day (dose based on renal function); pegylated interferon (peg-IFN) α2a, α2b SC weekly (3)[A] • Entecavir, tenofovir, and peg-IFN are preferred first-line agents (3)[A]. • Extended oral regimens are indicated (3)[A]: – If HBeAg+, treat 6 to 12 months postloss of HBeAg and gain of HBeAb, and monitor after cessation. – If HBeAg−, treat indefinitely or until HBsAg clearance and HBsAb development. • Change/add drug based on resistance: – Confirm medication adherence before assuming resistance. – Adherence to therapy lowers rate of resistance. • Adjust dosing for renal function. • Peg-IFN preferred to standard interferon: – Weekly peg-IFN (Pegasys) injections for 48 weeks – Most efficacious for genotype A – Contraindicated if decompensated cirrhosis

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• Goals of therapy: undetectable HBV DNA, normal ALT, loss of HBeAg, gain of HBeAb; loss of HBsAg and gain of HBsAb • Precautions: – Oral drugs: renal insufficiency – Peg-IFN: coagulopathy, myelosuppression, depression/suicidal ideation

Second Line Emtricitabine suppresses viral load; not FDA approved

ISSUES FOR REFERRAL • Refer all persistent HBsAg+ patients to evaluate for potential antiviral therapy. • Immediate referral for liver transplant if fulminant acute hepatitis, end-stage liver disease, or HCC

SURGERY/OTHER PROCEDURES Liver transplantation, operative resection, radiofrequency ablation for HCC

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Worsening course (marked increase in bilirubin, transaminases, or symptoms) • Hepatic failure (high PT, encephalopathy)

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Serial ALT and HBV DNA: – High ALT + low HBV DNA associated with favorable response to therapy • Serologic markers: See table.

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• CBC for WBC and platelets if on interferon therapy • Monitor HBV DNA q3–6mo during therapy: – Undetectable DNA at week 24 of oral drug therapy associated with low resistance at year 2 • Monitor for complications (ascites, encephalopathy, variceal bleed) in cirrhosis. • Vaccinate household contacts and sexual partners. • Ultrasound q6–12mo to screen for HCC starting at age 40 years in men and age 50 years in women (3)[B].

DIET Avoid alcohol.

PATIENT EDUCATION • Acute HBV – Review transmission precautions. • Chronic HBV – Alcohol and tobacco use accelerate progression. – Emphasize medication compliance to prevent flare. • Patient education materials: http://www.cdc.gov/hepatitis/Resources/PatientEdMaterials.htm

PROGNOSIS • Acute infection: 95% of adults recover. • Severity of encephalopathy predicts survival in fulminant hepatic failure. • Acute HBV: mortality 1% • Acute HBV + HDV: mortality 2–20%

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• Chronic HBV – Spontaneous resolution: 0.5% per year – Premature death from cirrhosis or HCC: 25% – Risk of HCC rises with rate of viral replication, even if no cirrhosis.

COMPLICATIONS • Hepatic necrosis; cirrhosis; hepatic failure • HCC (all chronic HBV patients are at risk) • Severe flare of chronic HBV with corticosteroids and other immunosuppressants: Avoid if possible. • Reactivation of infection if immunosuppressed (e.g., chemotherapy): Premedicate prophylactically if HBsAg+ or if HBcAb+ and receiving systemic chemotherapy (1)[A].

REFERENCES 1. Weinbaum CM, Williams I, Mast EE, et al. Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. MMWR Recomm Rep. 2008;57(RR-8):1–20. 2. Borgia G, Carleo MA, Gaeta GB, et al. Hepatitis B in pregnancy. World J Gastroenterol. 2012;18(34):4677–4683. 3. McMahon BJ. Chronic hepatitis B virus infection. Med Clin North Am. 2014;98(1):39–54.

ADDITIONAL READING • Centers for Disease Control and Prevention. Updated CDC recommendations for the management of hepatitis B virus–infected health-care providers and students. MMWR Recomm Rep. 2012;61(RR-3):1–12. • Terrault NA, Bzowej NH, Chang K-M, et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology. 2016;63(1):261–283.

SEE ALSO • Cirrhosis of the Liver; Hepatitis A; Hepatitis C

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• Algorithm: Hyperbilirubinemia, Cirrhosis, and Jaundice

CODES ICD10 • B19.10 Unspecified viral hepatitis B without hepatic coma • B16.9 Acute hepatitis B w/o delta-agent and without hepatic coma • B18.1 Chronic viral hepatitis B without delta-agent

CLINICAL PEARLS • All patients born in endemic countries should be screened for HBV infection with HBsAg. • Patients with chronic HBV need lifetime monitoring for disease progression and HCC. • HBV is the second most common worldwide carcinogen (behind tobacco).

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HEPATITIS C Christopher Lin-Brande, MD • Amy M. Davis, MD BASICS DESCRIPTION Systemic viral infection (acute and chronic) primarily involving liver

EPIDEMIOLOGY • Highest incidence ages 20 to 39 years; highest prevalence ages 40 to 59 years • Males and non-Hispanic blacks (1).

Geriatric Considerations Age >60 years less responsive to therapy; treat early.

Pregnancy Considerations • Routine HCV testing is not indicated. • Vertical transmission 6/100 births; risk doubles if HIV coinfection. • Breastfeeding is safe if no fissures.

Pediatric Considerations • Prevalence: 0.3% • Test children born to HCV-positive mothers with HCV Ab at 18 months or HCV RNA at 1 to 2 months • More likely to clear spontaneously; slower rate of progression

Incidence Incidence has been rising since 2010. In 2014, there were 2,194 cases of acute HCV reported to the CDC, with an estimated 30,500 total new cases in the United States.

Prevalence • 2.7 to 3.9 million in the US have chronic HCV (Ab+). • Prevalence highest if born 1945 to 1965 (2.6%) (1). • HCV-related deaths are more common than HIV-related deaths. • HCV is most common cause of chronic liver disease and transplantation in US

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• Six genotypes (GT) are known with .50 subtypes. GT 1 is predominant form in the US (75%). GT predicts response to treatment.

ETIOLOGY AND PATHOPHYSIOLOGY Single-stranded RNA virus of Flaviviridae family

RISK FACTORS • Exposure risks – Chronic hemodialysis – Blood/blood product transfusion or organ transplantation before July 1992 – Hemophilia treatment before 1987 – Household or health care–related exposure to HCV-infected body fluids (1.8% risk) – Children born to HCV-positive mothers • Risk behaviors and/or medical conditions – Prior history of injection drug use – Intranasal illicit drug use – History of incarceration – Tattooing in unregulated settings – Current sexual partners of HCV-positive persons – HIV and hepatitis B infection

GENERAL PREVENTION • Primary prevention – Do not share razors/toothbrushes/nail clippers. – Use and dispose needles properly through harm reduction programs. – Practice safer sex. – Cover cuts and sores. • Secondary prevention – No vaccine or postexposure prophylaxis available – Substance abuse treatment – Reinforce use of barrier contraception for HIV-seropositive coinfected with HCV. – Assess for degree of liver fibrosis/cirrhosis.

COMMONLY ASSOCIATED CONDITIONS

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Diabetes, metabolic syndrome, iron overload, depression, substance abuse/recovery, autoimmune and hematologic disease, HIV, and hepatitis B coinfection

DIAGNOSIS HISTORY • Determine exposure risk: detailed social history including alcohol and IV drug use, psychiatric and medical comorbidities, coinfections • Chronic HCV: Most cases are mildly symptomatic (nonspecific fatigue) or asymptomatic (elevated alanine/aspartate aminotransferase-ALT, AST). • Acute HCV: If symptoms develop (rare) – Onset typically 4 to 12 weeks postexposure – Jaundice, dark urine, steatorrhea, nausea, abdominal pain (right upper quadrant [RUQ]), fatigue, low-grade fevers, myalgias, arthralgias

PHYSICAL EXAM • Typically normal unless advanced fibrosis/cirrhosis • May have RUQ tenderness/hepatomegaly • Spider angioma, caput medusa, palmar erythema, jaundice, gynecomastia, Terry nails • Arthralgias/myalgias, neuropathy, glomerulonephritis, livedo reticularis, lichen planus, pruritus, sicca syndrome, cold agglutinin disease

DIFFERENTIAL DIAGNOSIS Hepatitis A or B; Epstein-Barr virus (EBV), cytomegalovirus (CMV); alcoholic hepatitis; nonalcoholic steatohepatitis (NASH); hemochromatosis; Wilson disease, α1–antitrypsin deficiency; ischemic, drug-induced, or autoimmune hepatitis

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Screening for adults born between 1945 and 1965, exposure risks, current and former IV drug users, HIV-positive individuals, men who have sex with men (MSM) and persistently elevated ALT.

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• CDC algorithm – HCV Ab If nonreactive, no further action unless recent exposure is suspected (test with HCV RNA). If reactive, test HCV RNA. – HCV RNA If not detected, no current HCV infection. No further action. • HCV Ab detected 3–12 weeks after infection. • HCV RNA detected 1–2 weeks after infection. • RNA detectability precedes ALT elevation. • AST/ALT: often normal but may be persistently elevated in chronic HCV; ALT usually is 1 to 2 times upper limit of normal; AST may be normal/elevated, but typically less so than ALT. – Acute hepatitis C can cause marked elevation of transaminases and bilirubin (direct and indirect). • AST/ALT ratio ≥1 associated with cirrhosis – If AST/ALT ratio >2, rule out alcohol abuse. • Persistent HCV RNA >6 months = chronic HCV Follow-Up Tests & Special Considerations • CBC metabolic panel, TSH (if using PEG), vitamin D (may predict response) • Hepatic function panel, coagulation factors • HCV GT and resistance testing • IL28B testing: C/C homozygote more likely to clear • HBV and HIV coinfection • Vaccinate if seronegative for hepatitis A/B. • Pneumococcal polysaccharide vaccine (PPSV23)

Diagnostic Procedures/Other Evaluate for advanced hepatic fibrosis. • Indirect markers: AST-to-platelet ratio index (APRI), FIB-4, FibroIndex, Forns index, HepaScore/FibroScore, FibroSure – Factors such as age, gender, AST, ALT, platelets, bilirubin estimate fibrosis. • Direct markers: FIBROSpect II • Liver imaging: US, CT scan, MRI, transient ultrasound elastography, MR

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elastography • Liver biopsy (gold standard) – Indications: discordant indirect marker results, concurrent non-HCV liver disease, elastography not available – Not necessary to diagnose hepatocellular carcinoma if diagnosis is clear based on imaging

Test Interpretation • Biopsy measures grade (degree of inflammation) and stage (amount of existing fibrosis) • Scoring systems: Batts and Ludwig, METAVIR, International Association for the Study of the Liver (IASL)

TREATMENT GENERAL MEASURES • Report acute HCV to health department. • Consider treating all patients who demonstrate virologic evidence of HCV. • Pretreatment counseling includes a thorough behavioral health and substance abuse history. • Optimize medical therapy for comorbid conditions prior to treatment. • Discuss treatment plan and likelihood of success based on individual factors such as BMI, genotype, race, stage of fibrosis, and viral load. • Goal is sustained virologic response (SVR): undetectable HCV RNA after 12 to 24 weeks of treatment • HCV cascade: Of those with chronic HCV, only 50% are diagnosed, 25% are HCV RNA confirmed, 15% are prescribed treatment, and 10% achieve SVR (2).

MEDICATION First Line • Acute HCV: Treatment may be delayed 12 to 16 weeks after suspected inoculation to allow chance for spontaneous clearance. Regimen is the same as for chronic HCV.

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• Chronic HCV treatment traditionally based on pegylated interferon (PEG) and ribavirin (RBV) is poorly tolerated. – Major side effects: depression, fatigue, insomnia, headache • New oral-only agents more tolerable (but expensive)

ISSUES FOR REFERRAL

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• Involve a consultant experienced with HCV. • Refer to liver transplant program if fulminant acute hepatitis, at first complication of end-stage disease, or at diagnosis of HCC.

COMPLEMENTARY & ALTERNATIVE MEDICINE No evidence for effective complementary therapy in HCV/cirrhosis/HCC.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS • Treat early to prevent fibrosis. If cirrhosis is already present, treatment may not prevent decompensation. • Monitor serial viral load only if on antiviral therapy. • Consider abdominal ultrasound every 6 to 12 months to monitor for hepatocellular carcinoma (expert opinion). AFP is no longer in AASLD guidelines.

Patient Monitoring • Serial ALT/AST, renal function, and CBCs • For 12-week course, follow-up 4 weeks after starting therapy and 12 weeks after completing therapy – 4-week HCV RNA: If detectable, recheck at week 6. If RNA has increased >10 times, stop therapy. – SVR12: Undetectable HCV RNA 12 weeks after completing therapy generally translates to long-term cure (goal of therapy). • SVR decreases risk of portal hypertension, hepatic decompensation, and hepatocellular carcinoma (HCC). Monitor for decompensation (low albumin, ascites, encephalopathy, GI bleed).

DIET • Low-fat, high-fiber diet and exercise to treat obesity/fatty liver • Extra protein and fluids while on IFN therapy

PATIENT EDUCATION • Avoid alcohol, tobacco, and illicit drugs (including marijuana); refer to

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rehabilitation/12-step program and monitor for relapse as appropriate. • Warn against claims of false cures. • Caution with nutritional supplements and hepatotoxic medications (may contain hepatotoxins) • http://www.cdc.gov/knowmorehepatitis/

PROGNOSIS • For every 100 persons infected with HCV – 75 to 85 will develop chronic infection. – 60 to 70 will develop chronic liver disease. – 10 to 20 will develop cirrhosis over 20 to 30 years (more rapid if older age at infection, male gender, alcohol/substance abuse, HIV/HBV coinfection, or diabetes/insulin resistance). 1–5% annual risk of HCC 3–6% annual risk of hepatic decompensation • Chronic HCV is curable in ~70% of cases; in noncirrhotic genotype 2 or 3, cure rate is ~90%.

COMPLICATIONS • Fibrosis and cirrhosis typically develop within the first 5 to 10 years of infection. • Acute/subacute hepatic necrosis, liver failure, hepatocellular carcinoma, transplant and complications, death • Risk factors for cirrhosis: age, white race, hypertension, alcohol use, anemia. Risk for decompensation: diabetes, hypertension, anemia

REFERENCES 1. Denniston MM, Jiles RB, Drobeniuc J, et al. Chronic hepatitis C virus infection in the United States, National Health and Nutrition Examination Survey 2003 to 2010. Ann Intern Med. 2014;160(5):293–300. 2. Yehia BR, Schranz AJ, Umscheid CA, et al. The treatment cascade for chronic hepatitis C virus infection in the United States: a systematic review and meta-analysis. PLoS One. 2014;9(7):e101554.

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SEE ALSO • Hepatitis A; Hepatitis B; Cirrhosis of the Liver; HIV/AIDS • Algorithm: Jaundice • http://www.hepatitisc.uw.edu/ • http://www.hcvguidelines.org/

CODES ICD10 • B19.20 Unspecified viral hepatitis C without hepatic coma • B17.10 Acute hepatitis C without hepatic coma • B18.2 Chronic viral hepatitis C

CLINICAL PEARLS • 1 of every 10 patients with hepatitis C has no identifiable risk factors. • 15–25% of HCV-infected persons spontaneously resolve their infection without specific treatment. • Look for coinfections (HBV/HIV) and comorbid substance abuse in patients infected with HCV.

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HERNIA Margaret Fairhurst, DO BASICS DESCRIPTION Hernias are areas of weakness or frank disruption of the fibromuscular tissues of the body wall through which intracavity structures pass. • Types – Inguinal Direct inguinal: acquired; herniation through defect in transversalis fascia of abdominal wall medial to inferior epigastric vessels; increased frequency with age as fascia weakens Indirect inguinal: congenital; herniation lateral to the inferior epigastric vessels through internal inguinal ring into inguinal canal. A “complete hernia” is one that descends into the scrotum, whereas an “incomplete hernia” remains within the inguinal canal. – Pantaloon: combination of direct and indirect inguinal hernia with protrusion of abdominal wall on both sides of the epigastric vessels – Femoral: herniation that descends through the femoral canal deep to the inguinal ligament. Because of the narrow neck of a femoral hernia, this type of hernia is especially prone to incarceration and strangulation. – Incisional or ventral: herniation through a defect in the anterior abdominal wall at the site of a prior surgical incision – Congenital: herniation through fascial defect in abdominal wall, secondary to collagen deficiency disease – Umbilical: Defect occurs at umbilical ring tissue. – Epigastric: protrusion through the linea alba above the level of the umbilicus. These may develop at exit points of small paramidline nerves and vessels, or through an area of congenital weakness in the linea alba. – Interparietal (e.g., Spigelian hernia): Hernia sac insinuates itself between layers of the abdominal wall; strangulation common, often mistaken for tumor or abscess.

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– Other: obturator, sciatic, perineal • Definitions – Reducible: Extruded sac and its contents can be returned to original intraabdominal position, either spontaneously or with gentle manual manipulation. – Irreducible/incarcerated: Extruded sac and its contents cannot be returned to original intra-abdominal position. – Strangulated: Blood supply to hernia sac contents is compromised. – Richter: Partial circumference of the bowel is incarcerated or strangulated. Partial wall damage may occur, increasing potential for bowel rupture and peritonitis. – Sliding: wall of a viscus forms part of the wall of the inguinal hernia sac (i.e., R-cecum, L-sigmoid colon)

Geriatric Considerations Abdominal wall hernias increase with advancing age, with significant increase in risk during surgical repair.

Pregnancy Considerations • Increased intra-abdominal pressure and hormone imbalances with pregnancy may contribute to increased risk of abdominal wall hernias. • Umbilical hernias are associated with multiple, prolonged deliveries.

EPIDEMIOLOGY Incidence • 75–80% groin hernias: inguinal and femoral • 2–20% incisional/ventral, depending on whether a prior surgery was associated with infection or contamination • 3–10% umbilical, considered congenital • 1–3% other • Groin – 6–27% lifetime risk in adult men – Two-peak theory: most inguinal hernias present before 1 year of age or after 55 years of age – ∼50% of children 3 months of age) immunocompetent is weight-based dosing (40 to 80 mg/kg/day [max 1,000 mg/day] divided q8h for 5 to 7 days). – Safe in pregnancy and lactation—Category B – Recurrent herpes labialis: 800 to 1,600 mg/day for prevention (3,4,5)[B] • Penciclovir (Denavir): 1% cream. Apply to oral lesions q2h during waking hours for 4 days (6)[B]. • Valacyclovir (Valtrex) – Primary genital herpes: 1 g PO BID for 7 to 10 days. Recurrent genital herpes: 500 mg PO BID for 3 days; suppression: 500 to 1,000 mg PO daily (depending on frequency of outbreaks); labialis HSV (cold sores/oral lesions): 2,000 mg PO q12h for 1 day (3,4,5)[B] – 500-mg daily dose if suppression is needed/desired – Recurrent herpes labialis: 500 mg/day for 4 months for prevention (3,4)[B] • Famciclovir (Famvir) – Primary genital herpes: 250 mg PO TID for 7 to 10 days – Recurrence: 125 mg PO BID for 5 days or 1,000 mg PO BID for 1 day

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– Suppression: 250 mg PO BID • Precautions – Renal dosing for all oral antivirals – Significant possible interactions: Probenecid with IV acyclovir and possibly probenecid with valacyclovir may reduce renal clearance and elevate antiviral drug levels.

Second Line • Foscarnet – Drug of choice for acyclovir resistance in immunocompromised persons with systemic HSV – 40 mg/kg IV q8h (assume valacyclovir and famciclovir resistance also if acyclovir resistance occurs) • Other topicals – Ophthalmic preparations for herpes keratoconjunctivitis; acyclovir, vidarabine (Vira-A), ganciclovir, trifluridine – Topical acyclovir and penciclovir improve recurrent herpes labialis healing times by ~10% (3)[B]. – Topical analgesics: Lidocaine 2% or 5% helps reduce pain associated with vulvar and penile outbreaks. • Over-the-counter topical antivirals: docosanol

ISSUES FOR REFERRAL Refer recurrent cases of herpes keratoconjunctivitis to an ophthalmologist.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Pregnancy considerations – Cesarean section and/or acyclovir are indicated if any active genital lesions (or prodrome) present at time of delivery; consider cesarean delivery if primary genital herpes is suspected within previous 4 weeks (6)[B]. – Daily oral antivirals from 36 weeks onward in women with history of recurrent genital herpes to prevent outbreak near to/at time of delivery – Avoid fetal scalp electrodes, forceps, vacuum extractor, and artificial rupture of membranes if mother has history of genital HSV.

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– Risk of viral shedding at delivery from asymptomatic recurrent genital HSV is low (~1.6%). • Pediatric considerations – Neonates with likely exposure (high index of suspicion) to HSV at birth or those who exhibit signs of HSV infection should have all body fluids cultured and immediately start treatment with IV acyclovir.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS • For most cases, follow-up is not necessary. Lesions and symptoms resolve rapidly within 10 days. Extensive cases should be rechecked in 1 week; monitor for secondary bacterial infections. • Consider long-term suppression.

DIET If oral lesions are present, avoid salty, acidic, or sharp foods (e.g., snack chips, orange juice).

PATIENT EDUCATION • Explain the natural history that timing of exposure is difficult to determine and that the virus will remain in the body indefinitely. Acknowledging and discussing psychological impact of the diagnosis helps to reduce stigmatization. • Emphasize personal hygiene to avoid self-spreading to other body areas (autoinoculation) or exposing others. Frequent hand washing; avoid scratching; cover active, moist lesions. • Reinforce safe sexual practices.

PROGNOSIS • Usual duration of primary disease is 5 days to 2 weeks. • Antiviral treatment shortens duration, reduces complications, and mitigates recurrences (if used for suppression). • Viral shedding during recurrence is briefer than with primary disease; frequency of recurrence is variable and depends on individual host factors.

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• Newborns/immunocompromised individuals are at highest risk for major morbidity/mortality. • HSV is never eliminated from the body but stays dormant in dorsal root ganglia and can reactivate, causing recurrent symptoms and lesions.

COMPLICATIONS • Herpes encephalitis: Brain biopsy may be needed for diagnosis. • Herpes pneumonia

REFERENCES 1. Sauerbrei A. Optimal management of genital herpes: current perspectives. Infect Drug Resist. 2016; 9:129–141. 2. Pinninti SG, Kimberlin DW. Neonatal herpes simplex virus infections. Pediatr Clin North Am. 2013;60(2):351–365. doi:10.1016/j.pcl.2012.12.005. 3. Rahimi H, Mara T, Costella J, et al. Effectiveness of antiviral agents for the prevention of recurrent herpes labialis: a systematic review and metaanalysis. Oral Surg Oral Med Oral Pathol Oral Radiol. 2012;113(5):618– 627. 4. Harmenberg J, Oberg B, Spruance S. Prevention of ulcerative lesions by episodic treatment of recurrent herpes labialis: a literature review. Acta Derm Venereol. 2010;90(2):122–130. 5. Sawleshwarkar S, Dwyer DE. Antivirals for herpes simplex viruses. BMJ. 2015;351:h3350. doi:10.1136/bmj.h3350. 6. Obiero J, Mwethera PG, Wiysonge CS. Topical microbicides for prevention of sexually transmitted infections. Cochrane Database Syst Rev. 2012; (6):CD007961.

ADDITIONAL READING Wang X, Zhou F, Zhao J, et al. Elevated risk of opportunistic viral infection in patients with Crohn’s disease during biological therapies: a meta analysis of randomized controlled trials. Eur J Clin Pharmacol. 2013;69(11):1891–1899.

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SEE ALSO • Herpes, Genital • Algorithm: Genital Ulcers

CODES ICD10 • B00.9 Herpesviral infection, unspecified • A60.00 Herpesviral infection of urogenital system, unspecified • B00.1 Herpesviral vesicular dermatitis

CLINICAL PEARLS • Up to 25–30% of the U.S. population has serologic evidence of genital herpes (HSV-2), and >80% is seropositive for HSV-1. • Most individuals are unaware they are infected, allowing for asymptomatic viral transmission. • Viral suppression therapy for patients with frequent recurrences reduces transmission and decreases outbreak frequency.

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HERPES ZOSTER (SHINGLES) Robert J. Hyde, MD, MA BASICS DESCRIPTION • Results from reactivation of latent varicella-zoster virus (human herpesvirus type 3) infection • Postherpetic neuralgia (PHN) is defined as pain persisting at least 1 month after rash has healed. The term zoster-associated pain is more clinically useful. • Usually presents as a painful unilateral vesicular eruption with a dermatomal distribution • System(s) affected: nervous; integumentary; exocrine • Synonym(s): shingles

EPIDEMIOLOGY Predominant sex: male = female

Incidence • Incidence increases with age. 2/3 of cases occur in adults age ≥50 years. Incidence is increasing overall as the U.S. population ages. • Herpes zoster: 4/1,000 person-years • PHN: 18% in adult patients with herpes zoster; 33% in patients ≥79 years of age

Prevalence Nearly 1 million new cases of herpes zoster annually

Pregnancy Considerations May occur during pregnancy

Geriatric Considerations • Increased incidence of zoster outbreaks • Increased incidence of PHN

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Pediatric Considerations • Occurs less frequently in children • Has been reported in newborns infected in utero

ETIOLOGY AND PATHOPHYSIOLOGY Reactivation of varicella-zoster virus from dorsal root/cranial nerve ganglia. Upon reactivation, the virus replicates within neuronal cell bodies, and virions are carried along axons to dermatomal skin zones, causing local inflammation and vesicle formation.

RISK FACTORS • Increasing age • Immunosuppression (malignancy or chemotherapy) • HIV infection • Spinal surgery

GENERAL PREVENTION • Herpes zoster vaccination (Zostavax) is recommended by Advisory Committee on Immunization Practices (ACIP) for patients ≥60 years (FDA approved for patients >50 years) (1,2): – Vaccine reduces cases of zoster and the incidence of PHN (3,4). • Patients with active zoster may transmit disease-causing varicella virus (chickenpox) to susceptible persons.

COMMONLY ASSOCIATED CONDITIONS Immunocompromised individuals, HIV infection, posttransplantation, immunosuppressive drugs, and malignancy

DIAGNOSIS HISTORY • Prodromal phase (sensory changes over involved dermatome prior to rash) – Tingling, paresthesias – Itching – Boring “knife-like” pain

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• Acute phase – Constitutional symptoms (e.g., fatigue, malaise, headache, low-grade fever) are variable. – Dermatomal rash

PHYSICAL EXAM • Acute phase – Rash: initially erythematous and maculopapular; evolves rapidly to grouped vesicles – Vesicles become pustular and/or hemorrhagic in 3 to 4 days. – Weakness (1% have weakness in distribution of rash) – Resolution of rash, with crusts separating by 14 to 21 days • Possible sine herpete (zoster without rash) and other chronic disorders associated with varicella-zoster virus without the typical rash – Herpes zoster ophthalmicus (HZO). Vesicles on tip of the nose (Hutchinson sign) indicate involvement of the external branch of cranial nerve V; associated with increased incidence of ocular zoster • Chronic phase – PHN (15% overall; increases with age) – A small percentage (1–5%) may affect the motor nerves, causing weakness (zoster motorius), facial nerve (e.g., Ramsay Hunt syndrome), spinal motor radiculopathies.

DIFFERENTIAL DIAGNOSIS • Rash – Herpes simplex virus – Coxsackievirus – Contact dermatitis – Superficial pyoderma • Pain – Cholecystitis – Appendicitis – Nephrolithiasis – Pleuritis – Myocardial infarction

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– Diabetic neuropathy

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) Rarely necessary. Clinical appearance is distinct. Follow-Up Tests & Special Considerations • Viral culture • Tzanck smear (does not distinguish from herpes simplex, and false-negative results occur) • Polymerase chain reaction • Immunofluorescent antigen staining • Varicella-zoster–specific IgM

Test Interpretation • Multinucleated giant cells with intralesional inclusion • Lymphatic infiltration of sensory ganglia with focal hemorrhage and nerve cell destruction

TREATMENT GENERAL MEASURES • Direct treatment to control symptoms and prevent complications • Antiviral therapy decreases viral replication, lessens inflammation and nerve damage, and reduces the severity and duration of long-term pain. • Prompt analgesia may shorten the duration of zoster-associated pain. • Lotions, such as calamine and colloidal oatmeal, may help reduce itching and burning.

MEDICATION First Line • Acute treatment – Antiviral agents initiated within 72 hours of skin lesions help relieve symptoms, speed resolution, and prevent or mitigate PHN (5)[A]. – Valacyclovir: 1,000 mg PO TID for 7 days

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– Famciclovir: 500 mg PO TID for 7 days – Acyclovir: 800 mg q4h (5 doses daily) for 7 days • Analgesics (acetaminophen, NSAIDs) • Corticosteroids given acutely during zoster infection do not prevent PHN. – Tricyclic antidepressants (TCAs; amitriptyline 25 mg at bedtime and other low-dose TCAs) relieve pain acutely and may reduce pain duration; dose may be titrated up to 75 to 150 mg/day as tolerated. – Lidocaine patch 5% (Lidoderm) applied over painful areas (limit 3 patches simultaneously or trim a single patch) for up to 12 hours may be effective. – Gabapentin: 100 to 600 mg TID for pain and other quality-of-life indicators; limited by adverse effects – Capsaicin cream and other analgesics may be useful adjuncts. Use opioids sparingly. – Pregabalin: 50 to 100 mg TID reduces pain, but usefulness is limited by side effects. • Prevention of PHN and zoster-associated pain: Nothing has been shown to prevent PHN completely, but treatment may shorten duration and/or reduce severity of symptoms. – Antiviral therapy with valacyclovir, famciclovir, or acyclovir given during acute skin eruption may decrease the duration of pain. – Low-dose amitriptyline (25 mg at bedtime) started within 72 hours of rash onset and continued for 90 days may reduce PHN incidence/duration. – Insufficient evidence to suggest that corticosteroids reduce incidence, severity, or duration of PHN • Precautions – Assess renal function prior to using valacyclovir, famciclovir, or acyclovir. – Valacyclovir, famciclovir, and acyclovir are pregnancy Category B.

Second Line Numerous therapies have been advocated, but supporting evidence to routinely recommend is lacking.

COMPLEMENTARY & ALTERNATIVE MEDICINE Studies on cupping therapy (traditional Chinese medicine) show potential benefit, but evidence is conflicting (6)[A].

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ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS Outpatient treatment, unless disseminated or occurring as complication of serious underlying disease requiring hospitalization

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Refer to ophthalmology if concern that ophthalmic branch of the trigeminal nerve is involved.

Patient Monitoring Follow duration of symptoms—particularly PHN. Consider hospitalization if symptoms are severe; patients are immunocompromised; >2 dermatomes are involved; serious bacterial superinfection, disseminated zoster, or meningoencephalitis develops.

DIET No special diet

PATIENT EDUCATION • The duration of rash is typically 2 to 3 weeks. • Encourage good hygiene and proper skin care. • Warn of potential for dissemination (dissemination must be suspected with constitutional illness signs and/or spreading rash). • Warn of potential PHN. • Warn of potential risk of transmitting illness (chickenpox) to susceptible persons. • Seek medical attention if any eye involvement.

PROGNOSIS • Immunocompetent individuals should experience spontaneous and complete recovery within a few weeks. • Acute rash typically resolves within 14 to 21 days. • PHN may occur in patients despite antiviral treatment.

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COMPLICATIONS • PHN • Herpes zoster ophthalmicus: 10–20% • Superinfection of skin lesions • Meningoencephalitis • Disseminated zoster • Hepatitis; pneumonitis; myelitis • Cranial and peripheral nerve palsies • Acute retinal necrosis

REFERENCES 1. Hales CM, Harpaz R, Ortega-Sanchez I, et al. Update on recommendations for use of herpes zoster vaccine. MMWR Morb Mortal Wkly Rep. 2014;63(33):729–731. 2. Schmader KE, Levin MJ, Gnann JW Jr, et al. Efficacy, safety, and tolerability of herpes zoster vaccine in persons aged 50-59 years. Clin Infect Dis. 2012;54(7):922–928. 3. Chen N, Li Q, Zhang Y, et al. Vaccination for preventing postherpetic neuralgia. Cochrane Database Syst Rev. 2011;(3):CD007795. 4. Langan SM, Smeeth L, Margolis DJ, et al. Herpes zoster vaccine effectiveness against incident herpes zoster and post-herpetic neuralgia in an older US population: a cohort study. PLoS Med. 2013;10(4):e1001420. 5. McDonald EM, de Kock J, Ram FS. Antivirals for management of herpes zoster including ophthalmicus: a systematic review of high-quality randomized controlled trials. Antivir Ther. 2012;17(2):255–264. 6. Cao H, Li X, Liu J. An updated review of the efficacy of cupping therapy. PLoS One. 2012;7(2):e31793.

SEE ALSO • Bell Palsy; Chickenpox (Varicella Zoster); Herpes Eye Infections; Herpes Simplex • Algorithm: Genital Ulcers

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CODES ICD10 • B02.9 Zoster without complications • B02.29 Other postherpetic nervous system involvement

CLINICAL PEARLS • Patients with herpes zoster should begin antiviral therapy within 72 hours of the onset of rash to be most effective. • Patients with active herpes zoster can transmit clinically active disease (chickenpox) to susceptible individuals. • Zoster vaccine is recommended for patients ≥60 years of age and is approved for patients >50 years.

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HERPES, GENITAL Cecilia M. Kipnis, MD BASICS DESCRIPTION • Chronic, recurrent infection of any area innervated by the sacral ganglia • Due to herpes simplex virus (HSV) type 1 or 2 • HSV-1 causes anogenital and orolabial lesions. • HSV-2 causes anogenital lesions. • Primary episode: occurs in the absence of preexisting antibodies to HSV-1 or HSV-2 (may be asymptomatic) • First episode nonprimary: initial genital eruption; preexisting antibodies are present. • Reactivation: recurrent episodes • Synonym(s): herpes genitalis

EPIDEMIOLOGY • Predominant age of infection 15 to 30 years; prevalence increases with age due to cumulative likelihood of exposure. • Predominant sex: female > male • Predominant race: non-Hispanic blacks

Incidence >700,000 new cases per year in the United States

Prevalence • Overall prevalence of HSV-2 is 10–40% in the general population and up to 60–95% in the HIV-positive population (1). • Up to 90% of seropositive persons lack formal diagnosis. • >50 million are infected with HSV-2 in the United States.

ETIOLOGY AND PATHOPHYSIOLOGY • HSV is a double-stranded DNA virus of the Herpetoviridae family (1). • Spread via genital-to-genital contact, oral-to-genital contact, and via

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maternal–fetal transmission (2). • Incubation is 4 to 7 days after exposure. • Risk of transmission highest when lesions are present • Viral shedding is possible in the absence of lesions, increasing the risk of transmission since precautions may not be followed (abstinence, condom use). Viral shedding occurs intermittently and unpredictably. • HSV infection increases the risk for HIV.

RISK FACTORS • Risk increases with age, number of lifetime partners, history of sexually transmitted infections (STIs), history of HIV, sexual encounters before the age of 17 years, and partner with HSV-1 or HSV-2. • Infection with HSV-1 increases the risk of being infected with HSV-2 by 3fold. • Immunosuppression, fever, stress, and trauma increases risk of reactivation.

COMMONLY ASSOCIATED CONDITIONS Syphilis, HIV, chlamydia, gonorrhea, and other STIs

DIAGNOSIS HISTORY • Many patients are asymptomatic (74% of HSV-1 and 63% of HSV-2) or do not recognize clinical manifestations of disease (2). • If symptoms are present during primary episode, they are often more severe, longer in duration, and associated with constitutional symptoms. • Common presenting symptoms (primary episode): multiple genital ulcers, dysuria, pruritus, fever, tender inguinal lymphadenopathy, headache, malaise, myalgias, cervicitis/dyspareunia, urethritis (watery discharge) • First episode, nonprimary: In general, symptoms are less severe than primary episode. • Common presenting symptoms for recurrent episodes: prodrome of tingling, burning, or shooting pain (2 to 24 hours before lesion appears); single ulcer; lesion can be atypical in appearance; dysuria; pruritus (lasting 4 to 6 days on

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average) • Recurrent episodes are more frequent with HSV-2 than with HSV-1, especially the first year after infection. Recurrences are less frequent over time. • Less common presentations: constipation (from anal involvement causing tenesmus), proctitis, stomatitis, pharyngitis, sacral paresthesias

PHYSICAL EXAM • Lesions occur in “boxer short” distribution and within anus, vagina, and on cervix. • Lesion may appear as papular, vesicular, pustular, ulcerated, or crusted; can be in various stages • Inguinal lymphadenopathy • Extragenital manifestations include meningitis, recurrent meningitis (Mollaret syndrome), sacral radiculitis/paresthesias, encephalitis, transverse myelitis, and hepatitis

Pediatric Considerations • Neonatal infection occurs in 20 to 50/100,000 live births; 80% of infections result from asymptomatic maternal viral shedding during an undiagnosed primary infection in the 3rd trimester. • Transmission ranges from 30–50% if the primary episode is near time of delivery. Neonatal disease is associated with high morbidity and mortality. • Suspect sexual abuse with genital lesions in children.

DIFFERENTIAL DIAGNOSIS • HIV; syphilis; chancroid • Herpes zoster • Ulcerative balanitis • Granuloma inguinale • Lymphogranuloma venereum • Cytomegalovirus; Epstein-Barr virus • Drug eruption • Trauma • Behçet syndrome • Neoplasia

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DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Confirm clinical diagnosis with laboratory testing • Viral isolation from lesion (swab or scraping) – Culture and PCR are preferred (3)[A]. – Use Dacron or polyester-tipped swabs with plastic shafts (cotton tips/wood shafts inhibit viral growth and/or replication) (1). – Culture by unroofing vesicle to obtain fluid sample. Specificity >99%; sensitivity depends on sample: 52–93% for vesicle, 41–72% for ulcer, 19– 30% for crusted lesion (1,3). – Culture requires timely transport of live virus to the laboratory in appropriate medium at 4°C. – PCR has the greatest sensitivity (98%) and specificity (>99%) but is also expensive and not readily available. It can increase detection rates by up to 70% (4). Used primarily for CSF (1) • Type-specific serologic assays – Western blot (gold standard) and type-specific IgG antibody (glycoprotein G) enzyme-linked immunosorbent assay (ELISA) are used to discriminate between HSV-1 and HSV-2 (3)[B]. – Western blot is >97–99% sensitive and specific but labor intensive and not readily available (1,3). – ELISA 81–100% sensitive; 93–100% specific (1). – Seroconversion occurs 10 days to 4 months after infection (3). Antibody testing is not necessary if a positive culture or PCR has been obtained. – IgM antibody testing is not useful because HSV IgM is often present with recurrent disease and does not distinguish new from old infection. – Screening with type-specific antibody in the general population is not recommended (3) but may be considered in: Asymptomatic patients with HIV infection Discordant couples (one partner with known HSV, the other without) Patients with recurrent symptoms but no active lesions

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TREATMENT GENERAL MEASURES • Ice packs to perineum, sitz baths, topical anesthetics • Analgesics, NSAIDs

MEDICATION Antiviral medications should be started within 72 hours of onset of symptoms (including prodrome). If presentation is >72 hours, antivirals may be helpful if new lesions continue to form or patient is experiencing significant pain.

First Line • Acyclovir (4)[A]: the most studied antiviral in genital herpes. Decreases pain, duration of viral shedding, and time to full resolution – Primary episode 400 mg PO TID for 7 to 10 days 200 mg PO 5 times a day for 7 to 10 days Longer if needed for incomplete healing – Episodic therapy 200 mg 5 times per day for 5 days 400 mg TID for 5 days 800 mg BID for 5 days 800 mg TID for 2 days – Daily suppression 400 mg BID – Severe, complicated infections requiring IV therapy 5 to 10 mg/kg/dose q8h until clinical improvement; switch to PO therapy to complete a 10-day course. – HIV infection: 400 mg PO 3 to 5 times per day until clinical resolution is attained – Precautions Modify dose in renal insufficiency. • Valacyclovir (Valtrex) (4)[A]: prodrug of acyclovir, improved bioavailability, less frequent dosing

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– Primary episode 1 g PO BID for 7 to 10 days – Episodic therapy 500 mg PO BID for 3 to 5 days 1 g PO daily for 5 days – Daily suppression 500 mg PO daily 1 g PO daily • Famciclovir (Famvir) (4)[A] – Primary episode 250 mg PO TID for 7 to 10 days – Episodic therapy 125 mg PO BID for 5 days 1 g PO BID for 1 day – Daily suppression: 250 mg PO BID

ISSUES FOR REFERRAL • For acyclovir-resistant HSV, in consultation with infectious disease specialist (4)[A]: – Foscarnet: 40 mg/kg/dose IV q8h until clinical resolution Associated with significant toxicity – Cidofovir: 5 mg/kg IV once weekly

Pregnancy Considerations ACOG Clinical Management Guidelines (4)[A],(5)[C]: • SCREENING: Pregnant women who test antibody negative for HSV-1 and HSV-2 should avoid sexual contact in the 3rd trimester if their partner is antibody positive. • SUPPRESSIVE THERAPY: Pregnant women with a history of genital herpes should be offered suppression treatment starting at 36 gestational weeks until delivery to decrease reactivation rate. Goal is to reduce the risk of neonatal infection. Recommended regimens to continue until delivery: – Acyclovir 400 mg PO TID – Valacyclovir 500 mg PO BID • Monitor for outbreaks during pregnancy and examine for any lesions at the

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onset of labor. C-section is recommended if prodromal symptoms or lesions are present at onset of labor to reduce neonatal transmission.

Pediatric Considerations • High-risk infants include those with active symptoms or lesions, those delivered vaginally with maternal lesions present, and those born during a primary maternal episode. Monitor closely; obtain diagnostic laboratory specimens (HSV PCR and ocular, nasal, anal, and oral cultures). If symptomatic, will require prolonged treatment: – Acyclovir 20 mg/kg IV q8 for 14 days if skin or mucosal lesions, 21 days if disseminated or CNS disease (4)[A] • Low-risk infants who are asymptomatic can be observed while obtaining serum HSV PCR and ocular, nasal, anal, and oral cultures. • Infants with possible HSV infection should be isolated from other neonates; maternal separation is not necessary and breastfeeding is not contraindicated.

ONGOING CARE GENERAL PREVENTION • Use barrier contraception and avoid sexual contact when symptoms/lesions are present to decrease risk of transmission. • Abstinence is the only means of complete protection.

Patient Monitoring Test for HIV and other STIs.

PATIENT EDUCATION • Counseling is extremely important for treating subsequent outbreaks and for reducing risk of transmission: – Treatment options include daily suppressive therapy versus episodic therapy – Alert partners of history prior to sexual activity – Avoid sexual contact when symptoms or lesions are present. – Viral shedding and thus transmission can occur even when symptoms/lesions are NOT present.

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Shedding is increased with HSV-2 disease and with HIV. – Condom use 100% of the time can reduce the risk of transmission of HSV-2 by 30% (6)[A]. – Sexual activity between concordant couples (i.e., both partners with the same type of herpes [HSV-1 or HSV-2]) does not increase risk of outbreaks. – Alert physician of history in pregnancy. • Herpes Resource Center: http://www.ashasexualhealth.org/stdsstis/herpes/ • Centers for Disease Control and Prevention: http://www.cdc.gov/

PROGNOSIS • Resolution of signs/symptoms: 3 to 21 days • Average recurrence rate is 1 to 4 episodes per year (2). • Antivirals do not eliminate virus from body but can reduce transmission, shedding, and outbreaks.

Pediatric Considerations Neonatal infection survival rates: localized >95%, CNS 85%, systemic 30%

COMPLICATIONS Behavioral issues include lowered self-esteem, guilt, anger, depression, fear of rejection, and fear of transmission to partner.

REFERENCES 1. LeGoff J, Péré H, Bélec L. Diagnosis of genital herpes simplex virus infection in the clinical laboratory. Virol J. 2014;11:83. 2. Hofstetter AM, Rosenthal SL, Stanberry LR. Current thinking on genital herpes. Curr Opin Infect Dis. 2014;27(1):75–83. 3. Geretti AM. Genital herpes. Sex Transm Infect. 2006;82(Suppl 4):iv31–iv34. 4. Centers for Disease Control and Prevention. 2015 sexually transmitted diseases treatment guidelines. http://www.cdc.gov/std/tg2015. Accessed October 6, 2016. 5. ACOG Committee on Practice Bulletins. ACOG practice bulletin. Clinical management guidelines for obstetrician-gynecologists. No. 82 June 2007. Reaffirmed 2016. Management of herpes in pregnancy. Obstet Gynecol. 2007;109(6):1489–1498.

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6. Martin ET, Krantz E, Gottlieb SL, et al. A pooled analysis of the effect of condoms in preventing HSV-2 acquisition. Arch Intern Med. 2009;169(13):1233–1240.

ADDITIONAL READING • Dhankani V, Kutz JN, Schiffer JT. Herpes simplex virus-2 genital tract shedding in not predictable over month or years in infected persons. PLoS Comput Biol. 2014;10(11):e1003922. • Gnann JW Jr, Whitley RJ. Genital herpes. N Engl J Med. 2016;375(7):666– 674. • Money D, Steben M. SOGC clinical practice guidelines: guidelines for the management of herpes simplex virus in pregnancy. Number 208, June 2008. Int J Gynaecol Obstet. 2009;104(2):167–171. • Tavares F, Cheuvart B, Heineman T, et al. Meta-analysis of pregnancy outcomes in pooled randomized trials on a prophylactic adjuvanted glycoprotein D subunit herpes simplex virus vaccine. Vaccine. 2013;31(13):1759–1764. • Tobian AA, Grabowski MK, Serwadda D, et al. Reactivation of herpes simplex virus type 2 after initiation of antiretroviral therapy. J Infect Dis. 2013;208(5):839–846.

SEE ALSO Algorithm: Genital Ulcers

CODES ICD10 • A60.00 Herpesviral infection of urogenital system, unspecified • A60.04 Herpesviral vulvovaginitis • A60.09 Herpesviral infection of other urogenital tract

CLINICAL PEARLS • Genital herpes can be caused by HSV-1 and HSV-2.

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• Many seropositive individuals are unaware that they are infected. • Most primary episodes are asymptomatic. • Viral shedding occurs in the absence of lesions. • Regular (100%) condom use decreases transmission significantly.

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HICCUPS Vanessa W. McNair, MD, MPH • Jeannette M. McIntyre, MD • Steven B. Sapida, DO BASICS DESCRIPTION • Hiccups are caused by a repetitive sudden involuntary contraction of the inspiratory muscles (predominantly the diaphragm) terminated by abrupt closure of the glottis, which stops the inflow of air and produces a characteristic sound. • Hiccups are classified based on their duration: Acute hiccups last 48 hours but 1 month. • System(s) affected: nervous, pulmonary • Synonym(s): hiccoughs; singultus

Geriatric Considerations Can be a serious problem, particularly among the elderly

Pregnancy Considerations • Fetal hiccups are noted as rhythmic fetal movements (confirmed sonographically) that can be confused with contractions. • Fetal hiccups are a sign of normal neurologic development (1).

EPIDEMIOLOGY • Predominant age: all ages (including fetus) • Predominant sex: male > female (4:1)

Prevalence Self-limited hiccups are extremely common, as are intra- and postoperative hiccups.

ETIOLOGY AND PATHOPHYSIOLOGY • Results from stimulation of ≥1 limbs of the hiccup reflux arc (vagus and

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phrenic nerves) with a “hiccup center” located in the upper spinal cord and brain (2) • In men, >90% have an organic basis; whereas in women, a psychogenic cause is more common. • Specific underlying causes include the following: – Alcohol abuse – CNS lesions (brain stem tumors, vascular lesions, Parkinson disease, multiple sclerosis, syringomyelia, hydrocephalus) – CNS infections (encephalitis, meningitis) – Seizure disorder – Diaphragmatic irritation (tumors, pericarditis, eventration, splenomegaly, hepatomegaly, peritonitis) – Irritation of the tympanic membrane – Pharyngitis, laryngitis – Mediastinal and other thoracic lesions (pneumonia, aortic aneurysm, tuberculosis [TB], myocardial infarction [MI], lung cancer, rib exostoses) – Esophageal lesions (reflux esophagitis, achalasia, Candida esophagitis, carcinoma, obstruction) – Gastric lesions (ulcer, distention, cancer) – Hepatic lesions (hepatitis, hepatoma) – Pancreatic lesions (pancreatitis, pseudocysts, cancer) – Inflammatory bowel disease – Cholelithiasis, cholecystitis – Prostatic disorders – Appendicitis – Postoperative, abdominal procedures – Toxic metabolic causes (uremia, hyponatremia, gout, diabetes) – Drug-induced (dexamethasone, methylprednisolone, anabolic steroids, benzodiazepines, α-methyldopa, propofol) – Psychogenic causes (hysterical neurosis, grief, malingering) – Idiopathic

RISK FACTORS • General anesthesia; conscious sedation • Postoperative state

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• Genitourinary disorders • Irritation of the vagus and phrenic nerve (or branches) • Gastroesophageal reflux • Structural, vascular, infectious, neoplastic, or traumatic CNS lesions

GENERAL PREVENTION • Identify and correct the underlying cause if possible. • Avoid gastric distention. • Acupuncture shows promise in comparison to chronic drug therapy to control hiccups (3).

COMMONLY ASSOCIATED CONDITIONS See “Etiology.”

DIAGNOSIS • Hiccup attacks usually occur at brief intervals and last only a few seconds or minutes. Persistent bouts lasting >48 hours often imply an underlying physical or metabolic disorder. • Intractable hiccups may occur continuously for months or years (4). • Hiccups usually occur with a frequency of 4 to 60 per minute (4). • Persistent and intractable hiccups warrant further evaluation.

HISTORY • Recent surgery (especially genitourinary) • General anesthesia • Behavioral health history • Medications • Alcohol use/illicit drug use • GI, cardiac, neurologic, or pulmonary disorders (see “Etiology”)

PHYSICAL EXAM • Correlate exam with potential etiologies (e.g., rales with pneumonia; organomegaly with splenic or hepatic disease). • Examine the ear canal for foreign bodies. • Head and neck exam to look for neck masses and lymphadenopathy

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• Complete neurologic exam

DIFFERENTIAL DIAGNOSIS Hiccups may rarely be confused with burping (eructation).

DIAGNOSTIC TESTS & INTERPRETATION • If history suggests an underlying etiology, consider condition-specific testing as appropriate (e.g., CBC, metabolic panel, chest x-ray). • Fluoroscopy is useful to determine whether one hemidiaphragm is dominant.

Diagnostic Procedures/Other • Upper endoscopy; colonoscopy; CT scan (or other imaging) of brain, thorax, abdomen, and pelvis looking for underlying causes • The extent of the workup is often in proportion to the duration and severity of the hiccups (2,5).

TREATMENT • Outpatient (usually) • Inpatient (if elderly, debilitated, or intractable hiccups) • Many hiccup treatments are purely anecdotal.

GENERAL MEASURES • Seek medical attention for frequent bouts or persistent hiccups. • Treat any specific underlying cause when identified (2,4,5)[C] – Dilate esophageal stricture or obstruction. – Treat ulcers or reflux disease. – Remove hair or foreign body from ear canal. – Angostura bitters for alcohol-induced hiccups – Catheter stimulation of pharynx for operative and postoperative hiccups – Antifungal treatment for Candida esophagitis – Correct electrolyte imbalance. • Medical measures – Relief of gastric distention (gastric lavage, nasogastric aspiration, induced vomiting) – Counterirritation of the vagus nerve (supraorbital pressure, carotid sinus

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massage, digital rectal massage)—use with caution – Respiratory center stimulants (breathing 5% CO2) – Behavioral health modification (hypnosis, meditation, paced respirations) – Phrenic nerve block or electrical stimulation (or pacing) of the dominant hemidiaphragm – Acupuncture – Miscellaneous (cardioversion)

MEDICATION First Line Possible drug remedies (5–7)[B] • Baclofen, a GABA analog: 5 to 10 mg PO TID (2,4,5,8)[B] • Chlorpromazine (FDA approved for hiccups): 25 to 50 mg PO/IV TID • Haloperidol: 2 to 5 mg PO/IM followed by 1 to 2 mg PO TID • Phenytoin: 200 to 300 mg PO HS • Metoclopramide: 5 to 10 mg PO QID • Nifedipine: 10 to 20 mg PO daily to TID • Amitriptyline: 10 mg PO TID • Viscous lidocaine 2%: 5 mL PO daily to TID • Gabapentin (Neurontin): 300 mg PO HS; may increase up to 1,800 mg/day PO in divided doses (4)[B]; 1,200 mg/day PO for 3 days, then 400 mg/day PO for 3 days in patients undergoing stroke rehabilitation or in the palliative care setting where chlorpromazine adverse effects are undesirable (4)[B]. • Combination of lansoprazole 15 mg PO daily, clonazepam 0.5 mg PO BID, and dimenhydrinate 25 mg PO BID (6)[B]. • Contraindications: Refer to manufacturer’s literature. – Baclofen is not recommended in patients with stroke or other cerebral lesions or in severe renal impairment. • Precautions: Refer to manufacturer’s literature. – Abrupt withdrawal of baclofen should be avoided.

Second Line Possible drug therapies (2,6,8–10)[C] • Amantadine, carbidopa-levodopa in Parkinson disease • Steroid replacement in Addison disease

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• Antifungal agent in Candida esophagitis • Ondansetron in carcinomatosis with vomiting • Nefopam (a nonopioid analgesic with antishivering properties related to antihistamines and antiparkinsonian drugs) is available outside the United States in both IV and oral formulations. • Olanzapine 10 mg QHS • Pregabalin 375 mg/day

ISSUES FOR REFERRAL For acupuncture or phrenic nerve crush, block, or electrostimulation; cardioversion

SURGERY/OTHER PROCEDURES • Phrenic nerve crush or transaction or electrostimulation of the dominant diaphragmatic leaflet • Resection of rib exostoses

COMPLEMENTARY & ALTERNATIVE MEDICINE • Acupuncture is increasingly used to manage persistent or intractable hiccups, especially in cancer patients (3,4)[A]. • Simple home remedies (2,7)[C] – Swallowing a spoonful of sugar – Sucking on hard candy or swallowing peanut butter – Holding breath and increasing pressure on diaphragm (Valsalva maneuver) – Tongue traction – Lifting the uvula with a cold spoon – Inducing fright – Smelling salts – Rebreathing into a paper (not plastic) bag – Sipping ice water – Rubbing a wet cotton-tipped applicator between hard and soft palate for 1 minute

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS Most patients can be managed as outpatients; those with severe intractable

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hiccups may require rehydration, pain control, IV medications, or surgery.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring Until hiccups cease

DIET Avoid gastric distension from overeating, carbonated beverages, and aerophagia.

PATIENT EDUCATION See “General Measures.”

PROGNOSIS • Hiccups often cease during sleep. • Most acute benign hiccups resolve spontaneously or with home remedies. • Intractable hiccups may last for years or decades. • Hiccups have persisted despite bilateral phrenic nerve transection.

COMPLICATIONS • Inability to eat • Weight loss • Exhaustion, debility • Insomnia • Cardiac arrhythmias • Wound dehiscence • Death (rare)

REFERENCES 1. Witter F, Dipietro J, Costigan K, et al. The relationship between hiccups and heart rate in the fetus. J Matern Fetal Neonatal Med. 2007;20(4):289–292. 2. Calsina-Berna A, García-Gómez G, González-Barboteo J, et al. Treatment of chronic hiccups in cancer patients: a systemic review. J Palliat Med. 2012;15(10):1142–1150.

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3. Ge AX, Ryan ME, Giaccone G, et al. Acupuncture treatment for persistent hiccups in patients with cancer. J Altern Complement Med. 2010;16(7):811– 816. 4. Thompson DF, Brooks KG. Gabapentin therapy of hiccups. Ann Pharmacother. 2013;47(6):897–903. 5. Ramírez FC, Graham DY. Treatment of intractable hiccup with baclofen: results of a double-blind randomized, controlled, cross-over study. Am J Gastroenterol. 1992;87(12):1789–1791. 6. Maximov G, Kamnasaran D. The adjuvant use of lansoprazole, clonazepam and dimenhydrinate for treating intractable hiccups in a patient with gastritis and reflux esophagitis complicated with myocardial infarction: a case report. BMC Res Notes. 2013;6:327. 7. Lewis JH. Hiccups and their cures. Clin Perspect Gastroenterol. 2000;3(5):277–283. 8. Moretto EN, Wee B, Wiffen PJ, et al. Interventions for treating persistent and intractable hiccups in adults. Cochrane Database Syst Rev. 2013; (1):CD008768. 9. Marinella MA. Diagnosis and management of hiccups in the patient with advanced cancer. J Support Oncol. 2009;7(4):122–127, 130. 10. Matsuki Y, Mizogami M, Shigemi K. A case of intractable hiccups successfully treated with pregabalin. Pain Physician. 2014;17(2):E241– E242.

ADDITIONAL READING • Berger TJ. A rash case of hiccups. J Emerg Med. 2013;44(1):e107–e108. • Chang FY, Lu CL. Hiccup: mystery, nature and treatment. J Neurogastroenterol Motil. 2012;18(2):123–130. • Choi TY, Lee MS, Ernst E. Acupuncture for cancer patients suffering from hiccups: a systematic review and meta-analysis. Complement Ther Med. 2012;20(6):447–455. • Hurst DF, Purdom CL, Hogan MJ. Use of paced respiration to alleviate intractable hiccups (Singultus): a case report. Appl Psychophysiol Biofeedback. 2013;38(2):157–160. • Lewis JH. Hiccups: causes and cures. J Clin Gastroenterol. 1985;7(6):539–

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552. • Rizzo C, Vitale C, Montagnini M. Management of intractable hiccups: an illustrative case and review. Am J Hosp Palliat Care. 2014;31(2):220–224.

CODES ICD10 • R06.6 Hiccough • F45.8 Other somatoform disorders

CLINICAL PEARLS • Most hiccups resolve spontaneously. • An organic cause for persistent hiccups is more likely to be found in men and individuals with intractable hiccups. • Rule out a foreign body in the ear canal as hiccup trigger. • Baclofen and gabapentin are the only pharmacologic agents proven effective in a clinical trial. • Acupuncture may be effective for persistent hiccups.

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HIDRADENITIS SUPPURATIVA Travis C. Geraci, MD • Siva Vithiananthan, MD, FACS BASICS DESCRIPTION • Chronic follicular occlusive disease manifested as recurrent inflammatory nodules, abscesses, sinus tracts, and complex scar formation • Lesions are tender, malodorous, often with exudative drainage. • Common in intertriginous skin regions: axillae, groin, perianal, perineal, inframammary skin • System affected: skin • Synonym(s): acne inversa; Verneuil disease; apocrinitis; hidradenitis axillaris

Geriatric Considerations Rare after menopause

Pediatric Considerations Rarely occurs before puberty; occurrence in children is associated with premature adrenarche.

Pregnancy Considerations No Accutane (isotretinoin) or tetracycline treatment during pregnancy. Disease may ease during pregnancy and rebound after parturition.

EPIDEMIOLOGY Predominant sex: female > male (3:1)

Incidence Peak onset during 2nd and 3rd decades of life

Prevalence 0.3–4%

ETIOLOGY AND PATHOPHYSIOLOGY • Not fully understood; previously considered a disorder of apocrine glands

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• Inflammatory disorder of the hair follicle triggered by follicular plugging within apocrine gland–bearing skin. • Hormonally induced ductal keratinocyte proliferation leads to a failure of follicular epithelial shedding, causing follicular occlusion. • Mechanical stress on skin (intertriginous regions) precipitates follicular rupture and immune response. • Bacterial involvement is a secondary event. • Rupture and reepithelialization cause sinus tracts to form. • Obesity and smoking are major risk factors in disease onset and severity.

Genetics • Familiar occurrences suggest single gene transmission (autosomal dominant), but the condition may also be polygenic. • Estimated 40% of patients have an affected family member.

RISK FACTORS • Obesity • Smoking • Hyperandrogenism, oral contraceptive pills (OCPs) • Lithium may trigger onset of or exacerbate this condition.

GENERAL PREVENTION • Lose weight if overweight or obese. • Smoking cessation • Avoid constrictive clothing/synthetic fabrics, frictional trauma, heat exposure, excessive sweating, shaving, depilation, and deodorants. • Use of antiseptic soaps.

COMMONLY ASSOCIATED CONDITIONS • Acne vulgaris, acne conglobate • Perifolliculitis capitis abscedens et suffodiens (dissecting cellulitis of scalp) • Pilonidal disease • Arthritis and spondyloarthritis (seronegative) • Obesity (with diabetes, atopy, acanthosis) • Irritable bowel disease (Crohn disease) • Squamous cell carcinoma

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• PAPASH syndrome (pyogenic arthritis, pyoderma gangrenosum, acne, suppurative hydradenitis)

DIAGNOSIS HISTORY • Diagnostic criteria adopted by the 2nd International Conference on Hidradenitis Suppurativa, 2009 (1)[C] • All three criteria must be present for diagnosis: – Typical lesions: painful nodules, abscesses, draining sinus, bridged scars, and “tombstone” double-ended pseudocomedones in secondary lesions – Typical topography: axillae, groins, perineal and perianal region, buttocks, infra- and intermammary folds – Chronicity and recurrences, commonly refractory to initial treatments.

PHYSICAL EXAM • Tender nodules (dome-shaped) 0.5 to 3 cm in size are present. – Location corresponds with the distribution of apocrine-related mammary tissue and terminal hair follicles dependent on low androgen concentrations. – Sites ordered by frequency of occurrence: axillary, inguinal, perianal and perineal, mammary and inframammary, buttock, pubic region, chest, scalp, retroauricular, eyelid – Large lesions are often fluctuant; comedones may be present. – Possible malodorous discharge • Hurley clinical staging system – Stage I: abscess formation (singular or multiple) without sinus tracts or scarring – Stage II: widely separated, recurrent abscesses with tract formation and scarring – Stage III: diffuse, multiple interconnected tracts and abscesses • Sartorius clinical staging system (points attributed) – Anatomic region – Quantity and quality of lesions – Distance between lesions

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– Presence or absence of normal skin between lesions

DIFFERENTIAL DIAGNOSIS • Acne vulgaris, conglobate • Furunculosis/carbuncles • Infected Bartholin or sebaceous cysts • Lymphadenopathy/lymphadenitis • Cutaneous Langerhans cell histiocytosis • Actinomycosis • Granuloma inguinale • Lymphogranuloma venereum • Apocrine nevus • Crohn disease with anogenital fistula(s) (may coexist with hidradenitis suppurativa) • Cutaneous tuberculosis • Fox-Fordyce disease

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Cultures of skin or aspirates of boils are most commonly negative. When positive, cultures are often polymicrobial and commonly grow Staphylococcus aureus and Staphylococcus epidermidis. • Lesion biopsy usually unnecessary. Useful to rule out other disorders such as squamous cell carcinoma. • May note increased erythrocyte sedimentation rate (ESR), leukocytosis, decreased serum iron, normocytic anemia, or changes in serum electrophoresis pattern. Follow-Up Tests & Special Considerations • Consider biopsy of concerning lesions due to increased risk of squamous cell carcinoma. • If the patient is female, overweight, and/or hirsute, consider evaluating the following: – Dehydroepiandrosterone sulfate – Testosterone: total and free – Sex hormone-binding globulin

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– Progesterone

Diagnostic Procedures/Other • Incision and drainage, culture and biopsy • Ultrasound may be useful in planning an excision to identify the full extent of sinus tracts.

Test Interpretation • Dermis shows granulomatous inflammation and inflammatory cells, giant cells, sinus tracts, subcutaneous abscesses, and extensive fibrosis. • Hair follicular dilatation and occlusion by keratinized stratified squamous epithelium

TREATMENT Despite the prevalence of this condition, few large-scale randomized controlled trials have explored the safety and efficacy of treatment. Evidence is generally of poor quality (2)[A]. Treatment goals: Reduce extent of disease, prevent new lesions, remove chronic disease, and limit scar formation. • Conservative treatment includes all items under general prevention, plus use of warm compresses, sitz baths, topical antiseptics for inflamed lesions, and nonopioid analgesics. • Weight loss and smoking cessation result in marked improvement. • For stage I–II, attempt medical treatment. • Short medical trial may be appropriate in stage III prior to moving on to surgical therapies. • No medications are curative; relapse is almost inevitable, but the disease may be controlled.

GENERAL MEASURES • Education and psychosocial support • Appropriate hygiene including avoidance of shearing stress to skin (light clothing), daily cleansing with antibacterial soap • Diet: Avoid dairy and high glycemic loads. • Symptomatic treatment for acute lesions

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• Improve environmental factors that cause follicular blockage (see “General Prevention”). • Smoking cessation and weight loss

MEDICATION First Line • Stage I disease: Consider either systemic or topical antibiotics. – Topical antibiotics (clindamycin has the most evidence) (3)[B] Clindamycin 1% solution BID for 12 weeks with or without Benzoyl peroxide 5–10% solution Chlorhexidine 4% solution – Systemic antibiotics (initial 7- to 10-day course) Tetracycline 500 mg BID Doxycycline 100 mg q12h Augmentin 875 mg q8–12h Clindamycin 300 mg BID (4)[B] • Stage II–III disease – Address overlying bacterial infection with broad-spectrum coverage. Base antibiotic selection on disease location, characteristics; longer durations (3 to 6 months) may be required. – Tetracycline 500 mg BID – Minocycline 100 mg BID – Doxycycline 100 mg BID – Minor surgical procedures (punch débridement, local unroofing) to treat individual lesions or sinus tracts • Other modalities (rarely used) – Hormonal therapy: antiandrogenic therapy such as cyproterone acetate (may not be available in the United States), estrogen/norgestrel oral contraceptive, finasteride (5 mg daily) (5)[B] • Intralesional corticosteroids: accelerates healing, although efficacy not formally evaluated (triamcinolone acetonide 5 to 10 mg/mL)

Second Line • Combination of antibiotic regimens – Clindamycin and rifampin

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– Rifampin, moxifloxacin, and metronidazole • Dapsone 50 to 150 mg daily (6)[C] • Metformin: significant reduction in Sartorius score (7)[B] • Oral retinoids (Isotretinoin): poor efficacy, limited therapeutic effect (8)[B] • TNF-α inhibitors: – Infliximab: a majority of patients in the treatment group had a 50% or greater decrease in disease (9)[B] – Etanercept: no difference versus placebo (10)[A] – Adalimumab: limited efficacy

ISSUES FOR REFERRAL • Lack of response to treatment, stage II–III disease, or concern for malignancy (squamous cell carcinoma) is a reason to refer for surgical excision or radiation/laser treatment (stage II). • If significant psychosocial stress exists secondary to disease, refer for stress management or psychiatric evaluation. • Suspicion of hyperandrogenic states (e.g., polycystic ovary syndrome [PCOS]) should prompt investigation or referral. • Severe perianal/perivulvar disease or otherwise very extensive disease may prompt referral to plastic surgeon or reconstructive urologist.

SURGERY/OTHER PROCEDURES • Important mode of treatment • Could be used in conjunction with antibiotics or if first-line therapy fails • Various surgical approaches have been used for stage II–III disease (11,12) [B]: – Incision and drainage: may be necessary to treat as a temporizing method for acute flare-ups – Deroofing and marsupialization of the sinus tracts is often beneficial primarily for Hurley stage I–II disease, as healing time is reduced. Recurrences remain common but usually are smaller than original lesions (13)[B]. – Wide full-thickness excision with healing by granulation or flap placement is the most definitive treatment and rarely has local recurrence if all sinus tracts are excised. Rates of local recurrence (within 3 to 72 months):

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axillary (3%), perianal (0%), inguinoperineal (37%), submammary (50%) • Laser therapy for Hurley stage I–II disease (rarely used) – Consider monthly treatments with neodymium-doped yttrium aluminum garnet (Nd:YAG) laser for 3 to 4 months. – CO2 laser ablation with healing by secondary intention • Cryotherapy and photodynamic therapy have shown variable results, they are not routinely recommended.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Follow up monthly or sooner to evaluate progress and to assist with symptom management.

DIET • Avoid dairy, high glycemic loads. • Healthy diet that promotes weight loss. • May benefit from zinc supplementation

PATIENT EDUCATION • Severity can range from only 2 to 3 papules per year to extensive draining sinus tracts. • Medications are temporizing measures, rarely curative. Attempts at local surgical “cures” do not affect recurrence at other sites. • Smoking cessation and weight loss can improve symptoms significantly. Hidradenitis Suppurativa Foundation: www.hs-foundation.org

PROGNOSIS • Individual lesions heal slowly in 10 to 30 days. • Recurrences may last for several years. • Relentlessly progressive scarring and sinus tracts are likely with severe disease. • Radical wide-area excision, with removal of all hair-bearing skin in the affected area, shows the greatest chance for cure.

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COMPLICATIONS • Contracture and stricturing of the skin after extensive abscess rupture, scarring, and healing; or at sites of surgical excisions • Lymphatic obstruction, lymphedema • Psychosocial: anxiety, malaise, depression, self-injury • Anemia, amyloidosis, and hypoproteinemia (due to chronic suppuration) • Lumbosacral epidural abscess, sacral bacterial osteomyelitis • Squamous cell carcinoma may develop in indolent sinus tracts. • Disseminated infection or septicemia (rare) • Urethral, rectal, or bladder fistula (rare)

REFERENCES 1. Hidradenitis Suppurativa Foundation. http://www.hs-foundation.org. 2. Rambhatla PV, Lim HW, Hamzavi I. A systematic review of treatments for hidradenitis suppurativa. Arch Dermatol. 2012;148(4):439–446. 3. Jemec GB, Wendelboe P. Topical clindamycin versus systemic tetracycline in the treatment of hidradenitis suppurativa. J Am Acad Dermatol. 1998;39(6):971–974. 4. van der Zee HH, Boer J, Prens EP, et al. The effect of combined treatment with oral clindamycin and oral rifampicin in patients with hidradenitis suppurativa. Dermatology. 2009;219(2):143–147. 5. Searles GE. Daily oral finasteride 5 mg for hidradenitis suppurativa. Paper presented at: Annual Meeting of the Canadian Dermatology Association; July 3, 2009; Vancouver, British Columbia, Canada. 6. Kaur MR, Lewis HM. Hidradenitis suppurativa treated with dapsone: a case series of five patients. J Dermatolog Treat. 2006;17(4):211–213. 7. Verdolini R, Clayton N, Smith A, et al. Metformin for the treatment of hidradenitis suppurativa: a little help along the way. J Eur Acad Dermatol Venereol. 2013;27(9):1101–1108. 8. Soria A, Canoui-Poitrine F, Wolkenstein P, et al. Absence of efficacy of oral isotretinoin in hidradenitis suppurativa: a retrospective study based on patients’ outcome assessment. Dermatology. 2009;218(2):134–135. 9. Grant A, Gonzalez T, Montgomery MO, et al. Infliximab therapy for

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patients with moderate to severe hidradenitis suppurativa: a randomized, double-blind, placebo-controlled crossover trial. J Am Acad Dermatol. 2010;62(2):205–217. 10. Adams DR, Yankura JA, Fogelberg AC, et al. Treatment of hidradenitis suppurativa with etanercept injection. Arch Dermatol. 2010;146(5):501– 504. 11. Blok JL, van Hattem S, Jonkman MF, et al. Systemic therapy with immunosuppressive agents and retinoids in hidradenitis suppurativa: a systematic review. Br J Dermatol. 2013;168(2):243–252. 12. Kagan RJ, Yakuboff KP, Warner P, et al. Surgical treatment of hidradenitis suppurativa: a 10-year experience. Surgery. 2005;138(4):734–740; discussion 740–741. 13. van der Zee HH, Prens EP, Boer J. Deroofing: a tissue-saving surgical technique for the treatment of mild to moderate hidradenitis suppurativa lesions. J Am Acad Dermatol. 2010;63(3):475–480.

ADDITIONAL READING • Alikhan A, Lynch PJ, Eisen DB. Hidradenitis suppurativa: a comprehensive review. J Am Acad Dermatol. 2009;60(4):539–561. • Jemec GB. Clinical practice. Hidradenitis suppurativa. N Engl J Med. 2012;366(2):158–164. • Mandal A, Watson J. Experience with different treatment modules in hidradenitis suppuritiva: a study of 106 cases. Surgeon. 2005;3(1):23–26. • Slade DE, Powell BW, Mortimer PS. Hidradenitis suppurativa: pathogenesis and management. Br J Plast Surg. 2003;56(5):451–461.

CODES ICD10 L73.2 Hidradenitis suppurativa

CLINICAL PEARLS • Chronic inflammatory disease of the skin, often difficult to control with

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behavior changes and medication alone • First-line treatment for mild disease is topical and/or systemic antibiotics. • For patients with refractory or severe disease, wide local excision provides the only chance at a cure. Success rates depend on the location and extent of excision.

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HIRSUTISM Imola K. Osapay, MD • Andrea M. Konkoly, MD BASICS DESCRIPTION • Presence of excessive terminal (coarse, pigmented) hair of body and face, in a male pattern • May be present in normal adults as an ethnic characteristic or may develop as a result of androgen excess • Often seen in polycystic ovarian syndrome (PCOS) which is characterized by hirsutism, acne, menstrual irregularities, and obesity • System(s) affected: dermatologic, endocrine, metabolic, reproductive

EPIDEMIOLOGY Prevalence 5–10% of adult women

ETIOLOGY AND PATHOPHYSIOLOGY • Hirsutism is due to increased androgenic (male) hormones, either from increased peripheral binding (idiopathic) or increased production from the ovaries, adrenals, or fat. • Exogenous medications can also cause hirsutism.

Genetics Multifactorial

RISK FACTORS • Family history • Ethnicity—increased in Ashkenazi Jews and Mediterranean backgrounds • Anovulation • Obesity

GENERAL PREVENTION Women with late-onset congenital adrenal hyperplasia (CAH) should be

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counseled that they may be carriers for the severe early-onset childhood disease.

COMMONLY ASSOCIATED CONDITIONS • PCOS: most common cause of hirsutism. Variable presentation but commonly presents with a combination of excess androgen, abnormal menses, and insulin resistance. The most common cause of pre-menopausal hirsutism is PCOS (1). • Associated insulin resistance or PCOS can increase the risk of heart disease. • Prolonged amenorrhea and anovulation over time may put the patient at risk for endometrial hyperplasia or carcinoma. • Hypothyroidism or hyperprolactinemia • Late-onset CAH (21-hydroxylase deficiency): a genetic enzyme deficiency associated with more severe and earlier onset hirsutism in amenorrheic patients • Tumor: ovarian or adrenal; especially if associated with virilization (rapid onset, clitoromegaly, balding, deepening voice) (2) • Cushing syndrome: rare; characterized by central obesity, moon facies, striae, hypertension

DIAGNOSIS HISTORY • Severity, time course, and age of onset of hirsutism • Presence of virilization • Weight • Psychosocial impact on patient • Menstrual and fertility history, anovulation (defined as ovulatory cycle >35 days) • Severe acne, especially if treatment resistant • Medication history: Look for use of valproic acid, testosterone, danazol, glucocorticoids, and athletic performance drugs. • The presence of galactorrhea

PHYSICAL EXAM • Increased hair growth in premenopausal women, particularly over the chin,

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neck, sideburns, lower back, sternum, abdomen, shoulders, buttocks, perineal area, and inner thighs • Check skin for acne, striae, acanthosis nigricans (velvety black skin in the axilla or neck). • Virilization: Deep voice, male pattern balding, and clitoromegaly indicate risk of tumor. • The Ferriman-Gallwey scale (an instrument that rates hair growth in nine areas on a scale of 0 to 4, with >8 being positive) may be used for diagnosis but underrates patient’s perception of hirsutism and altered by previous cosmetic treatment (1).

DIFFERENTIAL DIAGNOSIS • PCOS (72–82%)—irregular menses, elevated androgens, polycystic ovaries on US, infertility, insulin resistance • Idiopathic hyperandrogenemia (6–15%)—hirsutism with normal ovaries on US, elevated androgen levels, no other explainable cause • Idiopathic hirsutism (4–7%)—hirsutism with normal menses, androgen levels, and ovaries on ultrasonography, no other explainable cause • Late-onset CAH (2–4%) presents in adolescence with severe hirsutism and irregular menses. • Androgen-secreting tumor (0.2%)—ovaries or adrenals; have rapid onset, virilization, resistance to treatment • Ovarian hyperthecosis—increase in testosterone by thecal cells. Gradual onset of hirsutism, frank virilization. Mostly affects postmenopausal women • Thyroid dysfunction • Hyperprolactinemia if accompanied by galactorrhea or amenorrhea • Rare endocrine disorders—Cushing (central obesity, stria, and hypertension), acromegaly (enlarging extremities and facial deformity)

DIAGNOSTIC TESTS & INTERPRETATION • Diagnosis is clinical. Empiric treatment without lab workup is an acceptable option in mild-to-moderate hirsutism (2)[C]. • PCOS is diagnosed by having two out of three signs: menstrual dysfunction, clinical or biochemical hyperandrogenemia, polycystic ovaries on US (2)[C]. • Lab testing is performed to rule out underlying tumor and pituitary diseases,

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which are rare.

Initial Tests (lab, imaging) • Basic workup of moderate hirsutism is a total testosterone level +/− thyroid screen (TSH) (1)[C]. • Testosterone: Random total testosterone level is usually sufficient. • Normal upper limit for serum total testosterone in adult women is approximately 40 to 60 ng/dL (1.4 to 2.1 nmol/L). Patients who have clinical features consistent with PCOS but have normal total testosterone should have repeat testing, preferably an early morning serum free testosterone level calculated from sex hormone binding globulin (SHBG). A morning free testosterone is 50% more sensitive (1,3). • If testosterone is >150 (some use 200) ng/dL, consider ovarian or adrenal tumor (2,4). Testosterone is made by both the ovaries and adrenals, so both areas should be imaged. US is best for the ovaries, and CT is best for the adrenals. • TSH elevation indicates hypothyroidism. • The workup for PCOS recommended by the American Congress of Obstetricians and Gynecologists (ACOG) includes the above plus: – Screening for metabolic syndrome with a fasting and 2-hour glucose after 75-g glucose load, lipid panel, waist circumference, and blood pressure (4) [C] • Ovarian US • If the patient is amenorrheic, check prolactin, FSH, LH, TSH, and a pregnancy test (5)[C]. An LH/FSH ratio >2 indicates PCOS. Follow-Up Tests & Special Considerations • 17-Hydroxyprogesterone (17-OHP) – Elevations of 17-OHP (>300) can indicate late-onset CAH. – Consider in patients with onset in early adolescence or high-risk group (Ashkenazi Jews) (2)[C]. – If elevated, order corticotropin stimulation test. • If prolactin level is high, MRI the pituitary. • If PCOS is diagnosed, ACOG recommends screening for dyslipidemia and DM type 2 (4)[C].

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• New studies show an inverse correlation between vitamin D levels and insulin resistance in women with PCOS. Screening women who are at risk of vitamin D deficiency and supplementation with vitamin D could be considered. • Dehydroepiandrosterone sulfate (DHEA-S) is no longer recommended routinely but should be checked in virilization (5)[C]. – Levels >700 may indicate adrenal tumor.

TREATMENT GENERAL MEASURES • Treatment in mild hirsutism depends on patient preference and psychosocial effect. • If patient desires pregnancy, induction of ovulation may be necessary. • Provide contraception, as needed. • Encourage patient to maintain ideal weight with lifestyle modification. A calorie-restricted diet is recommended in all overweight patients with PCOS. Weight loss has positive effect on fertility, metabolic profile, and may improve hirsutism (5). • Treat accompanying acne.

MEDICATION First Line • Treatment goal is to decrease new hair growth and improve metabolic disorders. • Oral contraceptives are first line to manage menstrual abnormalities and hirsutism/acne (3)[A]; they will suppress ovarian androgen production and increase SHBG, improve metabolic syndrome, and slow but not reverse hair growth. – Doses of 20 to 35 μg ethinyl estradiol effectively decrease ovarian androgen production. Those containing the progestins, norgestimate, desogestrel, or drospirenone have more androgen-blocking effects, but desogestrel and drospirenone are associated with more DVTs especially in severely obese patients (3),(4)[C]. – They take 6 months to show effect and are continued for years.

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– Oral preparations, compared to vaginal or transdermal, are better at controlling hirsutism and acne; by passing through the liver, they induce SHBG production (1). • Progesterone (depot or intermittent oral) can be used if estrogens are contraindicated (4). • Eflornithine (Vaniqa) HCl cream: Apply BID at least 8 hours apart; reduces facial hair in 40% of women (must be used indefinitely to prevent regrowth); only FDA-approved hirsutism treatment

Second Line • Antiandrogenic drugs will further reduce hirsutism to 15–25%. Usually begun 6 months after first-line therapy if results are suboptimal. Must be used in combination with oral contraceptives to prevent menorrhagia and potential fetal toxicity. All should be avoided in pregnancy (2,5)[C]. – Spironolactone, 50 to 200 mg/day: Onset of action is slow; use with oral contraceptives to prevent menorrhagia. Watch for hyperkalemia, especially with drospirenone-containing OCP (Yasmin); avoid use in pregnancy. – Finasteride: 5 mg/day decreases androgen binding; not approved by FDA. Use with contraception (pregnancy Category X). – Cyproterone, not available in the United States: 12.5 to 100 mg/day for days 5 to 15 of cycle combined with ethinyl estradiol 20 to 50 μg days 5 to 25 of cycle – Flutamide is not recommended (2). • Insulin sensitizers (metformin, pioglitazone): mildly effective but less so than oral contraceptives and antiandrogens. Can restore ovulation in 30–50% of patients with PCOS. May be used in patients with impaired glucose tolerance, diabetes, or if oral contraceptives are contraindicated. Metformin is more effective than pioglitazone (2)[A]. • Steroids: used in late-onset congenital adrenal hyperplasia – Dexamethasone: 2 mg/day • Cosmetic treatment: includes many methods of hair removal – Temporary: shaving, chemical depilation, plucking, waxing – Permanent: Laser epilation and photoepilation are preferred to electrolysis (4)[C].

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Pregnancy Considerations • May have related infertility. Offer intervention, if desired. • As hormone balance improves, fertility may increase; provide contraception, as needed. • Several medications used for treatment are contraindicated in pregnancy.

COMPLEMENTARY & ALTERNATIVE MEDICINE Several herbals including spearmint tea, saw palmetto, licorice, fennel, and soy have been shown in small (50 copies/mL) noted during therapy within 4 weeks prior to making management decisions (BIII). • Test fasting lipids and fasting glucose annually; basic chemistry, aspartate aminotransferase, alanine aminotransferase, T/D bilirubin every 6 to 12 months (3) • HLA-B 5701 if considering abacavir (3)

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• Pregnancy test women of childbearing age (3) • Urinalysis every 6 to 12 months or as clinically indicated (3) • Hepatitis C as clinically indicated (3)

DIET • Encourage good nutrition; avoid raw eggs and unpasteurized milk. • Discuss unknown and potentially harmful effects of supplement use including drug–drug interactions.

PATIENT EDUCATION Provide nonjudgmental, sex-positive prevention counseling, reviewing high-risk behaviors and viral transmission. American Foundation for AIDS Research: 212719-0033 (new treatments and research) www.aidsinfo.nih.gov

PROGNOSIS • Untreated HIV infection leading to the diagnosis of AIDS has an associated life expectancy of about 3 years, and if the patient has an OI, the life expectancy is about 1 year. • AIDS-defining opportunistic infections usually do not develop until CD4 axillary) • Splenomegaly • Hepatomegaly

DIFFERENTIAL DIAGNOSIS Non-Hodgkin lymphoma, infectious lymphadenopathy, solid tumor metastases, sarcoidosis, autoimmune disease, AIDS/HIV, drug reaction

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • CBC with differential • Comprehensive metabolic panel

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• LFT, LDH • ESR • HIV, EBV • Pregnancy test for women of childbearing age • Echocardiogram (in anticipation of treatment with anthracycline) • Pulmonary function tests (diffusion capacity of the lung for CO in anticipation of treatment with bleomycin) • Chest x-ray • CT with contrast of chest, abdomen, and pelvis • PET: for initial staging, midtreatment decision making, and end-of-treatment evaluation Follow-Up Tests & Special Considerations • Fertility considerations: – Semen cryopreservation if chemotherapy or pelvic radiation therapy – In vitro fertilization or ovarian tissue/oocyte cryopreservation • Radiation therapy (RT) considerations: – Splenic RT: pneumococcal, Haemophilus influenzae, meningococcal vaccine

Diagnostic Procedures/Other • Excisional lymph node biopsy • Immunohistochemistry • Bone marrow biopsy if cytopenia with negative PET (2) • Liver biopsy (in selected cases)

Test Interpretation RS cell characteristics include the following: • Diameter: 20 to 50 μm • Abundant acidophilic cytoplasm • Bi- or polylobulated nucleus • Acidophilic nucleoli • CD30+, CD15+, CD45−, CD3−, CD20+ in 40% of cases • RS cells necessary but not sufficient for diagnosis (needs inflammatory background)

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TREATMENT • Ann Arbor staging with Cotswold modification – Stage I: single lymph node or of a single extralymphatic organ or site – Stage II: ≥2 lymph node regions on the same side of diaphragm alone or with involvement of extralymphatic organ or tissue – Stage III: node groups on both sides of the diaphragm – Stage IV: dissemination involving extranodal organs (except the spleen, which is considered lymphoid tissue) – Subclasses: A = no systemic symptoms; B = systemic symptoms (fever, night sweats, weight loss >10% body weight); X = bulky disease (>1/3 intrathoracic, diameter, or >10-cm nodal mass) – Classified into three groups: early stage (I or II) favorable, early stage unfavorable (presence of either B symptoms, large mediastinal adenopathy, 3 or more nodal sites of disease, extranodal involvements, or an ESR >50), or advanced stage (III or IV) • Goal: Aim for cure. • All subsequent treatment and follow-up care recommendations based on National Comprehensive Cancer Network (NCCN) consensus. Please refer to NCCN Practice Guidelines in Oncology for Hodgkin lymphoma.

MEDICATION First Line • Stage IA/favorable: ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) × 2 then 20 Gy involved site radiation therapy (ISRT) (1): – Highly emetic, severe phlebitis – Doxorubicin: risk of cardiotoxicity; monitor LVEF. – Bleomycin: risk of pulmonary toxicity, death; test dose may be administered prior to first cycle. – Dacarbazine cannot be omitted without loss of efficacy. • Stage IIA/favorable (same as for I) or ABVD × 3 + additional ABVD × 1 pending PET response +/− 30 Gy ISRT, or ABVD x 2 or BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, prednisone) × 2 + 30 Gy ISRT, or Stanford V × 8 weeks + 30

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Gy ISRT • Stage I/II unfavorable/nonbulky: ABVD × 4 then ABVD × 2 +/− ISRT or Stanford V × 12 weeks + ISRT or BEACOPP + ISRT • Stage I/II unfavorable/bulky: same as for nonbulky but ABVD × 2 with ISRT or Stanford V × 12 with ISRT • Stage III/IV: ABVD × 2 then ABVD or BEACOPP × 4 +/− ISRT or Stanford V × 12 + ISRT unless refractory or BEACOPP × 6 +/− ISRT pending PET response

Second Line • Reserved for patients with relapse or disease refractory to first-line treatment • Standard is for chemotherapy agents not used for initial treatment and then high-dose therapy with autologous stem cell transplant (HDT/ASCT) +/− ISRT. – HDT/ASCT shows improved EFS/PFS compared with conventional chemotherapy but not overall survival; can achieve disease-free survival in 30–40% of patients after auto SCT – Allogeneic SCT to be considered if failed autologous SCT (used in trials only) • Brentuximab vedotin (anti-CD30 chimeric antibody conjugated to synthetic antimicrotubule agent monomethyl auristatin E) FDA approved for use as maintenance therapy × 1 year in relapsed HL after HDT/ASCT or failed two prior lines of multiagent chemotherapy. Improves PFS in those at risk for relapse or progression after transplantation (3). Recent phase II study data show 3-year OS and PFS rates were 73% and 58%, respectively (4,5). – Side effects include peripheral neuropathy, nausea, fatigue, neutropenia, diarrhea (4). – May also be used prior to HDT/ASCT to avoid toxicity with HDT (6) • Nivolumab (anti-PD1) may be used for patients who have failed HCT/ASCT and brentuximab vedotin therapy (6). • Rituximab may be considered as monotherapy or in combination with chemotherapy for refractory or relapsed lymphocyte-predominant/NLPHL (7). • Third-line novel agents undergoing studies: NF-κB inhibitors (bortezomib), mammalian target of rapamycin (mTOR) inhibitors (everolimus), immunomodulators (lenalidomide), cell signaling targets histone deacetylase

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(HDAC) inhibitors (vorinostat, panobinostat, mocetinostat) • Median survival 45 years – Male gender – Albumin 7.5% 10-year ASCVD risk: Concern that Pooled Cohort Equations significantly overestimate ASCVD risk Concern for significant overtreatment: one study showing 96% of men and 66% of women >55 years of age on statins based on recommendations – Many more patients treated and medications used in the United States than elsewhere in the world without substantial evidence for improved outcomes • United Kingdom: National Institute for Health and Care Excellence (NICE) cholesterol guidelines (3)[C] – No history of CV disease: If 10-year risk of CVD >10%, start atorvastatin 20 mg. – If eGFR 500, TG lowering becomes primary target until TG 50% – Moderate-intensity statin: should lower LDL-C 30–50% – Subsequent monitoring not indicating unless question of patient adherence

First Line HMG-CoA reductase inhibitors (statins) • Categorized based on intensity – High intensity Atorvastatin 40 to 80 mg/day Rosuvastatin 20 to 40 mg/day – Moderate intensity Atorvastatin 10 to 20 mg/day Rosuvastatin 5 to 10 mg/day Simvastatin 20 to 40 mg/day Pravastatin 40 to 80 mg/day Lovastatin 40 mg/day Fluvastatin XL 80 mg/day Fluvastatin 40 mg BID

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Pitavastatin 2 to 4 mg/day – Low intensity Simvastatin 10 mg/day Pravastatin 10 to 20 mg/day Lovastatin 20 mg/day Fluvastatin 20 to 40 mg/day Pitavastatin 1 mg/day • To be taken in the evening or at bedtime for best effect (exception: atorvastatin, rosuvastatin) • Effect is greatest in lowering LDL-C; shown to decrease CHD incidence and all-cause mortality, although number needed to treat may be high in primary prevention. • Contraindications: pregnancy, lactation, or active liver disease • Drug interactions: cyclosporine, macrolide antibiotics, various antifungal agents, HIV protease inhibitors, fibrates/nicotinic acid (to be used with caution) • Adverse reactions: – Mild myalgia is common. – Liver transaminase elevations: ALT before therapy to establish baseline; if ALT >3 times upper limit of normal, do not start statin; routine monitoring is not recommended; reasonable to measure hepatic function if symptoms suggesting hepatotoxicity occur. – Association with increased cases of diabetes: 0.1 excess cases of diabetes per 100 persons on moderate-intensity statin and 0.3 excess cases per 100 persons on high-intensity statin – Myopathies (considered rare but not well studied): Creatine kinase (CK) baseline reasonable for those at increased risk for adverse muscle events; routine monitoring not needed unless muscle symptoms occur Instruct patients to report immediately any muscle pain, muscle weakness, or brown urine. If myopathy or rhabdomyolysis is suspected, discontinue statin use and draw serum CK, creatinine, urine analysis. Can rechallenge statin at lower dose or different type after resolution of

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symptoms

ALERT FDA alert: Simvastatin should no longer be prescribed at 80 mg/day doses due to increased risk of myopathy. Patients who have been at this drug dosage for >1 year can continue if no signs of myopathy. Dose restrictions to reduce myopathy risk include the following: • Do not exceed simvastatin 10 mg/day with amiodarone, verapamil, and diltiazem. • Do not exceed simvastatin 20 mg/day with amlodipine and ranolazine.

ALERT Avoid grapefruit juice with statins.

Pregnancy Considerations • Statins contraindicated during pregnancy: class X • Lactation: possibly unsafe

Second Line • Second-line drugs are no longer recommended in any guidelines due to absence of evidence of improved patient outcomes, especially in patients already on statin therapy. • Ezetimibe – Can be taken by itself or in combination with a statin: monotherapy (Zetia 10 mg/day) or ezetimibe/simvastatin (Vytorin 10/10, 10/20, 10/40) – Effect: lowers LDL-C; one recent RCT shows combination therapy with statin has small benefit in reducing CV events and CV-related mortality after acute coronary syndromes. – Adverse reactions: generally well tolerated • Fibrates – Types: gemfibrozil (Lopid) 600 mg BID, fenofibrate (Antara, Lofibra, Tricor, Triglide) – Effect: most effective in lowering TG with moderate effect in lowering LDL and raising HDL. More recent studies fail to show benefit in most patients.

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– Contraindications: severe hepatic or renal insufficiency – Possible interactions: potentiates effects of warfarin and oral hypoglycemic agents – Adverse reactions: GI complaints; increased likelihood of gallstones • Nicotinic acid: raises HDL but no evidence for improved outcomes in recent trials and significant potential harms; should no longer be used in routine practice • Bile acid sequestrant: causes significant GI side effects, no evidence for improved outcomes, rarely used • Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors: – New medication requiring SC injections every 2 to 4 weeks with reduction in all-cause mortality, CV mortality and CV events – Very expensive and unclear role in therapy at this time

COMPLEMENTARY & ALTERNATIVE MEDICINE • Omega-3 fatty acids and fish oil intake: Sources are fish oil (salmon), plant sources (flaxseed, canola oil, soybean oil, nuts); mainly lower TG level but has some benefit in lowering LDL and raising HDL although overall CV benefit and mortality reduction is uncertain. Supplements do not reduce overall or CV mortality. Patients should be advised to eat a variety of oily fish twice a week. • β-Sitosterols and red yeast rice (contains natural lovastatin-analogue) can reduce TC and LDL. • Garlic: appears to have some lipid-lowering effect, but more studies are needed; effective dose not established but generally 1 to 2 cloves of raw garlic/day, 300 mg dried garlic powder tablet BID or TID, or 7.2 g of aged garlic extract/day.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Exercise: sustained exercise for 30 minutes, 3 to 4 times per week: increases HDL, lowers TC, and helps control weight

Patient Monitoring

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• Initially, lipid panel in 4 to 12 weeks after starting therapy, routine monitoring of LDL levels in patients on statin is not necessary. • Routine monitoring of LFTs is no longer recommended if initial ALT is within normal range.

REFERENCES

1. U.S. Preventive Services Task Force. Lipid disorders in adults (cholesterol, dyslipidemia): screening. http://www.uspreventiveservicestaskforce.org/Page/Document/UpdateSummaryFinal/lipiddisorders-in-adults-cholesterol-dyslipidemia-screening. Accessed September 22, 2016. 2. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014;129(25 Suppl 2):S1–S45. 3. National Institute for Health and Care Excellence. Cardiovascular disease: risk assessment and reduction, including lipid modification. http://www.nice.org.uk/guidance/cg181. Accessed September 22, 2016. 4. Reiner Z, Catapano AL, De Backer G, et al. ESC/EAS guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur Heart J. 2011;32(14):1769– 1818.

ADDITIONAL READING Taylor F, Huffman MD, Macedo AF, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2013;(1):CD004816.

SEE ALSO • Hypothyroidism, Adult • Algorithm: Hypercholesterolemia

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CODES ICD10 E78.0 Pure hypercholesterolemia

CLINICAL PEARLS • Hypercholesterolemia is a significant risk factor for ASCVD, but ASCVD is a multifactorial disease with many different risk factors. • Diet and exercise should be tried before pharmaceutical interventions. • Statins are considered first-line medications for hypercholesterolemia. Other medications show little evidence of benefit.

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HYPEREMESIS GRAVIDARUM Emma Brooks, MD BASICS DESCRIPTION • Hyperemesis gravidarum is persistent vomiting in a pregnant woman that interferes with fluid and electrolyte balance as well as nutrition: – Usually associated with the first 8 to 20 weeks of pregnancy – Believed to have biomedical and behavioral aspects – Associated with high estrogen and human chorionic gonadotropin (hCG) levels – Symptoms usually begin ~2 weeks after first missed period. • System(s) affected: endocrine/metabolic; gastrointestinal; reproductive • Synonym(s): morning sickness

Pregnancy Considerations Common condition during pregnancy, typically in the 1st and 2nd trimesters but may persist into the 3rd trimester.

EPIDEMIOLOGY Incidence Hyperemesis gravidarum occurs in 1–2% of pregnancies.

Prevalence Hyperemesis gravidarum is the most common cause of hospitalization in the first half of pregnancy and the second most common cause of hospitalization of pregnant women.

ETIOLOGY AND PATHOPHYSIOLOGY • Unknown • Possible psychologic factors • Hyperthyroidism • Hyperparathyroidism • Gestational hormones

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• Liver dysfunction • Autonomic nervous system dysfunction • CNS neoplasm • Addison disease

RISK FACTORS • Obesity • Nulliparity • Multiple gestations • Gestational trophoblastic disease • Gonadotropin production stimulated • Altered GI function • Hyperthyroidism • Hyperparathyroidism • Liver dysfunction • Female fetus • Helicobacter pylori infection (1)

GENERAL PREVENTION Anticipatory guidance in 1st and 2nd trimesters regarding dietary habits in hopes of avoiding dehydration and nutritional depletion.

Pregnancy Considerations • 2% of pregnancies have electrolyte disturbances. • 50% of pregnancies have at least some GI disturbance.

COMMONLY ASSOCIATED CONDITIONS Hyperthyroidism

DIAGNOSIS HISTORY • Hypersensitivity to smell • Alteration in taste • Excessive salivation • Poor appetite

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• Nausea • Vomiting with retching • Decreased urine output • Fatigue • Dizziness with standing

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Urinalysis: may see glucosuria, albuminuria, granular casts, and hematuria (rare); ketosis more common • Thyroid-stimulating hormone (TSH), T4 • Electrolytes, BUN, creatinine: – Electrolyte abnormalities due to nausea and vomiting and subsequent dehydration – Acidosis • Calcium • Uric acid • Hypoalbuminemia • No imaging is indicated for the diagnosis of hyperemesis gravidarum unless there is concern for hydatidiform mole or multiple gestation, in which case ultrasound may be obtained. Follow-Up Tests & Special Considerations • If hypercalcemia, consider checking parathyroid hormone (PTH) for hyperparathyroidism. • Drugs are unlikely to alter lab results.

Diagnostic Procedures/Other Indicated only if it is necessary to rule out other diagnoses, as listed in the following section

DIFFERENTIAL DIAGNOSIS Other common causes of vomiting must be considered: • Gastroenteritis • Gastritis • Reflux esophagitis

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• Peptic ulcer disease • Cholelithiasis • Cholecystitis • Pyelonephritis • Anxiety • Hyperparathyroidism • H. pylori infection

TREATMENT Pyridoxine and doxylamine (pregnancy Category A) are first-line treatments for hyperemesis gravidarum (2)[C]. This is followed by metoclopramide or ondansetron (pregnancy Category B), then prochlorperazine (pregnancy Category C), methylprednisolone (pregnancy Category C), or promethazine (pregnancy Category C).

GENERAL MEASURES • Patient reassurance • Bed rest • If dehydrated, IV fluids, either normal saline or 5% dextrose normal saline (with consideration for potential thiamine deficiency). Repeat if there is a recurrence of symptoms following initial improvement. • For severe cases, consider PO thiamine 25 to 50 mg TID or IV 100 mg in 100 mL of normal saline over 30 minutes once weekly and potential parental nutrition if needed. • Ondansetron carries an FDA warning regarding concerns for QT prolongation, but this is in the setting of high-dose IV administration and in patients with heart disease. It has unclear risk in the setting of pregnancy. The majority of the current studies appear to show no increased risk of fetal malformation with the use of ondansetron, but this is still an area of controversy (3)[C],(4) [B].

MEDICATION • Pyridoxine (vitamin B6) 25 mg PO or IV every 8 hours • Antihistamines (e.g., diphenhydramine [25 to 50 mg q4–6h] or doxylamine

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[12.5 mg PO BID]) (5)[C] • Combination product Diclegis (sustained-release pyridoxine 10 mg and doxylamine 10 mg) dosed (start 2 tabs PO q hs; if sx persist, increase to 1 tab in AM & 2 hs; if sx still persist, take 1 tab q AM, 1 mid day, and 2 hs; max 4 tablets/day) • Phenothiazines (e.g., promethazine or prochlorperazine): – Precautions: Phenothiazines are associated with prolonged jaundice, extrapyramidal effects, and hyper- or hyporeflexia in newborns. • Meclizine 25 mg PO q6h • Metoclopramide 10 mg PO q6 to 8h • Methylprednisolone 16 mg PO/IV q8h for 2 to 3 days, then taper over 2 weeks if initial 3-day treatment is effective. • Ondansetron 4 to 8 mg PO q8h

Pregnancy Considerations All medications taken during pregnancy should balance the risks and benefits both to the mother and the fetus.

COMPLEMENTARY & ALTERNATIVE MEDICINE • Ginger 350 mg PO TID may help (6)[A]. • Motion sickness wristbands are another nonpharmacologic intervention that may improve symptoms. Evidence is mixed regarding the impact of acupressure and acupuncture in treating hyperemesis gravidarum (7)[C]. • Medical hypnosis may be a helpful adjunct to the typical medical treatment regimen, but further study is needed (8)[C].

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Typically outpatient therapy • In some severe cases, parenteral therapy in the hospital or at home may be required. • Enteral volume and nutrition repletion may be indicated.

ONGOING CARE

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FOLLOW-UP RECOMMENDATIONS Activity as tolerated after improvement

Patient Monitoring • In severe cases, follow-up on a daily basis for weight monitoring. • Special attention should be given to monitor for ketosis, hypokalemia, or acid–base disturbances due to hyperemesis.

DIET • NPO for first 24 hours if patient is ill enough to require hospitalization. • For outpatient: a diet rich in carbohydrates and protein, such as fruit, cheese, cottage cheese, eggs, beef, poultry, vegetables, toast, crackers, rice. Limit intake of butter. Patients should avoid spicy meals and high-fat foods. Consider cold foods. Encourage small amounts at a time every 1 to 2 hours.

PATIENT EDUCATION • Attention should be given to psychosocial issues, such as possible ambivalence about the pregnancy. • Patients should be instructed to take small amounts of fluid frequently to avoid volume depletion. • Avoid individual foods known to be irritating to the patient. • Wet-to-dry nutrients (sherbet, broth, gelatin to dry crackers, toast)

PROGNOSIS • Self-limited illness with good prognosis if patient’s weight is maintained at >95% of prepregnancy weight. • With complication of hemorrhagic retinitis, mortality rate of pregnant patient is 50%.

COMPLICATIONS • Patients with >5% weight loss are associated with intrauterine growth retardation and fetal anomalies. • Poor weight gain is associated with slightly increased risk for small gestational age infant 5 mmol/L). • Hyperkalemia depresses cardiac conduction and can lead to fatal arrhythmias. • Normal K regulation – Ingested K enters portal circulation; pancreas releases insulin in response. Insulin facilitates K entry into cells. – K in renal circulation causes renin release from juxtaglomerular cells, leading to activation of angiotensin I, which is converted to angiotensin II in lungs. Angiotensin II acts in adrenal zona glomerulosa to stimulate aldosterone secretion. Aldosterone, at the renal collecting ducts, causes K to be excreted and sodium to be retained. • Four major causes – Increased load: either endogenous from tissue release or exogenous from a high intake, usually in association with impaired excretion – Decreased excretion: due to decreased glomerular filtration rate – Cellular redistribution: shifts from intracellular space (majority of K is intracellular) to extracellular space – Pseudohyperkalemia: related to red cell lysis during collection or transport of blood sample, thrombocytosis, or leukocytosis

Geriatric Considerations Increased risk for hyperkalemia because of decreases in renin and aldosterone as well as comorbid conditions

EPIDEMIOLOGY Prevalence • 1–10% of hospitalized patients

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• 2–3% in general population but as high as 50% in patients with chronic kidney disease (1) • Predominant sex: male = female • No age-related predilection

ETIOLOGY AND PATHOPHYSIOLOGY • Pseudohyperkalemia – Hemolysis of red cells in phlebotomy tube (spurious result is most common) – Thrombolysis – Leukocytosis – Thrombocytosis – Hereditary spherocytosis – Infectious mononucleosis – Traumatic venipuncture or fist clenching during phlebotomy (spurious result) • Transcellular shift (redistribution) – Metabolic acidosis – Insulin deficiency – Hyperglycemia (diabetic ketoacidosis or hyperosmolar hyperglycemic state) – Tissue damage (rhabdomyolysis, burns, trauma) (2) – Tumor lysis syndrome (3) – Cocaine abuse – Exercise with heavy sweating – Mannitol • Impaired K excretion – Renal insufficiency/failure – Addison disease – Mineralocorticoid deficiency – Primary hyporeninemia, primary hypoaldosteronism – Type IV renal tubular acidosis (hyporeninemic hypoaldosteronism) • Medication-induced – Excess K supplementation – Statins – ACE inhibitors

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– Angiotensin receptor blockers – β-Blockers – Cyclosporine – Digoxin toxicity – Ethinyl estradiol/drospirenone – Heparin – NSAIDs – Penicillin G potassium – Pentamidine – Spironolactone – Succinylcholine – Tacrolimus – Trimethoprim, particularly with other medications associated with hyperkalemia (4,5)

Genetics Associated with some inherited diseases and conditions • Familial hyperkalemic periodic paralysis • Congenital adrenal hyperplasia

RISK FACTORS • Impaired renal excretion of K • Acidemia • Massive cell breakdown (rhabdomyolysis, burns, trauma) • Use of K-sparing diuretics. • Excess K supplementation

GENERAL PREVENTION Diet and oral supplement compliance in those at risk

DIAGNOSIS HISTORY • Neuromuscular cramps • Diarrhea

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• Abdominal pain • Myalgias • Numbness • Muscle weakness or paralysis

PHYSICAL EXAM • Decreased deep tendon reflexes • Flaccid paralysis of extremities

DIAGNOSTIC TESTS & INTERPRETATION • Serum electrolytes • Renal function: BUN, creatinine • Urinalysis: K, creatinine, osmoles (to calculate fractional excretion of K and transtubular K gradient; both assess renal handling of K) • Disorders that may alter lab results – Acidemia: K shifts from the intracellular to extracellular space – Insulin deficiency – Hemolysis of sample • Cortisol and aldosterone levels to check for mineralocorticoid deficiency when other causes are ruled out

Diagnostic Procedures/Other EKG abnormalities usually occur when K ≥7 mEq/L • Peaked T wave with shortened QT interval in precordial leads (most common, usually earliest EKG change) (6) • Lengthening of PR interval • Loss of P wave • Widened QRS • Sine wave at very high K • Can eventually lead to arrhythmias including ventricular fibrillation and asystole

TREATMENT MEDICATION

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• Stabilize myocardial membranes. Initial treatment with calcium gluconate IV 1,000 mg (10 mL of 10% solution) over 2 to 3 minutes – With constant cardiac monitoring – Can repeat after 5 minutes if needed – Effect begins within minutes, but only lasts 30 to 60 minutes and should be used in conjunction with definitive therapies – Can also use calcium chloride (3 times as concentrated; however, it needs central or deep vein to avoid tissue necrosis) • Drive extracellular potassium into cells – Nebulized albuterol (at 10 to 20 mg/4 mL saline over 10 minutes—4 to 8 times bronchodilation dose) and other β-agonists have an additive effect with insulin and glucose – Dextrose 50% 1 amp (if plasma glucose 6.4 mEq/serving) include bananas, orange juice, other citrus fruits and their juices, tomatoes, tomato juice, cantaloupe, honeydew melon, peaches, potatoes, and salt substitutes. Multiple herbal medications can also increase K levels, including alfalfa, dandelion, horsetail nettle, milkweed, hawthorn berries, toad skin, oleander, foxglove, and ginseng.

PATIENT EDUCATION Consult with a dietitian about a low-K diet.

PROGNOSIS • Associated with poor prognosis in patients with heart failure and chronic kidney disease • Associated with poor prognosis in disaster medicine, with trauma, tissue necrosis, K+ supplementation, metabolic acidosis, if calcium gluconate administered for treatment of hyperkalemia, if AKI, or if prolonged duration of hyperkalemia (2,7)

COMPLICATIONS • Life-threatening cardiac arrhythmias • Hypokalemia • Potential complications of the use of ion-exchange resins for the treatment of hyperkalemia include volume overload and intestinal necrosis (8)[C].

REFERENCES 1. Palmer BF, Clegg DJ. Hyperkalemia. JAMA. 2015;314(22):2405–2406. 2. Zimmerman JL, Shen MC. Rhabdomyolysis. Chest. 2013;144(3):1058–1065. 3. Howard SC, Jones DP, Pui CH. The tumor lysis syndrome. N Engl J Med. 2011;364(19):1844–1854. 4. Antoniou T, Gomes T, Juurlink DN, et al. Trimethoprim-sulfamethoxazole– induced hyperkalemia in patients receiving inhibitors of the renin-angiotensin system: a population-based study. Arch Intern Med. 2010;170(12):1045– 1049. 5. Weir MA, Juurlink DN, Gomes T, et al. Beta-blockers, trimethoprim-

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sulfamethoxazole, and the risk of hyperkalemia requiring hospitalization in the elderly: a nested case-control study. Clin J Am Soc Nephrol. 2010;5(9):1544–1551. 6. Wong R, Banker R, Aronowitz P. Electrocardiographic changes of severe hyperkalemia. J Hosp Med. 2011;6(4):240. 7. Khanagavi J, Gupta T, Aronow WS, et al. Hyperkalemia among hospitalized patients and association between duration of hyperkalemia and outcomes. Arch Med Sci. 2014;10(2):251–257. 8. Sterns RH, Rojas M, Bernstein P, et al. Ion-exchange resins for the treatment of hyperkalemia: are they safe and effective? J Am Soc Nephrol. 2010;21(5):733–735. 9. Ingelfinger JR. A new era for the treatment of hyperkalemia? N Engl J Med. 2015;372(3):275–277.

ADDITIONAL READING • Bosch X, Poch E, Grau JM. Rhabdomyolysis and acute kidney injury. N Engl J Med. 2009;361(1):62–72. • Hall AB, Salazar M, Larison DJ. The sequencing of medication administration in the management of hyperkalemia. J Emerg Nurs. 2009;35(4):339–342. • Hollander-Rodriguez JC, Calvert JF Jr. Hyperkalemia. Am Fam Physician. 2006;73(2):283–290. • Jain N, Kotla S, Little BB, et al. Predictors of hyperkalemia and death in patients with cardiac and renal disease. Am J Cardiol. 2012;109(10):1510– 1513. • Noori N, Kalantar-Zadeh K, Kovesdy CP, et al. Dietary potassium intake and mortality in long-term hemodialysis patients. Am J Kidney Dis. 2010;56(2):338–347. • Pepin J, Shields C. Advances in diagnosis and management of hypokalemic and hyperkalemic emergencies. Emerg Med Pract. 2012;14(2):1–17. • Riccardi A, Tasso F, Corti L, et al. The emergency physician and the prompt management of severe hyperkalemia. Intern Emerg Med. 2012;7(Suppl 2):S131–S133.

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SEE ALSO • Addison Disease; Hypokalemia • Algorithm: Hyperkalemia

CODES ICD10 E87.5 Hyperkalemia

CLINICAL PEARLS • Emergency and urgent management of hyperkalemia takes precedent to a thorough diagnostic workup. Urgent treatment includes stabilization of the myocardium with calcium gluconate to protect against arrhythmias and pharmacologic strategies to move K from the extracellular (vascular) space into cells. • Calcium and dextrose/insulin are only temporizing measures and do not actually lower total body K levels. Definitive treatment with either dialysis or cation exchange resin (sodium polystyrene sulfonate) necessary. • To lower a patient’s risk of developing hyperkalemia, have the patient follow a low-K diet, use selective β1-blockers, such as metoprolol or atenolol, instead of nonselective β-blockers such as carvedilol. Avoid NSAIDs. Concomitant use of kaliuretic loop diuretics may be useful.

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HYPERNATREMIA Nilgun Ozturk, MD • Pang-Yen Fan, MD BASICS DESCRIPTION • Serum sodium (Na) concentration >145 mEq/L (1) • Usually represents a state of hyperosmolality (1) • Na concentration reflects balance between total body water (TBW) and total body Na. Hypernatremia occurs from deficit of water relative to Na. • Hypernatremia results from net water loss or, more rarely, from primary Na gain (1). • May exist with hypo-, hyper-, or euvolemia, although hypovolemia is by far most common type – Hypovolemic: occurs with a decrease in TBW and a proportionately smaller decrease in total body Na – Euvolemic: no change in TBW with a proportionate increase in total body Na – Hypervolemic: increase in TBW and a proportionately greater increase in total body Na • It has been shown to be an indicator for higher mortality in critically ill patients and patients with chronic kidney disease (CKD) (2)[B].

EPIDEMIOLOGY Incidence • More common in elderly and young • Occurs in 1% of hospitalized elderly patients (3) • Seen in about 9% of ICU patients (3). Gastroenteritis with diarrhea is the most common cause of hypernatremia in infants. • Women are at an increased risk due to decreased TBW, as compared with men.

ETIOLOGY AND PATHOPHYSIOLOGY • Pure water loss (total body Na normal) resulting from the following:

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– Adipsia/hypodipsia (e.g., impaired thirst regulation, decreased access to water) (4) – Nephrogenic diabetes insipidus (DI) (congenital or due to renal dysfunction, hypercalcemia, hypokalemia, medication-related, particularly lithium) – Central DI (due to head trauma, stroke, meningitis) (3) – Increased insensible water loss (e.g., fever, hyperventilation, hypermetabolic state, heat exposure, newborns under radiant warmers) • Hypotonic fluid loss (total body Na decreased) resulting from the following: – Loss of fluid containing relatively more water than Na (e.g., excessive sweating, severe burns) – Urinary loss Osmotic diuresis: hyperglycemia, mannitol Diuretics, especially loop diuretics Diabetes mellitus, particularly new presentation/decompensated Post acute tubular necrosis (ATN) or post obstructive diuresis Intrinsic renal disease – Gastrointestinal loss Diarrhea, especially in children Vomiting, nasogastric (NG) lavage Enterocutaneous fistula • Excess Na (increase in total body Na) resulting from the following: – IV NaCl or NaHCO3 during cardiopulmonary resuscitation, metabolic acidosis, or hyperkalemia (3) – Sea water ingestion – Excessive use of NaHCO3 antacid. – Incorrect infant formula preparation – Intrauterine NaCl for abortion – Excessive Na in dialysate solutions – Disorders of the adrenal axis (Cushing syndrome, Conn syndrome, congenital adrenal hyperplasia) – Tube feeding With acute hypernatremia, the rapid decrease in brain volume can cause rupture of the cerebral veins, leading to focal intracerebral and subarachnoid

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hemorrhages and possibly irreversible neurologic damage (5).

Genetics Some forms of DI may be hereditary.

RISK FACTORS • Patients at increased risk include those with an impaired thirst mechanism or restricted access to water, as well as those with increased water loss • Infants/children • Elderly patients (may also have a diminished thirst response to osmotic stimulation via an unknown mechanism) • Patients who are intubated/have altered mental status. • Diabetes mellitus • Prior brain injury • Surgery • Diuretic therapy, especially loop diuretics • Lithium treatment

GENERAL PREVENTION • Treatment/prevention of underlying cause • Properly prepare infant formula and never add salt to any commercial infant formula. • Keep patients well hydrated.

COMMONLY ASSOCIATED CONDITIONS • Gastroenteritis • Altered mental status • Burns • Hypermetabolic conditions • Head injury • Renal dysfunction

DIAGNOSIS HISTORY • Excessive thirst, nausea, vomiting, diarrhea, oliguria, polyuria

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• Fever, myalgia, muscle weakness • Neurologic symptoms common: altered mental status, seizure (especially if rapid development of hypernatremia), twitching, lethargy, irritability, coma, anophthalmos • Severe symptoms are likely to occur with acute increases in plasma Na levels or at concentrations >160 mEq/L. • Obtain list of current and recent medications. • Review recent illnesses and activities.

PHYSICAL EXAM • Sinus tachycardia, hypotension, orthostatic hypotension, poor O2 saturation • Dry mucous membranes, cool/gray skin • Neurologic abnormalities: lethargy, weakness, focal deficits (in cases of intracerebral bleeding/lesion), confusion, coma, seizures

DIFFERENTIAL DIAGNOSIS • DI • Hyperosmotic coma • Salt ingestion • Hypertonic dehydration • Hypothyroidism • Cushing syndrome

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Serum Na, potassium, BUN, creatinine, calcium, and osmolality (serum lithium if appropriate) • Urine Na and osmolality – DI: urine osmolality (usually 24 hours): – Maximum of 0.5 mEq/L/hr or 10 mEq/L/day (6)[C] – May correct at up to 1 mEq/L/hr if acute hypernatremia (10 mEq/L/day to prevent cerebral edema (4)[C] • Hypervolemia: Give furosemide along with hypotonic fluids. Dose varies depending on desired urine output. Loop diuretics with fluid restriction worsen hypernatremia (4)[C]. • Central DI – DDAVP acetate: Use parenteral form for acute symptomatic patients, and use intranasal or oral form for chronic therapy (4). – Free water replacement: may use 2.5% dextrose in water if giving large volumes of water in DI to avoid glycosuria – May consider sulfonylureas/thiazide diuretics for chronic, but not acute, treatment • Nephrogenic DI – Treat with diuretics and NSAIDs. – Lithium-induced nephrogenic DI: hydrochlorothiazide 25 mg PO BID or indomethacin 50 mg PO TID, or amiloride hydrochloride 5 to 10 mg PO BID (8) • Precautions – Rapid correction of hypernatremia can cause cerebral edema, central pontine myelinosis, seizures, or death (9). – Hypocalcemia and more rarely acidosis can occur during correction.

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– DI: High rates of dextrose 5% in water can cause hyperglycemia and glucose-induced diuresis.

Second Line • Consider NSAIDs in nephrogenic DI. • Modalities requiring further investigations • Continuous renal replacement therapy (CRRT): Multiple case reports and case series have shown success and safety in using CRRT to treat hypernatremia in critically ill patients with CHF and severe burns (7,10).

ISSUES FOR REFERRAL Underlying renal involvement associated with hypernatremia would benefit from a nephrology referral.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Symptomatic patient with serum Na >155 mEq/L requires IV fluid therapy. • IV fluids refer to “Medication” section. • Bed rest until stable or underlying condition resolved/controlled • Discharge criteria: stabilization of serum Na level and symptoms are minimal.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Frequent reexams in an acute setting • Frequent electrolytes and blood glucose: initially q4–6h • Urine osmolality and urine output in DI • Ensure adequate ingestion of calories because patients may ingest so much water that they feel full and do not eat. • Measure ongoing losses of water and solute and replace as needed. • Daily weights

DIET • Ensure proper nutrition during acute phase.

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• After resolution of acute phase, may want to consider Na-restricted diet for patient • Low-salt, low-protein diet in nephrogenic DI

PATIENT EDUCATION Patients with nephrogenic DI must avoid salt and drink large amounts of water.

PROGNOSIS Most recover but neurologic impairment can occur.

COMPLICATIONS • CNS thrombosis/hemorrhage • Seizures • Mental retardation • Hyperactivity • Chronic hypernatremia: >2 days duration has higher mortality • Serum Na >180 mEq/L (>180 mmol/L): often results in residual CNS damage • More common if rapid development of hypernatremia

REFERENCES 1. Adrogué HJ, Madias NE. Hypernatremia. N Engl J Med. 2000;342(20):1493–1499. 2. Kovesdy CP, Lott EH, Lu JL, et al. Hyponatremia, hypernatremia, and mortality in patients with chronic kidney disease with and without congestive heart failure. Circulation. 2012;125(5):677–684. 3. Bagshaw SM, Townsend DR, McDermid RC. Disorders of sodium and water balance in hospitalized patients. Can J Anaesth. 2009;56(2):151–167. 4. Hannon MJ, Finucane FM, Sherlock M, et al. Clinical review: disorders of water homeostasis in neurosurgical patients. J Clin Endocrinol Metab. 2012;97(5):1423–1433. 5. Sterns RH. Disorders of plasma sodium—causes, consequences, and correction. N Engl J Med. 2015;372(1):55–65. 6. Al-Absi A, Gosmanova EO, Wall BM. A clinical approach to the treatment of chronic hypernatremia. Am J Kidney Dis. 2012;60(6):1032–1038. 7. Huang C, Zhang P, Du R, et al. Treatment of acute hypernatremia in

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severely burned patients using continuous veno-venous hemofiltration with gradient sodium replacement fluid: a report of nine cases. Intensive Care Med. 2013;39(8):1495–1496. 8. Libber S, Harrison H, Spector D. Treatment of nephrogenic diabetes insipidus with prostaglandin synthesis inhibitors. J Pediatr. 1986;108(2):305–311. 9. Mastrangelo S, Arlotta A, Cefalo MG, et al. Central pontine and extrapontine myelinolysis in a pediatric patient following rapid correction of hypernatremia. Neuropediatrics. 2009;40(3):144–147. 10. Park HS, Hong YA, Kim HG, et al. Usefulness of continuous renal replacement therapy for correcting hypernatremia in a patient with severe congestive heart failure. Hemodial Int. 2012;16(4):559–563.

ADDITIONAL READING Waite MD, Fuhrman SA, Badawi O, et al. Intensive care unit–acquired hypernatremia is an independent predictor of increased mortality and length of stay. J Crit Care. 2013;28(4):405–412.

SEE ALSO • Diabetes Insipidus • Algorithm: Hypernatremia

CODES ICD10 E87.0 Hyperosmolality and hypernatremia

CLINICAL PEARLS • Occurs from water deficit in comparison to total body Na stores • Common causes include dehydration, DI, impaired access to fluids • Determine if the patient has hypervolemic, euvolemic, or hypovolemic hypernatremia in the differential diagnosis of etiology; most commonly

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hypovolemic; other entities rare • Avoid rapid correction of hypernatremia to prevent development of cerebral edema when hypernatremia is chronic (goal rate is 10 meq/L in 24 hours). • Use hypotonic fluids unless patient has hemodynamic compromise, which necessitates use of isotonic fluids. • Use oral replacement in conscious patients if possible. • Use the estimated water deficit, desired rate of correction, and estimation of ongoing free water losses to calculate a fluid repletion regimen.

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HYPERPARATHYROIDISM Robert A. Baldor, MD, FAAFP BASICS DESCRIPTION A dysfunction of the body’s normal regulatory feedback mechanisms resulting in excess production of parathyroid hormone (PTH) • Primary hyperparathyroidism (HPT): intrinsic parathyroid gland dysfunction resulting in excessive secretions of PTH with a lack of response to feedback inhibition by elevated calcium • Secondary HPT: excessive secretion of PTH in response to hypocalcemia, which can be caused by vitamin D deficiency or renal failure • Tertiary HPT: autonomous hyperfunction of the parathyroid gland in the setting of long-standing secondary HPT

EPIDEMIOLOGY Incidence Predominant sex: female > male (2:1)

Prevalence Primary HPT: 1/1,000 in the United States

ETIOLOGY AND PATHOPHYSIOLOGY • PTH is synthesized by the four parathyroid glands, which are located behind the four poles of the thyroid gland (locations can vary). • Ectopic (abnormal locations and most common is the thymus) or supernumerary glands (more than four glands) • PTH releases calcium from bone by osteoclastic stimulation (bone resorption). • PTH increases reabsorption of calcium in the distal tubules of the kidneys. • PTH stimulates conversion of 25-hydroxycholecalciferol (25[OH]D) to 1,25dihydroxycholecalciferol (1,25[OH]2D or active vitamin D) in the kidneys. – 1,25(OH)2D increases calcium absorption from the GI tract, increases calcium and phosphate reabsorption in the kidneys, and stimulates

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osteoclastic activity and bone resorption. • Primary HPT: unregulated PTH production and release, causing increase in serum calcium – Solitary adenoma (89%) – Double adenomas (5%) – Diffuse hyperplasia (6%) caused by multiple adenomas, multiple endocrine neoplasia (MEN) types 1 and 2a, and familial hypocalciuric hypercalcemia (FHH) – Parathyroid carcinoma (2.65 mmol/L), consider this true hypercalcemia which is consistent with hyperparathyroidism. • If hypercalcemia is confirmed, follow with intact PTH level (1)[B]. – High PTH (>3.0 pmol/L) suggests primary HPT. – Low PTH (0.02 suggests primary HPT; a ratio 5 years old: 250 mg PO BID

PATIENT EDUCATION Patients who are splenectomized should be counseled extensively about the risk of overwhelming postsplenectomy sepsis and the need to obtain prompt medical evaluation in the event of fevers, chills, or any other concerning symptoms.

REFERENCES 1. Bai YN, Jiang H, Prasoon P. A meta-analysis of perioperative outcomes of laparoscopic splenectomy for hematological disorders. World J Surg.

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2012;36(10):2349–2358. 2. Advisory Committee on Immunization Practices. Recommended adult immunization schedule: United States, 2012. Ann Intern Med. 2012;156(3):211–217. 3. American Academy of Pediatrics. Children with asplenia or functional asplenia. In: Pickering LK, Baker CJ, Kimberlin DW, et al, eds. Red Book: 2009 Report of the Committee on Infectious Diseases. 28th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2009:72. 4. American Academy of Pediatrics Committee on Infectious Diseases. Haemophilus influenzae type b conjugate vaccines: recommendations for immunization with recently and previously licensed vaccines. Pediatrics. 1993;92(3):480–488. 5. Centers for Disease Control and Prevention. Updated recommendations for use of meningococcal conjugate vaccines—Advisory Committee on Immunization Practices (ACIP), 2010. MMWR Morb Mortal Wkly Rep. 2011;60(3):72–76.

ADDITIONAL READING • Abdella HM, Abd-El-Moez AT, Abu El-Maaty ME, et al. Role of partial splenic arterial embolization for hypersplenism in patients with liver cirrhosis and thrombocytopenia. Indian J Gastroenterol. 2010;29(2):59–61. • Di Sabatino A, Carsetti R, Corazza GR. Post-splenectomy and hyposplenic states. Lancet. 2011;378(9785):86–97. • Feng K, Ma K, Liu Q, et al. Randomized clinical trial of splenic radiofrequency ablation versus splenectomy for severe hypersplenism. Br J Surg. 2011;98(3):354–361. • Iriyama N, Horikoshi A, Hatta Y, et al. Localized, splenic, diffuse large B-cell lymphoma presenting with hypersplenism: risk and benefit of splenectomy. Intern Med. 2010;49(11):1027–1030. • Jandl JH, Aster RH, Forkner CE, et al. Splenic pooling and the pathophysiology of hypersplenism. Trans Am Clin Climatol Assoc. 1967;78:9–27. • Kapoor P, Singh E, Radhakrishnan P, et al. Splenectomy in plasma cell dyscrasias: a review of the clinical practice. Am J Hematol. 2006;81(12):946–

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954. • Mourtzoukou EG, Pappas G, Peppas G, et al. Vaccination of asplenic or hyposplenic adults. Br J Surg. 2008;95(3):273–280. • Shatz DV, Schinsky MF, Pais LB, et al. Immune responses of splenectomized trauma patients to the 23-valent pneumococcal polysaccharide vaccine at 1 versus 7 versus 14 days after splenectomy. J Trauma. 1998;44(5):760–765.

SEE ALSO Anemia, Autoimmune Hemolytic; Malaria; Polycythemia Vera; Tuberculosis

CODES ICD10 D73.1 Hypersplenism

CLINICAL PEARLS • Splenectomy is not necessary to make the diagnosis. • Avoid splenectomy in patients unless absolutely necessary. Splenectomized patients are at lifelong risk for overwhelming postsplenectomy infection and sepsis. • If splenectomy is to be performed, give immunization for pneumococcus, meningococcus, Haemophilus, and influenza at least 14 days prior to surgery. Otherwise, wait until the 14th postop day to immunize.

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HYPERTENSION, ESSENTIAL Lisa M. Schroeder, MD • Sobia Ahmad, MD BASICS DESCRIPTION • Hypertension (HTN) is defined (Joint National Committee [JNC] 8) as ≥2 elevated BPs – Age 60 years or older: systolic BP (SBP) ≥150 mm Hg and/or diastolic BP (DBP) ≥90 mm Hg at ≥2 visits (1) – Age 140 and/or DBP >90 mm Hg • HTN is a strong risk factor for cardiovascular disease and strokes. • Synonym(s): benign, chronic, idiopathic, familial, or genetic HTN; high BP

Geriatric Considerations • Isolated systolic HTN is common. • Therapy has been shown to be effective and beneficial at preventing stroke, although target SBP is higher than in younger patients (~150 mm Hg systolic), and adverse reactions to medications are more frequent. The benefit of therapy has been conclusively demonstrated in older patients for SBP ≥160 mm Hg. • New evidence suggests that an aggressive target for the elderly is both beneficial and safe (2)[A].

Pediatric Considerations • Measure BP during routine exams for >3 years of age. • Defined as SBP or DBP ≥95th percentile on repeated measurements (3) • Pre-HTN: SBP or DBP between 90th and 95th percentile (3)

Pregnancy Considerations • Elevated BP during pregnancy may be either chronic HTN or pregnancyinduced preeclampsia. ACE inhibitors and angiotensin II receptor blockers (ARBs) are contraindicated.

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• Maternal and fetal mortality benefit from treatment of severe HTN. Evidence is not clear for mild HTN (see topic “Preeclampsia”). • Methyldopa, labetalol, hydralazine, or nifedipine preferred agents

EPIDEMIOLOGY Incidence • Lifetime risk for men and women aged 55 to 65 years by age 80 to 85 years is >90%. • Predominant age: essential (primary, benign, idiopathic) onset usually in the 20s to 30s • Predominant sex: male > female; males tend to run higher than females and have a significantly higher risk of cardiovascular disease at any given pressure.

Prevalence In 2009 to 2010, prevalence in adults was 28.6% (2009–2010 National Health and Nutrition Examination Survey [NHANES]).

ETIOLOGY AND PATHOPHYSIOLOGY • >90% of HTN has no identified cause. • Secondary causes of HTN (see “Hypertension, Secondary and Resistant”): renal parenchymal: glomerulonephritis, pyelonephritis, polycystic kidneys; endocrine: primary hyperaldosteronism, pheochromocytoma, hyperthyroidism, Cushing syndrome; vascular: coarctation of aorta, renal artery stenosis; chemical: commonly, oral contraceptives, NSAIDs, decongestants, corticosteroids, black licorice, caffeine; sleep apnea

Genetics BP levels are strongly familial, but no clear genetic pattern exists. Familial risk for cardiovascular diseases should be considered.

RISK FACTORS Family history, obesity, alcohol use, excess dietary sodium, stress, physical inactivity, tobacco abuse, insulin resistance

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DIAGNOSIS HISTORY • HTN is asymptomatic except in extreme cases or after related cardiovascular complications develop. • Headache can be seen with higher BP, often present on awakening and occipital in nature.

PHYSICAL EXAM • Evaluate signs of end-organ damage. • Retinopathy: narrowed arteries, arteriovenous (AV) nicking, copper or silver wiring of retinal arterioles • Increased/louder S2 (aortic component heart sound) • Synchronous radial and femoral pulse can help to rule out coarctation of the aorta.

DIFFERENTIAL DIAGNOSIS • Secondary HTN: Because of the low incidence of reversible secondary HTN, special tests should be considered only if the history, physical exam, or basic laboratory evaluation indicate the possibility. (See “Hypertension, Secondary and Resistant.”) • White coat hypertension: elevation of BP in office setting and normal BP outside office • Masked HTN: elevated BP at home and normal BP in office

DIAGNOSTIC TESTS & INTERPRETATION MEASURING BP: • Caffeine, exercise, and smoking avoided >30 minutes before measurement • Patient seated quietly for 5 minutes with feet on floor • Patient’s arm supported at heart level • Correct cuff size • Average of two or more measurements

Initial Tests (lab, imaging) • Hemoglobin and hematocrit or CBC • Complete urinalysis (may reveal proteinuria)

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• Potassium, calcium, creatinine, and uric acid • Lipid panel (total, HDL, LDL, triglyceride [TG]) • Fasting blood glucose, hemoglobin A1c • ECG to evaluate possible presence of left ventricular hypertrophy (LVH) or rhythm abnormalities affecting therapy Follow-Up Tests & Special Considerations • Special tests (only if history, physical, or labs indicates) (See “Hypertension, Secondary and Resistant.”) • Ambulatory (24-hour) BP monitoring if “white coat” HTN is suspected, episodic HTN, or autonomic dysfunction • Home BP monitoring is effective, especially if white coat HTN is a consideration; elevated home BPs correlate with adverse outcomes, possibly more so than office BPs, and normal readings are reassuring.

Diagnostic Procedures/Other • Age 60 years or older: SBP ≥150 mm Hg and/or DBP ≥90 mm Hg at ≥2 visits • Age 60 years of age, because of the risk of atrial fibrillation.

Diagnostic Procedures/Other Neck US will show increased diffuse vascularity in GD.

Test Interpretation • GD: hyperplasia • Toxic nodule: nodule formation

TREATMENT • Decision of which patients to treat and how to treat should be individualized. • Observation may be appropriate for patients with mild hyperthyroidism (TSH >0.1 or with no symptoms) especially those who are young and with low risk of complications (Afib, osteoporosis). • Antithyroid medication is contraindicated in patients with thyroiditis.

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Treatment for subacute thyroiditis is supportive with NSAIDs and β-blockers. Steroids can be used for 2 to 3 weeks (3). GD or TNMG can be managed by either antithyroid medication, radioactive iodine therapy (RAIT), or thyroidectomy. • RAIT: most common definitive treatment used in United States for GD and TMNG • Pretreatment with antithyroid drugs is preferred to avoid worsening thyrotoxicosis after RAIT. MMI is preferred over PTU as pretreatment because of decreased relapse, but it is held 3 to 5 days before therapy (3)[A]. • Usually, patients become hypothyroid 2 to 3 months after RAIT; therefore, antithyroid medications are continued after ablation. • Glucocorticoids: reduce the conversion of active T4 to the more active T3. In Graves ophthalmopathy, the use of prednisone before and after RAIT prevents worsening ophthalmopathy (3)[B]. • Smoking in GD patients is a risk factor for ophthalmopathy, especially after RAIT. • For GD, due to the chance of remission, 12- to 18-month trial of antithyroid medications may be considered prior to offering RAIT. • For TMNG, the treatment of choice is RAIT. Medical therapy with antithyroid medications has shown a high recurrence rate. Surgery is considered only in special cases (3)[B]. • For amiodarone-induced thyrotoxicosis (AIT) type I, the treatment is antithyroid drugs and β-blockers. Thyroidectomy is the last option. AIT type II is self-limited but may use glucocorticoids.

MEDICATION First Line • Antithyroid drugs: MMI and PTU are thioamides that inhibit iodine oxidation, organification, and iodotyrosine coupling. PTU can block peripheral conversion of T4 to active T3. Both can be used as primary treatment for GD and prior to RAIT or surgery (1)[A]. • Duration of treatment: 12 to 18 months; 50–60% relapse after stopping; treatment beyond 18 months did not show any further benefit on remission rate. The most serious side effects are hepatitis (0.1–0.2%), vasculitis, and

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agranulocytosis; baseline CBC recommended: – MMI (preferred): adults: 10 to 15 mg q12–24h; children aged 6 to 10 years: 0.4 mg/kg/day PO once daily – PTU: adults (preferred in thyroid storm and 1st trimester of pregnancy): 100 to 150 mg PO q8h, not to exceed 200 mg/day during pregnancy • β-Adrenergic blocker: Propranolol in high doses (>160 mg/day) inhibits T3 activation by up to 30%. Atenolol, metoprolol, and nadolol can be used. • Glucocorticoids: reduce the conversion of active T4 to the more active T3 • Cholestyramine: anion exchange resin that decreases thyroid hormone reabsorption in the enterohepatic circulation; dose: 4 g QID (1)[B] • Other agents: – Lithium: inhibits thyroid hormone secretion and iodotyrosine coupling; use is limited by toxicity. – Lugol solution or saturated solution of potassium iodide (SSKI); blocks release of hormone from the gland but should be administered at least 1 hour after thioamide was given; otherwise, acts as a substrate for hormone production (Jod-Basedow effect) – RAIT: See “Treatment” section.

ISSUES FOR REFERRAL Patients with Graves ophthalmopathy should be referred to an experienced ophthalmologist.

SURGERY/OTHER PROCEDURES Thyroidectomy for compressive symptoms, masses, and thyroid malignancy may be performed in the 2nd trimester of pregnancy only.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Repeat thyroid tests q3mo, CBC and liver function tests (LFTs) on thioamide therapy; continue therapy with thioamides for 12 to 18 months. • After RAIT, thyroid function tests at 6 weeks, 12 weeks, 6 months, and

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annually thereafter if euthyroid; TSH may remain undetectable for months even after patient is euthyroid; follow T3 and T4.

DIET Sufficient calories to prevent weight loss

PROGNOSIS Good (with early diagnosis and treatment)

COMPLICATIONS • Surgery: hypoparathyroidism, recurrent laryngeal nerve damage, and hypothyroidism • RAIT: postablation hypothyroidism • GD: high relapse rate with antithyroid drug as primary therapy • Graves ophthalmopathy, worsening heart failure if cardiac condition, atrial fibrillation, muscle wasting, proximal muscle weakness, increased risk of cerebrovascular accident (CVA) and cardiovascular mortality

REFERENCES 1. Bahn Chair RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and the American Association of Clinical Endocrinologists. Thyroid. 2011;21(6):593–646. 2. Cappola AR, Fried LP, Arnold AM, et al. Thyroid status, cardiovascular risk, and mortality in older adults. JAMA. 2006;295(9):1033–1041. 3. Bahn RS, Burch HB. Cooper DS, et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Endocr Pract. 2011;17(3):456–520. 4. Abraham P, Avenell A, Park CM, et al. A systematic review of drug therapy for Graves’ hyperthyroidism. Eur J Endocrinol. 2005;153(4):489–498.

CODES ICD10

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• E05.90 Thyrotoxicosis, unspecified without thyrotoxic crisis or storm • E05.20 Thyrotoxicosis w toxic multinod goiter w/o thyrotoxic crisis • E06.1 Subacute thyroiditis

CLINICAL PEARLS • Not all thyrotoxicoses are secondary to hyperthyroidism. • GD presents with hyperthyroidism, ophthalmopathy, and goiter. • Medical treatment for GD has a high relapse rate after stopping medications. • Thyroid storm is a medical emergency that needs hospitalization and aggressive treatment. • Serum TSH level may be misleading and remain low in the early period after initiating treatment, even when T4 and T3 levels have decreased.

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HYPERTRIGLYCERIDEMIA S. Lindsey Clarke, MD, FAAFP BASICS DESCRIPTION • Hypertriglyceridemia is a common form of dyslipidemia characterized by an excess fasting plasma concentration of triglycerides (TG). – TG are fatty molecules made of glycerols that are esterified by fatty acids at all three hydroxyl groups. – They occur naturally in vegetable oils and animal fats and are major sources of dietary energy. TG are packaged into chylomicrons and very-low-density lipoproteins. – Hypertriglyceridemia is independently associated with cardiovascular disease risk, but the degree to which excess TG cause atherosclerosis is uncertain and debatable. – Lowering TG has not been proven to reduce cardiovascular risk. • Hypertriglyceridemia is a biomarker of risk for premature coronary artery disease in both men and women at levels ≥200 mg/dL and for pancreatitis at levels ≥1,000 mg/dL. • Classifications of TG levels in adults after a 12-hour fast: – Normal: female • Predominant race: Hispanic, white > black

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Prevalence • 33% of U.S. population has TG levels ≥150 mg/dL. • 1.7% has TG levels ≥500 mg/dL. • Highest prevalence at age 50 to 70 years • The most common genetic syndromes with hypertriglyceridemia are familial combined hyperlipidemia and familial hypertriglyceridemia (≤1% of general population each).

ETIOLOGY AND PATHOPHYSIOLOGY • Primary – Familial – Acquired (sporadic) • Secondary – Obesity and overweight – Physical inactivity – Cigarette smoking – Excess alcohol intake – Very high carbohydrate diets (>60% of total caloric intake) – Certain medications Interferon-α Atypical antipsychotics β-Blockers other than carvedilol Bile acid sequestrants Corticosteroids Oral estrogens Protease inhibitors Raloxifene Retinoic acid Tamoxifen Thiazides – Medical conditions Type 2 diabetes mellitus Hypothyroidism Chronic renal failure, nephrotic syndrome

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Autoimmune disorders (e.g., systemic lupus erythematosus) Paraproteinemias (e.g., macroglobulinemia, myeloma, lymphoma, lymphocytic leukemia) Pregnancy (usually physiologic and transient)

Genetics • Familial hypertriglyceridemia: autosomal dominant • Familial dysbetalipoproteinemia: autosomal recessive • Familial combined hyperlipidemia: unknown

RISK FACTORS • Genetic susceptibility • Obesity, overweight • Lack of exercise • Diabetes • Alcoholism • Certain medications (see “Etiology and Pathophysiology”) • Medical conditions (see “Etiology and Pathophysiology”)

GENERAL PREVENTION • Weight reduction • Moderation of dietary fat and carbohydrates • Regular aerobic exercise

COMMONLY ASSOCIATED CONDITIONS • Coronary artery disease • Diabetes mellitus type 2 and insulin resistance • Dyslipidemias – Decreased high-density lipoprotein (HDL) cholesterol – Increased low-density lipoprotein (LDL), non-HDL, and total cholesterol – Small, dense LDL particles • Metabolic syndrome (three of the following): – Abdominal obesity (waist circumference >40 inches in men, >35 inches in women) – TG ≥150 mg/dL – Low HDL cholesterol (1:128 and ≥1:40 is significant. • Specific antibodies to EBV-associated antigens – Develop regularly in IM – Viral capsid-specific IgM and IgG are present early in illness. – Viral capsid-IgM disappears after several weeks; viral capsid-IgG persists for life. • Liver tests: hypertransaminasemia, hyperbilirubinemia are common; jaundice is rare. • Atypical lymphocytes are not specific for EBV infections and may be present in other clinical conditions, including rubella, infectious hepatitis, allergic rhinitis, asthma, and atypical pneumonia. • Abdominal ultrasound to monitor for splenic enlargement is not supported routinely. • Consider ultrasound for those wishing to return to strenuous activity/contact sports at day 21 of illness to ensure resolution of splenomegaly. Follow-Up Tests & Special Considerations • Abnormal hepatic enzymes persist in 80% of patients for several weeks; hepatomegaly in 15–20% • In transplant recipients, quantitative polymerase chain reaction (PCR) used to monitor EBV loads

Diagnostic Procedures/Other

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Chest x-ray • Hilar adenopathy may be observed in IM with extensive lymphoid hyperplasia.

Test Interpretation • Mononuclear infiltrations involve lymph nodes, tonsils, spleen, lungs, liver, heart, kidneys, adrenal glands, skin, and CNS. • Bone marrow hyperplasia with small granulomas formation may be present; these findings are nonspecific and have no prognostic significance.

TREATMENT • Treatment is mostly supportive. • NSAIDs or acetaminophen • During acute stage, limit activity for 4 weeks to reduce potential complications (e.g., splenic rupture). • Transplant recipients who develop EBV infection may require reduction in immunosuppression as well as administration of monoclonal anti-CD20 (rituximab).

MEDICATION • In primary infections: – Antimicrobial agents (usually penicillin) only if throat culture is positive for group A β-hemolytic streptococci. Previously, ampicillin rash in presumed group B Streptococcus (GBS) was thought to be highly suggestive of IM. Incidence of rash is much lower than historically thought (4)[B]. – Warm saline gargles for oropharyngeal pain – Corticosteroids May provide some symptomatic relief but no improvement in resolution of illness Consider in severe pharyngotonsillitis with oropharyngeal edema and airway encroachment. Dexamethasone 0.3 mg/kg/day may be used for 1 to 3 days. Also for patients with marked toxicity/major complications (e.g.,

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hemolytic anemia, thrombocytopenic purpura, neurologic sequelae, myocarditis, pericarditis) (5)[B] • Antiviral medications (acyclovir) evaluated in small randomized controlled trials (RCTs) have been found to shorten recovery time and improve subjective symptoms in acute EBV infection.

ISSUES FOR REFERRAL Most cases can be managed as an outpatient without the need for specialty referral. Consider referral for complications such as oropharyngeal edema with airway compromise needing intubation or ventilator support.

SURGERY/OTHER PROCEDURES • With profound thrombocytopenia, refractory to corticosteroid therapy, splenectomy may be necessary. • Only current effective treatment for XLP is hematopoietic stem cell transplantation. • Inability to eat food or drink fluids • Immune suppressed • Splenic rupture

ONGOING CARE FOLLOW-UP RECOMMENDATIONS ALERT Rupture of the spleen may be fatal if not recognized; it requires blood transfusions, treatment for shock, and splenectomy. Occurrence is estimated at 0.1%.

Patient Monitoring • Avoid contact sports, heavy lifting, and excess exertion until spleen and liver have returned to normal size (ultrasound can verify). • Eliminate alcohol/exposure to other hepatotoxic drugs until LFTs return to normal. • Monitor patients closely during the first 2 to 3 weeks after the onset of

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symptoms as rates of complications are highest during this period. • Alert patients that symptoms (malaise, fatigue, intermittent sore throat, lymphadenopathy) may persist for months.

DIET No restrictions. Hydration during acute phase is very important.

PROGNOSIS • Most recover in ~4 weeks. • Fatigue may persist for months.

COMPLICATIONS • Neurologic (rare) – Aseptic meningitis – Bell palsy – Meningoencephalitis – Guillain-Barré syndrome – Transverse myelitis – Cerebellar ataxia – Acute psychosis • Hematologic (rare) – Thrombocytopenia, slight to moderate, early in illness – Hemolytic anemia with marked neutropenia during early weeks – Aplastic anemia – Agammaglobulinemia • Pneumonitis • Splenic rupture – Rare, but most often occurs in first 21 days of illness

REFERENCES 1. Grywalska E, Rolinski J. Epstein-Barr virus-associated lymphomas. Semin Oncol. 2015;42(2):291–303. 2. Dowd JB, Palermo T, Brite J, et al. Seroprevalence of Epstein Barr virus infections in the U.S. children ages 6-19, 2003-2010. PLoS One. 2013;8(5):e64921.

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3. Thorley-Lawson DA, Hawkins JB, Tracy SI, et al. The pathogenesis of Epstein-Barr virus persistent infection. Curr Opin Virol. 2013;3(3):227–232. 4. Chovel-Sella A, Ben Tov A, Lahav E, et al. Incidence of rash after amoxicillin treatment in children with infectious mononucleosis. Pediatrics. 2013;131(5):e1424–e1427. 5. Odumade O, Hogquist K, Balfour H. Progress and problems in understanding and managing primary Epstein-Barr virus infections. Clin Microbiol Rev. 2011;24(1):193–209.

ADDITIONAL READING • Almohmeed YH, Avenell A, Aucott L, et al. Systematic review and metaanalysis of the sero-epidemiological association between Epstein Barr virus and multiple sclerosis. PLoS One. 2013;8(4):e61110. • Klein G, Klein E, Kashuba E. Interaction of Epstein-Barr virus (EBV) with human B-lymphocytes. Biochem Biophys Res Commun. 2010;396(1):67–73.

CODES ICD10 • B27.00 Gammaherpesviral mononucleosis without complication • B27.09 Gammaherpesviral mononucleosis with other complications • B27.01 Gammaherpesviral mononucleosis with polyneuropathy

CLINICAL PEARLS • In cases of acute symptomatic IM, 98% manifest with fever, sore throat, cervical node enlargement, and tonsillar hypertrophy. • False-negative monospot (heterophile antibody) common in the first 10 to 14 days of illness. 90% will have heterophile antibodies by week 3 of illness. • Lymphocytosis (not monocytosis) is common in IM.

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INFERTILITY Sharon L. Koehler, DO, FACS • Sonia Rivera-Martinez, DO, FACOFP BASICS DESCRIPTION Definition: failure of a couple to conceive after ≥12 months of regular unprotected intercourse or after ≥6 months if the woman is ≥35 years. Primary: Couple has never been pregnant. Secondary: Couple has been pregnant. Fecundability: the probability of achieving pregnancy in one menstrual cycle.

EPIDEMIOLOGY Incidence Incidence is the probability of achieving a pregnancy within 1 year. ~85% of couples will conceive within 12 months of unprotected intercourse.

Prevalence • In the United States, 5–15% of women currently trying to conceive are infertile. • ~11.5% of married couples between ages 15 and 34 years and 42% between ages 35 and 44 years meet the criteria for being infertile. • May increase as more women delay childbearing; 20% of women in the United States have their first child >35 years.

ETIOLOGY AND PATHOPHYSIOLOGY • Most cases multifactorial: Approximately 50% of cases due to female factors (of which 20% are due to ovulatory dysfunction and 30% due to tubal and pelvic pathology), 30% due to male factors, and 20% are of unknown etiology. • Acquired: Most common cause of infertility in the United States is pelvic inflammatory disease (PID) secondary to chlamydia, endometriosis, polycystic ovary syndrome (PCOS), premature ovarian failure, and increased maternal age.

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• Diminished ovarian reserve (DOR): low fertility due to low quantity or functional quality of oocytes • Congenital: anatomic and genetic abnormalities

Genetics • Higher incidence of genetic abnormalities among infertile population, including Klinefelter syndrome (47XXY), Turner syndrome (45X or mosaic), and fragile X syndrome • Y chromosomal microdeletions are associated with isolated defects of spermatogenesis → found in 16% of men with azoo-/severe oligospermia. • Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation causing congenital bilateral absence of vas deferens (CBAVD)

RISK FACTORS • Female – Gynecologic history: irregular/abnormal menses, sexually transmitted infections (STIs), dysmenorrhea, fibroids, prior pregnancy – Medical history: endocrinopathy, autoimmune disease, undiagnosed celiac disease (1), collagen vascular diseases, thrombophilia, obesity, and cancer – Surgical history: appendicitis, pelvic surgery, intrauterine surgery, tubal ligation – Social history: smoking, alcohol/substance abuse, eating disorders, exercise, advanced maternal age • Male – Medical history: STI, prostatitis, medication use (i.e., β-blockers, calcium channel blocker, antiulcer medication), endocrinopathy, cancer – Surgical history: orchiopexy, hernia repair, vasectomy with/without reversal – Social: smoking, alcohol/substance abuse, anabolic steroids, environmental exposures, occupations leading to increased scrotal temperature

GENERAL PREVENTION Normal diet and exercise, avoid smoking and other substance abuse, prevention of STIs

COMMONLY ASSOCIATED CONDITIONS • Sexual behavior increasing risk for STIs

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• Pelvic pathology: endometriosis, ovarian cysts, endometrial polyps, and uterine fibroids • Endocrine dysfunction (thyroid, glucose metabolism, menstrual cycle abnormalities, prolactin) • Anovulation is commonly associated with hyperandrogenism and PCOS.

DIAGNOSIS HISTORY • Complete reproductive history: – Age at menarche, regularity of menstrual cycle, physical development, previous methods of contraception, history of abnormal Pap smears and treatment – History of abortion, D&Cs, bilateral tubal ligation, vasectomy, or other pelvic/abdominal surgery • Frequency of intercourse and sexual dysfunction • Abdominal pain or other abdominal symptoms • STI • History of endocrine abnormalities • History of malignancy or chronic illness • Family history: close relatives with congenital abnormalities or mental retardation; infertility or early menopause in close relatives of female partner • Medications: drug abuse, allergies, occupation, and exposure to environmental hazards

PHYSICAL EXAM • BMI and distribution of body fat • Female – Pubertal development with Tanner staging – Signs of PCOS: androgen excess, obesity, signs of insulin resistance – Breast exam: galactorrhea – Vaginal exam: describe rugation, discharge, anatomic variation – Uterine size/shape, mobility, tenderness – Adnexal tenderness infection or mass

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• Male – Abnormalities of the penis or urethral meatus – Testes: volume, symmetry, masses (varicocele, hydrocele), presence/absence of vas deferens

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) Evaluation is directed by history: • Assessment of ovulation – Irregular or infrequent menses, not accompanied by consistent premenstrual or moliminal characteristics, which are inconsistent in flow and duration, are indicative of ovulatory dysfunction. – Luteal-phase progesterone ≥3 ng/mL confirms ovulation has recently occurred but does not indicate when it occurred. – Luteinizing hormone (LH) testing kit: identifies midcycle LH surge, which occurs approximately 14 to 26 hours prior to ovulation. Greatest fertility on day of LH surge until 2 days after. Predicts time of ovulation in advance so couples can time intercourse. – Basal body temperature (BBT): ~1 degree increase in BBT taken upon wakening indicates ovulation has occurred: Greatest fertility spans 7 days PRIOR to rise in BBT. Not preferred. • Assessment of ovarian reserve – Follicle-stimulating hormone (FSH)/estradiol (E2): FSH and E2 levels on cycle days (CD) 2 to 5 are used to predict response to ovulation induction and pregnancy. High FSH levels >10 mIU/mL and high estradiol (>80 pg/mL) indicate a low chance of pregnancy with in vitro fertilization (IVF). – Anti-müllerian hormone (AMH) and antral follicle counts (AFCs): The number of antral follicles measured by transvaginal ultrasound (US) at any one time in the ovary is termed the “antral follicle count.” AMH is secreted by the granulosa cells of the antral follicles and decreases as a woman approaches menopause. AMH 65 years

ETIOLOGY AND PATHOPHYSIOLOGY • Transient/intermittent (30 days) – Medical: gastroesophageal reflux disease, sleep apnea, chronic pain, congestive heart failure, Alzheimer disease, Parkinson disease, chronic fatigue syndrome, irritable bowel syndrome – Psychiatric: mood, anxiety, psychotic disorders – Primary sleep disorder: idiopathic, psychophysiologic (heightened arousal and learned sleep-preventing associations), paradoxical (sleep state misperception) – Circadian rhythm disorder: irregular pattern, jet lag, delayed/advanced sleep phase, shift work – Environmental: light (liquid crystal display [LCD] clocks), noise (snoring, household, traffic), movements (partner/young children/pets) – Behavioral: poor sleep hygiene, adjustment sleep disorder – Substance induced – Medications: antihypertensives, antidepressants, corticosteroids, levodopacarbidopa, phenytoin, quinidine, theophylline, thyroid hormones

Pregnancy Considerations Transient insomnia occurs secondary to change of sleep position, nocturia, gastritis, back pain, anxiety.

RISK FACTORS • Age • Female gender • Medical comorbidities • Unemployment • Psychiatric illness • Impaired social relationships • Lower socioeconomic status • Shift work • Separation from spouse or partner • Drug and substance abuse

GENERAL PREVENTION

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• Practice consistent sleep hygiene: – Fixed wake-up times and bedtimes regardless of amount of sleep obtained (weekdays and weekends) – Go to bed only when sleepy. – Avoid naps. – Sleep in a cool, dark, quiet environment. – No activities or stimuli in bedroom associated with anything but sleep or sex. – 30-minute wind-down time before sleep – If unable to sleep within 20 minutes, move to another environment and engage in quiet activity until sleepy. • Limit caffeine intake to mornings. • No alcohol after 4 PM. • Fixed eating times • Avoid medications that interfere with sleep. • Regular moderate exercise

COMMONLY ASSOCIATED CONDITIONS • Psychiatric disorders • Painful musculoskeletal conditions • Obstructive sleep apnea • Restless leg syndrome • Drug or alcohol addiction/dependence

DIAGNOSIS HISTORY • Daytime sleepiness and napping • Unintended sleep episodes (driving, working) • Insomnia history – Duration, time of problem – Sleep latency, difficulty in maintaining sleep (repeated awakening), early morning awakening, nonrestorative sleep, or patterns (weekday vs. weekend, with or without bed partner, home vs. away)

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• Sleep hygiene – Bedtime/wakening time – Physical environment of sleep area: LED clocks, TV, room lighting, ambient noise – Activity: nighttime eating, exercise, sexual activity – Intake: caffeine, alcohol, herbal supplements, diet pills, illicit drugs, prescriptions, over-the-counter (OTC) sleep aids • Symptoms or history of depression, anxiety, obsessive-compulsive disorder, or other major psychological symptomatology • Symptoms of restless leg syndrome and periodic limb movement disorder • Symptoms of heightened arousal • Snoring and other symptoms of sleep apnea • Symptoms or history of drug or alcohol abuse • Current medication use • Chronic medical conditions • Acute change or stressors such as travel or shift work • Sleep diary: sleep log for 7 consecutive days

DIFFERENTIAL DIAGNOSIS • Sleep-disordered breathing such as obstructive sleep apnea • CNS hypersomnias (e.g., narcolepsy) • Circadian rhythm sleep disturbances • Sleep-related movement disorders (e.g., restless leg syndrome) • Substance abuse • Insomnia due to medical or neurologic disorder • Mood and anxiety disorders such as depression or anxiety

DIAGNOSTIC TESTS & INTERPRETATION • Diagnostic testing usually not required; consider polysomnography if sleep apnea or periodic limb movement disorder is suspected (1)[C]. • Primary insomnia – Symptoms for at least 1 month: difficulty in initiating/maintaining sleep or nonrestorative sleep – Impairment in social, occupational, or other important areas of functioning – Does not occur exclusively during narcolepsy, breathing-related sleep

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disorder, circadian rhythm sleep disorder, or parasomnia – Does not occur exclusively during major depressive disorder, generalized anxiety disorder, delirium – Is not secondary to physiologic effects of substance or general medical condition – Sleep disturbance (or resultant daytime fatigue) causes clinically significant distress. • Secondary insomnia – Due to substance abuse, medication induced (diuretics, stimulants, etc.), primary depressive disorder, generalized anxiety disorder or phobias, acute situational stress, posttraumatic stress disorder, pain

Initial Tests (lab, imaging) Testing to consider based on history and physical exam: • Thyroid-stimulating hormone • Urine toxicology

Diagnostic Procedures/Other Polysomnography or multiple sleep latency test not routinely indicated but may be considered if • Initial diagnosis is uncertain. • Treatment interventions have proven unsuccessful.

TREATMENT • Transient insomnia – May use medications for short-term use only; hypnotic sedatives favored – Self-medicating with alcohol can increase awakenings and sleep-stage changes. • Chronic insomnia – Treatment of underlying condition (major depressive disorder, generalized anxiety disorder, medications, pain, substance abuse) – Advise good sleep hygiene. – Cognitive-behavioral therapy is first-line treatment for chronic insomnia, especially in >60 years population, especially when sedatives are not

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advantageous (2)[A]. – Behavioral therapy is an effective treatment for insomnia and a potentially more effective long-term treatment than pharmacotherapy (3)[B]. – Ramelteon is the only agent without abuse potential (4)[B].

MEDICATION • Reserved for transient insomnia such as with jet lag, stress reactions, transient medical condition • Nonbenzodiazepine hypnotics – Act on benzodiazepine receptor so have abuse potential Zaleplon (Sonata) 5 to 20 mg; half-life 1 hour Zolpidem (Ambien) 5 to 10 mg (males); 5 mg (females); half-life 2.5 to 3 hours Zolpidem (Ambien CR) 6.25 to 12.5 mg (males); 6.25 mg (females); halflife 2.5 to 3 hours Eszopiclone (Lunesta) 1 to 3 mg; half-life 6 hours • Benzodiazepine hypnotics – Short acting Triazolam (Halcion) 0.25 mg; half-life 1.5 to 5.5 hours – Intermediate acting Temazepam (Restoril) 7.5 to 30 mg; half-life 8.8 hours – Long acting: Lorazepam (Ativan) 1 to 4 mg; half-life 14 hours Diazepam (Valium) 5 to 10 mg; half-life 30 to 60 hours Estazolam 1 to 2 mg; half-life 10 to 24 hours • Contraindications/precautions are as follows: – Not indicated for long-term treatment due to risks of tolerance, dependency, daytime attention and concentration compromise, incoordination, rebound insomnia – Long-acting benzodiazepines associated with higher incidence of daytime sedation and motor impairment – Avoid in elderly, pregnant, breastfeeding, substance abusers, and patients with suicidal or parasuicidal behaviors. – Avoid in patients with untreated obstructive apnea and chronic pulmonary disease.

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– No good evidence for benzodiazepines for patients undergoing palliative care (5)[A]. – Nonbenzodiazepine receptor agonists may occasionally induce parasomnias (sleepwalking, sleep eating, sleep driving). • Melatonin receptor agonist – Ramelteon 8 mg; half-life 1 to 2.6 hours Recommended as first-line pharmacologic treatment option per AASM Consensus Effective to reduce sleep time onset for short- and long-term use in adults, without abuse potential; no comparative studies with older agents have been completed. Onset of effect may take up to 3 weeks (4)[B]. • Serotonergic antidepressants – Trazodone 25 to 200 mg; half-life 3 to 9 hours – Doxepin 10 to 50 mg; half-life 15 hours Only antidepressant with FDA approval for insomnia New formulation of medication is available at dosage 3 to 6 mg QHS. – Amitriptyline 25 to 50 mg; half-life 10 to 26 hours – Mirtazapine 7.5 to 15 mg; half-life 20 to 40 hours • Sedating antihistamines are not recommended and should be used conservatively for insomnia due to insufficient evidence of efficacy and significant concerns about risks of these medications.

Geriatric Considerations Caution (risk of falls and confusion) when prescribing benzodiazepines or other sedative hypnotics; if absolutely necessary, use short-acting nonbenzodiazepine agonists at half the dosage or melatonin agonists for short-term treatment.

ADDITIONAL THERAPIES Associated with hypertension, congestive heart failure, anxiety and depression, and obesity; management of these chronic conditions will help with incidence and symptoms of insomnia.

COMPLEMENTARY & ALTERNATIVE MEDICINE • Melatonin: decreases sleep latency when taken 30 to 120 minutes prior to bedtime, but there is no good evidence for efficacy in insomnia, and long-term

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effects are unknown (6)[B]. • Valerian: Inconsistent evidence supporting efficacy and its slow onset of action (2 to 3 weeks) makes it unsuitable for the acute treatment of insomnia. • Acupuncture: insufficient evidence on effect of needle acupuncture and its variants (7) • Antihistamines: insufficient evidence; should not be recommended for use • Cognitive-behavioral therapy (including relaxation therapy): effective and considered more useful than medications; recommended initial treatment for patients with chronic insomnia; no improvement of efficacy when combined with medication • Mindfulness awareness practices: improved sleep quality and sleep-related daytime impairment for older adults per small randomized trial (8)

ONGOING CARE FOLLOW-UP RECOMMENDATIONS • Daily exercise improves quality of sleep and may be more effective than medication. • Avoid exercise within 4 hours of bedtime.

Patient Monitoring • Reassess need for medications periodically; avoid standing prescriptions. • Caution patients that nonbenzodiazepine agonists (zolpidem, zaleplon, eszopiclone), as well as benzodiazepines, can be habit forming. • Studies suggest an association between receiving a hypnotic prescription and a >3-fold increase in hazards of death, even when prescribed female: 1.6:1 for mild ID, 1.2:1 for severe ID (1)

Prevalence In the United States, 1% of the general population. The prevalence for severe ID is 6/1,000 (1).

ETIOLOGY AND PATHOPHYSIOLOGY • Causes: – Maternal substance abuse (e.g., alcohol); FAS is a leading environmental cause of ID. – Maternal infections: TORCH viruses (toxoplasma, other infections, rubella, cytomegalovirus, and herpes simplex) – Down syndrome – Sex chromosome abnormalities: fragile X, Turner syndrome, Klinefelter syndrome – Autosomal dominant conditions: neurocutaneous syndromes (e.g., neurofibromatosis, tuberous sclerosis) – Autosomal recessive conditions: Amino acid metabolism (e.g., phenylketonuria, maple syrup urine disease) Carbohydrate metabolism (e.g., galactosemia, fructosuria) Lipid metabolism Tay-Sachs disease

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Gaucher disease Niemann-Pick disease (e.g., mucopolysaccharidosis) Purine metabolism (e.g., Lesch-Nyhan disease) Other (e.g., Wilson disease) • Maternal use of prescription medications (e.g., Accutane, dilantin) • Perinatal factors: – Prematurity – Birth injuries – Perinatal anoxia • Postnatal factors: – Childhood diseases (e.g., meningitis, encephalitis, hypothyroidism, seizure disorders) – Trauma (e.g., accidents, physical abuse, hypoxia) – Severe deprivation – Poisoning (e.g., lead, carbon monoxide, household products)

Genetics A number of genetic and epigenetic causes are known, and more are under investigation (3).

RISK FACTORS • Maternal substance abuse during pregnancy • Maternal infection during pregnancy • For some causes, family history

GENERAL PREVENTION • Public health efforts to reduce alcohol and drug use by pregnant women • Prenatal folic acid supplementation

COMMONLY ASSOCIATED CONDITIONS • Seizures • Mood disorders • Behavioral disorders • Constipation

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DIAGNOSIS A diagnosis of ID should be made only through a psychodiagnostic assessment conducted by a mental health provider who is trained and licensed to conduct formal psychological testing.

HISTORY • Children with profound/severe ID are typically diagnosed at birth or during the newborn period and may have dysmorphic features. • Children with ID are often identified because they fail to meet motor/language milestones.

PHYSICAL EXAM Careful examination by a physician trained in the assessment of morphologic features suggestive of a specific etiology for ID (e.g., microcephaly) (4)

DIFFERENTIAL DIAGNOSIS • Brain tumors • Auditory, visual, and/or speech/language impairment • Autism spectrum disorder (language and social skills are more affected than other cognitive abilities); however, 75% of individuals with an autistic disorder may meet criteria for a comorbid diagnosis of ID. • Expressive/receptive language disorders • Cerebral palsy • Emotional/behavioral disturbance • Learning disorders (reading, math, written expression) • Auditory/sensory processing difficulties • Lack of environmental opportunities for appropriate development

DIAGNOSTIC TESTS & INTERPRETATION • Visual and hearing tests to rule out these etiologies as a cause of impairment and provide an assessment of visual and auditory functioning, which are often impaired in children and adults with ID. • Formal testing of intellectual and adaptive functioning: – A child’s communication skills must be considered in test selection. For example, a patient with auditory processing issues/limited

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expressive/receptive language skills may need to be assessed using a nonverbal IQ test, such as the Leiter-R, Test of Nonverbal Intelligence, or other nonverbal measures. – Commonly used intelligence tests (e.g., Bayley Scales of Infant Development, Stanford-Binet Intelligence Scale, Wechsler Intelligence Scales) are determined by age/developmental level of the child. – Common tests of adaptive functioning include the Vineland Adaptive Behavior Scales, 2nd ed., and Adaptive Behavior Assessment System, 2nd ed. These tests assess areas of functioning such as age-appropriate communication, social skills, activities of daily living, and motor skills. • Metabolic screening is not routine unless history and physical suggest or no newborn screening done (5).

Initial Tests (lab, imaging) • Lead (5)[B] • Thyroid-stimulating hormone if systemic features present/no newborn screening (5)[B] • Routine cytogenetic testing (karyotype) (5)[B]: – Fragile X screening (FMR1 gene), particularly with a family history of ID – Rett syndrome (MECP2 gene) in women with unexplained moderate to severe ID (5) • Molecular screening, such as array comparative genomic hybridization, is used increasingly and may yield a diagnosis in 10% of undiagnosed cases (4) [B]. • Neuroimaging (MRI more sensitive than CT) is routinely recommended. The presence of physical findings (microcephaly, focal motor deficit) will increase the yield of a specific diagnosis (5)[B]. • MRI may show mild cerebral abnormalities but is unlikely to establish etiology of ID (4). Follow-Up Tests & Special Considerations • Electroencephalogram is not routine unless epilepsy or a specific epileptiform syndrome is present (5)[C]. • Assessment of quality of life provides salient information about a patient’s general sense of well-being and life satisfaction; however, quality of life may

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be difficult to assess when significant behavioral issues confound an individual’s self-report and socialization.

TREATMENT • Early intervention services tailored to the individual’s specific needs • Caregiver support, including: – Training caregiver(s) to address behavioral issues, discipline, and support socialization development – Encouraging caregivers to create a structured home environment that is based on the child’s developmental level and specific needs rather than ageappropriate expectations. – Providing caregiver(s) with an opportunity to address their reactions to the diagnosis and their child’s special needs – Informing caregivers about advocacy groups and available community, state, and national resources (6–8) – Encouraging caregiver(s) to seek social support to increase overall sense of well-being – Encouraging caregivers to seek respite care as needed to ensure that they have an opportunity to engage in health self-care. • Individualized education plans and, depending on the level of impairment, social skills and behavioral plans/training • Refer to job training programs and independent living opportunities, if appropriate. • Notice all changes in behavior, which may be indicative of pain/illness, particularly in individuals with limited communication skills. • Assess for abuse and neglect.

MEDICATION Medication may be appropriate for comorbid conditions (e.g., anxiety, ADHD, depression).

ONGOING CARE

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The physician should match his or her communication of exam procedures, test results, and treatment recommendations to the patient’s level of cognitive functioning and receptive language skills. • Most patients with ID will fall within the mild range and are fully capable of understanding information if it is provided at the appropriate level. • Provide oral and written explanations directly to the patient instead of solely to his or her caregivers. The dignity of the patient must be respected at all times. This includes providing honest information, responding to patient’s questions with respect, and not infantilizing the patient due to his or her ID.

FOLLOW-UP RECOMMENDATIONS • Many adults and children with ID exhibit poor physical fitness. Preliminary studies suggest structured exercise programs are effective to engage this population in healthy activities (9)[A]. • Linkage to community-based resources for job training, independent living, caregiver support, school-based services

Patient Monitoring • Primary care with attention to associated medical conditions • Vision testing at least once before age 40 years (age 30 years in Down syndrome) and every 2 years thereafter (10)[B] • Hearing evaluations every 5 years after age 45 years (every 3 years throughout life in Down syndrome) (10)[B] • Screen for sexual activity and offer contraception and testing for STIs (10)[B]. • Abuse and neglect of people with ID are common. Screen at least annually and if behavior change is noted. Report abuse/neglect to appropriate protective agencies (10)[B]. • Dysphagia and aspiration are common; consider speech pathology evaluation and swallowing study (11)[B]. • Monitor for and treat constipation (11)[B]. • Osteoporosis: common; low threshold to order imaging studies after traumatic injury (11)[B]

DIET No restrictions, except in cases of metabolic and storage disorders (e.g.,

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phenylketonuria)

PATIENT EDUCATION • The Arc of the United States (The Arc): www.thearc.org • American Association of Intellectual and Developmental Disabilities: www.aaidd.org • Family support groups (Parent to Parent, local Down Syndrome, or Autism Association) • Special Olympics: www.specialolympics.org

PROGNOSIS Although ID is a lifelong diagnosis, individuals with ID are capable of living a fulfilling, purposeful life that includes having a career, living independently, marrying/participating in a committed relationship, and becoming a parent. Also, the level of severity and support needed may vary over the course of the individual’s life.

COMPLICATIONS • Constipation is a commonly overlooked problem and can lead to significant morbidity. • Polypharmacy, often associated with psychotropic medication use to control behaviors, should be addressed to minimize adverse side effects.

REFERENCES 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013. 2. Centers for Disease Control and Prevention. Developmental disabilities. http://www.cdc.gov/ncbddd/developmentaldisabilities/index.html. Accessed 2014. 3. Grant ME. The epigenetic origins of mental retardation. Clin Genet. 2008;73(6):528–530. 4. van Karnebeek CD, Jansweijer MC, Leenders AG, et al. Diagnostic investigations in individuals with mental retardation: a systematic literature review of their usefulness. Eur J Hum Genet. 2005;13(1):6–25.

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5. Shevell M, Ashwal S, Donley D, et al. Practice parameter: evaluation of the child with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2003;60(3):367– 380. 6. Shogren KA, Bradley VJ, Gomez SC, et al. Public policy and the enhancement of desired outcomes for persons with intellectual disability. Intellect Dev Disabil. 2009;47(4):307–319. 7. Rizzolo MC, Hemp R, Braddock D, et al. Family support services for persons with intellectual and developmental disabilities: recent national trends. Intellect Dev Disabil. 2009;47(2):152–155. 8. Samuel PS, Hobden KL, LeRoy BW, et al. Analysing family service needs of typically underserved families in the USA. J Intellect Disabil Res. 2012;56(1):111–128. 9. Heller T, Hsieh K, Rimmer JH. Attitudinal and psychosocial outcomes of a fitness and health education program on adults with down syndrome. Am J Ment Retard. 2004;109(2):175–185. 10. Sullivan WF, Heng J, Cameron D, et al. Consensus guidelines for primary health care of adults with developmental disabilities. Can Fam Physician. 2006;52(11):1410–1418. 11. Prater CD, Zylstra RG. Medical care of adults with mental retardation. Am Fam Physician. 2006;73(12):2175–2183.

CODES ICD10 • F79 Unspecified intellectual disabilities • F70 Mild intellectual disabilities • F71 Moderate intellectual disabilities

CLINICAL PEARLS • The term mental retardation may be interpreted as culturally insensitive and disrespectful to patients and their caregivers. ID or intellectual developmental

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disorder is the correct diagnosis. • Overall functioning with ID is highly variable and influenced by multiple factors, including appropriateness of school placement/special education services, exposure to early intervention, behavioral therapy, parent training, self-esteem, and social skills. • Previous stereotypes of people with ID (e.g., always happy, poor prognosis, unable to function independently) have been refuted. People with ID are showing a level of functioning variability that parallels what is found in the non-ID population. • Be aware of the unique parenting needs that caregivers may face. Link families to community and national resources that can provide practical and emotional support when appropriate. • Because children with developmental disabilities are at higher risk of being abused than their peers without developmental disabilities, discuss with caregivers how to educate children about safety precautions in a developmentally appropriate manner.

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INTERSTITIAL CYSTITIS Rebecca R. Yeager, MD • Montiel T. Rosenthal, MD BASICS DESCRIPTION • A condition of pain or discomfort in the bladder associated with a need to urinate frequently and urgently • A disease of unknown cause, probably representing a final common pathway from several etiologies • Likely, pathogenesis is disruption of urothelium, impaired lower urinary tract defenses, and loss of bladder muscular wall elasticity. The symptoms in many patients are insidious, and the disease progresses for years before diagnosis is established. • Newer research implicates urine and serum inflammatory proteins antiproliferative factor, epidermal growth factor, heparin-binding epidermal growth factor, glycosaminoglycans, and bladder nitric oxide as contributing factors. • Mild: normal bladder capacity under anesthesia; ulceration, cracking, or glomerulation of mucosa (or not) with bladder distention under anesthesia; no incontinence symptoms wax and wane and may not progress. Interstitial cystitis is a bladder sensory problem. • Severe: progressive bladder fibrosis; small true bladder capacity under anesthesia; poor bladder wall compliance. In 5–10% of cases, Hunner ulcers present at cystoscopy; may have overflow incontinence and/or chronic bacteriuria unresponsive to antibiotics • System(s) affected: renal/urologic • Synonym(s): urgency frequency syndrome; IC/bladder pain syndrome (BPS)

Pregnancy Considerations Unpredictable symptom improvement or exacerbation during pregnancy; no known fetal effects from interstitial cystitis; usual problems of unknown effect on fetus with medications taken during pregnancy

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EPIDEMIOLOGY • Occurs predominantly among whites • Predominant sex: female > male (10:1) • Patients 60 years more commonly have nocturia, urinary incontinence, or Hunner ulcer disease. • Predominant age – Mild: 20 to 40 years – Severe: 20 to 70 years • Pediatric considerations – 8 voids in 24 hours • Pain with full bladder that resolves with bladder emptying (except if bacteriuria is present) • Urge urinary incontinence if bladder capacity is small. • Sleep disturbance • Dyspareunia, especially with full bladder • Secondary symptoms from chronic pain and sleeplessness, especially depression

HISTORY • Pelvic Pain and Urgency/Frequency Patient Symptom Scale: self-reporting questionnaire for screening potential interstitial cystitis patients (1)[B] (http://www.wgcaobgyn.com/files/urgency_frequency_pt_symptom_scale.pdf) • Frequent UTIs, vaginitis, or symptoms during the week before menses • O’Leary/Sant Voiding and Pain Indices (http://www.ichelp.org/wpcontent/uploads/2015/06/OLeary_Sant.pdf)

PHYSICAL EXAM • Perineal/prostatic pain in men • Anterior vaginal wall pain in women

DIFFERENTIAL DIAGNOSIS

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• Uninhibited bladder (urgency, frequency, urge incontinence, less pain, symptoms usually decrease when asleep) • Urinary infection: cystitis, prostatitis • Bladder neoplasm • Bladder stone • Neurologic bladder disease • Nonurinary pelvic disease (STIs, endometriosis, pelvic relaxation)

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Urinalysis: normal except with chronic bacteriuria (rare) • Urine culture from catheterized specimen: normal except with chronic bacteriuria (rare) or partial antibiotic treatment • Urine cytology – Normal: reserve for men >40 years old and women with hematuria

Diagnostic Procedures/Other • Cystoscopy (especially in men >40 years old or women with hematuria) – Bladder wall visualization – Hydraulic distention: no improved diagnostic certainty over history and physical alone – No role for urodynamic testing • Intravesical lidocaine can help to pinpoint the bladder as the source of pain in patients with pelvic pain; this can be both diagnostic and therapeutic. • Potassium sensitivity test – Insert catheter, empty bladder, instill 40 mL H2O over 2 to 3 minutes, rank urgency on scale of 0 to 5 in intensity, rank pain on scale of 0 to 5 in intensity, drain bladder, instill 40 mL potassium chloride (KCl) 0.4 mol/L solution: – If immediate pain, flush bladder with 60 mL H2O and treat with bladder instillations. If no immediate pain, wait for 5 minutes and rate the urgency and pain. • If urgency or pain >2, treat as above. • Pain or urgency >2 is considered a positive test and strongly correlates with interstitial cystitis if no radiation cystitis or acute bacterial cystitis is present.

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Test Interpretation • Nonspecific chronic inflammation on bladder biopsies • Urine cytology negative for dysplasia and neoplasia • Possible mast cell proliferation in mucosa

TREATMENT GENERAL MEASURES • Appropriate health care: outpatient • Self-care (eliminate foods and liquids that exacerbate symptoms on individual basis, fluid management) (2)[C] • Biofeedback bladder retraining (2)[C]

MEDICATION • Randomized controlled trials of most medications for interstitial cystitis demonstrate limited benefit over placebo; there are no clear predictors of what will benefit an individual. Prepare the patient that treatment may involve trial and error. • Behavioral therapy combined with oral agents found improved outcomes compared to medications alone. • Intravesical injections of botulinum toxin are not effective in the treatment of ulcer-type interstitial cystitis.

First Line • Note: AUA consensus states medicines should be considered second-line therapy after patient education, stress reduction, behavior modification, and self-care (2)[C]. • Pentosan polysulfate (Elmiron) 100 mg TID on empty stomach; may take several months (3 to 6) to become effective; rated as modestly beneficial in systematic drug review (only FDA-approved treatment for interstitial cystitis) • Amitriptyline: most effective at higher doses (≥50 mg/day); however, initiate with lower doses to minimize side effects (3)[B]. • Hydroxyzine 25 to 50 mg HS • Sildenafil 25 mg/day (4)[B]

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• Cimetidine 400 mg BID (2)[C] • Triple-drug therapy: 6 months of pentosan, hydroxyzine, doxepin • Antibacterials for bacteriuria • Oxybutynin, hyoscyamine, tolterodine, and other anticholinergic medications decrease frequency. • Prednisone (only for ulcerative lesions) • Montelukast has shown some benefit. • NSAIDs for pain and any inflammatory component • Bladder instillations – Lidocaine, sodium bicarbonate, and heparin or pentosan polysulfate sodium – Dimethyl sulfoxide (DMSO) every 1 to 2 weeks for 3 to 6 weeks, then PRN – Heparin sometimes added to DMSO – Intravesical liposomes – Other agents: steroids, silver nitrate, oxychlorosene (Clorpactin) – Contraindication – No anticholinergics for patients with close-angle glaucoma – Significant possible interaction – Refer to manufacturer’s profile of each drug.

Second Line • Phenazopyridine, a local bladder mucosal anesthetic, usually is not very effective. • Intravesicular injection of botulinum type A for nonulcer interstitial cystitis • Cyclosporin A (2)[C] • Hyaluronic acid instillations (5)[C] • Chondroitin sulfate instillations (single or in combination with hyaluronic acid) have shown mixed results (5)[C].

ISSUES FOR REFERRAL • Need for clarity with respect to diagnosis • Surgical intervention

ADDITIONAL THERAPIES Myofascial physical therapy (targeted pelvic, hip girdle, abdominal trigger point massage) (6)[B]

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SURGERY/OTHER PROCEDURES • Hydraulic distention of bladder under anesthesia: symptomatic but transient relief • Cauterization of bladder ulcer • Augmentation cystoplasty to increase bladder capacity and decrease pressure with or without partial cystectomy. Expected results in severe cases: much improved, 75%; with residual discomfort, 20%; unchanged, 5% • Urinary diversion with total cystectomy only if disease is completely refractory to medical therapy • Sacral neuromodulation • Transurethral electro- or laser fulguration (effective for Hunner lesions). Pain relief may persist from several months to 2 years (5)[C].

COMPLEMENTARY & ALTERNATIVE THERAPIES Guided imagery

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring Not specifically needed unless symptoms are unresponsive to treatment

DIET • Variable effects from person to person • Common irritants include caffeine, chocolate, citrus, tomatoes, carbonated beverages, potassium-rich foods, spicy foods, acidic foods, and alcohol.

PATIENT EDUCATION Interstitial Cystitis Association, 110 Washington St. Suite 340, Rockville, MD 20850; 1-800-HELPICA: http://www.ichelp.org/

PROGNOSIS • Mild: exacerbations and remissions of symptoms; may not be progressive; does not predispose to other diseases • Severe: progressive problems that usually require surgery to control symptoms

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COMPLICATIONS Severe, with long-term, continuous high bladder pressure could be associated with renal damage.

REFERENCES 1. Parsons CL, Dell J, Stanford EJ, et al. Increased prevalence of interstitial cystitis: previously unrecognized urologic and gynecological cases identified using a new symptom questionnaire and intravesical potassium sensitivity. Urology. 2002;60(4):573–578. 2. Hanno PM, Erickson D, Moldwin R, et al. Diagnosis and treatment of interstitial cystitis/bladder pain syndrome: AUA guideline amendment. J Urol. 2015;193(5):1545–1553. 3. Foster HE Jr, Hanno PM, Nickel JC, et al. Effect of amitriptyline on symptoms in treatment naïve patients with interstitial cystitis/painful bladder syndrome. J Urol. 2010;183(5):1853–1858. 4. Chen H, Wang F, Chen W, et al. Efficacy of daily low-dose sildenafil for treating interstitial cystitis: results of a randomized, double-blind, placebocontrolled trial—treatment of interstitial cystitis/painful bladder syndrome with low-dose sildenafil. Urology. 2014;84(1):51–56. 5. Homma Y, Ueda T, Tomoe H, et al. Clinical guidelines for interstitial cystitis and hypersensitive bladder updated in 2015. Int J Urol. 2016;23(7):542–549. 6. FitzGerald MP, Payne CK, Lukacz ES, et al. Randomized multicenter clinical trial of myofascial physical therapy in women with interstitial cystitis/painful bladder syndrome and pelvic floor tenderness. J Urol. 2012;187(6):2113– 2118.

ADDITIONAL READING Rais-Bahrami S, Friedlander JI, Herati AS, et al. Symptom profile variability of interstitial cystitis/painful bladder syndrome by age. BJU Int. 2012;109(9):1356– 1359.

SEE ALSO

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• Urinary Tract Infection (UTI) in Females • Algorithm: Pelvic Girdle Pain (Pregnancy or Postpartum Pelvic Pain)

CODES ICD10 • N30.10 Interstitial cystitis (chronic) without hematuria • N30.11 Interstitial cystitis (chronic) with hematuria

CLINICAL PEARLS • The potassium sensitivity test has been the most useful in confirming an initial diagnosis of interstitial cystitis. • At present, there is no definitive treatment for interstitial cystitis. • Most patients with severe disease receive multiple treatment approaches. Regular multidisciplinary follow-up, pharmacologic therapy, avoidance of symptom triggers, and psychological and supportive therapy are all important because this disease tends to wax and wane. Monitor patients for comorbid depression. • Empowering patients to manage their symptoms, communicate regularly with their physicians, and learn as much as they can about this disease which may help them to optimize their outcome

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INTERSTITIAL NEPHRITIS Roger P. Holland, MD, PhD BASICS DESCRIPTION • Acute and chronic tubulointerstitial diseases result from the interplay of renal cells and inflammatory cells and their products. Lethal or sublethal injury to renal cells leads to expression of new local antigens, inflammatory cell infiltration, and activation of proinflammatory and chemoattractant cytokines. These cytokines are produced by macrophages and lymphocytes and also by the renal cells (i.e., proximal tubule, vascular endothelial cells, interstitial cells, fibroblasts). The outcome can be acute interstitial nephritis (AIN) or chronic interstitial nephritis (CIN). • AIN presents as acute kidney injury (AKI) after the use of offending drugs or agents (OFA) and is associated with typical findings of proteinuria, hematuria, and white cell casts. Less frequently, AIN is secondary to infection or systemic diseases (e.g., sarcoidosis, mixed connective tissue disease [MCTD], SLE, Sjögren syndrome). • System(s) affected: renal/urologic, endocrine/metabolic, immunologic • Synonym(s): acute interstitial allergic nephritis

EPIDEMIOLOGY Pediatric Considerations • Children with history of lead poisoning are more likely to develop CIN as young adults. • Tubulointerstitial nephritis with uveitis (TINU) presents in adolescent females.

Incidence • AIN and CIN account for 10–15% of kidney disease. • Peak incidence in women 60 to 70 years of age

Geriatric Considerations

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The elderly (≥65 years) have more severe disease and increased risk of permanent damage due to their increased use of OFA, specifically more druginduced AIN (87% vs. 64%), proton-pump inhibitor-induced AIN (18% vs. 6%), but less AIN due to autoimmune or systemic causes (7% vs. 27%) than younger adults (1)[B].

ETIOLOGY AND PATHOPHYSIOLOGY • AIN – Delayed drug hypersensitivity reactions – Causes AKI – Renal dysfunction generally is usually partially or completely reversible, possibly reflecting the regenerative capacity of tubules with a preserved basement membrane. – Hypersensitivity to drugs (75%): not dose dependent. The three top drug causes were omeprazole (12%), amoxicillin (8%), and ciprofloxacin (8%) in a recent case series (2)[C]. Antibiotics (e.g., penicillins, cephalosporins, sulfonamides, tetracycline, vancomycin, fluoroquinolones, macrolides, TB meds) Proton pump inhibitors Antivirals (Indinavir) NSAIDs (all, including Cox-2 inhibitors) Diuretics (thiazide, loop, and triamterene) Miscellaneous (allopurinol, H2 blockers, diphenylhydantoin, and 5aminosaliclates such as Azulfidine and mesalamine) – Infections: Legionella, Leptospira, streptococci, CMV, Mycobacterium tuberculosis (5–10%) – Autoimmune disorders (e.g., SLE, Sjögren syndrome, sarcoidosis, Wegener granulomatosis, cryoglobulinemia) (10–15%) – Toxins (e.g., snake bite venom) • CIN – Follows long-term exposure to OFA (e.g., heavy metals, especially lead) – Often found on routine labs or evaluation for hypertension (HTN) – Characterized by interstitial scarring, fibrosis, and tubular atrophy, resulting in progressive chronic kidney disease (CKD)

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GENERAL PREVENTION • Early recognition and prompt discontinuation of OFA • Avoid further nephrotoxic substances.

COMMONLY ASSOCIATED CONDITIONS CIN • Chronic pyelonephritis • Abuse of analgesics • Lithium use • Gout and gout therapy • Immune disorders • Malignancy (lymphoma, multiple myeloma) • Amyloidosis • Exposure to heavy metals (e.g., lead, cadmium) • Renal papillary necrosis

DIAGNOSIS • AIN: suspected in a patient who presents with nonspecific signs and symptoms of AKI (e.g., malaise, fever, nausea, vomiting) with an elevated serum creatinine and an abnormal urinalysis – AKI Elevated creatinine, BUN, and electrolyte abnormalities (e.g., hyperkalemia, low serum bicarbonate) Decreased urine output (oliguria in 51%) Signs of fluid overload or depletion – Signs of systemic allergy (e.g., fever [27%], maculopapular rash [15%], peripheral eosinophilia [23%], arthralgias [45%] but less commonly found when NSAIDs are the OFA) – White cells, red cells, and white cell casts • CIN – HTN – Decreased urine output or polyuria – Inability to concentrate urine

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– Polydipsia – Metabolic acidosis – Anemia – Fanconi syndrome

HISTORY • Medications: Onset of AIN following drug exposure ranges from 3 to 5 days (as occurs with a second exposure to an OFA) to as long as several weeks to many months (the latter with NSAIDs, especially) (2)[B]. • Infections: may have symptoms related to an associated infection or systemic condition • TINU patients present with interstitial nephritis and uveitis and occasionally systemic findings. • Exposure to heavy metals • Post organ transplant

PHYSICAL EXAM • Increased BP • Fluid retention/extremity swelling/weight gain • Rash accompanying renal findings in acute AIN • Lung crackles if fluid is overloaded • Pericardial rub if uremic pericarditis

DIFFERENTIAL DIAGNOSIS • AKI secondary to other causes: – Prerenal (e.g., hypovolemia, shock, sepsis, renal artery emboli) – Intrarenal (e.g., acute tubular necrosis, hypertensive nephropathy, DM nephropathy) – Postrenal (e.g., obstructive uropathy) – Some OFA that cause AIN can produce other forms of AKI as well: NSAIDs can exacerbate prerenal disease. Aminoglycosides can cause acute tubular necrosis. • CKD secondary to long-standing HTN, diabetes, and chronic pyelonephritis

DIAGNOSTIC TESTS & INTERPRETATION • Chemistry

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– Elevated plasma creatinine: seen in all patients, with 40% requiring dialysis – Hyperkalemia and acidosis • CBC – Eosinophilia (80%): NSAID-induced AIN is only associated with eosinophilia in ~15% of cases. – Anemia • Urinalysis with urine electrolytes – Hematuria (95%) – Mild and variable proteinuria: usually 1%) indicative of tubular damage – Normal urinalysis does not rule out AIN. • CXR to evaluate for pulmonary tuberculosis, sarcoidosis, and other infections • Serologic testing for immunologic disease (e.g., sarcoidosis, Sjögren syndrome, Wegener granulomatosis, Behçet syndrome) or infectious causes (e.g., histoplasmosis, coccidiomycosis, toxoplasmosis, EBV) – Serum levels of angiotensin-converting enzyme and serum Ca++ for sarcoidosis – Antinuclear antibody (ANA) and dsDNA to exclude SLE – Urinary antigen to exclude Legionella infection – Anti-Ro/SSA, anti-La/SSB antibodies, CRP, and rheumatoid factor to exclude Sjögren syndrome • Liver function tests: elevated serum transaminase levels in patients with associated drug-induced liver injury • Renal US may demonstrate kidneys that are normal to enlarged in size with increased cortical echogenicity, but no US findings will reliably confirm or exclude AIN versus other causes of AKI. • IV pyelography (IVP) and CT scans with contrast are relatively contraindicated because of the associated nephrotoxicity and limited diagnostic yield.

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Initial Tests (lab, imaging) Follow-Up Tests & Special Considerations Patients who do not recover renal function and those with CIN should receive long-term follow-up care to protect kidneys from further potentially nephrotoxic therapies.

Diagnostic Procedures/Other • Renal biopsy is the definitive method of establishing the diagnosis of AIN. Ideally, it should be performed to: – Patients treated with an OFA known to cause AIN but have normal urinalysis – Patients who are being considered for steroid therapy – Patients who are not on glucocorticosteroid therapy initially and do not have spontaneous recovery following cessation of the OFA – Patients with advanced renal failure of recent onset (50 for colorectal cancer.

Test Interpretation None

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TREATMENT • Goals: Relieve symptoms and improve quality of life (3). – Determine if diarrhea predominant, constipation predominant, or mixed type. • Lifestyle modification – Exercising 3 to 5 times per week decreases severity (3). – Food diary to determine triggers (3) • Medications – Fiber supplementation (psyllium) increases stool bulk; does not typically relieve abdominal pain; may be used for all types (3)[B] • Medications that improve abdominal pain, global symptoms, and symptom severity in all types: – Antispasmodics such as hyoscyamine 0.125 to 0.25 mg PO/SL q4h PRN and dicyclomine 20 to 40 mg PO BID can be used for all types but have adverse effects such as dry mouth, dizziness, and blurred vision (3). – Probiotics such as Lactobacillus, Bifidobacterium, and Streptococcus (4)[C] • Diarrhea predominant – Antidiarrheal such as loperamide 4 to 8 mg/day orally divided into once a day to 3 times a day as needed to decrease stool frequency and increase stool consistency; does not help with abdominal pain; may also use diphenoxylate/atropine (3) – Antibiotics such as 2-week course of rifaximin improve bloating, pain, and stool consistency (5). – Alosetron (Lotronex 0.5 mg orally twice a day), for women with severe symptoms. Associated with ischemic colitis, constipation, and death in a small number of patients. • Constipation-predominant – Laxatives such as polyethylene glycol (MiraLAX) may improve stool frequency but not pain. – Antibiotics such as neomycin and selective chloride channel activators such as lubiprostone (Amitiza) 8 mg twice a day can improve global symptoms and severity (3)[B]. – Linaclotide (guanylate cyclase-C agonist) has been shown to improve

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bowel function and reduces abdominal pain and overall severity in adults only (6). • Mixed – Use medications to match symptoms (3). • Treat underlying behavioral issues: – Tricyclic antidepressants can help control IBS symptoms in moderate to severe cases. – Behavioral therapy helps reduce symptoms (5).

ISSUES FOR REFERRAL • Behavioral health referral may help with management of affective or personality disorders. • Gastroenterology referral for difficult to control cases

ADDITIONAL TREATMENT Probiotics use may result in reducing IBS symptoms and decreasing pain and flatulence. There is no difference among Lactobacillus, Streptococcus, Bifidobacterium, and combinations of probiotics.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring The IBS Severity Score is a validated measure to assess the severity of IBS symptoms and can help monitor response to treatment. IBS Severity Score: • How severe has your abdominal pain been over the last 10 days? • On how many of the last 10 days did you get pain? • How severe has your abdominal distension (bloating, swollen, or tight) been over the last 10 days? • How satisfied have you been with your bowel habit (frequency, ease, etc.) over the last 10 days? • How much has your IBS been affecting/interfering with your life in general over the last 10 days?

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DIET • Low FODMAPs diet: This diet contains fermentable oligosaccharides, disaccharides, and monosaccharides, and polyols that are carbohydrates (sugars) found in foods. FODMAPs are osmotic, so they may not be digested or absorbed well and could be fermented upon by bacteria in the intestinal tract when eaten in excess. • A low FODMAP diet may help reduce symptoms, which will limit foods high in fructose, lactose, fructans, galactans, and polyols. – Increase fiber slowly to avoid excess intestinal gas production. – During initial evaluation, consider 2 weeks of lactose-free diet to rule out lactose intolerance. – Avoid large meals, fatty foods, and caffeine, which can exacerbate symptoms. – A gluten-free diet resolves symptoms for some patients (especially diarrhea predominant IBS) despite negative testing for celiac disease.

PATIENT EDUCATION IBS is not a psychiatric illness.

PROGNOSIS • IBS is a disorder that reduces quality of life. Many patients have behavioral health issues. IBS does not increase mortality (1). • Expect recurrences, especially when under stress. • Evidence suggests that “symptom shifting” occurs in some patients, whereby resolution of functional bowel symptoms is followed by the development of functional symptoms in another system (1).

REFERENCES 1. Canavan C, West J, Card T. The epidemiology of irritable bowel syndrome. Clin Epidemiol. 2014;6:71–80. 2. Reddymasu SC, Sostarich S, McCallum RW. Small intestinal bacterial overgrowth in irritable bowel syndrome: are there any predictors? BMC Gastroenterol. 2010;10:23. 3. Wilkins T, Pepitone C, Alex B, et al. Diagnosis and management of IBS in

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adults. Am Fam Physician. 2012;86(5):419–426. 4. Ciorba MA. A gastroenterologist’s guide to probiotics. Clin Gastroenterol Hepatol. 2012;10(9):960–968. 5. Schey R, Rao SS. The role of rifaximin therapy in patients with irritable bowel syndrome without constipation. Expert Rev Gastroenterol Hepatol. 2011;5(4):461–464. 6. Videlock EJ, Cheng V, Cremonini F. Effects of linaclotide in patients with irritable bowel syndrome with constipation or chronic constipation: a metaanalysis. Clin Gastroenterol Hepatol. 2013;11(9):1084.e3–1092.e3.

SEE ALSO Algorithm: Diarrhea, Chronic

CODES ICD10 • K58.9 Irritable bowel syndrome without diarrhea • K58.0 Irritable bowel syndrome with diarrhea

CLINICAL PEARLS • Use Rome III criteria to establish the diagnosis of IBS. • Goals of treatment are to relieve symptoms and improve quality of life. • If patient does not respond to initial treatment, consider further evaluation (including imaging and/or referral for endoscopy) to exclude organic pathology.

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KAWASAKI SYNDROME Zachariah Clark, MD • Scott P. Grogan, DO, MBA, FAAFP BASICS DESCRIPTION • Kawasaki syndrome (KS) is a self-limited acute, febrile, systemic vasculitis of small- and medium-sized arteries that predominantly affects patients age 6 months to 5 years and is the most prominent cause of acquired coronary artery disease in pediatric populations. – Vasculitis of coronary arteries resulting in aneurysms/ectasia, further leading to myocardial infarction (MI)/ischemia or sudden death • System(s) affected: cardiovascular, gastrointestinal, hematologic/lymphatic/immunologic, musculoskeletal, nervous, pulmonary, renal/urologic, skin/exocrine • Synonym(s): mucocutaneous lymph node syndrome (MCLS), infantile polyarteritis, Kawasaki disease

ALERT KS should be considered in any child with extended high fever unresponsive to antibiotics or antipyretics, rash, and nonexudative conjunctivitis.

EPIDEMIOLOGY Incidence • Worldwide: affects all races but most prevalent in Asia; Japan annual incidence rate 265/100,000 in children 50% develop KS within 10 days of first case. Increased occurrence of KS in children whose parents also had illness in childhood. • Populations at higher risk and family link suggest a genetic predisposition.

GENERAL PREVENTION No preventive measures available

DIAGNOSIS ≥5 days of fever and ≥4 of the following 5 principal clinical features; or 35 mg/L in 80% cases), erythrocyte sedimentation rate (ESR) (>60 mm/hr in 60% cases), and α1-antitrypsin

ALERT ESR can be artificially high after intravenous immunoglobulin (IVIG) therapy. • Hyponatremia • Moderately elevated AST, ALT, GGT, and bilirubin • Decreased albumin and protein • CSF pleocytosis may be seen (lymphocytic with normal protein and glucose). • N-terminal brain natriuretic peptide might be elevated in acute phase. • Sterile pyuria but not seen in suprapubic collection • Nasal swab to rule out adenovirus

Initial Tests (lab, imaging) • If KS is suspected, obtain ECG and echocardiogram. – ECG may show arrhythmias, prolonged PR interval, and ST/T wave changes. – Echocardiography has a high sensitivity and specificity for detection of abnormalities of proximal left main coronary artery, and right coronary artery may show perivascular brightening, ectasia, decreased left ventricular contractility, pericardial effusion, or aneurysms. – Cardiac stress test if CAA seen on echocardiogram • Baseline chest x-ray (CXR): may show pleural effusion, atelectasis, and

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congestive heart failure (CHF) • Hydrops of the gallbladder may be associated with abdominal pain or may be asymptomatic.

Diagnostic Procedures/Other • No laboratory study is diagnostic; diagnosis rests on constellation of clinical features and exclusion of other illnesses. • Magnetic resonance coronary angiography is noninvasive modality to visualize coronary arteries for stenosis, thrombi, and intimal thickening (1). • Patients with complex coronary artery lesions may benefit from coronary angiography after the acute inflammatory process has resolved; generally recommended in 6 to 12 months

TREATMENT GENERAL MEASURES Use antibiotics until bacterial etiologies are excluded (e.g., sepsis or meningitis).

MEDICATION • Optimal therapy is IVIG 2 g/kg IV over 10 to 12 hours with high-dose aspirin preferably within 7 to 10 days of fever, followed by low-dose aspirin until follow-up echocardiograms indicate a lack of coronary abnormalities. – IVIG lowers the risk of CAA and may shorten fever duration. – The extreme irritability often resolves very quickly after IVIG is given. • Retreatment with IVIG if clinical response is incomplete or fever persists/returns >36 hours after start of IVIG treatment. – ≥10% of patients do not respond to initial IVIG treatment. 2/3 of nonresponders respond to the second dose of IVIG. – Nonresponders tend to have ↑ bands, ↓ albumin, and an abnormal echo. • Aspirin, 80 to 100 mg/kg/day in 4 doses beginning with IVIG administration. Switch to low-dose aspirin (3 to 5 mg/kg/day) when afebrile for 48 to 72 hours, or continue until day 14 of illness. Maintain low dose for 6 to 8 weeks until follow-up echocardiogram is normal and CRP and/or ESR are normal. Continue salicylate regimen in children with coronary abnormalities long term or until documented regression of aneurysm (2)[C].

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• Aspirin does not appear to reduce CAA (3)[B]. • Contraindications – IVIG: documented hypersensitivity, IgA deficiency, anti-IgE/IgG antibodies, severe thrombocytopenia, coagulation disorders – Aspirin: vitamin K deficiency, bleeding disorders, liver damage, documented hypersensitivity, hypoprothrombinemia • Precautions – No statistically significant difference is noted between different preparations of IVIG. – High-dose aspirin therapy can result in tinnitus, decrease of renal function, and increased transaminases. – Do not use ibuprofen in children with CAAs who are taking aspirin for antiplatelet effects. – Significant possible interactions: Aspirin therapy has been associated with Reye syndrome in children who develop viral infections, especially influenza B and varicella. Yearly influenza vaccination thus is recommended for children requiring long-term treatment with aspirin. Delay any live vaccines for 11 months after IVIG treatment.

Second Line • Corticosteroids should be used only if ≥2 IVIG treatments have failed. The addition of corticosteroids to IVIG and aspirin during initial treatment might improve CAA outcomes but lacks consistent evidence (4)[C]. • In patients refractory to IVIG and steroids, consider infliximab or cyclosporine (5)[B]. • Plasma exchange may decrease likelihood of CAA in IVIG nonresponders (6) [B].

ISSUES FOR REFERRAL Pediatric cardiologist if abnormalities on echo or if extensive stenosis

ADDITIONAL THERAPIES • Treatment and prevention of thrombosis are crucial. • Antiplatelet agents (clopidogrel, dipyridamole), heparin, low-molecularweight heparin, or warfarin are sometimes added to the low-dose aspirin

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regimen, depending on severity of coronary involvement.

SURGERY/OTHER PROCEDURES • Rarely needed; coronary artery bypass grafting for severe obstruction/recurrent MI. Younger patients have a higher mortality rate. • Coronary revascularization via percutaneous coronary intervention for patients with evidence of ischemia on stress testing

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Normal saline (NS) for rehydration and 1/2 NS for maintenance • Discharge if afebrile after IVIG treatment for 24 hours.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS With aneurysms, contact and high-risk sports should be avoided.

Patient Monitoring • Repeat ECG and echocardiogram at 6 to 8 weeks. If abnormal, repeat at 6 to 12 months. • Patients with complex coronary artery lesions may benefit from coronary angiography at 6 to 12 months.

PROGNOSIS • Usually self-limited • Moderate-sized aneurysms usually regress in 1 to 2 years, resolving in 50– 66% of cases. • Recurrence (3% in Japan, 2 weeks, fever >48 hours

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after IVIG treatment • Mortality of 0.08–0.17% is due to cardiac disease.

REFERENCES 1. JCS Joint Working Group. Guidelines for diagnosis and management of cardiovascular sequelae in Kawasaki disease (JCS 2008)—digest version. Circ J. 2010;74(9):1989–2020. 2. Baumer JH, Love SJ, Gupta A, et al. Salicylate for the treatment of Kawasaki disease in children. Cochrane Database Syst Rev. 2006;(4):CD004175. 3. Lee G, Lee SE, Hong YM, et al. Is high-dose aspirin necessary in the acute phase of Kawasaki disease? Korean Circ J. 2013;43(3):182–186. 4. Chen S, Dong Y, Yin Y, et al. Intravenous immunoglobulin plus corticosteroid to prevent coronary artery abnormalities in Kawasaki disease: a meta-analysis. Heart. 2013;99(2):76–82. 5. Patel RM, Shulman ST. Kawasaki disease: a comprehensive review of treatment options. J Clin Pharm Ther. 2015;40(6):620–625. 6. Hokosaki T, Mori M, Nishizawa T, et al. Long-term efficacy of plasma exchange treatment for refractory Kawasaki disease. Pediatr Int. 2012;54(1):99–103.

ADDITIONAL READING • Huang SK, Lin MT, Chen HC, et al. Epidemiology of Kawasaki disease: prevalence from national database and future trends projection by system dynamics modeling. J Pediatr. 2013;163(1):126.e1–131.e1. • Newburger JW, Takahashi M, Gerber MA, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Circulation. 2004;110(17):2747–2771. • Oates-Whitehead RM, Baumer JH, Haines L, et al. Intravenous immunoglobulin for the treatment of Kawasaki disease in children. Cochrane Database Syst Rev. 2003;(4):CD004000. • Sing S, et al. The epidemiology of Kawasaki disease: a global update. Arch

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Dis Child 2015; 100:1084–1088. • Takahashi K, Oharaseki T, Yokouchi Y. Update on etio and immunopathogenesis of Kawasaki disease. Curr Opin Rheumatol. 2014;26(1):31–36.

CODES ICD10 M30.3 Mucocutaneous lymph node syndrome [Kawasaki]

CLINICAL PEARLS • The diagnosis of KS rests on a constellation of clinical features. • Once KS is suspected, all patients need an inpatient cardiac evaluation, including ECG and echocardiogram. • Expert recommendation for optimal therapy is IVIG 2 g/kg IV over 10 hours, with high-dose aspirin 80 to 100 mg/kg/day in 4 doses.

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KERATOACANTHOMA Carl Bryce, MD • Matthew J. Snyder, DO BASICS DESCRIPTION • Rapidly proliferating, solitary, dome-shaped, erythematous or flesh-colored papule or nodule with a central keratinous plug, typically reaching 1 to 2 cm in diameter • Highly debated as to whether keratoacanthoma (KA) is a benign or malignant variant of squamous cell carcinoma (SCC). Majority are benign and resolve spontaneously, but lesions do have the potential for invasion and metastasis; therefore require treatment. • Three clinical stages of KAs (1): – Proliferative: rapid growth of the lesion over weeks to several months – Maturation/stabilization: Lesion stabilizes and growth subsides. – Involution: spontaneous resolution of the lesion, leaving a hypopigmented, depressed scar; most but not all lesions will enter this stage. • System(s) affected: integumentary

EPIDEMIOLOGY • Greatest incidence over the age of 50 years but may occur at any age • Presentation increased during summer and early fall seasons • Most frequently on sun-exposed, hair-bearing skin but may occur anywhere • Predominant sex: male > female (2:1) • Most commonly in fair-skinned individuals; highest rates in Fitzpatrick I–III • 104 cases per 100,000 individuals

ETIOLOGY AND PATHOPHYSIOLOGY • Derived from an abnormality causing hyperkeratosis within the follicular infundibulum • Squamous epithelial cells proliferate to extend upward around the keratin plug and proceed downward into the dermis; followed by invasion of elastic and collagen fibers

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• Cellular mechanism responsible for the hyperkeratosis is currently unknown; role of human papillomavirus has been discussed but has no established causality (2). • Regression may be due to immune cytotoxicity or terminal differentiation of keratinocytes. • Multiple etiologies have been suggested: – UV radiation – May be provoked by surgery, cryotherapy, chemical peels or laser therapy – Viral infections: human papillomavirus (HPV) or Merkel cell polyomavirus – Genetic predisposition: Muir-Torre syndrome, xeroderma pigmentosum, Ferguson-Smith syndrome – Immunosuppression – Chemical carcinogen exposure

Genetics • Mutation of p53 or H-ras • Ferguson-Smith (AD) • Witten-Zak (AD) • Muir-Torre (AD) • Xeroderma pigmentosum (AR) • Gzybowski (sporadic) • Incontinentia pigmenti (XLD)

RISK FACTORS • UV exposure/damage: outdoor and/or indoor tanning • Fitzpatrick skin type I–III • Trauma (typically appears within 1 month of injury): laser resurfacing, surgery, cryotherapy, tattoos • Chemical carcinogens: tar, pitch, and smoking • Immunocompromised state • Discoid lupus erythematosus

GENERAL PREVENTION Sun protection

COMMONLY ASSOCIATED CONDITIONS

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• Frequently, the patient has concurrent sun-damaged skin: solar elastosis, solar lentigines, actinic keratosis, nonmelanoma skin cancers (basal cell carcinoma, SCC) • In Muir-Torre syndrome, KAs are found with coexisting sebaceous neoplasms and malignancy of the GI and GU tracts.

DIAGNOSIS HISTORY • Lesion begins as a small, solitary, pink macule that undergoes a rapid growth phase; classically reaching a diameter of 1 to 2 cm; size may vary. • Once the proliferative stage has subsided, lesion size remains stable. • May decrease in size, indicating regression • Asymptomatic, occasionally tender • If multiple lesions present, important to elicit a family history and recent therapies or treatments. • If sebaceous neoplasms present, must review history for signs/symptoms of GI or GU malignancies

PHYSICAL EXAM • Firm, solitary, erythematous or flesh-colored, dome-shaped papule or nodule with a central keratin plug, giving a crateriform appearance • Surrounding skin and borders of lesion may show telangiectasia, atrophy, or dyspigmentation. • Solitary; although multiple lesions can occur. • Most commonly seen on sun-exposed areas: face, neck, scalp, dorsum of upper extremities, and posterior legs • May also be seen on areas without sun exposure: buttocks, anus, subungual, mucosal surfaces • Subungual KAs are very painful and seen on the first 3 digits of the hands. • Examine for regional lymphadenopathy due to chance of lesion invasion and metastasis. • Dermoscopy (3)[B] – Central keratin

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– White circles, blood spots – Cannot reliably distinguish between AK and SCC

DIFFERENTIAL DIAGNOSIS • SCC • Nodular or ulcerative basal cell carcinoma • Cutaneous horn • Hypertrophic actinic keratosis • Amelanotic melanoma • Merkel cell carcinoma • Metastasis to the skin • Molluscum contagiosum • Prurigo nodularis • Verruca vulgaris • Verrucous carcinoma • Sebaceous adenoma • Hypertrophic lichen planus • Hypertrophic lupus erythematosus • Deep fungal infection • Atypical mycobacterial infection • Nodular Kaposi sarcoma

DIAGNOSTIC TESTS & INTERPRETATION • Excisional biopsy including the center of the lesion as well as the margin is the best diagnostic test (2)[C]. • A shave biopsy may be insufficiently deep to distinguish KA from an SCC. • If unable to perform an excisional biopsy, a deep shave (saucerization) of the entire lesion, extending into the subcutaneous fat, can be done. • Punch biopsies should be avoided because they give an insufficient amount of tissue to represent the entire lesion.

Initial Tests (lab, imaging) • Subungual KA: radiograph of the digit to monitor for osteolysis (cup-shaped radiolucent defect) • Aggressive tumors may need CT with contrast for evaluation of lymph nodes

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and MRI if there is concern of perineural invasion. • Most lesions do not need any form of imaging.

Test Interpretation • Pathology of biopsy: a well-demarcated central core of keratin surrounded by well-differentiated, mildly pleomorphic, atypical squamous epithelial cells with a characteristic glassy eosinophilic cytoplasm • May see elastic and collagen fibers invading into the squamous epithelium • Histologic differentiation of a KA from an SCC may be difficult and unreliable, although immunochemical staining for cellular protein Ki-67 may help do this (4). • KAs have a greater tendency than SCC to display fibrosis and intraepidermal abscesses of neutrophils and eosinophils. • Regressing KA shows flattening and fibrosis at base of lesion.

TREATMENT • Treatment of choice is an excisional procedure plus electrodessication and curettage; however, there are many treatment options available (2)[C]. • Aggressive tumors (>2 cm) or lesions in cosmetically sensitive areas (face, digits, genitalia) that require tissue sparing, consider Mohs micrographic surgery – Mohs is the treatment of choice in cases with perineural or perivascular invasion. • Small lesions (2 cm, numerous, mucosal, or subungual

ADDITIONAL THERAPIES • Photodynamic therapy with methyl aminolevulinic acid and red light, successful case reports (6)[B] but also reported aggravation following treatment • Cryotherapy • Argon or YAG lasers • Radiotherapy, primary or adjuvant: KAs may regress with low doses of radiation but may require doses up to 25 to 50 Gy in low-dose (5 to 10 Gy) fractions for possible SCC (7)[B]. • Erlotinib (EGFR inhibitor) 150 mg daily for 21 days, single case report (8)[B]

SURGERY/OTHER PROCEDURES Excisional and office-based procedures as discussed above.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS After the surgical site has healed or lesion has resolved, patient should be seen every 6 months due to increased risk of developing new lesions or skin cancers, annually at minimum (3)[C].

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Patient Monitoring • Skin self-exams should be routinely performed with detailed instructions (see “Additional Reading”). • If multiple KAs are present in patient or family members, evaluate for MuirTorre syndrome and obtain a colonoscopy beginning at age 25 years, as well as testing for genitourinary cancer (3)[C].

PATIENT EDUCATION • Sun protection measures: sun block with SPF >30, wide-brimmed hats, long sleeves, dark clothing, avoiding indoor tanning • Arc welding may produce harmful UV radiation and skin should not be exposed. • Tar, pitch, and smoking should be avoided.

PROGNOSIS • Atrophic scarring and hypopigmentation can occur with self-resolution but may be significantly reduced by intervention. • 52 of 445 cases (12%) spontaneously regressed without treatment and none of these recurred (2). • 393 (88%) regressed following medical or excisional treatment (2). • 445 cases reported with no metastases or deaths attributable to the KA (2). • 4–8% recurrence • Mucosal and subungual lesions do not regress, must undergo treatment

REFERENCES 1. Zalaudek I, Bonifazi E, Ferrara G, et al. Keratoacanthomas and spitz tumors: are they both “self-limiting” variants of malignant cutaneous neoplasms? Dermatology. 2009;219(1):3–6. 2. Savage JA, Maize JC Sr. Keratoacanthoma clinical behavior: a systematic review. Am J Dermatopathol. 2014;36(5):422–429. 3. Rosendahl C, Cameron A, Argenziano G, et al. Dermoscopy of squamous cell carcinoma and keratoacanthoma. Arch Dermatol. 2012;148(12):1386–1392. 4. Scola N, Segert HM, Stücker M, et al. Ki-67 may be useful in differentiating between keratoacanthoma and cutaneous squamous cell carcinoma. Clin Exp

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Dermatol. 2014;39(2):216–238. 5. Chitwood KL, Etzkorn J, Cohen G. Topical and intralesional treatment of nonmelanoma skin cancer: efficacy and cost comparisons. Dermatol Surg. 2013;39(9):1306–1316. 6. Jeon HC, Choi M, Paik SH, et al. Treatment of keratoacanthoma with 5% imiquimod cream and review of the previous report. Ann Dermatol. 2011;23(3):357–361. 7. Bruscino N, Corradini D, Campolmi P, et al. Superficial radiotherapy for multiple keratoacanthomas. Dermatol Ther. 2014;27(3):163–167. 8. Reid DC, Guitart J, Agulnik M, et al. Treatment of multiple keratoacanthomas with erlotinib. Int J Clin Oncol. 2010;15(4):413–415.

ADDITIONAL READING • The American Academy of Dermatology: https://www.aad.org/spot-skincancer/learn-about-skin-cancer/types-of-skin-cancer • The Skin Cancer Foundation: http://www.skincancer.org/

SEE ALSO Squamous Cell Carcinoma, Cutaneous

CODES ICD10 • D23.9 Other benign neoplasm of skin, unspecified • D48.5 Neoplasm of uncertain behavior of skin • L85.8 Other specified epidermal thickening

CLINICAL PEARLS • Suspect KA with a solitary, dome-shaped, erythematous or flesh-colored papule or nodule with a central keratinous plug. • If KA is in the differential diagnosis, elicit time frame of onset during patient encounter; rapid onset supports diagnosis.

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• Due to the broad differential diagnosis of a suspected KA and unreliable clinical differentiation between these, strongly consider surgical excision as first-line diagnostic test and therapy. • Medical and radiation therapies are reasonable and effective options available for patients who are not surgical candidates or for lesions that are not amenable for surgery.

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KERATOSIS, ACTINIC Zoltan Trizna, MD, PhD BASICS DESCRIPTION • Common, usually multiple, premalignant lesions of sun-exposed areas of the skin. Many resolve spontaneously, and a small proportion progress to squamous cell carcinoma • Common consequence of excessive cumulative ultraviolet (UV) light exposure • Synonym(s): solar keratosis

Geriatric Considerations Frequent problem

Pediatric Considerations Rare (if child, look for freckling and other stigmata of xeroderma pigmentosum)

EPIDEMIOLOGY Incidence • Rates vary with age group and exposure to sun. • Predominant age: ≥40 years; progressively increases with age • Predominant sex: male > female • Common in those with blonde and red hair; rare in darker skin types

Prevalence • Age-adjusted prevalence rate for actinic keratoses (AKs) in U.S. Caucasians is 6.5%. • For 65- to 74-year-old males with high sun exposure: ~55%; low sun exposure, ~18%

ETIOLOGY AND PATHOPHYSIOLOGY • The epidermal lesions are characterized by atypical keratinocytes at the basal layer with occasional extension upward. Mitoses are present. The

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histopathologic features resemble those of squamous cell carcinoma (SCC) in situ or SCC, and the distinction depends on the extent of epidermal involvement. • Cumulative UV exposure

Genetics The p53 chromosomal mutation has been shown consistently in both AKs and SCCs. Many new genes have been shown recently to have similar expression profiles in AKs and SCCs.

RISK FACTORS • Exposure to UV light (especially long-term and/or repeated exposure due to outdoor occupation or recreational activities, indoor or outdoor tanning) • Skin type: burns easily, does not tan • Immunosuppression, especially organ transplantation

GENERAL PREVENTION Sun avoidance and protective techniques are helpful.

COMMONLY ASSOCIATED CONDITIONS • SCC • Other features of chronic solar damage: lentigines, elastosis, and telangiectasias

DIAGNOSIS HISTORY • The lesions are frequently asymptomatic; symptoms may include pruritus, burning, and mild hyperesthesia. • Lesions may enlarge, thicken, or become more scaly. They also may regress or remain unchanged. • Most lesions occur on the sun-exposed areas (head and neck, hands, forearms).

PHYSICAL EXAM • Usually small (90% of AKs – Less scarring than cryotherapy – May be superior to cryotherapy, especially in the case of more extensive skin involvement • Curettage and electrocautery (electrodesiccation and curettage [ED&C]; “scraping and burning”) • Medium-depth peels, especially for the treatment of extensive areas • CO2 laser therapy • Dermabrasion • Surgical excision (excisional biopsy)

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ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring Depends on associated malignancy and frequency with which new AKs appear

PATIENT EDUCATION • Teach sun-protective techniques. – Limit outdoor activities between 10 AM and 4 PM. – Wear protective clothing and wide-brimmed hat. – Proper use (including reapplication) of sunscreens with SPF >30, preferably a preparation with broad-spectrum (UV-A and UV-B) protection • Teach self-examination of skin (melanoma, squamous cell, basal cell). • Patient education materials – http://dermnetnz.org/lesions/solar-keratoses.html – www.skincarephysicians.com/actinickeratosesnet/index.html – www.skincancer.org/Actinic-Keratosis-and-Other-Precancers.htm

PROGNOSIS Very good. A significant proportion of the lesions may resolve spontaneously (4), with regression rates of 20–30% per lesion per year.

COMPLICATIONS • AKs are premalignant lesions that may progress to SCCs. The rate of malignant transformation is unclear; the reported percentages vary (4) but range from 0.1% to a few percent per year per lesion. • Patients with AKs are at increased risk for other cutaneous malignancies. • Approximately 60% of SCCs arise from an AK precursor.

REFERENCES 1. Helfand M, Gorman AK, Mahon S, et al. Actinic Keratoses. Rockville, MD: Agency for Healthcare Research and Quality; 2001. 2. de Berker D, McGregor JM, Hughes BR. Guidelines for the management of actinic keratoses. Br J Dermatol. 2007;156(2):222–230.

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3. Gupta AK, Paquet M. Network meta-analysis of the outcome “participant complete clearance” in nonimmunosuppressed participants of eight interventions for actinic keratosis: a follow-up on a Cochrane review. Br J Dermatol. 2013;169(2):250–259. 4. Criscione VD, Weinstock MA, Naylor MF, et al. Actinic keratoses: natural history and risk of malignant transformation in the Veterans Affairs Topical Tretinoin Chemoprevention Trial. Cancer. 2009;115(11):2523–2530.

ADDITIONAL READING • Kanellou P, Zaravinos A, Zioga M, et al. Genomic instability, mutations and expression analysis of the tumour suppressor genes p14(ARF), p15(INK4b), p16(INK4a) and p53 in actinic keratosis. Cancer Lett. 2008;264(1):145–161. • Rossi R, Mori M, Lotti T. Actinic keratosis. Int J Dermatol. 2007;46(9):895– 904.

CODES ICD10 L57.0 Actinic keratosis

CLINICAL PEARLS • AKs are premalignant lesions. • Often more easily felt than seen • Therapy-resistant lesions should be biopsied, especially on the face.

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KERATOSIS, SEBORRHEIC Jelaun Newsome, DO BASICS DESCRIPTION • One of the most common benign tumors of the epidermis • Formed from keratinocytes • Frequently appears in multiples on the head, neck, and trunk of older individuals but may occur on any hair-bearing area of the body. Lesions spare the palms and soles. • Typically are light brown to black, sharply demarcated, round, or elongated lesions with a velvety, verrucous-like, “stuck-on” appearance; lesions may also appear waxy yellow or pink. • Clinical variants include the following: – Common seborrheic keratosis – Dermatosis papulosa nigra – Stucco keratosis – Flat seborrheic keratosis – Pedunculated seborrheic keratosis • System(s) affected: integumentary • Synonym(s): verruca seborrhoica; seborrheic wart; senile wart; basal cell papilloma; verruca senilis; basal cell acanthoma; benign acanthokeratoma

EPIDEMIOLOGY Incidence • Predominant age – Usually appear after the 3rd decade – Most commonly seen during middle and older age – Can occasionally arise as early as adolescence • Predominant sex: male = female • Most common among Caucasians, except for the dermatosis papulosa nigra variant, which usually presents in darker skinned individuals

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Prevalence • 69–100% in patients >50 years of age • The prevalence rate increases with advancing age.

ETIOLOGY AND PATHOPHYSIOLOGY • Seborrheic keratoses are monoclonal tumors. • Etiology still is largely unclear. • Ultraviolet (UV) light and genetics are thought to be involved. • The role of human papillomavirus is uncertain.

Genetics An autosomal dominant inheritance pattern is suggested.

RISK FACTORS • Advanced age • Exposure to UV light and genetic predisposition are possible factors (1).

GENERAL PREVENTION Sun protection methods may help prevent seborrheic keratoses from developing.

COMMONLY ASSOCIATED CONDITIONS • Sign of Leser-Trélat: A paraneoplastic syndrome characterized by a sudden eruption of multiple seborrheic keratoses in association with an internal malignancy, most commonly stomach or colon adenocarcinoma. Usually represents a poor prognosis. The validity of this syndrome as a marker for internal malignancy is controversial (2)[B]. • Documentation of other cutaneous lesions, such as basal cell carcinoma, malignant melanoma, Bowen disease, or squamous cell carcinoma, growing adjacent to or within a seborrheic keratosis, has been reported. The exact relationship between lesions is unclear.

DIAGNOSIS HISTORY • Usually asymptomatic • Trauma or irritation of the lesion may result in pruritus, erythema, bleeding,

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pain, and/or crusting.

PHYSICAL EXAM • Typically begin as oval- or round-shaped, flat, dull, sharply demarcated patches • As they mature, may develop into thicker, elevated, uneven, verrucous-like papules, plaques, or peduncles with a waxy or velvety surface, and appear “stuck on” to the skin (3) • Commonly appear on sun-exposed areas of the body, predominately the head, neck, or trunk but may appear on any hair-bearing skin • Vary in color from black, brown, tan, gray to white, or skin-colored, and range in size, from 1 mm to 4 cm • Usually occur as multiples, with patients having >100 is not uncommon. • May grow along folds on truncal skin, forming a “Christmas tree” pattern • If irritated, may be bleeding, inflamed, painful, pruritic, or crusted • Common clinical variants include the following (4): – Common seborrheic keratoses: on hair-bearing skin, usually on the face, neck, and trunk; verrucous-like, waxy, or velvety lesions that appear “stuck on” to the skin – Dermatosis papulosa nigra: Small black papules that usually appear on the face, neck, chest, and upper back; most common in darker skinned individuals, more common in females; most have a positive family history. – Stucco keratoses: small gray-white, rough, verrucous papules; usually occur in large numbers on the lower extremities or forearms; more common in men – Flat seborrheic keratoses: oval-shaped, brown patches or macules on face, chest, and upper extremities; increases with age – Pedunculated seborrheic keratoses: Hyperpigmented peduncles appear on areas of friction (neck, axilla).

DIFFERENTIAL DIAGNOSIS Consider the following diagnoses if the seborrheic keratosis is: • Pigmented – Malignant melanoma – Melanocytic nevus

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– Angiokeratoma – Pigmented basal cell carcinoma • Lightly pigmented – Basal cell carcinoma – Bowen disease – Condyloma acuminatum – Fibroma – Verruca vulgaris – Eccrine poroma – Invasive squamous cell carcinoma – Acrochordon – Acrokeratosis verruciformis of Hopf – Follicular infundibulum tumor • Flat – Solar lentigo – Verrucae planae juveniles • Hyperkeratotic – Actinic keratosis

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) Not needed unless internal malignancy is suspected

Diagnostic Procedures/Other • The diagnosis can usually be made based on clinical appearance. • Dermoscopy – Can aid in diagnosis – Common findings are comedo-like openings, fissures, ridges, sharply demarcated borders, milia-like cysts, pseudofollicular openings, hairpin vessels, and horn pseudocysts (5,6). • Biopsy and histologic exam should be performed if the seborrheic keratosis – Is atypical – Has inflammation – Recently changed in appearance – Diagnosis remains unclear.

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Test Interpretation • Histologic findings include the following: – Acanthosis and papillomatosis due to basaloid cell proliferation – “Squamous eddies” or squamous epithelial cell clusters – Hyperpigmentation – Hyperkeratosis – Horn cysts – Pseudocysts • Several histologic variants exist.

TREATMENT • Treatment is not usually necessary due to the benign nature of the lesions. • Removal of seborrheic keratoses may be indicated if – Symptomatic – Aesthetically displeasing or undesirable (common) – There is a question of malignancy.

MEDICATION Current topical treatments of seborrheic keratoses are less effective than a surgical approach.

ISSUES FOR REFERRAL • New seborrheic keratoses appear abruptly. • A seborrheic keratosis becomes inflamed or changes in appearance.

SURGERY/OTHER PROCEDURES • A surgical approach to treatment is preferred. • Choice depends on physician preference and availability of the treatment. • The following procedures are used: – Cryotherapy (liquid nitrogen) Spray flat lesions for 5 to 10 seconds; may require more time or additional treatments if the seborrheic keratosis is thicker Possible complications include scarring, hypopigmentation, recurrence. – Curettage

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– Electrodessication – Shave excision – Excisional biopsy – Chemical peel • Use of following laser treatments have been reported: – Ablative CO2 – Ablative erbium-YAG – Argon – 492 nm – 510 nm – Alexandrite lasers • No statistically significant differences were found in patient’s ratings of cosmetic appearance between cryotherapy and curettage. The majority of patients preferred cryotherapy over curettage due to decreased postoperative wound care, despite the increased discomfort experienced and increased frequency of seborrheic keratosis remaining after cryotherapy when compared to curettage (7)[B].

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring After initial diagnosis, follow-up is not usually required unless • Inflammation or irritation develops. • There is a change in appearance. • New seborrheic keratoses suddenly appear.

PATIENT EDUCATION • Sun-protective methods may help reduce seborrheic keratosis development. • Patient education materials – http://www.aad.org/dermatology-a-to-z/diseases-and-treatments/q– t/seborrheic-keratoses – www.cdc.gov/cancer/skin/basic_info/prevention.htm

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PROGNOSIS • Seborrheic keratoses generally do not become malignant. • Sign of Leser-Trélat usually represents a poor prognosis.

COMPLICATIONS • Irritation and inflammation due to mechanical irritation (i.e., from clothing, jewelry) • Possible complications of surgical treatment include hypopigmentation, hyperpigmentation, scarring, incomplete removal, and recurrence. • Misdiagnosis (rare)

REFERENCES 1. Saeed AK, Salmo N. Epidermal growth factor receptor expression in mice skin upon ultraviolet B exposure — seborrheic keratosis as a coincidental and unique finding. Adv Biomed Res. 2012;1:59. 2. Ponti G, Luppi G, Losi L, et al. Leser-Trélat syndrome in patients affected by six multiple metachronous primitive cancers. J Hematol Oncol. 2010;3:2. 3. Luba MC, Bangs SA, Mohler AM, et al. Common benign skin tumors. Am Fam Physician. 2003;67(4):729–738. 4. Noiles K, Vender R. Are all seborrheic keratoses benign? Review of the typical lesion and its variants. J Cutan Med Surg. 2008;12(5):203–210. 5. Marghoob AA, Usatine RP, Jaimes N. Dermoscopy for the family physician. Am Fam Physician. 2013;88(7):441–450. 6. Takenouchi T. Key points in dermoscopic diagnosis of basal cell carcinoma and seborrheic keratosis in Japanese. J Dermatol. 2011;38(1):59–65. 7. Wood LD, Stucki JK, Hollenbeak CS, et al. Effectiveness of cryosurgery vs curettage in the treatment of seborrheic keratoses. JAMA Dermatol. 2013;149(1):108–109.

ADDITIONAL READING • Culbertson GR. 532-nm diode laser treatment of seborrheic keratoses with color enhancement. Dermatol Surg. 2008;34(4):525–528. • Draelos ZD, Rizer RL, Trookman NS. A comparison of postprocedural wound

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care treatments: do antibiotic-based ointments improve outcomes? J Am Acad Dermatol. 2011;64(Suppl 3):S23–S29. • Garcia MS, Azari R, Eisen DB. Treatment of dermatosis papulosa nigra in 10 patients: a comparison trial of electrodesiccation, pulsed dye laser, and curettage. Dermatol Surg. 2010;36(12):1968–1972. • Georgieva IA, Mauerer A, Groesser L, et al. Low incidence of oncogenic EGFR, HRAS, and KRAS mutations in seborrheic keratosis. Am J Dermatopathol. 2014;36(8):635–642. • Hafner C, Vogt T. Seborrheic keratosis. J Dtsch Dermatol Ges. 2008;6(8):664–677. • Herron MD, Bowen AR, Krueger GG. Seborrheic keratoses: a study comparing the standard cryosurgery with topical calcipotriene, topical tazarotene, and topical imiquimod. Int J Dermatol. 2004;43(4):300–302. • Krupashankar DS. Standard guidelines of care: CO2 laser for removal of benign skin lesions and resurfacing. Indian J Dermatol Venereol Leprol. 2008;74(Suppl):S61–S67. • Rajesh G, Thappa DM, Jaisankar TJ, et al. Spectrum of seborrheic keratoses in South Indians: a clinical and dermoscopic study. Indian J Dermatol Venereol Leprol. 2011;77(4):483–488. • Taylor SC, Averyhart AN, Heath CR. Postprocedural wound-healing efficacy following removal of dermatosis papulosa nigra lesions in an African American population: a comparison of a skin protectant ointment and a topical antibiotic. J Am Acad Dermatol. 2011;64(3 Suppl):S30–S35.

CODES ICD10 • L82.1 Other seborrheic keratosis • L82.0 Inflamed seborrheic keratosis

CLINICAL PEARLS • Seborrheic keratoses are one of the most common benign tumors of the epidermis.

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• Prevalence increases with age. • Underlying internal malignancy should be considered if large numbers of seborrheic keratoses appear suddenly.

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KNEE PAIN Kimberly Sikule, MD • J. Herbert Stevenson, MD BASICS DESCRIPTION A common outpatient complaint with a broad differential • Knee pain may be acute, chronic, or an acute exacerbation of a chronic condition. • Trauma, overuse, and degenerative change are frequent causes. • A detailed history, including patient age, pain onset and location, mechanism of injury, and associated symptoms can help narrow the differential diagnosis. • A thorough and focused examination of the knee (as well as the back, hips, and ankles) helps to establish the correct diagnosis and appropriate treatment.

EPIDEMIOLOGY Incidence • Knee pain accounts for 1.9 million primary care visits annually. • The incidence of knee osteoarthritis is 240 cases/100,000 person/year.

Prevalence • The knee is a common site of lower extremity injury. – Patellar tendinopathy and patellofemoral syndrome are the most common causes of knee pain in runners (1). • Osteoarthritis (OA) of the hip/knee is 11th cause of global disability and 38th most common cause of disability-adjusted life years (DALYS)

ETIOLOGY AND PATHOPHYSIOLOGY • Trauma (ligament or meniscal injury, fracture, dislocation) • Overuse (tendinopathy, patellofemoral syndrome, bursitis, apophysitis) • Age (arthritis, degenerative conditions in older patients; apophysitis in younger patients) • Rheumatologic (rheumatoid arthritis [RA], gout, pseudogout) • Infectious (bacterial, postviral, Lyme disease)

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• Referred pain (hip, back) • Vascular: popliteal artery aneurysm, deep vein thrombosis • Others: tumor, cyst, plica

RISK FACTORS • Obesity • Malalignment • Poor flexibility, muscle imbalance, or weakness • Rapid increases in training frequency and intensity • Improper footwear, training surfaces, technique • Activities that involve cutting, jumping, pivoting, deceleration, kneeling • Previous injuries

GENERAL PREVENTION • Maintain normal body mass index. • Proper exercise technique, volume, and equipment; avoid overtraining. • Correct postural strength and flexibility imbalances.

COMMONLY ASSOCIATED CONDITIONS • Fracture, contusion • Effusion, hemarthrosis • Patellar dislocation/subluxation • Meniscal or ligamentous injury • Tendinopathy, bursitis • Osteochondral injury • OA, septic arthritis • Muscle strain

DIAGNOSIS HISTORY • Pain location, quality and mechanism of injury guide diagnostic reasoning (also see Differential Diagnosis): – Diffuse pain: OA, patellofemoral pain syndrome, chondromalacia – Pain ascending/descending stairs: meniscal injury, patellofemoral pain

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syndrome – Pain with prolonged sitting, standing from sitting: patellofemoral pain syndrome – Mechanical symptoms (locking): meniscal injury • Mechanism of injury: – Hyperextension, deceleration, cutting: anterior cruciate ligament (ACL) injury – Hyperflexion, fall on flexed knee, “dashboard injury”: posterior cruciate ligament (PCL) injury – Lateral force (valgus load): medial collateral injury – Twisting on planted foot: meniscal injury • Effusion: – Rapid onset (2 hours): ACL tear, patellar subluxation, tibial plateau fracture. Hemarthrosis is common. – Slower onset (24 to 36 hours), smaller: meniscal injury, ligament sprain – Swelling behind the knee: popliteal cyst. Prepatellar: bursitis.

PHYSICAL EXAM • Observe gait (antalgia), patellar tracking. • Inspect for malalignment, atrophy, swelling, ecchymosis, or erythema. • Palpate for effusion, warmth, and tenderness. • Evaluate active and passive range of motion (ROM) and flexibility of quadriceps and hamstrings. • Evaluate strength and muscle tone. • Note joint instability, locking, and catching. • Evaluate hip ROM, strength, and stability. • Special tests: – Patellar apprehension test: patellar instability. Patellar grind test: patellofemoral pain or OA (1) – Lachman test (more sensitive and specific), pivot shift, anterior drawer: ACL integrity – Posterior drawer, posterior sag sign: PCL integrity – Valgus/varus stress test: medial/lateral collateral ligament (MCL/LCL) integrity – McMurray test, Apley grind, Thessaly test: meniscal injury

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– Ober test: iliotibial band (ITB) tightness – Dial test: positive with posterolateral corner laxity – Patellar tilt test and squatting may help suggest patellofemoral pain syndrome, but there is not yet one definitive test. – Patella facet tenderness suggests OA or patellofemoral pain syndrome (1) [A].

DIFFERENTIAL DIAGNOSIS • Acute onset: fracture, contusion, cruciate or collateral ligament tear, meniscal tear, patellar dislocation/subluxation. If systemic symptoms: septic arthritis, gout, pseudogout, Lyme disease, osteomyelitis. • Insidious onset: patellofemoral pain syndrome/chondromalacia, ITB syndrome, OA, RA, bursitis, tumor, tendinopathy, loose body, bipartite patella, degenerative meniscal tear • Anterior pain: patellofemoral pain syndrome, patellar injury, patellar tendinopathy, pre- or suprapatellar bursitis, tibial apophysitis, fat pad impingement, quadriceps tendinopathy, OA (1) • Posterior pain: PCL injury, posterior horn meniscal injury, popliteal cyst or aneurysm, hamstring or gastrocnemius injury, deep venous thrombosis (DVT) • Medial pain: MCL injury, medial meniscal injury, pes anserine bursitis, medial plica syndrome, OA • Lateral pain: LCL injury, lateral meniscal injury, ITB syndrome, OA

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Suspected septic joint, gout, pseudogout: – Arthrocentesis with cell count, Gram stain, culture, protein/glucose, synovial fluid analysis • Suspected RA: – CBC, erythrocyte sedimentation rate (ESR), rheumatoid factor • Consider Lyme titer. • Radiographs to rule out fracture in patients with acute knee trauma (Ottawa rules): – Age >55 years or – Tenderness at the patella or fibular head or

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– Inability to bear weight 4 steps or – Inability to flex knee to 90 degrees • Radiographs help diagnose OA, osteochondral lesions, patellofemoral pain syndrome: – Weight bearing, upright anteroposterior, lateral, merchant/sunrise, notch/tunnel views Follow-Up Tests & Special Considerations • MRI is a “gold standard” for soft tissue imaging. • Ultrasound may help diagnose tendinopathy (2)[B]. • CT can further elucidate fracture.

Diagnostic Procedures/Other Arthroscopy may be beneficial in the diagnosis of certain conditions, including meniscus and ligament injuries.

Geriatric Considerations OA, degenerative meniscal tears, and gout are more common in middle-aged and elderly populations.

Pediatric Considerations • 3 million pediatric sports injuries occur annually. • Look for physeal/apophyseal and joint surface injuries in skeletally immature: – Acute: patellar subluxation, avulsion fractures, ACL tear – Overuse: patellofemoral pain syndrome, apophysitis, osteochondritis dissecans, patellar tendonitis, stress fracture – Others: neoplasm, juvenile RA, infection, referred pain from slipped capital femoral epiphysis

TREATMENT GENERAL MEASURES Acute injury: PRICEMM therapy (protection, relative rest, ice, compression, elevation, medications, modalities)

MEDICATION

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First Line • Oral medications: – Acetaminophen: up to 3 g/day. Safe and effective in OA. – Nonsteroidal anti-inflammatory drugs (NSAIDs): Ibuprofen: 200 to 800 mg TID Naproxen: 250 to 500 mg BID: Useful for acute sprains, strains Useful for short-term pain reduction in OA. Long-term use is not recommended due to side effects. Not recommended for fracture, stress fracture, chronic muscle injury; may be associated with delayed healing; low dose and brief course only if necessary – Tramadol/opioids: not recommended as first-line treatment; can be used with acute injuries for severe pain – Celecoxib: 200 mg QD may be effective in OA with less GI side effects than NSAIDs (3)[A]. • Topical medications: – Topical NSAIDs may provide pain relief in OA and are more tolerable than oral medications. – Topical capsaicin may be an adjuvant for pain management in OA. • Injections: – Intra-articular corticosteroid injection may provide short-term benefit in knee OA stage 2 or 3 (2)[A]. – Viscosupplementation may reduce pain and improve function in patients with OA (2)[A]. Peak effectiveness is 5 to 13 weeks. – Equivocal evidence for platelet-rich plasma (PRP) compared to viscosupplementation – Stem cell therapy with insufficient data

ISSUES FOR REFERRAL • Acute trauma, young athletic patient • Joint instability • Lack of improvement with conservative measures • Salter-Harris physeal fractures (pediatrics)

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ADDITIONAL THERAPIES • Physical therapy is recommended as initial treatment for patellofemoral pain (4) and tendinopathies (2)[A]. • Muscle strengthening improves outcome in OA. • Foot orthoses, taping, acupuncture • May need bracing for stability (4) • Botulinum toxin A for patellofemoral pain syndrome (5)[B]

SURGERY/OTHER PROCEDURES • Surgery may be indicated for certain injuries (e.g., ACL tear in competitive athletes or Grade IV OA). • Chronic conditions refractory to conservative therapy may require surgical intervention.

COMPLEMENTARY & ALTERNATIVE MEDICINE May reduce pain and improve function in early OA: • Glucosamine sulfate (500 mg TID) • Chondroitin (400 mg TID) • Turmeric or curcumin 1,000 mg/day (6) • Collagen hydrolysates 10 g daily • S-adenosylmethionine (SAMe), ginger extract, methylsulfonylmethane: less reliable improvement with inconsistent supporting evidence • Acupuncture: need to do 4 weeks or 10 sessions

ONGOING CARE FOLLOW-UP RECOMMENDATIONS • Activity modification in overuse conditions • Rehabilitative exercise in OA: – Low-impact exercise: walking, swimming, cycling – Strength, ROM, and proprioception training

Patient Monitoring • Rehabilitation after initial treatment of acute injury • In chronic and overuse conditions, assess functional status, rehabilitation

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adherence, and pain control at follow-up visit.

DIET Weight reduction by 10% improved function by 28%.

PATIENT EDUCATION • Review activity modifications. • Encourage active role in the rehabilitation process. • Review medication risks and benefits.

PROGNOSIS Varies with diagnosis, injury severity, chronicity of condition, patient motivation to participate in rehabilitation, and whether surgery is required

COMPLICATIONS • Disability • Arthritis • Chronic joint instability • Deconditioning

REFERENCES 1. Hong E, Kraft MC. Evaluating anterior knee pain. Med Clin North Am. 2014;98(4):697–717. 2. Ayhan E, Kesmezacar H, Akgun I. Intraarticular injections (corticosteroid, hyaluronic acid, platelet rich plasma) for the knee osteoarthritis. World J Orthop. 2014;5(3):351–361. 3. Bijlsma JW, Berenbaum F, Lafeber FP. Osteoarthritis: an update with relevance for clinical practice. Lancet. 2011;377(9783):2115–2126. 4. Bolgla LA, Boling MC. An update for the conservative management of patellofemoral pain syndrome: a systematic review of the literature from 2000 to 2010. Int J Sports Phys Ther. 2011;6(2):112–125. 5. Chen JT, Tang AC, Lin SC, et al. Anterior knee pain caused by patellofemoral pain syndrome can be relieved by Botulinum toxin type A injection. Clin Neurol Neurosurg. 2015;129(Suppl 1):S27–S29. 6. Cross M, Smith E, Hoy D, et al. The global burden of hip and knee

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osteoarthritis: estimates from the global burden of disease 2010 study. Ann Rheum Dis. 2014;73(7):1323–1330.

ADDITIONAL READING • Collins NJ, Bisset LM, Crossley KM, et al. Efficacy of nonsurgical interventions for anterior knee pain: systematic review and meta-analysis of randomized trials. Sports Med. 2012;42(1):31–49. • Lopes AD, Hespanhol Júnior LC, Yeung SS, et al. What are the main runningrelated musculoskeletal injuries? A systematic review. Sports Med. 2012;42(10):891–905. • Nunes GS, Stapait EL, Kirsten MH, et al. Clinical test for diagnosis of patellofemoral pain syndrome: systematic review with meta-analysis. Phys Ther Sport. 2013;14(1):54–59. • Ziltener JL, Leal S, Fournier PE. Non-steroidal anti-inflammatory drugs for athletes: an update. Ann Phys Rehabil Med. 2010;53(4):278–282.

SEE ALSO Algorithms: Knee Pain; Popliteal Mass

CODES ICD10 • M25.569 Pain in unspecified knee • M17.9 Osteoarthritis of knee, unspecified • M76.50 Patellar tendinitis, unspecified knee

CLINICAL PEARLS • A careful history (location/quality of pain and mechanism of injury) targets diagnosis for most causes of knee pain. • Consider ligamentous injury, meniscal tear, and fracture for patients presenting with acute knee pain. • Consider OA, patellofemoral pain syndrome, tendinopathy, bursitis, and stress

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fracture in patients presenting with more chronic symptoms. • Consider physeal, apophyseal, or articular cartilage injury in young patients presenting with knee pain. • The presence of an effusion in a patient 50 g elicit symptoms in most individuals.

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• Symptoms may arise 30 minutes to 2 hours after consumption of lactosecontaining products. • Symptoms include bloating, cramping, abdominal discomfort, vomiting diarrhea or loose stools, and flatulence. • Symptoms tend to appear 30 minutes to 2 hours after eating. • Abdominal pain may be crampy in nature and often is localized to the periumbilical area or lower quadrant. • Stools usually are bulky, frothy, and watery • Only 1/3 to 1/5 of individuals with lactose malabsorption develop symptoms.

PHYSICAL EXAM Borborygmi may be audible on physical examination and to the patient. The exam is otherwise typically nonspecific.

DIFFERENTIAL DIAGNOSIS • Sucrase deficiency • Cow’s milk protein allergy • IBS • Bacterial overgrowth • Celiac disease • Inflammatory bowel disease

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • The lactose breath hydrogen test (LBT) is the best diagnostic test for lactose intolerance. It is noninvasive, easy to perform, and cost effective. It is limited by suboptimal sensitivity (2)[B]. Intestinal bacteria digest carbohydrates and produce hydrogen and methane that are measurable in expired air: – Oral lactose is administered in the fasting state, (2 g/kg; max dose 25 g). Breath hydrogen is sampled at baseline and at 30-minute intervals for 3 hours. The postlactose and baseline values are compared. A breath hydrogen value of 10 ppm is normal. Values between 10 and 20 ppm may be indeterminate unless accompanied by symptoms; values >20 ppm are considered diagnostic of lactose malabsorption. • The biochemical assay of lactase activity on duodenal sampling is as sensitive

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as LBT in detecting lactase deficiency. It is more accurate than LBT in predicting the clinical response to a lactose-free diet. Cost and invasiveness limit clinical utility • For patients with symptoms of lactose intolerance who are undergoing endoscopy for other reasons, a biochemical assay on duodenal biopsies can rule out lactose malabsorption. • A positive LBT confirms lactose malabsorption but does not define the etiology.

Diagnostic Procedures/Other Lactose absorption test is an alternative to LBT in adults (more invasive and equivalent in sensitivity and specificity to breath test). Following oral administration of a 50-g test dose in adults (2 g/kg in children), blood glucose levels are monitored at 0, 60, and 120 minutes. An increase in blood glucose of 2 weeks in adults with history of smoking or alcohol abuse to rule out malignancy • pH probe (24-hour): no difference in incidence of pharyngeal reflux as measured by pH probe between patients with chronic reflux laryngitis and

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healthy adults (2)[A] • Strobovideo laryngoscopy for diagnosis of subtle lesions (e.g., vocal cord nodules or polyps)(4)[A]

TREATMENT • Limited but good evidence that treatment beyond supportive care is ineffective (4)[A] • Supportive care consists of hydration, voice rest, humidification, and limitation of caffeine (1)[A]. • Antibiotics appear to have no benefit, as etiologies are predominantly viral (1,5)[A]. • Corticosteroids in severe cases of laryngitis to reduce inflammation such as croup • May need voice training, if voice overuse • Nebulized epinephrine reduces croup symptoms 30 minutes posttreatment; evidence does not favor racemic epinephrine or L-epinephrine or IPPB over simple nebulization. Racemic epinephrine reduces croup symptoms at 30 minutes, but effect lasts only 2 hours (5)[A].

GENERAL MEASURES • Acute: – Usually a self-limited illness lasting 2 to 3 weeks) or concern for foreign

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body • Consider otolaryngologic evaluation and biopsy for laryngitis lasting >3 weeks in adults, especially in those with history of smoking or alcohol abuse to rule out malignancy. • Consider GI consult to rule out GERD/LPRD.

SURGERY/OTHER PROCEDURES • Vocal cord biopsy of hyperplastic mucosa and areas of leukoplakia if cancer or TB is suspected • Removal of nodules or polyps if voice therapy fails

COMPLEMENTARY & ALTERNATIVE MEDICINE The following, although not well studied, have been recommended by some experts: • Barberry, black currant, Echinacea, Eucalyptus, German chamomile, goldenrod, goldenseal, warmed lemon and honey, licorice, marshmallow, peppermint, saw palmetto, slippery elm, vitamin C, zinc

ONGOING CARE PATIENT EDUCATION • Educate on the importance of voice rest, including whispering. • Provide assistance with smoking cessation. • Help the patient with modification of other predisposing habits or occupational hazards.

PROGNOSIS Complete clearing of the inflammation without sequelae

COMPLICATIONS Chronic hoarseness

REFERENCES 1. Wood JM, Athanasiadis T, Allen J. Laryngitis. BMJ. 2014;349:g5827. 2. Pratt MP, Brook CD, Kuperstock J, et al. What role does allergy play in

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chronic ear disease and laryngitis? Curr Allergy Asthma Rep. 2016;16(10):76. 3. Hamdan AL, Sarieddine D. Laryngeal manifestations of rheumatoid arthritis. Autoimmune Dis. 2013;2013:103081. 4. Reiter R, Hoffmann TK, Pickhard A, et al. Hoarseness—causes and treatments. Dtsch Arztebl Int. 2015;112(19):329–337. 5. Reveiz L, Cardona AF. Antibiotics for acute laryngitis in adults. Cochrane Database Syst Rev. 2015;(5):CD004783.

CODES ICD10 • J04.0 Acute laryngitis • J37.0 Chronic laryngitis • J04.2 Acute laryngotracheitis

CLINICAL PEARLS • Laryngitis is usually self-limited and needs only comfort care. Standard treatment is voice rest, hydration, humidification, and limit caffeine intake. • Refer to ENT for direct visualization of vocal cords for prolonged laryngitis. • Corticosteroids have some benefits for children with moderately severe croup. • Voice training useful for chronic laryngitis

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LAXATIVE ABUSE Matthew E. Bryant, MD BASICS DESCRIPTION • A chronic watery diarrhea caused by intentional or unintentional misuse of laxatives due to self-medication or provider error • System(s) affected: gastrointestinal, nervous, psychiatric, skin, and renal • Synonym(s): factitious diarrhea; cathartic colon; as part of Münchausen syndrome (self or by proxy)—most dramatic form

EPIDEMIOLOGY • Predominant age: 18 to 40 years associated with bulimia or anorexia nervosa • Common in the elderly as a result of treatment for constipation, either by health care professional or self-directed (unintentional) • Associated with athletes in sports with weight limits (wrestling) • Predominant sex (intentional abuse): female (90%) > male • More common in upper socioeconomic classes

Prevalence Laxative abuse in different groups • 0.7–5.5% in the general population • As many as 15% undergoing evaluation for chronic diarrhea • Unexplained chronic diarrhea after routine investigations: 4–7% • Up to 70% of patients with binging/purging anorexia and bulimia nervosa abuse laxatives but rarely as the sole method of purging. • Chronic use of constipating medications (opioids)

Pediatric Considerations Children may be given excess laxatives by caregivers (Münchausen syndrome by proxy).

Geriatric Considerations Elderly in nursing homes are at increased risk for laxative overuse (usually

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inadvertent).

ETIOLOGY AND PATHOPHYSIOLOGY • Four types of chronic diarrhea: secretory, osmotic, inflammatory, and fatty. Rule out other causes, laxative abuse is a diagnosis of exclusion (1). • Chronic ingestion of any laxative agent – Stimulant (most common, rapid onset of action) Diphenylmethane (Bisacodyl) Anthraquinones (Senna, Cascara, Castor oil) – Saline and osmotic products (sodium phosphate, magnesium sulfate/citrate and hydroxide, lactulose, polyethylene glycol) – Bulking agents (psyllium) – Surfactants (docusate) • Psychologic factors – Bulimia or anorexia nervosa (associated with behavioral pathology) – Secondary gain (attention-seeking): disability claims or need for concern, caring from others – Inappropriate perceptions of “normal” bowel habits

RISK FACTORS In patients with eating disorders • Longer duration of illness • Comorbid psychiatric diagnoses (e.g., major depression, obsessivecompulsive disorder, posttraumatic stress disorder, anxiety, borderline personality disorder) • Early age of eating disorder symptoms

GENERAL PREVENTION • Educate patients about proper nutrition, normal bowel function, potential adverse effects of excessive laxative use, and medications (e.g., magnesiumcontaining antacids) that can cause diarrhea. • Ask patients specifically about laxative use; inadvertent overuse is common.

COMMONLY ASSOCIATED CONDITIONS • Anorexia nervosa, bulimia nervosa • Use of constipating medications (opioids, iron supplements).

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• Any chronic disorder associated with constipation • Depression and anxiety • Borderline personality • Self-injurious behaviors/suicidal ideation • Impulsive behavior • Münchausen syndrome/Münchausen syndrome by proxy (children) may have associated factitious symptoms involving diverse organ systems. • Fictitious disorders • Patient is dependent on a caregiver.

DIAGNOSIS HISTORY • Suspect in patients with undiagnosed, refractory chronic diarrhea. • Assess over-the-counter medication use, and take thorough dietary history (2). • Signs and symptoms: increasing frequency of bowel movements; large volume, watery diarrhea; nocturnal bowel movements (typically absent in osmotic diarrhea or in irritable bowel syndrome) (2,3). • Additional symptoms: abdominal pain, rectal pain, nausea, vomiting, weight loss, malaise, muscle weakness, or chronic constipation. • Assess “doctor shopping” and potential factitious symptoms.

PHYSICAL EXAM • No specific findings but may include cachexia, evidence of dehydration, abdominal pain or distension, and edema; fever may be due to self-infected wounds or thermometer manipulation (2). • Bulimics or anorexics who purge may have Russell sign (excoriation of fingers from repeated self-induced retching) (4); clubbing, cyclic edema, skin pigmentation changes, parotid hypertrophy • Rarely, severe cases may be associated with renal failure, cardiac arrhythmias, skeletal muscle paralysis, anemia from blood-letting or self-induced skin wounds.

DIFFERENTIAL DIAGNOSIS Any etiology of chronic diarrhea, especially in high-risk groups

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DIAGNOSTIC TESTS & INTERPRETATION If patient has not had an initial workup for chronic diarrhea, rule out infectious, inflammatory, and malignant causes based on patient demographics and risk factors.

Initial Tests (lab, imaging) • Serum electrolytes hypokalemia, hypernatremia, hyperphosphatemia – Acute diarrhea: metabolic acidosis (hypovolemia) – Chronic diarrhea: metabolic alkalosis secondary to hypokalemia-induced inhibition of chloride uptake with inhibited bicarbonate secretion • CBC, stool cultures, Clostridium difficile polymerase chain reaction (PCR) to rule out infectious cause if history is suspicious (fecal leukocytes, ova and parasites (O&P)—check for giardia, isospora, and cryptosporidia specifically) (2,3). • Colonoscopy, small-bowel endoscopy, or imaging studies are not usually necessary but help to evaluate other causes of chronic diarrhea (2). • Melanosis coli on sigmoidoscopy or colonoscopy indicate overuse of anthracene laxatives. Follow-Up Tests & Special Considerations The following algorithm can be used to confirm diagnosis and determine what laxative is being used (1,5)[B]. • Collect 24-hour stool: If stool is solid, workup is over. • Obtain stool osmolality, stool electrolytes, and calculate osmolal gap [−290 −2 (Na+ + K+)], Na+ and K+ are stool concentrations. – If osmolality >400 mOsm/kg, rule out urine contamination of stool. Measure urea and creatinine of sample. – If osmolality 50: unmeasured solute; check fecal fat and stool magnesium levels. Gap female (1:1 in childhood)

Prevalence • Centers for Disease Control and Prevention (CDC) estimates half a million U.S. children aged 1 to 5 years have blood Pb levels >5 μg/dL, but levels are variable among communities and populations. • Case prevalence rate blood Pb level ≥10 μg/dL is 22.5 per 100,000 employed adults, CDC 2012 data

ETIOLOGY AND PATHOPHYSIOLOGY • Inhalation of Pb dust or fumes, or ingestion of Pb • Pb replaces calcium in bones. Pb interferes with heme synthesis, causes interstitial nephritis, and interferes with neurotransmitters, especially glutamine; high levels affect blood–brain barrier and lead to encephalopathy, seizures, and coma. • Early life Pb exposure causes methylation changes leading to epigenetic alterations that may lead to brain dysfunction.

RISK FACTORS • Children with pica or with iron-deficiency anemia • Residence in or frequent visitor to deteriorating pre-1960 housing with Pbpainted surfaces or recent renovation • Soil/dust exposure near older homes, Pb industries, or urban roads

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• Sibling or playmate with current or past Pb poisoning • Dust from clothing of Pb worker or hobbyist • Pb dissolved in water from Pb or Pb-soldered plumbing (Example: Flint Michigan 2014 to 2015) • Pb-glazed ceramics especially with acidic food or drink • Recent refugee • Folk remedies and cosmetics – Mexico: Azarcon, Greta – Dominican Republic: Litargirio, a topical agent – Asia and Middle East: Chuifong tokuwan, pay-loo-ah, ghasard, bali goli, kandu, ayurvedic herbal medicine from South Asia, kohl (alkohl, ceruse), surma, saoott, cebagin • Hobbies: glazed pottery making, target shooting, Pb soldering, preparing Pb shot or fishing sinkers, stained-glass making, car or boat repair, home remodeling • Occupational exposure: plumbers, pipe fitters, Pb miners, auto repairers, glass manufacturers, shipbuilders, printer operators, plastic manufacturers, Pb smelters and refiners, steel welders or cutters, construction workers, rubber product manufacturers, battery manufacturers, bridge reconstruction workers • Dietary: zinc or calcium deficiency • Imported toys with Pb

Pediatric Considerations • Children are at increased risk because of incomplete development of the blood–brain barrier at 5 μg/dL (0.24 μmol/L) collected with Pb-free container • Use a laboratory that can achieve routine performance within 2 μg/dL. • In 2012, CDC recommended using a reference value as the basis for management, currently >5 μg/dL • Screening capillary Pb levels >5 μg/dL (0.24 μmol/L) should be confirmed with a venous sample. • Hemoglobin and hematocrit slightly low; eosinophilia or basophilic stippling on peripheral smear may be seen but is not diagnostic of Pb toxicity. • Renal function is decreased in late stages. • Abdominal radiograph for Pb particles in gut if recent ingestion is suspected • Radiograph of long bones may show lines of increased density in the metaphyseal plate resulting from growth arrest but does not usually alter management and is not routinely recommended. • X-ray fluorescence for the total body burden of Pb is experimental.

TREATMENT Blood level (μg/dL) ≥ref value–9 10–44 45–59 60–69 ≥70

Time to confirmation testing 1–3 months 1 week–1 month 48 hours 24 hours Urgently as emergency test

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ALERT • For any blood Pb levels persistently >15 μg/dL, contact local public health department for home inspection. • If Pb level is between 5 and 45 μg/dL, the higher the Pb level, the more urgent the need for confirmation testing. • For all elevated levels: Educate family on sources of Pb. • Pb level > ref level to 70: Hospitalize for chelation therapy (4)[C].

MEDICATION • Consider oral chelation for asymptomatic and Pb >45 and 70 or symptomatic Pb 35 μg/dL • Outpatient care unless parenteral chelation or immediate removal from

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contaminated environment is required. • If Pb source is in the home, the patient must reside elsewhere until the abatement process is completed. • Avoid visit to any site of potential contamination.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • After chelation, check for rebound Pb level in 7 to 10 days. Follow with regular monitoring, initially biweekly or monthly. • Correct iron deficiency or any other nutritional deficiencies present. • Once Pb 60 to 65 years of age) remain a therapeutic challenge. These patients are offered so-called reduced-intensity or nonmyeloablative BMT. • Adding growth factors (granulocyte-colony stimulating factor [G-CSF]) may reduce toxicity in older patients (but is not broadly accepted). • Hypomethylating agent, such as 5-azacitidine, significantly prolongs survival in older adults with low marrow blast count (65 years of age) remains a challenge. These patients have poor performance status, more likely secondary AML, higher incidence of unfavorable cytogenetics, comorbidities, shorter remissions, and shorter overall survival. – Intensive chemotherapy may be feasible for patients with good performance status; alternative regimens with mitoxantrone, fludarabine, and clofarabine. New drugs (hypomethylating agents as above, FLT3 inhibitors, monoclonal antibodies, etc.) are being studied in clinical trials (5)[A]. • Contraindications: comorbidities; therapy has to be individualized. • Precautions – If organ failure, some drugs may be avoided or dose reduced (e.g., no anthracyclines in patients with preexisting cardiac problems). – Patients will be immunosuppressed during treatment. Avoid live vaccines. Administer varicella-zoster or measles immunoglobulin as soon as exposure of patient occurs. • Significant possible interactions: Allopurinol accentuates the toxicity of 6mercaptopurine.

Second Line Healthy, younger patients usually are offered reinduction chemotherapy and allogeneic BMT.

ISSUES FOR REFERRAL • AML should be managed by specialized team led by a hematologist/oncologist. • Refer patient to a transplant center early because a search for a donor may be necessary.

SURGERY/OTHER PROCEDURES • BMT: Decision between myeloablative and nonmyeloablative approach should be based on patient’s performance status, comorbidities, and AML risk

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factors. – Allogeneic BMT is usually indicated in first remission in intermediate- or high-risk AML or in second remission in all other AML patients. Matched related donor used to be preferred over matched unrelated donor (lower risk of graft-versus-host disease); recent data suggest equal outcomes, as allogeneic transplant regimens and posttransplant care have improved significantly. • Haploidentical transplants and cord blood have emerged as alternative sources of hematopoietic stem cells for adults that show comparable outcomes as well. • Autologous BMT may be acceptable in specific situations (e.g., no donor is available).

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Induction treatment for AML requires inpatient care, usually on a specialized ward. Episodes of febrile neutropenia typically require admission and IV antibiotics. • Appropriate hydration to prevent TLS • IV may lead to chemical burns in the event of extravasation.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Ambulatory, as tolerated; no intense or contact sports; no aspirin due to risk of bleeding

Patient Monitoring • Repeat bone marrow studies to document remission and also if a relapse is suspected. • Follow CBC with differential, coagulation studies, uric acid level, and other chemistries related to TLS (creatinine, potassium, phosphate, calcium); monitor urinary function at least daily during induction phase and less frequently later. • Physical evaluation, including weight and BP, should be done frequently

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during treatment.

DIET Ensure adequately balanced calorie/vitamin intake. Total parenteral nutrition (TPN) in case of severe mucositis

PATIENT EDUCATION • Leukemia Society of America, 600 Third Avenue, New York, NY 10016, 212573-8484 • National Cancer Institute, Bethesda, MD, has pamphlets and telephone education. • Baker LS. You and Leukemia: A Day at a Time. Philadelphia, PA: Saunders; 1978.

PROGNOSIS AML remission rate is 60–80%, with only 20–40% long-term survival. The wide variable prognosis is due to prognostic group (age, cytogenetics, and genetics).

COMPLICATIONS • Acute side effects of chemotherapy, including febrile neutropenia • TLS • DIC • Late-onset cardiomyopathy in patients treated with anthracyclines • Chronic side effects of chemotherapy (secondary malignancies) • Graft-versus-host disease in patients who have received allogeneic BMT

REFERENCES 1. Döhner H, Estey EH, Amadori S, et al. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood. 2010;115(3):453–474. 2. Patel JP, Gönen M, Figueroa ME, et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N Engl J Med. 2012;366(12):1079–1089. 3. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-

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risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol. 2009;10(3):223–232. 4. Koreth J, Schlenk R, Kopecky KJ, et al. Allogeneic stem cell transplantation for acute myeloid leukemia in first complete remission: systematic review and meta-analysis of prospective clinical trials. JAMA. 2009;301(22):2349– 2361. 5. Fenaux P, Mufti GJ, Hellström-Lindberg E, et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol. 2010;28(4):562–569.

ADDITIONAL READING O’Donnell MR, Appelbaum FR, Coutre SE, et al. Acute myeloid leukemia. J Natl Compr Canc Netw. 2008;6(10):962–993.

SEE ALSO Disseminated Intravascular Coagulation; Leukemia, Acute Lymphoblastic in Adults (ALL); Leukemia, Chronic Myelogenous; Myelodysplastic Syndromes; Myeloproliferative Neoplasms

CODES ICD10 • C92.00 Acute myeloblastic leukemia, not having achieved remission • C92.01 Acute myeloblastic leukemia, in remission • C92.02 Acute myeloblastic leukemia, in relapse

CLINICAL PEARLS • Prognosis of leukemia depends on the cytogenetic and molecular profile of the disease. • Allogeneic transplant remains the only therapy with curative potential for patients with intermediate- and high-risk AML.

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LEUKEMIA, CHRONIC LYMPHOCYTIC Jan Cerny, MD, PhD • Amy E. Pratt, DO BASICS DESCRIPTION • Chronic lymphocytic leukemia (CLL) is a monoclonal disorder characterized by a progressive accumulation of mature but functionally incompetent lymphocytes. • CLL should be distinguished from prolymphocytic leukemia (PLL); based on percentage of prolymphocytes, the disease may be regarded as CLL (55% prolymphocytes), or CLL/PLL (>10% and 55 years. • Predominant sex: male > female (1.7:1) • The incidence is higher among Caucasians than among African Americans.

ETIOLOGY AND PATHOPHYSIOLOGY • The cell of origin in CLL is a clonal B cell arrested in the B-cell differentiation pathway, intermediate between pre–B cells and mature B cells. In the peripheral blood, these cells resemble mature lymphocytes and typically show B-cell surface antigens: CD19, CD20, CD21, and CD23. In addition, they express CD5 (usually found on T cells).

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• The bcl2 proto-oncogene is overexpressed in B-CLL. Bcl2 is a known suppressor of apoptosis (programmed cell death), resulting in extremely long life of the affected lymphocytes. – Genetic mutations leading to disrupted function and prolonged survival of affected lymphocytes are suspected but unknown.

Genetics CLL is an acquired disorder, and reports of truly familial cases are exceedingly rare. CLL has been shown, however, to occur at higher frequency among firstdegree relatives of patients with the disease, and several somatic gene mutations have been identified at significantly higher rates among CLL patients.

RISK FACTORS • As in the case of most malignancies, the exact cause of CLL is uncertain. • Possible chronic immune stimulation is suspected but is still being evaluated. • Monoclonal B-cell lymphocytosis: 1% risk progression to CLL.

GENERAL PREVENTION Unknown

COMMONLY ASSOCIATED CONDITIONS • Immune system dysregulation is common. • Conditions that may accompany CLL: – Autoimmune hemolytic anemia (AIHA) – Immune thrombocytopenia purpura (ITP) – Pure red cell aplasia (PRCA)

DIAGNOSIS HISTORY • Insidious onset. It is not unusual for CLL to be discovered incidentally (up to 40% of patients are asymptomatic at the time of diagnosis). • Others may have the following symptoms: – B symptoms: fevers, night sweats, >10% weight loss – Fatigue and/or other symptoms of anemia – Enlarged lymph nodes (lymphadenopathy = LAD)

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– Mucocutaneous bleeding and/or petechiae – Early satiety and/or abdominal discomfort related to an enlarged spleen – Recurrent infection(s)

PHYSICAL EXAM • Lymphadenopathy, localized or generalized • Organomegaly (splenomegaly, hepatomegaly) • Mucocutaneous bleeding (thrombocytopenia) • Skin: petechiae (thrombocytopenia), pallor (anemia), rash (leukemia cutis)

DIFFERENTIAL DIAGNOSIS • Infectious: – Bacterial (tuberculosis, pertussis) – Viral (mononucleosis) • Neoplastic: – Leukemic phase of non-Hodgkin lymphomas – Hairy cell leukemia – PLL – Large granular lymphocytic leukemia – Waldenstrom macroglobulinemia

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (labs, imaging) • CBC with differential: B cell absolute lymphocytosis with >5,000 B lymphocytes/μL; often also shows anemia and/or thrombocytopenia • Blood smear: ruptured lymphocytes (“smudge” cells) and morphologically small mature-appearing lymphocytes • Confirm diagnosis with immunophenotyping: CLL cells are positive for CD19, CD20, CD23, and CD5; low levels of surface membrane immunoglobulin (Ig)—either IgM or IgM&D; only a single Ig light chain is expressed (κ or λ) confirming monoclonality. • Additional labs: – Hemolysis labs (in cases associated with high disease activity or AIHA): high LDH and indirect bilirubin, low haptoglobin, +/− elevated reticulocyte count (bone marrow infiltration)

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– High plasma β2-microglobulin (poor prognosis) – Hypogammaglobulinemia • Liver/spleen ultrasound: may demonstrate organomegaly and enlarged abdominal lymph nodes • CT scan of chest/abdomen/pelvis: not necessary for staging but may identify compression of organs or internal structures from enlarged lymph nodes • Positron emission tomography (PET) scan: not recommended unless Richter transformation suspected and biopsy necessary (see “Prognosis”) Follow-Up Tests & Special Considerations Frequency and type of follow-up depend on severity of symptoms as well as risk factors (see “Prognosis”).

Diagnostic Procedures/Other • Bone marrow biopsy: has prognostic value (diffuse infiltration is a risk factor) but not performed routinely • Lymph node biopsy: Consider if lymph node(s) begins to rapidly enlarge in a patient with known CLL to assess the possibility of transformation to a highgrade lymphoma (Richter syndrome), especially when accompanied by fever, weight loss, and painful LAD.

Test Interpretation • Bone marrow biopsy aspirate usually shows >30% lymphocytes. • Cytogenetics (fluorescence in situ hybridization) may show chromosomal changes, which are prognostic: – Unfavorable: del(17p), del(11q) – Neutral: normal, trisomy 12 – Favorable: del(13q), del(6q)

TREATMENT GENERAL MEASURES Patients with CLL with frequent infections associated with hypogammaglobulinemia are likely to benefit from infusions of intravenous immunoglobulin (IVIG).

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MEDICATION First Line • Standard of care for new diagnosis with no symptoms or early stage disease: observation • Standard of care for new diagnosis with symptoms (B symptoms, symptomatic anemia and/or thrombocytopenia, AIHA and/or thrombocytopenia poorly responsive to corticosteroids, progressive organomegaly) or progressive lymphocytosis (increase >50% in 2 months or a doubling time of 40 years old with peak in the 60s. • Males twice as often as females

Geriatric Considerations Malignant transformation to carcinoma is more common in older patients.

ETIOLOGY AND PATHOPHYSIOLOGY Hyperkeratosis or dyskeratosis of the oral squamous epithelium • Tobacco use in any form • Alcohol consumption/alcoholism • Periodontitis • Candida albicans infection may induce dysplasia and increase malignant transformation. • Human papillomavirus, types 11 and 15 • Sunlight • Vitamin deficiency • Syphilis • Dental restorations/prosthetic appliances

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• Estrogen therapy • Chronic trauma or irritation • Epstein-Barr virus (oral hairy leukoplakia) • Areca nut/betel (Asian populations) • Mouthwash preparations and toothpaste containing the herbal root extract sanguinaria

Genetics • Dyskeratosis congenital and epidermolysis bullosa increase the likelihood of oral malignancy • P53 overexpression correlates with leukoplakia and particularly squamous cell carcinoma

RISK FACTORS • 70–90% of oral leukoplakia is related to tobacco, particularly smokeless tobacco or areca/betel nut use. • Alcohol increases risk 1.5-fold. • Repeated or chronic mechanical trauma from dental appliances or cheek biting • Chemical irritation to oral regions • Diabetes • Age • Socioeconomic status • Risk factors for malignant transformation of leukoplakia – Female – Long duration of leukoplakia – Nonsmoker (idiopathic leukoplakia) – Located on tongue or floor of mouth – Size >200 mm2 – Nonhomogenous type – Presence of epithelial dysplasia

GENERAL PREVENTION • Avoid tobacco of any kind, alcohol, habitual cheek biting, tongue chewing. • Use well-fitting dental prosthesis. • Regular dental check-ups to avoid bad restorations

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• Diet rich in fresh fruits and vegetables may help to prevent cancer. • HPV vaccination may be preventive.

COMMONLY ASSOCIATED CONDITIONS • HIV infection is closely associated with hairy leukoplakia. • Erythroplakia in association with leukoplakia, “speckled leukoplakia,” or erythroleukoplakia is a marker for underlying dysplasia.

DIAGNOSIS Leukoplakia is an asymptomatic white patch on the oral mucosa.

HISTORY • Usually asymptomatic • History of tobacco or alcohol use or oral exposure to irritants

PHYSICAL EXAM • Location – 50% on tongue, mandibular alveolar ridge, and buccal mucosa – Also seen on maxillary alveolar ridge, palate, and lower lip – Infrequently seen on floor of the mouth and retromolar areas – Floor of mouth, ventrolateral tongue, and soft palate complex are more likely to have dysplastic lesions. • Appearance – Varies from homogeneous, nonpalpable, faintly translucent white areas to thick, fissured, papillomatous, indurated plaques – May feel rough or leathery – Lesions can become exophytic or verruciform. – Color may be white, gray, yellowish white, or brownish gray. – Cannot be wiped or scraped off • World Health Organization classification – Homogeneous refers to color Flat, corrugated, wrinkled, or pumice – Nonhomogeneous refers to color and texture (more likely to be dysplastic or malignant).

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Erythroleukoplakia (mixture of red and white) Exophytic: papillary or verrucous texture

DIFFERENTIAL DIAGNOSIS • White oral lesions that can be wiped away: acute pseudomembranous candidiasis • White oral lesions that cannot be rubbed off: – Morsicatio buccarum (habitual cheek-biting), generally benign – Chemical injury – Acute pseudomembranous candidiasis – Traumatic or frictional keratosis (e.g., linea alba) – Leukoedema (benign milky opaque lesions that disappear with stretching) – Aspirin burn (from holding aspirin in cheek) – Lichen planus (bilateral fairly symmetric lesions, reticular pattern of slightly raised gray-white lines) – Lichenoid reaction – Verrucous carcinoma – Discoid lupus erythematosus – Skin graft (known history) – Squamous cell carcinoma – Oral hairy leukoplakia, commonly on the lateral border of the tongue with a bilateral distribution (in HIV patients with Epstein-Barr virus infection) – Smoker’s palate (leukokeratosis nicotina palati) – White sponge nevus (congenital benign spongy lesions) – Syphilitic oral lesion – Dyskeratosis congenita (a rare inherited multisystem disorder)

DIAGNOSTIC TESTS & INTERPRETATION Biopsy is the gold standard.

Initial Tests (lab, imaging) • Laboratory tests generally are not indicated. – Consider saliva culture if C. albicans infection is suspected. • No imaging is indicated. Follow-Up Tests & Special Considerations

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• Biopsy is necessary to rule out carcinoma if lesion is persistent, changing, or unexplained. • Consider CBC, rapid plasma reagin (RPR).

Diagnostic Procedures/Other • Oral cytology is superior to conventional oral examination (1)[A]. • Computer-assisted cytology or liquid-based cytology is not superior to oral cytology (1)[A]. • Noninvasive brush biopsy and analysis of cells with DNA–image cytometry constitute a sensitive and specific screening method. • Patients with dysplastic or malignant cells on brush biopsy should undergo more formal excisional biopsy. • Excisional biopsy is definitive procedure.

Test Interpretation • Biopsy specimens range from hyperkeratosis to invasive carcinoma. • At initial biopsy, 6% are invasive carcinoma. • 0.13–6% subsequently undergo malignant transformation. • Location is important: 60% on floor of mouth or lateral border of tongue are cancerous; buccal mucosal lesions are generally not malignant but require biopsy if not resolving.

TREATMENT • All oral leukoplakias should be treated. • Treatment may include the following: – For 2 to 3 circumscribed lesions, surgical excision – For multiple or large lesions where surgery would cause unacceptable deformity, consider cryosurgery or laser surgery (2)[C]. – Removal of predisposing habits (alcohol and tobacco) • Complete excision is standard treatment for dysplasia or malignancy. • After treatment, up to 30% of leukoplakia recurs, and some leukoplakia still transforms to squamous cell carcinoma (2)[B]. • Oral hairy leukoplakia may be treated with podophyllin with acyclovir cream.

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GENERAL MEASURES • Eliminate habitual lip biting. • Correct ill-fitting dental appliances, bad restorations, or sharp teeth. • Stop smoking and using alcohol. • Some small lesions may respond to cryosurgery. • β-Carotene, lycopene, retinoids, and cyclooxygenase 2 (COX-2) inhibitors may cause partial regression. • For hairy tongue: tongue brushing

MEDICATION Carotenoids; vitamins A, C, and K; bleomycin, and photodynamic therapy ineffective to prevent malignant transformation and recurrence

ISSUES FOR REFERRAL Consider otolaryngologist or oral surgery referral for extensive disease.

SURGERY/OTHER PROCEDURES • Scalpel excision, laser ablation, electrocautery, or cryoablation • Cryotherapy slightly less effective than photodynamic therapy response (73% vs. 90%) and recurrence (27% vs. 24%) (3)[A] • CO2 laser had 20% recurrence and 10% malignant transformation within 5 years (4)[B].

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Eliminate etiologic factors. • Reevaluate in 7 to 14 days. • Biopsy if lesion is persistent.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Regular, close follow-up, even after successful treatment • Biopsy as needed

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DIET Regular

PATIENT EDUCATION • If biopsy is negative, stress importance of periodic and careful follow-up. • Initiate a dental referral to eliminate dental factors. • Stress importance of stopping tobacco and alcohol use. • Encourage participation in smoking cessation program.

PROGNOSIS • Most leukoplakia is benign. • Leukoplakia may regress, remain stable, or progress. • 0.13–6% of initially benign lesions subsequently develop into cancer. • Size >4 cm increases risk of malignant transformation. • 5-year survival rate of oral cancer is 50%.

COMPLICATIONS • New lesions may develop after treatment. • Risk of malignant transformation to squamous cell carcinoma is approximately 5–17% (5)[B]. • Larger lesions and nonhomogeneous leukoplakia are associated with higher rates of malignant transformation.

REFERENCES 1. Fuller C, Camilon R, Nguyen S, et al. Adjunctive diagnostic techniques for oral lesions of unknown malignant potential: systematic review with metaanalysis. Head Neck. 2015;37(5):755–762. 2. Feller L, Lemmer J. Oral leukoplakia as it relates to HPV infection: a review. Int J Dent. 2012;2012:540561. 3. Kawczyk-Krupka A, Waśkowska J, Raczkowska-Siostrzonek A, et al. Comparison of cryotherapy and photodynamic therapy in treatment of oral leukoplakia. Photodiagnosis Photodyn Ther. 2012;9(2):148–155. 4. Jerjes W, Upile T, Hamdoon Z, et al. CO2 laser of oral dysplasia: clinicopathological features of recurrence and malignant transformation. Lasers Med Sci. 2012;27(1):169–179.

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5. Rhodus NL, Kerr AR, Patel K. Oral cancer: leukoplakia, premalignancy, and squamous cell carcinoma. Dent Clin North Am. 2014;58(2):315–340.

ADDITIONAL READING • Messadi DV. Diagnostic aids for detection of oral precancerous conditions. Int J Oral Sci. 2013;5(2):59–65. • Nair DR, Pruthy R, Pawar U, et al. Oral cancer: premalignant conditions and screening—an update. J Cancer Res Ther. 2012;8(Suppl 1):S57–S66. • Reamy BV, Derby R, Bunt CW. Common tongue conditions in primary care. Am Fam Physician. 2010;81(5):627–634. • Yardimci G, Kutlubay Z, Engin B, et al. Precancerous lesions of oral mucosa. World J Clin Cases. 2014;2(12):866–872.

SEE ALSO Infectious Mononucleosis, Epstein-Barr Virus Infections; HIV/AIDS

CODES ICD10 • K13.21 Leukoplakia of oral mucosa, including tongue • K13.3 Hairy leukoplakia

CLINICAL PEARLS • Excisional biopsy is indicated for any undiagnosed leukoplakia. • After treatment, up to 30% of leukoplakia recurs, and some leukoplakia still transforms to squamous cell carcinoma; thus, long-term surveillance is essential. • To lessen risk of malignant transformation, encourage tobacco and alcohol cessation and consider C. albicans eradication.

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LICHEN PLANUS Mercedes E. Gonzalez, MD, FAAD • Herbert P. Goodheart, MD BASICS Lichen planus (LP) is an idiopathic eruption with characteristic shiny, flat-topped (Latin: planus, “flat”) purple (violaceous) papules and plaques on the skin, often accompanied by characteristic mucous membrane lesions. Itching may be severe.

DESCRIPTION • Classic (typical) LP is a relatively uncommon inflammatory disorder of the skin and mucous membranes; hair and nails may also be affected. – Skin lesions are small, flat, angular, red-to-violaceous, shiny, pruritic papules and/or plaques with overlying fine, white lines (called Wickham striae), or gray-white puncta; most commonly seen on the flexor surfaces of the upper extremities, extensor surfaces of the lower extremities, the genitalia, and on the mucous membranes – On the oral mucosa, lesions typically appear as raised white lines in a lacelike pattern seen most often on the buccal mucosa. – Onset is abrupt or gradual. Course is unpredictable; may resolve spontaneously, recur intermittently, or persist for many years • Drug-induced LP – Clinical and histopathologic findings may mimic those of classic LP. Lesions usually lack Wickham striae (see in the following text) and oral involvement is rare. – There is generally a latent period of months from drug introduction until lesions appear. – Lesions resolve when the inciting agent is discontinued, often after a prolonged period. • LP variants – Follicular: also called lichen planopilaris; typically seen on the scalp, can

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lead to scarring alopecia – Annular: Papules spread centrifugally as central area resolves; occur on glans penis, axillae, and oral mucosa – Linear: may be an isolated finding – Hypertrophic: itchy, hyperkeratotic, thick plaques on dorsal legs and feet – Atrophic: rare, most often the result of resolved lesions – Bullous LP: Intense inflammation in the dermis leads to blistering of epidermis. – LP pemphigoides: a combination of LP and bullous pemphigoid (IgG autoantibodies to collagen 17) – Nail LP: affects the nail matrix, lateral thinning, longitudinal ridging, and fissuring • System(s) affected: skin/exocrine • Synonym(s): lichenoid eruptions

EPIDEMIOLOGY • Predominant age: 30 to 60 years old; rare in children and the geriatric population • Predominant sex: female > male

Prevalence In the United States, 450/100,000

ETIOLOGY AND PATHOPHYSIOLOGY LP is considered to be a T-cell–mediated autoimmune response to self-antigens on damaged keratinocytes.

RISK FACTORS Exposure to certain drugs or chemicals • Thiazides, furosemide, β-blockers, sulfonylureas, antimalarials, penicillamine, gold salts, and angiotensin-converting enzyme inhibitors • Rarely: photo-developing chemicals, dental materials, tattoo pigments

COMMONLY ASSOCIATED CONDITIONS • An association has been noted between LP and hepatitis C virus infection, particularly in certain geographic regions (Asia, South America, the Middle

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East, Europe) (1). Hepatitis should be considered in patients with widespread presentations of LP and those with primarily oral disease. • In addition, chronic active hepatitis, lichen nitidus, and primary biliary cirrhosis have been noted to coexist with LP. • Association with dyslipidemia has been reported (2)[B]. • LP has also been reported in association with other diseases of altered immunity, more often than would be expected by chance. – Bullous pemphigoid – Alopecia areata – Myasthenia gravis – Vitiligo – Ulcerative colitis – Graft-versus-host reaction – Lupus erythematosus (lupus erythematosus–LP overlap syndrome) – Morphea and lichen sclerosis et atrophicus

DIAGNOSIS LP is most commonly diagnosed by its appearance despite its range of clinical presentations. A skin biopsy should be performed if the diagnosis is in doubt.

HISTORY A minority of patients have a family history of LP. Affected families have an increased frequency of human leukocyte antigen B7 (HLA-B7). A thorough drug history should be performed.

PHYSICAL EXAM • Skin (often severe pruritus) – Papules: 1 to 10 mm, shiny, flat-topped (planar) lesions that occur in crops; lesions may have a fine scale. – Evidence of scratching (i.e., crusts and excoriations) is usually absent. – Color: violaceous, with white lacelike pattern (Wickham striae) on surface of papules. Wickham striae are best seen after topical application of mineral oil and, if present, are virtually pathognomonic for LP. – Shape: polygonal or oval. Annular lesions may appear on trunk and mucous

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membranes. Various shapes and sizes may be noted (polymorphic). – Arrangement: may be grouped, linear, or scattered individual lesions – Koebner phenomenon (isomorphic response): New lesions may be noted at sites of minor injuries, such as scratches or burns. – Distribution: ventral surface of wrists and forearms, dorsa hands, glans penis, dorsa feet, groin, sacrum, shins, and scalp. Hypertrophic (verrucous) lesions may occur on lower legs and may be generalized. – Postinflammatory hyperpigmentation: Lesions typically heal, leaving darkly pigmented macules in their wake. • Mucous membranes (40–60% of patients with skin lesions; 20% have mucous membrane lesions without skin involvement) – Most commonly asymptomatic, nonerosive, milky-white lines with an elegant, lacy, netlike streaked pattern – Usually seen on buccal mucosa but may appear on tongue, gingiva, palate, or lips – Less commonly, LP may be erosive; rarely bullous – Painful, especially if ulcers present – Lesions may develop into squamous cell carcinoma (1–3%). – Glans penis, labia minora, vaginal vault, and perianal areas may be involved. • Hair/scalp – LP of the hair follicle (lichen planopilaris) presents with keratotic plugs at the follicle orifice with a violaceous rim; may result in atrophy and permanent destruction of hair follicles (scarring alopecia) • Nails (10%) – Involvement of nail matrix may cause proximal-to-distal linear grooves and partial or complete destruction of nail bed with pterygium formation.

DIFFERENTIAL DIAGNOSIS • Skin – Lichen simplex chronicus – Eczematous dermatitis – Psoriasis – Discoid lupus erythematosus – Other lichenoid eruptions (those that resemble LP)

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– Pityriasis rosea – Lichen nitidus • Oral mucous membranes – Leukoplakia – Oral hairy leukoplakia – Candidiasis – Squamous cell carcinoma (particularly in ulcerative lesions) – Aphthous ulcers – Herpetic stomatitis – Secondary syphilis • Genital mucous membranes – Psoriasis (penis and labia) – Nonspecific balanitis, Zoon balanitis – Fixed drug eruption (penis) – Candidiasis (penis and labia) – Pemphigus vulgaris, bullous pemphigoid, and Behçet disease (all rare) • Hair and scalp – Scarring alopecia (central centrifugal cicatricial alopecia)

DIAGNOSTIC TESTS & INTERPRETATION If suggested by history • Serology for hepatitis • Liver function tests

Diagnostic Procedures/Other • Skin biopsy • Direct immunofluorescence helps to distinguish LP from discoid lupus erythematosus.

Test Interpretation • Dense, bandlike (lichenoid) lymphocytic infiltrate of the upper dermis • Vacuolar degeneration of the basal layer • Hyperkeratosis and irregular acanthosis, increased granular layer • Basement membrane thinning with “saw-toothing” • Degenerative keratinocytes, known as colloid or Civatte bodies, are found in

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the lower epidermis. • Melanin pigment in macrophages

TREATMENT Although LP can resolve spontaneously, treatment is usually requested by patients who may be severely symptomatic or troubled by its cosmetic appearance.

GENERAL MEASURES • Goal is to relieve itching and resolve lesions. • Asymptomatic oral lesions require no treatment.

MEDICATION First Line • Skin • Superpotent topical steroids (e.g., 0.05% clobetasol propionate) twice daily. – Potent topical steroids such as triamcinolone acetonide 0.1% or fluocinonide 0.05% under occlusion – Intralesional corticosteroids (e.g., triamcinolone [Kenalog] 5 to 10 mg/mL) for recalcitrant and hypertrophic lesions – Antihistamines (e.g., hydroxyzine, 25 mg PO q6h) have limited benefit for itching but may be helpful for sedation at bedtime. – “Soak and smear” technique: can lead to a rapid improvement of symptoms in even 1 to 2 days and may obviate the need for systemic steroids. Soaking allows water to hydrate the stratum corneum and allows the antiinflammatory steroid in the ointment to penetrate more deeply into the skin. Smearing of the ointment traps the water in the skin because water cannot move out through greasy materials. Soaking is done in a bathtub using lukewarm plain water for 20 minutes, then, without drying the skin, the affected area is immediately smeared with a thin film of the steroid ointment containing clobetasol or another superpotent topical steroid. Soak and smear may be done for 4 to 5 days or longer, if necessary. The treatments are best done at night because the greasy ointment applied to

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the skin gets on pajamas (instead of on daytime clothes) and the ointment is on the skin during sleep. A topical steroid cream is applied thereafter during the daytime hours, if necessary. • Mucous membranes – For oral, erosive, painful LP, a Cochrane review found at best weak evidence for the effectiveness of any intervention (3)[A]. Topical corticosteroids (0.1% triamcinolone [Kenalog] in Orabase) or 0.05% clobetasol propionate ointment BID Intralesional corticosteroids Topical 0.1% tacrolimus (Protopic ointment) BID or 1% pimecrolimus (Elidel) cream BID. A Cochrane review found no evidence that calcineurin inhibitors are better than placebo (4)[A]. Topical retinoids (e.g., 0.05% tretinoin [retinoic acid] in Orabase)

Pediatric Considerations Children may absorb a proportionally larger amount of topical steroid because of larger skin surface-to-weight ratio.

Second Line Skin and mucous membranes • Intralesional corticosteroids • Topical 0.1% tacrolimus (Protopic ointment) BID or topical 1% pimecrolimus (Elidel) cream BID • Oral prednisone: used only for a short course (e.g., 30 to 60 mg/day for 2 to 4 weeks) or IM triamcinolone (Kenalog) 40 to 80 mg every 6 to 8 weeks – Precautions with systemic steroids Systemic absorption of steroids may result in hypothalamic-pituitaryadrenal axis suppression, Cushing syndrome, hyperglycemia, or glucosuria. Increased risk with high-potency topical steroids (i.e., use over large surface area, prolonged use, occlusive dressings) In pregnancy: usually safe, but benefits must outweigh the risks • Oral retinoids: Isotretinoin in doses of 10 mg PO daily for 2 months, acitretin 30 mg, or alitretinoin 30 mg PO daily have resulted in improvement in some refractory cases. Observe carefully for resultant dyslipidemia.

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• Oral metronidazole 500 mg BID for 20 to 60 days can be given as a safer alternative to systemic corticosteroids. • Cyclosporine may be used in severe cases, but cost and potential toxicity limit its use; topical use for severe oral involvement refractory to other treatments • Thalidomide • Psoralen ultraviolet-A (PUVA), broad- or narrow-band ultraviolet B (UVB) (5)[A] • Griseofulvin (5)[A] • Azathioprine • Mycophenolate mofetil • Metronidazole

ALERT Avoid oral and topical retinoids during pregnancy.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS Outpatient care

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring Serial oral examinations for erosive/ulcerative lesions

PATIENT EDUCATION • Oral, erosive, or ulcerative LP: annual follow-up to screen for malignancy (6) [A] • Avoid spicy foods, cigarettes, and excessive alcohol. • Avoid dry crispy foods such as corn chips, pretzels, and toast.

PROGNOSIS • Spontaneous resolution in weeks is possible, but disease may persist for years, especially oral lesions and hypertrophic lesions on the shins. • There is a tendency toward relapse.

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• Recurrence in 12–20%, especially in those with generalized involvement

COMPLICATIONS • Alopecia • Nail destruction • Squamous cell carcinoma of the mouth or genitals

REFERENCES 1. Shengyuan L, Songpo Y, Wen W, et al. Hepatitis C virus and lichen planus: a reciprocal association determined by a meta-analysis. Arch Dermatol. 2009;145(9):1040–1047. 2. Arias-Santiago S, Buendía-Eisman A, Aneiros-Fernández J, et al. Cardiovascular risk factors in patients with lichen planus. Am J Med. 2011;124(6):543–548. 3. Cheng S, Kirtschig G, Cooper S, et al. Interventions for erosive lichen planus affecting mucosal sites. Cochrane Database Syst Rev. 2012;(2):CD008092. 4. Thongprasom K, Carrozzo M, Furness S, et al. Interventions for treating oral lichen planus. Cochrane Database Syst Rev. 2011;(7):CD001168. 5. Atzmony L, Reiter O, Hodak E, et al. Treatments for cutaneous lichen planus: a systematic review and meta-analysis. Am J Clin Dermatol. 2016;17(1):11– 22. 6. Fitzpatrick SG, Hirsch SA, Gordon SC. The malignant transformation of oral lichen planus and oral lichenoid lesions: a systematic review. J Am Dent Assoc. 2014;145(1):45–56.

ADDITIONAL READING • Fazel N. Cutaneous lichen planus: a systematic review of treatments. J Dermatolog Treat. 2015;26(3):280–283. • Kolios AG, Marques Maggio E, Gubler C, et al. Oral, esophageal and cutaneous lichen ruber planus controlled with alitretinoin: case report and review of the literature. Dermatology. 2013;226(4):302–310.

CODES

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ICD10 • L43.9 Lichen planus, unspecified • L43.0 Hypertrophic lichen planus • L43.1 Bullous lichen planus

CLINICAL PEARLS • Remember the 7 P’s of LP: purple, planar, polygonal, polymorphic, pruritic (not always), papules that heal with postinflammatory hyperpigmentation. • Serial oral or genital exams are indicated for erosive/ulcerative LP lesions to monitor for the development of squamous cell carcinoma. • An association has been noted between LP and hepatitis C virus infection, chronic active hepatitis, and primary biliary cirrhosis. • The “soak and smear” technique can lead to a rapid improvement of symptoms in 1 to 2 days and may obviate the need for systemic steroids.

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LICHEN SIMPLEX CHRONICUS Geoffrey Strider Farnsworth, MD BASICS DESCRIPTION • Lichen simplex chronicus (LSC) is a chronic dermatitis resulting from chronic, repeated rubbing or scratching of the skin. Skin becomes thickened with accentuated lines (“lichenification”). • System(s) affected: skin • Synonym(s): LSC; lichen simplex; localized neurodermatitis; neurodermatitis circumscripta

EPIDEMIOLOGY Geriatric Considerations Most common in middle aged and elderly

Pediatric Considerations Rare in preadolescents

Incidence • Common • Peak incidence 35 to 50 years • Predominant sex: females > males (2:1)

Prevalence Common

ETIOLOGY AND PATHOPHYSIOLOGY • Itch–scratch cycle leads to a chronic dermatosis. Repeated scratching or rubbing causes inflammation and pruritus, which leads to continued scratching. • Primary LSC: Scratching secondary to nonorganic pruritus, habit or a conditioned response to stress/anxiety • Common triggers are excess dryness of skin, heat, sweat, and psychological

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stress. • Secondary LSC: begins as a pruritic skin disease that evolves into neurodermatitis, which persists after resolution of the primary condition. Precursor dermatoses include atopic dermatitis, contact dermatitis, lichen planus, stasis dermatitis, psoriasis, tinea, and insect bites. • There is a possible relation between disease development and underlying neuropathy, particularly radiculopathy or nerve root compression. • Pruritus-specific C neurons are temperature sensitive, which may explain itching that occurs in warm environments.

RISK FACTORS • Anxiety disorders • Dry skin • Insect bites • Pruritic dermatosis

GENERAL PREVENTION Avoid common triggers such as psychological distress, environmental factors such as heat and excessive dryness, skin irritation, and the development of pruritic dermatoses.

COMMONLY ASSOCIATED CONDITIONS • Prurigo nodularis is a nodular variety of the same disease process. • Atopic dermatitis • Anxiety, depression, and obsessive-compulsive disorders

DIAGNOSIS HISTORY • Gradual onset • Begins as a localized area of pruritus • Most patients acknowledge that they respond with vigorous rubbing, itching, or scratching, which brings temporary satisfaction. • Pruritus is typically paroxysmal, worse at night, and may lead to scratching during sleep.

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• Can be asymptomatic with patient scratching at night while asleep

PHYSICAL EXAM • Well-circumscribed lichenified plaques with varying amounts of overlying excoriation or scaling • Lichenification: accentuation of normal skin lines • Hyperpigmentation or hypopigmentation can be seen. • Scarring is uncommon with typical LSC; can be seen following ulcer formation or secondary infection. • Most commonly involves easily accessible areas – Lateral portions of lower legs/ankles – Nape of neck (lichen simplex nuchae) – Vulva/scrotum/anus – Extensor surfaces of forearms – Palmar wrist – Scalp

DIFFERENTIAL DIAGNOSIS • Lichen sclerosis • Psoriasis • Atopic dermatitis • Contact, irritant, or stasis dermatitis • Extramammary Paget disease • Lichen planus • Mycosis fungoides • Lichen amyloidosis • Tinea • Nummular eczema

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • No specific diagnostic test • Microscopy (i.e., KOH prep) and culture preparation may be helpful in identifying possible bacterial or fungal infection.

Diagnostic Procedures/Other

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• Skin biopsy if diagnosis is in question. • Patch testing may be used to rule out a contact dermatitis.

Test Interpretation • Hyperkeratosis • Acanthosis • Lengthening of rete ridges • Hyperplasia of all components of epidermis • Mild to moderate lymphohistiocytic inflammatory infiltrate with prominent lichenification

TREATMENT GENERAL MEASURES • Patient education is critical. • Low likelihood of resolution if patient unable to avoid scratching. • Treatment aimed at reducing inflammation and pruritus.

MEDICATION First Line • Reducing inflammation – Topical steroids are first-line agents (1,2)[C]. – High-potency steroids alone, such as 0.05% betamethasone dipropionate cream or 0.05% clobetasol propionate cream, can be used initially but should be avoided on the face, anogenital region, or intertriginous areas. They should be used on small areas only, for no longer than 2 weeks except under the close supervision of a physician. – Switch to intermediate- or low-potency steroids as response allows. – An intermediate-potency steroid, such as 0.1% triamcinolone cream, may be used for initial, brief treatment of the face and intertriginous areas, and for maintenance treatment of other areas. – A low-potency steroid, such as 1% hydrocortisone cream, should be used for maintenance treatment of the face and intertriginous areas. – Steroid tape, flurandrenolide, has optimized penetration and provides a

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barrier to continued scratching. Change tape once daily. – Intralesional steroids, such as triamcinolone acetate, are also safe and effective for severe cases. • Preventing scratching – Topical antipruritic agents – 1st-generation oral antihistamines such as diphenhydramine and hydroxyzine for antipruritic and sedative effects – Sedating tricyclics, such as doxepin and amitriptyline, for nighttime itching – Itching may occur at night while the patient is asleep; occlusive dressings may be helpful in these cases.

ALERT High-dose and prolonged treatment with topical steroids can cause dermal/epidermal atrophy as well as pigmentary changes and should not be used on the face, intertriginous areas, or anogenital region. Duration of treatment on other parts of the body should not exceed 3 weeks without close physician supervision.

Second Line All recommendations • Topical aspirin has been shown to be helpful in treating neurodermatitis (3) [C]. • Topical 5% doxepin cream has significant antipruritic activity (3)[C]. • Topical capsaicin cream can be helpful for treatment of early disease manifestations (3)[C]. • 0.1% tacrolimus applied twice daily over 6 weeks for as an effective alternative treatment (4)[C] • Gabapentin was found to decrease symptoms in patients who are nonresponsive to steroids. • Topical lidocaine can be effective in decreasing neuropathic pruritus (3)[C]. • Intradermal botulinum toxin injections has been reported to improve symptoms in patients with recalcitrant pruritus. • Transcutaneous electrical nerve stimulation may relieve pruritus in patients for whom topical steroids were not effective (5)[C]. • A case report showed NB-UVB as a possible off-label treatment of refractory

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LSC (6)[C]. • SSRIs may be effective in controlling compulsive scratching secondary to psychiatric diagnosis.

ISSUES FOR REFERRAL • No response to treatment • Presence of signs and symptoms suggestive of a systemic cause of pruritus • Consultation with a psychiatrist for patients with severe stress, anxiety, or compulsive scratching • Consultation with an allergist for patients with multisystem atopic symptoms

ADDITIONAL THERAPIES • Cooling of the skin with ice or cold compresses • Soaks and lubricants to improve barrier layer function • Occlusion of lesion with bandages or Unna boots. • Nail trimming • Silk underwear to decrease friction in genital LSC.

COMPLEMENTARY & ALTERNATIVE MEDICINE • Acupuncture has been shown as an effective treatment for pruritus (7)[C]. • Cognitive-behavioral therapy may improve awareness and help to identify coping strategies. • Hypnosis may be beneficial in decreasing pruritus and preventing scratching. • Homeopathic remedies (i.e., thuja and graphite) have been used.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring Patients should be followed for response to therapy, complications from therapy (especially topical steroids), and secondary infections.

DIET Regular balanced diet

PATIENT EDUCATION

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• Patients should understand the cause of this disease and the critical role they play in its resolution: – Emphasize that scratching and rubbing must stop for lesions to heal. Medications ineffective if scratching continues • Stress reduction techniques can be useful for patients for whom stress plays a role. • Avoid exposure to known triggers.

PROGNOSIS • Often chronic and recurrent • Good prognosis if the itch–scratch cycle can be broken • After healing, the skin should return to normal appearance but may also retain accentuated skin markings or post inflammatory pigmentary changes that may be slow to resolve.

COMPLICATIONS • Secondary infection • Scarring is rare without ulceration or secondary infection. • Complications related to therapy, as mentioned in medication precautions • Squamous cell carcinoma within affected regions is rare.

REFERENCES 1. Lynch PJ. Lichen simplex chronicus (atopic/neurodermatitis) of the anogenital region. Dermatol Ther. 2004;17(1):8–19. 2. Datz B, Yawalkar S. A double-blind, multicenter trial of 0.05% halobetasol propionate ointment and 0.05% clobetasol 17-propionate ointment in the treatment of patients with chronic, localized atopic dermatitis or lichen simplex chronicus. J Am Acad Dermatol. 1991;25(6 Pt 2):1157–1160. 3. Patel T, Yosipovitch G. Therapy of pruritus. Expert Opin Pharmacother. 2010;11(10):1673–1682. 4. Tan ES, Tan AS, Tey HL. Effective treatment of scrotal lichen simplex chronicus with 0.1% tacrolimus ointment: an observational study. J Eur Acad Dermatol Venereol. 2015;29(7):1448–1449. 5. Mohammad Ali BM, Hegab DS, El Saadany HM. Use of transcutaneous electrical nerve stimulation for chronic pruritus. Dermatol Ther.

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2015;28(4):210–215. 6. Virgili A, Minghetti S, Borghi A, et al. Phototherapy for vulvar lichen simplex chronicus: an ‘off-label use’ of a comb light device. Photodermatol Photoimmunol Photomed. 2014;30(6):332–334. 7. Ma C, Sivamani RK. Acupuncture as a treatment modality in dermatology: a systematic review. J Altern Complement Med. 2015;21(9):520–529.

ADDITIONAL READING • Aschoff R, Wozel G. Topical tacrolimus for the treatment of lichen simplex chronicus. J Dermatolog Treat. 2007;18(2):115–117. • Engin B, Tufekci O, Yazici A, et al. The effect of transcutaneous electrical nerve stimulation in the treatment of lichen simplex: a prospective study. Clin Exp Dermatol. 2009;34(3):324–328. • Gencoglan G, Inanir I, Gunduz K. Therapeutic hotline: treatment of prurigo nodularis and lichen simplex chronicus with gabapentin. Dermatol Ther. 2010;23(2):194–198. • Goldstein AT, Parneix-Spake A, McCormick CL, et al. Pimecrolimus cream 1% for treatment of vulvar lichen simplex chronicus: an open-label, preliminary trial. Gynecol Obstet Invest. 2007;64(4):180–186. • Heckmann M, Heyer G, Brunner B, et al. Botulinum toxin type A injection in the treatment of lichen simplex: an open pilot study. J Am Acad Dermatol. 2002;46(4):617–619. • Hercogová J. Topical anti-itch therapy. Dermatol Ther. 2005;18(4):341–343. • Kirtak N, Inaloz HS, Akçali C, et al. Association of serotonin transporter gene-linked polymorphic region and variable number of tandem repeat polymorphism of the serotonin transporter gene in lichen simplex chronicus patients with psychiatric status. Int J Dermatol. 2008;47(10):1069–1072. • Konuk N, Koca R, Atik L, et al. Psychopathology, depression and dissociative experiences in patients with lichen simplex chronicus. Gen Hosp Psychiatry. 2007;29(3):232–235. • Lotti T, Buggiani G, Prignano F. Prurigo nodularis and lichen simplex chronicus. Dermatol Ther. 2008;21(1):42–46. • Shenefelt PD. Biofeedback, cognitive-behavioral methods, and hypnosis in dermatology: is it all in your mind? Dermatol Ther. 2003;16(2):114–122.

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• Solak O, Kulac M, Yaman M, et al. Lichen simplex chronicus as a symptom of neuropathy. Clin Exp Dermatol. 2009;34(4):476–480. • Wu M, Wang Y, Bu W, et al. Squamous cell carcinoma arising in lichen simplex chronicus. Eur J Dermatol. 2010;20(6):858–859. • Yosipovitch G, Sugeng MW, Chan YH, et al. The effect of topically applied aspirin on localized circumscribed neurodermatitis. J Am Acad Dermatol. 2001;45(6):910–913. • Yüksek J, Sezer E, Aksu M, et al. Transcutaneous electrical nerve stimulation for reduction of pruritus in macular amyloidosis and lichen simplex. J Dermatol. 2011;38(6):546–552.

CODES ICD10 L28.0 Lichen simplex chronicus

CLINICAL PEARLS • LSC is a chronic inflammatory condition that results from repeated scratching and rubbing. • Primary LSC originates de novo, whereas secondary LSC occurs in the setting of a preexisting pruritic dermatologic condition. • LSC is a clinical diagnosis based on history and skin examination with biopsy only indicated in difficult or unclear cases. • Stopping the itch–scratch cycle through patient education, skin lubrication, and topical medications is key. • Treatment aimed at decreasing both inflammation and pruritus utilizing topical steroids and antipruritics.

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LONG QT INTERVAL Carl Bryce, MD • Matthew J. Snyder, DO BASICS DESCRIPTION • QT interval: electrocardiogram (ECG) measurement that measures the duration of repolarization of myocardial cells. Measured from the onset of the QRS complex to the end of the T wave • Corrected QT interval (QTc): QT interval corrected for heart rate (interval shortens with increased rate). See formulas. • Prolonged QTc is generally defined as >470 ms for adult males and >480 ms for adult females (1): – 440 to 460 ms considered borderline in men – 440 to 470 ms considered borderline in women – 440 to 460 ms considered borderline in children aged 1 to 15 years old (2) • Most cases of prolonged QT are acquired, but genetic mutations can also cause hereditary long QT syndromes (LQTS). • Prolonged QTc from any cause can precipitate polymorphic ventricular tachycardia (VT) called torsade de pointes (TdP), leading to dizziness, syncope, and sudden cardiac death from ventricular fibrillation (VF).

EPIDEMIOLOGY Incidence Incidence of medication-induced QTc prolongation and TdP varies with medication and a host of other factors. Exact incidences are difficult to estimate but may be 1:2,000 to 1:2,500. (1).

Prevalence • Hereditary LQTS is estimated to occur in 1/2,500 to 1/7,000 births. • Five thousand people across the United States may die yearly due to LQTSrelated cardiac arrhythmia (2).

ETIOLOGY AND PATHOPHYSIOLOGY

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• Acquired – Electrolyte abnormalities such as hypokalemia, hypomagnesemia – Hypothyroidism – Underlying heart disease – Medications (3)[A] Antiarrhythmic medications (quinidine, procainamide, dofetilide, sotalol, disopyramide, and amiodarone) Antipsychotic medications, especially if given IV (haloperidol*, chlorpromazine*, thioridazine*, pimozide*) Many antidepressants (SSRIs, SNRIs, trazodone, TCAs) Antibiotics/antivirals/antifungals (clarithromycin*, erythromycin* which are also CYP3A4 inhibitors) Antiemetics (metoclopramide, ondansetron, promethazine) Opioids (methadone*, buprenorphine) Antihistamines (cetirizine, hydroxyzine, diphenhydramine) Decongestants (pseudoephedrine, phenylephrine Stimulants (albuterol, phentermine) Misc: chloroquine*, pentamidine* *Denote “high-risk” medication for TdP. • Congenital – Defective membrane proteins that work as channels for sodium and potassium in myocytes • Pathophysiology – Depolarization of the myocardium results from the rapid influx of sodium through sodium channels and causes myocyte contraction, with resulting cardiac muscle contraction and systole (seen on ECG as the QRS complex). – During repolarization, there is an efflux of potassium from the cell through both rapid (IKr) and slow (IKs) potassium channels. The T wave on an ECG represents myocyte repolarization. – Drug-induced QT prolongation due to blockade of IKr leading to delayed repolarization (2). – Medications, medical conditions, electrolyte disturbances, and genetic mutations that affect functioning of these membrane channels can cause delayed repolarization.

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– Delayed repolarization can lead to a propensity for reentry and initiate TdP. – TdP type rhythm may be self-limited but symptomatic (syncope or near syncope). It can also degrade into VF.

Genetics • 12 different genes have been linked to LQTS (3). • Incomplete penetrance makes both diagnosis and management of asymptomatic disease challenging. • LQTS 1 (42–54%) is the most common. Mutation causes a defect in the IKs transport protein. Arrhythmias can be triggered by tachycardia due to exercise (swimming seems to be especially problematic) and other high catecholamine states. • LQTS 2 (35–45%) is a defect in the IKr transport protein that is sensitive to catecholamine surges. Sudden loud noises or emotional arousal can provoke arrhythmias. • LQTS 3 (8%) is a defect in the sodium channel that allows an excess of sodium into the cell, increasing repolarization time. Arrhythmias tend to manifest more during rest or sleep. • Jervell and Lange-Nielsen syndrome: Autosomal recessive form of LQTS that features homozygous mutations affect the IKs channel and presents with severe form of LQTS 1. Features also include deafness. • Romano-Ward syndrome: autosomal dominant form of LQTS with variable penetrance. Hearing is normal.

RISK FACTORS For the feared complication, TdP, risk factors include the following (3): • Female (∼2 times increased risk) • QTc >500 ms (2 to 3 times increased risk) • QTc >60 ms over previous baseline • History of syncope or presyncope • History of TdP • Bradycardia • Liver or kidney disease (by increasing blood levels of QT prolonging medications) • Medications that cause QTc prolongation

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– High doses – Fast infusions – Combination of medications • Electrolyte abnormalities – Hypokalemia – Hypomagnesemia – Hypocalcemia • For hereditary LQTS – Catecholamine surges from exercise (especially swimming), emotional stress, loud noises

GENERAL PREVENTION • Avoid (or use with caution) causative medications, including combinations with potentially additive effects. Replete electrolytes (goal Mg >2, K 4.5 to 5.0) (4)[C] • Treat underlying medical disease (hypothyroidism, cardiac disease). • Avoid strenuous sports in LQTS. • Avoid sudden loud noises in LQTS (alarm clocks, doorbells, telephones). • 36th Bethesda Conference recommends restriction of athletes from participation to class 1A activities (e.g., bowling, golf, riflery) although evidence regarding safe participation is emerging (1)[C].

DIAGNOSIS HISTORY • Evaluate for syncope, near syncope, and associated precipitating events (such as emotional triggers, swimming, diving). • Evaluate for history of seizures in patient or in family (tonic–clonic movement may due to cerebral hypoperfusion during episodes of ventricular arrhythmia or due to seizure-like activity during a syncopal episode.). • Detailed medication history • Evaluate for family history of sudden death and syncope. • Congenital deafness

PHYSICAL EXAM

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• Usually normal physical exam • If underlying cardiac disease present, may have findings specific to cardiac condition • Evaluate for signs of hypothyroidism. • Congenital deafness may be present in some forms of LQTS.

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • ECG • Metabolic panel • Calcium level • Magnesium level • TSH Follow-Up Tests & Special Considerations • Echocardiogram to evaluate for cardiomyopathy • Outpatient cardiac rhythm monitoring • Consider provocative testing (epinephrine infusion, exercise stress testing) to evaluate for QTc interval changes and/or to evaluate for coronary artery disease (2)[C]. – Genetic testing for LQTS mutations

Test Interpretation • QTc calculation using ECG is best done by measuring the QT interval in lead II and measuring the RR interval immediately preceding this QT interval. The Bazett formula is commonly used, although it overcorrects for tachycardia and undercorrects for bradycardia (2). • Bazett formula: QTc = QT/√(RR) (all measurements in seconds, and RR obtained by direct measurement or 60/heart rate) • Fridericia formula is similar to Bazett but uses a cube root instead of a square root of the RR interval. QTc = QT/(RR)1/3

TREATMENT GENERAL MEASURES

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• VT, TdP, and VF should be treated emergently as per ACLS guidelines. • Cardiac pacing may be needed emergently for drug-induced TdP to prevent bradycardia. • Withdraw offending agents, correct electrolytes (2)[C].

MEDICATION First Line • For Tdp: magnesium sulfate 2 g infused over 2 to 15 minutes, followed by continuous infusion of 2 to 4 mg/min if needed. Monitor for magnesium toxicity in those with renal insufficiency (2)[C]. • For hereditary LQTS, to prevent life-threatening arrhythmias: Propranolol or nadolol are generally regarded as the best β-blockers for management of LQTS, though rigorous studies are lacking (4)[B]. • β-Blockers are effective in decreasing but not eliminating the risk of fatal arrhythmias. • For high-risk patients or those who remain symptomatic on a β-blocker, implantable cardiac defibrillators (ICDs) with or without pacemaker is an important consideration (2)[B].

Second Line • Atenolol or metoprolol may be used, although switching from other βblockers may precipitate lethal or near-lethal events (4)[B].

ISSUES FOR REFERRAL • Refer to cardiologist for establishing diagnosis, especially for hereditary LQTS. • Symptomatic prolonged QT

SURGERY/OTHER PROCEDURES • ICD for those with a history of major cardiac events • Left cervical-thoracic sympathetic denervation was used for symptomatic LQTS prior to the advent of β-blockers. It is still an option for those patients with LQTS who are refractory to β-blocker therapy (3)[B].

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS

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• Patients with TdP, VT, and VF should be promptly treated as per ACLS guidelines. Correct electrolytes on an emergent basis. Evaluate for acquired QT prolongation. If no cause is found, consider hereditary LQTS. • Patients with prolonged QTc and syncope/near syncope should be monitored on telemetry during evaluation. • Monitor ECG if initiating medications or combining medications that may prolong QT, suggest at baseline, within 30 days, and then annually (3)[C]. • Monitor electrolytes and urgently treat hypomagnesemia and hypokalemia in those with significantly prolonged QT, and discontinue or change offending medications (5)[C]. • Avoid sudden loud noises or emotional stress for those who have LQTS. • Review adherence to β-blocker therapy. • Notify others if telemetry monitoring reveals prolonged QT interval in hospitalized patients—they are at risk for poor outcomes (6).

ONGOING CARE FOLLOW-UP RECOMMENDATIONS On routine visits, ask about syncope, presyncope, and palpitations in those who have QTc prolongation. • Patient monitoring: Consider ECG and/or outpatient cardiac rhythm monitoring with any medication additions or dosage changes that may cause further prolongation of the QTc. • For those who may have symptomatic QTc prolongation of any cause, prompt evaluation is warranted. • Check labs for electrolyte imbalances, correct as needed.

PATIENT EDUCATION • Educate patients with QTc prolongation about medications side effects and possibility of medication interactions. • Patients with congenital forms of LQTS should be aware of, and avoid situations that may trigger torsade (depending on their specific gene mutation) • Large emotional and psychological impact of diagnosis. Additional reading by Fortescue shares personal impact of LQTS.

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• Information and support from groups listed (see “Additional Reading”) may be helpful.

PROGNOSIS Untreated, quite poor. Perhaps 20% of untreated patients presenting with syncope die within 1 year, 50% within 10 years (3).

REFERENCES 1. Abrams DJ, Macrae CA. Long QT syndrome. Circulation. 2014;129(14):1524–1529. 2. Kallergis EM, Goudis CA, Simantirakis EN, et al. Mechanisms, risk factors, and management of acquired long QT syndrome: a comprehensive review. ScientificWorldJournal. 2012;2012:212178. 3. Clarke CJ, McDaniel GM. The risk of long QT syndrome in the pediatric population. Curr Opin Pediatr. 2009;21(5):573–578. 4. Wilde AA, Ackerman MJ. Beta-blockers in the treatment of congenital long QT syndrome: is one beta-blocker superior to another? J Am Coll Cardiol. 2014;64(13):1359–1361. 5. QT prolongation, torsades de pointes, and medication safety. Pharmacist’s Letter/Prescriber’s Letter. 2010;26(4):260421. 6. Laksman Z, Momciu B, Seong YW, et al. A detailed description and assessment of outcomes of patients with hospital recorded QTc prolongation. Am J Cardiol. 2015;115(7):907–911.

ADDITIONAL READING • Chockalingam P, Crotti L, Girardengo G, et al. Not all beta-blockers are equal in the management of long QT syndrome types 1 and 2: higher recurrence of events under metoprolol. J Am Coll Cardiol. 2012;60(20):2092–2099. • Fortescue EB. A piece of my mind. Keeping the pace. JAMA. 2014;311(23):2383–2384. • Levine E, Rosero SZ, Budzikowski AS, et al. Congenital long QT syndrome: considerations for primary care physicians. Cleve Clin J Med. 2008;75(8):591–600. • Morita H, Wu J, Zipes DP. The QT syndromes: long and short. Lancet.

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2008;372(9640):750–763. • van Noord C, Eijgelsheim M, Stricker BH. Drug- and non-drug-associated QT interval prolongation. Br J Clin Pharmacol. 2010;70(1):16–23. • Webster G, Berul CI. Congenital long-QT syndromes: a clinical and genetic update from infancy through adulthood. Trends Cardiovasc Med. 2008;18(6):216–224. • Yap YG, Camm AJ. Drug induced QT prolongation and torsades de pointes. Heart. 2003;89(11):1363–1372. • http://www.crediblemeds.org (Medication lists and additional resources related to long QT and torsade de pointes) • Cardiac Arrhythmias Research and Education Foundation (http://www.longqt.org) • Sudden Arrhythmia Death Syndromes Foundation (http://www.sads.org)

SEE ALSO Algorithms: Cardiac Arrhythmias; Arrhythmias, Torsade de Pointes Ventricular Tachycardia

CODES ICD10 I45.81 Long QT syndrome

CLINICAL PEARLS • Evaluate for acquired causes before making a diagnosis of hereditary LQTS. • For accurate diagnosis, calculate QTc manually. • The ideal management of TdP is prevention; avoid multiple “stacking” risk factors and seek alternates to high-risk medications, correct electrolytes, and monitor treatment with serial ECGs if no alternatives exist. • Magnesium sulfate is the treatment of choice during ACLS for TdP. • β-Blockers are initial treatment of choice for hereditary LQTS.

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LUNG, PRIMARY MALIGNANCIES Brian P. Bateson, DO • Nathaniel Walsh, MD • Carsten Schroeder, MD, PhD BASICS DESCRIPTION • Lung cancers (primary) are the leading cause of cancer-related death in the United States (estimated 159,260 deaths in 2015, 27% of all cancer-related deaths). • Divided into two broad categories – Non–small cell lung cancer (NSCLC) (>85% of all lung cancers); normally originate in periphery Adenocarcinoma (~40% of NSCLC): Most common type in the United States, most common type in nonsmokers, metastasizes earlier than squamous cell, poor prognosis; lipidic growth, a subtype of adenocarcinoma has better prognosis. Squamous cell carcinoma (~25% of NSCLC): dose-related effect with smoking; slower growing than adenocarcinoma Large cell (~10% of NSCLC): prognosis similar to adenocarcinoma – Small cell lung cancer (SCLC) (16% of all lung cancers): centrally located, early metastases, aggressive • Other: mesothelioma and carcinoid tumor • Staging – Both NSCLC and SCLC: staged from I to IV based on: primary tumor (T), lymph node status (N), and presence of metastasis (M) – SCLC further staged by: Limited disease: confined to ipsilateral hemithorax, which may include malignant pleural or pericardial effusion or hematogenous metastases (stage IV) Extensive disease: beyond ipsilateral hemithorax (stages IIIB and IV) Tumor locations: upper: 60%; lower: 30%; middle: 5%; overlapping and main stem: 5%

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May spread by local extension to involve chest wall, diaphragm, pulmonary vessels, vena cava, phrenic nerve, esophagus, or pericardium Most commonly metastasize to lymph nodes (pulmonary, mediastinal), then liver, adrenal, bone, brain

EPIDEMIOLOGY Incidence • Estimated 224,210 new cases in the United States in 2015 • Predominant age: >40 years; peak at 70 years • Predominant sex: male > female

Prevalence • Most common cancer worldwide • Lifetime probability: men: 1 in 13; women: 1 in 16

ETIOLOGY AND PATHOPHYSIOLOGY Multifactorial; see “Risk Factors.”

Genetics NSCLC • Oncogenes: Ras family (H-ras, K-ras, N-ras) • Tumor suppressor genes: retinoblastoma, p53

RISK FACTORS • Smoking (relative risk [RR] 10 to 30) • Secondhand smoke exposure • Radon • Environmental and occupational exposures – Asbestos exposure (synergistic increase in risk for smokers) – Air pollution – Ionizing radiation – Mutagenic gases (halogen ethers, mustard gas, aromatic hydrocarbons) – Metals (inorganic arsenic, chromium, nickel) • Lung scarring from tuberculosis • Radiation therapy to the breast or chest

GENERAL PREVENTION

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• Smoking cessation and prevention programs • Screening recommended by and NCCN and shown to reduce mortality in National Lung Screening Trial (NLST) (1)[A]. • Annual screening recommended with low-dose computed tomography in adults ages 55 to 74 years who have a 30 pack-year smoking history and currently smoke or have quit within the past 15 years. • Screening should be discontinued once a person has not smoked for 15 years or develops a health problem that substantially limits life expectancy or the ability or willingness to have curative lung surgery. • Prevention via aggressive smoking cessation counseling and therapy; a 20– 30% risk reduction occurs within 5 years of cessation. • Avoid hormone replacement therapy in postmenopausal smokers or former smokers (increased risk of death from NSCLC).

COMMONLY ASSOCIATED CONDITIONS • Paraneoplastic syndromes: hypertrophic pulmonary osteoarthropathy, Lambert-Eaton syndrome, Cushing syndrome, hypercalcemia from ectopic parathyroid-releasing hormone, syndrome of inappropriate antidiuretic hormone (SIADH) • Hypercoagulable state • Pancoast syndrome • Superior vena cava syndrome • Pleural effusion • Chronic obstructive pulmonary disease (COPD), other sequelae of cigarette smoking

DIAGNOSIS HISTORY • May be asymptomatic for most of course • Respiratory – Cough (new or change in chronic cough) – Wheezing and stridor – Dyspnea

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– Hemoptysis – Pneumonitis (fever and productive cough) • Constitutional – Malaise – Bone pain (metastatic disease) – Fatigue – Weight loss, anorexia – Fever – Anemia – Clubbing of digits • Other presentations: – Chest pain (dull, pleuritic) – Shoulder/arm pain (Pancoast tumors) – Dysphagia – Plethora (redness of face or neck) – Hoarseness (involvement of recurrent laryngeal nerve) – Horner syndrome – Neurologic abnormalities (e.g., headaches, syncope, weakness, cognitive impairment) – Pericardial tamponade (pericardial invasion)

PHYSICAL EXAM • General: fever, chills, night sweats, weight loss • Head, eye, ear, nose, throat (HEENT): Horner syndrome, dysphonia, stridor, scleral icterus • Neck: supraclavicular/cervical lymph nodes, mass • Lungs: effusion, wheezing, airway obstruction, pleural effusion • Abdomen/groin: hepatomegaly or lymphadenopathy • Extremities: signs of hypertrophic pulmonary osteoarthropathy, deep venous thrombosis (DVT) • Neurologic: Rule out cognitive and focal motor defects.

DIFFERENTIAL DIAGNOSIS • COPD (may coexist) • Granulomatous (tuberculosis, sarcoidosis)

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• Cardiomyopathy • Congestive heart failure (CHF)

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Serum – CBC – Comprehensive metabolic panel (CMP) – Hypercalcemia (paraneoplastic syndrome) – Hyponatremia (SIADH) – Lactate dehydrogenase (LDH) • Sputum cytology • Chest x-ray (CXR) (compare with prior XRs) – Nodule or mass, especially if calcified – Persistent infiltrate – Atelectasis – Mediastinal widening – Hilar enlargement – Pleural effusion • CT scan of chest (with IV contrast) – Nodule or mass (central or peripheral) – Lymphadenopathy • Evaluation for metastatic disease – Positron emission tomography (PET) scan to evaluate metastasis mediastinal lymphadenopathy (replacing CT abdomen/pelvis and bone scan) – Brain MRI: lesions may be necrotic, bleeding. – CT (abdomen/pelvis and bone scan) Follow-Up Tests & Special Considerations CBC, BUN, serum creatinine, LFTs prior to each cycle of chemotherapy

Diagnostic Procedures/Other • Pulmonary function tests – Bronchoscopy – Transbronchial biopsy (Wang needle)

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– Enlarged mediastinal lymph nodes necessitate staging by mediastinoscopy, video-assisted thoracoscopy, endobronchial ultrasound or fine needle aspiration • Biopsy with pathology review • In patients with advanced NSCLC, determination of epidermal growth factor receptor (EGFR)-activating mutations, KRAS/NRAS mutations, and ALK gene rearrangements in patients with nonsquamous or mixed squamous histology • Cervical mediastinoscopy (biopsy of upper and lower paratracheal and subcarinal lymph nodes) • Video-assisted thoracoscopy (associated pleural disease and suspected mediastinal nodal spread) • Bone marrow aspirate (small cell)

Test Interpretation Pathologic changes from smoking are progressive: basal cell proliferation, development of atypical nuclei, stratification, metaplasia of squamous cells, carcinoma in situ, and then invasive disease.

TREATMENT GENERAL MEASURES • NSCLC – Stage I, stage II, and selected stage III tumors are surgically resectable. Neoadjuvant or adjuvant therapy is recommended for many patients with high risk IB, II, and IIIA NSCLC. Patients with resectable disease who are not surgical candidates may receive radiation therapy. – Patients with unresectable or N2, N3 disease are treated with concurrent chemoradiation. Selected patients with T3 or N2 disease can be treated effectively with surgical resection and either pre- or postoperative chemotherapy or chemoradiation therapy. – Patients with distant metastases (M1B) can be treated with radiation therapy or chemotherapy for palliation or best supportive care alone. • SCLC – Limited stage: concurrent chemoradiation

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– Extensive stage: combination chemotherapy – Consider prophylactic cranial irradiation (PCI) in patients achieving a complete or partial response (2)[A]. • Quality-of-life assessments: Karnofsky performance scale (KPS) (http://www.hospicepatients.org/karnofsky.html); Eastern Cooperative Oncology Group (ECOG) • Discussions with patient and family about end-of-life care

MEDICATION • Chemotherapy is the mainstay of treatment. • Adjuvant chemotherapy following surgery improves survival in patients with fully resected stage II–III NSCLC. • Palliative measures: analgesics • Dyspnea: oxygen, morphine

First Line • NSCLC – Stages II–III: neoadjuvant or adjuvant chemotherapy Cisplatin-based doublets (combination with paclitaxel, etoposide, vinorelbine, docetaxel, gemcitabine) Carboplatin alternative for patients unlikely to tolerate cisplatin Cisplatin plus pemetrexed (nonsquamous cell) – Unresectable stage IIA, IIIB Concurrent chemoradiation Cisplatin plus etoposide, vinblastine, or pemetrexed (nonsquamous cell) plus concurrent radiation Carboplatin plus pemetrexed (nonsquamous cell) plus concurrent radiation • Stage IV – No chemotherapy regimen can be recommended for routine use. – Cisplatin or carboplatin-based doublets – +/− bevacizumab (nonsquamous cell) – Erlotinib or afatinib for patients with EGFR mutations – Crizotinib for patients with EML4-ALK translocations Ceritinib for patients that fail or are intolerant to crizotinib

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– Maintenance therapy after 4 to 6 cycles in patients achieving a response or stable disease Continuation of bevacizumab, pemetrexed (nonsquamous cell), gemcitabine, erlotinib, or crizotinib or switch to pemetrexed (nonsquamous cell), erlotinib (EGFR mutations), docetaxel or observation • SCLC – Cisplatin or carboplatin plus etoposide

Second Line • NSCLC – Cisplatin-based doublets +/− bevacizumab (nonsquamous cell) if not previously used – Docetaxel, pemetrexed (nonsquamous cell), erlotinib, gemcitabine, ramucirumab plus docetaxel, or nivolumab (squamous cell) • SCLC – Topotecan or CAV (cyclophosphamide, doxorubicin, vincristine), gemcitabine, docetaxel, paclitaxel

ADDITIONAL THERAPIES • Immunotherapy – Anti PD-L1 (programmed cell death ligand) antibody therapy • Smoking cessation counseling • Consider IV bisphosphonates or denosumab in patients with bone metastases to reduce skeletal-related events.

SURGERY/OTHER PROCEDURES • Resection for NSCLC, for stages I, II, and IIIA, if medically fit to undergo surgery • Resection of isolated, distant metastases has been achieved and may improve survival. • Resection involves lobectomy in 71%, wedge in 16%, and complete pneumonectomy in 18%. • Resection should be accompanied by lymph node dissection for pathologic staging.

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ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Depends on clinical history; in general, postoperative visits every 3 to 6 months in the first 2 years after surgery with physical exam and CT scan • Follow-up usually lifelong with CT scans, following NCCN criteria

PATIENT EDUCATION • National Cancer Institute: http://www.cancer.gov/ • Smokefree.gov:http://smokefree.gov/

PROGNOSIS • For combined, all types and stages, 5-year survival rate is 16% (NSCLC: 17%; SCLC 6%). • NSCLC – Localized disease (stages I and II): 49% – Regional disease: 16% – Distant metastatic disease: 2% • SCLC – Without treatment: median survival from diagnosis of only 2 to 4 months – 5-year survival rate: ranges from 2% (stage IV) to 31% (stage I) – Extensive-stage disease: median survival of 6 to 12 months; long-term disease-free survival is rare.

COMPLICATIONS • Development of metastatic disease, especially to brain, bones, adrenals, and liver • Local recurrence of disease • Postoperative complications • Side effects of chemotherapy or radiation

REFERENCES 1. Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with

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low-dose computed tomographic screening. N Engl J Med. 2011;365(5):395– 409. 2. Slotman B, Faivre-Finn C, Kramer G, et al. Prophylactic cranial irradiation in extensive small-cell lung cancer. N Engl J Med. 2007;357(7):664–672.

ADDITIONAL READING National Cancer Institute. Small cell lung cancer treatment (PDQ)–health professional version. http://www.cancer.gov/types/lung/hp/small-cell-lungtreatment-pdq#section/_1CODES. Accessed October 11, 2016.

CODES ICD10 • C34.90 Malignant neoplasm of unsp part of unsp bronchus or lung • C34.10 Malignant neoplasm of upper lobe, unsp bronchus or lung • C34.30 Malignant neoplasm of lower lobe, unsp bronchus or lung

CLINICAL PEARLS • 2 types: NSCLC and SCLC – NSCLC (>85% of all lung cancers); normally originate in periphery Adenocarcinoma (~40% of NSCLC) Squamous cell carcinoma (~25% of NSCLC): Large cell (~10% of NSCLC): – SCLC centrally located, early metastases, aggressive • Prognosis and treatment of lung cancer differs greatly between small cell- and non–small cell histologies. • Adjuvant cisplatin-based chemotherapy improves survival in patients with completely resected stage II–III NSCLC. • Chemotherapy, with or without radiation, can be offered to patients with advanced NSCLC or SCLC. • There is little role for surgery in the treatment of SCLC.

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LUPUS ERYTHEMATOSUS, SYSTEMIC (SLE) Katherine M. Tromp, PharmD • Hershey S. Bell, MD, MS, FAAFP BASICS DESCRIPTION • Systemic lupus erythematosus (SLE) is a multisystem autoimmune inflammatory disease characterized by a chronic relapsing/remitting course; can be mild to severe and may be life-threatening (CNS and renal forms) • System(s) affected: mucocutaneous; musculoskeletal; renal; nervous; pulmonary; cardiac; hematologic; vascular; gastrointestinal (GI) • Synonym(s): SLE; lupus

ALERT Women with SLE have a 7- to 50-fold increased risk of coronary artery disease and may present with atypical/nonspecific symptoms.

EPIDEMIOLOGY Predominant age: 15 to 45 years

Incidence • Per year, 1.6 to 7.6/100,000 and increasing due to better diagnosis • Most common: African American women (8.1 to 11.4/100,000/year) • Least common: Caucasian men (0.3 to 0.9/100,000/year)

Prevalence Occurs in 30 to 50/100,000 and increasing due to increased survival

ETIOLOGY AND PATHOPHYSIOLOGY • Skin: photosensitivity; scaly erythematous, plaques with follicular plugging, dermal atrophy, and scarring; nonscarring erythematous psoriasiform/annular rash; alopecia; mucosal ulcers • Musculoskeletal: nonerosive arthritis; ligament and tendon laxity, ulnar deviation, and swan neck deformities; avascular necrosis

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• Renal: glomerulonephritis • Pulmonary: pleuritis, pleural effusion, alveolar hemorrhage, pneumonitis, interstitial fibrosis, pulmonary hypertension, pulmonary embolism (PE) • Cardiac: nonbacterial verrucous endocarditis, pericarditis, myocarditis, atherosclerosis • CNS: thrombosis of small intracranial vessels ± perivascular inflammation resulting in micro- or macroinfarcts ± hemorrhage • Peripheral nervous system: mononeuritis multiplex, peripheral neuropathy • GI: pancreatitis, peritonitis, colitis • Hematologic: hemolytic anemia, thrombocytopenia, leukopenia, lymphopenia • Vascular: vasculitis, thromboembolism • Most cases are idiopathic with possible environmental factors. • Drug-induced lupus: hydralazine, D penicillamine, quinidine, procainamide, minocycline, isoniazid, etc.

Genetics • Identical twins: 24–58% concordance • Fraternal twins and siblings: 2–5% concordance • 8-fold risk if first-degree relative with SLE • Major histocompatibility complex associations: HLA-DR2, HLA-DR3 • Deficiency of early complement components, especially C1q, C1r/s, C2, and C4 • Immunoglobulin receptor polymorphisms: FCγR2A, FCγR3A, and others • Polymorphism in genes associated with regulation of programmed cell death, protein tyrosine kinases, and interferon production

RISK FACTORS • Race: African Americans, Hispanics, Asians, and Native Americans • Predominant sex: females > males (8:1) • Environmental: UV light, infectious agents, stress, diet, drugs, hormones, vitamin D deficiency, and tobacco

COMMONLY ASSOCIATED CONDITIONS • Overlap syndromes: rheumatoid arthritis (RA), Sjögren syndrome, scleroderma

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• Antiphospholipid syndrome; coronary artery disease; nephritis; depression

DIAGNOSIS Consider SLE in multisystem disease including fever, fatigue, and signs of inflammation.

HISTORY • Fever, fatigue, malaise, weight loss, headache • Rash (butterfly/hyperpigmented ears or scalp), photosensitivity, alopecia • Oral/nasal ulcers (usually painless) • Arthritis, arthralgia, myalgia, weakness • Pleuritic chest pain, cough, dyspnea, hemoptysis • Early stroke (age 0.5 g/day or >3+) OR cellular casts (red cell, hemoglobin, granular, tubular, or mixed) – Neurologic disorder: psychosis/seizures – Hematologic disorder: hemolytic anemia, leukopenia (5 WBC/hpf in absence of infection, or cellular casts—RBC or WBC casts) (1) • Clinical manifestations primarily due to immune complex–mediated glomerular disease. Tubulointerstitial and vascular involvement often coexist. Diagnosis is based on clinical findings, urine abnormalities, autoantibodies, and renal biopsy. • Treatment and prognosis depend on International Society of Nephrology/Renal Pathology Society (ISN/RPS) histologic class—risk of end-stage renal disease (ESRD) highest in class IV. • Delay in diagnosis/treatment increases risk of ESRD.

EPIDEMIOLOGY • Peak incidence of SLE is 15 to 45 years of age. • Predominant sex: female > male (10:1) • Once SLE develops, lupus nephritis (LN) affects both genders equally; it is more severe in children and men and less severe in older adults.

Incidence • SLE: 1.4 to 21.9/100,000 • Up to 60% of SLE patients develop LN over time, and 25–50% of SLE patients have nephritis as the initial presentation.

Pediatric Considerations LN is more common and more severe in children: 60–80% have LN at or soon

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after SLE onset.

Prevalence SLE: 7.4 to 159.4/100,000

ETIOLOGY AND PATHOPHYSIOLOGY • Immune complex–mediated inflammation injures glomeruli, tubules, interstitium, and vasculature. • Glomeruli: Varying degrees of mesangial proliferation, crescent formation (see “Test Interpretation”), and fibrinoid necrosis cause reduced glomerular filtration rate (GFR). • Persistent inflammation (chronicity) leads to sclerosis and glomerular loss. • Tubulointerstitial injury (edema, inflammatory cell infiltrate acutely; tubular atrophy in chronic phase) with or without tubular basement membrane immune complex deposition leads to reduced renal function. • Vascular lesions: immune complex deposition and noninflammatory necrosis in arterioles • SLE is a multifactorial disease, with a multigenic inheritance; exact etiology remains unclear. • Defective T-cell autoregulation and polyclonal B-cell hyperactivity contribute to dysregulated apoptosis. Impaired clearance of apoptotic cells inhibits selftolerance to nuclear antigen • Anti-DNA, anti-C1q, anti-α-actin, and other nuclear component autoantibodies develop. • Deposition of circulating immune complexes or autoantibodies attaching to local nuclear antigens leads to complement activation, inflammation, and tissue injury. • Interaction of genetic, hormonal, and environmental factors leads to great variability in LN severity.

Genetics Multigenic inheritance; clustering in families, ~25% concordance in identical twins

RISK FACTORS Younger age, African American or Hispanic race, more ACR criteria for SLE,

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longer disease duration, hypertension, lower socioeconomic status, family history of SLE, anti-dsDNA antibodies

COMMONLY ASSOCIATED CONDITIONS Skin, hematologic, cerebral, pulmonary, GI, and cardiopulmonary systems are often involved in SLE.

DIAGNOSIS HISTORY Assess for risk factors and other signs/symptoms of SLE: rash, photosensitivity, arthritis, neurologic complaints, fever, weight loss, alopecia.

PHYSICAL EXAM • Hypertension, fever • Pleural/pericardial rub • Skin rash • Edema • Arthritis • Alopecia • Oral ulcers

DIFFERENTIAL DIAGNOSIS • Primary glomerular disease • Secondary renal involvement in other systemic disorders such as antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, Henoch-Schönlein purpura (HSP), antiglomerular basement membrane disease, and viral infections • Mixed connective tissue disorder may have glomerulonephritis indistinguishable from LN.

DIAGNOSTIC TESTS & INTERPRETATION • Renal biopsy is the gold standard for diagnosing and classifying LN. • Combine clinical data with serologic and renal biopsy patterns to differentiate LN from other conditions. • Active urine sediment suggests nephritis.

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• Autoantibodies, low C3, C4, and CH50 complement levels support LN diagnosis.

Initial Tests (lab, imaging) • Urinalysis may show hematuria, proteinuria, and active urine sediment (2)[C]. • Serum electrolytes, BUN, creatinine, albumin, routine serologic markers of SLE such as antinuclear antibody (ANA), anti-dsDNA, anti-Ro, anti-La, antiRNP, anti-Sm, antiphospholipid antibody, C3, C4, CH50, CBC with differential, and C-reactive protein (CRP) (2)[C] • CBC may show anemia, thrombocytopenia, and leukopenia. • Renal ultrasound (2)[C] Follow-Up Tests & Special Considerations • Monitor disease activity q3mo (2)[C]: urinalysis for hematuria and proteinuria; blood for C3, C4, anti-dsDNA, serum albumin, and creatinine. • Patients with estimated glomerular filtration rate (eGFR) of 50% “classic” subfoveal CNVMs. Verteporfin is administered IV, and a diode laser at 689 nm is applied to the CNVM. – Patients should be informed of a 50% blood in the Comparison of Age-Related Macular Degeneration Treatments Trials (CATT). Ophthalmology. 2015;122(2):391.e5–398.e5. 5. Berg K, Pedersen TR, Sandvik L, et al. Comparison of ranibizumab and bevacizumab for neovascular age-related macular degeneration according to LUCAS treat-and-extend protocol. Ophthalmology. 2015;122(1):146–152. 6. Heier JS, Boyer D, Nguyen QD, et al. The 1-year results of CLEAR-IT 2, a phase 2 study of vascular endothelial growth factor trap-eye dosed as-

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needed after 12-week fixed dosing. Ophthalmology. 2011;118(6):1098– 1106. 7. Chang AA, Li H, Broadhead GK, et al. Intravitreal aflibercept for treatmentresistant neovascular age-related macular degeneration. Ophthalmology. 2014;121(1):188–192. 8. Schmidt-Erfurth U, Waldstein SM, Deak GG, et al. Pigment epithelial detachment followed by retinal cystoid degeneration leads to vision loss in treatment of neovascular age-related macular degeneration. Ophthalmology. 2015;122(4):822–832. 9. Dirani A, Ambresin A, Marchionno L, et al. Factors influencing the treatment response of pigment epithelium detachment in age-related macular degeneration. Am J Ophthalmol. 2015;160(4):732.e2–738.e2. 10. Shienbaum G, Garcia Filho CA, Flynn HW Jr, et al. Management of submacular hemorrhage secondary to neovascular age-related macular degeneration with anti-vascular endothelial growth factor monotherapy. Am J Ophthalmol. 2013;155(6):1009–1013. 11. Bhisitkul RB, Mendes TS, Rofagha S, et al. Macular atrophy progression and 7-year vision outcomes in subjects from the ANCHOR, MARINA, and HORIZON Studies: the SEVEN-UP study. Am J Ophthalmol. 2015;159(5):915.e2–924.e2.

CODES ICD10 • H35.30 Unspecified macular degeneration • H35.32 Exudative age-related macular degeneration • H35.31 Nonexudative age-related macular degeneration

CLINICAL PEARLS • Patients frequently notice distortion of central vision. • Patients may notice straight lines appear crooked (e.g., telephone poles). • Hyperopia is a risk factor for ARMD. • The AREDS study found that a high-dose regimen of antioxidant vitamins and

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mineral supplements reduces progression of ARMD in some cases. • Tobacco cessation should be strongly encouraged.

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MALARIA Paul M. Arguin, MD BASICS DESCRIPTION • Acute or chronic infection transmitted to humans by Anopheles spp. mosquitoes • Most morbidity and mortality is caused by Plasmodium falciparum. An estimated 214 million cases occur annually, including 438,000 deaths, most of which occur in children 99%) are imported. • ~1,500 cases and 5 deaths per year in the United States (2)

Prevalence • Predominant age: all ages • Predominant sex: male = female

ETIOLOGY AND PATHOPHYSIOLOGY • Malarial parasites digest red blood cell (RBC) proteins and alter the RBC membrane, causing hemolysis, increased splenic clearance, and anemia. • RBC lysis stimulates release of cytokines and tumor necrosis factor-α (TNF-

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α) causing fever and systemic symptoms. • P. falciparum alters RBC viscosity, causing obstruction and end-organ ischemia.

Genetics Unknown genetic predilection but inherited conditions may affect disease severity and susceptibility (glucose-6-phosphate dehydrogenase deficiency, sickle cell disease or trait, and hereditary elliptocytosis)

RISK FACTORS • Travel to or migration from endemic areas (primarily sub-Saharan Africa) • Rarely, blood transfusion, mother-to-fetus transmission, and local autochthonous transmission

GENERAL PREVENTION • Mosquito avoidance: Use of insect repellent, wear clothing to cover exposed skin, use mosquito nets treated with permethrin, and avoid outdoor activity from dusk to dawn. • Malarial chemoprophylaxis when in endemic area – Mefloquine: Begin at least 2 weeks before arrival and continue for 4 weeks after leaving area. Adults, 250 mg (1 tablet) weekly; children ≤9 kg, 5 mg/kg; children >9 to 19 kg, 1/4 tablet weekly; children >19 to 30 kg, 1/2 tablet weekly; children >30 to 45 kg, 3/4 tablet weekly; children >45 kg as adult Caution: mefloquine-resistant areas – Atovaquone/proguanil: Begin 1 to 2 days before arrival and continue for 1 week after leaving area. Adults, 1 adult tablet daily; children 5 to 8 kg, 1/2 pediatric tablet daily; children 9 to 10 kg, 3/4 pediatric tablet daily; children 11 to 20 kg, 1 pediatric tablet daily; children 21 to 30 kg, 2 pediatric tablets daily; children 31 to 40 kg, 3 pediatric tablets daily; children >40 kg, 1 adult tablet daily – Doxycycline: Begin 1 to 2 days before arrival and continue for 4 weeks after leaving area. Adults, 100 mg daily; children, 2 mg/kg up to 100 mg daily (not for children 40 kg: 4 adult tablets once per day for 3 days – Artemether-lumefantrine (Coartem): tablet contains 20 mg artemether and 120 mg lumefantrine. Persons 5 to 2 weeks despite a normal-appearing TM. • Hospitalize all patients with acute mastoiditis for IV antibiotics. Consult ENT for drainage procedure. • Treat with broad-spectrum IV antibiotics; collect middle ear fluid cultures to guide-specific therapy. • If conservative treatment fails after 3 to 5 days, perform mastoidectomy to

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avoid intracranial complications.

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MEASLES, GERMAN (RUBELLA) Cody D. Mead, DO • Jeffrey M. Milch, DO, CPT, MC, FS, USA BASICS DESCRIPTION • A generally self-limited viral infection of children and adults, characterized by a mild, maculopapular rash, lymphadenopathy, and slight fever. Complications in normal populations are rare; however, nonimmune women who become infected with rubella while pregnant may have devastating fetal effects. • 25–50% of all rubella infections are asymptomatic (1,2)[A]. • System(s) affected: hematologic; nervous; pulmonary; exocrine; ophthalmologic; skeletal • Synonym(s): German measles; 3-day measles

Pregnancy Considerations • Pregnancy-associated rubella infection may lead to congenital rubella syndrome (CRS) with potentially devastating fetal outcomes. • CRS is present in up to 90% of fetuses exposed during the 1st trimester (2) [A]. • Screening pregnant women for rubella immunity and vaccinating nonimmune women is the most effective means to prevent CRS (2)[A]. • Although no case of vaccine-associated CRS has been reported, women should not become pregnant for at least 28 days after vaccination because vaccine-type virus can cross the placenta (2)[A]. • Polymerase chain reaction (PCR) detection of viral RNA in amniotic fluid and fetal blood sampling allow for rapid diagnosis of fetal infection after 15 weeks’ gestation (3)[B].

EPIDEMIOLOGY • 50- to 70-nm RNA togavirus of genus Rubivirus (1)[A] • 13 genotypes have been identified (4)[A]. • A live attenuated vaccine has been available in United States since 1969—

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primarily to prevent CRS. • Since 2004, all cases of rubella in United States have been imported, typically in travelers with inadequate immunity (1)[A]. • Average incubation: 14 days; range 12 to 23 days • Infectious period between 7 days before and 5 to 7 days after rash onset • Transmitted primarily via respiratory droplets • Most common in late winter and early spring • Humans are only natural hosts (1)[A].

Incidence • U.S. incidence: 6 months. • IVIG can be given for severe thrombocytopenia; most cases, however, are self-limited.

ONGOING CARE

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FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Individuals immune to rubella through natural infection or vaccine may be reinfected when reexposed; such infection is usually asymptomatic and detectable only by serology. Those who have received the vaccine have lower measurable IgG levels than those who had the natural disease. • In CRS, it is important to detect auditory and visual impairment early (2)[A]. • 2/3 of internationally adopted children have no written record of immunizations (4)[A].

PATIENT EDUCATION http://www.cdc.gov/rubella/

PROGNOSIS • Postnatal rubella: Complete recovery is typical. • CRS – Varied and unpredictable spectrum, ranging from stillbirth to normal infancy/childhood (1,2)[A] – Detectable levels of IgG persist for years and then may decline (does not drop at the expected 2-fold dilution/month). By age 5 years, 20% have no detectable antibody (2)[A]. – IgM may not be detectable until 1 month after birth and may persist for 6 to 12 months (2)[A]. – Overall mortality (up to 10%) is greatest during first 6 months. – 70% of encephalitis cases develop residual neurologic defects, including autistic syndrome. – Prognosis is excellent if only minor congenital defects are present.

COMPLICATIONS • Frequently leads to arthralgia/arthritis in women (up to 70%) (6) • Postinfectious encephalitis (1/5,000 cases) • Thrombocytopenic purpura (1/3,000 cases) • CRS: incidence dependent on trimester exposed • Rubella vaccine may rarely cause encephalitis or ITP. – ITP is self-limited and is not a contraindication to vaccination.

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REFERENCES 1. Centers for Disease Control and Prevention. Chapter 14: rubella. In: McLean H, Redd S, Abernathy E, et al, eds. Manual for the Surveillance of VaccinePreventable Diseases. 5th ed. Atlanta, GA: Centers for Disease Control and Prevention; 2014. http://www.cdc.gov/vaccines/pubs/surv-manual/chpt14rubella.html. Accessed July 29, 2016. 2. Centers for Disease Control and Prevention. Chapter 15: congenital rubella syndrome. In: McLean H, Redd S, Abernathy E, et al, eds. Manual for Surveillance of Vaccine—Preventable Diseases. 5th ed. Atlanta, GA: Centers for Disease Control and Prevention; 2014. http://www.cdc.gov/vaccines/pubs/surv-manual/chpt15-crs.html. Accessed July 29, 2016. 3. Abernathy ES, Hubschen JM, Muller CP, et al. Status of global virologic surveillance for rubella viruses. J Infect Dis. 2011;204(Suppl 1):S524–S532. 4. McLean HQ, Fiebelkorn AP, Temte JL, et al. Prevention of measles, rubella, congenital rubella syndrome, and mumps, 2013: summary recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2013;62(RR-04):1–34. 5. Lai J, Fay KE, Bocchini JA. Update on childhood and adolescent immunizations: selected review of US recommendations and literature: part 2. Curr Opin Pediatr. 2011;23(4):470–481. 6. White SJ, Boldt KL, Holditch SJ, et al. Measles, mumps, and rubella. Clin Obstet Gynecol. 2012;55(2):550–559.

ADDITIONAL READING • Centers for Disease Control and Prevention. Rubella. In: Atkinson W, Wolfe C, Hamborsky J, eds. Epidemiology and Prevention of Vaccine-Preventable Diseases. 13th ed. Atlanta, GA: Centers for Disease Control and Prevention; 2012:325–340. www.cdc.gov/vaccines/pubs/pinkbook/rubella.html. Accessed January 21, 2016. • Mongua-Rodriguez N, Díaz-Ortega JL, García-García L, et al. A systematic review of rubella vaccination strategies implemented in the Americas: impact on the incidence and seroprevalence rates of rubella and congenital rubella

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syndrome. Vaccine. 2013;31(17):2145–2151.

CODES ICD10 • B06.9 Rubella without complication • B06.00 Rubella with neurological complication, unspecified • P35.0 Congenital rubella syndrome

CLINICAL PEARLS • Rubella is typically a self-limited viral exanthematous infection of children and adults. • Nonimmune women who are infected with rubella while pregnant may have devastating fetal effects (CRS). • Immunization is the key prevention strategy.

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MEASLES (RUBEOLA) Herbert L. Muncie, Jr., MD • Nicholas E. Seeliger, MD BASICS DESCRIPTION • A highly communicable, acute viral illness characterized by an exanthematous maculopapular rash that begins at the head and spreads inferiorly to the trunk and extremities • Rash is preceded by fever and the classic triad of cough, coryza, and conjunctivitis (3 Cs). Koplik spots are pathognomonic lesions of the oral mucosa. • Public health problem in the developing world, with significant morbidity and mortality • System(s) affected: hematologic; lymphatic; immunologic; pulmonary; skin • Synonym: rubeola

EPIDEMIOLOGY • Transmission: direct contact with infectious droplets; highly contagious; 90% of nonimmune close contacts likely to become infected on exposure – Droplets can remain in the air for hours. • Infectivity is greatest during the prodromal phase. – Patients are considered contagious from 4 days before symptoms until 4 days after rash appears. – Immunocompromised patients are considered contagious for the entire duration of disease. • Incubation period: averages 12.5 days from exposure to onset of prodromal symptoms • Predominant age: varies based on local vaccine practices and disease incidence. In developing countries, most cases occur in children 4 weeks after first measles vaccine; the 5% of initial nonresponders almost always develop immunity after the second dose. Health care workers should have immunity verified and, if not immune, receive the vaccine (if not otherwise contraindicated). – Common adverse vaccine reactions Fever Febrile seizures are rare (102°F (39–40.5°C); can precipitate febrile seizures Fever onset >3 days after rash suggests complicated course. – “3 Cs” triad: cough, coryza, and conjunctivitis – Cough may persist for 2 weeks. – Prodromal symptoms typically intensify over 2 to 4 days, peaking on first day of rash before subsiding. • Other symptoms include loose stools, malaise, irritability, photophobia (from iridocyclitis), sore throat, headache, and abdominal pain.

PHYSICAL EXAM • Koplik spots – Pathognomonic of prodromal measles – 2- to 3-mm, gray–white, raised lesions on erythematous base on buccal mucosa – Occur ~48 hours before measles exanthem • Exanthematous rash (characteristic but not pathognomonic) – Maculopapular blanching rash – Begins at ears and hairline and spreads head to toe, reaching hips by day 2 – Discrete erythematous patches become confluent over time, particularly on the upper body. – Clinical improvement usually occurs within 48 hours after rash appears. – Rash fades in 3 to 4 days changing to a brownish color, followed by fine desquamation. • Lymphadenopathy and pharyngitis may be seen during exanthematous period.

DIFFERENTIAL DIAGNOSIS • Drug eruption • Rubella • Mycoplasma pneumoniae infection • Infectious mononucleosis • Parvovirus B19 infection, roseola • Enteroviruses • Rocky Mountain spotted fever, dengue

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• Toxic shock syndrome • Meningococcemia • Kawasaki disease

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Obtain serum sample and throat (or nasopharyngeal) swab. Molecular testing of serum and respiratory specimens is the most accurate method to confirm measles infection. IgM assay and measles RNA by real-time polymerase chain reaction (RT-PCR) • Measles virus–specific IgM assay from serum and saliva. Antibodies may be undetectable on first day of exanthem but are usually detectable by day 3. – Sensitivity: 77% within 72 hours of rash onset; 100% within 4 to 11 days after rash onset. If negative but rash lasts >72 hours, repeat. – IgM falls to undetectable levels 4 to 8 weeks after rash onset. • Measles virus–specific IgG may be undetectable up to 7 days after exanthem; levels peak 14 days after exanthem. – A 4-fold increase in IgG titers 14 days after an initial titer that was measured at least 7 days after rash onset is confirmatory. • Viral cultures for measles are not usually performed. • Mild neutropenia is common. • Liver transaminases and pancreatic amylase may be elevated, particularly in adults. • Chest x-ray if concern for secondary pneumonia

ALERT Report suspected measles cases to public health authorities.

TREATMENT GENERAL MEASURES • Place all patients with measles in respiratory isolation until 4 days after onset of rash; immunocompromised patients should be isolated for duration of illness.

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• Supportive therapy (i.e., antipyretics, antitussives, humidification, increased oral fluid consumption)

MEDICATION • No approved antiviral therapy is available. • Ribavirin – Measles virus is susceptible to ribavirin in vitro; data is limited. – Immunosuppressed children with severe measles have been treated with IV or aerosolized ribavirin.This use is not FDA approved. – In one trial of 100 children with measles treated with ribavirin or supportive care, ribavirin group had a shorter duration of fever, constitutional symptoms, and length of hospitalization. • Vitamin A: WHO recommends two consecutive days of dosages if living in vitamin A deficient region: – Children 12 months of age 200,000 IU • Antibiotics – Reserved for patients with clinical signs of bacterial superinfection (pneumonia, purulent otitis, pharyngitis/tonsillitis) (4)[B] – A small randomized, double-blinded trial resulted in an 80% (number needed to treat [NNT] = 7) decrease in measles-associated pneumonia with prophylactic antibiotics; consider in patients with a high risk of complications. • Outbreak control – A single measles case constitutes an outbreak. – Immunize contacts (individuals exposed or at risk of having been exposed) within 72 hours. Monovalent vaccine may be given to infants 6 months to 1 year of age, but two further doses of vaccine after 12 months must be given for immunization to be considered adequate. Monovalent or combination vaccine may be given to all measles-exposed susceptible individuals age >1 year if not contraindicated. Individuals not immunized within 72 hours of exposure should be

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excluded from school, child care, and health care settings (social quarantine) until 2 weeks after onset of rash in the last reported case of measles. – Immunoglobulin therapy (passive immunity) may be necessary for the following high-risk individuals exposed to measles and for whom vaccination is inappropriate: Children age 2 weeks of symptoms (3). • Bone scintigraphy

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– Diffuse linear vertical uptake in the posterior tibial cortex on the lateral view. – Stress fractures demonstrate a focal ovoid uptake. • High-resolution MRI reveals abnormal periosteal and bone marrow signals, which are useful for early discrimination of tibial stress fractures. • Increased pain and localized tenderness warrants further imaging with MRI due to concern for tibial stress fracture. • Exclude compartment syndrome using intracompartmental pressure testing.

TREATMENT GENERAL MEASURES • Activity modification with a gradual return to training based on improvement of symptoms • Patients should maintain fitness with low-impact activities such as swimming and cycling. • Continue activity modification until pain free on ambulation. • Good supportive footwear is recommended.

MEDICATION • Analgesia with acetaminophen or other oral nonsteroidal anti-inflammatory agent • Cryotherapy (ice massage) is also advised to relieve acute-phase symptoms (4)[C].

ADDITIONAL THERAPIES • Stretching of the gastrocnemius, soleus, and peroneal muscles are treatment mainstays (4)[C]. • Calf stretch, peroneal stretch, TheraBand exercises, and eccentric calf raises may improve endurance and strength (5)[A]. • Compression stockings have been used to treat MTSS with mixed results. • Structured running programs with warm-up exercises have not been demonstrated to reduce pain in young athletes (6)[B].

SURGERY/OTHER PROCEDURES

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• Surgical intervention includes a posterior medial fascial release in individuals with both – Severe limitation of physical activity and – Failure of 6 months of conservative treatment – Counsel patients that complete return of activity to sport may not be always achieved postoperatively. Surgical risks include infection and hematoma formation. • Extracorporeal shock wave therapy (ESWT) may decrease recovery time when added to a running program (5)[A].

COMPLEMENTARY & ALTERNATIVE MEDICINE • Individualized polyurethane orthoses may help chronic running injuries. • Special insoles, low-energy laser treatment, pulsed electromagnetic field, and knee braces have not been shown to improve outcomes (5)[A]. • Ultrasound, acupuncture, aquatic therapy, electrical stimulation, whirlpool baths, cast immobilization, taping, and steroid injection may help improve pain. • Physical therapy approaches including Kinesio tape and fascial distortion massage may yield quicker return to activity.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Avoid premature return to preinjury running pace. • Maintain stretching and strengthening exercises. • Identify and correct preinjury training errors. • Allow a gradual return to activity dictated by symptoms (pain).

PROGNOSIS The condition is usually self-limiting, and most patients respond well with rest and nonsurgical intervention.

COMPLICATIONS • Stress fractures and compartment syndrome

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• Undiagnosed MTSS or chronic exertional compartment syndrome can lead to a complete fracture or tissue necrosis, respectively.

REFERENCES 1. Fullem BW. Overuse lower extremity injuries in sports. Clin Podiatr Med Surg. 2014;32(2):239–251. 2. Hutchinson M. Chronic exertional compartment syndrome. Br J Sports Med. 2011;45(12):952–953. 3. Chang GH, Paz DA, Dwek JR, et al. Lower extremity overuse injuries in pediatric athletes: clinical presentation, imaging findings, and treatment. Clin Imaging. 2013;37(5):836–846. 4. Fields KB, Sykes JC, Walker KM, et al. Prevention of running injuries. Curr Sports Med Rep. 2010;9(3):176–182. 5. Winters M, Eskes M, Weir A, et al. Treatment of medial tibial stress syndrome: a systematic review. Sports Med. 2013;43(12):1315–1333. 6. Moen MH, Holtslag L, Bakker E, et al. The treatment of medial tibial stress syndrome in athletes; a randomized clinical trial. Sports Med Arthrosc Rehabil Ther Technol. 2012;4:12.

ADDITIONAL READING • Abelson B. The Tibialis Anterior Stretch–Kinetic Health. https://www.youtube.com/watch?v=6Z6XM63x2TM. Accessed June 19, 2014. • Hamstra-Wright KL, Bliven KC, Bay C. Risk factors for medial tibial stress syndrome in physically active individuals such as runners and military personnel: a systematic review and meta-analysis. Br J Sports Med. 2015;49(6):362–369. • Reshef N, Guelich DR. Medial tibial stress syndrome. Clin Sports Med. 2012;31(2):273–290.

CODES ICD10

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• S86.899A Other injury of other muscle(s) and tendon(s) at lower leg level, unspecified leg, initial encounter • S86.891A Other injury of other muscle(s) and tendon(s) at lower leg level, right leg, initial encounter • S86.892A Other injury of other muscle(s) and tendon(s) at lower leg level, left leg, initial encounter

CLINICAL PEARLS • MTSS is the preferred term for “shin splints.” • Diagnosis is based on a reliable history of repetitive overuse accompanied by characteristic shin pain. • MTSS pain is typically along the middle and distal third of the posteromedial tibial surface, worsened with activity, and relieved with rest. • Treatment includes ice, activity modification, analgesics, eccentric stretching, gait retraining, and a gradual return to activity. • Symptoms recur if return to activity is “too much too fast.”

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MELANOMA Carl Bryce, MD • Matthew J. Snyder, DO BASICS DESCRIPTION • Melanoma is a tumor arising from malignant transformation of cells from the melanocytic system. – Most arise in the skin but may also present as a primary lesion in any tissue: ocular, GI, GU, lymph node, and leptomeninges. – Metastatic spread to any site in the body • Main types of cutaneous melanoma include the following (1): – Superficial-spreading melanoma: 50–80% cases; occurs in sun-exposed areas (trunk, back, and extremities); most ~6 mm diameter at diagnosis; when seen in younger patients, presents as a flat, slow growing, irregularly bordered lesion – Nodular: 20–30%, present in older patients, often ulcerate and hemorrhage, most commonly thick and pigmented – Lentigo maligna (subtype of melanoma in situ): slowest growing; older population; occurs in sun-exposed areas (head, neck, forearms). Lentigo maligna melanoma (LMM) is its invasive counterpart. – Amelanotic melanoma (5 cm) are risk factors and have a >2% lifetime risk of malignant conversion. Blistering sunburns in childhood significantly increase risk.

Pregnancy Considerations No increased risk of melanoma in pregnancy. However, it is suggested waiting 1 to 2 years if further pregnancy is desired in case of recent melanoma. Melanoma can spread to the placenta.

EPIDEMIOLOGY Incidence • In 2016, an estimated 76,380 Americans were diagnosed with melanoma, with 10,130 expected deaths (2). • Predominant age: median age: 62 and 54 years for men and women respectively, >50% of all individuals with melanoma are between 20 and 40 years of age. • Predominant sex: male > female (1.5 times) • Incidence among whites greater than that among minority groups; ~20 times higher than blacks (1) • Minority groups demonstrate increased rates of metastasis, advanced stages at diagnosis, thicker initial lesions, earlier age at diagnosis, and overall poorer outcomes. • Low socioeconomic status associated with higher incidence of melanoma

Prevalence • Lifetime risk: men: 1/37; female: 1/56 • 2% of all cancer deaths • The most common cancer affecting women 25 to 29 years of age and second only to breast cancer in women 30 to 34 years of age (1)

ETIOLOGY AND PATHOPHYSIOLOGY

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• DNA damage by UV-A/UV-B exposure • Tumor progression: initially may be confined to epidermis with lateral growth, may then grow into dermis with vertical growth

Genetics • Dysplastic nevus syndrome is a risk factor for development of melanoma. Close surveillance is warranted. • 8–12% of patients with melanoma have a family history of disease. • Mutation in CDKN2A (p16) is found in 1/3 of patients with family incidence of melanoma. • Mutations in BRAF (V600E) implicated in 50–60% of cutaneous melanomas • Familial atypical mole malignant melanoma (FAMMM) syndrome characterized by >50 atypical moles, +FH of melanoma, clinical diagnosis (3)

RISK FACTORS • Genetic predisposition • UV-A and UV-B exposure • History of >5 sunburns during lifetime • History of intense intermittent sun exposure • Previous pigmented lesions (especially dysplastic melanocytic nevi) • Fair complexion, freckling, blue eyes, blond/red hair • Highest predictor of risk is increased number of nevi (>100). • Family/personal history of melanoma • Tanning bed use: 75% increased risk if first exposure before age 35 years • Changing nevus • Large (>5 cm) congenital nevi • Other skin cancers • Chronic immunosuppression (chronic lymphocytic leukemia, non-Hodgkin lymphoma, AIDS, or posttransplant) • Blistering sunburns in childhood • Living at high altitude (>700 meters or 2,300 feet above sea level) • Occupational exposure to ionizing radiation

GENERAL PREVENTION • Avoidance of sunburns, especially in childhood

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• Use of sunscreen with at least SPF 30 to all skin exposed to sunlight, reapplying regularly and after toweling or swimming • Avoid tanning beds; class 1 carcinogen by World Health Organization (WHO) • Screening of high-risk individuals, especially males >50 years • Education for proper diagnosis plays a large factor in prevention. • Any suspicious lesions should be biopsied with a narrow excision encompassing the entire breadth plus sufficient depth of the lesion. Options include elliptical excisions, punch, or shave biopsies.

COMMONLY ASSOCIATED CONDITIONS • Dysplastic nevus syndrome • >50 nevi. These individuals have higher lifetime risk of melanoma than the general population, as 50% of all melanoma arise in preexisting nevi. • Giant congenital nevus: 6% lifetime incidence of melanoma • Xeroderma pigmentosum is a rare condition associated with an extremely high risk of skin cancers, including melanoma. • Psoriasis after psoralen-UV-A (PUVA) therapy

DIAGNOSIS HISTORY • Change in a pigmented lesion: either hypo- or hyperpigmentation, bleeding, scaling, ulceration, or changes in size or texture • Obtain family and personal history of melanoma or nonmelanoma skin cancer. • Obtain social history including occupation, sunbathing, tanning, and other sun exposure.

PHYSICAL EXAM • ABCDE: Asymmetry, Border irregularity, Color variegation (especially red, white, black, blue), Diameter >6 mm, Evolution over time • Any new and/or changing nevus, bleeding/ulcerated • Location on Caucasians is primarily back and lower leg; on African Americans is the hands, feet, and nails • May include mucosal surfaces (nasopharynx, conjunctiva) • Individuals at high risk for melanoma should have careful ocular exam to

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assess for presence of melanoma in the iris and retina.

DIFFERENTIAL DIAGNOSIS • Dysplastic and blue nevi • Vascular skin tumor • Pigmented actinic keratosis • Traumatic hematoma • Pigmented squamous cell and basal cell carcinomas, seborrheic keratoses, other changing nevi

DIAGNOSTIC TESTS & INTERPRETATION • Lactate dehydrogenase (LDH), chest/abdomen/pelvic CT, MRI, and/or PET CT at baseline and in monitoring progression in metastatic disease (stage IV) (4) • Imaging studies only helpful in detecting and evaluating for progression of metastatic disease

Diagnostic Procedures/Other • Dermoscopy allows for magnification of lesions, allowing for a decreased number of biopsies of benign skin lesions in addition to providing increased sensitivity in detecting melanoma and basal cell carcinoma (5)[B]. • Surgical biopsy remains the standard of care. Any suspicious nevus should be excised, either by elliptical excision; a scoop shave (saucerization) technique may be appropriate, as long as a full-thickness can be achieved (1)[C]. • Sentinel lymph node biopsy, a staging procedure, remains an important factor for prognosis (4)[A].

Test Interpretation • Nodular melanoma is primarily vertical growth, whereas the other three types are horizontal. • Estimated that 1/10,000 dysplastic nevi become melanoma annually • Immunohistochemical testing increases sensitivity of lymph node biopsies. • Staging is based on the tumor-node-metastasis (TNM) criteria by current American Joint Committee on Cancer (AJCC) criteria, including: – (T) Thickness (mm) and ulceration – (N) Number of regional lymph nodes involved

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– (M) Distant metastases and serum LDH

TREATMENT GENERAL MEASURES Full surgical excision of melanoma is the standard of care. See below for recommended surgical margins.

MEDICATION • For stages I to III, surgical excision is curative in most cases; in patients with stage IV disease, systemic treatment with chemotherapy is recommended. • Preferred regimens (4)[A] include the following: – Ipilimumab (monoclonal antibody against CTLA-4) in combination with nivolumab (anti-PD-1 monoclonal antibody) demonstrated 61% response versus ipilimumab alone (6)[A]. – Vemurafenib (Zelboraf) or dabrafenib are BRAF inhibitors approved for metastatic, unresectable melanoma expressing BRAF V600E or V600K mutations. – High-dose interleukin-2 controversial (significant toxicity, 1–2% mortality related to treatment) – Referral for enrollment in clinical trials • Additional active regimens (e.g., dacarbazine [DTIC], temozolomide, paclitaxel, carmustine [BCNU], cisplatin, carboplatin, vinblastine); often limited to those who are not candidates to preferred regimens. • Imatinib (Gleevec) in tumors with C-KIT mutation • Interferon-α as adjuvant therapy received FDA approval in 1995 (high dose) and 2011 (pegylated) to treat stage IIB to III melanoma; shown to improve 4year relapse rate but no overall effect on survival; 1/3 of patients will discontinue due to toxicity (granulocytopenia, hepatotoxicity). Biochemotherapy is advocated by some (i.e., chemo + immunotherapy combination), although optimal regimen remains uncertain given disease heterogeneity (4)[B].

ISSUES FOR REFERRAL

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• Consultation with oncologist for consideration of chemotherapeutic options • Plastic surgery sometimes needed after final excision

ADDITIONAL THERAPIES Targeted immunotherapy using various vaccine preparations continues to demonstrate promising results, and randomized prospective trials are needed (7) [B].

SURGERY/OTHER PROCEDURES • Standard of care for melanoma includes early surgical excision with the following recommended margins (4)[A]: – In situ tumors: 0.5 cm margin has been the standard of care but may be insufficient in lentigo maligna. – Thickness of 1.01 to 2.00 mm: 1 to 2 cm margins – Thickness of >2.00 mm: 2 cm margins • Sentinel lymph node biopsy is indicated in patients with T2-, T3-, and T4staged melanomas. – Selected patients with stage T1b melanoma should also be considered for sentinel lymph node biopsy. – Not recommended in melanoma in situ or T1a • Mohs surgery is often used for lesions with ill-defined borders or lesions of head and neck. • Radiotherapy can be used to treat lentigo maligna in addition to certain head and neck lesions. • Palliative radiation therapy can be used with metastatic melanoma.

COMPLEMENTARY & ALTERNATIVE MEDICINE Molecular and mouse tumor model studies support role of topical silymarin (milk thistle derivative) in decreasing UV radiation–induced inflammation, oxidative stress, and carcinogenesis.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS Most treatments are done as outpatients with no stabilization needed.

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ONGOING CARE FOLLOW-UP RECOMMENDATIONS After diagnosis and treatment, close follow-up and skin protection (i.e., sunblock, UV protective clothing) are highly advised.

Patient Monitoring • Routine screening clinical skin examination annually for all persons >40 years is controversial and without proven benefit. • Total body photography and dermoscopy should be used for surveillance of skin lesions, most commonly used for patients with >5 atypical nevi. • For patients with a history of cutaneous melanoma, specialty guidelines suggest every 3 to 12 months depending on recurrence risk (4)[C], general agreement to plan annual examinations after 5 years stable. • Lab and imaging tests after diagnosis and treatment of stage I to II melanoma are low yield, have high false-positive rates, and are not recommended (4)[B].

DIET No data to support specific dietary manipulations; general recommendations from American Cancer Society for cancer prevention

PATIENT EDUCATION • Teach patients who are at risk, or have had melanoma, the principles of ABCDE examinations. • High-risk patients should perform monthly skin self-examinations and be taught to examine inaccessible areas. • Educating patients and their significant others to perform skin examinations regularly is of proven benefit to melanoma survivors. • Patients with a history of melanoma or dysplastic nevus syndrome should have regular total body examinations.

PROGNOSIS • Breslow depth (thickness) in millimeters remains among strongest predictors of prognosis. • Median age at death 68 years

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• Highest survival seen in women male (1.3:1) • Race/ethnicity: white, Northern European > blacks

Incidence Estimates 1 to 150/100,000 per year

Prevalence Varies from 7.5 to >200/100,000

ETIOLOGY AND PATHOPHYSIOLOGY • Not fully understood; theories include increased pressure of the endolymph fluid due to increased fluid production or decreased resorption. This may be caused by endolymphatic sac pathology, abnormal development of the vestibular aqueduct, or inflammation caused by circulating immune

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complexes. Increased endolymph pressure may cause rupture of membranes and changes in endolymphatic ionic gradient. • Ménière syndrome may be secondary to injury or other disorders (e.g., reduced middle ear pressure, allergy, endocrine disease, lipid disorders, vascular, viral, syphilis, autoimmune). Any disorder that could cause endolymph hydrops could be implicated in Ménière syndrome.

Genetics Some families show increased incidence, but genetic and environmental influences are incompletely understood.

RISK FACTORS May include • Stress • Allergy • Increased salt intake • Caffeine, alcohol, or nicotine • Chronic exposure to loud noise • Family history of Ménière • Certain vascular abnormalities (including migraines) • Certain viral exposures (especially herpes simplex virus [HSV])

GENERAL PREVENTION Reduce known risk factors: stress; salt, alcohol, and caffeine intake; smoking; noise exposure; ototoxic drugs (e.g., aspirin, quinine, aminoglycosides).

COMMONLY ASSOCIATED CONDITIONS • Anxiety (secondary to the disabling symptoms) • Migraines • Hyperprolactinemia • Hypothyroidism

DIAGNOSIS Diagnosis is clinical.

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HISTORY • Symptomatic episodes are typically spontaneous but may be preceded by an aura of increasing fullness in the ear and tinnitus. These may occur in clusters, with long periods of symptom-free remissions. • Formal criteria for diagnosis from American Academy of Otolaryngology– Head and Neck Surgery: – At least two episodes of rotational-horizontal vertigo >20 minutes in duration – Tinnitus or aural fullness – Hearing loss: Low frequency (sensorineural) is confirmed by audiometric testing. – Other causes (e.g., acoustic neuroma) excluded. – During severe attacks: pallor, sweating, nausea, vomiting, falling, prostration – Symptoms are exacerbated by motion.

PHYSICAL EXAM • Physical exam rules out other conditions; no finding is unique to Ménière disease. • Horizontal nystagmus may be seen during attacks. • Otoscopy is typically normal. • Triggering of attacks in the office with Dix-Hallpike maneuver suggests diagnosis of benign paroxysmal positional vertigo, not Ménière disease.

DIFFERENTIAL DIAGNOSIS • Acoustic neuroma or other CNS tumor • Syphilis • Third window syndromes • Endolymphatic sac tumor • Viral labyrinthitis • Transient ischemic attack (TIA), migraine • Vertebrobasilar disease • Other labyrinthine disorders (e.g., Cogan syndrome, benign positional vertigo, temporal bone trauma) • Diabetes or thyroid dysfunction

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• Vestibular neuronitis • Medication side effects • Otitis media • Autoimmune inner ear disease • Autosomal dominant sensorineural hearing loss

DIAGNOSTIC TESTS & INTERPRETATION Testing is done to rule out other conditions but does not necessarily confirm or exclude Ménière disease.

Initial Tests (lab, imaging) • Consider serologic tests specific for Treponema pallidum in at-risk populations. • Thyroid, fasting blood sugar, and lipid studies • Consider MRI to rule out acoustic neuroma or other CNS pathology, including tumor, aneurysm, and multiple sclerosis (MS).

Diagnostic Procedures/Other • Auditory – Audiometry using pure tone and speech to show low-frequency sensorineural (nerve) loss and impaired speech discrimination; usually shows low-frequency sensorineural hearing loss – Tuning fork tests (i.e., Weber and Rinne) ABR or MRI to rule out acoustic neuroma – Electrocochleography may be useful to confirm etiology. • Vestibular – Caloric testing: Reduced activity on either side is consistent with Ménière diagnosis but is not itself diagnostic. – Head-impulse testing (1)[C]

Test Interpretation • Histologic temporal bone analysis (at autopsy); dilation of inner ear fluid system, neuroepithelial damage with hair cell loss, basement membrane thickening, and perivascular microvascular damage • Cytochemical analysis can reveal altered AQP4 and AQP6 expression in the supporting cell, altered cochlin, and mitochondrial protein expression (2)[B].

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• Familial Ménière disease has been associated with DTNA and FAM136A genes (3)[B].

TREATMENT • Usually managed in outpatient setting • A paucity of evidence-based guidelines exists; therefore, there is no gold standard treatment. • Medications are primarily for symptomatic relief of vertigo and nausea. • During attacks, bed rest with eyes closed prevents falls. Attacks rarely last >4 hours.

MEDICATION First Line • Acute attack: Initial goal is stabilization and symptom relief. For severe episodes – Benzodiazepines (such as diazepam): decrease vertigo and anxiety – Antihistamines (meclizine/dimenhydrinate): decrease vertigo and nausea – Anticholinergics (transdermal scopolamine): reduces nausea and emesis associated with motion sickness – Antidopaminergic agents (metoclopramide, promethazine): decrease nausea, anxiety – Rehydration therapy and electrolyte replacement – Steroid taper for acute hearing loss • Maintenance (goal is to prevent/reduce attacks) – Lifestyle changes (e.g., low-salt diet) are needed. – Diuretics may help reduce attacks by decreasing endolymphatic pressure and volume; there is insufficient evidence to recommend routine use: Hydrochlorothiazide; hydrochlorothiazide/triamterene (Dyazide, Maxzide) Acetazolamide (Diamox) • Contraindications/warnings: – Atropine: cardiac disease, especially supraventricular tachycardia and other arrhythmias, prostatic enlargement

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– Scopolamine: children and elderly, prostatic enlargement – Diuretics: electrolyte abnormalities, renal disease • Precautions: – Sedating drugs should be used with caution, particularly in the elderly. Patients are cautioned not to operate motor vehicles or machinery. Atropine and scopolamine should be used with particular caution. – Diuretics: Monitor electrolytes. • Significant possible interactions: transdermal scopolamine: anticholinergics, antihistamines, tricyclic antidepressants, other

Second Line • Steroids, both intratympanic and systemic (PO or IV) have been used for longer treatment of hearing loss: – Addition of prednisone 30 mg/day to diuretic treatment reduced severity and frequency of tinnitus and vertigo in one pilot study. • In Europe, betahistine, a histamine agonist is routinely used (unavailable in the United States). Other vasodilators, such as isosorbide dinitrate, niacin, and histamine, have also been used; evidence of their effectiveness is incomplete. • Evidence is lacking for routine use of Famvir; may improve hearing more than balance • Intratympanic gentamicin has shown to improve vertigo (4)[B].

ISSUES FOR REFERRAL • Consider ear, nose, throat/neurology referral. • Patients should have formal audiometry to confirm hearing loss.

ADDITIONAL THERAPIES • Application of intermittent pressures via a myringotomy using a Meniett device has been shown to relieve vertigo (5)[B]: – Safe; requires a long-term tympanostomy tube • Vestibular rehabilitation may be beneficial for patients with persistent vestibular symptoms: – Safe and effective for unilateral vestibular dysfunction

SURGERY/OTHER PROCEDURES • Interventions that preserve hearing:

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– Endolymphatic sac surgery, either decompression or drainage of endolymph into mastoid or subarachnoid space Less invasive; may decrease vertigo; may influence hearing/tinnitus – Endolymphatic sac surgery is effective in controlling vertigo in short- and long-term follow-up in at least 75% of patients with Ménière disease who failed medical therapy (6)[A]. – Vestibular nerve section (intracranial procedure) More invasive Decreases vertigo and preserves hearing – Tympanostomy tube: may decrease symptoms by decreasing the middle ear pressure • Interventions for patients with no serviceable hearing: – Labyrinthectomy: very effective at controlling vertigo but causes deafness – Vestibular neurectomy – Endoscopic vestibular nerve section (7)[B] – Cochlear implantation has shown to improve tinnitus and quality of life (8) [B].

COMPLEMENTARY & ALTERNATIVE MEDICINE Insufficient evidence to support effectiveness, but many integrative techniques have been tried, including the following: • Acupuncture, acupressure, tai chi • Niacin, bioflavonoids, Lipoflavonoids, ginger, ginkgo biloba, and other herbal supplements

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring Due to the possibility of progressive hearing loss despite decrease in vertiginous attacks, it is important to monitor changes in hearing and to monitor for more serious underlying causes (e.g., acoustic neuroma).

DIET

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• Diet is usually not a factor, unless attacks are brought on by certain foods. • A low salt is often recommended but not proven effective in randomized controlled trials.

PROGNOSIS • Alert patients about the nature of alternating attacks and remission. • Between attacks, patient may be fully active but is often limited due to fear or lingering symptoms. This can be severely disabling. • 50% resolve spontaneously within 2 to 3 years. • Some cases last >20 years. • Severity and frequency of attacks diminish, but hearing loss is often progressive. • 90% can be treated successfully with medication; 5–10% of patients require surgery for incapacitating vertigo.

COMPLICATIONS Loss of hearing; injury during attack; inability to work

REFERENCES 1. Lee SU, Kim HJ, Koo JW, et al. Comparison of caloric and head-impulse tests during the attacks of Meniere’s disease [published online ahead of print June 16, 2016]. Laryngoscope. 2. Ishiyama G, Lopez IA, Sepahdari AR, et al. Meniere’s disease: histopathology, cytochemistry, and imaging. Ann N Y Acad Sci. 2015;1343:49–57. 3. Frejo L, Giegling I, Teggi R, et al. Genetics of vestibular disorders: pathophysiological insights. J Neurol. 2016;263 Suppl 1:S45–S53. 4. Casani AP, Cerchiai N, Navari E, et al. Intratympanic gentamicin for Meniere’s disease: short- and long-term follow-up of two regimens of treatment. Otolaryngol Head Neck Surg. 2014;150(5):847–852. 5. Ahsan SF, Standring R, Wang Y. Systematic review and meta-analysis of Meniett therapy for Meniere’s disease. Laryngoscope. 2015;125(1):203–208. 6. Setty P, Babu S, LaRouere MJ, et al. Fully endoscopic retrosigmoid vestibular nerve section for refractory Meniere disease. J Neurol Surg B Skull Base. 2016;77(4):341–349.

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7. Sood AJ, Lambert PR, Nguyen SA, et al. Endolymphatic sac surgery for Ménière’s disease: a systematic review and meta-analysis. Otol Neurotol. 2014;35(6):1033–1045. 8. Mick P, Amoodi H, Arnoldner C, et al. Cochlear implantation in patients with advanced Ménière’s disease. Otol Neurotol. 2014;35(7):1172–1178.

SEE ALSO • Hearing Loss; Labyrinthitis; Tinnitus • Algorithm: Vertigo

CODES ICD10 • H81.09 Meniere’s disease, unspecified ear • H81.01 Meniere’s disease, right ear • H81.02 Meniere’s disease, left ear

CLINICAL PEARLS • Ménière disease is characterized by vertigo, hearing loss, and tinnitus +/− aural fullness. • There is a wide differential diagnosis for Ménière disease; therefore, one must fully investigate symptoms. • Multiple medical, surgical, and rehabilitative treatments are available to decrease the severity and frequency of attacks.

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MENINGITIS, BACTERIAL Felix B. Chang, MD, DABMA, FAAMA BASICS DESCRIPTION • A potentially life-threatening bacterial infection of the meninges • System affected: nervous

EPIDEMIOLOGY • Predominant age: neonates, infants, and elderly • Predominant sex: male = female

Incidence • CT > LP). • Vigorous supportive care to ensure prompt recognition of seizures and prevention of aspiration

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MEDICATION Empiric antibiotic IV therapy (with dexamethasone when indicated) until culture results are available • Consider local patterns of bacterial sensitivity.

First Line • Neonates • Ampicillin: 150 mg/kg/day divided q8h AND • Cefotaxime 150 mg/kg/day divided q8h • Infants >4 weeks of age (3,4)[A] – Ceftriaxone: 100 mg/kg/day divided q12–24h or cefotaxime 225 to 300 mg/kg/day divided q6–8h AND – Vancomycin: 60 mg/kg/day divided q6h • Adults (3,4)[A] – Vancomycin: loading dose 25 to 30 mg/kg IV then 15 to 20 mg/kg q8–12h with goal trough of 15 to 20 AND – Ceftriaxone: 2 g IV q12h OR – Cefotaxime: 2 g IV q4–6h – >50 years, add ampicillin: 2 g IV q4h for Listeria – Immunocompromised use vancomycin, ampicillin, ceftazidime, and acyclovir. • Precaution: aminoglycoside ototoxicity • Penicillin-allergic patients (3,4)[A] – Chloramphenicol: 1 g IV q6h AND – Vancomycin: loading dose 25 to 30 mg/kg IV then 15 to 20 mg/kg q8–12h (goal trough of 15 to 20) • Treatment duration – S. pneumoniae: 10 to 14 days – N. meningitidis, H. influenzae: 7 to 10 days – Group B Streptococcus organisms, E. coli, L. monocytogenes: 14 to 21 days – Neonates: 12 to 21 days or at least 14 days after a repeated culture is sterile • Corticosteroids (5)[A] – Pediatrics Early treatment with dexamethasone (0.15 mg/kg IV q6h for 2 to 4 days)

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decreases mortality and morbidity for patients >1 month of age with acute bacterial meningitis with no increased risk of GI bleeding. Corticosteroids are associated with lower rates of hearing loss and neurologic sequelae. – Adults (5)[A] Initiate in adults, and continue only if CSF Gram stain is gram-positive diplococcus or if blood or CSF positive for S. pneumoniae. Nonsignificant reduction in mortality (RR) 0.90, 95% CI 0.53–1.05. pvalue = 009 Lower rates of severe hearing loss (RR 0.67, 95% CI 0.51–0.88), any hearing loss (RR 0.74, 95% CI 0.63–0.87), and neurological sequelae (RR.0.83, 95% CI 0.69–1.00) Decreased mortality in Streptococcus pneumonia (RR 0.8, 95% CI 0.20– 0.59) but not in H. influenza or N. meningitidis Associated with increased recurrent fever (RR 1.27, 95% CI 1.09–1.47) – Dexamethasone: 0.15 mg/kg IV q6h (start 15 to 20 minutes before or with antibiotic) for 4 days – Dexamethasone should only be continued if the CSF Gram stain and/or CSF or blood culture reveal Streptococcus pneumonia.

Second Line Antipseudomonal penicillins • Aztreonam • Quinolones (e.g., ciprofloxacin) • Meropenem

ISSUES FOR REFERRAL Consultation from infectious disease and/or critical care specialist

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Bacterial meningitis requires hospitalization. – ICU monitoring may be needed. – Patients with suspected meningococcal infection require respiratory isolation for 24 hours.

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• Consider home therapy to complete IV antibiotics once clinically stable and culture/sensitivity results are known.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Brainstem auditory—evoked response hearing test for infants before hospital discharge • Vaccinations – 4 doses Hib conjugate vaccine recommended during infancy – Meningococcal conjugate vaccine quadrivalent (MCV4) is given to children aged 11 to 12 years with a booster at 16 years. – Immunizing infants 48 hours with normal neurologic exam in an immunocompetent patient with confirmed normal level of alertness, BM is extremely unlikely and LP is not warranted. Others argue that BM cannot be excluded clinically and to exercise caution discharging meningitic patients without LP. – Bacterial Meningitis Score (BMS): The BMS is a validated clinical decision rule to identify children (≥29 days of age) at very low risk of BM with sensitivity of 99.6%. Low-risk features include negative CSF Gram stain, CSF absolute neutrophil count (ANC) 1.5 cm2 and mean pressure gradient 1.5 cm2, severe MS: 75 years, Diabetes mellitus, and prior Stroke or transient ischemic attack) score 5 mm or valve redundancy) and a history of stroke, warfarin therapy may be considered (3) [C].

ADDITIONAL THERAPIES • Endocarditis prophylaxis is no longer recommended for patients with MVP. • Patients with prior endocarditis undergoing dental, respiratory tract, infected skin, or musculoskeletal procedures should receive prophylaxis for endocarditis with amoxicillin 30 to 60 minutes prior to procedure. Ampicillin, cefazolin, or ceftriaxone IM or IV may be used if unable to tolerate oral medications (3)[B].

SURGERY/OTHER PROCEDURES • Referral for surgery is recommended for patients with severe MR with impaired LV systolic function or flail leaflet owing to ruptured chordae tendineae (3)[C]. • One recent meta-analysis of observational studies suggests a benefit for an early surgical approach to MVP with severe MR (5)[A] even for asymptomatic patients; prospective studies are lacking. • Minimally invasive mitral valve repair patients have shorter postoperative hospital stay compared with conventional median sternotomy open repair for patients with bileaflet prolapse and severe MR. • Surgical repair of MR due to isolated posterior leaflet prolapse is associated with a low reoperation rate (6)[A].

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• Asymptomatic patients with atrial fibrillation or pulmonary hypertension should be considered for intervention as well (2)[C].

ONGOING CARE FOLLOW-UP RECOMMENDATIONS • Asymptomatic MVP patients with no significant MR can be followed clinically every 3 to 5 years (3)[C]. • Patients who are symptomatic or have high-risk features on initial echocardiogram, including moderate to severe MR, may need serial echocardiograms and should be followed clinically once per year (3)[C]. • Patients with MVP and severe MR may require coronary angiography and transesophageal echocardiography if cardiac surgical referral is planned (3) [C].

PATIENT EDUCATION • No contraindication to pregnancy • Restriction from competitive sports if patient has MVP with one of the following features: – A history of syncope associated with documented arrhythmia – A family history of MVP-related sudden cardiac death – Sustained or repetitive and nonsustained supraventricular tachycardia or frequent and/or complex ventricular tachyarrhythmias on ambulatory Holter monitoring – Severe MR – A prior embolic event – LV systolic dysfunction • Explain the hereditary nature of familial MVP.

PROGNOSIS • Excellent prognosis for asymptomatic patients • For patients with severe MR or reduced ejection fraction, the prognosis is similar to that for nonischemic MR.

COMPLICATIONS

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• Sudden cardiac death: not clearly established. May be secondary to ventricular arrhythmias especially if significant MR is present • Chordae rupture with acute mitral insufficiency (higher risk of cardiac death; up to 2% per year) • Infectious endocarditis (risk increased if murmur present) • Cerebrovascular ischemic event • Fibrin emboli • Heart failure with progressive MR • Arrhythmias such as atrial and ventricular premature beats, paroxysmal supraventricular tachycardias may all be seen. Risk increases with coexistent MR. • Pulmonary hypertension

REFERENCES 1. Freed LA, Levy D, Levine RA, et al. Prevalence and clinical outcome of mitral-valve prolapse. N Engl J Med. 1999;341(1):1–7. 2. Verma S, Mesana TG. Mitral-valve repair for mitral-valve prolapse. N Engl J Med. 2009;361(23):2261–2269. 3. Bonow RO, Carabello BA, Chatterjee K, et al. 2008 Focused update incorporated into the ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1998 guidelines for the management of patients with valvular heart disease). Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol. 2008;52(13):e1–e142. 4. Shah PM. Current concepts in mitral valve prolapse—diagnosis and management. J Cardiol. 2010;56(2):125–133. 5. Goldstone AB, Patrick WL, Cohen JE, et al. Early surgical intervention or watchful waiting for the management of asymptomatic mitral regurgitation: a systematic review and meta-analysis. Ann Cardiothorac Surg. 2015;4(3):220– 229. 6. Johnston DR, Gillinov AM, Blackstone EH, et al. Surgical repair of posterior

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mitral valve prolapse: implications for guidelines and percutaneous repair. Ann Thorac Surg. 2010;89(5):1385–1394.

ADDITIONAL READING Zuppiroli A, Mori F, Favilli S, et al. Arrhythmias in mitral valve prolapse: relation to anterior mitral leaflet thickening, clinical variables, and color Doppler echocardiographic parameters. Am Heart J. 1994;128(5):919–927.

CODES ICD10 I34.1 Nonrheumatic mitral (valve) prolapse

CLINICAL PEARLS • MVP patients may have orthostatic hypotension and tachycardia. • Asymptomatic MVP patients with no significant MR can be followed clinically every 3 to 5 years. Patients who are symptomatic or have high-risk features on initial echocardiogram, including moderate to severe MR, may need serial echocardiograms and should be followed clinically once per year. • Consider an early surgical approach for MVP with severe MR. • Endocarditis prophylaxis is no longer recommended for MVP.

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MOLLUSCUM CONTAGIOSUM Erica F. Crannage, PharmD, BCPS, BCACP • Rupal Trivedi, MD BASICS DESCRIPTION Molluscum contagiosum is a common, benign, viral (poxvirus) skin infection, characterized by small (2 to 5 mm), waxy white or flesh-colored, dome-shaped papules with central umbilication. When lesions are opened, a creamy, whitegray material can be expressed. Molluscum contagiosum is highly contagious and spreads by autoinoculation, skin-to-skin contact, sexual contact, and shared clothing/towels. Molluscum contagiosum is a self-limited infection in immunocompetent patients but can be difficult to treat and disfiguring in immunocompromised patients.

EPIDEMIOLOGY Prevalence • 1% in the United States, occurring mainly in children 2 to 15 years and sexually active young adults • 5–18% HIV population

ETIOLOGY AND PATHOPHYSIOLOGY • DNA virus; Poxviridae family • Four genetic virus types, clinically indistinguishable • Virions invade and replicate in cytoplasm of epithelial cells causing abnormal cell proliferation • Genome encodes proteins to evade host immune system. • Incubation period: 2 to 6 weeks • Time to resolution: 6 to 24 months • Not associated with malignancy • No cross-hybridization or reactivation by other poxviruses

RISK FACTORS

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• Skin-to-skin contact with infected person • Contact sports • Swimming • Eczema, atopic dermatitis • Sexual activity with infected partner • Immunocompromised: HIV, chemotherapy, corticosteroid therapy, transplant patients

GENERAL PREVENTION • Avoid skin-to-skin contact with host (e.g., contact sports, sexual activity). • Avoid sharing clothing and towels.

COMMONLY ASSOCIATED CONDITIONS • Atopic dermatitis • Immunosuppression medications: corticosteroids, chemotherapy • HIV/AIDS

DIAGNOSIS HISTORY • Contact with known infected person • Participation in contact sports • Sexual activity

PHYSICAL EXAM • Perform thorough skin exam including conjunctiva and anogenital area • Discrete, firm papules with a central umbilication • Umbilication is not obvious in small children. • White curdlike core under umbilicated center • Lesions are flesh, pearl, or red in color. • May have surrounding erythema or dermatitis • Immunocompetent hosts: average of 11 to 20 lesions, 2 to 5 mm diameter (range: 1 to 10 mm) • Hosts with HIV/AIDS: hundreds of widespread lesions • Children: trunk, extremities, face, anogenital region

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• Sexually active: inner thighs, anogenital area

Pediatric Considerations • Infants 50 lesions, limited response to therapy, consider immunodeficiency • Children: anogenital lesions, consider autoinoculation/possible sexual abuse

DIFFERENTIAL DIAGNOSIS • AIDS patients: cryptococcus, penicilliosis, histoplasmosis, coccidioidomycosis • Basal cell carcinoma • Benign appendageal tumors: syringomas, hydrocystomas, ectopic sebaceous glands • Condyloma acuminatum • Dermatofibroma • Eyelid: abscess, chalazion, foreign-body granuloma • Folliculitis/furunculosis • Keratoacanthoma • Oral squamous cell carcinoma • Trichoepithelioma • Verruca vulgaris • Warty dyskeratoma

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Virus cannot be cultured. • Culture lesion if concern is secondary infection • Sexual transmission: Test for other sexually transmitted infections, including HIV. • Microscopy: scrape lesion – Core material has characteristic Henderson-Paterson intracytoplasmic viral inclusion bodies. – Crush prep with 10% potassium hydroxide will show characteristic inclusion bodies as well.

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– Alternatively, hematoxylin-eosin-stained formalin-fixed tissue shows same confirmatory features.

Diagnostic Procedures/Other Clinical; using magnifying lens

Tests Interpretation Molluscum cytoplasmic inclusion bodies within keratinocytes

TREATMENT GENERAL MEASURES • In healthy patients, molluscum contagiosum is generally self-limited and heals spontaneously. • No single intervention is shown to be convincingly more effective than any other in treating molluscum contagiosum (1)[B]. • No treatment is FDA-approved for treatment of molluscum contagiosum. • Three categories of treatment: destructive, immune-enhancing, and antiviral

MEDICATION First Line • Cantharidin 0.7–0.9% solution: In office application to lesions, cover with dressing; wash off in 2 to 6 hours or sooner if blistering. Repeat treatment every 2 to 4 weeks until lesions resolve (1)[B],(2,3)[C]. – Not commercially available in the United States but may be obtained from Canada – Adverse effects: blistering, erythema, pain, pruritus – Precautions: Do not use on face or on genital mucosa.

Second Line • Benzoyl peroxide 10% cream: Apply to each lesion twice daily for 4 weeks (1)[B]. – Inexpensive – Adverse effects: mild dermatitis • For immunocompromised patients with refractory lesions, consider

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– Starting or maximizing HAART therapy in patients with HIV/AIDS (4)[C] – Cidofovir 3% cream applied to lesions once daily, 5 days/week for 8 weeks (4)[C] 1% cream applied to lesions once daily, 5 days/week for 2 weeks, repeat in 1 month, if necessary (4)[C] Adverse effects with topical use: erythema, pain, pruritus, erosions 3 to 5 mg/kg IV weekly for 1 to 2 weeks, followed by IV infusions every other week, until clinical clearance or up to 9 infusions (5)[C] Adverse effects with IV use: nephrotoxicity, neutropenia Monitoring with IV use: renal function and complete blood counts prior to and 24 to 48 hours after infusions Precaution: Must coadminister oral probenecid and provide IV hydration with each IV infusion; refer to cidofovir manufacturer’s recommendations on dosing. – Ingenol mebutate 0.015% gel applied to lesions once daily for 3 days; may repeat once if needed (6)[C] very expensive Adverse effects: erythema, irritation

SURGERY/OTHER PROCEDURES Considered first line • Cryotherapy: 5 to 10 seconds with 1- to 2-mm margins; repeat every 3 to 4 weeks as needed until lesions disappear (7)[B]. – Adverse effects: erythema, edema, pain, blistering – Contraindications: cryoglobulinemia, Raynaud disease • Curettage under local or topical anesthesia (1)[A],(8)[B] – Adverse effects: pain, scarring

COMPLEMENTARY & ALTERNATIVE MEDICINE • Australian lemon myrtle oil: Apply 10% solution once daily for 21 days (9) [B]. • Potassium hydroxide 5–10% solution: Apply 1 to 2 times a day until the lesions disappeared completely (10)[B].

Pediatric Considerations • Surgical interventions: Second line in small children due to associated pain

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• Pain control: Pretreat with topical lidocaine or EMLA before surgical treatment. • Note: Adverse effect: – Lidocaine or EMLA over large body surface area: Methemoglobinemia and CNS toxicity. Refer to manufacturer’s recommendations on dosing and use in children.

Pregnancy Considerations Safe in pregnancy: curettage, cryotherapy, incision, and expression

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring Depends on type of treatment

PATIENT EDUCATION • Cover lesions to prevent spread. • Avoid scratching. • Avoid contact sports. • Avoid sharing towels and clothing. • Avoid sexual activity when lesions present.

PROGNOSIS • Immunocompetent: self-limited, resolves in 3 to 12 months (range: 2 months to 4 years) • Immunocompromised: lesions difficult to treat; may persist for years

COMPLICATIONS • Secondary infection • Scarring, hyper-/hypopigmentation

REFERENCES 1. van der Wouden JC, Menke J, Gajadin S, et al. Interventions for cutaneous molluscum contagiosum. Cochrane Database Syst Rev. 2006;

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(2):CD004767. 2. Moye V, Cathcart S, Burkhart CN, et al. Beetle juice: a guide for the use of cantharidin in the treatment of molluscum contagiosum. Dermatol Ther. 2013;26(6):445–451. 3. Silverberg NB, Sidbury R, Mancini AJ. Childhood molluscum contagiosum: experience with cantharidin therapy in 300 patients. J Am Acad Dermatol. 2000;43(3):503–507. 4. Chen X, Anstey AV, Bugert JJ. Molluscum contagiosum virus infection. Lancet Infect Dis. 2013;13(10):877–888. 5. Erikson C, Driscoll M, Gaspari A. Efficacy of intravenous cidofovir in the treatment of giant molluscum contagiosum in a patient with human immunodeficiency virus. Arch Dermatol. 2011;147(6):652–654. 6. Javed S, Tyring SK. Treatment of molluscum contagiosum with ingenol mebutate. J Am Acad Dermatol. 2014;70(5):e105. 7. Al-Mutairi N, Al-Doukhi A, Al-Farag S, et al. Comparative study on the efficacy, safety, and acceptability of imiquimod 5% cream versus cryotherapy for molluscum contagiosum in children. Pediatr Dermatol. 2010;27(4):388–394. 8. Hanna D, Hatami A, Powell J, et al. A prospective randomized trial comparing the efficacy and adverse effects of four recognized treatments of molluscum contagiosum in children. Pediatr Dermatol. 2006;23(6):574– 579. 9. Burke BE, Baillie JE, Olson RD. Essential oil of Australian lemon myrtle (Backhousia citriodora) in the treatment of molluscum contagiosum in children. Biomed Pharmacother. 2004;58(4):245–247. 10. Can B, Topaloglu F, Kavlale M, et al. Treatment of pediatric molluscum contagiosum with 10% potassium hydroxide solution. J Dermatolog Treat. 2014;25(3):246–248.

ADDITIONAL READING • Brown J, Janniger CK, Schwartz RA, et al. Childhood molluscum contagiosum. Int J Dermatol. 2006;45(2):93–99. • Dohil MA, Lin P, Lee J, et al. The epidemiology of molluscum contagiosum in children. J Am Acad Dermatol. 2006;54(1):47–54.

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• Olsen JR, Gallacher J, Piguet V, et al. Epidemiology of molluscum contagiosum in children: a systematic review. Fam Pract. 2014;31(2):130– 136. • Ting PT, Dytoc MT. Therapy of external anogenital warts and molluscum contagiosum: a literature review. Dermatol Ther. 2004;17(1):68–101.

CODES ICD10 B08.1 Molluscum contagiosum

CLINICAL PEARLS • Natural resolution is preferred treatment in healthy patients. • Reassure parents that lesions will heal naturally and generally resolve without scarring. • No specific treatment has been identified as superior to any other. • Consider topical corticosteroids for pruritus or associated dermatitis.

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MORTON NEUROMA (INTERDIGITAL NEUROMA) Catherine Mygatt, MD • J. Herbert Stevenson, MD BASICS DESCRIPTION • Perineural fibrosis of the common digital nerve as it passes between metatarsals – The interspace between the 3rd and 4th metatarsals is most commonly affected. – Between the 2nd and 3rd metatarsals is the next most common site. • System(s) affected: musculoskeletal, nervous • Synonym(s): plantar digital neuritis; Morton metatarsalgia; intermetatarsal neuroma

EPIDEMIOLOGY Prevalence • Unknown • Mean age: 45 to 50 years • Predominant sex: female > male (8:1)

ETIOLOGY AND PATHOPHYSIOLOGY • Lateral plantar nerve joins a portion of medial plantar nerve, creating a nerve with a larger diameter than those going to other digits. • Nerve lies in SC tissue, deep to the fat pad of foot, just superficial to the digital artery and vein. • Overlying, the nerve is the strong, deep transverse metatarsal ligament that holds the metatarsal bones together. • With each step the patient takes, the inflamed nerve becomes compressed between the ground and the deep transverse metatarsal ligament. This can generate perineural fibrotic reaction with subsequent neuroma formation.

RISK FACTORS

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• High-heeled shoes – Transfer more weight to the forefoot. • Shoes with tight toe boxes – Cause lateral compression • Pes planus (flat feet) – Pulls nerve medially, increasing irritation • Obesity • Female gender • Ballet dancing, basketball, aerobics, tennis, running, and similar activities

GENERAL PREVENTION • Wear properly fitting shoes. • Avoid high heels and shoes with narrow toe boxes.

DIAGNOSIS HISTORY • Most common complaint is pain localized to interspace between 3rd and 4th toes. • Pain is less severe when not bearing weight. • Pain, cramping, or numbness of the forefoot during weight bearing or immediately after strenuous foot exertion • Radiation of pain to the toes • Pain is relieved by removing shoes and massaging the foot. • Patients often complain of “walking on a marble.” • Burning pain in the ball of the foot radiating to the toes • Tingling or numbness in the toes • Aggravated by wearing tight or narrow shoes

PHYSICAL EXAM • Intense pain when pressure applied between metatarsal heads, sometimes with a palpable nodule • Assess midfoot motion and digital motion to determine if arthritis or synovitis. • Palpate along metatarsal shafts to assess for metatarsalgia or stress fractures.

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DIFFERENTIAL DIAGNOSIS • Stress fracture • Hammer toe • Metatarsophalangeal synovitis • Metatarsalgia • Arthritis • Bursitis • Foreign body

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Predominantly a clinical diagnosis; imaging should be reserved for when the diagnosis is unclear or more than one web space is involved (1)[A],(2)[B]. • Radiographs may help to rule out osseous pathology if diagnosis is in question, but films usually are normal in patients with a Morton neuroma (1) [A]. • US has 79% specificity and 99% sensitivity for Morton neuromas but is poor at assessing the size of the lesion. Specificity declines to 50% for lesions 5 mm and younger patients are more likely to undergo invasive treatment (12)[B].

PATIENT EDUCATION Wear properly fitting comfortable shoes.

PROGNOSIS • 40–50% improve with 3 months of conservative treatment. • 45–60% improve with steroid injection (6)[A]. • 96% improve with surgery.

COMPLICATIONS Hip and knee pain related to gait changes

REFERENCES 1. Sharp RJ, Wade CM, Hennessy MS, et al. The role of MRI and ultrasound imaging in Morton’s neuroma and the effect of size of lesion on symptoms. J Bone Joint Surg Br. 2003;85(7):999–1005. 2. Pastides P, El-Sallakh S, Charalambides C. Morton’s neuroma: a clinical versus radiological diagnosis. Foot Ankle Surg. 2012;18(1):22–24. 3. Mahadevan D, Venkatesan M, Bhatt R, et al. Diagnostic accuracy of clinical

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tests for Morton’s neuroma compared with ultrasonography. J Foot Ankle Surg. 2015;54(4):549–553. 4. Owens R, Gougoulias N, Guthrie H, et al. Morton’s neuroma: clinical testing and imaging in 76 feet, compared to a control group. Foot Ankle Surg. 2011;17(3):197–200. 5. Saygi B, Yildirim Y, Saygi EK, et al. Morton’s neuroma: comparative results of two conservative methods. Foot Ankle Int. 2005;26(7):556–559. 6. Thomson CE, Beggs I, Martin DJ, et al. Methylprednisolone injections for the treatment of Morton neuroma: a patient-blinded randomized trial. J Bone Joint Surg Am. 2013;95 (9):790–798. 7. Musson RE, Sawhney JS, Lamb L, et al. Ultrasound guided alcohol ablation of Morton’s neuroma. Foot Ankle Int. 2012;33(3):196–201. 8. Hughes RJ, Ali K, Jones H, et al. Treatment of Morton’s neuroma with alcohol injection under sonographic guidance: follow-up of 101 cases. AJR Am J Roentgenol. 2007;188(6):1535–1539. 9. Climent JM, Mondéjar-Gómez F, Rodríguez-Ruiz C, et al. Treatment of Morton neuroma with botulinum toxin A: a pilot study. Clin Drug Investig. 2013;33(7):497–503. 10. Thomson CE, Gibson JN, Martin D. Interventions for the treatment of Morton’s neuroma. Cochrane Database Syst Rev. 2004;(3):CD003118. 11. Akermark C, Crone H, Skoog A, et al. A prospective randomized controlled trial of plantar versus dorsal incisions for operative treatment of primary Morton’s neuroma. Foot Ankle Int. 2013;34(9):1198–1204. 12. Mahadevan D, Salmasi M, Whybra N, et al. What factors predict the need for further intervention following corticosteroid injection of Morton’s neuroma? Foot Ankle Surg. In press.

ADDITIONAL READING • Jain S, Mannan K. The diagnosis and management of Morton’s neuroma: a literature review. Foot Ankle Spec. 2013;6(4):307–317. • Schreiber K, Khodaee M, Poddar S, et al. Clinical inquiry. What is the best way to treat Morton’s neuroma? J Fam Pract. 2011;60(3):157–158, 168.

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CODES ICD10 • G57.60 Lesion of plantar nerve, unspecified lower limb • G57.61 Lesion of plantar nerve, right lower limb • G57.62 Lesion of plantar nerve, left lower limb

CLINICAL PEARLS • Morton neuroma is usually a clinical diagnosis. • Footwear modification is the mainstay of treatment. • Corticosteroid injection into, or US-guided alcohol ablation of the neuroma may be helpful. • Neurectomy is the definitive treatment. Patients should be aware of the likelihood of postoperative dysesthesias.

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MOTION SICKNESS Courtney I. Jarvis, PharmD • Allison Hargreaves, MD BASICS DESCRIPTION • Motions sickness is not a true sickness but a normal response to a situation in which sensory conflict about body motion exists among visual receptors, vestibular receptors, and body proprioceptors. • Also can be induced when patterns of motion differ from those previously experienced • System affected: nervous • Synonym(s): car sickness; sea sickness; air sickness; space sickness; physiologic vertigo

EPIDEMIOLOGY Incidence Predominant sex: female > male

Prevalence Estimation is complex; syndrome occurs in ~25% due to travel by air, ~29% by sea, and ~41% by road. Estimates for vomiting are 0.5% by air, 7% by sea, and 2% by road.

ETIOLOGY AND PATHOPHYSIOLOGY • Precise etiology unknown; thought to be due to a mismatch of vestibular and visual sensations • Rotary, vertical, and low frequency motions produce more symptoms than linear, horizontal, and high-frequency motions. • Nausea and vomiting occur as a result of increased levels of dopamine and acetylcholine, which stimulate chemoreceptor trigger zone and vomiting center in CNS.

Genetics Heritability estimates range from 55% to 75%.

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RISK FACTORS • Motion (auto, plane, boat, amusement rides) • Travel • Visual stimuli (e.g., moving horizon) • Poor ventilation (fumes, smoke, carbon monoxide) • Emotions (fear, anxiety) • Zero gravity • Pregnancy, menstruation, oral contraceptive use • History of migraine headaches, especially vestibular migraine • Other illness or poor health

GENERAL PREVENTION See “General Measures.”

Pediatric Considerations • Rare in children 12 years of age: 25 to 50 mg q24h – Children 10% of hematologic malignancies in the United States • Median age of diagnosis is 69 years. • Slight male predominance. Blacks about 2 to 3 times more commonly affected than whites; less common in Asians.

Incidence 4 to 5 new cases/100,000 annually

Prevalence In 2012, there were 89, 658 cases in the United States.

ETIOLOGY AND PATHOPHYSIOLOGY • Clonal proliferation of plasma cells derived from postgerminal center B cells

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• Plasma cells undergo multiple chromosomal mutations to progress to MM. • Genetic damage in developing B lymphocytes at time of isotype switching, transforming normal plasma cells into malignant cells, arising from single clone • Earliest chromosomal translocations involve immunoglobulin heavy chains on chromosome 14q32, with the translocation at t(4;14), t(14;16), t(14;20), and deletion, del(17p) having a poorer prognosis. • Malignant cells multiply in bone marrow, suppressing normal bone marrow cells and producing large quantities of monoclonal immunoglobulin (M) protein. • Malignant cells stimulate osteoclasts that cause bone resorption and inhibit osteoblasts that form new bone, causing lytic bone lesions.

Genetics Rare family clusters; the hyperphosphorylated form of Paratarg-7, a protein of unknown significance, is inherited as an autosomal dominant trait in familial cases of MM and MGUS, suggesting a potential pathogenic role.

RISK FACTORS • Most cases have no known risks associated. • Older age; immunosuppression; and chemicals like dioxin, herbicides, insecticides, petroleum, heavy metals, plastics, and ionizing radiation increase the risk of MM. • MGUS stage consistently precedes MM.

COMMONLY ASSOCIATED CONDITIONS Secondary amyloidosis commonly due to MM

DIAGNOSIS HISTORY • 34% of patients are asymptomatic at the time of presentation. • Hypercalcemia (28%): anorexia, nausea, somnolence, and polydipsia • Renal failure (20–50%) • Anemia (73%)

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• Bony lesions (80%): lytic lesions causing bone pain (58%) (1), osteoporosis, or pathologic fracture (26–34%) • Other symptoms: fatigue (32%), peripheral neuropathy, weight loss (24%), recurrent infections, hyperviscosity syndrome, and cord compression

PHYSICAL EXAM • Dehydration • Skin findings of amyloidosis: waxy papules, nodules, or plaques that may be evident in the eyelids, retroauricular region, neck, or inguinal and anogenital regions; petechiae and ecchymosis; “pinch purpura” • Extramedullary, plasmacytomas can present as large, purplish, subcutaneous masses. • Hyperviscosity syndrome in 7%: retinal hemorrhages, prolonged bleeding, neurologic changes • Tender bones and masses

DIFFERENTIAL DIAGNOSIS • MGUS • Smoldering MM • Metastatic carcinoma (kidney, breast, non–small cell lung cancer) • Waldenström macroglobulinemia • AL amyloidosis • Solitary plasmacytoma • Polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes (POEMS) syndrome

DIAGNOSTIC TESTS & INTERPRETATION Criteria for diagnosis: The diagnosis of MM requires the following (2)[A]: • Bone marrow (BM) involvement with ≥10% of plasma cells (PC) or the presence of a plasmacytoma and any one or more of the following myeloma defining events: • Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically: – Hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)

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– Renal insufficiency: creatinine clearance 177 μmol/L (>2 mg/dL) – Anemia: hemoglobin value of >20 g/L below the lower limit of normal or a hemoglobin value 1 focal lesions on MRI studies

Initial Tests (lab, imaging) • CBC with differential to evaluate anemia and other cytopenias with evaluation of peripheral blood smear • BUN, creatinine (elevated creatinine due to myeloma cast nephropathy) • Serum electrolytes, serum albumin, serum calcium • Serum lactate dehydrogenase (LDH), β2-microglobulin • Serum protein electrophoresis (SPEP), serum immunofixation electrophoresis (SIFE): M protein level elevated • Quantitative serum immunoglobulin levels: immunoglobulin (Ig) G, IgA, and IgM • Quantitative serum FLC levels: κ and λ chains • Elevated ESR, C-reactive protein • Urine analysis: 24-hour urine for protein, urine protein electrophoresis (UPEP), urine immunofixation electrophoresis (UIFE); 20% positive urine protein (3)[A]: – Urinalysis dip is often negative for protein, as this test identifies albumin, and the protein in MM is Bence-Jones (BJ) monoclonal protein. • Bone marrow aspirate and biopsy for histology, immunohistochemistry, flow cytometry, cytogenetics, and fluorescence in situ hybridization (FISH) • Skeletal survey: for lytic bone lesions, osteopenia, osteoporosis, or compression fractures • MRI for any back pain or earliest signs/symptoms of spinal cord compression • Bone scan can be falsely negative in myeloma; use MR to confirm lesions

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from skeletal survey Follow-Up Tests & Special Considerations • CT scan: if high suspicion for bone lesions despite normal skeletal survey; can differentiate malignant from benign vertebral compression fractures in patients who are not MRI candidates • PET scans: used if bone involvement is suspected despite a normal skeletal survey, MRI, and CT • Baseline bone densitometry may be indicated (3)[A]. • Bone marrow aspiration and biopsy to monitor response to treatment • SPEP with SIFE: M protein helps to track progression of myeloma and response to treatment. • Serum immunoglobulins and FLCs can be used to monitor response or relapse. • Plasma cell labeling index may be helpful to identify the fraction of the myeloma cell population that is proliferating (3)[A].

Diagnostic Procedures/Other Staging: • Durie Salmon stage – Stage I: low cell mass: 10 g/dL, M protein 5 g/dL if IgA, urine BJ protein >12 g/24 hr, advanced lytic bone lesions • International staging system (ISS) – Stage I: albumin ≥3.5 g/dL and β2-microglobulin 3%

Test Interpretation Bone marrow involvement with plasma cells ≥10%; Russell bodies

TREATMENT • Treatment varies depending on level of disease activity and stage of MM. • Key determinant factor in choosing chemotherapy regimen is to establish if the patient is an autologous stem cell transplant (ASCT) candidate or not. • Treatment protocols vary by institution and patient. • ASCT following induction chemotherapy is standard of care for patients with symptomatic disease.

GENERAL MEASURES Maintain adequate hydration to prevent renal insufficiency. All patients receiving primary melanoma therapy should be given bisphosphonates initially (3)[A].

MEDICATION • Induction chemotherapy for ASCT-eligible patients (1)[C]: – Standard risk: (lenalidomide/low-dose dexamethasone) – Intermediate risk: (bortezomib/cyclophosphamide/dexamethasone) – High risk: (bortezomib/lenalidomide/dexamethasone) – After ASCT, maintenance can include a bortezomib compound for the highor intermediate-risk group; lenalidomide can be considered for the standard group. Maintenance lenalidomide after ASCT has shown to improve progression-free survival (PFS) of 41 versus 23 months with placebo and has shown to be an effective treatment for MM (4)[A]. • Induction chemotherapy for ASCT-ineligible patients: – Same regimens as ASCT-eligible patients, however, the number of treatment cycles are increased (1)[C].

First Line

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• Bortezomib – A proteasome inhibitor; it blocks the ubiquitin-proteasome catalytic pathway in cells by binding to the 20S proteasome complex. – Toxicity: peripheral neuropathy, cytopenia, nausea – Consider herpes simplex virus (HSV) prophylaxis. • Cyclophosphamide – Nitrogen mustard–derivative alkylating agent – Often used in combination with prednisone or thalidomide in cases of relapsed disease – Toxicity: cytopenia, anaphylaxis, interstitial pulmonary fibrosis, secondary malignancy, impaired fertility • Immunomodulators – Thalidomide and lenalidomide Works by antiangiogenesis inhibition, immunomodulation, and inhibition of tumor necrosis factor Toxicity: birth defects, deep vein thrombosis (DVT), neuropathy, rash, nausea, bradycardia DVT prophylaxis, usually with aspirin • Dexamethasone – Low doses (40 mg/week) superior to higher doses – Increases risk of DVT • Bisphosphonates (5)[A] – No effect on mortality but decrease pain, pathologic vertebral fractures, and fractures of other bones – IV pamidronate or zoledronic acid can be used; evidence that zoledronic acid may be superior in preventing skeletal-related events. – Dose-adjust/monitor renal function. – Monitor for osteonecrosis of jaw. • Alternative options: – As first-line treatment for transplant-ineligible patients with newly diagnosed MM, bortezomib/melphalan/prednisone was associated with significantly increased PFS compared with melphalan/prednisone (6)[A].

Second Line

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• May be treated with any of the agents not already used • The following agents can be used as salvage therapy to treat relapsed or refractory MM: – Bortezomib/lenalidomide – Liposomal doxorubicin – Carfilzomib: 2nd-generation selective proteasome inhibitor • Emerging options: pomalidomide, thalidomide analog • Bortezomib is a highly effective option in previously treated/relapse patients and is well-tolerated. • Interferon-α may be appropriate in selected patients, but because of its toxicity and availability of better alternatives, it has a limited role in treating MM.

ISSUES FOR REFERRAL For spinal or other bone pathology, refer to orthopedics for support.

ADDITIONAL THERAPIES • Local radiation therapy for bone pain • Effective pain management: Avoid NSAIDs due to nephrotoxicity. • Kyphoplasty/vertebroplasty: consider for symptomatic vertebral compressions • Plasmapheresis: for hyperviscosity syndrome (a rare complication) • Erythropoietin: for selected patients with anemia • Patients should receive vaccines for pneumococcus and influenza. • Do not administer zoster vaccine and other live-virus vaccines.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS Indications: pain, infections, cytopenia, renal failure, bone complications, spinal cord compression • Avoid IV radiographic contrast materials due to risk for contrast-induced nephropathy. • Adequate hydration • Manage hypercalcemia and control hyperuricemia.

ONGOING CARE

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PATIENT EDUCATION • http://myeloma.org/Main.action • http://www.nccn.org/patients/guidelines/myeloma/index.html

PROGNOSIS • Median survival overall is 3 years. The 5-year survival rate is around 35%. • Median survival by ISS stage: – Stage I: 62 months – Stage II: 44 months – Stage III: 29 months • Median survival in patients with high-risk MM (see staging for definition) is Africans or Asians

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RISK FACTORS • Genetic: DRB1 locus on chromosome 6 has strongest MS risk association; DRB1*15 and *16 produce major histocompatibility complexes (MHC) with high binding affinity to myelin basic proteins (MBPs) (3,5). • Geographic: Previously, distance from equator showed association with increased risk, though now declining. However, sun exposure (ultraviolet B [UVB] radiation necessary for endogenous vitamin D production) appears to have inverse relation to MS incidence (3). • Infectious: viral infections (especially EBV, HHV) (3,5) • Race: Caucasian > African, Asian, Native American, although this is decreasing (5) • Others: tobacco smoking (6)

GENERAL PREVENTION No known preventive strategies

COMMONLY ASSOCIATED CONDITIONS • Internuclear ophthalmoplegia (INO): Injury to the medial longitudinal fasciculus (MLF) causes impaired adduction to the affected eye. • Optic neuritis: inflammation of optic nerve resulting in loss of vision • Uhthoff phenomenon: Symptoms worsen with exposure to higher than usual temperature. • Lhermitte sign: electric-like shocks extending down the spine caused by neck movement, especially flexion

DIAGNOSIS • A person with MS can present with a number of neurologic signs and symptoms depending on the locations of the lesions within the CNS (5)[C]. • Clinical diagnosis: ≥2 attacks; objective clinical evidence of ≥2 lesions or objective clinical evidence of 1 lesion with history of a previous episode. Flare-up duration must be at least >24 hours. Relapses must be separated by ≥1 month. ≥1 out of 2 neurologic signs must be present. The second clinical sign may be obtained through an abnormal paraclinical exam such as MRI or evoked potentials (EPs) or may be supported by an abnormal paraclinical

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exam (5,7)[C]. • For patients with steady decline of neurologic function for ≥6 months without flares, intrathecal IgG may be used to support the diagnosis (5)[C].

HISTORY Symptoms may include fatigue, depression, emotional instability, epilepsy, memory loss, diplopia, sudden vision loss, facial palsy, dysarthria, dysphagia, muscle weakness or spasms, ataxia, vertigo, falls, hyperesthesia or paresthesia, pain, bowel or bladder incontinence, urinary frequency or retention, or impotence (5)[C].

PHYSICAL EXAM • Optic disc swelling or pallor • INO • Nystagmus in abducting eye • Ataxia • Intention tremor • Hypesthesia or paresthesia • Cerebellar dysarthria (scanning speech) • Spasticity (especially in lower extremities)

DIFFERENTIAL DIAGNOSIS • Lyme disease • Systemic lupus erythematosus (SLE) • Antiphospholipid antibody syndrome • Epilepsy • Progressive multifocal leukoencephalopathy (PML) • CNS neoplasms • Guillain-Barré syndrome • Metachromatic leukodystrophy • Sarcoidosis • Stroke • Vascular malformation • HIV, neurosyphilis • Cobalamin (vitamin B12) deficiency

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• Acute disseminated encephalomyelitis (ADEM) • Behçet disease • Normal pressure hydrocephalus

DIAGNOSTIC TESTS & INTERPRETATION • CSF: increased monocyte cell count and intrathecally formed IgG levels. Total protein within CSF may be normal or increased. The presence of oligoclonal bands (OCB) is used to determine amount of IgG intrathecally synthesized. ≥2 OCBs is diagnostic (5)[B]. • Tests used for exclusion of alternative diagnoses: antinuclear antibodies (ANAs), serum cobalamin level, erythrocyte sedimentation rate (ESR), and testing for syphilis • MRI of head/spine (more sensitive than CT): – T2 (spin-echo) image: hyperintense lesions – T2 image: hypointense lesions – Gadolinium (Gd): Given IV, leakage of Gd into the parenchyma represents an increase in BBB permeability due to vascular breakdown. • McDonald criteria (5): – Dissemination in space: ≥1 T2 lesion on MRI in at least 2 out of 4 CNS regions typically affected by MS: periventricular, juxtacortical, infratentorial, or spinal cord or by waiting for another clinical attack implying a different CNS location – Dissemination in time: simultaneous presentation of asymptomatic Gdenhanced and nonenhancing lesions at any moment or a new T2 and/or Gdenhanced lesion on an MRI when compared baseline scans.

Diagnostic Procedures/Other EPs: Assess function in visual, auditory, and somatosensory or motor CNS pathways by measuring CNS electric potentials evoked by stimulation of either the brain or selected peripheral nerves; a marked delay in a provoked CNS EP, without a clinical manifestation, is suggestive of a demyelinating disorder (5).

TREATMENT

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GENERAL MEASURES • Three main categories currently exist for MS treatment: treatment for acute relapses, treatment for reducing MS-related activity using disease-modifying agents and symptomatic therapy (2,5)[B] • For apparent acute relapse, rule out infectious etiology prior to treatment.

MEDICATION • Acute relapses (2)[B] – Methylprednisolone 1 g/day IV for 3 to 5 days; without subsequent oral tapering; a second course may be given. Adverse effects: fluid retention, potassium loss, weight gain, GI disturbances, acne, and emotional lability • Reduction of MS biologic activity, interferon-β (IFN-β) (1,5,8) – Avonex (IFN-β1a) 30 μg IM weekly – Rebif (IFN-β1a) 22 or 44 μg SC 3 times per week – Betaseron (IFN-β1b) 0.25 mg SC every other day – Extavia (IFN-β1b) 0.25 mg SC every other day CBC w/ diff., Plt, LFTs at 1, 3, and 6 months after starting Tx TFTs every 6 months if Hx of thyroid dysfunction. Reduction of MS biologic activity, non-IFN-β (1,5,8) Glatiramer acetate (Copaxone) 20 mg SC daily or 40 mg 3 times per week Common adverse reactions: injection site reaction, nausea, chest pain, hypertonia, diaphoresis No recommended routine tests – Natalizumab (Tysabri): 300 mg IV every 4 weeks Restricted distribution in the United States; call 1-800-456-2255 for more information. MRI at baseline Alemtuzumab (Lemtrada) 12 mg IV daily for 5 days, then 12 months later 12 mg IV for 3 days Premedicate with corticosteroids (methylprednisolone 1,000 mg) first 3 days of each treatment. Also consider antihistamines, antipyretics; antiviral prophylaxis (for herpetic viral infections) beginning on the first

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day of treatment and continue at least 2 months and until CD4+ lymphocyte count is ≥200/mm3 – Fingolimod (Gilenya): 0.5 mg PO daily ECG at baseline Serious adverse reactions: QT prolongation, AV block; 6-hour observation following first dose – Teriflunomide (Aubagio): 7 to 14 mg PO daily Avoid pregnancy, teratogenic; pregnancy test at baseline Use reliable contraception during Tx. • Symptomatic therapies (5)[B]: – Ataxia: clonazepam, propranolol, ondansetron – Spasticity: baclofen, diazepam, tizanidine, dantrolene, cyclobenzaprine hydrochloride – Pain: NSAIDs, carbamazepine, gabapentin, phenytoin, amitriptyline, mexiletine – Bladder dysfunction: (urgency) propantheline bromide, oxybutynin, tolterodine tartrate; (retention) phenoxybenzamine, terazosin hydrochloride, bethanechol – Constipation: high-fiber diets, fluids, natural or other laxatives, stool softeners, bulk-producing agents, suppositories – Sexual dysfunction: tadalafil, sildenafil, vardenafil – Weakness/fatigue: dalfampridine, amantadine, methylphenidate – Tremors: clonazepam, β-blockers, primidone – Depression: fluoxetine, other SSRIs, tricyclic antidepressants, nontricyclic antidepressants

ADDITIONAL THERAPIES • Cognitive behavioral therapy • Physical and occupational therapy • Water therapy: Swimming, in cool water, is typically well-tolerated. • Strenuous physical activity appears to confer protective benefit and slow the disease progression in pediatric patients.

COMPLEMENTARY & ALTERNATIVE MEDICINE Omega-3s have immunomodulary properties.

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ONGOING CARE FOLLOW-UP RECOMMENDATIONS Treat relapses with corticosteroids to minimize disease progression and duration of relapse. Maintain regular activity but avoid overwork and fatigue. Rest during periods of acute relapse (2)[B].

Patient Monitoring Assessing the severity of neurologic impairment from MS can be done using the Kurtzke Expanded Disability Status Scale (EDSS): 0 indicates a normal neurologic exam and 10 indicates death due to MS. The EDDS uses a functional status (FS) score, covering the following: pyramidal symptoms, cerebellar, brainstem, sensory, bowel and bladder, visual/optic, and cerebral/mental functions. EDDS scoring system (9)[C]: • 1.0—no disability, minimal signs in 1 FS • 2.0—minimal disability in 1 FS • 3.0—moderate disability in 1 FS or mild disability in 3 to 4 FS, but fully ambulatory • 4.0—ambulatory without aid or rest for ~500 m • 5.0—ambulatory without aid or rest for ~200 m • 6.0—intermittent/constant unilateral assistance (cane, crutch, or brace) must be able to walk 100 m • 7.0—unable to walk beyond 5 m even with aid; essentially restricted to wheelchair, wheels self and transfers alone; active in wheelchair for ~12 hr/day • 8.0—essentially restricted to bed, chair, or wheelchair; may be out of bed most of the day; retains self-care functions, generally effective use of arms • 9.0—helpless, bed-bound; but patient can communicate, eat • 10.0—death due to MS

DIET High fiber, bulk laxatives, fluids to prevent constipation

PATIENT EDUCATION National Multiple Sclerosis Society: 1-800-344-4867 or

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www.nationalmssociety.org/

PROGNOSIS • Differs in each individual; depends on the form of MS, the individual’s sex and age, the initial presentation of the disease, and the amount of disability • Average life expectancy is 5 to 10 years less than unaffected people. • Specific clinical features suggesting more favorable course: early onset, RRMS form, female sex, 1,500 cases • Mumps is unusual in children 104°F (40°C): – High fever frequently is associated with complications.

PHYSICAL EXAM • Painful parotid swelling (unilateral or bilateral) obscures angle of mandible and elevates earlobe • Meningeal signs in 15%, encephalitis in 0.5% • Rarely arthritis, orchitis, thyroiditis, mastitis, pancreatitis, oophoritis, myocarditis • Rare maculopapular, erythematous rash • Up to 50% of cases may be very mild. • Redness at opening of Stensen duct but no pus

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• Swelling in sternal area; rare but pathognomonic of mumps

DIFFERENTIAL DIAGNOSIS • If not epidemic, other viruses are more common: parainfluenza parotitis, Epstein-Barr virus, coxsackievirus, adenovirus, parvovirus B19 • Suppurative parotitis: often associated with Staphylococcus aureus (presence of pus within Wharton duct when parotid is massaged essentially excludes diagnosis of mumps) • Recurrent allergic parotitis • Salivary calculus with intermittent swelling • Lymphadenitis from any cause, including HIV infection • Cytomegalovirus parotitis (immunocompromised patients) • Mikulicz syndrome: chronic, painless parotid and lacrimal gland swelling of unknown cause that occurs in tuberculosis, sarcoidosis, lupus, leukemia, lymphosarcoma, and salivary gland tumors • Sjögren syndrome, diabetes mellitus, uremia, malnutrition • Drug-related parotid enlargement (iodides, guanethidine, phenothiazine) • Other causes of the complications of mumps (meningoencephalitis, orchitis, oophoritis, pancreatitis, polyarthritis, nephritis, myocarditis, prostatitis) • Mumps orchitis must be differentiated from testicular torsion and from chlamydial or bacterial orchitis. (Testicular sonogram can be useful.)

DIAGNOSTIC TESTS & INTERPRETATION • Three special tests used to confirm an outbreak—if positive, report to health department (3)[A] – IgM titer (positive by day 5 in 100% of nonimmunized patients) – Swab of parotid duct or other affected salivary ducts for viral culture – Rise in IgG titer samples; order if patient previously immunized: first sample within 5 days of onset, and second, 2 weeks later. • Other potential findings: elevated serum amylase; CSF leukocytosis, or leukopenia • Testicular ultrasound may help differentiate mumps orchitis from testicular torsion.

Diagnostic Procedures/Other

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If meningitis is present, lumbar puncture to exclude bacterial process. CSF pleocytosis, usually lymphocytes, is found in 65% of patients with parotitis.

Test Interpretation Periductal edema and lymphocytic infiltration in affected glands on biopsy

TREATMENT • No specific antiviral therapy, only supportive care (3)[A],(4)[C] • Analgesics to relieve pain • Avoid corticosteroids for mumps orchitis because they can reduce testosterone concentrations and increase testicular atrophy. • IVIG only successful for certain autoimmune-based sequelae: – Postinfectious encephalitis – Guillain-Barré syndrome – ITP • Interferon-α2b improved severe bilateral orchitis but did not decrease testicular atrophy in small studies (5)[B].

GENERAL MEASURES • Rarely need to hospitalize patients with high fever, pancreatitis, or CNS symptoms for supportive care, steroids, or interferon. Use isolation precautions. • Orchitis – Ice packs to scrotum can help to relieve pain. – Scrotal support with adhesive bridge while recumbent and/or athletic supporter while ambulatory

MEDICATION First Line • Analgesics and anti-inflammatory medications (acetaminophen, nonsteroidal anti-inflammatory drugs [NSAIDs]) may diminish pain and swelling in acute orchitis and arthritis mumps. • May use acetaminophen for fever and/or pain • Precautions: Avoid aspirin for pain in children as previously associated with

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Reye syndrome.

Second Line • Interferon-α2b (5)[B] • Medicinal herbs and acupuncture have not shown benefit in randomized controlled trials.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Hospitalize only if CNS symptoms occur. • Outpatient supportive care if no complications • IV fluids if severe nausea or vomiting accompanies pancreatitis

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Mumps orchitis: • Bed rest and local supportive clothing (e.g., two pairs of briefs) or adhesivetape bridge • Withhold from school until no longer contagious (9 days after onset of pain)

Patient Monitoring Most cases will be mild. Monitor hydration status.

DIET Liquid diet if unable to chew

PATIENT EDUCATION Orchitis is common in older children but rarely results in sterility, even if bilateral.

PROGNOSIS • Complete recovery is typical; immunity is lifelong. • Transient sensorineural hearing loss in 4% of adults • Recurrence after 2 weeks may be nonepidemic parotitis.

COMPLICATIONS

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• May precede, accompany, or follow salivary gland involvement and may occur (rarely) without primary involvement of the parotid gland • Orchitis is common (30%) in postpubertal boys: – It starts within 8 days of onset of parotitis. – Impaired fertility in 13%; absolute sterility is rare. • Meningitis (1–10%) or encephalitis (0.1%) may present 5 to 10 days after first symptoms of illness. Aseptic meningitis is typically mild, but meningoencephalitis may lead to seizures, paralysis, hydrocephalus, or (in 2% of cases) death. • Acute cerebellar ataxia has been reported after mumps infections; selfresolving in 2 to 3 weeks • Oophoritis in 7% of postpubertal females; no decreased fertility • Pancreatitis, usually mild • Nephritis, thyroiditis, and arthralgias are rare. • Myocarditis: usually mild but may depress ST segment; may be linked to endocardial fibroelastosis • Deafness: 1/15,000 unilateral nerve deafness; may not be permanent • Inflammation about the eye (keratouveitis) is rare. • Dacryoadenitis, optic neuritis

Pediatric Considerations • Orchitis is more common in adolescents. • Young children are less likely to develop complications. • Most complications occur in postpubertal group. • Avoid aspirin use in children with viral symptoms.

Pregnancy Considerations Disease may increase the rate of spontaneous pregnancy loss in 1st trimester. Perinatal mumps often has a benign course.

REFERENCES 1. Gouma S, Sane J, Gijselaar D, et al. Two major mumps genotype G variants dominated recent mumps outbreaks in The Netherlands (2009–2012). J Gen Virol. 2014;95(Pt 5):1074–1082. 2. Fiebelkorn AP, Lawler J, Curns AT, et al. Mumps postexposure prophylaxis

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with a third dose of measles-mumps-rubella vaccine, Orange County, New York, USA. Emerg Infect Dis. 2013;19(9):1411–1417. 3. Centers for Disease Control and Prevention. Mumps outbreak at a university and recommendation for a third dose of measles-mumps-rubella vaccine— Illinois, 2015–2016. MMWR Morb Mortal Wkly Rep. 2016;65(29):731–734. 4. Davis NF, McGuire BB, Mahon JA, et al. The increasing incidence of mumps orchitis: a comprehensive review. BJU Int. 2010;105(8):1060–1065. 5. Pal G. The effects of pegylated interferon—alpha2B on mumps orchitis. J Indian Med Assoc. 2013;111(9):612–614.

ADDITIONAL READING • Aoki Y, Matoba Y, Tanaka S, et al. Chronological changes of mumps virus genotypes in Japan between 1999-2013. Infec Dis (Lond). 2016;(48):524–529. • Flaherty DK. The vaccine-autism connection: a public health crisis caused by unethical medical practices and fraudulent science. Ann Pharmacother. 2011;45(10):1302–1304. • He J, Zheng M, Zhang M, et al. Acupuncture for mumps in children. Cochrane Database Syst Rev. 2012;(9):CD008400. • Shu M, Zhang YQ, Li Z, et al. Chinese medicinal herbs for mumps. Cochrane Database Syst Rev. 2012;(9):CD008578. • Zamir CS, Schroeder H, Shoob H, et al. Characteristics of a large mumps outbreak: clinical severity, complications and association with vaccination status of mumps outbreak cases. Hum Vaccin Immunother. 2015;11(6):1413– 1417.

CODES ICD10 • B26.9 Mumps without complication • B26.1 Mumps meningitis • B26.2 Mumps encephalitis

CLINICAL PEARLS

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• Mumps is a clinical diagnosis based on swelling of ≥1 parotid glands for ≥2 days without other obvious cause. Confirmatory testing must be done in epidemic settings. • Ultrasound is useful to distinguish testicular torsion from testicular pain related to mumps orchitis. • A history of vaccination with MMR does not exclude mumps. The MMR vaccine is 68–95% effective after a series of two immunizations. Immunity commonly wanes over time.

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MUSCULAR DYSTROPHY Nimmy Thakolkaran, MD • George G.A. Pujalte, MD, FACSM BASICS • Primary inherited myopathies caused by dysfunctional proteins of muscle fibers and extracellular matrix • Distribution of weakness, other associated symptoms, and disease prognosis depend on the specific gene affected and severity of the mutation.

DESCRIPTION • Duchenne muscular dystrophy (DMD) – Highest incidence muscular dystrophy, X-linked inheritance, early onset, progressive – Patients are wheelchair-dependent prior to age 13 years. • Becker muscular dystrophy (BMD) – Less severe phenotype than Duchenne, also caused by mutation in DMD gene; later onset and milder clinical course – Distinction from DMD is clinical: Patients are usually wheelchairdependent after age 16 years. – Collectively referred to as dystrophinopathies • Myotonic muscular dystrophy (MMD) – Myotonia (slow relaxation after muscle contraction), distal and facial weakness – Second most common inherited muscle disease. • Facioscapulohumeral muscular dystrophy (FSHMD) – Facial and shoulder muscles most affected – Third most common inherited muscle disease. • Limb-girdle muscular dystrophy (LGMD) – Proximal weakness and atrophy, variable prognosis with many different identified mutations • Oculopharyngeal muscular dystrophy (OPMD)

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– Usually adult-onset, affects extraocular and pharyngeal muscles. Presents with ptosis and dysphagia • Emery-Dreifuss muscular dystrophy (EDMD) – Triad of early development of joint contractures, slowly progressive muscle wasting, and cardiomyopathy. Can present as sudden death in apparently healthy young adults • Congenital muscular dystrophies (CMD) – Heterogeneous group of autosomal recessive myopathic diseases presenting in infancy with generally poor prognosis – Includes Fukuyama CMD, Ullrich CMD, Walker-Warburg syndrome, muscle-eye-brain disease

EPIDEMIOLOGY Incidence • Duchenne: 1/3,600 male births (1) • Myotonic dystrophy: 1/10,000 births • Other muscular dystrophies vary widely by population but are generally rare.

ETIOLOGY AND PATHOPHYSIOLOGY Mutations affect proteins connecting cytoskeleton to cell membrane and extracellular matrix, causing muscle fibers to become fragile and easily damaged; muscle weakness and atrophy result. • DMD/BMD – Defective protein is dystrophin, product of the largest human gene, DMD; Duchenne phenotype results from mutations that cause profound loss of dystrophin, the protein involved in calcium transport in muscle cells and stabilizing fibers during contraction. – Becker phenotype results from less severe mutations in DMD gene; patients have low but detectable levels of functional dystrophin. • MMD: Trinucleotide repeat expansion in the untranslated region of the gene DMPK on chromosome 19; encodes myotonin–protein kinase • LGMD: mutations in genes encoding proteins associated with dystrophin: calpain-, dysferlin-, and fukutin-related proteins are affected most commonly. • EDMD: Dysfunctional proteins are associated with the nuclear membrane in muscle fibers; emerin in X-linked form, lamin A/C in autosomal forms

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• OPMD: Trinucleotide repeat expansion in PABPN1 results in nuclear inclusions in muscle cells by hampering normal transport of mRNA from the nucleus. • FSHMD: Deletion in untranslated region of chromosome 4; function of deleted genes is unclear, although the most accepted concept is that they likely affect the expression of multiple genes by epigenetic effects.

Genetics • X-linked – Duchenne and Becker muscular dystrophies – Gene located at Xp21 30% of affected males have a de novo mutation (mother is not a carrier). 20% of female carriers have some manifestation of the mutation (usually mild muscle weakness or cardiomyopathy). • Autosomal dominant – Generally later onset and less severe than diseases with recessive or Xlinked inheritance – FSHMD, OPMD, some forms of LGMD and EDMD – Myotonic dystrophy Trinucleotide repeat expansion with more severe phenotype in subsequent generations due to accumulation of repeats • Autosomal recessive – Most types of CMD

GENERAL PREVENTION Genetic counseling for carriers and prenatal diagnosis

COMMONLY ASSOCIATED CONDITIONS • Decreased IQ: on average, 1 SD below the mean in DMD; speech and language delay • Dilated cardiomyopathy and conduction abnormalities – Can be severe in EDMD – Can affect otherwise asymptomatic female carriers of DMD – Progressive scoliosis

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DIAGNOSIS HISTORY • DMD: normal attainment of early motor milestones with subsequent abnormal gait and slowing gross motor development: clumsiness, waddling gait, frequent falls, difficulty running or climbing stairs • BMD: progressive difficulty with ambulation and frequent falls in later childhood • MMD: slurred speech, muscle wasting, difficulty with ambulation; often with family history • LGMD: back pain, lordosis/inability to rise from a chair, climb stairs, and use arms overhead • FSHMD: facial weakness, inability to close eyes completely • EDMD: contractures of elbows and ankles, difficulty with ambulation in teenage years • OPMD: ptosis and dysphagia; often with family history

PHYSICAL EXAM • DMD/BMD – Proximal muscle weakness; Gower sign: use of arms to push upper body into standing posture from lying prone – Trendelenburg gait (hip waddling) – Hyporeflexia/areflexia – Winged scapulae and lordosis – Pseudohypertrophy of the calf (caused by replacement of muscle with fibroadipose tissue) – Contractures of lower extremity joints and elbows • MMD – Characteristic facial appearance: narrow face, open triangular mouth, higharched palate, concave temples, drooping eyelids, frontal balding in males – Myotonia: inability to relax muscles after contraction – Distal muscle weakness and wasting • CMD – Arthrogryposis (multiple joint contractures); diffuse hypotonia and muscle

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wasting in an infant

DIFFERENTIAL DIAGNOSIS • Glycogen storage diseases and other metabolic myopathies • Mitochondrial myopathies: MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes), MERRF (Myoclonus with Epilepsy and Ragged-Red Fibers) • Inflammatory myopathies: polymyositis, dermatomyositis, inclusion-body myositis • Neuromuscular junction diseases: myasthenia gravis, Lambert-Eaton syndrome • Motor neuron diseases: amyotrophic lateral sclerosis, spinal muscular atrophy • Charcot-Marie-Tooth disease • Friedreich ataxia

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Creatine kinase (CK): initial screening test if MD is suspected (2)[A] • Elevated in DMD (10 to 100 times); elevated at birth, peaks at time of presentation, and falls during illness • Initial detected lab abnormality may be elevated aspartate transaminase/alanine transaminase (AST/ALT) originating from muscle. • Genetic testing/molecular diagnosis – For definitive diagnosis in patient with characteristic presentation and elevated CK – Deletion and duplication analysis (MLPA or CGH) will identify most patients; followed by genomic sequencing of DMD gene for point mutations (3)[A]. – Genetic testing is available clinically for most other muscular dystrophies.

Diagnostic Procedures/Other • Muscle biopsy: rarely performed in DMD (dystrophin protein absent); may be helpful in other cases (4)[A] • Electromyography and nerve conduction studies are not necessary unless considering alternative diagnoses.

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• ECG: abnormalities found in >90% of males and up to 10% of female carriers of DMD; Q waves in anterolateral leads, tall R waves in V1, shortened PR interval, arrhythmias, resting sinus tachycardia

Test Interpretation • Heterogenic muscle fibers: atrophy and hypertrophy of fibers with proliferation of connective tissue in muscle • Immunohistochemical staining for dystrophin protein – DMD: no detectable dystrophin in most fibers; occasional revertant fibers with normal dystrophin – BMD: highly variable staining for dystrophin throughout muscle

TREATMENT Trials of agents that affect gene expression, such as antisense oligonucleotides, and small molecules that cause skipping of premature stop codons (ataluren) are ongoing; however, steroid treatment is the only clinically available therapy that affects disease progression.

GENERAL MEASURES • Ambulation prolonged by knee-ankle-foot orthoses • Serial casting to treat contractures • Diagnose sleep apnea with polysomnography; treat with noninvasive ventilation. • Adaptive devices to improve function • Avoid overexertion and strenuous exercise.

MEDICATION • Prednisone 0.75 mg/kg/day (4)[A] – Slows the decline in muscle function, progression to scoliosis, and degradation of pulmonary function; prolongs functional ambulation; prolongs lifespan; improved cardiac outcomes – Therapy should be initiated when there is no longer progress in motor skills, but prior to decline (2). – Monitor adverse effects.

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Bisphosphonates should be considered for preventing loss of bone density; annual exam for cataracts; hypertension should be monitored; no NSAIDs due to risk of peptic ulcer disease (PUD); stress-dose steroids during surgeries and illnesses due to adrenal suppression. Patients should be aware of immune suppression and notify emergency providers. • Deflazacort (0.9 mg/kg) is an alternative oral steroid that is also considered first-line therapy in DMD; it acts on muscle regeneration and differentiation; not available in the United States (3) • ACE inhibitors – Treatment of cardiomyopathy; may be used in conjunction with β-blockers

ISSUES FOR REFERRAL • Refer to neuromuscular diseases center for definitive diagnosis and coordinated multidisciplinary care (4). • Cardiology for management of cardiomyopathy • Pulmonology for monitoring of pulmonary function and clearance regimen • Physical medicine and rehabilitation for management of adaptive devices • Nutrition/swallowing: for normal weight gain, attention for dysphagia • Psychosocial: learning/behavior and coping assessment, social development (2)

ADDITIONAL THERAPIES Novel medication: Ataluren interferes with premature stop codons, allowing expression of dystrophin protein. In DMD patients with nonsense mutation; FDA approved orphan drug designation (3)

SURGERY/OTHER PROCEDURES • Spinal surgery for scoliosis—diminishes rate of deformity progression (5),(6) [A]. • Scapular fixation for scapular winging may be beneficial; also lacking clinical trials • Consider surgical treatment of ankle/knee contractures. • Surgical procedures should be performed at a center experienced in DMD; total IV anesthesia should be used.

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ONGOING CARE • Individualized education plan and developmental evaluation for school accommodations • Maintenance of current influenza and pneumococcal vaccination status

FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Electrocardiogram (ECG), echocardiogram, and consultation with a cardiologist at diagnosis and annually after age 10 years – Female carriers of DMD mutation should be monitored every 5 years. • Annual spinal radiography for scoliosis • Dual-energy x-ray absorptiometry (DEXA) scanning and serum marker testing for osteoporosis • Pulmonary function testing twice yearly if no longer ambulatory • Psychosocial: coping, emotional adjustment, depression

DIET • Obesity is common due to steroid treatment and wheelchair confinement: Weight control can improve quality of life. • Diet may be limited by dysphagia; swallow evaluation can determine appropriate foods; may require gastrostomy • Calcium and vitamin D supplementation for patients on steroids; monitor vitamin D levels.

PATIENT EDUCATION • Muscular Dystrophy Association: http://www.mda.org • Parent Project Muscular Dystrophy: http://www.endduchenne.org

PROGNOSIS • DMD/BMD – Progressive weakness, contractures, inability to walk – Kyphoscoliosis and progressive decline in respiratory vital capacity with recurrent pulmonary infections. – Significantly shortened lifespan (DMD: 16 ± 4 years; BMD: 42 ± 16 years). Respiratory failure cause of death in 90%; remaining due to myocardial

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disease (heart failure and dysrhythmia) (5) • Other types: slow progression and near-normal lifespan with functional limitations

COMPLICATIONS • Cardiac arrhythmia, cardiomyopathy • Dysphagia, gastroesophageal reflux disease (GERD), constipation • Scoliosis, joint contractures • Obstructive sleep apnea • Malignant hyperthermia–like reaction to anesthesia • Respiratory failure and early death

REFERENCES 1. Chung J, Smith AL, Hughes SC, et al. Twenty-year follow-up of newborn screening for patients with muscular dystrophy [published online ahead of print August 11, 2015]. Muscle Nerve. doi:10.1002/mus.24880. 2. Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management. Lancet Neurol. 2010;9(1):77–93. 3. Falzarano MS, Scotton C, Passarelli C, et al. Duchenne muscular dystrophy: from diagnosis to therapy. Molecules. 2015;20(10):18168–18184. 4. Bushby K, Finkel R, Birnkrant DJ, et al. Diagnosis and management of Duchenne muscular dystrophy, part 2: implementation of multidisciplinary care. Lancet Neurol. 2010;9(2):177–189. 5. Roberto R, Fritz A, Hagar Y, et al. The natural history of cardiac and pulmonary function decline in patients with Duchenne muscular dystrophy. Spine (Phila Pa 1976). 2011;36(15):E1009–E1017. 6. van Ruiten HJ, Straub V, Bushby K, et al. Improving recognition of Duchenne muscular dystrophy: a retrospective case note review. Arch Dis Child. 2014;99(12):1074–1077.

ADDITIONAL READING • American Academy of Pediatrics Section on Cardiology and Cardiac Surgery. Cardiovascular health supervision for individuals affected by Duchenne or

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Becker muscular dystrophy. Pediatrics. 2005;116(6):1569–1573. • Cheuk DKL, Wong V, Wraige E, et al. Surgery for scoliosis in Duchenne muscular dystrophy. Cochrane Database Syst Rev. 2013;(2):CD005375. • Cossu G, Sampaolesi M. New therapies for Duchenne muscular dystrophy: challenges, prospects and clinical trials. Trends Mol Med. 2007;13(12):520– 526. • Emery AE. The muscular dystrophies. Lancet. 2002;359(9307):687–695. • Fairclough RJ, Bareja A, Davies KE. Progress in therapy for Duchenne muscular dystrophy. Exp Physiol. 2011;96(11):1101–1113. • Manzur AY, Kuntzer T, Pike M, et al. Glucocorticoid corticosteroids for Duchenne muscular dystrophy. Cochrane Database Syst Rev. 2008; (1):CD003725. • Orrell RW, Copeland S, Rose MR. Scapular fixation in muscular dystrophy. Cochrane Database Syst Rev. 2010;(1):CD003278. • Schram G, Fournier A, Leduc H, et al. All-cause mortality and cardiovascular outcomes with prophylactic steroid therapy in Duchenne muscular dystrophy. J Am Coll Cardiol. 2013;61(9):948–954. • Takami Y, Takeshima Y, Awano H, et al. High incidence of electrocardiogram abnormalities in young patients with Duchenne muscular dystrophy. Pediatr Neurol. 2008;39(6):399–403. • van der Kooi EL, Lindeman E, Riphagen I. Strength training and aerobic exercise training for muscle disease. Cochrane Database Syst Rev. 2005; (1):CD003907.

CODES ICD10 • G71.0 Muscular dystrophy • G71.11 Myotonic muscular dystrophy • G71.2 Congenital myopathies

CLINICAL PEARLS • Primary care providers should have a low threshold to obtain serum CK as a

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screening test in the face of gross motor delay/muscular weakness, especially in boys. • Steroids should be initiated in patients with DMD when gross motor function ceases to progress. • High-quality care of patients requires a medical home; a multidisciplinary team of physicians, therapists, and other providers; and extensive patient and family support.

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MYASTHENIA GRAVIS Melody A. Jordahl-Iafrato, MD BASICS DESCRIPTION Primary disorder of neuromuscular transmission characterized by fluctuating muscle weakness: • Ocular myasthenia gravis (MG) (15%): weakness limited to eyelids and extraocular muscles • Generalized MG (85%): commonly affects ocular as well as a variable combination of bulbar, proximal limb, and respiratory muscles • 50% of patients who present with ocular symptoms develop generalized MG within 2 years. • Onset may be sudden and severe, but it is typically mild and intermittent over many years, maximum severity reached within 3 years for 85%. • System(s) affected: neurologic; hematologic; lymphatic; immunologic; musculoskeletal

EPIDEMIOLOGY Occurs at any age but a bimodal distribution to the age of onset: • Female predominance: 20 to 40 years • Male predominance: 60 to 80 years

Incidence Estimated annual incidence 2 to 21/1 million

Prevalence In the United States, 200/1 million; increasing over the past 5 decades

Pediatric Considerations A transient form of neonatal MG seen in 10–20% of infants born to mothers with MG. It occurs as a result of the transplacental passage of maternal antibodies that interfere with function of the neuromuscular junction; resolves in weeks to months.

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ETIOLOGY AND PATHOPHYSIOLOGY • Reduction in the function of acetylcholine receptors (AChR) at muscle endplates, resulting in insufficient neuromuscular transmission • Antibody-mediated autoimmune disorder • Antibodies are present in most cases of MG. – Seropositive/antiacetylcholine receptor (anti-AChR): a humoral, antibodymediated, T-cell–dependent attack of the AChRs or receptor-associated proteins at the postsynaptic membrane of the neuromuscular junction. Found in 85% of generalized MG and 50% of ocular MG. Thymic abnormalities common (1) – Muscle-specific kinase (MuSK). 5% of generalized MG patients. Typically females. Is a severe form, respiratory and bulbar muscles involved. Thymic abnormalities are rare (1). – In remainder of seronegative, 12–50% with anti-LRP4, a molecule that forms a complex with MuSK, clinical phenotype not well defined (1) – Seronegative MG (SNMG): 5%; may have anti-AChR detectable by cellbased assay. Clinically similar to anti-AChR, thymic hyperplasia may be present (1). • Also documented immediately after viral infections (measles, Epstein-Barr virus [EBV], HIV, and human T-lymphotropic virus [HTLV])

Genetics • Congenital MG syndrome describes a collection of rare hereditary disorders. This condition is not immune-mediated but instead, results from the mutation of a component of the neuromuscular junction (autosomal recessive). • Familial predisposition is seen in 5% of cases.

RISK FACTORS • Familial MG • D-penicillamine (drug-induced MG) • Other autoimmune diseases

COMMONLY ASSOCIATED CONDITIONS • Thymic hyperplasia (60–70%) • Thymoma (10–15%)

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• Autoimmune thyroid disease (3–8%)

DIAGNOSIS Myasthenia Gravis Foundation of America Clinical Classification (2)[C]: • Class I: any eye muscle weakness, possible ptosis, no other evidence of muscle weakness elsewhere • Class II: eye muscle weakness of any severity; mild weakness of other muscles: – Class IIa: predominantly limb or axial muscles – Class IIb: predominantly bulbar and/or respiratory muscles • Class III: eye muscle weakness of any severity; moderate weakness of other muscles: – Class IIIa: predominantly limb or axial muscles – Class IIIb: predominantly bulbar and/or respiratory muscles • Class IV: eye muscle weakness of any severity; severe weakness of other muscles: – Class IVa: predominantly limb/axial muscles – Class IVb: predominantly bulbar and/or respiratory muscles (can also include feeding tube without intubation) • Class V: intubation needed to maintain airway

HISTORY The hallmark of MG is fatigability. • Fluctuating weakness, often subtle, that worsens during the day and after prolonged use of affected muscles, may improve with rest • Early symptoms are transient with asymptomatic periods lasting days or weeks. • With progression, asymptomatic periods shorten, and symptoms fluctuate from mild to severe. • >50% of patients present with ocular symptoms (ptosis and/or diplopia). Eventually, 90% of patients with MG develop ocular symptoms. • Ptosis might be unilateral, bilateral, or shifting from eye to eye. • 15% present with bulbar symptoms.

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• 16.5 g/dL in women or other evidence of increased red cell volume and (ii) presence of JAK2V617F or other functionally similar mutation (e.g., JAK2 exon 12 mutation) (1)[B] – Minor criteria: (i) bone marrow biopsy showing hypercellularity for age with trilineage myeloproliferation, (ii) low serum erythropoietin level, (iii) endogenous erythroid colony formation in vitro

Initial Tests (lab, imaging) If clinical suspicion of MPN, obtain a CBC and peripheral blood smear; if suggestive, obtain bone marrow biopsy. • PMF: radiographic osteosclerosis in 25–66%

Diagnostic Procedures/Other • CML: Diagnosis with identification of Philadelphia chromosome: Fluorescence in situ hybridization is more sensitive than karyotyping and is routinely used. Polymerase chain reaction (P210) is done at baseline to help monitor response to tyrosine kinase inhibitors (TKIs). – Bone marrow biopsy: increased cellularity and increased myeloid to erythroid ratio

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• PMF, ET, and PV: genotypic analysis and bone marrow biopsy as described in earlier WHO criteria; “dry tap” is common in PMF. • Risk stratification – CML: three phases of CML (i) Chronic phase (85% patients at diagnosis; 20% blast counts) – PMF: International Prognostic Scoring System (IPSS) at diagnosis and Dynamic IPSS (DIPSS-plus) throughout disease IPSS: age >65 years, constitutional symptoms, hemoglobin 25 × 109, circulating blasts >1% Low risk = 0 of above; intermediate-1 risk = 1 of above; intermediate-2 risk = 2 of above; high risk = ≥3 of above DIPSS-plus: same 5 risk factors in the IPSS + the need for red cell transfusion, platelets 3.5 g/1.73 m2/24 hr), hypoalbuminemia (3 to 4 times ULN – Minimal risk of progressing to cirrhosis or liver failure – Synonym: steatosis • NASH: progressive form of NAFL (1) – Liver biopsy: fatty deposits in >50% of cells with ballooning, acute/chronic inflammation, ± fibrosis – ALT and AST elevated, generally female (slight)

Incidence Estimates vary widely from 31 to 86 cases of NAFLD per 10,000 person-years to 29/100,000 person-years (1).

Prevalence • United States estimate: 30–40% (3) • Worldwide: 6–33%, median 20% (1) • Present in 58–74% of obese persons (BMI >30) and 90% of morbidly obese persons (BMI >39) (1) • Among individuals with T2DM, rate of 69–87%; in patients with dyslipidemia, rate of 50% (1)

ETIOLOGY AND PATHOPHYSIOLOGY Primary mechanism is insulin resistance, which leads to increased lipolysis, triglyceride synthesis, and increased hepatic uptake of fatty acids. • NAFLD: excessive triglyceride accumulation in the liver and an impaired ability to remove fatty acids • NASH: “2-hit” hypothesis: (i) macrovesicular steatosis due to increased hepatic lipid synthesis, reduced transfer of lipids, and increased insulin resistance with hepatic oxidative stress and (ii) mitochondrial damage leading to impaired restoration of ADT stores, lipid peroxidation, and resultant inflammatory injury (1) • Other possible mechanism is lipotoxicity. Free-fatty acid metabolites cause endoplasmic reticular stress, hepatocyte apoptosis, necrosis, and inflammation. Hepatocellular injury triggers fibrogenesis and inflammation, hastening disease progression (3).

Genetics

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Largely unknown: Some familial clustering and increased heritability. NAFL: more first-degree relatives with cirrhosis than matched controls; NASH: 18% with affected first-degree relative. Carriers of hemochromatosis gene are more likely to be affected. Patatin-like phospholipase domain-containing 3 (PNPLA3) I148M polymorphism may play a role in NAFLD, hypertriglyceridemia and insulin resistance (1,2).

RISK FACTORS • Obesity (BMI >30), visceral obesity (waist circumference >102 cm for men or >88 cm for women), hypertension, dyslipidemia, high serum triglycerides and low serum high-density lipoprotein (HDL) levels, metabolic syndrome • Type 2 diabetes, cardiovascular disease, and chronic kidney disease (2) • Possible associations with hypothyroidism, hypopituitarism, hypogonadism, obstructive sleep apnea, pancreatoduodenal resection, osteoporosis, psoriasis, and polycystic ovary syndrome (2) • Increasing age associated with increased prevalence, severity, advanced fibrosis, and mortality • High fructose intake linked to intestinal dysbiosis and metabolic stress (4) • Protein–calorie malnutrition; total parenteral nutrition (TPN) >6 weeks • Severe weight loss (starvation, bariatric surgery) • Organic solvent exposure (e.g., chlorinated hydrocarbons, toluene); vinyl chloride; hypoglycin A • Gene for hemochromatosis/other conditions with increased iron stores • Smoking • Drugs: tetracycline, glucocorticoids, tamoxifen, methotrexate, valproic acid, fialuridine, many chemotherapy regimens, and nucleoside analogues

Pregnancy Considerations Acute fatty liver of pregnancy: Rare but serious complication in 3rd trimester. 50% of cases are associated with preeclampsia. • Symptoms: nausea, vomiting, headache, fatigue, right upper quadrant or epigastric gain, jaundice • Elevated ALT and AST >300 IU/L but usually 1 – If alcohol-induced, usually AST:ALT ≥2 – Nonspecific enzyme abnormalities may exist or may be normal with advanced cirrhosis (1). • Level of enzyme elevation does NOT correlate with degree of fibrosis (1). • Serum ferritin (1.5 times normal), alkaline phosphatase (2 to 3 times normal), and total/direct bilirubin often elevated (1). • Severity and chronicity are characterized by defects in ability to produce plasma proteins (serum albumin, PT) and thrombocytopenia (1). • Lipids abnormalities are common and include elevated cholesterol, lowdensity lipoprotein (LDL), and triglyceride and decreased HDL (1). • Biomarkers of inflammation, increased oxidative stress, or hepatocyte apoptosis such as leptin, adiponectin, CRP, serum caspase, and cytokeratin 18 may help differentiate NASH from NAFLD (1)[B]. • Serologic studies to exclude other etiologies of liver disease (celiac, α-1antitrypsin, iron, copper, HepA IgG, HepB SAg, HepC SAb, anti-smooth muscle antibody, ANA, serum gammaglobulin (1)[B] • Ultrasound (US) is first-line imaging modality for assessing liver chemistry abnormalities: fatty liver is hyperechoic on US. MRI/CT may also be used (1) [B]. • Liver-derived microparticles released in response to free-fatty acid induced lipotoxicity and volatile organic compounds (VOCs) in exhaled breath (5)[C]. Follow-Up Tests & Special Considerations • Imaging modalities help noninvasively quantify fibrosis by estimating liver stiffness (5)[B]; (i) vibration-controlled transient elastography (VCTE) or FibroScan, (ii) acoustic radiation force impulse (ARFI), (iii) magnetic resonance elastography (MRE) • No imaging modality has been found to accurately distinguish and diagnosis simple steatosis from steatohepatitis (6)[B].

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Diagnostic Procedures/Other • Liver biopsy is the gold standard for diagnosis—must have likelihood of changing management (1)[B]. • NAFLD fibrosis score age (>50 years), BMI (>30), platelet count, albumin, and AST/ALT ratio identifies patients at risk of developing fibrosis/cirrhosis (7)[B].

Test Interpretation • Liver biopsy is the gold standard for prognosis (1). • In NASH, steatosis, ballooning, and lobular inflammation are minimal criteria for diagnosis. Other common findings include mild to moderate portal inflammation, acidophil bodies, perisinusoidal zone 3 fibrosis, megamitochondria, and Mallory-Denk bodies (hyaline) in hepatocytes (1). • Staging is based largely on the extent of fibrosis (1).

TREATMENT • Sustained weight loss (3–5% body weight) through lifestyle modification is most successful treatment (1,7)[A]. Weight loss for those who are overweight or obese is the only therapy that has good evidence of benefits and safety. • Foregut bariatric surgery not yet proven to specifically treat NASH (1)[B] • Aerobic exercise 3 to 5 times per week for 20 to 45 minutes with reduced calorie intake/diet modifications (1)[B] • Tight control of diabetes (1,7)[B] • Treatment of metabolic syndrome—hypertension, dyslipidemia, and obesity (1,7)[B] • Limit alcohol consumption (60 mm Hg on high-flow supplemental oxygen PaCO2 >50 mm Hg – Remove wet clothing and initiate rewarming. – Core temperature reading for possible hypothermia – Rewarming with minimally invasive core rewarming such as warm IV fluids, warm/humidified oxygen, and external rewarming – Active core rewarming reserved for refractory cases and only when extracorporeal blood warming is unavailable, depending on physician comfort level, due to major complications that can develop including core temperature after drop, rewarming acidosis, and rewarming shock

MEDICATION First Line • High-flow oxygen, as needed (1)[A] • For bronchospasm: aerosolized bronchodilator (3)[C]: albuterol (Proventil, Ventolin), 3 mL of 0.083% solution or 0.5 mL of 0.5% solution diluted in 3 mL of saline • Pressors, as needed, for hypotension refractory to IV fluid resuscitation • Prophylactic antibiotics are not recommended (1)[B].

Second Line For pneumonia: antibiotics based on sputum or endotracheal lavage culture (1) [A]

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • All symptomatic patients • Patients with abnormalities in vital signs, mental status, oxygenation, CXR, or

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laboratory analysis • Continuous cardiac monitoring • Continuous pulse oximetry monitoring • Frequent monitoring of vital signs and clinical reassessment • Careful monitoring of neurologic status • Induced hypothermia with core temp maintained between 32°C and 34°C for 24 hours may be neuroprotective (1). • Patients can be discharged from the ED after 6 to 8 hours of observation if the following criteria are met: – GCS = 15 – Normal CXR, if indicated – Lack of clinical evidence of respiratory difficulty – Normal lung exam – Normal vital signs – Oxygen saturation ≥95% on room air (5)

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Appropriate follow-up with primary care provider, orthopedic, neurologic, cardiac, pulmonary, and additional specialists as indicated

Patient Monitoring • Continuous cardiac monitoring • Continuous pulse oximetry monitoring • Frequent monitoring of vital signs and clinical reassessment • Careful monitoring of neurologic status • ABG monitoring, as indicated • A pulmonary artery catheter may be needed for hemodynamic monitoring in unstable patients (3)[C]. • Intracranial pressure monitoring in selected patients (3)[C] • Serum electrolyte determinations

DIET NPO until mental status normalizes

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PATIENT EDUCATION Reemphasize preventive measures on discharge from hospital. Educate parents regarding supervision and preventive practices.

PROGNOSIS • 75% of drowning victims survive; 6% of these with residual neurologic deficits • Patients with an initial GCS ≥13 and an oxygen saturation ≥95% have a low risk of complications and an excellent chance for a full recovery. • Patients who are comatose or receiving CPR at the time of presentation as well as those who have dilated and fixed pupils and no spontaneous respiratory activity have a more guarded and often poor prognosis, often secondary to neurologic sequelae. • Neurogenic pulmonary edema may occur within 48 hours of initial presentation.

COMPLICATIONS • Early – Bronchospasm – Vomiting/aspiration – Hypoglycemia – Hypothermia – Seizure – Hypovolemia – Electrolyte abnormalities – Arrhythmia from hypoxia or hypothermia (rarely from electrolyte imbalance) – Hypotension • Late – ARDS – Anoxic encephalopathy – Pneumonia – Lung abscess/empyema – Renal failure – Coagulopathy

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– Sepsis – Barotrauma – Seizure

REFERENCES 1. Szpilman D, Bierens J, Handley AJ, et al. Drowning. N Engl J Med. 2012;362(22):2102–2110. 2. Centers for Disease Control and Prevention. Unintentional drowning: get the facts. http://www.cdc.gov/HomeandRecreationalSafety/WaterSafety/waterinjuries-factsheet.html/. Accessed September 13, 2016. 3. Mott T, Latimer K. Prevention and treatment of drowning. Am Fam Physician. 2016;93(7):576–582. 4. Berg R, Hemphill R, Abella BS, et al. Part 5: adult basic life support: 2010 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2010;122(18)(Suppl 3):S685– S705. 5. Salomez F, Vincent JL. Drowning: a review of epidemiology, pathophysiology, treatment and prevention. Resuscitation. 2004;63(3):261– 268.

CODES ICD10 • T75.1XXA Unsp effects of drowning and nonfatal submersion, init • T75.1XXD Unsp effects of drowning and nonfatal submersion, subs • T75.1XXS Unsp effects of drowning and nonfatal submersion, sequel

CLINICAL PEARLS • The single most important treatment for near-drowning victims is prompt reversal of the hypoxic state. This should form the cornerstone for all other treatment modalities. Without oxygenation, other treatment is futile. • Focus water safety counseling on prevention measures targeting epidemiologic concerns that combine physical, behavioral, medical, and

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community areas of interest for greatest effect (4). • Family physicians and pediatricians should review water safety tips and guidelines with parents and children at yearly visits. Encourage pool owners and parents with young children to become CPR certified. Prevention of drowning can save many lives each year. • Despite successful resuscitation, patients are at risk for ARDS due to delayed pulmonary edema that may start hours after their submersion incident. For this reason, careful monitoring of every resuscitated patient is essential. • Patients requiring intubation should be treated with lung-protective vent settings to prevent barotrauma. • Patients with an initial GCS ≥13 and an oxygen saturation ≥95% have a low risk of complications and an excellent chance for a full recovery.

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OBESITY Kimberly Bombaci, MD BASICS DESCRIPTION • Excess adipose tissue, typically quantified in adults by body mass index (BMI), ([kg]/ [m2]), ≥30 kg/m2. • Obesity is associated with negative health outcomes. Abdominal obesity increases the risk of morbidity and mortality. • System(s) affected: endocrine/metabolic, cardiac, respiratory, gastrointestinal, musculoskeletal, dermatologic, mental health • Synonym(s): overweight; adiposity

Geriatric Considerations Underweight BMI (≤18) is also associated with an increased risk of mortality.

EPIDEMIOLOGY • Predominant age: Incidence rises in the early 20s. • Predominant sex: female > male

Prevalence • 35% of U.S. adults are obese (1,2). • 40% of men and 25% of women are overweight.

Pediatric Considerations • Pediatric obesity is defined as a BMI ≥95th percentile, by age and sex specific WHO or CDC growth curves. • Obesity during adolescence and young adulthood is strongly associated with obesity in adulthood.

ETIOLOGY AND PATHOPHYSIOLOGY • Obesity is caused by an imbalance between food intake, absorption, and energy expenditure. • Underlying organic causes include psychiatric disturbances, hypothyroidism,

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hypothalamic disorders, insulinoma, and Cushing syndrome. • Medications that contribute to obesity include corticosteroids, neuroleptics (particularly atypical antipsychotics), and antidepressants.

Genetics • Genetic syndromes such as Prader-Willi and Bardet-Biedl are found in a minority of people with obesity. • Multiple genes are implicated in obesity.

RISK FACTORS • Parental obesity • Sedentary lifestyle • Consumption of calorie-dense food • Low socioeconomic status • >2 hr/day of television viewing

GENERAL PREVENTION • Encourage at least 1 hour of daily exercise, limited television viewing, and moderation in portion size. • Avoid calorie-dense and nutrient-poor foods such as sugar-sweetened beverages and processed foods.

DIAGNOSIS HISTORY • Diet and exercise habits • Prior attempts at weight loss • Reported readiness to change lifestyle • Social support and resources • Comorbidities: diabetes mellitus type 2, hypertension, hyperlipidemia, sleep apnea • Psychiatric history • Symptoms suggesting hypothyroidism, Cushing syndrome, and genetic syndromes

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PHYSICAL EXAM • Elevated BMI: – Overweight: BMI = 25 to 29.9 kg/m2 – Obese: BMI 30 to 39.9 kg/m2 – Morbid obesity: BMI ≥40 kg/m2 • Abdominal circumference: – Measure at the level of the umbilicus. Elevated: Male: >40 inches (102 cm) Female: >35 inches (88 cm)

DIAGNOSTIC TESTS & INTERPRETATION • Screen for underlying physiologic causes as well as associated comorbid conditions. • Labs should be done while fasting (nonfasting labs within normal limits are considered adequate). • Glucose, total insulin, hemoglobin A1C, lipids • Thyroid function tests • LFTs (fatty liver)

TREATMENT GENERAL MEASURES • Assess: – Motivation to lose weight – Patient-specific goals of therapy – Need for intensive counseling to enhance adherence with diet, exercise, and behavior modification recommendations • Goal is to achieve and sustain loss of at least 10% of body weight. • Track nutritional intake and physical activity habits. • Use of commercial weight loss programs (e.g., Weight Watchers) can be more effective than “standard of care” counseling (3)[B]. • Behavior therapy and cognitive-behavioral methods result in modest weight loss and are most effective when combined with dietary and exercise treatments.

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MEDICATION • Include diet, exercise, and behavior therapy for all patients without comorbid conditions who are considering pharmacologic treatment. • NIH guidelines suggest at least 6 months nonpharmacologic treatment. • Consider medication for unsatisfactory weight loss in those with: – BMI ≥30 – BMI ≥27 combined with associated risk factors (e.g., coronary artery disease, diabetes, sleep apnea, hypertension, hyperlipidemia) • Relapse common after medications are discontinued. • Treat comorbidities (such as diabetes and hyperlipidemia).

First Line • When compared to placebo, medications have been associated with at least 5% weight loss at 52 weeks (4)[B]. Orlistat (Xenical) is a lipase inhibitor that decreases the absorption of dietary fat. Dose: 120 mg PO TID with meals containing fat; omit dose if meal is skipped or does not contain fat. Patients must avoid taking fat-soluble vitamin supplements within 2 hours of taking orlistat. The FDA has approved orlistat (Alli) 60 mg PO TID to be sold over the counter as a weight loss aid. Adverse effects mainly GI (cramps, flatus, fecal incontinence) • Contraindications – Orlistat: chronic malabsorption syndromes, cholestasis, pregnancy

Second Line • Appetite suppressants recommended for short-term treatment (≤6 months) (5) [A] • Only beneficial in patients who exercise and eat reduced calorie diet – Naltrexone/bupropion (Contrave): 8 mg naltrexone/90 mg bupropion per tablet; slow titration up to 2 tablets PO BID by week 4; contraindicated if uncontrolled HTN, seizure disorder, chronic opioid use, pregnancy – Liraglutide (Saxenda): 1.203 mg SC once daily; GLP-1 agonist recently approved for obesity; discontinue if weight loss is 27 with associated risk factors.

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OBSESSIVE-COMPULSIVE DISORDER (OCD) Amar Kapur, DO, CPT, MC, USA BASICS DESCRIPTION • A psychiatric condition classified as an anxiety disorder characterized by pathologic obsessions (recurrent intrusive thoughts, ideas, or images) and compulsions (repetitive, ritualistic behaviors or mental acts) causing significant patient distress • Not to be confused with obsessive-compulsive personality disorder

EPIDEMIOLOGY Incidence • Predominant age: mean age of onset 22 to 36 years – Male = female (males present at younger age) – Child/adolescent onset in 33% of cases 1/3 of cases present by age 15 years – 85% of cases present at 50 years of age • Predominant gender: female > males but males more commonly affected in childhood

Pediatric Considerations Insidious onset; consider brain insult in acute presentation of childhood obsessive-compulsive disorder (OCD).

Geriatric Considerations Consider neurologic disorders in new-onset OCD in the elderly.

Prevalence • 2.3% lifetime in adults • 1–2.3% prevalence in children/adolescents (1)

ETIOLOGY AND PATHOPHYSIOLOGY • Exact pathophysiology is unknown.

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• Dysregulation of serotonergic pathways • Dysregulation of corticostriatal-thalamic-cortico (CSTC) pathway • Exact etiology unknown • Genetic and environmental factors • Pediatric autoimmune disorder associated with streptococcal infections

Genetics • Greater concordance in monozygotic twins • Positive family history: prevalence rates of 7–15% in first-degree relatives of children/adolescents with OCD

RISK FACTORS • Exact cause of OCD is not fully elucidated. • Combination of biologic and environmental factors likely involved the following: – Link between low serotonin levels and development of OCD – Link between brain insult and development of OCD (i.e., encephalitis, pediatric streptococcal infection, or head injury)

GENERAL PREVENTION • OCD cannot be prevented. • Early diagnosis and treatment can decrease patient’s distress and impairment.

COMMONLY ASSOCIATED CONDITIONS • Major depressive disorder • Panic disorder • Phobia/social phobia • Tourette syndrome/tic syndromes and other movement disorders • Substance abuse • Eating disorder/body dysmorphic disorder

DIAGNOSIS HISTORY • Patient presents with either obsessions or compulsions, which cause marked

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distress, are time-consuming (>1 hr/day) and cause significant occupational/social impairment. • Four criteria support diagnosis of obsessions: – Patients are aware that they are thinking the obsessive thoughts; thoughts are not imposed from outside (as in thought insertion). – Thoughts are not just excessive worrying about real-life problems. – Recurrent thoughts are persistent, intrusive, and inappropriate, causing significant anxiety and distress. – Attempts to suppress intrusive thoughts are made with some other thought/activity. • Two criteria support a diagnosis of compulsions: – The response to an obsession is to perform repetitive behaviors (e.g., hand washing) or mental acts (e.g., counting silently) rigidly. – Although done to reduce stress, the responses are either not realistically connected with the obsession or they are excessive. – In children, check for precedent streptococcal infection.

PHYSICAL EXAM • Dermatologic problems caused by excessive hand washing may be observed. • Hair loss caused by compulsive pulling/twisting of the hair (trichotillomania) may be observed.

DIFFERENTIAL DIAGNOSIS • Obsessive-compulsive personality disorder – In personality disorder, traits are ego-syntonic and include perfectionism and preoccupation with detail, trivia, or procedure and regulation. Patients tend to be rigid, moralistic, and stingy. These traits are often rewarded in the patient’s job as desirable. • Impulse-control disorders: compulsive gambling, sex, or substance abuse: The compulsive behavior is not in response to obsessive thoughts, and the patient derives pleasure from the activity. • Major depressive disorder • Eating disorder • Tics (in tic disorder) and stereotyped movements • Schizophrenia: Patient perceives thought to be true and coming from an

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external source. • Generalized anxiety disorder, phobic disorders, separation anxiety: similar response on heightened anxiety, but presence of obsessions and rituals signifies OCD diagnosis • Anxiety disorder due to a general medical condition: Obsessions/compulsions are assessed to be a direct physiologic consequence of a general medical condition.

DIAGNOSTIC TESTS & INTERPRETATION According to DSM-5, diagnostic criteria for OCD are the following (2)[C]: • Presence of obsessions, compulsions, or both • Obsessions are defined by: – Recurrent or persistent thoughts, urges, or images that are experienced at some time during the disturbance, as intrusive and unwanted, and that in most individuals cause marked anxiety or distress – The individual attempts to ignore or suppress such thoughts, urges, or images or to neutralize them with some other thought or actions (i.e., by performing compulsion). • Compulsions are defined by the following: – Repetitive behavior (e.g., hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) that the individual feels driven to perform in response to an obsession or according to rules that must be applied rigidly. – The behavior or mental acts are aimed at preventing or reducing anxiety or distress or preventing some dreaded event or situation. However, these behavior or mental acts are not connected in a realistic way with what they are designed to neutralize or prevent or are clearly excessive. • The obsessions or compulsions are time-consuming (e.g., take >1 hr/day) or cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. • The obsessive-compulsive symptoms are not attributable to the physiologic effects of a substance (e.g., a drug of abuse, a medication, or other medical condition). • The disturbance is not better explained by the symptoms of another mental disorder (e.g., excessive worries, as in generalized anxiety disorder,

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preoccupation with appearance, as in body dysmorphic disorder or skin picking). • Specify if: – With good or fair insight: The individual recognizes the OCD beliefs are definitely or probably not true or that they may or may not be true. – With poor insight: The individual thinks that OCD beliefs are probably true. – With absent insight/delusional beliefs: The individual is completely convinced that OCD beliefs are true. • Specify if: – Tic related: The individual has a current or past history of tic disorder.

Diagnostic Procedures/Other • Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) or CY-BOCS for children (1)[C] • Maudsley Obsessive-Compulsive Inventory (MOCI) (3)[C]

Test Interpretation • Compulsions are designed to relieve the anxiety of obsessions; they are not inherently enjoyable (ego-dynastic) and do not result in completion of a task. • Common obsessive themes – Harm (i.e., being responsible for an accident) – Doubt (i.e., whether doors/windows are locked or the iron is turned off) – Blasphemous thoughts (i.e., in a devoutly religious person) – Contamination, dirt, or disease – Symmetry/orderliness • Common rituals or compulsions – Hand washing, cleaning – Checking – Counting – Hoarding – Ordering, arranging – Repeating • Neither obsessions nor compulsions are related to another mental disorder (i.e., thoughts of food and presence of eating disorder). • 80–90% of patients with OCD have obsessions and compulsions.

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• 10–19% of patients with OCD are pure obsessional.

TREATMENT GENERAL MEASURES • Cognitive-behavioral therapy (CBT) is recommended as first-line treatment (1)[A]. • Five phases of treatment for CBT: – Family and individual psychoeducation – Cognitive training – Mapping OCD – Graded exposure and response training – Relapse prevention and generalization training • Combined medications and CBT is most effective (1,2)[A]. • Brain modulation available for severe OCD includes electroconvulsive therapy and transcranial magnetic stimulation in small groups of patients.

MEDICATION First Line • Adequate trial at least 10 to 12 weeks • Doses may exceed typical doses for depression. • Optimal duration for pediatrics unknown but recommended minimum of maintenance treatment: 6 months • Varying degrees of efficacy between agents (1) • SSRIs recommended first-line agents (1,4,5)[A] – Fluoxetine (Prozac) Adults: 20 mg/day; increase by 10 to 20 mg every 4 to 6 weeks until response; range: 20 to 80 mg/day Children (7 to 17 years of age): 10 mg/day; increase 4 to 6 weeks until response; range: 20 to 60 mg/day • Sertraline (Zoloft) – Adults: 50 mg/day; increase by 50 mg every 4 to 7 days until response; range: 50 to 200 mg/day; may divide if above 100 mg/day – Children (6 to 17 years of age): 25 mg/day; increase by 25 mg every 7 days

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until response; range: 50 to 200 mg/day • Paroxetine (Paxil) – Adults: 20 mg/day; increase by 10 mg every 4 to 7 days until response; range: 40 to 60 mg/day – Children: Safety and effectiveness in patients 7 days) may be troublesome if patient has an adverse reaction. – May cause drowsiness and dizziness when therapy was initiated; warn patients about driving and heavy equipment hazards.

Pregnancy Considerations All SSRIs are pregnancy Category C, except paroxetine, which is Category D.

Second Line • Try switching to another SSRI. • 40–60% of patients will remain refractory to SSRI • Tricyclic acid (TCA), clomipramine (Anafranil) – Adults: 25 mg/day; increase gradually over 2 weeks to 100 mg/day, then to 250 mg/day (max dose) over next several weeks, as tolerated.

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– Children (10 to 17 years of age): 25 mg/day; titrate as needed and tolerated up to 3 mg/kg/day or 200 mg/day (whichever is less). – Absolute clomipramine contraindications Within 6 months of a myocardial infarction (MI) Hypersensitivity to clomipramine or other TCA Concomitant use within 14 days of a MAOI 3rd-degree atrioventricular (AV) block – Relative clomipramine contraindications Narrow-angle glaucoma (increased intraocular pressure) Prostatic hypertrophy (urinary retention) 1st- or 2nd-degree AV block, bundle-branch block, and congestive heart failure (proarrhythmic effect) Pregnancy Category C – Precautions Dangerous in overdose Pretreatment ECG for patients >40 years of age Watch for suicidal behavior/worsening depression during first few months of therapy or after dosage changes with antidepressants, particularly in children, adolescents, and young adults. May cause drowsiness and dizziness when therapy is initiated; warn patients about driving and heavy equipment hazards.

ISSUES FOR REFERRAL • Psychiatric referral for CBT (in vivo exposure and prevention of compulsions) • Psychiatric evaluation if obsessions and compulsions significantly interfere with patient’s functioning in social, occupational, or educational situations

ADDITIONAL THERAPIES Dopamine receptor antagonists (antipsychotic agents) alone are not effective in treatment of OCD. They can be used as augmentation to SSRI therapy for treatment-resistant OCD; they also can worsen OCD symptoms (4)[C]. Some evidence show that addition of quetiapine or risperidone to antidepressants will increase efficacy; data with olanzapine too limited to draw conclusions (4)[A]. • Risperidone (Risperdal): initial dose: 0.5 mg/day; target dose: 0.5 to 2 mg/day • Quetiapine (Seroquel): initial dose: 25 mg/day; target dose: 600 mg/day

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ONGOING CARE FOLLOW-UP RECOMMENDATIONS Y-BCOS or MOCI surveys to track progress

Patient Monitoring Monitor for decrease in obsessions and time spent performing compulsions.

DIET No dietary modifications/restrictions recommended

PATIENT EDUCATION • Importance of medication adherence • Importance of psychotherapy (CBT) • International OCD Foundation, Boston, MA 617973-5801:https://iocdf.org/ • Obsessive Compulsive Anonymous, New Hyde Park, NY: http://obsessivecompulsiveanonymous.org

PROGNOSIS • Chronic waxing and waning course in most patients: – 24–33% fluctuating course – 11–14% phasic periods of remission – 54–61% chronic progressive course • Early onset a poor predictor

COMPLICATIONS • Depression in 1/3 patients with OCD • Avoidant behavior (phobic avoidance) – Children may drop out of education. – Adults may become homebound. • Anxiety and panic-like episodes associated with obsessions

REFERENCES 1. Skarphedinsson G, Weidle B, Thomsen PH. et al. Continued cognitivebehavior therapy versus sertraline for children and adolescents with

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obsessive–compulsive disorder that were non-responders to cognitivebehavior therapy: a randomized controlled trial. Eur Child Adolesc Psychiatry. 2015;24(5):591–602. 2. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association. 3. Gava I, Barbui C, Aguglia E, et al. Psychological treatments versus treatment as usual for obsessive compulsive disorder (OCD). Cochrane Database Sys Rev. 2007;(2):CD005333. 4. Stein DJ, Denys D, Gloster AT, et al. Obsessive-compulsive disorder: diagnostic and treatment issues. Psychiatr Clin North Am. 2009;32(3):665– 685. 5. Komossa K, Depping AM, Meyer M, et al. Second-generation antipsychotics for obsessive compulsive disorder. Cochrane Database Sys Rev. 2010; (12):CD008141.

ADDITIONAL READING Kakhi S, Soomro GM. Obsessive compulsive disorder in children and adolescents: duration of maintenance drug treatment [published online ahead of print June 3, 2015]. BMJ Clin Evid.

CODES ICD10 • F42 Obsessive-compulsive disorder • F63.9 Impulse disorder, unspecified • F63.3 Trichotillomania

CLINICAL PEARLS • CBT is the initial treatment of choice for mild OCD. • CBT plus an SSRI or an SSRI alone is the treatment choice for more severe OCD. • The majority of patients with OCD respond to first SSRI treatment. • Improvement in symptoms, however, is often incomplete, ranging from 25%

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to 60%.

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OCULAR CHEMICAL BURNS Robert J. Hyde, MD, MA BASICS DESCRIPTION • Chemical exposure to the eye can result in rapid, devastating, and permanent damage and is one of the true emergencies in ophthalmology. • Separate alkaline from acid chemical exposure. – Alkali burns: more severe. Alkaline compounds are lipophilic, penetrating rapidly into eye tissue; saponification of cells leads to necrosis and may produce injury to lids, conjunctiva, cornea, sclera, iris, and lens (cataracts). – Acid burns: Acid usually does not damage internal structures because its associated anion causes protein denaturation, creating a barrier to further acid penetration (hydrofluoric acid is an exception to this rule; see below). Injury is often limited to lids, conjunctiva, and cornea. • System(s) affected: nervous, skin/exocrine • Synonym(s): chemical ocular injuries

EPIDEMIOLOGY • Predominant age: can occur at any age, peak from 20 to 40 years of age • Predominant sex: male > female

Incidence • Estimated 300/100,000 per year • Alkali burns twice as common as acid burns

ETIOLOGY AND PATHOPHYSIOLOGY • Acidic compounds – Anion leads to protein denaturing and protective barrier formation by coagulation necrosis forming an eschar. This more superficial mechanism of injury tends to have prominent scarring that may lead to vision loss: Hydrofluoric acid is an exception. In its nonionized form, it behaves like an alkaline substance, capable of penetrating the corneal stroma and

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leading to extensive anterior segment lesions. When ionized, it may combine with intracellular calcium and magnesium to form insoluble complexes, leading to potassium ion movements and cell death. Once systemically absorbed, severe hypocalcemia can occur. • Alkaline compounds – Lipophilic compounds that penetrate into deep structures on disassociation into cations and hydroxide – Hydroxide causes saponification of fatty acids in cell membranes, leading to cell death. – Cation causes hydration of glycosaminoglycans, leading to corneal opacification and hydration of collagen, resulting in rapid shortening and thickening of collagen fibrils that leads to an acute elevation in intraocular pressure secondary to shrinking and contraction of the cornea and sclera. – Long-term elevation in intraocular pressure may occur from accumulation of inflammatory debris within the trabecular meshwork. – Penetration into deep structures may also affect perfusing vessels, leading to ischemia of affected area.

RISK FACTORS • Construction work (plaster, cement, whitewash) • Use of cleaning agents (drain cleaners, ammonia) • Automobile battery explosions (sulfuric acid)

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• Industrial work, including work in industrial chemical laboratories • Alcoholism • Any risk factor for assault (~10% of injuries due to deliberate assault)

GENERAL PREVENTION Safety glasses to safeguard eyes

COMMONLY ASSOCIATED CONDITIONS Facial (including eyelids) cutaneous chemical or thermal burns

DIAGNOSIS HISTORY • Most often, complaints of pain, photophobia, blurred vision, and a foreign body sensation • In alkali burns, can have initial pain that later diminishes • Mild burns: pain and blurred vision • Moderate to severe burns: severe pain and markedly reduced vision

PHYSICAL EXAM • Acidic compound may present with a ground-glass appearance secondary to superficial scar formation. • Alkaline compounds may present with corneal opacification secondary to glycosaminoglycan hydration; however, severe acid burns may also present with this finding. • Mild burns – Blurry vision – Eyelid skin erythema and edema – Corneal epithelial defects or superficial punctate keratitis – Conjunctival chemosis, hyperemia, and hemorrhages without perilimbal ischemia – Mild anterior chamber reaction • Moderate to severe burns – Reduced vision – 2nd- and 3rd-degree burns of eyelid skin

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– Corneal edema and opacification – Corneal epithelial defects – Marked conjunctival chemosis and perilimbal blanching – Moderate anterior chamber reaction – Increased intraocular pressure – Local necrotic retinopathy

DIFFERENTIAL DIAGNOSIS • Thermal burns • Ocular cicatricial pemphigoid • Other causes of corneal opacification • Ultraviolet radiation keratitis

DIAGNOSTIC TESTS & INTERPRETATION Not necessary unless suspicion of intraocular or orbital foreign body is present. In this case, CT should be used and MRI is contraindicated.

Diagnostic Procedures/Other • Measure pH of tear film with litmus paper or electronic probe: – Irrigating fluid with nonneutral pH (e.g., normal saline has pH of 4.5) may alter results. • Careful slit-lamp exam, fundus ophthalmoscopy, tonometry, and measurement of visual acuity • Full extent of damage from alkali burns may not be apparent until 48 to 72 hours after exposure.

Test Interpretation • Corneal epithelial defects or superficial punctate keratitis, edema, opacification • Conjunctival chemosis, hyperemia, and hemorrhages • Perilimbal ischemia • Anterior chamber reaction • Increased intraocular pressure

TREATMENT

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Copious irrigation and removal of corneal or conjunctival foreign bodies are always the initial treatment (1,2)[A]: • Passively open patient’s eyelid and have patient look in all directions while irrigating. • Be sure to remove all reservoirs of chemical from the eyes. • Continue irrigation until the tear film and superior/inferior cul-de-sac is of neutral pH (7 ± 0.1) and pH is stable (1)[C]: – Severe burns should be irrigated for at least 15 minutes to as much as 2 to 4 hours; this irrigation should not be interrupted during transportation to hospital (1)[C]. – Irrigation via Morgan lens (polymethylmethacrylate scleral lens) is a good way to achieve continuous irrigation over a prolonged period of time. – It is impossible to overirrigate. • Initial pH testing should be done on both eyes even if the patient claims to only have unilateral ocular pain/irritation so that a contralateral injury is not neglected. • Use whatever nontoxic fluid is available for irrigation on scene. In hospital, sterile water, normal saline, normal saline with bicarbonate, balanced salt solution (BSS), or lactated Ringer solution may be used: • A topical anesthetic can be used to provide patient comfort (e.g., proparacaine, tetracaine). • Sweep the conjunctival fornices every 12 to 24 hours to prevent adhesions (1) [C]. • Eye patching may relieve pain but has not been shown to improve outcomes (3)[C].

MEDICATION First Line • Further treatment (depending on severity and associated conditions) – Topical prophylactic antibiotics: any broad-spectrum agent (e.g., bacitracin–polymyxin B ointment q2–4h, ciprofloxacin drops q2–4h) Some experts suggest that systemic tetracycline 250 mg PO q6h and especially derivatives such as doxycycline 100 mg PO BID may be beneficial to encourage healing of persistent corneal epithelial defects by

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inhibiting metalloproteinases (4)[C]. – Tear substitutes: carboxymethylcellulose (Refresh Plus) drops q4h Most beneficial in those with impaired tear production (elderly patients) – Cycloplegics for photophobia and/or uveitis: cyclopentolate 1% TID or scopolamine 1/4% BID (1)[C] – Antiglaucoma for elevated intraocular pressure: latanoprost (Xalatan) 0.005% q24h, timolol (Timoptic) 0.5% BID, or levobunolol (Betagan) 0.5% BID, and/or acetazolamide (Diamox) 125 to 250 mg PO q6h, or methazolamide (Neptazane) 25 to 50 mg PO BID (1)[C] – Corticosteroids for intraocular inflammation: prednisolone (Pred-Forte) 1% or equivalent q1–4h for 7 to 10 days; if severe, prednisone 20 to 60 mg PO daily for 5 to 7 days. Taper rapidly if epithelium is intact by this time (1) [C]: Use of corticosteroids >10 days may do harm by inhibiting repair and cause corneoscleral melt (5)[C]. – Vitamin C (ascorbic acid) 500 mg PO QID and topical 10% ascorbate solution in artificial tears reduces the incidence of corneal thinning and ulceration (1)[C]. – Acetylcysteine (Mucomyst) 10–20% topically q4h to promote wound healing (1)[C] • Precautions – Timolol and levobunolol: history of heart failure (HF) or chronic obstructive pulmonary disease (COPD) – Acetazolamide and methazolamide: history of nephrolithiasis or metabolic acidosis – Mannitol: history of HF or renal failure – Scopolamine: history of urinary retention – Topical corticosteroids must be used with caution in the presence of damaged corneal epithelium because iatrogenic infection can occur. Daily follow-up or consultation with an ophthalmologist is recommended.

SURGERY/OTHER PROCEDURES • Goal of subacute treatment is restoration of the normal ocular surface anatomy, control of glaucoma, and restoration of corneal clarity. • Surgical options include the following:

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– Débridement of necrotic tissue – Conjunctival/tenon advancement (tenoplasty) to restore vascularity in severe burns – Tissue adhesive (e.g., isobutyl cyanoacrylate) for impending or actual corneal perforation of Tectonic keratoplasty for acute perforation >1 mm – Limbal autograft transplantation for epithelial stem cell restoration – Amniotic membrane transplantation (5)[C] or umbilical cord serum drops to promote epithelial regeneration (5)[C] – Conjunctival or mucosal membrane transplant to restore ocular surface in severe injury – Lamellar or penetrating keratoplasty for tectonic stabilization or visual rehabilitation

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS Based on ophthalmologic consultation and concomitant burn injuries

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Depending on severity of ocular injury – From daily to weekly visits initially • May be inpatient • If on mannitol or prednisone, consider frequent serum electrolytes.

PATIENT EDUCATION • Safety glasses • Need for immediate ocular irrigation with any available water following chemical exposure to the eyes

PROGNOSIS • Depends on severity of initial injury: Increased limbal involvement in clock hours and greater percentage of conjunctival involvement correlate with

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poorer prognosis (Dua classification system). • For mildly injured eyes, complete recovery is the norm. • For severely injured eyes, permanent loss of vision is not uncommon.

COMPLICATIONS • Orbital compartment syndrome • Persistent epitheliopathy • Fibrovascular pannus • Corneal ulcer/perforation • Corneal scarring • Progressive symblepharon • Neurotrophic keratitis • Lid malposition secondary to cicatricial ectropion and entropion • Glaucoma • Cataract • Hypotony • Phthisis bulbi • Blindness

REFERENCES 1. Singh P, Tyagi M, Kumar Y, et al. Ocular chemical injuries and their management. Oman J Ophthalmol. 2013;6(2):83–86. 2. Eslani M, Baradaran-Rafii A, Movahedan A, et al. The ocular surface chemical burns. J Ophthalmol. 2014;2014:196827. 3. Chau JP, Lee DT, Lo SH. A systematic review of methods of eye irrigation for adults and children with ocular chemical burns. Worldviews Evid Based Nurs. 2012;9(3):129–138. 4. Spector J, Fernandez WG. Chemical, thermal, and biological ocular exposures. Emerg Med Clin North Am. 2008;26(1):125–136. 5. Ralph RA. Tetracyclines and the treatment of corneal stromal ulceration: a review. Cornea. 2000;19(3):274–277.

ADDITIONAL READING • Fish R, Davidson RS. Management of ocular thermal and chemical injuries,

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including amniotic membrane therapy. Curr Opin Ophthalmol. 2010;21(4):317–321. • Gicquel JJ. Management of ocular surface chemical burns. Br J Ophthalmol. 2011;95(2):159–161. • Lin A, Patel N, Yoo D, et al. Management of ocular conditions in the burn unit: thermal and chemical burns and Stevens-Johnson syndrome/toxic epidermal necrolysis. J Burn Care Res. 2011;32(5):547–560. • Roblin I, Urban M, Flicoteau D, et al. Topical treatment of experimental hydrofluoric acid skin burns by 2.5% calcium gluconate. J Burn Care Res. 2006;27(6):889–894. • Sharma N, Lathi SS, Sehra SV, et al. Comparison of umbilical cord serum and amniotic membrane transplantation in acute ocular chemical burns. Br J Ophthalmol. 2015;99(5):669–673.

SEE ALSO Burns

CODES ICD10 • T26.50XA Corrosion of unsp eyelid and periocular area, init encntr • T26.60XA Corrosion of cornea and conjunctival sac, unsp eye, init • S05.00XA Inj conjunctiva and corneal abrasion w/o fb, unsp eye, init

CLINICAL PEARLS • Prompt irrigation of all chemical burns, even prior to arrival to the emergency department, is essential to ensure best outcomes. It is impossible to overirrigate. • All patients with chemical injuries to their eyes should have urgent ophthalmology consultation and/or referral.

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ONYCHOMYCOSIS Lauren M. Simon, MD, MPH, FAAFP, FACSM BASICS DESCRIPTION • Fungal infection of fingernails/toenails • Caused mostly by dermatophytes but also yeasts and nondermatophyte molds • Toenails are more commonly affected than fingernails. • System(s) affected: skin, exocrine • Synonym(s): tinea unguium; ringworm of the nail

EPIDEMIOLOGY Prevalence • Occurs in 2–10% of general population • Predominant age: 20% in adults >60 years of age • Rare before puberty • Prevalence 15–40% in persons with human immunodeficiency infection (1)

ETIOLOGY AND PATHOPHYSIOLOGY • Dermatophytes: Trichophyton (Trichophyton rubrum most common), Epidermophyton, Microsporum • Yeasts: Candida albicans (most common), Candida parapsilosis, Candida tropicalis, Candida krusei • Molds: Scopulariopsis brevicaulis, Hendersonula toruloidea, Aspergillus sp., Alternaria tenuis, Cephalosporium, Scytalidium hyalinum • Dermatophytes cause 90% of toenail and most of fingernail onychomycoses. • Fingernail onychomycosis is more often caused by yeasts, especially Candida. • Dermatophytes can invade normal keratin, whereas nondermatophyte molds invade altered keratin (dystrophic/injured nails).

RISK FACTORS • Older age • Tinea pedis

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• Occlusive footwear • Cancer/diabetes/psoriasis • Peripheral vascular disease • Cohabitation with others with onychomycosis • Immunodeficiency • Communal swimming pools • Smoking • Peripheral vascular disease • History of nail trauma • Autosomal dominant genetic predisposition

COMMONLY ASSOCIATED CONDITIONS • Immunodeficiency/chronic metabolic disease (e.g., diabetes) • Tinea pedis/manuum

DIAGNOSIS PHYSICAL EXAM • Dermatophytes: commonly preceded by dermatophyte infection at another site; 80% involve toenails, especially hallux; simultaneous infection of fingernails and toenails is rare. Five clinical forms occur. – Distal/lateral subungual onychomycosis (most common): mainly due to T. rubrum. Spreads from distal/lateral margins to nail bed to nail plate; subungual hyperkeratosis; onycholysis; nail dystrophy; discoloration— yellow-white or brown-black, yellow streaking laterally; can progress proximally, bois vermoulu (“worm-eaten wood”); onychomadesis – Proximal subungual onychomycosis (rare 60 years of age – More common in nails of hallux – Resembles distal and lateral onychomycosis

Pediatric Considerations • Candidal infection presents more commonly as superficial onychomycosis. • The U.S. Food and Drug Administration (FDA) has not approved any systemic antifungal agents for treatment of onychomycosis in children. Efficacy and safety profiles in children for some systemic antifungals are similar to those previously reported in adults (2).

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DIFFERENTIAL DIAGNOSIS • Psoriasis (most common alternate diagnosis) • Traumatic dystrophy • Lichen planus • Onychogryphosis (“ram’s horn nails”) • Eczematous conditions • Hypothyroidism • Drugs and chemicals • Yellow nail syndrome • Neoplasms (0.7–3.5%) of all melanoma cases are subungual. In a brownish yellow nail, if dark pigment extends into periungual skin fold, consider subungual melanoma.

DIAGNOSTIC TESTS & INTERPRETATION • Accurate diagnosis requires both laboratory and clinical evidence. • About 50% of nail dystrophy seen on visual inspection is not fungal in origin, so laboratory assessment improves diagnostic accuracy. • If onychomycosis is suspected clinically and initial diagnostic laboratory tests are negative, the tests should be repeated. • A nail plate biopsy or partial/full removal of nail with culture is needed to diagnose proximal subungual onychomycosis.

Initial Tests (lab, imaging) • Direct microscopy with potassium hydroxide (KOH) preparation (1)[C] – Clean nail with 70% isopropyl alcohol. – Using sterile clippers, remove diseased, discolored nail plate. – Collect debris from stratum corneum of most proximal area (beneath nail or crumbling nail itself) with 1-mm curette/scalpel. – Place sample on microscope slide with drop of 5–10% KOH. View after 5 minutes. – Gentle heat applied to slide can enhance keratin breakdown. – High sensitivity if >2 preparations were examined – Look for hyphae, pseudohyphae, or spores. • Cultures: False-negative finding in 30% (secondary to loss of dermatophyte viability; improved by immediate culture on Sabouraud cell culture medium);

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results may take 3 to 6 weeks. • In office dermatophyte test, medium culture indicates dermatophyte growth with yellow-to-red color change of the medium; results in 3 to 7 days; limited studies. • Histologic examination of nail clippings/nail plate punch biopsy: proximal lesions; stain both with periodic acid–Schiff (PAS) stain (1)[C]. • KOH-treated nail clipping stained with PAS: significantly higher rates of detection of onychomycosis as compared with standard methods of KOH preparation and fungal culture (3)[C] • Polymerase chain reaction (PCR) increases sensitivity of detection of dermatophytes in nail specimen, results available within 3 days can be used as complementary to direct microscope exam and fungal culture; not widely available. • Fluorescence microscopy can be used as a rapid screening tool for identification of fungi in nail specimens. • Commercial laboratories may use KOH with calcofluor white stain to improve view of fungal elements in fluorescent microscopy. • Discontinue all topical medication for at least 1 week before obtaining a sample.

Test Interpretation Pathogens within the nail keratin

TREATMENT GENERAL MEASURES • Avoid factors that promote fungal growth (i.e., heat, moisture, occlusion, tight-fitting shoes). • Treat underlying disease risk factors. • Treat secondary infections.

MEDICATION Pregnancy Considerations Oral antifungals and ciclopirox are pregnancy Category B (terbinafine,

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ciclopirox) or C (itraconazole, fluconazole, and griseofulvin). Griseofulvin is not advised in pregnancy due to risks of teratogenicity and conjoined twins. Ideally postpone treatment of onychomycosis until after pregnancy.

First Line • Oral antifungals are preferred due to higher rates of cure but have systemic adverse effects and many drug–drug interactions. • Terbinafine: 250 mg/day PO for 6 weeks for fingernails and 12 weeks for toenails; most effective in cure and prevention of relapse compared with other antifungals and with itraconazole pulse in meta-analysis for toenail onychomycosis I (4)[A] • Itraconazole pulse: 200 mg PO BID for 1 week, then 3 weeks off, repeat for two cycles for fingernails and three to four cycles for toenails; does not need to monitor liver function tests (LFTs) with pulse dosing • Itraconazole continuous: 200 mg/day PO for 6 weeks for fingernails and 12 weeks for toenails (less effective than itraconazole pulse for dermatophytes, more effective than terbinafine for Candida and molds)

Second Line • Fluconazole pulse: 150 to 300 mg PO weekly for 6 months (lower cure rate); not FDA-approved for onychomycosis • Griseofulvin: 500 to 1,000 mg/day PO for up to 18 months (lower cure rate, continue until the diseased nail is replaced) • Posaconazole: 100, 200, or 400 mg once daily for 24 weeks; 400 mg once daily for 12 weeks; higher cost • Topical agents: Use limited to disease not involving the lunula (proximal nail plate). Topical therapy does not cause systemic toxicity but is less effective than oral therapy. Head-to-head comparison of efficacy of available agents is generally not available. • Ciclopirox: 8% nail lacquer (available generically): Apply once daily to affected nails (if without lunula involvement) for up to 48 weeks; remove lacquer with alcohol every 7 days, then file away loose nail material and trim nails (low-cure rate, avoids systemic adverse effects, less cost-effective). Application after PO treatment may reduce recurrences. Systematic review >60% failure rate after 48 weeks of use (5)[A],(6)

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• Tavaborole 5% solution, a topical oxaborole antifungal is indicated for onychomycosis of the toenails due to Trichophyton rubrum or Trichophyton mentagrophytes. Complete or almost-complete cure 15–18% after 48 weeks (NNT compared to vehicle approx 7) • Efinaconazole solution 10% (7). Complete or almost-complete cure after 48 weeks in range of 15–18% (NNT compared to vehicle 7 to 10) • Contraindications for oral antifungals – Hepatic disease – Pregnancy (see “Pregnancy Considerations”) – Current/history of congestive heart failure (CHF) (itraconazole) – Ventricular dysfunction (itraconazole) – Porphyria (griseofulvin) • Precautions/adverse effects – Oral antifungals Hepatotoxicity/neutropenia Hypersensitivity Photosensitivity, lupus-like symptoms, proteinuria (griseofulvin) Chronic kidney disease (avoid terbinafine for patients with creatine clearance [CrCl] 2 mm – White/yellow or orange/brown streaks in the nail (includes dermatophytoma) – Total dystrophic onychomycosis (with matrix involvement) – Nonresponsive organisms (e.g., Scytalidium mold) – Patients with immunosuppression – Diminished peripheral circulation

COMPLICATIONS • Secondary infections with progression to soft tissue infection/osteomyelitis • Toenail discomfort/pain that can limit physical mobility or activity • Anxiety, negative self-image

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REFERENCES 1. Westerberg DP, Voyack MJ. Onychomycosis: current trends in diagnosis and treatment. Am Fam Physician. 2013;88(11):762–770. 2. Gupta AK, Paquet M. Systemic antifungals to treat onychomycosis in children: a systematic review. Pediatr Dermatol. 2013;30(3):294–302. 3. Eisman S, Sinclair R. Fungal nail infection: diagnosis and management. BMJ. 2014;348:g1800. 4. Gupta AK, Ryder JE, Johnson AM. Cumulative meta-analysis of systemic antifungal agents for the treatment of onychomycosis. Br J Dermatol. 2004;150(3):537–544. 5. Crawford F, Hollis S. Topical treatments for fungal infections of the skin and nails of the foot. Cochrane Database Syst Rev. 2007;(3):CD001434. 6. Gupta AK, Paquet M, Simpson FC. Therapies for the treatment of onychomycosis. Clin Dermatol. 2013;31(5):544–554. 7. Ameen M, Lear J, Madan V, et al. British Association of Dermatologists’ guidelines for the management of onychomycosis 2014. Br J Dermatol. 2014;171(5):937–958.

CODES ICD10 • B35.1 Tinea unguium • B37.2 Candidiasis of skin and nail

CLINICAL PEARLS • Psoriasis and chronic nail trauma are commonly mistaken for fungal infection. • Diagnosis should be based on both clinical and mycologic laboratory evidence.

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OPTIC NEURITIS Olga Cerón, MD • Pablo Hernandez Itriago, MD, MHCM, FAAFP BASICS DESCRIPTION • Inflammation of the optic nerve (cranial nerve II) • Most common form is acute demyelinating optic neuritis (ON), but other causes include infectious disease and systemic autoimmune disorders. • Optic disc may be normal in appearance at onset (retrobulbar ON, 67%) or swollen (papillitis, 33%). • Key features: – Abrupt visual loss (typically monocular) – Periorbital pain with eye movement (90%) – Pain in the distribution of the first division of the trigeminal nerve – Dyschromatopsia: color vision deficits – Relative afferent pupillary defect (RAPD) • Usually unilateral in adults; bilateral disease is more common in children. • Presenting complaint in 25% of patients with multiple sclerosis (MS) • In children, headaches are common. • System(s) affected: nervous • Synonym(s): papillitis; demyelinating optic neuropathy; retrobulbar ON

EPIDEMIOLOGY Incidence • 1 to 5/100,000 cases per year • More common in northern latitudes • More common in whites than in other races • Predominant age: 18 to 45 years; mean age 30 years • Predominant sex: female > male (3:1)

ETIOLOGY AND PATHOPHYSIOLOGY

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• In both MS-associated and isolated monosymptomatic ON, the cause is presumed to be a demyelinating autoimmune reaction. • Possible mechanisms of inflammation in immune-mediated ON are the crossreaction of viral epitopes and host epitopes and the persistence of a virus in CNS glial cells. • Neuromyelitis optica (NMO) IgG autoantibody, which targets the water channel aquaporin-4 • Primarily idiopathic • MS • Viral infections: measles, mumps, varicella-zoster, coxsackievirus, adenovirus, hepatitis A and B, HIV, herpes simplex virus, cytomegalovirus • Nonviral infections: syphilis, tuberculosis, meningococcus, cryptococcosis, cysticercosis, bacterial sinusitis, streptococcus B, Bartonella, typhoid fever, Lyme disease, fungus • Systemic inflammatory disease: sarcoidosis, systemic lupus erythematosus, vasculitis • Local inflammatory disease: intraocular or contiguous with the orbit, sinus, or meninges • Toxic: lead, methanol, arsenic, radiation • Vascular lesions affecting the optic nerve • Posterior uveitis (i.e., birdshot retinochoroidopathy, toxoplasmosis, toxocariasis) • Tumors • Medications: ethambutol, chloroquine, isoniazid, chronic high-dose chloramphenicol, tumor necrosis factor α-antagonist, infliximab (Remicade), adalimumab (Humira), etanercept (Enbrel)

COMMONLY ASSOCIATED CONDITIONS • MS (common): ON is associated with an increased risk of MS. • Other demyelinating diseases: Guillain-Barré syndrome, Devic NMO, multifocal demyelinating neuropathy, acute disseminated encephalomyelitis

DIAGNOSIS

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HISTORY • Decreased visual acuity, deteriorating in hours to days, usually reaching lowest level after 1 week • Usually unilateral but can also be bilateral • Brow ache, globe tenderness, deep orbital pain exacerbated by eye movement (92%) • Retro-orbital pain may precede visual loss. • Desaturation of color vision (dull or faded colors), especially red tones • Apparent dimness of light intensities • Impairment of depth perception (80%); worse with moving objects (Pulfrich phenomenon) • Transient increase in visual symptoms with increased body temperature and exercise (Uhthoff phenomenon) • May present with a recent flulike viral syndrome • Detailed history and review of systems, looking for a history of demyelinating, infectious, or systemic inflammatory disease

PHYSICAL EXAM Complete general exam, full neurologic exam, and ophthalmologic exam looking for the following: • Decreased visual acuity and color perception • Central, cecocentral, arcuate, or altitudinal visual field deficits • Papillitis: swollen disc ± peripapillary flame-shape hemorrhage or often normal disc exam • Temporal disc pallor seen later at 4 to 6 weeks (1)[A] • RAPD (Marcus-Gunn pupil): The pupil of the affected eye dilates with a swinging light test unless disease is bilateral.

DIFFERENTIAL DIAGNOSIS • Demyelinating disease, especially MS • Infectious/systemic inflammatory disease • Neuroretinitis: virus, toxoplasmosis, Bartonella • Toxic or nutritional optic neuropathy • Acute papilledema (bilateral disc edema) • Compression:

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– Orbital tumor/abscess compressing the optic nerve – Intracranial tumor/abscess compressing the afferent visual pathway – Orbital pseudotumor – Carotid–ophthalmic artery aneurysm • Temporal arteritis or other vasculitides • Trauma or radiation • NMO (Devic disease) • Anterior ischemic optic neuropathy • Leber hereditary optic neuropathy • Kjer-type autosomal dominant optic atrophy • Severe systemic hypertension • Diabetic papillopathy

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • In typical presentations, ESR is standard, but other labs are unnecessary. Antinuclear antibodies (ANAs), angiotensin-converting enzyme level, fluorescent treponemal antibody absorption (FTA-ABS), and chest radiograph have been shown to have no value in typical cases (1)[A]. • In atypical presentations, including absence of pain, a very swollen optic nerve, >30 days without recovery, or retinal exudates, labs may be indicated to rule out underlying disorders: – CBC – ANA test – Rapid plasma reagin test – FTA-ABS test • MRI of brain and orbits: thin cuts (2 to 3 mm) gadolinium-enhanced and fatsuppression images to look for Dawson fingers of MS (periventricular white matter lesions oriented perpendicular to the ventricles) and also to look for enhancement of the optic nerve • CT scan of chest to rule out sarcoidosis if clinical suspicion is high • Ocular coherence tomography (OCT) of the retinal nerve fiber layer (RNFL); a noninvasive imaging technique of the optic nerve. May serve as a diagnostic tool to quantify thickness of the nerve fiber layer objectively and, thus,

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monitor structural change (axonal loss) of the optic nerve in the course of the disease. Follow-Up Tests & Special Considerations • Visual field test (Humphrey 30–2) to evaluate for visual field loss: diffuse and central visual loss more predominant in the affected eye at baseline (2)[A] • OCT of the optic nerve RNFL to detect and monitor axonal loss in the anterior visual pathways • Low-contrast visual acuity (as a measure of disease progression) • A novel blood test called NMO-IgG checks for antibodies for NMO.

Diagnostic Procedures/Other • In atypical cases, including bilateral deficits, young age, or suspicion of infectious etiology, lumbar puncture (LP) with neurology consultation is indicated. • LP for suspected MS is a physician-dependent decision. Some studies indicate that it may not add value to MRI for MS detection (1)[A], but no consensus on the subject exists.

TREATMENT Most persons with ON recover spontaneously.

MEDICATION First Line • IV methylprednisolone has been shown to speed up the rate of visual recovery but without significant long-term benefit; consider for patients who require fast recovery (i.e., monocular patients or those whose occupation requires high-level visual acuity). For significant vision loss, parenteral corticosteroids may be considered on an individualized basis: optic neuritis treatment trial (ONTT): – Observation and corticosteroid treatment are both acceptable courses of action. – High-dose IV methylprednisolone (250 mg q6h for 3 days) followed by oral corticosteroids (1 mg/kg/day PO for 11 days, taper over 1 to 2 weeks) (3)

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[A] • Others use IV Solu-Medrol infusion (1 g in 250 mL D5 1/2 normal saline infused over 1 hour daily for 3 to 5 days): – No evidence of long-term benefit (1)[A] – May decrease recovery time (3)[A] – May decrease risk of MS at 2 years but not 5 years (3)[A] • Give antiulcer medications with steroids.

Second Line • Disease-modifying agents, such as interferon-β1a (IFN-β1a; Avonex, Rebif) and IFN-β1b (Betaseron), are used to prevent or delay the development of MS in people with ON who have ≥2 brain lesions evident on MRI. – These medications have been proposed for use in patients with one episode of ON (clinically isolated syndrome) at high risk of developing MS (1+ lesion on brain MRI). • Decisions should be made individually with neurology consultation.

ALERT Never use oral prednisone alone as the primary treatment because this may increase the risk for recurrent ON (3)[A].

Pediatric Considerations • No systematic study defining high-dose corticosteroids in children with ON have been conducted. – Consensus recommends: 3 to 5 days of IV methylprednisolone (4 to 30 mg/kg per day), followed by a 2- to 4-week taper of oral steroids (4)[C] • Optic disc swelling and bilateral disease are more common in children as is severe loss of visual acuity (20/200 or worse). • Consider infectious and postinfectious causes of optic nerve impairment.

ISSUES FOR REFERRAL Referral to a neurologist and/or ophthalmologist

ONGOING CARE

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FOLLOW-UP RECOMMENDATIONS Patient Monitoring Monthly follow-up to monitor visual changes and steroid side effects

PATIENT EDUCATION • Provide reassurance about recovery of vision. • If the disease is believed to be secondary to demyelinating disease, patient should be informed of the risk of developing MS. • For patient education materials favorably reviewed on this topic, contact: – National Eye Institute, Information Officer, Department of Health and Human Services, 9000 Rockville Pike, Bethesda, MD 20892, 301-496-5248 – North American Neuro-Ophthalmology Society (NANOS), 5841 Cedar Lake Road, Suite 204, Minneapolis, MN 55416, 952-646-2037, Fax: 952545-6073, http://www.nanosweb.org/i4a/pages/index.cfm?pageid=3280

PROGNOSIS • Orbital pain usually resolves within 1 week. • Visual acuity – Rapid spontaneous improvement at 2 to 3 weeks and continues for several months (may be faster with IV corticosteroids) – Often returns to normal or near-normal levels (20/40 or better) within 1 year (90–95%), even after near blindness • Other visual disturbances (e.g., contrast sensitivity, stereopsis) often persist after acuity returns to normal. • Recurrence risk of 35% within 10 years: 14% affected eye, 12% contralateral, 9% bilateral; recurrence is higher in MS patients (48%). • ON is associated with an increased risk of developing MS; 35% risk at 7 years, 58% at 15 years (5)[A] – Brain MRI helps to predict risk: 0 lesions: 16% 1 to 2 lesions: 37% 3+ lesions: 51% Poor prognostic factors: • Absence of pain • Low initial visual acuity

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• Involvement of intracanalicular optic nerve Children with bilateral visual loss have a better prognosis than adults.

COMPLICATIONS Permanent loss of vision

REFERENCES 1. Vedula SS, Brodney-Folse S, Gal RL, et al. Corticosteroids for treating optic neuritis. Cochrane Database Syst Rev. 2007;(1):CD001430. 2. Keltner JL, Johnson CA, Cello KE, et al. Visual field profile of optic neuritis: a final follow-up report from the optic neuritis treatment trial from baseline through 15 years. Arch Ophthalmol. 2010;128(3):330–337. 3. Simsek I, Erdem H, Pay S, et al. Optic neuritis occurring with anti-tumour necrosis factor alpha therapy. Ann Rheum Dis. 2007;66(9):1255–1258. 4. Bonhomme GR, Mitchell EB. Treatment of pediatric optic neuritis. Curr Treat Options Neurol. 2012;14(1):93–102. 5. Optic Neuritis Study Group. Visual function 15 years after optic neuritis: a final follow-up report from the Optic Neuritis Treatment Trial. Ophthalmology. 2008;115(6):1079.e5–1082.e5. 6. Arnold AC. Evolving management of optic neuritis and multiple sclerosis. Am J Ophthalmol. 2005;139(6):1101–1108. 7. Balcer LJ. Clinical practice. Optic neuritis. N Engl J Med. 2006;354(12):1273–1280.

ADDITIONAL READING • Balk LJ, Cruz-Herranz A, Albrecht P, et al. Timing of retinal neuronal and axonal loss in MS: a longitudinal OCT study. J Neurol, 2016;263(7):1323– 1331. • Syc SB, Saidha S, Newsome SD, et al. Optical coherence tomography segmentation reveals ganglion cell layer pathology after optic neuritis. Brain. 2012;135(2):521–533.

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SEE ALSO Multiple Sclerosis

CODES ICD10 • H46.9 Unspecified optic neuritis • H46.00 Optic papillitis, unspecified eye • H46.10 Retrobulbar neuritis, unspecified eye

CLINICAL PEARLS • MRI is the procedure of choice for determining relative risk and possible therapy for MS prevention. • The ONTT showed that high-dose IV methylprednisolone followed by oral prednisone accelerated visual recovery but did not improve the 6-month or 1year visual outcome compared with placebo, whereas treatment with oral prednisone alone did not improve the outcome and was associated with an increased rate of recurrence of ON (1,2)[A],(6)[B],(7)[C].

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OSGOOD-SCHLATTER DISEASE (TIBIAL APOPHYSITIS) David P. Sealy, MD • Robert J. Tiller, MD, FAAFP BASICS DESCRIPTION • Osgood-Schlatter Disease (OSD) is a syndrome associated with traction apophysitis and patellar tendinosis that is most common in adolescent boys and girls. – Patients present with pain and swelling of the anterior tibial tubercle • System(s) affected: musculoskeletal • Synonym: Tibial tubercle apophysitis

EPIDEMIOLOGY Incidence Incidence in girls increasing with increased participation in organized youth sports; still more common in boys

Prevalence • A common apophysitis in childhood and adolescence affecting athletes (21%) and nonathletes (4.5%) (1)[B] • Approximately 10% remain symptomatic as adults (2)[C]. • 10% of all adolescent knee pain is due to OSD.

ETIOLOGY AND PATHOPHYSIOLOGY Traction apophysitis of the tibial tubercle due to repetitive strain on the secondary ossification center of the tibial tuberosity, concurrent patellar tendinosis, and disruption of the proximal tibial apophysis • Basic etiology unknown, exacerbated by exercise – Jumping and pivoting sports place highest strain on the tibial tubercle. Repetitive trauma is the most likely inciting factor. • Possible association with tight hip flexors and tight quadriceps; increased quadriceps strength in adolescence relative to hamstring strength

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• Early sports specialization increases the risk for OSD 4-fold (3)[B].

RISK FACTORS • Affects children and adolescents most commonly from the ages of 8 to 18 years – Girls 8 to 14 years – Boys 10 to 18 years • OSD is slightly more common in boys. • Rapid skeletal growth • Participation in repetitive-jumping sports and sports with heavy quadriceps activity (football, volleyball, basketball, hockey, soccer, skating, gymnastics) • Ballet (2-fold risk compared with nonathletes) • Potential increased risk of OSD in adolescents with ADD/ADHD (4)[C]

GENERAL PREVENTION • Avoid sports with heavy quadriceps loading (especially deceleration activities —eccentric loading). • Patients may compete if pain is minimal. • Increase hamstring and quadriceps flexibility.

COMMONLY ASSOCIATED CONDITIONS • Shortened (tight) rectus femoris found in 75% with OSD • Possible association with ADD/ADHD; adolescents with ADD/ADHD are at risk for other musculoskeletal injuries. • Sinding-Larsen-Johansson apophysitis

DIAGNOSIS HISTORY • Unilateral or bilateral (30%) pain of the tibial tuberosity • Pain exacerbated by exercise, especially jumping and landing after jumping • Pain upon kneeling on the affected side(s) • Antalgic or straight-legged gait

PHYSICAL EXAM • Knee pain with squatting or crouching

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• Absence of effusion or condyle tenderness • Tibial tuberosity swelling and tenderness • Pain increased with resisted knee extension or kneeling • Erythema over tibial tuberosity • Functional testing: Single-leg squat (SLS) and standing broad jump reproduce pain (3)[C].

DIFFERENTIAL DIAGNOSIS • Stress fracture of the proximal tibia • Pes anserinus bursitis • Quadriceps tendon avulsion • Patellofemoral stress syndrome • Chondromalacia patellae (retropatellar pain) • Proximal tibial neoplasm • Osteomyelitis of the proximal tibia • Tibial plateau fracture • Sinding-Larsen-Johansson syndrome (patellar apophysitis)—pain over inferior patellar tendon • Patellar fracture • Infrapatellar bursitis • Patellar tendinitis—pain over inferior patellar tendon and inferior pole of patella

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Generally a clinical diagnosis. No tests are indicated unless other diagnoses are under consideration. • Radiographic imaging of the proximal tibia and knee may show heterotopic calcification in the patellar tendon: – X-rays are rarely diagnostic, but appearance of a separate fragment at the tibial tuberosity identifies candidates for potential surgical intervention. – Calcified thickening of the tibial tuberosity with irregular ossification at tendon insertion on the tibial tubercle (5)[B]

Diagnostic Procedures/Other

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• Bone scan may show increased uptake in the area of the tibial tuberosity: – Increased uptake in apophysis is normal in children, but with OSD, there may be more uptake on the opposite side. • Ultrasound is an excellent alternative, showing thickening of the distal patellar tendon and infrapatellar bursa effusion. • MRI shows fragmentation of the tibial tubercle and bone edema.

Test Interpretation Biopsy is not necessary but would show osteolysis and fragmentation of the tibial tubercle.

TREATMENT GENERAL MEASURES • Frequent ice applications 2 to 3 times per day for 15 to 20 minutes • Rest and activity modification—avoid activities that increase pain and/or swelling. • Physical therapy helps with hamstring and quadriceps strengthening and stretching. • Open- and closed-chain eccentric quadriceps strengthening • Avoid aggressive stretching if pain is significant to avoid risk of tibial tubercle avulsion (1)[B]. • Consult orthopedic surgery for tibial tuberosity fracture or complete avulsion. • Electrical stimulation and iontophoresis may be beneficial (1)[B]. • Patients with marked pronation may benefit from orthotics. • A single study showed benefit from an infrapatellar strap and many experts recommend the use of a knee brace with an H- or U-shaped buttress (1)[C].

MEDICATION First Line • Any analgesic may be considered. • NSAIDs may help control pain. • Opioids are not recommended as first line.

Second Line

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• More potent analgesics, such as opioids, may be considered for short-term use in extreme situations. • Corticosteroid injections are not recommended. • Hypertonic glucose and/or Xylocaine injections have shown recent benefit (6) [C].

ISSUES FOR REFERRAL When conservative therapy is unsuccessful, consider surgical referral.

SURGERY/OTHER PROCEDURES • Débridement of a thickened, cosmetically unsatisfactory tibial tubercle (rare) or removal of mobile heterotopic bone • Surgical excision of a painful tibial tubercle is rarely needed (40 years of age. • Leading cause of disability in patients >65 years old • Predominant sex: male = female • 90% of hip OA is primary.

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• Hip OA is more common in whites.

Prevalence • ~60 million patients • Increases with age; radiographic evidence of OA is present in many patients >65 years old. • Moderate to severe hip OA in 3–6% of whites; 50 years • Age as a risk factor is greatest for hip and knee OA. • Hand OA is most common in postmenopausal women. • Obesity (weight-bearing joints) • Small critical shoulder angle (2-cm deep increases likelihood in diabetic foot ulcers. • In patients with diabetes, classic signs and symptoms of infection may be masked due to vascular disease and neuropathy.

DIFFERENTIAL DIAGNOSIS • Systemic infection from other source • Aseptic bone infarction • Localized inflammation or infection of overlying skin and soft tissues (e.g., gout) • Brodie abscess (subacute osteomyelitis)

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• Neuropathic joint disease (Charcot foot) • Fractures/trauma • Tumor

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) Labs • WBC is not reliable (can be normal with infection). • CRP is usually elevated but nonspecific. • ESR is high in most cases: – ESR >70 mm/hr increases likelihood. • Antimicrobial agents given prior to culture may alter culture results. • Disorders that may alter lab results: immunosuppression (including diabetes), chronic inflammatory disease, other/adjacent sites of infection (1)[C] • Routine radiography is first-line imaging: Classic triad for osteomyelitis is demineralization, periosteal reaction, and bone destruction: – Bone destruction is not apparent on plain films until after 10 to 21 days of infection. – Bone must undergo 30–50% destruction before damage is evident on films. – Bone scan is typically first test after plain x-ray in setting of joint prosthesis. • Radionuclide scanning (e.g., technetium, indium, or gallium) is useful when diagnosis is ambiguous or extent of disease is in question but is limited by low sensitivity and specificity. • MRI – Best for visualization of septic arthritis, spinal infection, and diabetic foot infections (1)[C] – T1-weighted image: low signal intensity – T2-weighted image: high signal intensity – MRI with gadolinium: sensitivity and specificity range from 60–100% to 50–90%, respectively – MRI is not helpful in assessing the response to therapy due to persistence of bony edema. • CT

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– Better than standard radiography in fragments and sequestration, but inferior to MRI in soft tissue and bone marrow assessment – Helps define soft tissues and identify sequestra Follow-Up Tests & Special Considerations • A persistently elevated CRP (4 to 6 weeks) can be associated with persistent osteomyelitis. • Patients receiving prolonged antimicrobial therapy should be monitored with: – Weekly CBC – Liver and kidney function tests

Diagnostic Procedures/Other • Cultures – Definitive diagnosis is made by blood culture (hematogenous) or by needle aspiration/bone biopsy, with identification of the microorganism by culture and sensitivity or histology. – Patients with positive blood cultures and with radiographic evidence of osteomyelitis may not need bone culture. – Wound swabs and sinus tract cultures correlate well with the presence of S. aureus in deep cultures. • Image-guided bone biopsy for vertebral osteomyelitis (unless positive blood culture and positive radiographic evidence)

Test Interpretation Inflammatory process of bone with pyogenic bacteria, necrosis

TREATMENT GENERAL MEASURES • Adequate nutrition • Smoking cessation • Control diabetes

MEDICATION • Direct empiric therapy toward probable organism and tailor once culture results are available.

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• Optimal antimicrobial concentration at infection site is essential (consider vascular perfusion to site). • Antibiotic dosing altered for renal function • Duration of therapy 4 to 6 weeks for acute osteomyelitis and generally >8 weeks for chronic osteomyelitis or MRSA infection • In children, early transition from IV to oral therapy, (after 3 to 4 days if responding well) followed by oral therapy for 3 weeks may be as effective as longer courses for uncomplicated acute osteomyelitis (2)[B].

First Line • S. aureus or coagulase-negative staphylococci – MSSA: β-lactam at high dose (nafcillin or oxacillin 2 g IV q4h) or cefazolin 2 g IV q8h – MRSA: vancomycin 15 mg/kg IV q8–12h (use q8h interval if CrCl >70 mL/min) with target trough of 15 to 20 μg/mL • Streptococcus sp. – Ceftriaxone 2 g IV q24h or cefazolin 2 g IV q8h • Enterobacter sp. – Fluoroquinolone (levofloxacin 750 mg IV/PO q24h) or ceftriaxone 2 g IV q24h • Pseudomonas aeruginosa – Ciprofloxacin 750 mg PO BID or levofloxacin 750 mg PO q24h • Anaerobes – Clindamycin 600 mg IV q8h (300 to 450 mg PO q6–8h)

Second Line • S. aureus – MSSA: fluoroquinolone plus rifampin (levofloxacin 750 mg IV/PO q24h plus rifampin 300 mg PO q12h or 600 mg PO q24h) – MRSA: linezolid 600 mg PO/IV q12h or daptomycin 6 mg/kg IV q24h • Streptococcus sp. – Penicillin G 4 million U q4–6h • Enterobacter sp. (quinolone-resistant, including extended-spectrum βlactamase–producing Escherichia coli) – Carbapenem (imipenem/cilastatin) 500 mg IV q6h

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• P. aeruginosa – Cefepime or ceftazidime 2 g IV q8h (consider adding aminoglycoside) • Anaerobes – Metronidazole 500 mg IV/PO q6–8h

ADDITIONAL THERAPIES • Hyperbaric oxygen therapy may be a useful adjunct. • Negative pressure wound therapy is a possible adjunctive treatment.

SURGERY/OTHER PROCEDURES Surgical drainage, dead space management, adequate soft tissue coverage, restoration of blood supply, and removal of necrotic tissues improve cure rates.

Pediatric Considerations Medullary osteomyelitis (stage 1) in children may be treated without surgical intervention (2)[B].

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Correct electrolyte imbalances, hyperglycemia, azotemia, and acidosis; control pain. • Bed rest and immobilization of the involved bone and/or joint • Discharge criteria clinical and laboratory evidence of resolving infection and appropriate outpatient therapy

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring Blood levels of antimicrobial agents, ESR, CRP, and repeat plain radiography as clinical course dictates

PATIENT EDUCATION Diabetic glycemic control and foot care

PROGNOSIS

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• Superficial and medullary osteomyelitis treated with antimicrobial and surgical therapy have a response rate of 90–100%. • Up to 36% recurrence rate in diabetics • Increased mortality after amputation

COMPLICATIONS • Abscess formation • Bacteremia • Fracture/nonunion • Loosening of prosthetic implant • Postoperative infection • Sinus tract formation can be associated with neoplasms, especially in presence of long-standing infection.

REFERENCES 1. Malhotra R, Chan CS, Nather A. Osteomyelitis in the diabetic foot. Diabet Foot Ankle. 2014;5. doi:10.3402/dfa.v5.24445. 2. Howard-Jones AR, Isaacs D. Systematic review of duration and choice of systemic antibiotic therapy for acute haematogenous bacterial osteomyelitis in children. J Paediatr Child Health. 2013;49(9):760–768.

ADDITIONAL READING • Bhavan KP, Marschall J, Olsen MA, et al. The epidemiology of hematogenous vertebral osteomyelitis: a cohort study in a tertiary care hospital. BMC Infect Dis. 2010;10:158. • Dinh MT, Abad CL, Safdar N. Diagnostic accuracy of the physical examination and imaging tests for osteomyelitis underlying diabetic foot ulcers: meta-analysis. Clin Infect Dis. 2008;47(4):519–527. • Fraimow HS. Systemic antimicrobial therapy in osteomyelitis. Semin Plast Surg. 2009;23(2):90–99. • Stumpe KD, Strobel K. Osteomyelitis and arthritis. Semin Nucl Med. 2009;39(1):27–35. • Vardakas KZ, Kontopidis I, Gkegkes ID, et al. Incidence, characteristics, and outcomes of patients with bone and joint infections due to community-

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associated methicillin-resistant Staphylococcus aureus: a systematic review. Eur J Clin Microbiol Infect Dis. 2013;32(6):711–721. • Zimmerli W. Clinical practice. Vertebral osteomyelitis. N Engl J Med. 2010;362(11):1022–1029.

CODES ICD10 • M86.9 Osteomyelitis, unspecified • M86.00 Acute hematogenous osteomyelitis, unspecified site • M86.10 Other acute osteomyelitis, unspecified site

CLINICAL PEARLS • Hematogenous osteomyelitis is usually monomicrobial, whereas osteomyelitis due to contiguous spread or direct inoculation is usually polymicrobial. • Acute osteomyelitis typically presents with gradual onset of pain. • Treatment of osteomyelitis often requires both surgical débridement and at least 6 weeks of antimicrobial therapy.

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OSTEOPOROSIS AND OSTEOPENIA Andrew J. McBride, MD • Rahul Kapur, MD BASICS DESCRIPTION A skeletal disease characterized by low bone mass, deterioration of bone tissue, and disruption of bone architecture that leads to compromised bone strength and an increased risk of fracture

EPIDEMIOLOGY • Most common bone disease in humans • Predominant age: elderly >60 years of age • Predominant sex: female > male (80%/20%)

Incidence There is poor data on incidence of osteoporosis and osteopenia. However, there is an estimated 2 million fractures yearly attributed to osteoporosis.

Prevalence • >10.2 million Americans have osteoporosis. • >43.4 million Americans have osteopenia. • Women >50 years of age: osteoporosis 15.4% and osteopenia 51.4% • Men >50 years of age: osteoporosis 4.3% and osteopenia 35.2% • One in three women will experience an osteoporotic fracture, as will one in five men.

ETIOLOGY AND PATHOPHYSIOLOGY • Imbalance between bone resorption and bone formation • Aging • Hypoestrogenemia

Genetics • Familial predisposition • More common in Caucasians and Asians than in African Americans and

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Hispanics

RISK FACTORS • Nonmodifiable – Advanced age (>65 years) – Female gender and menopause – Caucasian or Asian – Family history of osteoporosis – History of atraumatic fracture • Modifiable – Low body weight (58 kg or body mass index [BMI] 3 drinks/day) – Medications: See “Commonly Associated Conditions.”

GENERAL PREVENTION The aim in the prevention and treatment of osteoporosis is to prevent fracture: • Regularly perform weight-bearing exercise. • Consume a diet that includes adequate calcium (1,000 mg/day for men aged 50 to 70 years; 1,200 mg/day for women aged 51+ years and men 70+ years) and vitamin D (800 to 1,000 IU/day). • The USPSTF has concluded that vitamin D supplementation is effective in preventing falls in community-dwelling adults aged 65 years or older who are at increased risk for falls (1)[B]. • Evidence is insufficient to assess the balance of the benefits and harms of daily supplementation with >400 IU of vitamin D3 and >1,000 mg of calcium for the primary prevention of fractures in noninstitutionalized postmenopausal women (1)[B]. • USPSTF recommends against daily supplementation with 400 IU or less of vitamin D3 and 1,000 mg or less of calcium for the primary prevention of fractures in noninstitutionalized postmenopausal women (1)[B]. • Avoid smoking. • Limit alcohol consumption (50 years of age with ≤10-year fracture risk (using the WHO’s Fracture Risk Assessment [FRAX] Tool) >9.3% – The current evidence is insufficient to recommend screening for osteoporosis in men; however, the National Osteoporosis Foundation recommends screening men age >70 years, especially if at increased risk.

COMMONLY ASSOCIATED CONDITIONS • Malabsorption syndromes: gastrectomy, inflammatory bowel disease, celiac disease • Hypoestrogenism: menopause, hypogonadism, eating disorders, female athlete triad • Endocrinopathies: hyperparathyroidism, hyperthyroidism, hypercortisolism, diabetes mellitus • Hematologic disorders: hemophilia, sickle cell disease, multiple myeloma, thalassemia, hemochromatosis • Other disorders: multiple sclerosis, end stage renal disease, rheumatoid arthritis, lupus, chronic obstructive pulmonary disease (COPD), HIV/AIDS • Medications: antiepileptics, aromatase inhibitors (raloxifene), chronic corticosteroids (>5 mg prednisone or equivalent for >3 months), medroxyprogesterone acetate, heparin, SSRI, thyroid hormone (in supraphysiologic doses), PPI

DIAGNOSIS HISTORY • Review modifiable and nonmodifiable risk factors. • Online risk factor assessment tools are available: – FRAX: http://www.shef.ac.uk/FRAX/ • Assess for any commonly associated conditions.

PHYSICAL EXAM

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• Thoracic kyphosis, poor balance, deconditioning • Historical height loss >1.5 cm (difference between current height and peak height at age 20 years) • Prospective height loss >2 cm (difference between current height and previously documented height)

DIFFERENTIAL DIAGNOSIS • Multiple myeloma/other neoplasms • Osteomalacia • Type I collagen mutations • Osteogenesis imperfecta

DIAGNOSTIC TESTS & INTERPRETATION Dual-energy x-ray absorptiometry (DEXA) of the lumbar spine/hip is considered the gold standard for the diagnosis of osteoporosis.

Initial Tests (lab, imaging) Consider in screening for secondary osteoporosis: • Serum 25-hydroxyvitamin D and parathyroid hormone • CBC • Serum chemistry, including calcium, phosphorus, magnesium, total protein, albumin, liver enzymes, creatinine, alkaline phosphatase, and thyroidstimulating hormone • Urinalysis (24-hour collection) for calcium, sodium, and creatinine (to identify calcium malabsorption of hypercalciuria) • DEXA of the lumbar spine/hip is the gold standard for measuring bone mineral density (BMD). • A BMD at the hip or lumbar spine that is ≤2.5 standard deviations (SDs) below the mean BMD of a young-adult reference population is diagnostic of osteoporosis. • A minimum of 2 years may be needed to reliably measure a change in BMD. • BMD is expressed in terms of T-scores and Z-scores: – T-score is the number of SDs a patient’s BMD deviates from the mean for young, normal (age 25 to 40 years) control individuals of the same sex. – WHO defines normal BMD as a T-score ≥−1, osteopenia as a T-score

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between −1 and −2.5, and osteoporosis as a T-score ≤−2.5. – WHO thresholds can be used for postmenopausal women and men >50 years of age. – The Z-score is a comparison of the patient’s BMD with an age-matched population. – A Z-score 65 years (2). • Plain radiographs lack sensitivity to diagnose osteoporosis, but an abnormality (e.g., widened intervertebral spaces, rib fractures, vertebral compression fractures) should prompt evaluation. Follow-Up Tests & Special Considerations Further labs depending on initial evaluation, Z-score −2.5, or lower or young age. • Iron and ferritin (hemochromatosis) • Testosterone levels (hypogonadism in men) • Serum protein electrophoresis and free κ and λ light chains (multiple myeloma) • Urinary-free cortisol (Cushing disease) • Tissue transglutaminase antibodies (celiac disease) • Markers of bone resorption (urine N-telopeptides of type 1 collagen, serum Ctelopeptides of type 1 collagen, serum N-terminal propeptide of type 1 procollagen): no prospective studies supporting use in osteoporosis diagnosis and management; potential role for identifying patients at high risk for fracture and monitoring response to therapy

Diagnostic Procedures/Other Bone biopsy may be recommended for patients with bone disease and renal failure to establish the correct diagnosis as it can assess the degree of mineralization and microarchitecture and specific bone loss mechanisms.

Test Interpretation • In osteoporosis, can see reduced skeletal mass; trabecular bone thinned or lost

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more than cortical bone • Can assess osteoclast and osteoblast relative activity • Can rule out other metabolic bone diseases • Can assess if bone marrow is normal or atrophic

TREATMENT • Criteria for patients who benefit from Treatment for their Osteoporosis includes: – All patients with a T-score ≤−2.5 with no risk factors – All postmenopausal women who have had an osteoporotic vertebral/hip fracture – All postmenopausal women who have BMD values consistent with osteoporosis (T-score ≤2.5) at the lumbar spine, femoral neck, or total hip region – Postmenopausal women with T-scores from −1.0 to −2.5 and a 10-year risk, based on FRAX calculator, of an osteoporotic fracture (spine, hip, shoulder, and wrist) of at least 20% or hip of at least 3% – Treat men >50 years of age who present with a hip or vertebral fracture or a T-score 2 years of use (8). • Denosumab: 60 mg SQ every 6 months – Human monoclonal antibody receptor activator of nuclear factor kappa-B ligand (RANKL) receptor – Inhibits osteoclast formation • Estrogen 0.625 mg PO daily (with progesterone if patient has a uterus): effective in prevention and treatment of osteoporosis (34% reduction in hip and vertebral fractures after 5 years of use), but the risks (e.g., increased rates of myocardial infarction, stroke, breast cancer, pulmonary embolus, and deep vein thrombosis) must be weighed against the benefits • Strontium 2 g PO daily – Appears to inhibit bone resorption and increase bone formation – Available for use in Europe • Calcitonin – PTH antagonist that reduces osteoclastic activity, therefore decreasing bone turnover – FDA approved for treatment of osteoporosis in women who are at least 5 years postmenopausal when alternative treatments are not suitable – Calcitonin reduces vertebral fracture occurrence in those with prior vertebral. – Has been associated with an increased risk for malignancy

ISSUES FOR REFERRAL Endocrinology for recurrent bone loss/fracture

ADDITIONAL THERAPIES • Weight-bearing exercise 30 minutes 3 times per week • Smoking cessation • Physical therapy to help with muscle strengthening

SURGERY/OTHER PROCEDURES Options for patients with painful vertebral compression fractures failing medical treatment:

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• Vertebroplasty: Orthopedic cement is injected into the compressed vertebral body. • Kyphoplasty: A balloon is expanded within the compressed vertebral body to reconstruct volume of vertebrae. Cement is injected into the space.

COMPLEMENTARY & ALTERNATIVE MEDICINE • Isoflavones not better than placebo for fracture risk • Beneficial effect of Chinese herbal medicines in improving BMD is still uncertain.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Inpatient care for pain control of acute back pain secondary to new vertebral fractures and for acute treatment of femoral and pelvic fractures • Rehabilitation, nursing home, or home care may be needed following hospitalization for fractures.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Weight-bearing exercises, such as walking, jogging, stair climbing, and tai chi, have been shown to decrease falls and fracture risk. • Yearly height measurement is essential to determination of osteoporosis treatment efficacy. Patients who lose >2 cm in height should have repeat vertebral imaging to determine if any new vertebral fractures have occurred (2). • While there is no consensus, most recommendations suggest BMD testing by DEXA scanning retesting 2 years after starting bisphosphonate therapy. • For many women, 3 to 5 years of treatment with a bisphosphonate is as good as 10 years of treatment. • A comprehensive risk assessment should be performed after 3 to 5 years of treatment. Those at high risk for vertebral fracture or with very low BMD may benefit by continuing treatment beyond 5 years.

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• Physicians prescribing bisphosphonates should advise patients of the small risk of osteonecrosis and encourage dental examinations (2).

DIET • Diet to maintain normal body weight • Calcium and vitamin D (see “General Prevention”)

PATIENT EDUCATION National Osteoporosis Foundation: http://nof.org/

PROGNOSIS • With treatment, 80% of patients stabilize skeletal manifestations, increase bone mass and mobility, and have reduced pain. • 15% of vertebral and 20–40% of hip fractures may lead to chronic care and/or premature death.

COMPLICATIONS Severe, disabling pain and recurrent fractures

REFERENCES 1. Christenson ES, Jiang X, Kagan R, et al. Osteoporosis management in postmenopausal women. Minerva Ginecol. 2012;64(3):181–194. 2. Cosman F, de Beur SJ, LeBoff MS, et al. Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int. 2014;25(10):2359–2381. 3. Poole KE, Compston JE. Bisphosphonates in the treatment of osteoporosis. BMJ. 2012;344:e3211. 4. Heng C, Badner VM, Vakkas TG, et al. Bisphosphonate-related osteonecrosis of the jaw in patients with osteoporosis. Am Fam Physician. 2012;85(12):1134–1141. 5. Zhou J, Ma X, Wang T, et al. Comparative efficacy of bisphosphonates in short-term fracture prevention for primary osteoporosis: a systematic review with network meta-analyses [published online ahead of print June 7, 2016]. Osteoporos Int. 6. McClung M, Harris ST, Miller PD, et al. Bisphosphonate therapy for osteoporosis: benefits, risk, and drug holiday. Am J Med. 2013;126(1):13–20.

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7. Rao SS, Budhwar N, Ashfaque A. Osteoporosis in men. Am Fam Physician. 2010;82(5):503–508.

CODES ICD10 • M85.80 Other specified disorders of bone density and structure, unspecified site • M81.0 Age-related osteoporosis w/o current pathological fracture • M80.00XA Age-rel osteopor w current path fracture, unsp site, init

CLINICAL PEARLS • Regular weight-bearing exercise from adolescence onward is recommended for prevention. • Screen all women ≥65 years of age with DEXA scans. • Premenopausal women with osteoporosis should be screened for secondary causes, such as malabsorption syndromes, hyperparathyroidism, hyperthyroidism, and medication sensitivity. • Evaluate and treat all patients presenting with fractures from minimal trauma. • Bisphosphonates are first line for treatment of osteoporosis in most patients. • For Osteopenia, treat with weight bearing exercise, diet high in calcium, Vitamin D, limiting alcohol and smoking cessation • If the patient is not responding to treatment, consider screening for a secondary, treatable cause of osteoporosis.

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OTITIS EXTERNA Douglas S. Parks, MD BASICS DESCRIPTION Inflammation of the external auditory canal: • Acute diffuse otitis externa: the most common form; an infectious process; usually bacterial; occasionally fungal (10%) • Acute circumscribed otitis externa: synonymous with furuncle; associated with infection of the hair follicle, a superficial cellulitic form of otitis externa • Chronic otitis externa: same as acute diffuse but of longer duration (>6 weeks) • Eczematous otitis externa: may accompany typical atopic eczema or other primary skin conditions • Necrotizing malignant otitis externa: an infection that extends into the deeper tissues adjacent to the canal; may include osteomyelitis and cellulitis; rare in children • System(s) affected: skin/exocrine • Synonym(s): swimmer’s ear

EPIDEMIOLOGY Incidence • Unknown; higher in the summer months and in warm, wet climates • Predominant age: all ages • Predominant sex: male = female

Prevalence • Acute, chronic, and eczematous: common • Necrotizing: uncommon

ETIOLOGY AND PATHOPHYSIOLOGY • Acute diffuse otitis externa – Traumatized external canal (e.g., from use of cotton swab) – Bacterial infection (90%): Pseudomonas (67%), Staphylococcus,

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Streptococcus, gram-negative rods – Fungal infection (10%): Aspergillus (90%), Candida, Phycomycetes, Rhizopus, Actinomyces, Penicillium • Chronic otitis externa: bacterial infection: Pseudomonas • Eczematous otitis externa (associated with primary skin disorder) – Eczema – Seborrhea – Psoriasis – Neurodermatitis – Contact dermatitis – Purulent otitis media – Sensitivity to topical medications • Necrotizing otitis externa – Invasive bacterial infection: Pseudomonas, increasing incidence of methicillin-resistant Staphylococcus aureus (MRSA) – Associated with immunosuppression

RISK FACTORS • Acute and chronic otitis externa – Traumatization of external canal – Swimming – Hot, humid weather – Hearing aid use • Eczematous: primary skin disorder • Necrotizing otitis externa in adults – Advanced age – Diabetes mellitus (DM) – Debilitating disease – AIDS – Immunosuppression • Necrotizing otitis externa in children (rare) – Leukopenia – Malnutrition – DM – Diabetes insipidus

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GENERAL PREVENTION • Avoid prolonged exposure to moisture. • Use preventive antiseptics (acidifying solutions with 2% acetic acid [white vinegar] diluted 50/50 with water or isopropyl alcohol, or 2% acetic acid with aluminum acetate [less irritating]) after swimming and bathing. • Treat predisposing skin conditions. • Eliminate self-inflicted trauma to canal with cotton swabs and other foreign objects. • Diagnose and treat underlying systemic conditions. • Use ear plugs when swimming.

DIAGNOSIS HISTORY Variable-length history of itching, plugging of ear, ear pain, and discharge from ear

PHYSICAL EXAM • Ear canal: red, containing purulent discharge and debris • Pain on manipulation of the pinnae • Possible periauricular adenitis • Possible eczema of pinna • Cranial nerve (VII, IX to XII) involvement (extremely rare)

DIFFERENTIAL DIAGNOSIS • Idiopathic ear pain • Otitis media with perforation • Hearing loss • Cranial nerve (VII, IX to XII) palsy with necrotizing otitis externa • Wisdom tooth eruption • Basal cell or squamous cell carcinoma

DIAGNOSTIC TESTS & INTERPRETATION • Gram stain and culture of canal discharge (occasionally helpful) • Antibiotic pretreatment may affect results.

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• Radiologic evaluation of deep tissues in necrotizing otitis externa with highresolution CT scan, MRI, gallium scan, and bone scan

Test Interpretation • Acute and chronic otitis externa: desquamation of superficial epithelium of external canal with infection • Eczematous otitis externa: pathologic findings consistent with primary skin disorder; secondary infection on occasion • Necrotizing otitis externa: vasculitis, thrombosis, and necrosis of involved tissues; osteomyelitis

TREATMENT Outpatient treatment, except for resistant cases and necrotizing otitis externa

GENERAL MEASURES • Cleaning the external canal may facilitate recovery. • Analgesics as appropriate for pain • Antipruritic and antihistamines (eczematous form) • Ear wick (Pope) for nearly occluded ear canal

MEDICATION • Trial data is of generally poor quality and may not be fully relevant to primary care settings (1)[A]. • Resistance is an increasing problem. Pseudomonas is the most common bacteria, and it is more susceptible to fluoroquinolones such as ciprofloxacin or ofloxacin, whereas Staphylococcus is equally susceptible to both fluoroquinolones and polymyxin B combinations (2)[B]. If a patient has recurring episodes or is not improved in 2 weeks, change the class of antibacterial and consider cultures and sensitivities. • There is evidence that using of a topical antibiotic with a corticosteroid shortens time to symptom resolution, although there is no evidence that it increases overall cure rate. There is not enough evidence to demonstrate that any antibiotic regimen is clearly superior to any other (3)[B]. • Oral antibiotics are indicated only if there is associated otitis media. Oral

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antibiotics alone are not effective and markedly increase the risk of progressing to chronic otitis externa. • Analgesics as needed; narcotics may be necessary. Recurrent otitis externa may be prevented by applying equal parts white vinegar and isopropyl alcohol (over-the-counter [OTC] rubbing alcohol) to external auditory canals after bathing and swimming.

First Line • Acute bacterial and chronic otitis externa – Ciprofloxacin 0.3% and dexamethasone 0.1% suspension (expensive as brand): 4 drops BID for 7 days or ofloxacin: 0.3% solution (inexpensive generic) 10 drops once a day for 7 days (1)[A]. Less ototoxicity and reported antibiotic resistance (4)[A]. – Neomycin/polymyxin B/hydrocortisone (Cortisporin, generics): 5 drops QID. If the tympanic membrane is ruptured, use the suspension; otherwise, the solution may be used; may be ototoxic and resistance-developing in Staphylococcus and Streptococcus sp. (5)[B]; not expensive – Acetic acid 2% with hydrocortisone 1%: 3 to 5 drops q4–6h for 7 days; may cause minor local stinging. An inexpensive generic. This is as effective as neomycin–polymyxin B (6)[B]. It may take up to 2 days longer to achieve resolution of symptoms (3)[A]. A wick may be helpful in severe cases by keeping the canal open and keeping antibiotic solution in contact with infected skin. • Fungal otitis externa – Topical therapy, antiyeast for Candida or yeast: 2% acetic acid 3 to 4 drops QID; clotrimazole 1% solution; itraconazole oral – Parenteral antifungal therapy: amphotericin B – Patients with Ramsay-Hunt syndrome: acyclovir IV • Eczematous otitis externa: topical therapy – Acetic acid 2% in aluminum acetate – Aluminum acetate (5%; Burow solution) – Steroid cream, lotion, ointment (e.g., triamcinolone 0.1% solution) – Antibacterial, if superinfected • Necrotizing otitis externa

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– Parenteral antibiotics: antistaphylococcal and antipseudomonal – 4 to 6 weeks of therapy – Fluoroquinolones PO for 2 to 4 weeks

Second Line • Acute bacterial and chronic otitis externa – Betamethasone 0.05% solution may be as effective as a polymyxin B combination without the risk of ototoxicity or antibiotic resistance. However, the data are not very robust, and more study is needed (3)[A]. • Azole antifungals for fungal otitis externa

ISSUES FOR REFERRAL Resistant cases or those requiring surgical intervention

SURGERY/OTHER PROCEDURES For necrotizing otitis externa or furuncle

COMPLEMENTARY & ALTERNATIVE MEDICINE • OTC white vinegar; 3 drops in affected ear for minor case • Tea tree oil in various concentrations has been used as an antiseptic. Ototoxicity has been reported in animal studies at very high doses. • Grapefruit seed extract in various concentrations has been described as useful in the lay literature.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Admission criteria/initial stabilization: necrotizing otitis media requiring parenteral antipseudomonal antibiotics • Discharge criteria: resolution of infection

ONGOING CARE FOLLOW-UP RECOMMENDATIONS No restrictions

Patient Monitoring

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• Acute otitis externa – 48 hours after therapy instituted to assess improvement – At the end of treatment • Chronic otitis externa – Every 2 to 3 weeks for repeated cleansing of canal – May require alterations in topical medication, including antibiotics and steroids • Necrotizing otitis externa – Daily monitoring in hospital for extension of infection – Baseline auditory and vestibular testing at beginning and end of therapy

DIET No restrictions

PROGNOSIS • Acute otitis externa: rapid response to therapy with total resolution • Chronic otitis externa: With repeated cleansing and antibiotic therapy, most cases will resolve. Occasionally, surgical intervention is required for resistant cases. • Eczematous otitis externa: Resolution will occur with control of the primary skin condition. • Necrotizing otitis externa: usually can be managed with débridement and antipseudomonal antibiotics; recurrence rate is 100% when treatment is inadequate. Surgical intervention may be necessary in resistant cases or if there is cranial nerve involvement. Mortality rate is significant, probably secondary to the underlying disease.

COMPLICATIONS • Mainly a problem with necrotizing otitis externa; may spread to infect contiguous bone and CNS structures • Acute otitis externa may spread to pinna, causing chondritis.

REFERENCES 1. Kaushik V, Malik T, Saeed SR. Interventions for acute otitis externa. Cochrane Database Syst Rev. 2010;(1):CD004740.

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2. Dohar JE, Roland P, Wall GM, et al. Differences in bacteriologic treatment failures in acute otitis externa between ciprofloxacin/dexamethasone and neomycin/polymyxin B/hydrocortisone: results of a combined analysis. Curr Med Res Opin. 2009;25(2):287–291. 3. Rosenfeld RM, Schwartz SP, Cannon CR, et al. Clinical practice guideline: acute otitis externa. Otolaryngol Head Neck Surg. 2014;150(1 Suppl):S1– S24. 4. Mösges R, Nematian-Samani M, Hellmich M, et al. A meta-analysis of the efficacy of quinolone containing otics in comparison to antibiotic-steroid combination drugs in the local treatment of otitis externa. Curr Med Res Opin. 2011;27(10):2053–2060. 5. Cantrell HF, Lombardy EE, Duncanson FP, et al. Declining susceptibility to neomycin and polymyxin B of pathogens recovered in otitis externa clinical trials. South Med J. 2004;97(5):465–471. 6. van Balen FA, Smit WM, Zuithoff NP, et al. Clinical efficacy of three common treatments in acute otitis externa in primary care: randomised controlled trial. BMJ. 2003;327(7425):1201–1205.

ADDITIONAL READING • Block SL. Otitis externa: providing relief while avoiding complications. J Fam Pract. 2005;54(8):669–676. • Farnan TB, McCallum J, Awa A, et al. Tea tree oil: in vitro efficacy in otitis externa. J Laryngol Otol. 2005;119(3):198–201.

SEE ALSO Algorithm: Ear Pain

CODES ICD10 • H60.90 Unspecified otitis externa, unspecified ear • H60.339 Swimmer’s ear, unspecified ear

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• H60.509 Unsp acute noninfective otitis externa, unspecified ear

CLINICAL PEARLS • Acute diffuse otitis externa is the most common form: bacterial (90%), occasionally fungal (10%). • Acute circumscribed otitis externa is associated with infection of a hair follicle. • Chronic otitis externa is the same as acute diffuse but of longer duration (>6 weeks). • Eczematous otitis externa may accompany typical atopic eczema or other primary skin conditions. • Necrotizing malignant otitis externa is an infection that extends into the deeper tissues adjacent to the canal. It may include osteomyelitis and cellulitis; it is rare in children.

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OTITIS MEDIA Paul George, MD, MHPE BASICS DESCRIPTION • Inflammation of the middle ear; usually accompanied by fluid collection • Acute otitis media (AOM): inflammation of the middle ear. Rapid onset; cause may be infectious, either viral (AOM-v) or bacterial (AOM-b), but there is also a sterile etiology (AOM-s). • Recurrent AOM: ≥3 episodes in 6 months or ≥4 episodes in 1 year with ≥1 in the past 6 months • Otitis media with effusion (OME): fluid in the middle ear without signs or symptoms of infection • Chronic otitis media with or without cholesteatoma • System(s) affected: nervous, ENT • Synonym(s): secretory or serous otitis media

EPIDEMIOLOGY Incidence • AOM – Predominant age: 6 to 24 months; declines >7 years; rare in adults – Predominant gender: male > female – By age 7 years, 93% of children have had ≥1 episodes of AOM; 39% have had ≥6. – Placement of tympanostomy tubes is second only to circumcision as the most frequent surgical procedure in infants. – Increased incidence in the fall and winter • OME – By age 4 years, 90% of children have had at least one episode.

Prevalence • Most common infection for which antibacterial agents are prescribed in the United States

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• Diagnosed 5 million times per year in the United States

ETIOLOGY AND PATHOPHYSIOLOGY • AOM-b (bacterial): usually, a preceding viral upper respiratory infection (URI) produces eustachian tube dysfunction – Streptococcus pneumoniae: 20–35%, Haemophilus influenzae: 20–30%, Moraxella (B.) catarrhalis: 15%, group A streptococci: 3%, Staphylococcus aureus: 12% produce β-lactamases that hydrolyze amoxicillin and some cephalosporins. • AOM-v (viral): 15–44% of AOM infections are caused primarily by viruses (e.g., respiratory syncytial virus, parainfluenza, influenza, enteroviruses, adenovirus, human metapneumovirus, and parechovirus). • AOM-s (sterile/nonpathogens): 25–30% • OME: Eustachian tube dysfunction; allergic causes are rarely substantiated.

Genetics • Strong genetic component in twin studies for recurrent and prolonged AOM • May be influenced by skull configuration or immunologic defects

RISK FACTORS • Age • Bottlefeeding while supine • Routine daycare attendance • Frequent pacifier use after 6 months of age • Environmental smoke exposure • Male gender • Absence of breastfeeding • Low socioeconomic status • Family history of recurrent otitis • AOM before age 1 year is a risk for recurrent AOM. • Presence of siblings in the household • Underlying ENT disease (e.g., cleft palate, Down syndrome, allergic rhinitis)

GENERAL PREVENTION • Pneumococcal vaccine (PCV)-7 immunization reduces the number of cases of AOM by about 6–28% (however, evidence shows that this is offset by an

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increase in AOM caused by other bacteria). The effect of the introduction of the PCV-13 vaccine on the incidence of AOM has yet to be studied (1,2)[B]. • Influenza vaccine reduces AOM. • Breastfeeding for ≥6 months is protective. • Avoiding supine bottlefeeding, passive smoke, and pacifiers >6 months may be helpful. • Secondary prevention: Adenoidectomy and adenotonsillectomy for recurrent AOM has limited short-term efficacy and is associated with its own adverse risks. • Vitamin D supplementation (1,000 U/day to maintain vitamin D levels >30) may be helpful in reducing recurrent AOM (3)[B], but further trials are needed.

COMMONLY ASSOCIATED CONDITIONS URI

DIAGNOSIS HISTORY • AOM: acute history, signs, and symptoms of middle ear inflammation and effusion – Earache – Preceding or accompanying URI symptoms – Decreased hearing • In adults, earache without fever or hearing loss may be the only presenting feature.

ALERT • AOM in infants and toddlers: – May cause few symptoms in the first few months of life – Irritability may be the only symptom. • OME: usually asymptomatic – Decreased hearing

PHYSICAL EXAM

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• Infectious AOM: – Fever (not required for diagnosis) – Decreased eardrum mobility (with pneumatic otoscopy) – Moderate to severe bulging of tympanic membrane – Otorrhea – Redness alone is not a reliable sign. • OME: – Eardrum often dull but not bulging – Decreased eardrum mobility (pneumatic otoscopy) – Presence of air-fluid level – Weber test is positive to affected ear for an ear with effusion.

DIFFERENTIAL DIAGNOSIS • Tympanosclerosis • Trauma • Referred pain from the jaw, teeth, or throat • TMJ in adults • Otitis externa • Otitis-conjunctivitis syndrome • Temporal arteritis in adults

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) WBC count may be higher in bacterial AOM than in sterile AOM, but this is almost never useful.

Diagnostic Procedures/Other • To document the presence of middle ear fluid, pneumatic otoscopy can be supplemented with tympanometry and acoustic reflex measurement. • Hearing testing is recommended when hearing loss persists for ≥3 months or at any time suspecting language delay, significant hearing loss, or learning problems. • Language testing should be performed for children with hearing loss. • Tympanocentesis for microbiologic diagnosis is recommended for treatment failures; may be followed by myringotomy

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TREATMENT • Significant disagreement exists about the usefulness of antibiotic treatment for this often self-resolving condition. Studies suggest that ~15 children need to be treated with antibiotics to prevent one case of persisting AOM pain at 1 to 2 weeks; the number needed to treat to cause harm (primarily diarrhea) is 8 to 10 (2)[B]. • If antibiotics are not used, 81% of patients >2 years of age are better in 1 week versus 94% if antibiotics are used. • Delay of antibiotics found a modest increase in mastoiditis from 2/100,000 to 4/100,000. • American Academy of Pediatrics/American Academy of Family Physicians (AAP/AAFP) guidelines recommend the following for observation versus antibacterial therapy, although these guidelines are not rigorously evidence based (2)[B]: – 25 dB or for high-risk individuals at any time. • Tympanostomy tubes may reduce recurrence of AOM minimally, but it does not lower the risk of hearing loss (9)[A]. • Adenoidectomy is indicated in specific cases; tonsillectomy or myringotomy is never indicated.

COMPLEMENTARY & ALTERNATIVE MEDICINE • It is unclear whether alternative and homeopathic therapies are effective for AOM, including mixed evidence about the effectiveness of zinc supplementation of reducing AOM. • Xylitol, probiotics, herbal ear drops, and homeopathic interventions may be beneficial in reducing pain duration, antibiotic use, and bacterial resistance.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS Outpatient, except if surgery is indicated, or for AOM in febrile infants age 6 months of age) who do not have severe illness or otorrhea. • First-line treatment is amoxicillin, 80 to 90 mg/kg/day for 10 days for children age 2 years of age. • Erythema and effusion can persist for weeks. • Antibiotics, antihistamines, and steroids are not indicated for OME. • OME rarely develops in adults. Persistent unilateral effusion should be investigated to rule out neoplasm, particularly if there is a cranial nerve palsy.

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OTITIS MEDIA WITH EFFUSION Hobart Lee, MD, FAAFP BASICS DESCRIPTION • Also called serous otitis media, secretory otitis media, nonsuppurative otitis media, “ear fluid,” or “glue ear” • Otitis media with effusion (OME) is defined as the presence of fluid in the middle ear in the absence of acute signs or symptoms of infection. • More commonly, a pediatric disease • May occur spontaneously from poor eustachian tube function or as an inflammatory response after acute otitis media

EPIDEMIOLOGY Incidence Approximately 90% of children have OME before school age, mostly between the ages of 6 months and 4 years.

Prevalence • Approximately 2.2 million new cases annually in the United States • Less prevalent in adults and is usually associated with an underlying disorder

ETIOLOGY AND PATHOPHYSIOLOGY • Chronic inflammatory condition where an underlying stimulus causes an inflammatory reaction with increased mucin production creating a functional blockage of the eustachian tube and thick accumulation of mucin-rich middle ear effusion • Young children are more prone to OME due to shorter and more horizontal eustachian tubes, which become more vertical around 7 years of age. • Biofilms, anatomic variations, and acute otitis media (AOM) caused by viruses or bacteria have been implicated as stimuli causing OME. The common pathogens causing AOM include nontypeable Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis.

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• In adults, OME is often associated with paranasal sinus disease (66%), smoking-induced nasopharyngeal lymphoid hyperplasia and adult onset adenoidal hypertrophy (19%), or head and neck tumors (4.8%).

RISK FACTORS • Risk factors include a family history of OME, early daycare, exposure to cigarette smoke, bottlefeeding, and low socioeconomic status (1). • Eustachian tube dysfunction may be a predisposing factor, although the evidence is unclear (2). • Gastroesophageal reflux is associated with OME (2).

GENERAL PREVENTION OME is generally not preventable, although lowering smoke exposure, breastfeeding, and avoiding daycare centers at an early age may decrease the risk.

DIAGNOSIS HISTORY • OME is transient and asymptomatic in many pediatric patients. • Most common reported symptom is hearing loss (2). There may be mild discomfort present in the ear, fullness, or “popping.” • Infants may have ear rubbing, excessive irritability, sleep problems, or failure to respond appropriately to voices or sounds. • Clinical features may include “a history of hearing difficulties, poor attention, behavioral problems, delayed speech and language development, clumsiness, and poor balance” (2). • There may be a history of recent or recurrent episodes of acute otitis media or a recent upper respiratory tract infection (2).

PHYSICAL EXAM • Cloudy tympanic membrane (TM) with distinctly impaired mobility. Air-fluid level or bubble may be visible in the middle ear (1,2). • Color may be abnormal (yellow, amber, or blue), and the TM may be retracted or concave (2).

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• Distinct redness of the tympanic membrane may be present in approximately 5% of OME cases (1). • Clinical signs and symptoms of acute illness should be absent in patients with OME (1).

DIFFERENTIAL DIAGNOSIS • Acute otitis media • Bullous myringitis • Tympanosclerosis (may cause decreased/absent motion of the TM) • Sensorineural hearing loss

DIAGNOSTIC TESTS & INTERPRETATION Diagnostic Procedures/Other • The primary standard to make the diagnosis is pneumatic otoscopy, which demonstrates reduced/absent mobility of the TM secondary to fluid in the middle ear. Pneumatic otoscopy has 94% sensitivity and 80% specificity for diagnosing OME. Accuracy of diagnosis with an experienced examiner is between 70% and 79% (1)[C]. • Myringotomy is the gold standard but is not practical for clinical use (2)[C]. • Tympanometry may also be used to support or exclude the diagnosis in infants >4 months old, especially when the presence of middle ear effusion is difficult to determine (1)[C]. • Acoustic reflectometry (64% specificity and 80% sensitivity) may be considered instead of tympanometry (3)[B]. • Audiogram may show mild conductive hearing loss (2)[C]. • Hearing tests are recommended for OME lasting >3 months (1)[C]. • Language testing is recommended for children with abnormal hearing tests (1) [C].

TREATMENT • OME improves or resolves without medical intervention in most patients within 3 months, especially if secondary to AOM (1)[C]. • Current guidelines support a 3-month period of observation with optional serial exams, tympanometry, and language assessment during that wait time

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(1,2)[C]. • Adults found to have OME should be screened for an underlying disorder and treated accordingly (2)[C].

MEDICATION • The 2016 AAOHNS/AAFP/AAP guideline and a 2012 Cochrane review recommend against routine use of antibiotics in treatment of OME. No longterm benefits of antibiotics have been proven, and often, prescribed antibiotics have adverse side effects such as diarrhea, vomiting, rashes, and allergic reactions (1)[C],(4)[A]. • The 2016 AAOHNS/AAFP/AAP and a 2006 Cochrane review found that antihistamines and decongestants have no benefit over placebo in the treatment of OME with possible adverse side effects such as insomnia, hyperactivity, and drowsiness (4)[A],(5)[C]. • The 2016 AAOHNS/AAFP/AAP guideline recommends against administering oral or intranasal corticosteroids. No long-term benefit was shown and adverse side effects such as weight gain and behavioral changes are possible (5)[C]. • In adults, eustachian tube dysfunction secondary to allergic rhinitis or recent upper respiratory infection can be the cause of OME. It is unknown whether decongestants, antihistamines, or nasal steroids improve outcomes in adults.

ISSUES FOR REFERRAL The following are indications for referral to a surgeon for evaluation of tympanostomy tube placement (6)[C]: • Chronic bilateral OME (≥3 months) with hearing difficulty • Chronic OME with symptoms (e.g., vestibular problems, poor school performance, behavioral issues, ear discomfort, or reduced quality of life) • At-risk children (speech, language, or learning problems due to baseline sensory, physical, cognitive, or behavioral factors) with chronic OME or type B (flat) tympanogram

ADDITIONAL THERAPIES • Hearing aids may be an acceptable alternative to surgery (2)[C]. • Autoinflation, which refers to the process of opening the eustachian tube by

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raising intranasal pressure (e.g., by forced exhalation with closed mouth and nose) may be beneficial in improving patients’ tympanogram or audiometry and quality of life scores (6)[A].

SURGERY/OTHER PROCEDURES • Tympanostomy tubes are recommended as initial surgery. Risks include purulent otorrhea, myringosclerosis, retraction pockets, and persistent tympanic membrane perforations (1,2,5)[C]. • Adenoidectomy with myringotomy has similar efficacy to tympanostomy tubes in children >4 years of age but with added surgical and anesthetic risks (1)[C]. • Adenoidectomy should not be performed in children with persistent OME alone unless there is a distinct indication for the procedure for another problem (e.g., adenoiditis/chronic sinusitis/nasal obstruction) (1,5)[C]. • Adenoidectomy (and concurrent tube placement) may be considered when repeat surgery for OME is necessary (e.g., when effusion recurs after tubes have fallen out or are removed). In these cases, adenoidectomy has been shown to decrease the need for future procedures for OME (1,2)[C]. • Tonsillectomy or myringotomy alone is not recommended for treatment (1) [C].

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Children who are at risk for developmental difficulties should be evaluated for OME at the time of diagnosis and at 12 to 18 months (if initial diagnosis occurred younger than 12 months). At risk conditions include permanent hearing loss independent of OME, suspected or confirmed speech and language delay, autism spectrum disorder or other pervasive developmental disorder, Down syndrome or other craniofacial disorder, blindness or other uncorrectable visual impairment, cleft palate, unspecified developmental delay (5)[C]. • For patients diagnosed with OME, reevaluation and repeat hearing tests

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should be performed every 3 to 6 months until the effusion has resolved or until the child develops an indication for surgical referral (1)[C].

PROGNOSIS Approximately 50% of children >3 years of age have OME resolution within 3 months.

COMPLICATIONS • The most significant complication of OME is permanent hearing loss, leading to possible language, speech, and developmental delays. • Underventilation of the middle ear can cause a cholesteatoma (1)[C].

REFERENCES 1. American Academy of Family Physicians, American Academy of Otolaryngology-Head and Neck Surgery, American Academy of Pediatrics Subcommittee on Otitis Media With Effusion. Otitis media with effusion. Pediatrics. 2004;113(5):1412–1429. 2. Qureishi A, Lee Y, Belfield K, et al. Update on otitis media—prevention and treatment. Infect Drug Resist. 2014;7:15–24. 3. Shekelle P, Takata G, Chan LS, et al. Diagnosis, natural history, and late effects of otitis media with effusion. Evid Rep Technol Assess (Summ). 2002; (55):1–5. 4. Griffin G, Flynn CA. Antihistamines and/or decongestants for otitis media with effusion (OME) in children. Cochrane Database Syst Rev. 2011; (9):CD003423. 5. Rosenfeld RM, Shin JJ, Schwartz SR, et al. Clinical practice guideline: otitis media with effusion executive summary (update). Otolaryngol Head Neck Surg. 2016;154(2):201–214. 6. Perera R, Haynes J, Glasziou P, et al. Autoinflation for hearing loss associated with otitis media with effusion. Cochrane Database Syst Rev. 2006;(4):CD006285.

ADDITIONAL READING • Browning GG, Rovers MM, Williamson I, et al. Grommets (ventilation tubes)

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for hearing loss associated with otitis media with effusion in children. Cochrane Database Syst Rev. 2010;(10):CD001801. • Casselbrant ML, Mandel EM, Rockette HE, et al. Adenoidectomy for otitis media with effusion in 2-3-year-old children. Int J Pediatr Otorhinolaryngol. 2009;73(12):1718–1724. • Rosenfeld RM, Schwartz SR, Pynnonen MA, et al. Clinical practice guideline: tympanostomy tubes in children. Otolaryngol Head Neck Surg. 2013;149 (1 Suppl):S1–S35. • Simpson SA, Lewis R, van der Voort J, et al. Oral or topical nasal steroids for hearing loss associated with otitis media with effusion in children. Cochrane Database Syst Rev. 2011;(5):CD001935. • van Zon A, van der Heijden GJ, van Dongen TM, et al. Antibiotics for otitis media with effusion in children. Cochrane Database Syst Rev. 2012; (9):CD009163. • Williamson I, Vennik J, Harnden A, et al. Effect of nasal balloon autoinflation in children with otitis media with effusion in primary care: an open randomized controlled trial. CMAJ. 2015;187(13):961–969.

CODES ICD10 • H65.90 Unspecified nonsuppurative otitis media, unspecified ear • H65.00 Acute serous otitis media, unspecified ear • H65.20 Chronic serous otitis media, unspecified ear

CLINICAL PEARLS • OME is defined as the presence of a middle ear effusion in the absence of acute signs of infection. • In children, OME most often arises following an acute otitis media. In adults, it often occurs in association with eustachian tube dysfunction. • The primary standard for diagnosis is pneumatic otoscopy. • There is no benefit to the routine use of antibiotics, antihistamines, decongestants, or corticosteroids for the treatment of OME in children.

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• Management includes watchful waiting and surgery (when indicated); which strategy is chosen depends on many factors, including the risk/presence of any associated speech, language, or learning delays, and on the severity of any associated hearing loss.

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OVARIAN CANCER Celeste E. Straight, MD • Susan Zweizig, MD BASICS There are >22,000 new cases of ovarian cancer annually, and approximately 15,000 women will die of their disease, making this the most lethal of gynecologic cancers. This accounts for 2.4% of all cancer deaths nationally.

DESCRIPTION Malignancy that arises from the epithelium (90%), stroma, or germ cells of the ovary as well as tumors metastatic to the ovary Histologic types include the following: • Epithelial – Serous (tubal epithelium) – Mucinous (cervical and GI mucinous epithelium) – Endometrioid (endometrial epithelium) – Clear cell (mesonephroid) – Brenner (transitional cell epithelium) – Carcinosarcoma • Stromal – Granulosa cell tumor – Theca cell tumor – Sertoli–Leydig cell tumors – Gynandroblastoma – Lipid cell tumor • Germ cell – Teratoma (immature) – Dysgerminoma – Embryonal carcinoma – Gonadoblastoma – Endodermal sinus tumor – Embryonal carcinoma – Choriocarcinoma

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• Metastatic disease from the following: – Breast – Endometrium – Lymphoma – GI tract (Krukenberg tumor) – Primary peritoneal • System(s) affected: GI; reproductive; endocrine; metabolic

EPIDEMIOLOGY Incidence • 22,280 new cases/year in the United States; 14,240 deaths/year • Leading cause of gynecologic cancer death in women; mortality from ovarian cancer has decreased only slightly during the past 4 decades (1)[A]. • 75% diagnosed at advanced stage • Predominant age – Epithelial: mid-50s – Germ cell malignancies: usually observed in patients 80% • 5-year survival rates for ovarian cancer based on International Federation of Gynecology and Obstetrics (FIGO) data • For most recent FIGO staging criteria, see “References” (7)[A].

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COMPLICATIONS • Pleural effusion • Pseudomyxoma peritonei • Ascites • Toxicity of chemotherapy • Bowel obstruction • Malnutrition • Electrolyte disturbances • Fistula formation

REFERENCES 1. Schorge JO, Modesitt SC, Coleman RL, et al. SGO white paper on ovarian cancer: etiology, screening and surveillance. Gynecol Oncol. 2010;119(1):7– 17. 2. Beral V, Doll R, Hermon, et al. Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. Lancet. 2008;371(9609):303–314. 3. Goff BA, Mandel LS, Drescher CW, et al. Development of an ovarian cancer symptom index. Cancer. 2007;109(2):221–227. 4. Armstrong DK, Bundy B, Wenzel L, et al. Intraperitoneal cisplatin and paclitaxel in ovarian cancer. N Engl J Med. 2006;354(1):34–43. 5. Orlando M, Costanzo MV, Chacon RD, et al. Randomized trial of combination chemotherapy (combo) versus monotherapy (mono) in relapsed ovarian carcinoma (ROC): a meta-analysis of published data. J Clin Oncol. 2007;25:5524. 6. Gadducci A, Cosio S, Zola P, et al. Surveillance procedures for patients treated for epithelial ovarian cancer: a review of the literature. Int J Gynecol Cancer. 2007;17(1):21–31.

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7. Prat J. Staging classification for the cancer of the ovary, fallopian tube, and peritoneum. Int J Gynecol Obstetr. 2014;124(1):1–5.

ADDITIONAL READING • Salani R, Backes F, Fung M, et al. Posttreatment surveillance and diagnosis of recurrence in women with gynecologic malignancies: Society of Gynecologic Oncologists recommendations. Am J Obstet Gynecol. 2011;204(6):466–478. • Schumer ST, Cannistra SA. Granulosa cell tumor of the ovary. J Clin Oncol. 2003;21(6):1180–1189.

CODES ICD10 • C56.9 Malignant neoplasm of unspecified ovary • C56.1 Malignant neoplasm of right ovary • C56.2 Malignant neoplasm of left ovary

CLINICAL PEARLS • Family history of ovarian cancer or early-onset breast cancer is the most significant risk factor for the development of ovarian cancer, yet the vast majority of cases remain sporadic. • The diagnosis of ovarian cancer should be suspected in women with persistent bloating, upper abdominal discomfort, or GI symptoms of unknown etiology. • Surgery is the mainstay of diagnosis and treatment for ovarian cancer. Many patients benefit from adjuvant chemotherapy. • The prognosis of advanced ovarian cancer is poor and requires close followup by physical exam, tumor markers, and imaging when indicated.

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OVARIAN CYST, RUPTURED Heather O’Connor Greer, MD • Patricia Beauzile, MD BASICS • Ovarian cysts are frequent in reproductive-aged women. • Most ovarian cysts are benign physiologic follicles created by the ovary at the time of ovulation. • Ovarian cysts can cause symptoms when they become enlarged and exert a mass effect on surrounding structures, or when they rupture and the cyst contents cause irritation of the peritoneum or nearby pelvic organs. • Patients with a symptomatic ruptured cyst will usually complain of acute onset unilateral lower abdominal pain. • Evaluation of the patient should include exclusion of ectopic pregnancy, ovarian torsion, and nongynecologic sources of acute unilateral lower abdominal pain. • Once the diagnosis of a ruptured cyst is confirmed, most patients can be managed conservatively as outpatients with adequate pain control. Surgical intervention is rarely indicated.

DESCRIPTION A suspected ruptured ovarian cyst should be treated as an unknown adnexal mass (mass of the ovary, fallopian tube, and surrounding tissue) until proven otherwise.

EPIDEMIOLOGY • The actual incidence of ovarian cysts is difficult to calculate as many ruptured cysts are asymptomatic or found incidentally. • Ovarian cysts can be seen on transvaginal ultrasounds in nearly all premenopausal women and in up to 18% of postmenopausal women. The vast majority of these cysts are benign or functional. • Most ruptured ovarian cysts are self-limiting, and expectant management with pain control is usually sufficient. • About 13% of ovarian masses in reproductive-aged women are malignant, as

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opposed to 45% in postmenopausal women.

RISK FACTORS As benign physiologic cysts are a result of ovulation; medications or conditions associated with increased ovulation increase risk of cyst rupture. Examples include: • Ovulation induction agents (i.e., Clomid, aromatase inhibitors, GnRH agonists) • Tamoxifen increases the risk of ovarian cysts in reproductive-aged women. • Rare risk factors for increased ovarian cyst formation include fibrous dysplasia/McCune-Albright syndrome.

GENERAL PREVENTION Ovulation suppression with combined oral contraceptives is the mainstay therapy for prevention of recurrent ovarian cysts.

DIAGNOSIS • When a ruptured ovarian cyst is suspected, a pregnancy test should be performed to rule out an ectopic pregnancy. • Ultrasound imaging is standard for determining whether or not a patient with a ruptured cyst can be managed conservatively, or immediate intervention is indicated. Hemoperitoneum or hemodynamic instability is an indication for emergent intervention (1)[B]. • Sonographic imaging can also determine the characteristics of the cysts and can aid in separating malignant versus benign etiologies. • Additionally, ultrasound is useful in confirming normal Doppler flow to affected ovary.

HISTORY • A general past medical and surgical history should be reviewed. • Specific questions that should be addressed if you suspect a ruptured cyst include: – Onset and characteristics of pain – Pain associated with sexual intercourse or strenuous activity

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– Date of last menstrual period – Vaginal bleeding – Nausea or vomiting – Shoulder pain • Symptoms of circulatory collapse, including palpitation, shortness of breath, sensation of being hot or clammy, dizziness • Additional information that will guide diagnosis should include patient age, symptom onset, particularly in relation to menstrual cycle, anatomic location, and imaging studies.

ALERT Patients with bleeding diathesis or undergoing anticoagulation therapy may experience significant bleeding from hemorrhagic cysts.

PHYSICAL EXAM • Vital signs are usually normal unless significant blood loss has occurred. • Rupture characterized by significant blood loss may be present in the form of pallor, pale mucosal membranes, and tachycardia. • Patient will have significant tenderness to palpation or an acute abdomen if the peritoneum is irritated or inflamed. • On some occasions, a palpable adnexal mass can be felt on bimanual exam. Care should be taken not to cause further injury with a forceful exam.

DIFFERENTIAL DIAGNOSIS Should include all causes of acute abdominal pain, both gynecologic and nongynecologic

ALERT • Ectopic pregnancy should always be excluded with a negative pregnancy test. • Benign nongynecologic causes of acute lower abdominal pain include: – Appendicitis – Diverticulitis – Infections of the urinary tract – Renal colic • Malignant nongynecologic causes of acute lower abdominal pain can be

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attributed to neoplastic processes of the lower GI tract. • Benign gynecologic etiologies include: – Functional ovarian cysts – Ovarian torsion – Ectopic pregnancy – Tubo-ovarian abscess – Teratomas – Fibroids – Endometrioma – Cystadenoma (mucinous or serous) – Hydrosalpinx • Malignant gynecologic etiologies can usually be attributed to the various gynecologic cancers of the reproductive tract.

DIAGNOSTIC TESTS & INTERPRETATION • Urinalysis, STD testing, and a complete blood count should be obtained to evaluate for infectious causes, PID, or symptomatic renal stones. There are no laboratory tests that can definitively diagnose ovarian cyst rupture (2)[C]. • A type and screen is indicated if surgical intervention is planned or blood products are being considered. • Transvaginal ultrasound is helpful in determining the presence of an ovarian mass, its characteristics, and the presence of intraperitoneal fluid (1)[A]. • CT, MRI, or PET imaging are not indicated for initial evaluation; however, these modalities are useful if malignancy is suspected (1)[A].

TREATMENT GENERAL MEASURES • Cyst rupture in a stable healthy patient can be managed conservatively with analgesia, bleeding and symptoms precautions, and outpatient follow-up (1) [A]. • For many patients, pain associated with a ruptured cyst will be transient and self-limiting. • Scheduled NSAIDs or oral narcotics can be prescribed depending on pain

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severity. • Unstable patients with hemodynamic compromise or patients with significant intraperitoneal fluid should be resuscitated, and laparoscopy or a laparotomy should be considered. Surgical exploration should also be considered if there is a concern for malignancy.

ISSUES FOR REFERRAL • OB-GYN – Consider referral to an obstetrician if an adnexal mass is diagnosed during pregnancy. Such masses have a low risk of malignancy or acute complication for the pregnancy. • GYNECOLOGIC ONCOLOGY – Referral to a gynecologic oncologist should be considered for complex adnexal masses with an elevated CA125 and associated symptoms concerning for malignancy such as ascites, early satiety, pleural effusion, enlarging abdominal mass, or bowel obstruction. • GENERAL SURGERY – Acute lower abdominal pain that is nongynecologic and suspicious for bowel involvement should be referred to general surgery or a gastroenterologist.

SURGERY/OTHER PROCEDURES • Although the need for surgical intervention is rare, it is usually of an emergent nature. • In most cases, laparoscopy will be sufficient to evaluate intra-abdominal bleeding. The decision to proceed with cystectomy or oophorectomy should be made intraoperatively after a thorough evaluation of the intra-abdominal environment has been completed. • The advantages of a laparoscopic approach include a shorter length of stay, and most patients can be discharged home the same day. Postoperative recovery time as well as patient satisfaction is significantly improved with a minimally invasive approach. • Laparotomy should be performed in cases of critical hemodynamic instability or lack of laparoscopically trained surgeons. If there is concern for malignancy or metastases, laparotomy may be the preferred method of

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surgery.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS Patients who require inpatient management should be managed with serial abdominal exams, analgesia, and intravenous resuscitation as indicated by their initial presentation.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS • Follow up for patients managed conservatively should be scheduled 1 to 2 weeks from the initial onset of symptoms. Patients should present sooner for new or worsening symptoms. • Patients with complete resolution of symptoms within a few days can followup as needed. However, these patients should be counseled on ovarian cysts and options for prevention. • Patient in whom surgical intervention was indicated, postop follow-up should be scheduled 2 weeks from the date of surgery. • Patients in whom an ovarian cyst was diagnosed incidentally should follow-up based on the size of their cyst. • Simple cysts up to 10 cm in diameter on ultrasound findings are almost always benign and may safely be followed without intervention in pre- and postmenopausal patients. These patients should also be referred to a gynecologist (3)[B].

Pregnancy Considerations Adnexal masses in pregnancy have a low risk of malignancy or acute complications to the pregnancy, so in most cases, they can be managed expectantly (1)[C].

PATIENT EDUCATION Reassurance of the benign nature of most ovarian cysts is an important cornerstone of patient education.

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REFERENCES 1. Prakash A, Li T, Ledger WL. The management of ovarian cysts in premenopausal women. The Obstetrician and Gynecologist. 2004;6:12–15. 2. McDonald JM, Modesitt SC. The incidental postmenopausal adnexal mass. Clin Obstet Gynecol. 2006;49(3):506–516. 3. Pavlik EJ, Ueland FR, Miller RW, et al. Frequency and disposition of ovarian abnormalities followed with serial transvaginal ultrasonography. Obstet Gynecol. 2013;122(2 Pt 1):210–217.

ADDITIONAL READING • American College of Obstetricians and Gynecologists. ACOG practice bulletin. Management of adnexal masses. Obstet Gynecol. 2007;110(1):201– 214. • Bottomley C, Bourne T. Diagnosis and management of ovarian cyst accidents. Best Pract Res Clin Obstet Gynaecol. 2009;23(5):711–724. • Collins MT, Singer FR, Eugster E. McCune-Albright syndrome and the extraskeletal manifestations of fibrous dysplasia. Orphanet J Rare Dis. 2012;7(Suppl 1):S4. • Hoo WL, Yazbek J, Holland T, et al. Expectant management of ultrasonically diagnosed ovarian dermoid cysts: is it possible to predict outcome? Ultrasound Obstet Gynecol. 2010;36(2):235–240. • Kaunitz AM. Oral contraceptive health benefits: perception versus reality. Contraception. 1999;59(1 Suppl):29S–33S. • Mimoun C, Fritel X, Fauconnier A, et al. Epidemiology of presumed benign ovarian tumors. J Gynecol Obstet Biol Reprod (Paris). 2013;42(8):722–729. • Møller LM. Complications of gynaecological operations. A one-year analysis of a hospital database. Ugeskr Laeger. 2005;167(49):4654–4659. • Raziel A, Ron-El R, Pansky M, et al. Current management of ruptured corpus luteum. Eur J Obstet Gynecol Reprod Biol. 1993;50(1):77–81. • Roch O, Chavan N, Aquilina J, et al. Radiological appearances of gynaecologic emergencies. Insights Imaging. 2012;3(3):265–275. • Saunders BA, Podzielinski I, Ware RA, et al. Risk of malignancy in sonographically confirmed septated cystic ovarian tumors. Gynecol Oncol.

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2010;118(3):278–282. • Stany MP, Hamilton CA. Benign disorders of the ovary. Obstet Gynecol Clin North Am. 2008;35(2):271–284. • Suzuki S, Yasumoto M, Matsumoto R, et al. MR findings of ruptured endometrial cyst: comparison with tubo-ovarian abscess. Eur J Radiol. 2012;81(11):3631–3637.

CODES ICD10 • N83.20 Unspecified ovarian cysts • N83.0 Follicular cyst of ovary • N83.1 Corpus luteum cyst

CLINICAL PEARLS • Functional ovarian cysts are very common in reproductive-age women and are usually self-limiting. • Always exclude ectopic pregnancy. • Management of symptomatic ruptured cysts is usually accomplished with outpatient pain control with follow-up. • In cases where the patient with a ruptured cyst is unstable or presents with signs of an acute abdomen, surgical intervention is indicated.

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PALLIATIVE CARE Erika Oleson, DO, MS BASICS Palliative care is a specialty that focuses on preventing and alleviating suffering of patients (and their families) living with life-limiting illness at any stage of that illness.

DESCRIPTION • Palliative care’s principal aim is to prevent and alleviate suffering—whether physical (pain, breathlessness, nausea, etc.), emotional, social, or spiritual regardless of underlying diagnosis. • The goal of palliative care is to improve or maintain quality of life of both patient and family despite serious illness. • Palliative care is available for patients with serious, life-limiting illness, at any stage of their disease, with or without concurrent curative care. • Location of care: Patients and their families may access palliative care services in hospital, rehabilitative or skilled nursing facility, and ambulatory setting. • Hospice: In the United States, hospice is available for patients whose average life expectancy is 6 months or less and whose principal goal is to stay home (including long-term care or assisted living facility), avoid hospitalizations, and disease-directed care with a curative intent. Unlike regular nursing services in the home, hospice does not require a patient to be homebound and offers backup support for patients 24 hours a day and 7 days per week.

COMMONLY ASSOCIATED CONDITIONS Symptoms/syndromes commonly treated in palliative care: • Pain – Chronic pain – Headache – Neuropathic pain – Pain from bone metastases

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– Pruritus • GI symptoms (~60% incidence) – Ascites – Anorexia/cachexia – Nausea (and vomiting) Consider underlying etiology and treat accordingly. GI causes: constipation, bowel (full or partial) obstruction, ileus, heart burn, reflux, inflammation Intrathoracic causes: cardiac, effusions (cardiac, pulmonary), mediastinal causes, esophageal Autonomic dysfunction Centrally mediated: intracranial pressure change, inflammation, cerebellar, vestibular, medication or metabolic cause stimulating vomiting center and/or chemoreceptor trigger zone – Bowel obstruction – Constipation and impaction of stool – Diarrhea – Dysphagia – Mucositis/stomatitis – Sialorrhea • General medical – Delirium (40–85%) • Pulmonary symptoms – Cough, chronic – Breathlessness or dyspnea (60%): often due to heart failure, COPD, lung cancer, and so forth • Psychological symptoms – Anxiety – Depression – Insomnia • Skin – Decubitus ulcer – Pruritus – Complex wounds (fungating tumors, etc.)

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DIAGNOSIS The PEACE tool evaluates the following (1): • Physical symptoms • Emotive and cognitive symptoms • Autonomy and related issues • Communication: contribution to others and closure of life affairs–related issues • Economic burden and other practical issues, also transcendent and existential issues

HISTORY A comprehensive palliative care assessment includes addressing the following: • Underlying medical conditions and their associated physical symptoms • Comprehensive pain and symptom assessment and review of systems (consider use of Edmonton Symptom Assessment Tool) • Psychological symptom assessment • Cultural, social, and practical concerns • Spiritual and existential issues – FICA assessment (Faith, Importance and influence, Community, Address— how does the patient wish to be addressed?) – HOPE (sources of Hope/strength/comfort, Organized religion’s role, Personal spirituality and practices, Effects on medical care and end-of-life care) (2) • Patient’s identified presence and sources of suffering: personhood concerns • Goals of care: including posthospital care, practical needs, hopes, and fears • Prognosis: including functional status and patient’s interest in knowing prognosis

PHYSICAL EXAM Comprehensive physician examination is warranted, especially as directed by underlying diagnosis, symptoms, and functional decline.

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging)

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Per diagnosis and symptoms

TREATMENT GENERAL MEASURES • Targeted interventions to maximize quality of life and minimize symptom burden while taking into consideration the patient’s values, goals, fears, and social setting. • Treatment should involve an interdisciplinary team—addressing potential and realized suffering, whether physical, emotional, social, or spiritual.

MEDICATION • Attempt to minimize polypharmacy • Consider discontinuing medications that offer little improvement in the quality of life. • Medication should focus on symptom management. • Continue to use appropriate disease-modifying medications especially if they lessen symptom burden and enhance immediate quality of life. • Improve compliance by addressing patient/caregiver understanding. • Pain (3)[A] – Use immediate-release opioids PO/IV/SC and titrate to control. – Once pain is controlled, convert to long-acting opioids with short-acting agents made available as tolerance develops and/or patient develops breakthrough pain. • Bone pain: NSAIDs added to narcotics are more effective than narcotics alone. • Neuropathic pain: may use adjuvant treatment, such as gabapentin, other anticonvulsants. Glucocorticoids may also help.

ALERT Avoid morphine in patients with renal failure, can induce delirium, hyperalgesia, agitation, and seizures. • Vomiting associated with a particular opioid may be relieved by substitution with an equianalgesic dose of another opioid or a sustained-release

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formulation (4). – Dopamine receptor antagonists (metoclopramide, prochlorperazine, promethazine) are commonly used. Haloperidol may help with nausea. – Droperidol: insufficient evidence to advise on the use for the management of nausea and vomiting • Constipation: Consider prophylactic stool softeners (docusate) and stimulants (bisacodyl or senna) or osmotic laxatives.

ALERT Laxatives should be started when opioid treatment has begun to avoid constipation. • SC methylnaltrexone is effective in inducing bowel movements without inducing withdrawal with opioid-induced constipation. • Dyspnea: consider oxygen, if congestive heart failure (CHF); diuretics and/or long-acting nitrates, benzodiazepines – In addition to treating the underlying cause of breathlessness, as the disease advances, low-dose opioids may be beneficial to patients (3,5)[C]. Immediate-release opioids PO/IV treat dyspnea effectively and typically at doses lower than necessary for the relief of moderate pain. • Delirium: lowest doses necessary of benzodiazepines or antipsychotics (haloperidol, etc.) – Monitor patient safety and use nonpharmacologic strategies to assist orientation (clocks, calendars, environment, and redirection). – Droperidol: When cause of delirium cannot be identified/corrected rapidly, consider neuroleptics (haloperidol or risperidone). • Pruritus: no optimal therapy • Anxiety: insufficient data for recommendations of specific medication, but anxiolytics and/or other agents may be tried • Megestrol acetate improves appetite and slight weight gain in patients with anorexia-cachexia syndrome.

ISSUES FOR REFERRAL • Referral to palliative care – Any patient with a serious, life-limiting illness who could benefit from help with burdensome symptoms or suffering and/or complex goals of care

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discussion. – Early referral to palliative care may improve quality of life and longevity for patients with advanced cancer. • Referral to hospice care – Any patient with an average life expectancy of 6 months or less. Consider the question, “Would you be surprised if the patient died within the next 6 months?” If the answer is no, they likely meet prognostic criteria for hospice. Consider patients who have multiple hospitalizations and/or emergency department visits in the prior 6 months. Refer to local hospice guidelines for additional disease-specific criteria.

REFERENCES 1. Okon TR, Evans JM, Gomez CF, et al. Palliative educational outcome with implementation of PEACE tool integrated clinical pathway. J Palliat Med. 2004;7(2):279–295. 2. Anandarajah G, Hight E. Spirituality and medical practice: using the HOPE questions as a practical tool for spiritual assessment. Am Fam Physician. 2001;63(1):81–89. 3. Lorenz KA, Lynn J, Dy SM, et al. Evidence for improving palliative care at the end of life: a systematic review. Ann Intern Med. 2008;148(2):147–159. 4. Smith HS, Smith JM, Smith AR. An overview of nausea/vomiting in palliative medicine. Ann Palliat Med. 2012;1(2):103–114. 5. Ben-Aharon I, Gafter-Gvili A, Paul M, et al. Interventions for alleviating cancer-related dyspnea: a systematic review. J Clin Oncol. 2008;26(14):2396–2404.

CODES ICD10 Z51.5 Encounter for palliative care

CLINICAL PEARLS

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• Early referral to palliative care may help enhance the quality of life and potential longevity of patients living with serious illness. • Consider the type of pain: the addition of adjuvant treatments such as NSAIDs or gabapentin to narcotics may be more effective than narcotics alone. • Laxatives should be started when opioid treatment has begun to avoid constipation.

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PANCREATIC CANCER Marcelle Meseeha, MD • Maximos Attia, MD, FAAFP BASICS DESCRIPTION • Adenocarcinoma of the exocrine pancreas (90% of pancreatic cancers) is the fourth most common cause of cancer death in the United States and the ninth most common cancer in women. • Rarely curable: overall 5-year relative survival rate of 7.7% • 60–70% occurs in the head, 20% in the body and tail, 20% diffusely involve the gland. • As few as 9% are localized at diagnosis. For localized, small cancers ( 25 mg/dL, impaired mental status, systemic inflammatory response syndrome (SIRS)—a score of 0 predicts mortality of 3× ULN (Severity is not related to degree of elevation.) • Elevated serum lipase >3× ULN (may stay elevated longer than amylase in mild cases) • Elevated total bilirubin. If >3 mg/dL, consider common bile duct obstruction. • Transaminases rise quickly with acute bile duct obstruction. They also fall rapidly as alkaline phosphatase rises; a 3-fold elevation in the alanine aminotransferase (ALT) in the setting of acute pancreatitis has a 95% positive predictive value for gallstone pancreatitis. Triglyceride levels >1,000 mg/dL suggest hypertriglyceridemia as the cause. • Glucose is increased in severe disease. • Calcium is decreased in severe disease. • WBC elevation to 10,000 to 25,000/μL possible and not indicative of active infection • Elevated baseline hematocrit >44 or rising hematocrit are poor prognostic signs (severe 3rd spacing with associated hemoconcentration) (1)[A].

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• Rising BUN and creatinine imply volume depletion or acute renal failure (1) [A].

DIFFERENTIAL DIAGNOSIS • Penetrating peptic ulcer • Acute cholecystitis or cholangitis • Macroamylasemia, macrolipasemia • Mesenteric vascular occlusion and/or infarction • Perforation of a viscus • Intestinal obstruction • Aortic aneurysm (dissecting or rupturing) • Inferior wall myocardial infarction • Lymphoma

Initial Tests (lab, imaging) • Use follow-up labs to assess renal function, hydration, sepsis, biliary obstruction, and tissue oxygenation. • Plain film of abdomen helps rule out mechanical small bowel obstruction. Ileus is common. • Chest x-ray (CXR) to evaluate for early acute respiratory distress syndrome (ARDS) and pleural effusion; can also rule out subdiaphragmatic air (perforated viscus) • Ultrasound to look for gallbladder/biliary stones • CT scan – Confirms the diagnosis, assesses severity, establishes a baseline, and rules out most other pathologies (excluding noncalcified cholelithiasis) – IV contrast is not essential for the initial CT scan; avoid contrast in volumedepleted patients. – If not contraindicated, a CT scan with IV contrast on day 3 can assess the degree of necrosis if necrotizing pancreatitis is suspected. • Magnetic resonance cholangiopancreatography (MRCP) helps assess choledocholithiasis, pancreas divisum, dilated pancreatic duct, and ductal changes. • Esophagogastroduodenoscopy (EGD) may be necessary to rule out a penetrating duodenal ulcer or an obstructing ampullary neoplasm.

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• ERCP may be necessary to decompress common bile duct due to an impacted stone. • Endoscopic ultrasonography (EUS) is useful if patients present with “idiopathic pancreatitis” (2)[B]. • FNA may be added to EUS if autoimmune pancreatitis is suspected (3)[B]. Follow-Up Tests & Special Considerations If renal function is stable, a contrast-enhanced CT scan at day 3 to assess for necrosis. Later in the course, if there is a spike in the temperature, CT guidance assists aspiration and drainage of abscess.

TREATMENT MEDICATION First Line • Analgesia: no consensus; guidelines vary widely on types and dosing for analgesia. – Hydromorphone (Dilaudid) 0.5 to 1 mg IV q1–2h PRN – AVOID Demerol due to the potential of accumulation of a toxic metabolite. • Antibiotics – The use of prophylactic antibiotics is no longer recommended, even with necrotizing pancreatitis, in the clear absence of infection. – In patients with ascending cholangitis or necrotizing pancreatitis, β-lactam/ β-lactamase inhibitor (e.g., piperacillin/tazobactam 4.5 g IV q8h) can be considered for initial treatment, before cultures (especially of aspirated collections) return, if there is a strong suspicion of active infection. – Levofloxacin 500 mg QD IV if cholangitis and there is an allergy to penicillin – Be vigilant for fungal superinfections when giving prophylactic antibiotics.

GENERAL MEASURES Most cases of acute pancreatitis require hospitalization; ICU if multiorgan dysfunction or hypotension/respiratory failure; 15–20% of cases of acute pancreatitis progress from mild to severe (including persistent organ failure) • Fluid resuscitation

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– Significant volume deficit due to 3rd spacing – Infuse bolus of 1,000 to 2,000 mL (lactated Ringers may be better than normal saline, unless hypercalcemic), followed by 250 to 300 mL/hr, adjusted on the basis of age, weight, hemodynamic response, and comorbid conditions. – Target urine output should be 0.5 to 1 mL/kg/hr. Lower infusion rate when this goal is achieved or once BUN decreases; 4 L should be the maximum fluid on day 1. • Eliminate unnecessary medications, especially those potentially causing pancreatitis. • Nasogastric (NG) tube for intractable emesis • Follow renal function, volume status, calcium, and oxygenation. Organ failure is more important prognostic indicator than pancreatic necrosis. • Intermittent pneumatic compression device • Begin oral alimentation after pain, tenderness, and ileus have resolved; small amounts of high-carbohydrate, low-fat, and low-protein foods; advance as tolerated; NPO or NG tube if vomiting persists • Enteral nutrition at level of ligament of Treitz if oral feeding not possible within 5 to 7 days (preferable to total parenteral nutrition [TPN] due to decreased infection rate and decreased mortality). Discontinue with increases in pain, amylase/lipase levels, or fluid retention. • TPN (without lipids if triglycerides are elevated) if oral or nasoenteric feedings are not tolerated (4)[A]

ISSUES FOR REFERRAL Refer to a tertiary center if pancreatitis is severe or actively evolving and when advanced imaging or endoscopic therapy is being considered.

SURGERY/OTHER PROCEDURES • Consider cholecystectomy before discharge in patients with cholelithiasis and nonnecrotizing pancreatitis to reduce risk of recurrent acute gallstone pancreatitis. • Necrosectomy should be performed nonsurgically for either infected or noninfected necrosis. Walled-off necrosis should be observed for 4 weeks (treated with antibiotics if infected), followed by percutaneous or dual-

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modality drainage if available (5)[B]. • ERCP early if evidence of acute cholangitis or at 72 hours if evidence of ongoing biliary obstruction; ERCP with pancreatic ductal stent placement, if ductal disruption persists longer than 1 to 2 weeks • Resection or embolization for bleeding pseudoaneurysms • Plasma exchange with insulin if necrotizing pancreatitis secondary to hypertriglyceridemia

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS Discharge Criteria • Pain controlled • Tolerating oral diet • Alcohol rehabilitation and tobacco cessation • Low-grade fever and mild leukocytosis do not necessarily indicate infection and may take weeks to resolve. Infections may occur even after 10 days (33% of patients with necrotizing pancreatitis) due to secondary infection of necrotic material, requiring surgical débridement.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS • Follow-up imaging studies in several weeks, if the original CT scan showed a fluid collection or necrosis or if the amylase/lipase continues to be elevated. Follow-up findings may include: – Pseudocyst (occurs in 10%) or abscess (sudden onset of fever): Conservative management is an option for asymptomatic pseudocysts up 6 cm in diameter. – Splenic vein thrombosis (gastric variceal hemorrhage rarely occurs) – Pseudoaneurysm (splenic, gastroduodenal, intrapancreatic) hemorrhage can be life-threatening. • Mild exocrine and endocrine dysfunction is usually subclinical. Patients with necrotizing pancreatitis, steatorrhea, or ductal obstruction, however, should receive enzyme supplementation.

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• After the first episode of acute pancreatitis, the risk of lifetime diabetes doubles. • After the first episode of acute pancreatitis, the risk of developing acute recurrent pancreatitis is ~17%. The risk for developing chronic pancreatitis is ~8%.

DIET Continue to advance diet as tolerated; dietary modification to reduce dietary fats, alcohol, and added sugars

PROGNOSIS 85–90% of cases of acute pancreatitis resolve spontaneously; 3–5% mortality (17% in necrotizing pancreatitis)

REFERENCES 1. Koutroumpakis E, Wu BU, Bakker OJ, et al. Admission hematocrit and rise in blood urea nitrogen at 24 h outperform other laboratory markers in predicting persistent organ failure and pancreatic necrosis in acute pancreatitis: a post hoc analysis of three large prospective databases. Am J Gastroenterol. 2015;110(12):1707–1716. 2. Munigala S, Kanwal F, Xian H, et al. Increased risk of pancreatic adenocarcinoma after acute pancreatitis. Clin Gastroenterol Hepatol. 2014;12(7):1143.e1–1150.e1. 3. Iwashita T, Yasuda I, Doi S, et al. Use of samples from endoscopic ultrasound-guided 19-gauge fine-needle aspiration in diagnosis of autoimmune pancreatitis. Clin Gastroenterol Hepatol. 2012;10(3):316–322. 4. Gravante G, Garcea G, Ong SL, et al. Prediction of mortality in acute pancreatitis: a systematic review of the published evidence. Pancreatology. 2009;9(5):601–614. 5. Trikudanathan G, Attam R, Arain MA, et al. Endoscopic interventions for necrotizing pancreatitis. Am J Gastroenterol. 2014;109(7):969–981.

ADDITIONAL READING • Ahmed Ali U, Issa Y, Hagenaars JC, et al. Risk of recurrent pancreatitis and

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progression to chronic pancreatitis after a first episode of acute pancreatitis. Clin Gastroenterol Hepatol. 2016;14(5):738–746. • Lu X, Aoun E. Complications of acute pancreatitis. Pract Gastroenterol. 2012;36:11–22. • Nitsche CJ, Jamieson N, Lerch MM, et al. Drug induced pancreatitis. Best Pract Res Clin Gastroenterol. 2010;24(2):143–155. • Oláh A, Romics L Jr. Evidence-based use of enteral nutrition in acute pancreatitis. Langenbecks Arch Surg. 2010;395(4):309–316. • Wang SQ, Li SJ, Feng QX, et al. Overweight is an additional prognostic factor in acute pancreatitis: a meta-analysis. Pancreatology. 2011;11(2):92–98. • Wu BU, Banks PA. Clinical management of patients with acute pancreatitis. Gastroenterology. 2013;144(6):1272–1281.

CODES ICD10 • K85.9 Acute pancreatitis, unspecified • K85.8 Other acute pancreatitis • K85.2 Alcohol induced acute pancreatitis

CLINICAL PEARLS • Pancreatitis remains a common indication for hospitalization. Alcohol misuse and gallstones are the leading causes for pancreatitis • The BISAP score is easier to apply than Ranson criteria and is just as accurate for predicting mortality in patients with acute pancreatitis. • Review all medications and discontinue any that may cause (or contribute to) pancreatitis. • Patients with mild pancreatitis can progress to severe pancreatitis over the initial 48 hours, often due to inadequate fluid replacement. • Referral to tertiary center is needed if acute pancreatitis is severe or evolving/worsening.

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PANIC DISORDER Yash Kothari, MD • Hugh Peterson, MD, FACP BASICS DESCRIPTION • A classic panic attack that is characterized by rapid onset of a brief period of sympathetic nervous system hyperarousal accompanied by intense fear. • In panic disorder, multiple panic attacks occur (including at least one without a recognizable trigger). Worried anticipation of additional attacks, which can be disabling, is present for at least 1 month, and often, maladaptive (e.g., avoidance) behaviors develop.

EPIDEMIOLOGY Incidence • Predominant age: All ages; in school-aged children, panic disorder can be confused with conduct disorder and school avoidance. • Peak age of onset is early to mid-20s. • Predominant sex: female > male (2:1)

Prevalence • Lifetime prevalence: 4.7% • 4–8% of patients in a primary care practice population have panic disorder. • Of patients presenting with chest pain in the emergency room, 25% have panic disorder. • Chest pain is more likely due to panic if atypical, younger age, female, and known problems with anxiety.

ETIOLOGY AND PATHOPHYSIOLOGY Unknown • Biologic theories focus on limbic system malfunction in dealing with anxietyevoking stimuli. • Psychological theories posit deficits in managing strong emotions such as fear and anger.

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• Noradrenergic neurotransmission from the locus coeruleus causes increased sympathetic stimulation throughout the body. • Current neurobiologic research focuses on abnormal responses to anxietyproducing stimuli in the hippocampus, amygdala, and prefrontal cortex; for example, there appears to be limbic kindling in which an original frightening experience dominates future responses even when subsequent exposures are not objectively threatening. • Brain pH disturbances (e.g., excess lactic acid) from normal mentation in genetically vulnerable patients may activate the amygdala and generate unexpected fear responses.

Genetics Twin and family studies support a genetic predisposition.

RISK FACTORS • Life stressors of any kind can precipitate attacks. • History of sexual abuse and physical abuse, anxious, and overprotective parents • Substance abuse, bipolar disorder, major depression, obsessive-compulsive disorder (OCD), and simple phobia

COMMONLY ASSOCIATED CONDITIONS • Of patients with panic disorder, >70% also have ≥1 other psychiatric diagnoses: PTSD (recalled trauma precedes panic attack), social phobia (fear of scrutiny precedes panic attack), simple phobia (fear of something specific precedes panic), major depression, bipolar disorder, substance abuse, OCD, separation anxiety disorder. • Panic disorder is more common in patients with asthma, migraine headaches, hypertension, mitral valve prolapse, reflux esophagitis, interstitial cystitis, irritable bowel syndrome, fibromyalgia, nicotine dependence, and suicidality.

DIAGNOSIS • Panic attack: an abrupt surge of intense fear, reaching a peak within minutes in which ≥4 of the following symptoms develop abruptly: (i) palpitations,

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pounding heart, or accelerated heart rate; (ii) sweating; (iii) trembling or shaking; (iv) sensations of shortness of breath or feeling smothered; (v) a choking sensation; (vi) chest pain or discomfort; (vii) nausea or abdominal distress; (viii) feeling dizzy, unsteady, lightheaded, or faint; (ix) derealization (feelings of unreality) or depersonalization (feeling detached from oneself); (x) fear of losing control or going crazy; (xi) fear of dying; (xii) paresthesias; (xiii) chills or hot flashes (1)[C] • Panic disorder: recurrent unexpected panic attacks not better accounted for by another psychiatric condition (e.g., PTSD, OCD, separation anxiety disorder, social anxiety disorder, or specific phobia) and not induced by drugs of abuse, medical conditions, or prescribed drugs and with >1 month of at least one of the following: (i) worry about additional attacks or worry about the implications of the attack (e.g., losing control, having a heart attack, “going crazy”); (ii) a significant maladaptive change in behavior related to the attacks (1)[C] • Unlike DSM-IV, DSM-5 defines agoraphobia as separate from panic disorder (1)[C].

HISTORY • The best way to get a good history is through tactful, nonjudgmental questioning after the worst of the attack is over. Use open-ended questions and be unhurried. Interviewing family members may also be helpful. • A thorough medication and substance abuse history is important. • Patients must have a month of fear of out-of-the-blue panic attacks to diagnose panic disorder.

PHYSICAL EXAM • During an attack, there will be tachycardia, hyperventilation, and sweating. • Check the thyroid for fullness or nodules. • Cardiac exam to check for a murmur or arrhythmias • Lung exam to rule out asthma (limited airflow, wheezing)

DIFFERENTIAL DIAGNOSIS • Medication use may mimic panic disorder and create anxiety: Antidepressants to treat panic may paradoxically initially cause panic; antidepressants in

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bipolar patients can cause anxiety/mania/panic; short-acting benzodiazepines (alprazolam), β-blockers (propranolol), and short-acting opioids can cause interdose rebound anxiety; benzodiazepine treatment causes panic when patients take too much and run out of these medicines early; bupropion, levodopa, amphetamines, steroids, albuterol, sympathomimetics, fluoroquinolones, and interferon can cause panic. • Substances of abuse: alcohol withdrawal, benzodiazepine withdrawal, opioid withdrawal, caffeine, marijuana (panic with paranoia), amphetamine abuse, MDMA, hallucinogens (PCP, LSD), dextromethorphan abuse, synthetic cathinones (bath salts) abuse. • Medical conditions: hypo-/hyperthyroidism, asthma/chronic obstructive pulmonary disease (COPD), reflux esophagitis with hyperventilation, tachyarrhythmias, premenstrual dysphoric disorder, menopause, pregnancy, hypoglycemia (in diabetes), hypoxia, inner ear disturbances (labyrinthitis), myocardial infarction (MI), pulmonary embolus (PE), transient ischemic attacks (TIAs), carcinoid syndrome, pre- and postictal states (e.g., in TLE), autoimmune disease, pheochromocytoma, Cushing syndrome, hyperaldosteronism, Wilson disease • Psychiatric conditions that have overlapping symptomatology include mood, anxiety, and personality disorders such as major depression, bipolar disorder, PTSD, borderline personality disorder, social phobia, OCD, and generalized anxiety disorder. In PTSD, there is always a recollection or visual image that precedes the panic attack. In social phobia, fear of scrutiny precedes the panic attack. In bipolar disorder, major depression, borderline personality disorder, and particularly substance abuse, the patient often complains first of panic symptoms and anxiety and minimizes other potentially relevant symptoms and behaviors. • Somatic symptom disorder is also an illness of multiple unexplained medical symptoms, but the presenting picture is usually one of chronic symptoms rather than the acute, dramatic onset of a panic attack. Somatic symptom disorder and panic disorder can be (and often are) diagnosed together.

DIAGNOSTIC TESTS & INTERPRETATION Consider ECG and pulse oximetry to rule out certain serious causes of panic; consider Holter monitoring. No specific lab tests are indicated except to rule out

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conditions in the differential diagnosis. • Finger stick blood sugar in acute setting in a diabetic patient • Thyroid-stimulating hormone (TSH), electrolytes, CBC • Consider ordering echocardiogram if you suspect mitral valve prolapse.

Diagnostic Procedures/Other • If a medical cause of anxiety is strongly suspected, do the workup appropriate for that condition. • Panic Disorder Severity Scale (PDSS) is a physician- or self-administered instrument for monitoring changes in severity of symptoms and response to treatment (2). – https://www.outcometracker.org/library/PDSS.pdf

TREATMENT Combined antidepressant therapy and psychotherapy is superior to either alone during initial treatment for panic disorder (3)[A]. Cognitive-behavioral therapy (CBT) provides long-lasting treatment, often without subsequent need for medications.

GENERAL MEASURES CBT, tailored for panic disorder, consists of several steps: education, changing cognitions about the attack and the illness, relaxation and controlled breathing techniques, and, if appropriate, exposure to anxiety-provoking conditions coupled with in vivo relaxation exercises.

MEDICATION • Medication management is indicated if psychotherapy is not successful (or not available) and may be combined with psychotherapy. • Patient preference plays a big part in this decision. • Because patients typically are anxious about their treatment, the therapeutic alliance is critical for the chronic care of this disorder. • If medications are started, they should be maintained for at least 6 months after symptom control.

First Line

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• FDA-approved choices for the treatment of panic disorder include sertraline, paroxetine, fluoxetine, alprazolam, and clonazepam, but avoid giving benzodiazepines to those with a history of substance abuse or who are currently abusing alcohol or benzodiazepines, unless following a detoxification protocol. • Most antidepressants except bupropion may treat panic disorder, but fluoxetine and selegiline patch can cause more initial nervousness than other antidepressants. • In nonbipolar patients, start a low-dose SSRI, e.g., 5 mg (escitalopram), 25 mg (sertraline), 10 mg (paroxetine), and consider doubling the dose after 2 to 4 weeks; while waiting for the antidepressant to work, schedule frequent visits, give the patient reassurance, teach a relaxation technique, encourage the patient to do vigorous aerobic exercise as soon as a panic attack begins (if medically appropriate and in an appropriate situation); refer the patient to a competent therapist for CBT (4)[A]. • In bipolar patients, panic symptoms often resolve when treated with a mood stabilizer rather than an antidepressant (which may cause mania).

Second Line • Among serotonin-norepinephrine reuptake inhibitors, venlafaxine extended release (ER) is effective. Start at 37.5 mg/day and titrate up to 75 mg/day after 7 days (maximum dose of 225 mg/day). Taper slowly over weeks to discontinue. Risk of hypertension at higher doses (5)[A]. • Tricyclic antidepressants, particularly imipramine (start 25 mg/day in the evening and increase up to 25 mg every 3 days to a maximum of 200 mg/day); slower titration and lower doses are often as effective. Imipramine is as efficacious as SSRIs in the treatment of panic disorder. Tricyclic antidepressants are considered second line because of difficulty in dosing, more side effects, and greater risk associated with overdose compared with SSRIs (6)[A]. • Benzodiazepines like alprazolam (start 0.5 mg TID and up to 5 mg/day) and clonazepam (0.25 mg BID to target 1 mg/day) are FDA approved for panic disorder. Clonazepam has a longer half-life, less interdose anxiety, and lower abuse potential than alprazolam.

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ISSUES FOR REFERRAL Consider referral to a psychiatrist for panic disorder that is comorbid with bipolar disorder, borderline personality disorder, schizophrenia, suicidality, alcohol, or substance abuse.

ADDITIONAL THERAPIES Aerobic exercise can be helpful to reduce symptoms.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • If certain life-threatening mimics of panic disorder have not been ruled out, such as an MI or PE, hospitalize patient to complete the evaluation. • If a panic disorder patient has concrete suicidal ideation, a psychiatric admission is indicated.

ONGOING CARE PATIENT EDUCATION • www.nlm.nih.gov/medlineplus/panicdisorder.html • Patient information handouts in American Family Physician. 2005;71:740 and 2006;74:1393. • http://www.nimh.nih.gov/health/publications/panic-disorder-when-fearoverwhelms/index.shtml

PROGNOSIS • Most patients recover with treatment. • It can recur, but treatment of recurrence is usually successful.

COMPLICATIONS • Iatrogenic benzodiazepine dependence • Iatrogenic mania in bipolar patients treated for panic with unopposed antidepressants • Misdiagnosis of more difficult-to-treat psychiatric conditions as panic and vice versa

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REFERENCES 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington, VA: American Psychiatric Association; 2013. 2. Furukawa TA, Katherine Shear M, Barlow DH, et al. Evidence-based guidelines for interpretation of the Panic Disorder Severity Scale. Depress Anxiety. 2009;26(10):922–929. 3. Furukawa TA, Watanabe N, Churchill R. Combined psychotherapy plus antidepressants for panic disorder with or without agoraphobia. Cochrane Database Syst Rev. 2007;(1):CD004364. 4. Otto MW, Tuby KS, Gould RA, et al. An effect-size analysis of the relative efficacy and tolerability of serotonin selective reuptake inhibitors for panic disorder. Am J Psychiatry. 2001;158(12):1989–1992. 5. Pollack MH, Lepola U, Koponen H, et al. A double-blind study of the efficacy of venlafaxine extended-release, paroxetine, and placebo in the treatment of panic disorder. Depress Anxiety. 2007;24(1):1–14. 6. Bakker A, van Balkom AJ, Spinhoven P. SSRIs vs. TCAs in the treatment of panic disorder: a meta-analysis. Acta Psychiatr Scand. 2002;106(3):163–167.

ADDITIONAL READING Kessler RC, Chiu WT, Demler O, et al. Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62(6):617–627.

SEE ALSO Algorithm: Anxiety

CODES ICD10 • F41.0 Panic disorder without agoraphobia • F40.01 Agoraphobia with panic disorder

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• F43.0 Acute stress reaction

CLINICAL PEARLS Encouraging patients (who are medically able) to do 10 minutes of vigorous aerobic exercise the moment a panic attack seems to be starting is often a very effective way to help patients feel safe during panic attacks. Always evaluate a patient with panic for suicidality. Patients with panic disorder are at increased risk for suicide, particularly if depressed.

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PARKINSON DISEASE Donald M. Chaffee, III, MD BASICS DESCRIPTION • Parkinson disease (PD) is a progressive neurodegenerative disorder caused by degeneration of dopaminergic neurons in the substantia nigra pars compacta. • Cardinal symptoms include resting tremor, rigidity, bradykinesia, and postural instability. • Diagnosis is based primarily on history and examination.

EPIDEMIOLOGY Incidence • Average age of onset: ~60 years • Slightly more common in men than women

Prevalence • Second most common neurodegenerative disease after Alzheimer disease • 0.3% of general population and 1–2% of those ≥60 years of age and up to 4% of those ≥80 years of age • Affects approximately 1 million people in the United States and 5 million worldwide

ETIOLOGY AND PATHOPHYSIOLOGY Dopamine depletion in the substantia nigra and the nigrostriatal pathways results in the major motor complications of PD. • Pathologic hallmark: selective loss of dopamine-containing neurons in the pars compacta of the substantia nigra • Loss of neurons accompanied by presence of Lewy bodies, pale bodies (predecessor of the Lewy body), and Lewy neuritis

Genetics Mutations in multiple autosomal dominant and autosomal recessive genes have been linked to PD/parkinsonian syndrome particularly when the age at symptom

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onset is male

ETIOLOGY AND PATHOPHYSIOLOGY • Acute: Staphylococcus aureus (1) most common and Streptococcus pyogenes (1); less frequently, Pseudomonas pyocyanea and Proteus vulgaris. In digits exposed to oral flora especially in pediatric age group, consider Eikenella corrodens, Fusobacterium, and Peptostreptococcus. • Chronic: eczematous reaction with secondary Candida albicans (~95%) (2)

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• A paronychial infection commonly starts in the lateral nail fold. • Recurrent inflammation, persistent edema, and fibrosis of nail folds cause nail folds to round up and retract, exposing nail grooves to irritants, allergens, and pathogens. • Inflammation compromises ability of proximal nail fold to regenerate cuticle leading to decreased vascular supply. This can cause decrease efficacy of topical medications. • Early in the course, cellulitis alone may be present. An abscess can form if the infection does not resolve quickly.

RISK FACTORS • Acute: direct or indirect trauma to cuticle or nail fold, manicure/sculptured nails, nail biting, and thumb sucking and predisposing conditions such as diabetes mellitus (DM) • Chronic: frequent immersion of hands in water with excoriation of the lateral nail fold (e.g., chefs, bartenders, housekeepers, swimmers, dishwashers, nurses), DM, immunosuppression (reported association with antiretroviral therapy for HIV and with use of epidermal growth factor inhibitors) (3)

GENERAL PREVENTION • Acute: Avoid trauma such as nail biting; prevent thumb sucking. • Chronic: Avoid allergens; keep fingers/hands dry; wear rubber gloves with a cotton liner. Prevent excoriation of the skin. • Keep nails short. Avoid manicures. Apply moisturizer after washing hands. • Good glycemic control in diabetic patients

COMMONLY ASSOCIATED CONDITIONS • DM • Eczema or atopic dermatitis • Certain medications: antiretroviral therapy (3) (especially protease inhibitors, indinavir, and lamivudine, in which toes more commonly involved) (3) • Immunosuppression (4)

DIAGNOSIS

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HISTORY • Localized pain or tenderness, swelling, and erythema of posterior or lateral nail folds – Acute: fairly rapid onset – Chronic: 4 to 6 weeks’ duration • Previous trauma (bitten nails, ingrown nails, manicured nails) • Contact with herpes infections • Contact with allergens or irritants (frequent water immersion, latex) (4)

PHYSICAL EXAM • Acute: red, warm, tender, tense posterior or lateral nail fold ± abscess • Chronic: swollen, tender, boggy nail fold ± abscess • Occasional elevation of nail bed • Separation of nail fold from nail plate • Red, painful swelling of skin around nail plate • Fluctuance, purulence at the nail margin, or purulent drainage • Secondary changes of nail platelike discoloration • Suspect Pseudomonas if with green changes in nail (chloronychia) (5). • Positive fluctuation when mild pressure over the area causes blanching and demarcation of the abscess • Chronic: retraction of nail fold and absence of adjacent healthy cuticle, thickening of nail plate with prominent transverse ridges known as Beau lines and discoloration

DIFFERENTIAL DIAGNOSIS • Felon (abscess of fingertip pulp; urgent diagnosis required) • Contact dermatitis • Herpetic whitlow (similar in appearance, very painful, often associated with vesicles) • Acute osteomyelitis of the distal phalanx • Psoriasis especially acute flare • Allergic contact dermatitis (latex, acrylic) • Reiter disease • Pustular psoriasis • Proximal/lateral onychomycosis (nail folds not predominantly involved)

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• Malignancy: squamous cell carcinoma of the nail, malignant melanoma, metastatic disease

DIAGNOSTIC TESTS & INTERPRETATION None required unless condition is severe; resistant to treatment or if recurrence or methicillin-resistant S. aureus (MRSA) is suspected, then • Gram stain • Culture and sensitivity • Potassium hydroxide wet mount plus fungal culture especially in chronic • Drugs that may alter lab results: Use of over-the-counter antimicrobials or antifungals.

Diagnostic Procedures/Other • Incision and drainage recommended for suppurative cases or cases not responding to conservative management or empiric antibiotics • Tzanck testing or viral culture in suspected viral cases • Biopsy in cases not responding to conservative management or when malignancy suspected

TREATMENT GENERAL MEASURES • Acute: warm compresses, elevation, splint protection if pain severe • Chronic: Keep fingers dry; apply moisturizing lotion after hand washing; avoid exposure to irritants; improved diabetic control

MEDICATION First Line • Tetanus booster when indicated • Acute (mild cases, no abscess formation) – Topical antibiotic cream alone or in combination with a topical steroid (6) [B] – Antibiotic cream applied TID–QID after warm| soak (e.g., mupirocin or gentamicin/neomycin/polymyxin B) for 5 to 10 days – If eczematous: low-potent topical steroid applied BID (e.g., betamethasone

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0.05% cream) for 7 to 14 days (7)[B] • Acute (no exposure to oral flora) – Dicloxacillin 250 mg TID for 7 days – Cephalexin 500 mg TID–QID for 7 days • Acute (suspected MRSA) – Trimethoprim/sulfamethoxazole 160 mg/800 mg BID for 7 days – Doxycycline 100 mg BID for 7 days • Acute (exposure to oral flora) – Amoxicillin clavulanate: 875 mg/125 mg BID or 500 mg/125 mg TID for 7 days; pediatric, 45 mg/kg q12h (for 1 recurrence per year, consult otolaryngologist for possible sialendoscopy, duct ligation, ductoplasty, or parotidectomy. • Sialendoscopy with cortisone irrigation is effective and safe for the treatment of juvenile recurrent parotitis (JRP); cortisone irrigation alone may be just as effective; performing parotid ultrasound is recommended first to differentiate JRP from ductal stones (2)[A],(3)[C]. • Sclerotherapy with methyl violet or tetracycline has been shown to be effective in the treatment of cysts in HIV parotitis and is also considered definitive treatment for chronic parotitis (4)[C].

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS Admission is recommended for patients with comorbidities, systemic involvement, and inability to tolerate PO, as well as neonates and patients for whom close outpatient follow-up is not feasible.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Antibiotic therapy initiated at diagnosis combined with adequate hydration should result in improvement within 48 hours. If not, patient should be reevaluated.

DIET • Ensure adequate fluid intake.

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• Hard or sour candies to promote salivary flow

PROGNOSIS • Viral infection in immunocompetent individuals often resolves with excellent prognosis. • Parotid cysts found in HIV-infected patients are usually benign lymphoepithelial lesions with infrequent malignant transformation. • Increased incidence of malignant lymphoma or lymphoepithelial carcinoma may be seen in patients with Sjögren syndrome.

COMPLICATIONS • For mumps, potential complications include orchitis, oophoritis, mastitis, aseptic meningitis, pancreatitis, myocarditis, sensorineural hearing loss, and nephritis. • Untreated bacterial parotitis can lead to local extension, abscess formation, and facial paralysis.

REFERENCES 1. Fiebelkorn AP, Lawler J, Curns AT, et al. Mumps postexposure prophylaxis with a third dose of measles-mumps-rubella vaccine, Orange County, New York, USA. Emerg Infect Dis. 2013;19(9):1411–1417. 2. Ramakrishna J, Strychowsky J, Gupta M, et al. Sialendoscopy for the management of juvenile recurrent parotitis: a systematic review and metaanalysis. Laryngoscope. 2015;125(6):1472–1479. 3. Roby BB, Mattingly J, Jensen EL, et al. Treatment of juvenile recurrent parotitis of childhoods: an analysis of effectiveness. JAMA Otolaryngol Head Neck Surg. 2015;141(2):126–129. 4. Berg EE, Moore CE. Office-based sclerotherapy for benign parotid lymphoepithelial cysts in the HIV-positive patient. Laryngoscope. 2009;119(5):868–870.

ADDITIONAL READING • Armstrong MA, Turturro MA. Salivary gland emergencies. Emerg Med Clin North Am. 2013;31(2):481–499.

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• Brook I. The bacteriology of salivary gland infections. Oral Maxillofac Surg Clin North Am. 2009;21(3):269–274. • Hernandez S, Busso C, Walvekar RR. Parotitis and sialendoscopy of the parotid gland. Otolaryngol Clin North Am. 2016;49(2):381–393. • Rubin S, Eckhaus M, Rennick LJ, et al. Molecular biology, pathogenesis and pathology of mumps virus. J Pathol. 2015;235(2):242–252.

CODES ICD10 • K11.20 Sialoadenitis, unspecified • K11.21 Acute sialoadenitis • K11.23 Chronic sialoadenitis

CLINICAL PEARLS • History and physical exam are usually sufficient for diagnosis (parotid swelling and tenderness with or without purulent drainage from Stensen duct). • In recurrent or chronic cases, consider other underlying etiologies such as HIV. • S. aureus and anaerobes (oral flora) are the most common organisms isolated in acute bacterial parotitis. • Encouraging good oral hygiene and adequate hydration in chronically ill, debilitated, and hospitalized patients can reduce parotitis occurrence.

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PARVOVIRUS B19 INFECTION David L. Anderson, MD • Thomas P. Garigan, MD, MA BASICS DESCRIPTION • Human parvovirus B19 is the primary cause of acute erythema infectiosum (EI, or fifth disease). • Complications in susceptible individuals with increased RBC turnover (e.g., sickle cell anemia [SS]) include transient aplastic crisis (TAC). In immunocompromised individuals, pure red cell aplasia (PRCA) and chronic anemia are significant complications. In normal hosts, arthritis and arthralgias are common. • System(s) affected: hematologic/lymphatic/immunologic, musculoskeletal, skin/exocrine, possibly central nervous system, cardiac, renal

Pregnancy Considerations A documented acute infection during pregnancy should prompt referral to a maternal–fetal medicine specialist. Maternal parvovirus B19 infection between 9 and 20 weeks’ gestation may carry a significant fetal risk.

EPIDEMIOLOGY • Infection is common in childhood. • EI has an extremely low mortality rate. • Peak age for EI is 4 to 12 years. • Males and females are equally affected. • Adult females are more likely to develop postinfectious arthritis. • No known racial predilection • In temperate climates, infections often occur from late winter to early summer. • Local outbreaks may occur every 2 to 4 years.

Prevalence Extremely common in the United States. Based on IgG serology: • 1 to 5 years of age: 2–15% seropositive

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• 6 to 15 years of age: 20–40% seropositive • 16 to 40 years of age: 50–60% seropositive • >40 years of age: 70–85% seropositive

ETIOLOGY AND PATHOPHYSIOLOGY • Small (20 to 25 mm), nonenveloped, single-stranded DNA virus in Parvoviridae family – Only known parvovirus to infect humans; does not cross-infect dogs or cats • Natural host of B19 is human erythroid progenitor. • Respiratory, hematogenous, and vertical transmission are sources of human spread. • 4- to 14-day incubation. Rash and joint symptoms occur 2 to 3 weeks after initial infection. • Most contagious 5 to 10 days after exposure • EI rash thought to be autoimmune due to IgM complexes concurrent with viral clearance. • Cytotoxic infection of proerythroblasts reduces RBC production.

Genetics Erythrocyte P antigen–negative individuals are resistant to infection.

RISK FACTORS • School-related epidemic and nonimmune household contacts have a secondary attack rate of 20–50%. • Highest secondary attack rates are for daycare providers and school personnel in contact with affected children. • Those with increased cell turnover (e.g., hemoglobinopathy, SS, thalassemia) are at risk for TAC. • Immunodeficiency (e.g., HIV, congenital) increases risk of PRAC and chronic anemia. • As many as 40% of pregnant women are not immune. 1.5% seroconversion rate per year

GENERAL PREVENTION • Respiratory spread. Standard measures include hand washing and barrier protection.

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• Droplet precautions are recommended around patients with TAC, chronic infection, or anemia. • Difficult to eliminate exposure because the period of maximal contagion occurs prior to the onset of clinical symptoms (rash). • Pregnant health care workers should avoid caring for patients with TAC. • No significant risk of infection based on occupational exposure. Exclusion from the workplace is neither necessary nor recommended. • No preventive vaccine is available.

COMMONLY ASSOCIATED CONDITIONS • Nondegenerative arthritis – In adults, 80% of patients may manifest polyarthritis and/or arthralgia (female > male). – In children, joint symptoms are less common. – Knees, hands, wrists, and ankles (frequently symmetric) are most commonly involved. – Joint symptoms usually subside within 3 weeks but may persist for months. Routine radiography is not necessary. • TAC – Involves patients with increased RBC turnover (SS, spherocytosis, thalassemia) or decreased RBC production (iron deficiency anemia). – Patients present with fatigue, weakness, lethargy, and pallor (anemia). – Aplastic event may be life-threatening but is typically self-limited. Reticulocytes typically reappear in 7 to 10 days and full recovery in 2 to 3 weeks. – In children with sickle cell hemoglobinopathies and heredity spherocytosis, fever is the most common symptom (73%). Rash is uncommon in these patients. • Chronic anemia – Seen in immunocompromised individuals (HIV, cancer, transplant) with poor IgM response – Usually no clinical manifestations (fever, rash, or joint symptoms) • Fetal/neonatal infection (1) – Risk of transplacental spread of virus is ~33% in infected mothers. – Test pregnant women with a rash or arthralgias consistent with parvovirus

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B19. – Clinical manifestations vary. Many patients are seroconvert without symptoms and have a normal pregnancy. Other patients develop variable degrees of fetal hydrops. 2nd- and 3rd-trimester pregnancy loss can occur without hydrops. – Suspect B19 infection in cases of nonimmune fetal hydrops. – Fetal bone marrow is primarily impacted. RBC survival is shortened, resulting in anemia and (potentially) high-output cardiac failure. – >95% of fetal complications (fetal hydrops and death) occur within 12 weeks of acute maternal parvovirus B19 infection. – Risk of fetal loss is highest (2–5%) in the 1st trimester. – Infants requiring intrauterine transfusions due to parvovirus B19 infection are at risk for long-term neurodevelopmental impairment. • Papular purpuric gloves and socks syndrome (PPGSS) is an uncommon dermatosis associated with parvovirus B19 infection. It results in a petechial and ecchymotic rash of the hands and feet associated with febrile tonsillopharyngitis and oral ulcerations (2).

DIAGNOSIS HISTORY • Rash • Headache • Pharyngitis • Coryza and rhinorrhea • Arthralgias and arthritis • Nausea and GI disturbances are more frequent and severe in adults (nonspecific flulike illness). • Pruritus (especially soles of feet) • Fever, myalgia, and malaise

PHYSICAL EXAM • “Slapped cheek” appearance is a well-known facial rash that spares the nasolabial folds.

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• A lacy, reticular rash on the trunk, buttocks, and limbs often follows 1 to 4 days later lasting 1 to 6 weeks. • The rash may be pruritic and recurrent, exacerbated by bathing, exercise, sun exposure, heat, or emotional stress. • B19 may manifest as painful pruritic papules and purpura on the hands and feet.

DIFFERENTIAL DIAGNOSIS • Rubella • Enteroviral disease • Systemic lupus erythematosus • Drug reaction • Lyme disease • Rheumatoid arthritis

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • No need for routine lab studies in typical cases. Diagnosis is clinical; illness is mild and self-limiting. • IgG and IgM serology in immunocompetent patients • B19-specific DNA polymerase chain reaction (PCR) testing for fetal infection (via cord blood or amniotic fluid) as well as for patients with chronic infection or those who are immunocompromised • PCR increases diagnostic sensitivity and specificity to confirm infections in IgM-negative patients. • For patients with TAC, CBC with reticulocyte count shows anemia and reticulocytopenia. IgM antibodies are present by day 3, and IgG antibodies are detectable at time of clinical recovery. PCR shows high levels of viremia. • Pregnant women exposed to B19 require serial IgG and IgM serology to assess fetal risk. Follow-Up Tests & Special Considerations Fetal/neonatal infection (3)[C] • To exclude congenital B19 in infants with negative B19 IgM, follow IgG serology over the 1st year of life. • Maternal serum α-fetoprotein may be increased with hydrops fetalis.

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• Documented acute maternal infection in the 1st trimester warrants serial fetal ultrasound to assess for hydrops: ascites, pericardial effusion, oligohydramnios, cardiomegaly, and placental thickening. • Weekly peak systolic velocity measurements of the middle cerebral artery by Doppler US is recommended to evaluate for heart failure fetal anemia and the potential need for intrauterine transfusion (>1.5 MoM). • Cerebral MRI to explore CNS damage in infected neonates with prolonged hydrops fetalis or hematocrit 60 years exhibit PLMs but not necessarily PLMD. • No predominant sex: male = female • PLMs in at least 15% of insomnia patients

Prevalence

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• PLMs in sleep: common and usually of no clinical consequence • PLMs constituting PLMD (causing sleep complaints and/or daytime consequences) much less common: 75 ng/mL.

TREATMENT Treatment paradigm similar to that for RLS, except that all medications are offlabel for PLMD (1,2,3)[B].

GENERAL MEASURES • Daily exercise, including evening if desired • Adequate nightly sleep • Warm the legs (long socks, leg warmers, electric blanket, etc.). • Hot bath before bedtime • Assess for and correct iron deficiency • Avoid nicotine and evening caffeine and alcohol.

MEDICATION • Use minimum effective dose. • Goals of medication: – Improve subjective sleep quality. – Eliminate symptoms and sequelae attributed to PLMs.

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• Consider risks, side effects, and interactions individually (e.g., benzodiazepines in elderly). • Low HS dosing minimizes daytime sleepiness side effect. Treatment should decrease instead of increase daytime somnolence.

First Line • Dopamine agonists: Take 1 hour before bed; titrate weekly to optimal dose (1,2,3)[C]: – Pramipexole (Mirapex): 0.125 to 0.5 mg; titrate by 0.125 mg. – Ropinirole (Requip): 0.25 to 4 mg; titrate by 0.25 mg. – Transdermal rotigotine (Neupro): 1 to 3 mg/24 hr patch; initiate with 1 mg/24 hr; titrate by 1 mg weekly to effectiveness. • Avoid dopamine agonists in psychotic patients, especially if taking dopamine antagonists.

Second Line • Voltage-gated calcium channel α2δ subunit ligands: useful for associated neuropathy (1,2,3)[C]: – Gabapentin enacarbil (Horizant): 600 mg/day – Pregabalin (Lyrica): 50 to 300 mg/day • Opioids: low risk for tolerance with bedtime dose – Hydrocodone: 5 to 20 mg/day – Oxycodone: 2.5 to 20 mg/day • Benzodiazepines and agonists (1,3)[C]: – Clonazepam (Klonopin): 0.5 to 3 mg/day – Zaleplon, zolpidem, temazepam, triazolam, alprazolam, diazepam

Pediatric Considerations • First-line treatment is nonpharmacologic. • Assess/correct iron deficiency. • Consider low-dose clonidine.

Pregnancy Considerations • Initial approach: iron supplementation, nonpharmacologic therapies • Avoid medications class C or D. • In 3rd trimester, low-dose opioids may be considered. Monitor for and address

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constipation.

Geriatric Considerations In weak or frail patients, avoid medications that may cause dizziness or unsteadiness.

ADDITIONAL THERAPIES • If iron deficient, iron supplementation: – 325 mg ferrous sulfate with 200 mg vitamin C between meals TID – Repletion may require months. – Symptoms continue without other treatment. • Vitamin/mineral supplements, including calcium, magnesium, vitamin B12, folate • Clonidine: 0.05 to 0.1 mg/day • Relaxis leg vibration device (see http://myrelaxis.com)

SURGERY/OTHER PROCEDURES Correction of orthopedic, neuropathic, or peripheral vascular problems

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Control during recovery from orthopedic procedures • Addition or withdrawal of medications that affect PLMD • Changes in medical status may require medication changes (e.g., Mirapex contraindicated in renal failure and Requip contraindicated in liver disease). • Consider iron infusion when oral supplementation is ineffective, not tolerated, or contraindicated. • When NPO, consider IV opiates. • Evening walks, hot baths, leg warming • Sleep interruption risks prolonged wakefulness.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring

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• At monthly intervals until stable • Annual and PRN follow-up thereafter • If iron deficient, remeasure ferritin to assess repletion.

DIET Avoid caffeine and alcohol late in the day.

PATIENT EDUCATION • National Sleep Foundation: http://sleepfoundation.org/ • American Academy of Sleep Medicine: http://www.sleepeducation.org/

PROGNOSIS • Primary PLMD: lifelong condition with no current cure • Secondary PLMD: may subside with resolution of cause(s) • Current therapies usually control symptoms. • PLMD often precedes emergence of RLS.

COMPLICATIONS • Tolerance to medications requiring increased dose or alternatives • Augmentation (increased PLMs and sleep disturbance, emergence of RLS) from prolonged use of dopamine agonists: – Higher doses increase risk. – Iron deficiency increases risk. – Add alternative medication and then detitrate dopaminergic agent. • Iatrogenic PLMD (from antidepressants, etc.)

REFERENCES 1. Aurora RN, Kristo DA, Bista SR, et al. The treatment of restless legs syndrome and periodic limb movement disorder in adults—an update for 2012: practice parameters with an evidence-based systematic review and meta-analyses: an American Academy of Sleep Medicine Clinical Practice Guideline. Sleep. 2012;35(8):1039–1062. 2. Fulda S. The role of periodic limb movements during sleep in restless legs syndrome: a selective update. Sleep Med Clin. 2015;10(3):241–248. 3. Garcia-Borreguero D, Silber MH, Winkelman JW, et al. Guidelines for the

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first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation. Sleep Med. 2016;21:1–11.

ADDITIONAL READING • Figorilli M, Puligheddu M, Ferri R. Restless legs syndrome/Willis-Ekbom disease and periodic limb movements in sleep in the elderly with and without dementia. Sleep Med Clin. 2015;10(3):331–342. • Goldstein C. Management of restless legs syndrome/Willis-Ekbom Disease in hospitalized and perioperative patients. Sleep Med Clin. 2015;10(3):303–310. • Högl B, Comella C. Therapeutic advances in restless legs syndrome (RLS). Mov Disord. 2015;30(11):1574–1579.

SEE ALSO Restless Legs Syndrome

CODES ICD10 G47.61 Periodic limb movement disorder

CLINICAL PEARLS • Many patients with PLMs may not require treatment; however, when sleep disturbance from PLMs causes insomnia and/or daytime consequences, PLMD exists and should be treated. • Many antidepressants and some antihistamines cause or exacerbate PLMs. • Sleep disturbance, including that from PLMs, may cause or exacerbate ADHD.

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PERIPHERAL ARTERIAL DISEASE Zhen Lu, MD BASICS DESCRIPTION Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis in which there is partial or total blockage in the arteries, exclusive of the coronary and cerebral vessels. Objectively, PAD is defined as a resting ankle-brachial index (ABI) of 40 years • Predominant sex: male > female (2:1), based on the Framingham study • Patients with symptomatic PAD have a 5-year mortality rate of 30%. • Highly prevalent syndrome that affects 8 to 12 million individuals in the United States

Incidence Incidence overall: 1 to 3/1,000/year

Prevalence • U.S. prevalence: 2.7 to 4.1% • Age-adjusted prevalence of PAD is close to 12%. • Up to 29% among patients in primary care practices

ETIOLOGY AND PATHOPHYSIOLOGY • In patients with PAD, arterial stenoses cause inadequate blood flow in distal limbs, which fails to meet the metabolic demand during exertion: – The degree of ischemia is proportional to the size and proximity of the occlusion to the end organ. – Acidic products of anaerobic metabolism build up within the muscle and result in claudication clinically. – Arterial occlusion also causes significantly diminished distal pressure in patients with PAD due to atherosclerotic lesions.

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• Most common cause of arterial stenoses is atherosclerosis.

Genetics Current NIH-funded research focuses on single-nucleotide polymorphisms in candidate genes that are regulated in the vasculature in an attempt to explore genetic factors responsible for PAD.

RISK FACTORS • Age >40 years • Cigarette smoking • Diabetes mellitus • Obesity • Hypertension • Hyperlipidemia • Hyperhomocysteinemia

GENERAL PREVENTION Control risk factors.

COMMONLY ASSOCIATED CONDITIONS • See “Risk Factors.” • Associated with other common complications of atherosclerosis, including myocardial infarction (MI), transient ischemic attack (TIA), stroke, and limb amputation • Occurs in ~40% of patients with cardiovascular disease

DIAGNOSIS HISTORY • Intermittent claudication, with symptoms typically resolving within 2 to 5 minutes of rest (although it is regarded as the classic symptom for PAD, intermittent claudication is present in only 10% of patients with PAD) • Rest leg pain (especially in a supine position) • Skin ulceration (in advanced PAD) • Gangrene (in advanced PAD) • Impotence

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PHYSICAL EXAM • Skin pallor when leg is elevated above the level of the heart (in mild PAD) • Dependent rubor • Dry and scaly skin • Poor nail growth • Hair loss • Reduced/absent extremity pulses (in advanced PAD)

DIFFERENTIAL DIAGNOSIS • Arterial embolism • Deep venous thrombosis • Thromboangiitis obliterans (Buerger disease) • Osteoarthritis • Restless legs syndrome • Peripheral neuropathy • Spinal stenoses (pseudoclaudication) • Intervertebral disc prolapse

DIAGNOSTIC TESTS & INTERPRETATION Serum glucose is recommended screening for diabetes mellitus in suspected or confirmed PAD.

Initial Tests (lab, imaging) • Fasting lipid profile is indicated for risk assessment of hyperlipidemia. • Duplex ultrasonography and Doppler color-flow imaging, which are useful in detecting stenosed segments and assessing lesion severity, are initial imaging tests of choice. • Magnetic resonance angiography, coupled with 3D reconstruction, is highly sensitive and specific for the localization of occluded lesions. • CT scanning has a limited role in the evaluation of PAD. • Angiography remains the gold standard in the diagnosis of PAD.

Diagnostic Procedures/Other • Doppler ABI measures the ratio of the higher systolic BPs between the dorsalis pedis and the posterior tibial artery versus the higher of the systolic BPs in the two brachial arteries: Values for the ABI should be reported as

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“incompressible” if >1.40, “normal” if 1.00 to 1.40, “borderline” if 0.91 to 0.99, and “abnormal” if ≤0.90. ABI 5 ng/mL, sensitivity 92% (6)[B]; not useful for detection of nonperforation secondary peritonitis • Criteria or clinical suspicion for secondary peritonitis necessitates emergent CT scan; not CT diagnostic for secondary peritonitis in 85% of cases (6)[B] – Abdominal or chest x-ray may show free air in peritoneal cavity, large/small bowel dilatation, intestinal wall edema in secondary peritonitis. Follow-Up Tests & Special Considerations • If asymptomatic bacterascites, recent antibiotic exposure, nosocomial atypical organism, or no clinical improvement, repeat paracentesis in 48 hours to determine resolution, defined as decrease in PMNs of 25% or negative cultures (1)[C]. • In hemorrhagic ascites, PMN count corrected by subtracting 1 PMN per 250 RBCs (3)[A].

TREATMENT GENERAL MEASURES • For SBP, control the effects of cirrhosis/ascites with salt restriction, spironolactone +/− furosemide, albumin infusion after large volume paracentesis, and/or lactulose for encephalopathy (6)[A]. • Avoid nephrotoxic medications (e.g., NSAIDs) or other renal insults (5)[C].

MEDICATION • SBP – Community-acquired SBP without recent β-lactam antibiotic use: 3rdgeneration cephalosporins, preferably cefotaxime, 2 g IV q8h for 5 days (6)

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[A] – SBP in absence of previous quinolone use/prophylaxis, vomiting, shock, hepatic encephalopathy, or serum creatinine >3 mg/dL: ofloxacin 400 mg PO can be substituted for cefotaxime (6)[B]. – Nosocomial SBP or recent β-lactam antibiotic: empiric therapy based on local susceptibility of patients with cirrhosis for resistant bacteria (6)[B] – Symptomatic bacterascites with PMN count 1 mg/dL, BUN >30 mg/dL, or total bilirubin >4 mg/dL): Add albumin 1.5 g/kg within 6 hours and 1 g/kg on day 3 (1)[A],(6)[B]. • Secondary bacterial peritonitis – Empiric broad spectrum antibiotic coverage for polymicrobial infection; IV cefotaxime or other 3rd- to 4th-generation cephalosporin plus metronidazole is one option for an initial regimen. – In peritoneal dialysis–associated infection, intraperitoneal route superior to IV. • Tertiary bacterial peritonitis – If no unrepaired perforations or leaks, then continue with medical management. This includes antibiotics (guided by prior susceptibilities) and early enteral nutrition to prevent atrophy and maintain immunocompetence (2)[B]. – In recurrent or persistent peritoneal dialysis–associated infection, removal of the PD catheter is warranted.

SURGERY/OTHER PROCEDURES • SBP – Medical management • Secondary bacterial peritonitis – Emergent surgical management, including source control with open laparotomy to repair any perforated viscus and eradicate infected material, is first-line treatment (2)[A],(6)[B].

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• Tertiary bacterial peritonitis – If no unrepaired perforations or leaks, additional surgery for severe abdominal infection is correlated with deterioration and significant mortality (2).

ALERT Mortality of secondary bacterial peritonitis approaches 100% if not treated surgically, whereas the mortality of SBP approaches 80% if the patient receives unnecessary exploratory laparotomy (1,3).

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Acute peritonitis typically warrants inpatient admission. • In patients with cardiogenic or septic shock, use invasive monitoring with early goal-directed fluid therapy. • Patients who present with peritonitis can be severely hypovolemic. In these cases, volume resuscitation is critical. In patients with significant renal or hepatic dysfunction, albumin decreases mortality (1)[A],(6)[B]. • Cirrhotic patients often take β-blockers as part of their outpatient regimen, but during an episode of SBP, β-blockers increase mortality, hepatorenal syndrome, and hospital stay in SBP patients (6)[B]. • Nasogastric tube placement can prevent aspiration in patients with vomiting or GI bleeding.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring Normalization of vital signs with resolution of leukocytosis indicates improvement. • SBP: If follow-up paracentesis is performed after 48 hours to evaluate resolution, PMN decrease >25% is expected. • Development of leukopenia indicates immune exhaustion and poor prognosis.

DIET

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• NPO, total parental nutrition as necessary • Resume enteral feeding after return of bowel function. • Sodium restriction can reduce future ascites (3)[A].

PROGNOSIS • SBP – For inpatients with first episode of SBP, mortality ranges from 10% to 50% (3). – Prognosis is improved if antibiotics are started early, prior to onset of shock or renal failure. – Strongest negative prognostic indicator is renal insufficiency. – Other poor prognostic factors include nosocomial acquisition, old age, high Child-Pugh-Turcotte or MELD score, malnutrition, malignancy, peripheral leukopenia, and antibiotic resistance (3). – Patients with prior SBP have 1-year recurrence rate of 40–70% and 1-year mortality of 31–93% (1,3). • Secondary bacterial peritonitis: – In-hospital mortality of treated patients is 67% (4). – Mortality approaches 100% if not treated surgically, especially if secondary to perforation (2,4). – Prognosis is worse in perforated etiologies.

COMPLICATIONS • Renal failure, liver failure, encephalopathy, coagulopathy • Secondary infection, iatrogenic infection, abscess, fistula formation, abdominal compartment syndrome • Sepsis/septic shock, cardiovascular collapse, adrenal insufficiency, respiratory failure, ARDS

REFERENCES 1. Alaniz C, Regal RE. Spontaneous bacterial peritonitis: a review of treatment options. P T. 2009;34(4):204–210. 2. Panhofer P, Izay B, Riedl M, et al. Age, microbiology and prognostic scores help to differentiate between secondary and tertiary peritonitis. Langenbecks

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Arch Surg. 2009;394(2):265–271. 3. Wiest R, Krag A, Gerbes A. Spontaneous bacterial peritonitis: recent guidelines and beyond. Gut. 2012;61(2):297–310. 4. Soriano G, Castellote J, Alvarez C, et al. Secondary bacterial peritonitis in cirrhosis: a retrospective study of clinical and analytical characteristics, diagnosis and management. J Hepatol. 2010;52(1):39–44. 5. Dever JB, Sheikh MY. Review article: spontaneous bacterial peritonitis— bacteriology, diagnosis, treatment, risk factors and prevention. Aliment Pharmacol Ther. 2015;41(11):1116–1131. 6. Runyon, B; AASLD. Introduction to the revised American Association for the Study of Liver Diseases practice guideline management of adult patients with ascites due to cirrhosis 2012. Hepatology. 2013;57(4):1651–1653.

ADDITIONAL READING • Bajaj JS, O’Leary JG, Wong F, et al. Bacterial infections in end-stage liver disease: current challenges and future directions. Gut. 2012;61(8):1219–1225. • Ballinger A, Palmer SC, Wiggins KJ, et al. Treatment for peritoneal dialysisassociated peritonitis. Cochrane Database Syst Rev. 2014;(4):CD005284. • Chaulk J, Carbonneau M, Qamar H, et al. Third-generation cephalosporinresistant spontaneous bacterial peritonitis: A single-centre experience and summary of existing studies. Can J Gastroenterol Hepatol. 2014;28(2):83–88. • Cheong HS, Kang CI, Lee JA, et al. Clinical significance and outcome of nosocomial acquisition of spontaneous bacterial peritonitis in patients with liver cirrhosis. Clin Infect Dis. 2009;48(9):1230–1236. • Deshpande A, Pasupuleti V, Thota P, et al. Acid-suppressive therapy is associated with spontaneous bacterial peritonitis in cirrhotic patients: a metaanalysis. J Gastroenterol Hepatol. 2013;28(2):235–242. • Jain P. Spontaneous bacterial peritonitis: few additional points. World J Gastroenterol. 2009;15(45):5754–5755. • Mandorfer M, Bota S, Schwabl P, et al. Nonselective β blockers increase risk for hepatorenal syndrome and death in patients with cirrhosis and spontaneous bacterial peritonitis. Gastroenterology. 2014;146(7):1680.e1–1690.e1.

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SEE ALSO Appendicitis, Acute; Cirrhosis of the Liver; Diverticular Disease; Peptic Ulcer Disease

CODES ICD10 • K65.0 Generalized (acute) peritonitis • K65.2 Spontaneous bacterial peritonitis • K65.8 Other peritonitis

CLINICAL PEARLS • Maintain a high index of suspicion for SBP in cirrhotic patients with ascites as up to 30% of cases may be asymptomatic. • Paracentesis is necessary to diagnose SBP. Ascitic fluid cultures collected via bedside inoculation with blood culture bottles prior to antibiotic administration increases culture yield significantly. • E. coli continues to be the most common bacterial isolate from cases of SBP, and 3rd-generation cephalosporins remain first-line treatment, but the incidence of gram-positive and resistant organisms is increasing. • Ascitic fluid analysis is essential to stratify patients that may be at risk for secondary peritonitis and in need of additional imaging. Emergent CT scan should be performed if there is suspicion based on history and/or ascitic fluid analysis. • Renal function is an important prognostic indicator for SBP. Albumin administration decreases the incidence of renal failure and mortality in patients with renal or hepatic impairment or large-volume paracentesis.

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PERSONALITY DISORDERS Moshe S. Torem, MD, DLFAPA BASICS DESCRIPTION • Personality disorders (PDs) are a group of conditions, with onset at or before adolescence, characterized by enduring patterns of maladaptive and dysfunctional behavior that deviates markedly from one’s culture and social environment, leading to functional impairment and distress to the individual, coworkers, and family. – These behaviors are perceived by patients to be “normal” and “right,” and they have little insight as to their ownership, responsibility, and abnormal nature of these behaviors. – These conditions are classified based on the predominant symptoms and their severity. • System(s) affected: nervous/psychiatric • Synonym(s): character disorder; character pathology

Geriatric Considerations Coping with the stresses of aging is challenging.

Pediatric Considerations A history of childhood neglect, abuse, and trauma is not uncommon.

Pregnancy Considerations Pregnancy adds pressures in coping with the activities of daily living (ADLs).

EPIDEMIOLOGY Prevalence • General population: 15% (1) • Cluster A: 5.7% • Cluster B: 6.0% • Cluster C: 9.1% • Outpatient psychiatric clinic: 3–30% (2)

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• In male prisoners, the prevalence of antisocial personality disorder is ~60%. • Predominant age: starts in adolescence and early 20s and persists throughout patient’s life • Predominant sex: male = female; some PDs are more common in females, and others are more common in males.

ETIOLOGY AND PATHOPHYSIOLOGY • Environmental and genetic factors (3) • Criteria for a PD includes an enduring pattern of the following: – Inner experience and behavior that deviates markedly from the expectations of one’s culture in ≥2 of the following areas: cognition, affectivity, interpersonal functioning, or impulse control – Inflexibility and pervasiveness across a broad range of personal and social situations – Significant distress or impairment in social or occupational functioning – The pattern is stable and of long duration. – The enduring pattern is not better explained as a manifestation of another psychiatric disorder. – The enduring pattern is not attributable to the effects of a drug or a medical condition. • PDs are classified into three major clusters: – Cluster A: eccentricity and oddness Paranoid PD: unwarranted suspiciousness and distrust of others Schizoid PD: emotional, cold, or detached; socially isolated Schizotypal PD: eccentric behavior, odd belief system/perceptions, social isolation, and general suspiciousness – Cluster B: dramatic, emotional, or erratic behavioral patterns Antisocial PD: aggressive, impulsive, irritable, irresponsible, dishonest, deceitful Borderline PD: unstable interpersonal relationships, high impulsivity from early adulthood, intense fear of abandonment, mood swings, poor self-esteem, chronic boredom, and feelings of inner emptiness Histrionic PD: needs to be the center of attention, with self-dramatizing behaviors and attention seeking in a variety of contexts Narcissistic PD: grandiose sense of self-importance and preoccupation

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with fantasies of success, power, brilliance, beauty, or ideal love; lack of empathy for other people’s pain or discomfort, demanding to get their way – Cluster C: anxiety, excessive worry, fear, and unhealthy patterns of coping with emotions Avoidant PD: social inhibition, feelings of inadequacy, hypersensitivity to negative evaluation, avoidance of occupational and interpersonal activities that involve the risk of criticism by others, views self as socially inept and personally unappealing or inferior to others Dependent PD: excessive need to be taken care of, leading to submissive and clinging behavior with fears of separation, avoids expressing disagreements with others due to fear of losing support and approval, usually seeks out strong and confident people as friends or spouses and feels more secure in such relationships Obsessive-compulsive PD: preoccupation with cleanliness, orderliness, perfectionism; preoccupation with excessive details, rules, lists, order, organization, and schedules to the extent that the major point of the activity is lost – Personality change due to another medical condition. It is a persistent personality disturbance that is caused by the physiologic effects of a medical condition such as frontal lobe lesion, epilepsy, MS, Parkinson disease, lupus, head trauma, postencephalitis or meningitis, and so forth. – Other specified PD and unspecified PD: A category provided for two situations: (i) the individual’s personality pattern meets the general criteria for PD and traits of several PDs are present, but the criteria for any specific PD are not met; (ii) the individual’s personality pattern meets the general criteria for PD, but the individual is considered to have a PD that is not included in DSM-5 classification such as passive-aggressive PD, depressive PD, masochistic PD, and dangerous and severe PD.

Genetics Major character traits are inherited; others result from a combination of genetics and environment.

RISK FACTORS

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• Positive family history • Pregnancy risk factors – Nutritional deprivation – Use of alcohol or drugs – Viral and bacterial infections • Dysfunctional family with child abuse/neglect

COMMONLY ASSOCIATED CONDITIONS Depression; other psychiatric disorders in patient and family members

DIAGNOSIS HISTORY • Comprehensive interview and mental status examination • Screen to rule out alcohol and drug abuse. • Interview of relatives and friends is helpful in establishing an enduring pattern of behavior.

DIAGNOSTIC TESTS & INTERPRETATION Psychological testing (e.g., MMPI-II)

Initial Tests (lab, imaging) • CBC • Comprehensive metabolic panel • Thyroid-stimulating hormone • HIV • Toxicology screen for substance abuse Follow-Up Tests & Special Considerations • EEG to rule out a chronic seizure disorder • CT and MRI of the brain may be necessary in newly developed symptoms to rule out organic brain disease (e.g., frontal lobe tumor).

DIAGNOSTIC TESTS & INTERPRETATION • Medical disorders with behavioral changes • Other psychiatric disorders with similar symptoms

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– In obsessive-compulsive disorder (OCD), symptoms are ego-dystonic (i.e., perceived as foreign and unwanted). In addition, OCD has a pattern of relapse and partial remission. – In obsessive-compulsive personality disorder (OCPD), symptoms are perceived as desirable behaviors (ego-syntonic) that the patient feels proud of and wants others to emulate. In addition, OCPD has a lifelong pattern (i.e., without significant relapse or remission).

TREATMENT Psychotherapy with family involvement is the foundation of treatment. No specific drugs are indicated to treat PDs; some medications can reduce the intensity, frequency, and dysfunctional nature of certain behaviors (4)[B].

GENERAL MEASURES • Long-term psychotherapy and cognitive-behavioral therapy (5)[B] • Group therapy is helpful in the use of therapeutic confrontation and increasing one’s awareness of and insight regarding the damaging effects of dysfunctional behavior patterns (6)[B].

MEDICATION Medications are effective in the treatment of comorbid conditions such as anxiety and depression.

First Line • Symptom management (7)[B] – Minipsychosis (associated with paranoid, schizoid, borderline, and schizotypal PDs): atypical antipsychotics: risperidone (Risperdal), quetiapine (Seroquel), olanzapine (Zyprexa), ziprasidone (Geodon), aripiprazole (Abilify), asenapine (Saphris), lurasidone (Latuda); start with a low dose, gradually adjusting to the patient’s needs. – Anxiety: anxiolytics (benzodiazepines, buspirone [Buspar], and serotonin reuptake inhibitors) – Depressed mood: antidepressants – Many patients with borderline PD respond well to small doses of atypical

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neuroleptics and mood stabilizers (8)[B]. • Precautions: Some atypical neuroleptic drugs may be associated with hyperglycemia and insulin-resistant metabolic syndrome.

Second Line Mood stabilizers: lithium carbonate, lamotrigine (Lamictal), carbamazepine (Tegretol, Equetro), and valproate (Depacon, Depakene, Depakote) (9)[B]

ISSUES FOR REFERRAL • When psychiatric comorbidity of other psychiatric disorders is present (e.g., mood disorders, anxiety disorders, substance abuse) • Suicidal ideation or attempts • Presence of psychotic symptoms • Thoughts and impulses for violent behavior • Management of complex pharmacotherapy • Presence of intense countertransference feelings • When the patient or family requests it

ADDITIONAL THERAPIES • Cognitive-behavioral therapy • Dialectical behavior therapy • Psychoanalytic therapy • Interactive psychotherapy • Ego-State therapy • Mindfulness-based psychotherapy • Group therapy

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS Disorders with complications of suicide attempts and other behaviors involving a risk to self or others

ONGOING CARE FOLLOW-UP RECOMMENDATIONS

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Continue outpatient treatment, potentially long term.

Patient Monitoring • Regular physical exercise (e.g., 30 to 60 min/day, helps with stress and improving the ADLs) • If substance abuse is suspected, check drug screens. • Infrequent sessions with relatives or friends are helpful in monitoring behavioral progress.

DIET Emphasize variety of healthy foods; avoid obesity.

PATIENT EDUCATION • Bibliotherapy and writing therapy, specific assignments, and watching certain movies to better understand the nature and origin of one’s specific condition are helpful. – Kreger R. The Essential Family Guide to Borderline Personality Disorder. Center City, MN: Hazelden; 2008. – Mason PT, Kreger R. Stop Walking on Eggshells. Oakland, CA: New Harbinger Publishers; 2010. • The movie As Good as It Gets illustrates someone with obsessive-compulsive behaviors and their impact on ADLs and relationships with family and friends. • The movie series The Godfather includes several characters with antisocial PD and shows how this affects their interpersonal relationships and their own physical and mental health. • The movie What About Bob? illustrates the challenges involved in treating certain patients with a borderline PD, especially in the management of boundaries in the doctor–patient relationship. • The movie A Streetcar Named Desire illustrates an example of a woman with a histrionic PD. • The movie Wall Street illustrates an example of a person with a narcissistic PD. • The movie The Caine Mutiny illustrates an example of a person with a paranoid PD. • The movie Four Weddings and a Funeral illustrates an example of a person

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with an avoidant PD.

PROGNOSIS PDs are enduring patterns of behavior throughout one’s lifetime and are not readily responsive to brief therapies.

COMPLICATIONS • Disruptive family life with frequent divorces and separations, alcoholism, substance abuse, and drug addiction • Disruptive behaviors in the workplace may cause absenteeism and loss of productivity. • Violation of the law and disregard for the concerns and rights of others

REFERENCES 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013:645–684. 2. Angstman KB, Rasmussen NH. Personality disorders: review and clinical application in daily practice. Am Fam Physician. 2011;84(11):1253–1260. 3. Reichborn-Kjennerud T. Genetics of personality disorders. Clin Lab Med. 2010;30(4):893–910. 4. Hadjipavlou G, Ogrodniczuk JS. Promising psychotherapies for personality disorders. Can J Psychiatry. 2010;55(4):202–210. 5. Clarkin JF. An integrated approach to psychotherapy techniques for patients with personality disorder. J Pers Disord. 2012;26(1):43–62. 6. Livesley WJ. Integrated treatment: a conceptual framework for an evidencebased approach to the treatment of personality disorder. J Pers Disord. 2012;26(1):17–42. 7. Ripoll LH, Triebwasser J, Siever LJ. Evidence-based pharmacotherapy for personality disorders. Int J Neuropsychopharmacol. 2011;14(9):1257–1288. 8. Ripoll LH. Clinical psychopharmacology of borderline personality disorder: an update on the available evidence in light of the Diagnostic and Statistical Manual of Mental Disorders-5. Curr Opin Psychiatry. 2012;25(1):52–58. 9. Lieb K, Völlm B, Rücker G, et al. Pharmacotherapy for borderline personality disorder: Cochrane systematic review of randomised trials. Br J

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Psychiatry. 2010;196(1):4–12.

ADDITIONAL READING • Bateman AW, Gunderson J, Mulder R. Treatment of personality disorder. Lancet. 2015; 385(9969):735–743. • Gerlach G, Loeber S, Herpertz S. Personality disorders and obesity: a systematic review. Obes Rev. 2016;17(8):691–723. • Sng AA, Janca A. Mindfulness for personality disorders. Curr Opin Psychiatry. 2016;29(1):70–76. • Tyrer P, Reed GM, Crawford M. Classification, assessment, and effect of personality disorder. Lancet. 2015; 385(9969):717–726. • Widiger TA. Assessment of DSM-5 personality disorder. J Pers Assess. 2015;97(5):456–466.

SEE ALSO Obsessive-Compulsive Disorder (OCD)

CODES ICD10 • F60.9 Personality disorder, unspecified • F60.0 Paranoid personality disorder • F60.1 Schizoid personality disorder

CLINICAL PEARLS • PDs are enduring patterns of behavior throughout one’s lifetime and are not readily responsive to brief treatments. • In spite of the initial lack of self-awareness and accepting responsibility for one’s dysfunctional behaviors, many patients can benefit from long-term treatment. • No specific drugs are effective to treat PDs; however, specific medications can reduce the intensity, frequency, and dysfunctional nature of certain behaviors,

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thoughts, and feelings. • Patients with a personality disorder frequently elicit intense feelings in others, such as anger, hostility, likability, or sexual attraction. • Health care professionals must be alert to potential blurring of interpersonal boundaries in the clinical care of these patients. • Most patients with a PD require a well-trained and experienced mental health professional. • A stable, trustful alliance with the patient is the foundation for any therapeutic progress. • Many PD patients begin treatment in a crisis involving symptoms of anxiety, fear of abandonment, depressed mood, and intense interpersonal conflict at home or work. The focus at this initial phase of treatment should be symptom control and behavioral stabilization with restoration of hope. • Lifelong pattens of dysfunctional behaviors should not be confronted at the initial phase of treatment. • Therapeutic confrontation of dysfunctional behavioral patterns is effective only after a working and therapeutic alliance has been established. • Showing genuine interest in the patient as a whole person including the patient’s life history and current life circumstances may be helpful in establishing a therapeutic and working alliance that is necessary for continuing treatment of PD patients. • Regular meetings with a spouse, another family member, or significant other are essential for receiving feedback on therapeutic progress.

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PERTUSSIS Mary Cataletto, MD, FAAP, FCCP • Margaret J. McCormick, MS, RN, CNE BASICS Highly contagious disease; aka whooping cough

DESCRIPTION • Human host: adults most common reservoir • Can affect all ages • Worldwide distribution • May be endemic or epidemic with outbreaks every 3 to 5 years • Seasonality: can occur year-round; peaks late summer–autumn • Transmission: person to person via aerosolized respiratory droplets • Effective vaccine available but neither vaccine nor infection confer lifelong or 100% immunity. • System(s) affected: respiratory • Synonym(s): whooping cough

EPIDEMIOLOGY Incidence 2012 was the most recent peak year with 48,277 reported cases in the United States (1)

ETIOLOGY AND PATHOPHYSIOLOGY • Toxin mediated • Infectious process with predilection for ciliated respiratory epithelium • Bordetella pertussis (responsible for ~95% of cases) • Bordetella parapertussis

RISK FACTORS • Exposure to a confirmed case • Non- or underimmunized infants and children • Pregnancy

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• Premature birth • Chronic lung disease • Immunodeficiency (e.g., AIDS) • Infants 1; glucose 80% predominance effusion; elevated levels of adenosine deaminase >50 U/L and interferon-γ >140 pg/mL; positive acid-fast bacillus (AFB) stain, culture; total protein >4 g/dL, nuclear acid amplification (NAA), LDH levels elevated in about 75% of patients (often >500 units/L) • Chylothorax: milky; triglycerides >110 mg/dL; lipoprotein electrophoresis (chylomicrons) • Amebic liver abscess: anchovy paste effusion; Waldenström macroglobulinemia and multiple myeloma: protein >7 g/dL • Esophageal rupture: high salivary amylase; pleural fluid acidosis, pH 7.3: rheumatoid pleurisy, empyema, malignant effusion, TB, esophageal rupture, or lupus nephritis • Mesothelial cells in exudates: TB is unlikely if there are >5% of mesothelial cells. • S. pneumoniae accounts for 50% of cases of parapneumonic effusions in AIDS patients, followed by Staphylococcus aureus, Haemophilus influenzae, Mycoplasma pneumoniae, Legionella, Nocardia, and Bordetella bronchiseptica. Exudate with low count of nucleated cells. • Pneumocystis jirovecii is an uncommon cause in HIV. Usually it is a small effusion, unilateral or bilateral, and serous to bloody in appearance. Demonstration of the trophozoite or cyst is mandatory. • Cancer-related HIV pleural effusion: Kaposi sarcoma, Castleman disease, and primary effusion lymphoma. Kaposi sarcoma: mononuclear predominance, exudate, pH >7.4; LDH, 111 to 330 IU/L; glucose >60 mg/dL. • Chest x-ray (CXR): posteroanterior–anteroposterior views – Upright x-rays show a concave meniscus in the costophrenic angle that suggests >250 mL of pleural fluid; homogeneous opacity, with visibility of pulmonary vessels through diffuse haziness and absence of air bronchogram; 75 mL of fluid will obliterate the posterior costophrenic sulcus. – Lateral x-rays show blunting of the posterior costophrenic angle and the posterior gutter; decubitus x-rays to exclude a loculated effusion and underlying pulmonary lesion or pulmonary thickening – Supine x-rays show costophrenic blunting, haziness, obliteration of the diaphragmatic silhouette, decreased visibility of the lower lobe vasculature, and widened minor fissure. • Ultrasonography (US): detects as 5 to 50 mL of pleural fluid; identifies loculated effusions; site for thoracocentesis, pleural biopsy, or pleural drainage • Chest CT scan with contrast for patients with undiagnosed pleural effusion. CT pulmonary angiography if PE is suspected.

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Follow-Up Tests & Special Considerations 75% of patients with exudative effusions have a non-CHF cause. • NT-ProBNP: biomarker of CHF-associated effusion; >1,500 pg/mL; sensitivity and specificity 94% (2)[A] • Observation in uncomplicated asymptomatic patients (i.e., CHF, cirrhosis), viral pleurisy, thoracic or abdominal surgery

Diagnostic Procedures/Other Diagnostic thoracentesis indicated for the following: • Clinically significant pleural effusion (>10 mm thick on US or lateral decubitus x-ray with no known cause) • CHF: asymmetric effusion, fever, chest pain, or failure to resolve after diuretics • Parapneumonic effusions

TREATMENT Oxygen support

GENERAL MEASURES • Therapeutic thoracentesis, if symptomatic • Chest tube thoracostomy drainage: >1/2 hemithorax; complicated parapneumonic effusion (positive Gram stain or culture, pH 19 years, previously given PPSV23 should receive a PPCV13 dose ≥1 year after last PPSV23. If additional PPSV23 is required, it should be given ≥8 weeks after PCV13 and 5 years after most recent dose of PPSV23. • Annual influenza vaccine

DIAGNOSIS History • Fever, chills, rigors, malaise, fatigue • Dyspnea

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• Cough, with/without sputum • Pleuritic chest pain • Myalgias • GI symptoms

ALERT High fever (>104°F [40°C]), male sex, multilobar involvement, and GI and neurologic abnormalities have been associated with CAP caused by Legionella.

Geriatric Considerations Older adults with pneumonia often present with weakness, mental status change, or history of falls.

PHYSICAL EXAM • Fever >100.4°F (38°C), tachypnea, tachycardia • Rales, rhonchi, egophony, increased fremitus, bronchial breath sounds, dullness to percussion, asymmetric breath sounds, abdominal tenderness

DIFFERENTIAL DIAGNOSIS Bronchitis, asthma exacerbation, pulmonary edema, lung cancer, pulmonary tuberculosis, pneumonitis

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Routine laboratory testing to establish an etiology in outpatients with CAP is usually unnecessary. • For hospitalized patients with CAP, a CBC, sputum Gram stain, procalcitonin, and two sets of blood cultures • More extensive diagnostic testing in patients with CAP is recommended if: – Blood cultures: ICU admission, cavitary infiltrates, leukopenia, alcohol abuse, severe liver disease, asplenia, positive pneumococcal urine antigen test (UAT), pleural effusion – Sputum Gram stain and cultures: ICU admission, failure of outpatient treatment, cavitary infiltrates, alcohol abuse, severe COPD/structural lung disease, positive Legionella UAT, positive pneumococcal UAT, pleural effusion

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– Legionella UAT: ICU admission, failure of outpatient treatment, alcohol abuse, travel in past 2 weeks, pleural effusion – Pneumococcal UAT: ICU admission, failure of outpatient treatment, leukopenia, alcohol abuse, severe liver disease, asplenia, pleural effusion • A chest x-ray (CXR) is indicated when pneumonia is suspected or with an acute respiratory infection and – Vital signs: temperature >100°F (37.8°C); heart rate (HR) >100 beats/min; respiratory rate (RR) >20 breaths/min – At least two of the following clinical findings: decreased breath sounds, rales, no asthma • Early in disease course, CXR may be negative. • Evidence of necrotizing/cavitary pneumonia should raise suspicion for MRSA pneumonia, especially with history of prior MRSA skin lesions.

Diagnostic Procedures/Other • For VAP/HAP: By bronchoscopic or nonbronchoscopic means, obtain a lower respiratory tract sample for culture prior to initiation/change of therapy. Serial evaluations may be needed (2)[A]. • Safe cessation of antibiotics can be done from a good quality negative sputum culture.

TREATMENT MEDICATION First Line • Adults – CAP, outpatient No significant differences in efficacy between antibiotic option in adults Previously healthy, no antibiotics in past 3 months Azithromycin 500 mg PO 1 time, then 250 mg PO daily for 4 days; clarithromycin 500 mg PO BID for 10 days; erythromycin 500 mg PO BID for 10 days, or Doxycycline 100 mg PO BID for 10 days Comorbid conditions, immunosuppressed, antibiotic use in past 3 months

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Levofloxacin 750 mg PO daily for 5 days; moxifloxacin 400 mg PO daily for 5 days; or Amoxicillin 1 g PO TID; amoxicillin-clavulanate 2 g PO BID + macrolide/doxycycline for 5 days Treatment may be stopped if Afebrile for >48 hours Supplemental oxygen no longer needed No more than one of the following: • HR >100 beats/min • RR >24 breaths/min • Systolic blood pressure (BP) ≤90 mm Hg – CAP, inpatient (non-ICU) IV antibiotics initially, then switch to oral after clinical improvement Treatment duration depends on clinical improvement. Cefotaxime; ceftriaxone; ampicillin-sulbactam + macrolide (clarithromycin; erythromycin) for 5 to 14 days or Moxifloxacin; levofloxacin for 5 to 14 days If Pseudomonas is a consideration Piperacillin-tazobactam; cefepime; imipenem; meropenem + levofloxacin or Piperacillin-tazobactam; cefepime; imipenem; meropenem + aminoglycoside and azithromycin or Piperacillin-tazobactam; cefepime; imipenem; meropenem + aminoglycoside + levofloxacin If MRSA is a consideration – Add vancomycin or linezolid HCAP/HAP/VAP. Use IV antibiotics. Early onset (65 years) (http://www.mdcalc.com/curb-65-severity-score-community-acquiredpneumonia/) is a severity of illness score for stratifying adults with CAP into different management groups. • The SMART-COP (systolic BP, multilobar chest radiography, albumin, RR, tachycardia, confusion, oxygen level, and arterial pH) is a new method to predict which patients will require intensive respiratory/vasopressor support. A score of ≥3 has sensitivity of 92% to identify those patients who will receive intensive treatment. • Patients with COPD or CHF are more likely to require ICU admission when suffering from CAP. • Clinical prediction tools do not replace a physician’s clinical judgment.

Pediatric Considerations Inpatient treatment of children is recommended in the following settings: infants ≤3 to 6 months; presence of respiratory distress (tachypnea, dyspnea, retractions, grunting, nasal flaring, apnea, altered mental status, O2 sat 0.6 mg/dL – Serum albumin 200 cells/μL for at least 3 months.

Patient Monitoring Serum lactate dehydrogenase levels, pulmonary function test results, and ABG measurements generally normalize with treatment.

DIET No special diet needed

PATIENT EDUCATION • Centers for Disease Control and Prevention: www.cdc.gov/ncidod/dpd/parasites/pneumocystis/default.htm • FamilyDoctor.org: http://familydoctor.org/familydoctor/en/diseasesconditions/hiv-and-aids/complications/pneumocystis-pneumonia-pcp-andhiv.html

REFERENCES 1. Catherinot E, Lanternier F, Bougnoux ME, et al. Pneumocystis jiroveci

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pneumonia. Infect Dis Clin North Am. 2010;24(1):107–138. 2. Limper AH, Knox KS, Sarosi GA, et al. An official American Thoracic Society statement: treatment of fungal infections in adult pulmonary and critical care patients. Am J Respir Crit Care Med. 2011;183(1):96–128. 3. D’Avignon LC, Schofield CM, Hospenthal DR. Pneumocystis pneumonia. Semin Respir Crit Care Med. 2008;29(2):132–140. 4. Krajicek BJ, Thomas CF Jr, Limper AH. Pneumocystis pneumonia: current concepts in pathogenesis, diagnosis, and treatment. Clin Chest Med. 2009;30(2):265–278. 5. Kovacs JA, Masur H. Evolving health effects of Pneumocystis: one hundred years of progress in diagnosis and treatment. JAMA. 2009;301(24):2578– 2585. 6. Skelly MJ, Holzman RS, Merali S. S-adenosylmethionine levels in the diagnosis of Pneumocystis carinii pneumonia in patients with HIV infection. Clin Infect Dis. 2008;46(3):467–471. 7. Briel M, Bucher HC, Boscacci R, et al. Adjunctive corticosteroids for Pneumocystis jiroveci pneumonia in patients with HIV-infection. Cochrane Database Syst Rev. 2006;(3):CD006150. 8. Fei WM, Kim EJ, Sant CA, et al. Predicting mortality from HIV-associated Pneumocystis pneumonia at illness presentation: an observational cohort study. Thorax. 2009;64(12):1070–1076.

ADDITIONAL READING • Benson CA, Kaplan JE, Masur H, et al. Treating opportunistic infections among HIV-infected adults and adolescents: recommendations from CDC, the National Institutes of Health, and the HIV Medicine Association/Infectious Disease Society of America. MMWR Recomm Rep. 2004;53(RR-15):1–112. • Green H, Paul M, Vidal L, et al. Prophylaxis for Pneumocystis pneumonia (PCP) in non-HIV immunocompromised patients. Cochrane Database Syst Rev. 2007;(3):CD005590. • Kaplan JE, Masur H, Holmes KK. Guidelines for preventing opportunistic infections among HIV-infected persons—2002. Recommendations of the U.S. Public Health Service and the Infectious Disease Society of America. http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5108a1.htm. Accessed

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October 3, 2016. • Shankar SM, Nania JJ. Management of Pneumocystis jiroveci pneumonia in children receiving chemotherapy. Paediatr Drugs. 2007;9(5):301–309. • Stringer JR, Beard CB, Miller RF, et al. A new name (Pneumocystis jiroveci) for Pneumocystis from humans. Emerg Infect Dis. 2002;8(9):891–896.

SEE ALSO HIV/AIDS

CODES ICD10 B59 Pneumocystosis

CLINICAL PEARLS • Colonization with P. jiroveci is common in the pediatric population. • PCP only occurs in immunocompromised patients. • Patients with HIV are at risk once their CD4 count is 200 cells/μL for 3 months. • Patients who are immunocompromised are also at risk. Currently, no clear clinical guidelines are available as to when to initiate or end prophylaxis. • The first-line treatment is TMP-SMX. The typical duration of therapy is 14 days in non–AIDS-infected patients and 21 days in AIDS-infected patients.

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POLYARTERITIS NODOSA Katherine S. Upchurch, MD • Rajandeep S. Paik, MD BASICS DESCRIPTION • Polyarteritis nodosa (PAN) is an antineutrophil cytoplasmic antibody (ANCA)-negative necrotizing arteritis of medium or small arteries without glomerulonephritis or vasculitis of arterioles, capillaries, or venules (1). • Involved systems include GI tract, peripheral nervous system (sensory and motor), central nervous system (CNS), renal (without glomerulonephritis), skin, testes/epididymis, heart (1–3) • Features depend on location of vasculitis: mesenteric ischemia–related symptoms, new onset or worsening hypertension, mononeuritis multiplex, purpuric or nodular skin lesions, or livedo reticularis (3). • Renal disease in PAN usually manifests as hypertension (HTN) and mild proteinuria with/without azotemia. Renal infarction may occur (3). • PAN formerly encompassed several distinct entities (classic PAN, microscopic PAN, cutaneous PAN). With the advent of ANCA testing, microscopic PAN appears unrelated to the other two, pathophysiologically. – Patients with classic PAN are typically ANCA-negative (1,4). – Patients with microscopic PAN have ANCAs directed against myeloperoxidase (MPO) and (generally) involvement of small arterioles (microscopic polyangiitis [MPA]). This is now classified as ANCAassociated vasculitis (1). – Cutaneous (or limited) PAN is a chronic disease with cutaneous lesions with characteristic histopathologic features of PAN. There are few systemic manifestations, although myalgias and peripheral motor neuropathy (mononeuritis multiplex) or sensory neuropathy may be present. ANCA positivity is variable (5). • Synonym(s): periarteritis; panarteritis; necrotizing arteritis

EPIDEMIOLOGY

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Incidence • Predominant age: Peak onset is in the 5th to 6th decade; incidence rises with age. • 1.5:1 male predominance (6)

Prevalence Rare: 2 to 33 cases/1 million adults (6)

ETIOLOGY AND PATHOPHYSIOLOGY • Segmental, transmural, necrotizing inflammation of medium and small muscular arteries, with intimal proliferation, thrombosis, and ischemia of the organ/tissue supplied by the affected arteries. Aneurysm formation at vessel bifurcations (3) • Hepatitis B–related PAN results in direct injury to the vessel due to viral replication or deposition of immune complexes, with complement activation and subsequent inflammatory response (3). • Most cases are idiopathic; 20% are related to hepatitis B or C infection (7). • In patients with PAN and hepatitis B, HBsAg has been recovered from involved vessel walls (7).

Genetics Mutations of adenosine deaminase 2 (ADA 2) have been identified in families with PAN (8).

RISK FACTORS Hepatitis B infection >> hepatitis C infection (cutaneous PAN) (7)

COMMONLY ASSOCIATED CONDITIONS • Hepatitis B (strong association with classic PAN) (7) • Hepatitis C (less strongly linked to cutaneous PAN) • Hairy cell leukemia • 27 existing case reports of systemic PAN following hepatitis B vaccination (9) • Minocycline (symptoms resolve on stopping drug, reoccur if rechallenged) (10) • Case reports also associating PAN with CMV infection, amphetamines, and interferon (11)

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DIAGNOSIS There are no formal diagnostic criteria for PAN (1,3). Suspect PAN in patients with the following: • Acute, sometimes fulminant multisystem disease with a relatively short prodrome (i.e., weeks to months) • Vasculitic skin rash with sensorimotor symptoms/findings • Recent-onset HTN with systemic symptoms • Unexplained sensory and/or motor neuropathy with systemic symptoms • Hepatitis B infection with multisystem disease

HISTORY General: systemic symptoms with multiorgan involvement (3) • Constitutional symptoms (fever, weight loss, malaise) • Organ-specific symptoms – Focal muscular weakness/extremity numbness – Myalgia and arthralgia – Rash – Recurrent postprandial pain, intestinal angina, nausea, vomiting, and bleeding – Altered mental status, headaches, mononeuritis multiplex – Testicular/epididymal pain, neurogenic bladder (rare)

PHYSICAL EXAM Related to involved organ system (may dominate clinical picture and course) (2,3) • Peripheral nervous system: peripheral neuropathy • Renal: HTN • Skin: purpura, urticaria, polymorphic rashes, subcutaneous nodules (uncommon, but characteristic), livedo reticularis; deep skin ulcers, especially in lower extremities; Raynaud phenomenon (rare); single digit gangrene (rare) • GI: acute abdomen; rebound, guarding, tenderness • CNS: seizures, altered mental status, papillitis • Lung: signs of pleural effusion―dullness to percussion; decreased breath sounds

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• Cardiac: signs of congestive heart failure and/or myocardial infarction―S3 gallop; pericarditis (friction rub is rare) • Genitourinary: testicular/epididymal tenderness (can mimic testicular torsion) • Musculoskeletal: arthritis (usually large joint in lower extremities)

DIFFERENTIAL DIAGNOSIS • Other forms of vasculitis (ANCA-associated, such as GPA, Churg-Strauss syndrome, and MPA; Henoch-Schönlein purpura, drug-induced vasculitis, cryoglobulinemia, Goodpasture syndrome) • Buerger disease • Systemic lupus erythematosus (SLE) • Embolic disease (atrial myxoma, cholesterol emboli) • Thrombotic disease (antiphospholipid antibody syndrome) • Dissecting aneurysm • Ehlers-Danlos syndrome • Multiple sclerosis, systemic amyloidosis • Infection (subacute endocarditis, HIV infection, trichinosis, rickettsial diseases)

DIAGNOSTIC TESTS & INTERPRETATION • No specific laboratory abnormalities. Confirm diagnosis with biopsy if possible (4)[C]. • Angiography (conventional, CT angiography, or MR angiography) may reveal microaneurysms and/or beading of bifurcating blood vessels. • Avoid contrast in renal disease. • Nonspecific laboratory abnormalities: – Elevated ESR and CRP – Mild proteinuria, elevated creatinine – Hepatitis B surface antigen positive in 10–50% – Hepatitis C antibody/hepatitis C virus RNA – ANCA, antiproteinase 3 (PR3), and anti-MPO are negative. Positive ANCA argues against PAN. – Rheumatoid factor may be positive. – Anemia of chronic disease (3,4):

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Initial Tests (lab, imaging) Lab tests performed to look for evidence of systemic disease and rule out other causes (3,4) are as follows: • CBC, ESR, CRP (elevated) (4)[C] • Chemistries: elevated creatinine/BUN (4)[C] • Hepatitis B serology: often positive; hepatitis C less commonly positive • LFTs: abnormal if involving the liver/biliary tract • Urinalysis: proteinuria/hematuria, generally no cellular casts or active urinary sediment (4)[C] • ANA, cryoglobulins (4)[C] • ANCA, anti-MPO, and anti-PR3 (4)[A] • Complement levels (C3, C4) • Angiographic demonstration of aneurysmal changes/beading of small and medium-sized arteries

Diagnostic Procedures/Other • Electromyography and nerve conduction studies in patients with suspected mononeuritis multiplex. If abnormal, consider sural nerve biopsy. • Arterial/tissue biopsy • Skin biopsy from edges of ulcers; include deep dermis and subcutaneous (SC) fat to assess small muscular artery involvement (excisional not punch biopsy) (3,4)

Test Interpretation • Necrotizing inflammation with fibrinoid necrosis of small and medium-sized muscular arteries; segmental, often at bifurcations and branchings. Venules not involved in classic PAN. • Capillaritis/other lung parenchymal involvement by vasculitis strongly suggests another process (microscopic PAN, granulomatosis with polyangiitis [GPA; formerly known as Wegener granulomatosis], Churg-Strauss syndrome, or antiglomerular basement membrane disease). • Acute lesions with infiltration of polymorphonuclear cells through vessel walls into perivascular area; necrosis, thrombosis, infarction of involved tissue • Aneurysmal dilatations, including aortic dissection • Peripheral nerves: 50–70% (vasa nervorum with necrotizing vasculitis)

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• GI vessels: 50% (at autopsy) with bowel necrosis; gallbladder and appendix vasculature: 10% • Muscle vessels: 50% • Testicular vessels involved in symptomatic males • The key differences from other necrotizing vasculitides are lack of granuloma formation and sparing of veins and pulmonary arteries (2,3).

TREATMENT GENERAL MEASURES Aggressively treat HTN to prevent associated complications (stroke, myocardial infarction, heart failure)

MEDICATION First Line • Severe (life-threatening) disease: corticosteroids (CS) (high-dose prednisone, methylprednisolone or parenteral Solu-Medrol) (4,10)[A] – Only 50% of patients achieve and maintain remission with CS. Other patients require additional immunosuppressive therapy. – Cyclophosphamide (CTX) in combination with CS: Improves survival and spares use of chronic steroids in moderate/severe PAN (4,10)[A] CTX has risk of infertility and malignancy. – Plasma exchange for refractory and renal disease (4,7)[A] – Rituximab use for refractory disease suggested by its efficacy in ANCA+ vasculitis (4,12,13)[C]. • Less severe disease: CS alone ± other immunosuppressive agents (azathioprine, (4)[A] methotrexate, mycophenolate mofetil (4,10,14)[B]) • HBV-associated PAN: antiviral agents, short-term CS, plasma exchange (7,10) [C]

Second Line • Tumor necrosis factor inhibitors anecdotally reported to be of use in PAN (15) • PAN disease activity correlates with serum IL-6 levels; tocilizumab, an inhibitor of IL-6 approved for use in rheumatoid arthritis; no evidence-based

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data for PAN (16).

ADDITIONAL THERAPIES • For patients receiving IV CTX, concurrent administration of mercaptoethane sulfonate reduces bladder exposure to carcinogenic metabolites (4)[C]. • Prophylactically treat patients on CTX for Pneumocystis jiroveci (carinii) pneumonia with trimethoprim sulfamethoxazole (use dapsone or atovaquone in intolerant/allergic patients) (4).

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS Depends on extent and involvement of specific organs

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • CBC, urinalysis, renal and hepatic function tests • Acute-phase reactants (e.g., ESR, CRP) may help monitor disease activity. • Be alert for the following: – Treatment specific side effects of CS and immunosuppressant medications – Delayed appearance of neoplasms after treatment, especially bladder malignancy in patients treated with CTX. (Check annual U/A, urinary cytology with urologic evaluation if microscopic hematuria.) (4)[C] – Steroid-induced osteoporosis

DIET Low salt (HTN)

PATIENT EDUCATION • Patient education materials are available from the Arthritis Foundation, 1314 Spring St, NW, Atlanta, GA 30309; 800-283-7800 • ACR website: www.rheumatology.org

PROGNOSIS • Expected course of untreated PAN is poor, with an estimated 5-year survival

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of 13% (17). • Steroid and cytotoxic treatment increase 5-year survival rate to 75–80% (3,17). • Survival is greater for hepatitis B–related PAN as a result of the introduction of antiviral treatments (7). • Patients presenting with proteinuria, renal insufficiency, GI tract involvement, cardiomyopathy, or CNS involvement have a worse prognosis.

COMPLICATIONS • End-organ damage from ischemia • Complications from immunosuppressive agents

REFERENCES 1. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1–11. 2. Ebert EC, Hagspiel KD, Nagar M, et al. Gastrointestinal involvement in polyarteritis nodosa. Clin Gastroenterol Hepatol. 2008;6(9):960–966. 3. Pagnoux C, Seror R, Henegar C, et al. Clinical features and outcomes in 348 patients with polyarteritis nodosa: a systematic retrospective study of patients diagnosed between 1963 and 2005 and entered into the French Vasculitis Study Group Database. Arthritis Rheum. 2010;62(2):616–626. 4. Mukhtyar C, Guillevin L, Cid MC, et al. EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis. 2009;68(3):310–317. 5. Nakamura T, Kanazawa N, Ikeda T, et al. Cutaneous polyarteritis nodosa: revisiting its definition and diagnostic criteria. Arch Dermatol Res. 2009;301(1):117–121. 6. Phillip R, Luqmani R. Mortality in systemic vasculitis: a systematic review. Clin Exp Rheumatol. 2008;26(5)(Suppl 51):S94–S104. 7. Guillevin L, Mahr A, Callard P, et al. Hepatitis B virus-associated polyarteritis nodosa: clinical characteristics, outcome, and impact of treatment in 115 patients. Medicine (Baltimore). 2005;84(5):313–322. 8. Navon Elkan P, Pierce SB, Segel R, et al. Mutant adenosine deaminase 2 in

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a polyarteritis nodosa vasculopathy. N Engl J Med. 2014;370(10):921–931. 9. de Carvalho JF, Pereira RM, Shoenfeld Y. Systemic polyarteritis nodosa following hepatitis B vaccination. Eur J Intern Med. 2008;19(8):575–578. 10. Culver B, Itkin A, Pischel K. Case report and review of minocyclineinduced cutaneous polyarteritis nodosa. Arthritis Rheum. 2005;53(3):468– 470. 11. Bourgarit A, Le Toumelin P, Pagnoux C, et al. Deaths occurring during the first year after treatment onset for polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome: a retrospective analysis of causes and factors predictive of mortality based on 595 patients. Medicine (Baltimore). 2005;84(5):323–330. 12. de Menthon M, Mahr A. Treating polyarteritis nodosa: current state of the art. Clin Exp Rheumatol. 2011;29(1)(Suppl 4):S110–S116. 13. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221–232. 14. Specks U, Merkel PA, Seo P, et al. Efficacy of remission-induction regimens for ANCA-associated vasculitis. N Engl J Med. 2013;369(5):417–427. 15. Ribi C, Cohen P, Pagnoux C, et al. Treatment of polyarteritis nodosa and microscopic polyangiitis without poor-prognosis factors: a prospective randomized study of one hundred twenty-four patients. Arthritis Rheum. 2010;62(4):1186–1197. 16. Chan M, Lugmani R. Pharmacotherapy of vasculitis. Expert Opin Pharmacother. 2009;10(8):1273–1289. 17. Murakami M, Nishimoto N. The value of blocking IL-6 outside of rheumatoid arthritis: current perspective. Curr Opin Rheumatol. 2011;23(3):273–277.

ADDITIONAL READING Kouchi M, Sato S, Kamono M, et al. A case of polyarteritis nodosa associated with cytomegalovirus infection. Case Rep Rheumatol. 2014;2014:604874.

SEE ALSO

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Hepatitis B; Hepatitis C

CODES ICD10 • M30.0 Polyarteritis nodosa • M30.1 Polyarteritis with lung involvement [Churg-Strauss] • M30.8 Other conditions related to polyarteritis nodosa

CLINICAL PEARLS • PAN is a necrotizing vasculitis of small- to medium-sized muscular arteries with lack of granuloma formation that spares veins and pulmonary arteries. • Clinical features of PAN depend on target organ involvement. • Skin biopsies at ulcer edges (include deep dermis and SC fat) improve diagnostic yield. • Check hepatitis B and C serologies. • ANCA is negative in classic PAN. • Treatment involves immunosuppression; choice of agent depends on extent and severity of disease.

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POLYCYSTIC KIDNEY DISEASE Maricarmen Malagon-Rogers, MD BASICS DESCRIPTION • A group of monogenic disorders that results in renal cyst development • The most frequent are two genetically distinct conditions: autosomal dominant polycystic kidney disease (ADPKD) and autosomal recessive polycystic kidney disease (ARPKD). • ADPKD is one of the most common human genetic disorders.

EPIDEMIOLOGY • ADPKD is generally late onset. – Mean age of end-stage kidney disease (ESKD) 57 to 69 years – More progressive disease in men than in women – Up to 90% of adults have cysts in the liver. • ARPKD usually present in infants. – A minority in older children and young adults may manifest as liver disease. – Nonobstructive intrahepatic bile dilatation is sometimes seen. – Found on all continents and in all races

Incidence • Mean age of ESKD: PKD1 mutation, 54.3 years versus PKD2 mutation, 74 years • ARPKD affects 1/20,000 live births; carrier level is 1/70. • ADPKD affects 1/400 to 1,000 live births.

Prevalence As ESKD, ADPKD: 8.7/1 million in the United States; 7/1 million in Europe

ETIOLOGY AND PATHOPHYSIOLOGY • ADPKD – PKD1 and PKD2 mutations disrupt the function of polycystins on the

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primary cilium, forming fluid-filled cysts that progressively increase in size, leading to gross enlargement of the kidney, and distortion of the renal architecture. – Glomerular hyperfiltration compensates for the progressive loss of healthy glomeruli, and therefore, by the time GFR decline becomes detectable, as much as ½ of the original functional glomeruli are irreversibly lost. – The majority of patients with ADPKD ultimately progress to ESKD (1). • ARPKD – PKHD1 product fibrocystin is also located in cilia. • ADPKD: Cysts arise from only 5% of nephrons: – Autosomal dominant pattern of inheritance but a molecularly recessive disease with the 2-hit hypothesis – Requires genetic and environmental factors • ARPKD: Mutations are scattered throughout the gene with genotype– phenotype correlation.

Genetics • ADPKD – Autosomal dominant inheritance – 50% of children of an affected adult are affected. – 100% penetrance; genetic imprinting and genetic anticipation are seen as well. – Two genes isolated PKD1 on chromosome 16p13.3 (85% of patients) encodes polycystin 1 PKD2 on chromosome 4q21 (15% of patients) encodes polycystin 2 • ARPKD – Autosomal recessive inheritance – Siblings have a 1:4 chance of being affected; gene PKHD1 on chromosome 6p21.1–p12 encodes fibrocystin.

RISK FACTORS • Large inter- and intrafamilial variability • A more rapidly progressive clinical course is predicted by onset of ESKD at 15 g/dL (women) if associated with a sustained increase of ≥2 g/dL from baseline that cannot be attributed to correction of iron deficiency. Presence of JAK2 V617F or similar mutation such as JAK2 exon 12 mutation

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– Minor criteria: Bone marrow trilineage myeloproliferation Serum erythropoietin level below normal Endogenous erythroid colony (EEC) growth • Diagnosis can be made reliably based on clinical symptoms, presence of JAK2 V617 mutation, and low EPO (2). • Other lab findings that are common but not specific – Hyperuricemia – Hypercholesterolemia – Elevated serum vitamin B12 levels – Prolonged PT, aPTT due to low plasma volume • CT or US to assess for splenomegaly, although not necessary for diagnosis • Arterial oxygen saturation (SaO2) and carboxyhemoglobin (COHb) • Bone marrow biopsy is not necessary.

Diagnostic Procedures/Other • Bone marrow aspiration if performed shows hypercellularity of erythroid, granulocytic and megakaryocytic lines, or myelofibrosis • Cytogenetic testing (JAK2 V617F)

Test Interpretation • If JAK2 V617F mutation testing is negative and the erythropoietin level is normal or high, then PV is excluded; investigate causes of secondary erythrocytosis. • Other causes of erythrocytosis such as ectopic erythropoietin production from a renal tumor, hypoxia from chronic lung, or cyanotic heart disease can be excluded with low or undetectable serum erythropoietin level and normal oxygen saturation.

TREATMENT GENERAL MEASURES • Risk factors: Patients older than 60 years with history of thrombosis are high risk. Those who are less than 60 years with no history of thrombosis but with

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elevated platelets (>150,000) are intermediate risk. Younger than 60 years, with normal platelets and no history of thrombosis are low risk. • Phlebotomy and low-dose aspirin is first-line therapy for all patients. • If secondary PV, address etiology: aggressive treatment of obstructive sleep apnea, COPD (esp. smoking cessation, renal disease, consider lowering dose in testosterone replacement. • Phlebotomy reduces the blood hyperviscosity, improves platelet function, restores systemic pressures, and decreases risk of thrombosis. • Phlebotomy: – Reduce hematocrit to 60 years or history of thrombotic event) and with splenomegaly and hepatomegaly. Common starting dose 500 to 1,500 mg PO daily, titrating to control hematocrit and platelet count. Be aware that hydroxyurea can lead to higher risk of leukemic transformation (5)[A]. – Radioactive phosphorous (32P) may control Hgb level and platelet count by destroying overactive marrow cells. May take up to 3 months before affecting cells. Consider for patients intolerant or nonadherent to hydroxyurea or short expected survival due to mutagenic potential. – Tyrosine kinase inhibitor imatinib 400 to 800 mg daily was shown to have moderate cytoreductive effects in PV (6)[B]. – Pegylated interferon-α-2a is effective in controlling erythrocytosis, although dosing is generally limited secondary to intolerable side effects. – Refer to hematologist/oncologist for further dosing and instructions. • Symptomatic/adjunctive: – Allopurinol 300 mg/day PO for uric acid reduction – Cyproheptadine 4 to 16 mg PO daily as needed for pruritus – H2-receptor blockers or antacids for GI hyperacidity; cimetidine is also used for pruritus. – SSRIs (paroxetine or fluoxetine) have shown some efficacy in controlling pruritus. – Ultraviolet light may help with pruritus.

Second Line Myelosuppression: chlorambucil or busulfan; busulfan at 2 to 4 mg daily may be effective option for elderly patients with advanced PV refractory or intolerant to hydroxyurea, but significant rate of transformation was observed.

ISSUES FOR REFERRAL Referral to a hematologist to assist in diagnosis and management

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring

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Monitor hematocrit often and phlebotomize as needed to maintain target goal.

DIET • Avoid high-sodium diet; can cause fluid retention • Avoid iron supplement, a permissive chronic state of iron deficiency can help decrease blood production.

PATIENT EDUCATION • Perform leg and ankle exercises to prevent clots. • Continuous education regarding possible complications and seeking treatment early for any change or increase in symptoms

PROGNOSIS • PV cannot be cured but can be controlled with treatment. • Survival is >15 years with treatment. • Patients are at risk for developing postpolycythemic myelofibrosis (PPMF) and an increased risk of malignant transformation.

COMPLICATIONS • Splenomegaly or hepatomegaly • Budd-Chiari syndrome • Vascular thrombosis (major cause of death) (20%) • Transformation to acute leukemia (5%) • Transformation to myelofibrosis (10%) • Hemorrhage • Peptic ulcer • Uric acid stones • Secondary gout • Increased risk for complications and mortality from surgical procedures. Assess risk/benefits and ensure optimal control of disorder before any elective surgery.

REFERENCES 1. Tefferi A, Thiele J, Vardiman JW. The 2008 World Health Organization classification system for myeloproliferative neoplasms: order out of chaos.

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Cancer. 2009;115(17):3842–3847. 2. Tefferi A. Polycythemia vera and essential thrombocythemia: 2013 update on diagnosis, risk-stratification, and management. Am J Hematol. 2013;88(6):507–516. 3. Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013;368(1):22– 33. 4. Squizzato A, Romualdi E, Passamonti F, et al. Antiplatelet drugs for polycythaemia vera and essential thrombocythaemia. Cochrane Database Syst Rev. 2013;(4):CD006503. 5. Mascarenhas J, Mughal TI, Verstovsek S. Biology and clinical management of myeloproliferative neoplasms and development of the JAK inhibitor ruxolitinib. Curr Med Chem. 2012;19(26):4399–4413. 6. Merx K, Fabarius A, Erben P, et al. Effects of imatinib mesylate in patients with polycythemia vera: results of a phase II study. Ann Hematol. 2013;92(7):907–915.

ADDITIONAL READING • Passamonti F. How I treat polycythemia vera. Blood. 2012;120(2):275–284. • Tefferi A, Fonseca R. Selective serotonin reuptake inhibitors are effective in the treatment of polycythemia vera-associated pruritus. Blood. 2002;99(7):2627.

SEE ALSO Myeloproliferative Neoplasms

CODES ICD10 • D45 Polycythemia vera • D75.1 Secondary polycythemia

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CLINICAL PEARLS • Erythrocytosis: Hb >18.5g/dL in men, >16.5g/dL in women • JAK2 mutations are an important component of myeloproliferative disorders. • Common complications include thrombosis, malignant transformation, and myelofibrosis. • All patients should take low-dose aspirin unless there is major bleeding or GI intolerance. • Phlebotomy is first-line treatment, and consultation with an experienced hematologist is recommended.

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POLYMYALGIA RHEUMATICA Ronald G. Chambers, Jr., MD, FAAFP • Megan Babb, DO BASICS DESCRIPTION • A clinical syndrome characterized by pain and stiffness of the shoulder, hip girdles, and neck. Some patients use the term stiffness and pain interchangeably (1). • Primarily impacts the elderly, associated with morning stiffness and elevated markers of inflammation • System(s) affected: musculoskeletal; hematologic/lymphatic/immunologic • Synonym(s): senile rheumatic disease, polymyalgia rheumatica (PMR) syndrome, pseudo-polyarthrite rhizomélique

Geriatric Considerations • Incidence increases with age • Average age of onset ~70 years

Pediatric Considerations Rare in patients male (2 to 3:1) • Most common in Caucasians, especially those of northern European ancestry

Prevalence Prevalence in those over 50 years old: 700/100,000

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ETIOLOGY AND PATHOPHYSIOLOGY • Unknown. Symptoms appear to be related to enhanced immune system and periarticular inflammatory activity. • Pathogenesis – Polygenic where multiple environmental and genetic factors play a role – Significant association found between histologic evidence of GCA and parvovirus B19 DNA in temporal artery specimen

Genetics Associated with human leukocyte antigen determinants (HLA-DRB1*04 and DRB1*01 alleles) (3)

RISK FACTORS • Age >50 years • Presence of GCA

COMMONLY ASSOCIATED CONDITIONS Concurrent GCA (temporal arteritis) in ~15–30% of patients; more commonly in females than males

DIAGNOSIS HISTORY • Suspect PMR in elderly patients with new onset of proximal limb pain and stiffness (neck, shoulder, hip). • Difficulty rising from chair or combing hair are signs of proximal muscle involvement. • Nighttime pain • Difficulty arising from a chair or raising the arms • Systemic symptoms in ~25% (fatigue, weight loss, low-grade fever)

PHYSICAL EXAM • Decreased range of motion (ROM) of shoulders, neck, and hips • Muscle strength is usually normal, although it may be limited by pain and/or stiffness. • Muscle tenderness

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• Disuse atrophy • Synovitis of the small joints and tenosynovitis • Coexisting carpal tunnel syndrome

DIFFERENTIAL DIAGNOSIS • Rheumatoid arthritis (RA) • Palindromic rheumatism • Late-onset seronegative spondyloarthropathies (e.g., psoriatic arthritis, ankylosing spondylitis) • Systemic lupus erythematosus; Sjögren syndrome; fibromyalgia • Polymyositis-dermatomyositis (check creatine phosphokinase, aldolase) • Thyroid disease • Hyperparathyroidism, hypoparathyroidism • Hypovitaminosis D • Osteoarthritis • Rotator cuff syndrome; adhesive capsulitis • RS3PE syndrome (remitting seronegative symmetrical synovitis with pitting edema) • Occult infection or malignancy (e.g., lymphoma, leukemia, myeloma, solid tumor) • Myopathy (e.g., steroid, alcohol, electrolyte depletion) • Depression

DIAGNOSTIC TESTS & INTERPRETATION • Consider PMR in patients older than 50 years of age with proximal pain and stiffness. Obtain laboratory work and consider a diagnostic/therapeutic trial of low-dose steroids. • Temporal artery biopsy if symptoms of GCA present • ESR (Westergren) elevation >40 mm/hr – ESR generally elevated, sometimes >100 mm/hr – ESR normal (40 mm/hr) • C-reactive protein • CBC • MRI is not necessary for diagnosis but may show periarticular inflammation, tenosynovitis, and bursitis. • US may show bursitis, tendinitis, and synovitis. • MRI, PET, and temporal artery US may help in diagnosis of PMR. • Recent ACR/EULAR Classification Criteria may help confirm the clinical diagnosis (4). • A scoring algorithm was devised consisting of the following: morning stiffness >45 minutes (2 points), hip pain/limited ROM (1 point), absence of RF and anti-citrullinated protein antibody (ACPA) (2 points), and absence of peripheral joint pain (1 point). A score of >4 has been associated with 68% sensitivity and 78% specificity. Sensitivity and specificity increase with a positive temporal artery US.

Diagnostic Procedures/Other Biopsy the temporal artery in patients with symptoms suggestive of GCA. Treat empirically pending biopsy results.

TREATMENT GENERAL MEASURES • Document diagnosis accurately as glucocorticoids can mask symptoms of

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other diseases. • Address risk of steroid-induced osteoporosis. – Obtain dual energy x-ray absorptiometry and check 25-OH vitamin D levels if necessary. – Consider antiresorptive therapies (bisphosphonates) based on recommendations for treatment of corticosteroid-induced osteoporosis. • Encourage adequate calcium (1,500 mg/day) and vitamin D (800 to 1,000 U/day) supplementation. • Physical therapy for ROM exercises, if needed

MEDICATION First Line • Prednisone: 10 to 20 mg/day PO initially; typically, expect a dramatic (diagnostic) response within days. 15 mg/day is effective in almost all patients. – May increase to 20 mg/day if no immediate response – If no response to 10 to 20 mg/day within a week, reconsider diagnosis. • Divided-dose steroids (BID or TID) may be useful initially (especially if symptoms recur in the afternoon). • Consider using delayed-release prednisone taken at bedtime, which may be more efficient in treating morning stiffness compared to conventional immediate-release prednisone. • Begin slow taper by 2.5 mg decrements every 2 to 4 weeks to a dose of 7.5 to 10 mg/day. Below this dose, taper by 1 mg/month to prevent relapse. • Increase prednisone for recurrence of symptoms (relapse common). • Corticosteroid treatment often lasts at least 1 to 2 years. • May be stopped at 6 to 12 months if patient is symptom free and there is a normal ESR on maintenance dose • Contraindications – Use steroids with caution in patients with chronic heart failure, diabetes mellitus (or other immunocompromised state), and systemic fungal or bacterial infection. – Must treat infections concurrently if steroids are absolutely necessary • Precautions

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– Long-term steroid use (>2 years) is associated with adverse effects, including sodium and water retention, exacerbation of chronic heart failure, hypokalemia, increased susceptibility to infection, osteoporosis, fractures, hypertension, cataracts, glaucoma, avascular necrosis, depression, and weight gain. – Patients may develop temporal arteritis while on low-dose corticosteroid treatment for polymyalgia. This requires an increase in dose to 40 to 60 mg. – Alternate-day steroids are not effective.

Second Line • NSAIDs usually are not adequate for pain relief. • Methotrexate has a modest effect in reducing relapse rate and lowering the cumulative dose of steroid therapy. • There is conflicting evidence for antitumor necrosis factor agents (anti-TNF) (infliximab, etanercept) regarding steroid-sparing effects. • Possibly use of anti-interleukin (anti-IL) 6 therapy in the future (5,6) • Corticosteroid injection in the shoulder may help reduce pain and duration of morning stiffness and allow for increased levels of activity.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Evaluate patients monthly initially and during medication taper; every 3 months otherwise • Follow ESR as steroids are tapered; both ESR and CRP should decline as symptoms improve. • Follow-up with patient for symptoms of GCA. Educate patient to report such symptoms immediately (e.g., headache, visual loss, and diplopia). • Monitor side effects of corticosteroid therapy such as osteoporosis, hypertension, and hyperglycemia. • If patient is asymptomatic, do not treat elevated ESR (i.e., do not increase the steroid dose in an attempt to normalize the ESR).

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DIET • Regular diet • Aim for adequate calcium and vitamin D.

PATIENT EDUCATION

• Review adverse effects of corticosteroids. • Discuss the symptoms of GCA and instruct the patient to present immediately if any occur. • Follow up if symptoms recur during the steroid taper. • Never abruptly stop steroids. • Ensure calcium and vitamin D requirements are met. • Patient resources: – Arthritis Foundation: www.arthritis.org/ – American College of Rheumatology: http://www.rheumatology.org/Practice/Clinical/Patients/Diseases_And_Conditions/Polym

PROGNOSIS • Most patients require at least 2 years of corticosteroid treatment. • Exacerbation common if steroids tapered too quickly. • Prognosis is very good with proper treatment. • Relapse is common (in 25–50% of patients). • Higher age at diagnosis, female sex, high baseline ESR, increased plasma viscosity, increased levels of soluble IL-6 receptor, or high initial steroid dose have been associated with a prolonged disease course and greater number of disease flares.

COMPLICATIONS • Complications related to chronic steroid use • Exacerbation of disease with taper of steroids; development of GCA (may occur when PMR is being treated adequately)

REFERENCES 1. Mackie SL, Hughes R, Walsh M, et al. An impediment to living life”: why and how should we measure stiffness in polymyalgia rheumatica? PLoS One. 2015;10(5):e0126758.

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2. Salvarani C, Gabriel SE, O’Fallon WM, et al. Epidemiology of polymyalgia rheumatica in Olmsted County, Minnesota, 1970–1991. Arthritis Rheum. 1995;38(3):369–373. 3. Weyand CM, Hunder NN, Hicok KC, et al. HLA-DRB1 alleles in polymyalgia rheumatica, giant cell arteritis, and rheumatoid arthritis. Arthritis Rheum. 1994;37(4):514–520. 4. Muratore F, Pazzola G, Pipitone N, et al. Recent advances in the diagnosis and treatment of polymyalgia rheumatica. Expert Rev Clin Immunol. 2016;12(10):1037–1045. 5. Seitz M. Polymyalgia rheumatica: what is the current status? Z Rheumatol. 2015;74(6):507–510. 6. Devauchelle-Pensec V. Has the time come for biotherapies in giant cell arteritis and polymyalgia rheumatica? Joint Bone Spine. 2016;83(5):471–472.

ADDITIONAL READING • Buttgereit F, Gibofsky A. Delayed-release prednisone: a new approach to an old therapy. Expert Opin Pharmacother. 2013;14(8):1097–1106. • Camellino D, Cimmino MA. Imaging of polymyalgia rheumatica: indications on its pathogenesis, diagnosis and prognosis. Rheumatology (Oxford). 2012;51(1):77–86. • Dasgupta B, Cimmino MA, Maradit-Kremers H, et al. 2012 provisional classification criteria for polymyalgia rheumatica: a European League Against Rheumatism/American College of Rheumatology collaborative initiative. Ann Rheum Dis. 2012;71(4):484–492. • Kreiner F, Galbo H. Effect of etanercept in polymyalgia rheumatica: a randomized controlled trial. Arthritis Res Ther. 2010;12(5):R176. • Michet CJ, Matteson EL. Polymyalgia rheumatica. BMJ. 2008;336(7647):765–769. • Régent A, Ly KH, Blet A, et al. Contribution of antiferritin antibodies to diagnosis of giant cell arteritis. Ann Rheum Dis. 2013;72(7):1269–1270.

SEE ALSO

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Arteritis, Temporal; Osteoarthritis; Arthritis, Rheumatoid (RA); Depression; Fibromyalgia; Polymyositis/Dermatomyositis

CODES ICD10 • M35.3 Polymyalgia rheumatica • M31.5 Giant cell arteritis with polymyalgia rheumatica

CLINICAL PEARLS • Consider PMR in patients over 50 years who present with hip, neck and/or shoulder pain and stiffness. • Normal ESR does not exclude the diagnosis of PMR. • If there is not a dramatic and rapid response to steroids, reconsider the diagnosis. • Adjust steroids according to symptoms, not ESR.

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POLYMYOSITIS/DERMATOMYOSITIS Christopher M. Wise, MD BASICS DESCRIPTION • Systemic connective tissue disease characterized by inflammatory and degenerative changes in proximal muscles, sometimes accompanied by characteristic skin rash – If skin manifestations (Gottron sign [symmetric, scaly, violaceous, erythematous eruption over the extensor surfaces of the metacarpophalangeal and interphalangeal joints of the fingers]; heliotrope [reddish violaceous eruption on the upper eyelids]) are present, it is designated as dermatomyositis. – Different types of myositis include the following (1): Idiopathic polymyositis Idiopathic dermatomyositis Polymyositis/dermatomyositis as an overlap (usually with lupus or systemic sclerosis or as part of mixed connective-tissue disease) Myositis associated with malignancy Necrotizing autoimmune myositis (often statin-associated) (2) HIV-associated myopathy • Inclusion-body myositis (IBM), a variant with atypical patterns of weakness and biopsy findings • System(s) affected: cardiovascular, musculoskeletal, pulmonary, skin/exocrine • Synonym(s): myositis; inflammatory myopathy; antisynthetase syndrome (subset with certain antibodies)

EPIDEMIOLOGY Incidence • Estimated at 1.2 to 19/million population/year (3) • Predominant age: 5 to 15 years, 40 to 60 years, peak incidence in mid-40s • Predominant sex: female > male (2:1)

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Prevalence 2.4 to 33.8 patients/100,000 population (3)

Geriatric Considerations Elderly patients with myositis or dermatomyositis are at increased risk of neoplasm.

Pediatric Considerations Childhood dermatomyositis is likely a separate entity associated with cutaneous vasculitis and muscle calcifications.

ETIOLOGY AND PATHOPHYSIOLOGY • Inflammatory process, mediated by T cells and cytokine release, leading to damage to muscle cells (predominantly skeletal muscles) • In patients with IBM, degenerative mechanisms may be important. • Unknown; potential viral, genetic factors

Genetics Mild association with human leukocyte antigen (HLA)–DR3, HLA-DRw52

RISK FACTORS Family history of autoimmune disease (e.g., systemic lupus, myositis) or vasculitis

COMMONLY ASSOCIATED CONDITIONS • Malignancy (in 15–25%) • Progressive systemic sclerosis • Vasculitis • Systemic lupus erythematosus (SLE) • Mixed connective tissue disease

DIAGNOSIS HISTORY • Symmetric proximal muscle weakness (1) causing difficulty when – Arising from sitting or lying positions

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– Climbing stairs – Raising arms • Joint pain/swelling • Dysphagia • Dyspnea • Rash on face, eyelids, hands, arms

PHYSICAL EXAM Proximal muscle weakness • Shoulder muscles • Hip girdle muscles (trouble standing from seated or squatting position, weak hip flexors in supine position) • Muscle swelling, stiffness, induration • Distal muscle weakness is seen only in patients with IBM. • Rash over face (eyelids, nasolabial folds), upper chest, dorsal hands (especially knuckle pads), fingers (“mechanic’s hands”) • Periorbital edema • Calcinosis cutis (childhood cases) • Mesenteric arterial insufficiency/infarction (childhood cases) • Cardiac impairment; arrhythmia, failure

DIFFERENTIAL DIAGNOSIS • Vasculitis • Progressive systemic sclerosis • SLE • Rheumatoid arthritis • Muscular dystrophy • Eaton-Lambert syndrome • Sarcoidosis • Amyotrophic lateral sclerosis • Endocrine disorders – Thyroid disease – Cushing syndrome • Infectious myositis (viral, bacterial, parasitic) • Drug-induced myopathies:

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– Cholesterol-lowering agents (statins) – Colchicine – Corticosteroids – Ethanol – Chloroquine – Zidovudine • Electrolyte disorders (magnesium, calcium, potassium) • Heritable metabolic myopathies • Sleep-apnea syndrome

DIAGNOSTIC TESTS & INTERPRETATION • Diagnosis of muscle component (myositis) usually relies on four findings: – Weakness – Creatine kinase (CK) and/or aldolase elevation – Abnormal electromyogram (EMG) – Findings on muscle biopsy • Presence of compatible skin rash of dermatomyositis

Initial Tests (lab, imaging) • Increased CK, aldolase • Increased serum AST (aspartate aminotransferase) • Increased LDH (lactate dehydrogenase) • Myoglobinuria • Increased ESR • Positive rheumatoid factor (50% of patients) • Leukocytosis (300 mg/24 hr or spot protein: creatinine ≥0.3) OR New-onset thrombocytopenia, renal insufficiency, impaired liver function, pulmonary edema, or cerebral/visual symptoms (1)[C]. – Define preeclampsia as either without or with severe features (see below) (1)[C]. • Eclampsia diagnosis: – New-onset grand mal seizure

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– No history of neurologic disease

HISTORY May be asymptomatic. In some cases, rapid excessive weight gain (>5 lb/week; >2.3 kg/week); more severe cases are associated with epigastric/right upper quadrant (RUQ) pain, headache, altered mental status, and visual disturbance.

PHYSICAL EXAM • BP criteria: – Preeclampsia without severe features: Elevated BP ≥140/90 mm Hg on two occasions at least 4 hours apart or more rapid diagnosis may be made with BP ≥160/110 mm Hg. – Preeclampsia with severe features: Elevated BP ≥160 systolic mm Hg or 110 mm Hg diastolic on two BP readings 4 hours apart while the patient is on bedrest, AND new onset of one or more of below: Platelets 2 times normal liver transaminase levels, severe persistent RUQ/epigastric pain, or both Creatinine >1.1 mg/dL or doubling of serum creatinine levels Pulmonary edema Cerebral or visual symptoms • Eclampsia: tonic-clonic seizure activity (focal/generalized) – Note: Headache, visual disturbance, and epigastric or RUQ pain often precede seizure. – Seizures may occur once/repeatedly. – Normal BP, even in response to treatment; does not rule out potential for seizures

DIFFERENTIAL DIAGNOSIS • Chronic HTN: HTN before pregnancy; high BP before the 20th week • Chronic HTN with superimposed preeclampsia • Gestational HTN: Increased BP first discovered after 20 weeks, often close to term, with no proteinuria and without evidence of organ dysfunction. BP becomes normal by 12 weeks postpartum, or it is reclassified as chronic HTN. • Seizures in pregnancy: epilepsy, cerebral tumors, meningitis/encephalitis, and

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ruptured cerebral aneurysm. Until other causes are proven, however, all pregnant women with convulsions should be considered to have eclampsia.

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Routine spot urine testing or urinalysis for protein should be done at each prenatal visit in all hypertensive patients. • Complete blood count (CBC), including platelets, creatinine, serum transaminase levels, and uric acid as baseline in hypertensive patients and if preeclampsia suspected or possible • Coagulation profiles: abnormalities suggest severe disease. • 24-hour urine or protein/creatinine ratio if urine protein dips 1+ on more than one occasion, or if preeclampsia is being considered • Daily fetal movement monitoring by mother (“kick counts”) • US imaging is used to monitor growth and cord blood flow; perform, as indicated, based on clinical stability and laboratory findings. • Nonstress test (NST) at diagnosis and then twice-weekly until delivery • Biophysical profile (BPP) if NST is nonreactive (1)[C]. • US imaging for growth progress every 3 weeks, and amniotic fluid volume at least once weekly (1)[C] • With seizures, CT scan and MRI should be considered if focal findings persist or uncharacteristic signs/symptoms are present. Follow-Up Tests & Special Considerations Disseminated intravascular coagulation, thrombocytopenia, liver dysfunction, and renal failure can complicate preeclampsia associated with HELLP syndrome.

Test Interpretation CNS: cerebral edema, hyperemia, focal anemia, thrombosis, and hemorrhage. Cerebral lesions account for 40% of eclamptic deaths.

TREATMENT GENERAL MEASURES • Preeclampsia without severe features:

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– Outpatient care – Maternal: daily home BP monitoring; daily weights; weekly labs (CBC, creatinine, liver function test [LFT]) – Fetal: Patient-measured: daily “kick counts” NST/BPP/US (see imaging section above) Delivery at 37 weeks (induction of labor) (1,2)[C] Steroids for gestation 2 KHz initially – Essential to determine global clinical hearing status and if etiology is conductive HL versus SNHL or pseudohypacusis (conversion)

TREATMENT • HAs – Types Analog HA: picks up sound waves through a microphone; converts them into electrical signals; amplifies and sends them through the ear canal to the tympanic membrane

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Digital HA: programmable; may reduce acoustic feedback, reduce background noise, detect and automatically accommodate different listening environments, control multiple microphones. – HAs have an average decibel gain of 16.3 dB. – Associated with hypersensitivity to loud sounds (“loudness recruitment”) • Hearing-assistive technologies (HATs) (6)[A] – Can be used alone or in combination with HAs (for difficult listening conditions) – Addresses face-to-face communication, broadcast or other electronic media (radio, TV), telephone conversation, sensitivity to alerting signals and environment stimuli (doorbell, baby’s cry, alarm clock, etc.) – Includes personal FM systems, infrared systems, induction loop systems, hardwired systems, telephone amplifier, telecoil, TDD (telecommunication device for the deaf), situation-specific devices (e.g., television), alerting devices • Aural rehabilitation (also known as audiologic orientation or auditory training) (4)[A] – Adjunct to HA or HATs – Involves education regarding proper use of amplification devices, coaching on how to manage the auditory environment, training in speech perception and communication, and counseling for coping strategies to deal with the difficulties of HAs or HATs

ISSUES FOR REFERRAL Refer to audiologist for formal evaluation and optimal fitting of HAs and/or HATs. • Individuals receiving postfitting orientation/education have significantly fewer HA returns. • Individuals receiving >2 hours of education and counseling report higher levels of satisfaction.

SURGERY/OTHER PROCEDURES • Cochlear implants (CIs) – Works by bypassing the ear canal, middle ear, and hair cells in the cochlea to provide electric stimulation directly to the auditory nerve

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– Indications include hearing no better than identifying ≤50% of key words in test sentences in the best aided condition in the worst ear and 60% in the better ear. – Incoming sounds are received through the microphone in the audio processor component (resembles a small HA), which converts them into electrical impulses and sends them to the magnetic coil (located on the skin). The impulses transmit these across intact skin via radio waves to the implanted component (directly subjacent to the coil). The pulses travel to the electrodes in the cochlea and stimulate the cochlea at high rates. – Receiving a unilateral CI is most common; some may receive bilateral CIs (either sequentially or in the same surgery). Others may wear a CI in 1 ear and an HA in the contralateral ear (bimodal fit). – Younger age at CI placement derives greatest benefit. • Active middle ear implants (AMEIs) (6)[B] – Suitable for elderly adults who cannot wear conventional HAs for medical or personal (cosmetic) reasons and whose HL is not severe enough for a CI – Comes in different models and may include components that are implantable under the skin • Electric acoustic stimulation: use of CI and HA together in one ear – Addresses the specific needs of patients presenting with good lowfrequency hearing (a mild to moderate sensorineural HL in frequencies up to 1,000 Hz) but poorer hearing in the high frequencies (sloping to 60 dB or worse HL above 1,000 Hz) Contraindications: progressive HL, autoimmune disease; HL related to meningitis, otosclerosis, or ossification; malformation of the cochlea; a gap in air conduction and bone conduction thresholds of >15 dB; external ear contraindications, active infection, or unwillingness to use amplification devices

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring

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• During follow-up visits, check for compliance of HA use. – 25–40% of adults will either stop wearing them or use them only occasionally. • Assess perceived benefit of HA and, if ineffective, for indications for possible surgical treatments. • Annual audiograms • Can follow up with audiologists for HA fittings if HA becomes uncomfortable • Asymmetric HL should have evaluation via MRI for acoustic neuroma. • Sudden SNHL is atypical and warrants urgent otolaryngologic evaluation/audiometry. The most recent recommendations by the American Academy of Otolaryngology recommend steroids empirically.

PATIENT EDUCATION • Should be face-to-face; spoken clearly and unhurriedly, without competing background noise (e.g., radio, TV); and include a confirmation that the message is received. • Formal speech reading classes may be beneficial; however, availability may be limited.

REFERENCES 1. Yamasoba T, Lin FR, Someya S, et al. Current concepts in age-related hearing loss: epidemiology and mechanistic pathways. Hear Res. 2013;303:30–38. 2. Yueh B, Collins MP, Souza PE, et al. Long-term effectiveness of screening for hearing loss: the screening for auditory impairment—which hearing assessment test (SAI-WHAT) randomized trial. J Am Geriatr Soc. 2010;58(3):427–434. 3. Chou R, Dana T, Bougatsos C, et al. Screening adults aged 50 years or older for hearing loss: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2011;154(5):347–355. 4. Pacala JT, Yueh B. Hearing deficits in the older patient: “I didn’t notice anything.” JAMA. 2012;307(11):1185–1194. 5. Humes L, Dubno J, Gordon-Salant S, et al. Central presbycusis: a review and evaluation of the evidence. J Am Acad Audiol. 2012;23(8):635–666. 6. Sprinzl GM, Riechelmann H. Current trends in treating hearing loss in elderly

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people: a review of the technology and treatment options—a mini-review. Gerontology. 2010;56(3):351–358.

ADDITIONAL READING • Bagai A, Thavendiranathan P, Detsky AS. Does this patient have hearing impairment? JAMA. 2006;295(4):416–428. • Cruickshanks KJ, Nondahl DM, Tweed TS, et al. Education, occupation, noise exposure history and the 10-yr cumulative incidence of hearing impairment in older adults. Hear Res. 2010;264(1–2):3–9. • Lin FR, Chien WW, Li L, et al. Cochlear implantation in older adults. Medicine (Baltimore). 2012;91(5):229–241. • Valente M. Summary guidelines: audiological management of adult hearing impairment. Audio Today. 2006;18:32–37.

CODES ICD10 • H91.10 Presbycusis, unspecified ear • H91.13 Presbycusis, bilateral • H91.11 Presbycusis, right ear

CLINICAL PEARLS • Presbycusis is an age-related HL, showing increased incidence with age. It is often bilateral and initially begins as high-frequency HL. It presents as difficulty communicating in noisy conditions. • There are more affected males than females. • Compliance is only 25–40% for those who own HA. A referral to an audiologist is key for optimal evaluation, fitting for HAs, and other assistive technologies or surgical treatment. • Indication for CIs include hearing no better than identifying ≤50% key words in test sentences in the best aided condition in the worst ear and 60% in the better ear. • Early audiology referral for individuals with suspected HL may improve

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treatment efficacy.

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PRESSURE ULCER Amy M. Zack, MD, FAAFP BASICS DESCRIPTION • A localized area of soft tissue injury resulting from pressure between an external surface and a bony prominence that causes local tissue breakdown classified in stages according to the National Pressure Ulcer Advisory Panel (NPUAP) classification. – Stage I: erythema of localized area, usually nonblanching over bony surface; may be painful, have consistency or temperature difference from surrounding tissue – Stage II: partial loss of dermal layer, resulting in pink ulceration; may be fluid-filled blister, or shiny, dry ulcer – Stage III: Full dermal loss often exposing subcutaneous tissue and fat. – Stage IV: Full-thickness ulceration exposing bone, tendon, or muscle. Osteomyelitis may be present. • Synonym(s): decubitus ulcer; bed sores

EPIDEMIOLOGY Incidence 2.5 million pressure ulcers treated yearly in United States in acute care facilities (1)

Prevalence • Acute care 0.4–38%; long-term care 2.2–23.9%; home care 0–17% • Majority occur in patients >65 years: 36% with hip fracture, 50% in ICU care (2)

ETIOLOGY AND PATHOPHYSIOLOGY • Pathophysiology of pressure ulcers is changing, differs depending on stage of ulceration. • Stages I to II result largely from prolonged moisture and friction and may not

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even be related to pressure and hypoxia, as previously believed (3). • Stages III to IV likely begin with compressive forces, causing muscle damage and tissue hypoxia and leading to reperfusion injury of the deep tissue. The skin ulcer forms after significant deep tissue damage is already under way (3). • Shearing and friction forces are also components of some ulcer formation, resulting in localized skin damage and early-stage ulcers (3).

RISK FACTORS • Immobility: greatest risk factor regardless of patient, temporary or permanent immobility (4) • Urinary and fecal incontinence present in >80% of immobile patients with pressure ulcers • Poor nutritional status: Hypoalbuminemia and low BMI are markers for poor ulcer outcome (4). • Poor skin perfusion, including vascular disease, diabetes, anemia, and tobacco use, increases risk. • Extended stay in hospital/nursing home, inadequate staffing (5) • Other risks include history of previous ulcer, age-related skin changes, immunocompromise, impaired skin sensation, and impaired awareness. • Assessment scales commonly used for risk evaluation include Braden and Norton scales. The use of these does not decrease incidence, but they are more accurate than clinical judgment alone (6)[A].

GENERAL PREVENTION • Up to 95% are preventable; identification of at-risk patients within 8 hours of admission, with early multidisciplinary care. • Skin assessment: policy in all health care settings (5)[B] – Increase frequency of assessments with decline in clinical condition (5)[C]. – Include erythema, edema, skin temperature, and consistency in all evaluation (5)[B]. – Assess around medical devices twice daily (5)[C]. • Pressure relief – Establish pressure relief schedule. – Proper patient positioning and the use of mattresses, cushions, heel protectors, and other devices to minimize pressure and friction

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– Regular turning of patients, including the use of angles and rotation of extremities, helps to minimize pressure. • Avoid positioning on area of erythema (5)[C]. • Minimize duration of immobility: adequate physical and occupational therapies when appropriate • Aggressive moisture prevention: management plan for incontinence (5)[C] • Nutrition – Complete assessment of nutritional status and form plan, particularly protein intake and albumin levels. – Reassess with all changes in condition. – Develop individualized nutritional care plan for protein, calories, vitamins, and hydration (5)[C]. • Manage skin health: clean and dry with mild cleansers, skin protection where appropriate. Avoid massage or rubbing skin prone to ulcers (5)[C]. • Microclimate control: emerging therapy, control moisture, and temperature when selecting support structure. Avoid use of heating devices (5)[C]. • Prophylactic dressings: emerging therapy, apply foam dressing to bony prominences to avoid friction and shear (5)[B]. • Textiles and fabrics: Sheets and clothing should be silk-like rather than cotton or other abrasives.

COMMONLY ASSOCIATED CONDITIONS See “Risk Factors.”

DIAGNOSIS HISTORY • Risk factors • Date of ulcer diagnosis • Treatment course

PHYSICAL EXAM • Do full skin examination on admission to hospital or extended-care facility and repeatedly throughout admission, best with bathing/bed changes. • 83% of hospitalized patients with decubitus ulcers develop them in first 5 days

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of hospitalization. • Classify ulcer based on NPUAP stages (see “Description”). – Focus on skin color, consistency, and temperature changes when classifying ulcer. – Assess and document location, category, size, tissue, color, edges, sinus tracts, exudate, odor. – Assess pain (5)[B].

DIFFERENTIAL DIAGNOSIS • Venous stasis ulcers • Arterial ulcers resulting from poor vascular supply • Diabetic ulcers • Pyoderma gangrenosum, cancers, vasculitides, and other dermatologic conditions

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Wound culture: Do not culture surface drainage. If culture necessary, do deep tissue culture/bone biopsy. • If systemic infection or that of bone, muscle is suspected, add infectious workup, including inflammatory markers, CBC, blood cultures, x-ray. MRI may be necessary to confirm osteomyelitis. • Nutritional assessment: BMI, protein and calorie intake, albumin, prealbumin, CBC for anemia. No clear evidence in support of specific nutritional supplements including zinc and vitamin C (7)[A],(8)[B]. Follow-Up Tests & Special Considerations Additional tests may be indicated when additional medical illness complicates assessment. This may include testing for diabetes, vascular disease, and other dermatologic diagnoses.

TREATMENT GENERAL MEASURES • Pressure reduction, minimize immobility, manage incontinence, and improve

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nutritional status and skin health (as described in “Prevention”) • Wound management by stage of ulcer – Stage I: aggressive preventive measures, thin film dressings for protection – Stage II: occlusive dressing to maintain healing, transparent films, hydrocolloids – Stages III to IV: débridement of necrotic tissue. Exudative ulcers will benefit from absorptive dressings such as calcium alginates, foams, hydrofibers. Dry ulcers require occlusive dressing to maintain moisture, including hydrocolloids, and hydrogels. – Débridement: type depends on extent of necrosis or eschar, or presence of biofilm; incisional with scalpel when extensive dry. Mechanical with wetdry dressings; enzymatic débridement is also frequently used. Débride only when there is adequate perfusion to wound. – Surgical closure may be necessary in advanced wounds. • Vacuum-assisted closure – Negative pressure reduces wound edema and improves local tissue perfusion. – Removes necrotic debris and reduces bacterial load – Literature review demonstrates the efficacy of negative-pressure wound therapy (9)[A]. • Dressings: mixed evidence for improvement (10)[B] – Select based on wound, exudate, ulcer stage. – Gauze: Avoid use, if no other options, wet-to-dry only. – Hydrocolloid: clean, shallow Stage II, not infected – Transparent: autolytic débridement, not for use on heavy exudate or over enzymatic debriding agents – Hydrogel: Stage II, shallow, minimal exudate, not infected – Alginate: Stage II to III, shallow with heavy exudate, infected, long duration dressing – Foam: Stage II to III, shallow with heavy exudate – Collagen-matrix: nonhealing Stage III to IV – Silver impregnated: infected or heavily colonized, high risk infection, short duration only – Honey impregnated: Stage II/III

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– Cadexomer iodine: Stage II/III with heavy exudate

MEDICATION First Line • See “General Measures” for first-line treatment. • Pain control • Aggressive management of contributing medical conditions • Infection: If suspected, treat appropriately for cellulitis or osteomyelitis. – High index of suspicion for infection: poor healing, odor, pain, warmth, drainage, necrosis, diabetes, malnutrition, poor perfusion, immunosuppression, culture with >105 cfu/g or GBS presence • Topical therapy – Débride as indicated – Nontoxic topical anesthetics including iodine, silver sulfadiazine, chlorhexidine (avoid hydrogen peroxide, Dakin solution) (5)[C]

Second Line Nutritional interventions as determined by nutritional assessment. Weak evidence to support protein supplementation to reduce wound size (10)[C]

ISSUES FOR REFERRAL • Vascular surgery is a consideration for improvement of blood flow to wound via vascular bypass. • Plastic surgery is a consideration for skin graft/flap.

ADDITIONAL THERAPIES • Alternative therapies – Light, laser, acoustic have little shown benefit. – Whirlpool contraindicated (5)[B] – Electrical stimulation shows some benefit (10)[B].

COMPLEMENTARY & ALTERNATIVE MEDICINE • Nutritional support as needed • Ultrasound and electrical stimulation create new vasculature in affected region (9)[C].

ADMISSION, INPATIENT, AND NURSING

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CONSIDERATIONS • Admission criteria/initial stabilization: refractory cellulitis, osteomyelitis, systemic infection, advanced nutritional decline, suspected patient mistreatment, inability to care for self • Dressing changes 1 to 3 times daily based on wound assessment and plan of care • Assess risk factors according to scales. • Assess for new or changing wounds. • Discharge criteria: clinical improvement in wound and systemic illness; when applicable, safe, and appropriate location for discharge

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Weekly assessment by nurse with wound experience; biweekly assessment by physician

Patient Monitoring • Home health nursing • Change in plan of care if no improvement in 2 to 3 weeks

DIET • 1 to 1.5 kg/day of protein • Good glycemic control • Include supply of micronutrients in diet or as supplements.

PATIENT EDUCATION • Check skin regularly. • Signs and symptoms of infection • Report new or increased pain. • Prevention of new wound where old wound healed • Skin care, moisture prevention

PROGNOSIS Variable, depending on the following:

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• Removal of pressure • Nutrition • Wound care

COMPLICATIONS • Infection • Amputation

REFERENCES 1. Reddy M, Gill S, Rochon P. Preventing pressure ulcers: a systematic review. JAMA. 2006;296(8):974–984. 2. Baumgarten M, Margolis DJ, Orwig DL, et al. Pressure ulcers in elderly patients with hip fracture across the continuum of care. J Am Geriatr Soc. 2009;57(5):863–870. 3. Sibbald RG, Krasner DL, Woo KY. Pressure ulcer staging revisited: superficial changes & Deep Pressure Ulcer Framework. Adv Skin Wound Care. 2011;24(12):571–580. 4. Cakmak S, Gül U, Ozer S, et al. Risk factors for pressure ulcers. Adv Skin Wound Care. 2009:22(9):412–415. 5. European Pressure Ulcer Advisory Panel and National Pressure Ulcer Advisory Panel. Prevention and Treatment of Pressure Ulcers: Quick Reference Guide. Washington, DC: National Pressure Ulcer Advisory Panel, European Pressure Ulcer Advisory Panel, Pan Pacific Pressure Injury Alliance; 2014. 6. Pancorbo-Hidalgo PL, Garcia-Fernandez FP, Lopez-Medina IM, et al. Risk assessment scales for pressure ulcer prevention: a systematic review. J Adv Nurs. 2006;54(1):94–110. 7. Langer G, Schloemer G, Knerr A, et al. Nutritional interventions for preventing and treating pressure ulcers. Cochrane Database Syst Rev. 2003; (4):CD003216. 8. Jamshed N, Schneider E. Is the use of supplemental vitamin C and zinc for the prevention and treatment of pressure ulcers evidence based? Ann LongTerm Care Med. 2010;18(3):28–32. 9. Gregor S, Maegele M, Sauerland S, et al. Negative pressure wound therapy:

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a vacuum of evidence? Arch Surg. 2008;143(2):189–196. 10. Qaseem A, Humphrey LL, Forciea MA, et al. Treatment of pressure ulcers: a clinical practice guideline from the American College of Physicians. Ann Intern Med. 2015;162(5):370–379.

ADDITIONAL READING Stansby G, Avital L, Jones K, et al. Prevention and management of pressure ulcers in primary and secondary care: summary of NICE guidance. BMJ. 2014;348:g2592.

CODES ICD10 • L89.95 Pressure ulcer of unspecified site, unstageable • L89.91 Pressure ulcer of unspecified site, stage 1 • L89.92 Pressure ulcer of unspecified site, stage 2

CLINICAL PEARLS • Create assessment and prevention protocols for all patients. • Identify risk, reduce pressure, maximize nutrition, regular skin checks, and assess and treat wound appropriately. • All care needs to be done in time-sensitive, patient-centered fashion.

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PRETERM LABOR Kara M. Coassolo, MD • John C. Smulian, MD, MPH BASICS DESCRIPTION Contractions occurring between 20 and 36 weeks’ gestation at a rate of 4 in 20 minutes or 8 in 1 hour with at least one of the following: cervical change over time or dilation ≥2 cm (1)

EPIDEMIOLOGY Preterm birth is the leading cause of perinatal morbidity and mortality in the United States.

Incidence 10–15% of pregnancies experienced at least one episode of preterm labor.

Prevalence ~12% of all births in the United States are preterm (9% spontaneous preterm births and 3% indicated preterm births).

ETIOLOGY AND PATHOPHYSIOLOGY • Premature formation and activation of myometrial gap junctions • Inflammatory mediator–stimulated contractions • Weakened cervix (structural defect or extracellular matrix defect) • Abnormal placental implantation • Systemic inflammation/infections (e.g., UTI, pyelonephritis, pneumonia, sepsis) • Local inflammation/infections (intra-amniotic infections from aerobes, anaerobes, Mycoplasma, Ureaplasma) • Uterine abnormalities (e.g., cervical insufficiency, leiomyomata, müllerian anomalies, diethylstilbestrol exposure) • Overdistension (by multiple gestation or polyhydramnios) • Preterm premature rupture of membranes • Trauma

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• Placental abruption • Immunopathology (e.g., antiphospholipid antibodies) • Placental ischemic disease (preeclampsia and fetal growth restriction)

Genetics Familial predisposition

RISK FACTORS • Demographic factors, including single parent, poverty, and black race • Short interpregnancy interval • No prenatal care • Prepregnancy weight 97% of patients will not deliver in 14 days, so can consider avoiding complicated or high-risk interventions. • Urinalysis and urine culture • Cultures for gonorrhea and chlamydia • Wet prep for bacterial vaginosis evaluation (although evidence for improved outcomes with treatment is weak) • Vaginal introitus and rectal culture for group B Streptococcus • pH and ferning test of vaginal fluid to evaluate for rupture of membranes • CBC with differential • Drug screen when appropriate

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• US to identify number of fetuses and fetal position, confirm gestational age, estimate fetal weight, quantify amniotic fluid, and look for conditions making tocolysis contraindicated. • Transvaginal US to evaluate cervical length, funneling, and dynamic changes after obtaining FFN (if clinical assessment of the cervix is uncertain or if the cervix is closed on digital exam) Follow-Up Tests & Special Considerations • Repeat FFN as indicated by symptoms. • After successful treatment, progressive changes of the cervix on repeat examination or US (in 1 to 2 weeks) may indicate need for hospitalization.

Diagnostic Procedures/Other • Monitor contractions with external tocodynamometer. • Consider amniocentesis at any preterm gestational age to evaluate for intraamniotic infection (cell count with differential, glucose, Gram stain, aerobic, anaerobic, Mycoplasma, Ureaplasma cultures).

Test Interpretation • Placental inflammation – Acute inflammation usually caused by infection – Chronic inflammation caused by immunopathology • Abruption

TREATMENT GENERAL MEASURES • Treat underlying risk factors (e.g., antibiotics for infections, hydration for dehydration). • Liquids only or NPO if delivery is imminent • Hospitalization is necessary if the patient is on IV tocolysis.

MEDICATION Tocolysis may allow time for interventions such as transfer to tertiary care facility and administration of corticosteroids but may not prolong pregnancy significantly (4)[A].

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First Line • Tocolysis – Nifedipine: 30 mg PO loading dose; then 10 to 20 mg q6h for 24 hours; then 10 to 20 mg PO q8h (do not use sublingual route); check BP often and avoid hypotension. Concurrent use with magnesium sulfate should be avoided to avoid theoretic risk of neuromuscular blockade. – Indomethacin: 50 to 100 mg PO initial dose; then 25 to 50 mg q6–8h for 24 hours (or, if available, 100-mg suppository per rectum q12h for 2 doses); then 25 mg q6–8h; use for no longer than 72 hours due to risk of premature closure of ductus arteriosus, oligohydramnios, and possibly neonatal necrotizing enterocolitis. Use with caution in patients with platelet dysfunction, liver dysfunction, or allergy to aspirin. – Contraindications to tocolysis: severe preeclampsia, hemorrhage, chorioamnionitis, advanced labor, intrauterine growth retardation, fetal distress, or lethal fetal abnormalities • Antibiotics: antibiotics for group B Streptococcus prophylaxis if culture is positive or unknown • Steroids: If mother is at 23 to 34 weeks’ gestation with no evidence of systemic infection, give glucocorticoids to decrease neonatal respiratory distress, intraventricular hemorrhage, necrotizing enterocolitis, and overall perinatal mortality. Betamethasone 12 mg IM × 2 doses 24 hours apart (preferred choice) or dexamethasone 6 mg IM q12h for 4 doses (5)[A] • Steroids may reduce the risk of respiratory morbidities in infants born in the late preterm period (34+0 to 36+6 weeks gestation). If delivery is likely during this time period, administration of steroids may be considered as above. Tocolysis is not recommended (6)[A].

Second Line • Magnesium sulfate by IV infusion has not been shown to be superior to placebo in prolonging pregnancy beyond 48 hours. The side effects are generally greater compared with calcium channel blockers or NSAIDs. Therefore, this agent should be used cautiously if at all (standard dosages for tocolysis start with a 4- to 6-g IV bolus over 20 minutes followed by 2 to 3 g/hr infusion until contractions stop).

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– Magnesium may decrease the risk of cerebral palsy when 12-hour course is given prior to an anticipated preterm birth. – Relative contraindications to magnesium sulfate include myasthenia gravis, hypocalcemia, renal failure, or concurrent use of calcium channel blockers. • Terbutaline 0.25 mg SC q30min for up to 3 doses until contractions stop and then 0.25 mg SC q6h for 4 doses (optional); if contractions persist or pulse >120 bpm, change to another tocolytic agent (may be poorly tolerated by mothers). • Terbutaline PO or by infusion pump has been used in the past for treatment or prevention of preterm labor. Due to reports of serious cardiovascular events and maternal deaths, PO or long-term SC administration of terbutaline should not be given. • Significant possible interactions include pulmonary edema from crystalloid fluids and tocolytic agents, especially magnesium sulfate. • PO maintenance therapy with any agent is ineffective and is not recommended.

ISSUES FOR REFERRAL • If delivery is inevitable but not immediate, consider transport to a tertiary care center or hospital equipped with a neonatal ICU. • Consider consultation with maternal–fetal medicine specialist.

ADDITIONAL THERAPIES • Pelvic rest (e.g., no douching or intercourse) and activity restriction are often recommended; however, data to prove the efficacy are lacking. Some reduction in physical activity may be reasonable; this should be individualized. • Strict bed rest has not been demonstrated to be effective in most situations.

SURGERY/OTHER PROCEDURES • For malpresentation or fetal compromise, consider cesarean delivery if labor is progressing. • Cerclage for cervical insufficiency (until 24 weeks’ gestation)

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS

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Suspected/threatened preterm labor • IV access • Continuous fetal and contraction monitoring • Assess cervix for dilatation and effacement. • Hydrate with 500 mL 5% dextrose normal saline solution or 5% dextrose lactated Ringer solution for first half hour; then at 125 mL/hr. • Monitor for fluid overload (input/output monitoring, symptoms, lung auscultation, pulse oximetry), especially with tocolysis and multiple gestations.

Discharge Criteria • Regular contractions and cervical change resolve. • If cervix is dilated ≥3 cm or FFN is positive, individualize decision to discharge by gestational age and patient circumstances.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Weekly office visits with contraction monitoring, cervical checks, or cervical US if at high risk for recurrence • Routine use of maintenance tocolysis is ineffective in preventing preterm birth.

DIET Regular

PATIENT EDUCATION Call physician or proceed to hospital whenever regular contractions last >1 hour, bleeding, increased vaginal discharge or fluid, decreased fetal movement.

PROGNOSIS • If membranes are ruptured and no infection is confirmed, delivery often occurs within 3 to 7 days. • If membranes are intact, 20–50% deliver preterm.

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COMPLICATIONS Labor resistant to tocolysis, pulmonary edema, infection with preterm rupture of membranes

REFERENCES 1. Practice Bulletin no. 159: management of preterm labor. Obstet Gynecol. 2016;127(1):e29–38. 2. Simhan HN, Caritis SN. Prevention of preterm delivery. N Engl J Med. 2007;357(5):477–487. 3. Berghella V, Rafael TJ, Szychowski JM, et al. Cerclage for short cervix on ultrasonography in women with singleton gestations and previous preterm birth: a meta-analysis. Obstet Gynecol. 2011;117(3):663–671. 4. Haas DM, Caldwell DM, Kirkpatrick P, et al. Tocolytic therapy for preterm delivery: systematic review and network meta-analysis. BMJ. 2012;345:e6226. 5. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2006;(3):CD004454. 6. Society for Maternal-Fetal Medicine (SMFM) Publications Committee. Implementation of the use of antenatal corticosteroids in the late preterm birth period in women at risk for preterm delivery. Am J Obstet Gynecol. 2016;215(2):B13–B15.

ADDITIONAL READING • American College of Obstetricians and Gynecologists Committee on Obstetric Practice; Society for Maternal-Fetal Medicine. Committee opinion no. 455: magnesium sulfate before anticipated preterm birth for neuroprotection. Obstet Gynecol. 2010;115(3):669–671. • Goldenberg RL, Goepfert AR, Ramsey PS. Biochemical markers for the prediction of preterm birth. Am J Obstet Gynecol. 2005;192(Suppl 5):S36– S34. • Tita AT, Rouse DJ. Progesterone for preterm birth prevention: an evolving intervention. Am J Obstet Gynecol. 2009;200(3):219–224.

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CODES ICD10 • O60.00 Preterm labor without delivery, unspecified trimester • O60.02 Preterm labor without delivery, second trimester • O60.03 Preterm labor without delivery, third trimester

CLINICAL PEARLS • Treatment of preterm labor may delay delivery to facilitate short-term interventions. • Steroids improve neonatal outcomes. • Progesterone therapy can prevent recurrence of preterm birth in next pregnancy.

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PRIAPISM Shenelle Wilson, MD • Kelvin A. Moses, MD, PhD BASICS DESCRIPTION • Penile erection that lasts for >4 hours and is unrelated to sexual stimulation or excitement • Classified into ischemic and nonischemic types • Ischemic (low-flow) priapism is painful and requires urgent clinical intervention. • Stuttering priapism is recurrent episodes of short-lived, self-limiting ischemic priapism over an extended period. • Nonischemic (high-flow) priapism is painless, could be related to prior trauma, and does not require urgent treatment. • Malignant priapism is a rare condition resulting most commonly from penile metastases from primary bladder, prostatic, rectosigmoid, and renal tumors. • System(s) affected: reproductive

Pediatric Considerations In children, nearly all priapism is caused by either sickle cell anemia or trauma (1).

EPIDEMIOLOGY Incidence In the United States, one study estimates 1,868 to 2,960 cases of priapism each year. They also noted an increasing incidence from 1998 to 2006, specifically in those from nonhematologic causes: • Mean age: 33.7 years. There has been an age shift in recent years toward men in their 40s. • Other studies have found the incidence of priapism to double in men aged >40 years (2.9 vs. 1.5/100,000 person-years). • Race: 61.1% black, 30% white, 6.3% Hispanic • Associations: sickle cell anemia (41.9%), drug abuse (7.9%), sickle cell trait

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(2.5%) • Anatomy and physiology – The penis consists of three longitudinally oriented corpora: two dorsolaterally paired corpora cavernosa that are responsible for penile erection and a single ventral corpus spongiosum that surrounds the glans penis and extends distally to form the glans penis. – In general, the penile artery (which is a branch of the internal pudendal artery that, in turn, is a branch from the internal iliac artery) supplies the penis. It divides into three branches: dorsal artery, bulbar artery (supplies the corpus spongiosum), and cavernosal artery (the main blood supply to the erectile tissue). – During an erection, smooth muscle relaxation of the cavernosal arterioles results in high-volume inflow to the sinusoids, resulting in compression of the exiting venules. This leads to significant volume expansion of the corpora cavernosa. – During the flaccid resting state, the sympathetic nervous system is predominantly in control. Penile tumescence and erection are driven by the parasympathetic nervous system through the generation of nitric oxide (NO). – Smooth muscle relaxation occurs via usage of the phosphodiesterase type 5 (PDE-5A) pathway, which generates cyclic guanosine monophosphate (cGMP).

ETIOLOGY AND PATHOPHYSIOLOGY • In ischemic priapism, decreased venous outflow results in increased intracavernosal pressure. This leads to erection, decreased arterial inflow, blood stasis, local hypoxia, and acidosis (a compartment syndrome). Eventually, penile tissue necrosis and fibrosis may occur. The exact mechanism is unknown and may involve trapping of erythrocytes in the veins, draining the erectile bodies. • In nonischemic priapism, there is increased arterial flow without decreased venous outflow. There is increased inflow and outflow, which results in a sustained, nonpainful, partially rigid erection. • Aberrations in the PDE-5A pathway have been proven in mice to be one mechanism of priapism.

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• Ischemic priapism – Idiopathic, estimated to about 50% (1) – Intracavernosal injections of vasoactive drugs for erectile dysfunction – Oral agents for erectile dysfunction – Pelvic vascular thrombosis – Prolonged sexual activity – Sickle cell disease and trait – Leukemia and other malignancies that can infiltrate the corpora – Other blood dyscrasias (G6PD deficiency, thrombophilia) – Pelvic hematoma or neoplasia (penis, urethra, bladder, prostate, kidney, rectal) – Cerebrospinal tumors – Asplenism – Fabry disease – Tertiary syphilis – Total parenteral nutrition, especially 20% lipid infusion (results in hyperviscosity) – Bladder calculus – Trauma to penis – UTIs, especially prostatitis, urethritis, cystitis – Several drugs suspected as causing priapism (e.g., chlorpromazine, prazosin, cocaine, trazodone, and some corticosteroids), anticoagulants (heparin and warfarin), phosphodiesterase inhibitors (sildenafil, others), immunosuppressants (tacrolimus); and antihypertensives (hydralazine, propranolol, guanethidine) – Intracavernous fat emulsion – Hyperosmolar IV contrast – Spinal cord injury – General or spinal anesthesia – Heavy alcohol intake or cocaine use • Nonischemic priapism – The most common cause is penile or perineal trauma resulting in a fistula between the cavernous artery and the corpora. – Acute spinal cord injury

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– Rarely, iatrogenic causes for the management of ischemic priapism can result in nonischemic priapism. – Certain urologic surgeries have also resulted in nonischemic priapism.

RISK FACTORS • Sickle cell anemia, lifetime risk of ischemic priapism 29–42% (1) • Dehydration

GENERAL PREVENTION • Avoid dehydration. • Avoid excessive sexual stimulation. • Avoid causative drugs (see “Etiology and Pathophysiology”) when possible. • Avoid genital and pelvic trauma.

COMMONLY ASSOCIATED CONDITIONS • Sickle cell anemia or sickle cell trait • Drug abuse • G6PD deficiency • Leukemia • Neoplasm

DIAGNOSIS HISTORY • Penile erection that is persistent, prolonged, painful, and tender (ischemic). • Duration of erection, degree of pain • Perineal or penile trauma • Prior episodes of priapism • Urination difficult during erection • History of any hematologic abnormalities • Cardiovascular disease • Medications • Recreational drugs • Loss of erectile function if treatment is not prompt and effective

PHYSICAL EXAM

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• Ischemic priapism – Penis is fully erect, corpora cavernosa are rigid and tender, and corpora spongiosum and glans are flaccid. Usually associated with tenderness and pain • Nonischemic priapism – Penis is partially erect and the corpora cavernosa are semirigid and nontender, with the glans and corpora spongiosum flaccid. Usually not tender or painful • Perineum, abdomen, and lymph node exam also valuable to rule out underlying condition • A complete penile and scrotal exam is necessary. Determine if a penile prosthesis is present.

DIAGNOSTIC TESTS & INTERPRETATION • CBC with reticulocyte count to detect leukemia or platelet abnormalities • Sickling hemoglobin (Hgb) solubility test and Hgb electrophoresis • Coagulation profile • Platelet count • Urinalysis • Urine toxicology if illicit drugs suspected • Corporal blood gas (CBG) should be used to distinguish ischemic from nonischemic priapism. • A color duplex ultrasound of the penis and perineum may be necessary to differentiate ischemic from nonischemic priapism. In ischemic priapism, there is no blood flow in the cavernosal arteries, whereas in nonischemic patients, there is high blood flow (1); may also see fistulas or pseudoaneurysms suggestive of nonischemic priapism • Penile arteriography can be used to identify the presence and site of fistulas in patients with nonischemic priapism.

Diagnostic Procedures/Other A physical exam is usually able to distinguish ischemic from nonischemic priapism; however, CBG is the most definitive method.

Test Interpretation

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• Pelvic vascular thrombosis • Partial thrombosis of corpora cavernosa of the penis • Corpus spongiosum, glans penis: no involvement • Arterial priapism will show arteriocavernous fistula.

TREATMENT • Ischemic priapism requires immediate treatment to preserve future erectile function (a longer delay in treatment means a higher chance of future impotence). – Cavernosal aspiration with a large bore needle with irrigation (success rate ~30%) (1,2) – Cavernosal injection of phenylephrine (α-adrenergic sympathomimetic) with monitoring of patient’s BP and pulse (success rate ~65%) (2). Inject q5–10min until detumescence. – Continue aspiration, irrigation, and phenylephrine for several hours. If this fails, shunt procedures are considered (first a distal shunt). • Nonischemic priapism – Initial observation – If this fails, arteriography and embolization with absorbable materials (5% rate of impotence vs. 39% with permanent materials) or surgical ligation as a last resort (2) • Treat the underlying condition (i.e., sickle cell disease). Do not delay intracavernous treatment.

GENERAL MEASURES • Reassure the patient about the outcome, if warranted. • Provide continuous caudal or spinal anesthesia if the etiology is neurogenic. • Treat any underlying cause. • In sickle cell anemia: IV hydration; supplemental oxygen; partial exchange or repeated transfusions to reduce percentage of sickle cells to 24 hours. • Despite early intervention, ischemic priapism is likely to result in impotence in up to 50% of men.

COMPLICATIONS Erectile dysfunction (i.e., impotence)

REFERENCES 1. Huang YC, Harraz AM, Shindel AW, et al. Evaluation and management of priapism: 2009 update. Nat Rev Urol. 2009;6(5):262–271. 2. Montague DK, Jarow J, Broderick GA, et al. American Urological Association guideline on the management of priapism. J Urol. 2003;170(4, Pt 1):1318–1324.

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ADDITIONAL READING • Burnett AL. Pathophysiology of priapism: dysregulatory erection physiology thesis. J Urol. 2003;170(1):26–34. • Pryor J, Akkus E, Alter G, et al. Priapism. J Sex Med. 2004;1(1):116–120. • Salonia A, Eardley I, Giuliano F, et al. European Association of Urology guidelines on priapism. Eur Urol. 2014;65(2):480–489.

SEE ALSO Anemia, Sickle Cell; Erectile Dysfunction

CODES ICD10 • N48.30 Priapism, unspecified • N48.39 Other priapism • N48.31 Priapism due to trauma

CLINICAL PEARLS • Priapism is a prolonged penile erection that lasts >4 hours and is unrelated to sexual stimulation. • In evaluating priapism, the clinician must distinguish ischemic from nonischemic priapism by history and physical exam, as well as blood gas and possibly ultrasound, if needed. • Ischemic priapism is an emergent condition that requires immediate urologic evaluation and treatment. • The most common causes of ischemic priapism are idiopathic, related to treatments for erectile dysfunction, or related to use of substances (medicinal or recreational). • If an underlying medical condition is identified (sickle cell anemia), proper concomitant treatment is necessary to increase the efficacy of treatment.

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PROSTATE CANCER Sara L. Valente, MD • Jason K. Frankel, MD • Joseph R. Wagner, MD BASICS DESCRIPTION • The prostate is a male reproductive organ that contributes seminal fluid to the ejaculate. • The prostate gland is about the size of a walnut, averaging 20 to 25 g in volume in an adult male; tends to enlarge after age 50 years • Three distinct zones delineate the functional anatomy of the prostate: peripheral zone (largest, neighbors rectal wall, palpable on DRE, most common location for prostate cancer), central zone (contains the ejaculatory ducts), and transition zone (located centrally, adjacent to the urethra). • Prostatic epithelial cells produce prostate-specific antigen (PSA), which is used as a tumor marker and in screening.

EPIDEMIOLOGY Incidence According to the National Cancer Institute SEER data, an estimated 180,890 men in the United States will be newly diagnosed with carcinoma of the prostate (CaP) in 2016 (1).

Prevalence • About 2.8 million men are living with CaP in the United States (1). • An estimated 26,120 men in the United States will die of CaP in 2016 (1). • Mean age at diagnosis is 66 years. • Prostate cancer is the most commonly diagnosed nonskin cancer in men in the United States (~14.0% lifetime risk) and second leading cause of cancer death in men (only ~3% of all CaP results in CaP-related death) (1). • Autopsy studies find foci of latent CaP in 50% of men in their 8th decade of life. • Probability of clinical CaP 10.9% (1 in 9) in men aged ≥70 years

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ETIOLOGY AND PATHOPHYSIOLOGY • Adenocarcinoma: >95%; nonadenocarcinoma: 50 years • African American race • Positive family history • Poorly understood environmental factors

GENERAL PREVENTION There are no FDA-approved drugs or diet modifications to prevent CaP. • Finasteride has been studied for this purpose in a phase III trial called the Prostate Cancer Prevention Trial. A moderate risk reduction associated with an increased risk of high-grade disease was encountered. Therefore, it has not been FDA approved for prevention (2)[A].

ALERT Screening for prostate cancer is controversial: • U.S. Preventive Services Task Force (USPSTF) recommends against PSAbased screen for prostate cancer, concluding the harm of screening outweighs benefit (3)[A]. • For men ages 55 to 69 years, the AUA panel recommends shared decision making between physician and patient regarding PSA screening. • PSA screening is not recommended in men under age 40 years, over age 70 years, or any man with 20% baseline for higher values increases CaP risk. – Free PSA and age/race-adjusted PSA helpful in evaluating risk. For patients with PSA between 4 and 10 ng/mL, a low percent free PSA is associated with higher risk of CaP. – PSAD (PSA density) ≥0.15 associated with higher prevalence of CaP. – Screening tests that utilize serum biomarkers in conjunction with clinical information to predict CaP risk are also available (e.g., 4Kscore, PHI). • Prostate biopsy – Decision to biopsy involves PSA, DRE findings, and overall clinical suspicion of CaP with consideration of comorbidities and life expectancy. – Standard biopsy includes systematic random cores from the peripheral zone-base, mid, and apex, generally 8 to 12 cores. – The Gleason Grade is the standard pathologic grading system: Ranks specimens from 1 (most differentiated) to 5 (least differentiated) based on architectural pattern identified Primary and secondary patterns are identified and reported, and the sum is the Gleason score (e.g., 3 + 4 = 7). Most prostate cancer are scored 6 to 10, with 10 having the worst prognosis. • Staging (5) – TNM (tumor, node, and metastasis) staging is used to generate a clinical and pathologic stage, which primarily directs treatment. Clinical staging is as follows: T1: cancer found incidentally on TURP or found on biopsy for elevated PSA T2: cancer found on DRE but confined to the prostate T3: cancer found to be extended locally outside of the prostate and/or the seminal vesicle T4: invading adjacent organs N1: denotes local lymph node spread M1: distant metastasis Follow-Up Tests & Special Considerations

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• Bone scan and/or CT scan and/or MRI may be indicated for high-risk cancers. • Biopsy if suspicious nodal findings • Alkaline phosphatase associated with bony mets • Genetic testing (e.g., Prolaris, Oncotype Dx, Decipher) is emerging as a prognostic modality.

TREATMENT Treatment options include: • Watchful waiting: monitoring with expectation to provide palliation with symptoms • Active surveillance: close monitoring of PSA, DRE, and repeat biopsy at regular intervals (6) • Radical prostatectomy: ± pelvic lymph node dissection (PLND) • Radiation therapy: external beam (EBRT) • ProtecT trial (2016) found watchful waiting had equal cancer-specific and allcause mortality compared to surgery or radiotherapy. In the treatment arms, there was approximately 50% less disease progression (including metastatic disease) but resulted in significantly more morbidity (urinary and bowel dysfunction, erectile dysfunction) (7)[B]. • Brachytherapy: radioactive implants placed in prostate; option for early clinical stage localized to the prostate • Androgen deprivation therapy (ADT) may be surgical or nonsurgical: – Bilateral orchiectomy (surgical castration) – Gonadotropin-releasing hormone (GnRH) agonist, antagonist, or antiandrogen (medical castration) • Chemotherapy: includes multiple chemotherapeutic agents used to treat castrate-resistant prostate cancer

RISK STRATIFICATION • Treatment options based on risk: low-, intermediate-, and high-risk categories; this is based on risk of recurrence after definitive treatment. Must meet all three criteria to be low risk; any one criterion moves patient to a higher risk group (5,8)[A]:

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• Localized CaP – Low risk: Mainstay of therapy is active surveillance. Radical prostatectomy and radiation therapy may be offered. – Intermediate risk: Mainstay of therapy is radical prostatectomy or radiation therapy. Radical prostatectomy has shown a possible survival benefit in intermediate- and high-risk prostate cancer (9)[A]. – High risk: Mainstay of therapy is radical prostatectomy or radiation therapy. Adjuvant radiation may be considered based on adverse pathologic findings after prostatectomy.

ALERT Life expectancy determination as well as educating the patient of the risks and benefits of surveillance and treatment options is critical. • Locally advanced CaP: – Mainstay of therapy is ADT and radiation. Surgery and adjuvant radiation may also play a role. • Metastatic CaP: – Mainstay of therapy is RT and ADT. – Early chemotherapy (docetaxel) may be considered for high-volume disease. – ADT specifics: GnRH agonists include leuprolide or goserelin. GnRH antagonists include degarelix: an alternative to GnRH agonists; suppresses testosterone production and avoids flare phenomenon observed with GnRH agonists Side effects of ADT: osteoporosis, gynecomastia, erectile dysfunction

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(ED), decreased libido, obesity, lipid alterations, greater risk of diabetes, and cardiovascular disease Flare phenomenon (disease flare: hot flashes, fatigue) can occur owing to transient increase in testosterone levels on initiation of GnRH agonist therapy. If spinal cord metastases are present, the concern for cord compression with a testosterone flare can be avoided by starting antiandrogen therapy prior to initiation of a GnRH agonist. Combined androgen blockade with GnRH agonist and antiandrogen (e.g., bicalutamide, nilutamide, or flutamide) may be used to prevent flare. • Castration-resistant prostate cancer (CRPC) – CRPC is defined as progression of disease following ADT. Treatment includes the following: Nonmetastatic Continue ADT, no further treatment has been shown to increase overall survival. Antiandrogen or androgen synthesis inhibitor (e.g., ketoconazole) may be added. Asymptomatic metastatic: no previous therapy with docetaxel: Abiraterone: inhibitor of CYP17A (adrenal androgen production), used with prednisone Enzalutamide: androgen receptor inhibitor Docetaxel: chemotherapeutic that inhibits microtubules Sipuleucel-T: immunotherapy Symptomatic metastatic: no previous therapy with docetaxel Abiraterone, enzalutamide, docetaxel Radum-223 (radiopharmaceutical) for patients with symptomatic bony metastases and no visceral metastasis Symptomatic metastatic: previous therapy with docetaxel: Good performance status: abiraterone, enzalutamide, cabazitaxel Poor performance status: Mainstay is palliative care; may attempt further therapy based on patient wishes

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ONGOING CARE FOLLOW-UP RECOMMENDATIONS • Prostatectomy: PSA and DRE are recommended at regular intervals. PSA threshold-defining biochemical recurrence is evolving; however, recent data suggests a cutoff of 0.2 ng/mL (8). A CT and bone scan are usually obtained. If the PSA recurrence is thought to be from local disease, salvage radiation is considered. For metastatic disease, androgen deprivation is considered (5). • XRT: PSA and DRE are recommended at regular intervals. Biochemical recurrence is defined as PSA increase ≥2 ng/mL above nadir; a CT and bone scan is usually obtained. If the PSA recurrence is thought to be from local disease, salvage prostatectomy or cryosurgery is considered. For metastatic disease, androgen deprivation is considered (5).

PROGNOSIS • Localized disease is frequently curable; advanced disease has a favorable prognosis if lesions are hormone sensitive. • 5-year CaP survival by stage: local 100%, regional 100%, distant 29.3% (1) • Recurrence risk increased if adverse pathologic features are present: extraprostatic extension, seminal vesicle invasion, positive surgical margins

COMPLICATIONS • Prostatectomy: Urinary incontinence and ED are the most common long-term issues. • Radiation therapy: urinary incontinence, ED, radiation cystitis, and radiation proctitis • Treatment options for ED: PDE5 inhibitors, intracavernosal injections, intraurethral suppositories, vacuum pump, penile prosthesis • Treatment options for incontinence: oral medications, urethral sling, artificial sphincter

REFERENCES 1. National Cancer Institute: http://seer.cancer.gov. 2. Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride

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on the development of prostate cancer. N Engl J Med. 2003;349(3):215–224. 3. Moyer VA; U.S. Preventive Services Task Force. Screening for prostate cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2012;157(2):120–134. 4. Oesterling JE, Jacobsen SJ, Chute CG, et al. Serum prostate-specific antigen in a community-based population of healthy men: establishment of age specific reference ranges. JAMA. 1993;270(7):860–864. 5. National Comprehensive Cancer Network. Clinical Practice Guidelines: prostate cancer. 2016. https://www.nccn.org. Accessed October 12, 2016. 6. Klotz L. Active surveillance for low-risk prostate cancer. F1000 Med Rep. 2012;4:16. 7. Hamdy FC, Donovan JL, Lane JA, et al. 10-Year outcomes after monitoring, surgery, or radiotherapy for localized prostate cancer. N Engl J Med. 2016;375:1415–1424. 8. D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA. 1998;280(11):969–974. 9. Wilt TJ, Brawer MK, Jones KM, et al. Radical prostatectomy versus observation for localized prostate cancer. N Engl J Med. 2012;367(3):203– 213.

ADDITIONAL READING • Lowrance WT, Scardino PT. Predictive models for newly diagnosed prostate cancer patients. Rev Urol. 2009;11(3):117–126. • Pastuszak AW, Pearlman AM, Lai WS, et al. Testosterone replacement therapy in patients with prostate cancer after radical prostatectomy. J Urol. 2013;190(2):639–644. • Schröder FH, Hugosson J, Roobol MJ, et al. Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet. 2014;384(9959):2027– 2035.

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CODES ICD10 C61 Malignant neoplasm of prostate

CLINICAL PEARLS • Prostate cancer is clinically diverse, ranging from low-risk/indolent disease to high-risk/aggressive disease. • Most men with CaP are asymptomatic. • The use of PSA for CaP screening is controversial and necessitates an open conversation between medical provider and patient regarding benefits/risks. • Active surveillance is an important treatment option to consider for low-risk patients. • Care must be taken when interpreting PSA levels in patients taking 5-αreductase inhibitors

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PROSTATIC HYPERPLASIA, BENIGN (BPH) Sara M. DeSpain, MD • James E. Hougas, III, MD, FAAFP BASICS • Benign prostatic hyperplasia (BPH) is due to proliferation of both the smooth muscle and epithelial cell lines of the prostate which causes increased volume and may cause compression of the urethra and obstructive symptoms. • Clinically presents with storage and/or voiding symptoms collectively referred to as lower urinary tract symptoms (LUTS). These include difficulty initiating stream, frequency, or dysuria. • Symptoms do not directly correlate to prostate volume. It is estimated that half of all men with histologic evidence of BPH experience moderate to severe LUTS. • Progression may result in upper and lower tract infections and may progress to direct bladder outlet obstruction and acute renal failure (ARF).

EPIDEMIOLOGY Age related, nearly universal development in men

Incidence Incidence increases with age; wide variety of estimates of prevalence ranging from 70% to 90% by the age of 80 years (estimated at 8–20% by age 40 years).

ETIOLOGY AND PATHOPHYSIOLOGY • Develops in prostatic periurethral or transition zone • Hyperplastic nodules of stromal and epithelial components increase glandular components. • Etiology is unknown.

COMMONLY ASSOCIATED CONDITIONS • LUTS – LUTS can be divided into two groups: filling/storage symptoms and voiding symptoms.

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Filling/storage symptoms include frequency, nocturia, urgency, and urge incontinence. Voiding symptoms include difficulty initiating stream, incomplete voiding, or weak stream. Can lead to acute or chronic obstructive symptoms • Sexual dysfunction, including erectile dysfunction and ejaculatory disorders. • LUTS can also be secondary to cardiovascular, respiratory, or renal disease (1).

RISK FACTORS • Most significant risk factor is age. • Increased risk with higher free prostate-specific antigen (PSA) levels, heart disease, and use of β-blockers • Low androgen levels from cirrhosis/chronic alcoholism can reduce the risk of BPH • Obesity and lack of exercise can cause LUTS to be more significant. • No evidence of increased or decreased risk with smoking, alcohol, or any dietary factors.

GENERAL PREVENTION • The disease appears to be part of the aging process. • Symptoms can be managed through weight loss, regulation of fluid intake, decreased intake of caffeine, and increased physical activity.

DIAGNOSIS HISTORY • Evaluate symptom severity with the American Urological Society Symptom Index or the International Prostate Symptom Score (IPSS). • Screen for other causes of symptoms such as infection, procedural history, or neurologic causes. Evaluate for comorbid conditions which may produce similar symptoms such as diabetes, congestive heart failure (CHF), or Parkinson disease. • Review medication list. Particularly diuretics and anticholinergic medications. Also, decongestants (increased sphincter tone), opiates (impaired autonomic

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function), or tricyclic antidepressants (anticholinergic effects) • Review family history for BPH and prostate cancer. • Screen for gross hematuria. • IPSS scoring of LUTS (patient survey tracking severity) (2): – Questionnaire: Over the past month, how often have you: 1. Had the sensation of not emptying your bladder completely after you finished urinating? 2. Had to urinate again 2 times per night, warrants a frequency/volume chart for 2 to 3 days to detect urinary patterns.

PHYSICAL EXAM • Digital rectal exam (DRE) finding of symmetrically enlarged prostate, but size does not always correlate with symptoms. • Signs of renal failure due to obstructive uropathy (edema, pallor, pruritus, ecchymosis, nutritional deficiencies) • If DRE is suggestive of prostate cancer, or if there is hematuria, recurrent

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infections, concern for stricture, or evidence of neurologic disease, the patient should be referred to urology.

DIFFERENTIAL DIAGNOSIS • Obstructive – Prostate cancer – Urethral stricture or valves – Bladder neck contracture (usually secondary to prostate surgery) – Inability of bladder neck or external sphincter to relax appropriately during voiding • Neurologic – Spinal cord injury – Stroke – Parkinsonism – Multiple sclerosis • Medical – Poorly controlled diabetes mellitus – CHF • Pharmacologic – Diuretics – Decongestants – Anticholinergics – Opioids – Tricyclic antidepressants • Other: – Bladder carcinoma – Overactive bladder – Nocturnal polyuria (>33% of the 24-hour urine volume occurs at night) – Bladder calculi – UTI – Prostatitis – Urethritis/sexually transmitted infections – Obstructive sleep apnea (OSA) (nocturia) – Caffeine – Polyuria (either isolated nocturnal polyuria or 24-hour polyuria)

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DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Urinalysis (UA) in all patients presenting with LUTS can help rule out other etiologies such as bladder/kidney stones, cancer, UTI, or urethral strictures • Discuss PSA should with men with a life expectancy of 10 years and who would be surgical candidates if prostate cancer was identified. • PSA levels also correlate with prostate volume which can help guide treatment choice. • With bladder cancer risk factors (smoking history or hematuria), obtain urine cytology. • If nocturia is the main concern, consider using a frequency volume chart for urine output. • Sleep study if OSA or primary nocturnal polyuria is suspected. • Serum creatinine measurement is not recommended (AUA recommendation). Follow-Up Tests & Special Considerations • No further testing is recommended in uncomplicated LUTS; further testing if symptoms do not respond to medical management or if initial evaluation suggests underlying disease. • Uroflow: volume voided per unit time (peak flow 100 mL = incomplete emptying) • Transrectal ultrasound: assessment of gland size; not necessary in the routine evaluation • Abdominal ultrasound: can demonstrate increased PVR or hydronephrosis; not necessary in the routine evaluation

Diagnostic Procedures/Other • Pressure-flow studies (urine flow vs. voiding pressures) to determine etiology of symptoms – Obstructive pattern shows high voiding pressures with low flow rate. • Cystoscopy – Demonstrates presence, configuration, cause (stricture, stone), and site of obstructive tissue – May help determine therapeutic option

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– Not recommended in initial evaluation unless other factors, such as hematuria, are present.

TREATMENT GENERAL MEASURES • Treatment ranges from watchful waiting to lifestyle modifications, medications, or surgical management. • Mild symptoms (score of 250 mL. • If patient also experiences erectile dysfunction phosphodiesterase-5 inhibitors have been shown to have mild improvement of LUTS. Can use Tadalafil (Cialis): 5 mg/day PO but avoid use in combination with α-blockers or in those with CrCl 8 and symptoms – Obstructive uropathy (renal insufficiency) – Recurrent or persistent UTIs due to prostatic obstruction – Recurrent gross hematuria due to enlarged prostate – Bladder calculi • Surgical procedures: TURP remains the gold standard of surgical procedures; however, for select patient populations, there are other options available. • Common complications of TURP: – Bleeding can be significant. – TURP syndrome: hyponatremia secondary to absorption of hypotonic

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irrigation fluid – Retrograde ejaculation – Urinary incontinence • Other options include transurethral needle ablation (TUNA) and transurethral microwave thermotherapy (TUMT), or transurethral incision of the prostate (TUIP). Open prostatectomy is more common when prostate exceeds 100 g. Transurethral laser ablation is an alternative option for patients on anticoagulants.

COMPLEMENTARY & ALTERNATIVE MEDICINE Saw palmetto (Serenoa repens) has been thoroughly studied in a subject in Cochrane review, and did not improve LUTS. Other agents including pygeum, Cernilton, and herbs with β-sitosterols have been studied less; however, no current evidence to support their use. Acupuncture failed to show improvement in LUTS in one clinical trial as well. There are no recommended complementary or alternative treatments for BPH.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Symptom index (IPSS) monitored every 3 to 12 months. • DRE yearly • PSA yearly: should not be checked while patient is in retention, recently catheterized, or within a week of any surgical procedure to the prostate. • Consider monitoring PVR, if elevated.

DIET Avoid large boluses of oral or IV fluids or alcohol intake, caffeine may exacerbate symptoms as well.

PATIENT EDUCATION National Kidney and Urologic Diseases Information Clearinghouse, Box NKUDIC, Bethesda, MD 20893; 301-468-6345

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PROGNOSIS • Symptoms improve or stabilize in 70–80% of patients. • 25% of men with LUTS will have persistent storage symptoms after prostatectomy. • Of men with BPH, 11–33% have occult prostate cancer.

COMPLICATIONS • Urinary retention (acute or chronic) • Bladder stones • Prostatitis • Hematuria

REFERENCES 1. McVary KT, Roehrborn CG, Avins AL, et al. Update on AUA guideline on the management of benign prostatic hyperplasia. J Urol. 2011;185(5):1793– 1803. 2. Pearson R, Williams PM. Common questions about the diagnosis and management of benign prostatic hyperplasia. Am Fam Physician. 2014;90(11):769–774.

ADDITIONAL READING • American Urological Association. American Urological Association guideline: management of benign prostatic hyperplasia (BPH). http://www.auanet.org. Accessed September 24, 2016. • Edwards JL. Diagnosis and management of benign prostatic hyperplasia. Am Fam Physician. 2008;77(10):1403–1410.

CODES ICD10 • N40.0 Enlarged prostate without lower urinary tract symptoms • N40.1 Enlarged prostate with lower urinary tract symptoms

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CLINICAL PEARLS • Although medical therapy has changed the management of BPH, it has only delayed the need for TURP by 10 to 15 years, not eliminated it. • Urinary retention, obstructive uropathy, recurrent UTIs, elevated PSA, bladder calculi, hematuria, and failure of medical therapy are indications for surgical management of BPH.

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PROSTATITIS Kyle B. Stephens, DO • Vincent Lo, MD, FAAFP BASICS DESCRIPTION • Painful or inflammatory condition affecting the prostate gland with or without bacterial etiology, often characterized by urogenital pain, voiding symptoms, and/or sexual dysfunction • Significant impact on quality of life • 50 years. • Bacterial prostatitis occurs more frequently in patients with HIV.

Prevalence • Affects approximately 8.2% of males • Lifetime probability of diagnosis >25% • Accounts for 8% of visits to urologists and 1% of visits to primary care physicians • Percentage of cases by class: Class I: 3.5 g/day; also called heavy proteinuria • Three pathologic types: – Glomerular proteinuria: increased permeability of proteins across glomerular capillary membrane – Tubular proteinuria: decreased proximal tubular reabsorption of proteins – Overflow proteinuria: increased production of low-molecular-weight proteins

Pediatric Considerations • Proteinuria: Normal is daily excretion of up to 100 mg/m2 (body surface area). • Nephrotic-range proteinuria: daily excretion of >1,000 mg/m2 (body surface area)

Pregnancy Considerations • Proteinuria in pregnancy beyond 20 weeks’ gestation is a hallmark of preeclampsia/eclampsia and demands further workup. • Proteinuria in pregnancy before 20 weeks’ gestation is suggestive of underlying renal disease.

ETIOLOGY AND PATHOPHYSIOLOGY • Glomerular proteinuria: increased filtration/larger proteins (albumin) due to the following: – Increased size of glomerular basement membrane pores and – Loss of proteoglycan negative charge barrier • Tubular proteinuria: Tubulointerstitial disease prevents proximal tubular reabsorption of smaller proteins (β2-microglobulin, immunoglobulin [Ig] light

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chains, retinol-binding protein, amino acids). • Overflow proteinuria: proximal tubular reabsorption overwhelmed by increased production of smaller proteins • Glomerular proteinuria – Primary glomerulonephropathy Minimal-change disease Idiopathic/primary membranous glomerulonephritis Focal segmental glomerulonephritis Membranoproliferative glomerulonephritis IgA nephropathy – Secondary glomerulonephropathy Diabetic nephropathy Autoimmune/collagen vascular disorders (e.g., lupus nephritis, Goodpasture syndrome) Amyloidosis Preeclampsia Infection (HIV, hepatitis B and C, poststreptococcal, endocarditis, syphilis, malaria) Malignancy (GI, lung, lymphoma) Renal transplant rejection Structural (reflux nephropathy, polycystic kidney disease) Drug-induced (NSAIDs, penicillamine, lithium, heavy metals, gold, heroin) • Tubular proteinuria – Hypertensive nephrosclerosis – Tubulointerstitial disease (uric acid nephropathy, hypersensitivity, interstitial nephritis, Fanconi syndrome, heavy metals, sickle cell disease, NSAIDs, antibiotics) – Acute tubular necrosis • Overflow proteinuria – Multiple myeloma (light chains; also tubulotoxic) – Hemoglobinuria – Myoglobinuria (in rhabdomyolysis) – Lysozyme (in acute monocytic leukemia)

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• Benign proteinuria – Functional (fever, exercise, cold exposure, stress, CHF) – Idiopathic transient – Orthostasis (postural)

RISK FACTORS • Hypertension • Diabetes • Obesity • Strenuous exercise • CHF • UTI • Fever

Genetics No known genetic pattern

GENERAL PREVENTION Control of weight, BP, and blood glucose reduces the risk of proteinuria.

COMMONLY ASSOCIATED CONDITIONS • Hypertension (common) • Diabetes mellitus (common) • Preeclampsia (common) • Multiple myeloma (rare)

DIAGNOSIS HISTORY • Frothy/foamy urine • Change in urine output • Blood- or cola-colored urine • Recent weight change • Swelling • Rule out systemic illness: diabetes, heart failure, autoimmune, poststreptococcal infection

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PHYSICAL EXAM • BP • Weight • Peripheral edema • Periorbital/facial edema • Ascites • Palpation of kidneys • Check lungs, heart for signs of CHF

DIFFERENTIAL DIAGNOSIS Includes all causes listed under “Etiology and Pathophysiology”

DIAGNOSTIC TESTS & INTERPRETATION Screening for proteinuria is not cost-effective unless directed at groups with hypertension/diabetes, older persons, and so forth.

Initial Tests (lab, imaging) • Urinalysis (UA) quantitatively estimates proteinuria: – Only sensitive to albumin; will not detect smaller proteins of overflow/tubular etiologies – False-positive finding if urine pH >7, highly concentrated (specific gravity [SG] >1.015), gross hematuria, mucus, semen, leukocytes, iodinated contrast agents, penicillin analogues, sulfonamide metabolites – False-negative finding if urine is dilute (SG 1.005), albumin excretion 0.5 cm during this time. • Massage beard area with washcloth, coarse sponge, or a soft brush several times daily. • Hydrocortisone 1–2.5% cream to relieve inflammation • Selenium sulfide if seborrhea is present and to help reduce pruritus • Systemic antibiotics if secondary infection is present

Pregnancy Considerations Do not use tretinoin (Retin-A), tetracycline, or benzoyl peroxide.

MEDICATION First Line • Topical or systemic antibiotic for secondary infection – Application of clindamycin (Cleocin T) solution BID or topical erythromycin

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– Low-dose erythromycin or tetracycline 250 to 500 mg PO BID for more severe inflammation – Benzoyl peroxide 5%– clindamycin 1% gel BID: Administer until papule/pustule resolves. • Mild cases: tretinoin 0.025% cream at bedtime; combination of the above therapies • Moderate disease/chemical depilatories – Disrupt cross-linking of disulfide bonds of hair to produce blunt (less sharp) hair tip. – Apply no more frequently than every 3rd day: 2% barium sulfide (Magic Shave) or calcium thioglycollate (Surgex); calcium hydroxide (Nair) • Contraindications – Clindamycin: hypersensitivity history; history of regional enteritis or ulcerative colitis; history of antibiotic-associated colitis – Erythromycin, tetracycline, tretinoin: hypersensitivity history • Precautions – Clindamycin: colitis, eye burning and irritation, skin dryness; pregnancy Category B – Erythromycin: Use cautiously in patients with impaired hepatic function; GI side effects, especially abdominal cramping; pregnancy Category B (erythromycin base formulation). – Chemical depilatories: Use cautiously; frequent use and prolonged application may lead to irritant contact dermatitis and chemical burns. – Tetracycline: Avoid in pregnancy. – Tretinoin: Severe skin irritation; avoid in pregnancy. – Benzoyl peroxide: skin irritation and dryness, allergic contact dermatitis – Hydrocortisone cream: local skin irritation, skin atrophy with prolonged use, lightening of skin color • Significant possible interactions – Erythromycin: increases theophylline and carbamazepine levels; decreases clearance of warfarin – Tetracycline: depresses plasma prothrombin activity

Second Line Chemical peels with either glycolic acid or salicylic acid

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ISSUES FOR REFERRAL • Worsening or poor response to the above therapies after 4 to 6 weeks should prompt dermatology consultation. • Occupational demands may also prompt earlier referral to dermatology for more aggressive therapy.

SURGERY/OTHER PROCEDURES Laser treatment with long-pulsed Nd:YAG is helpful for severe cases.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • As needed • Educate patient on curative and preventive treatment.

DIET • No restrictions • No dietary studies available

PATIENT EDUCATION • https://medlineplus.com/ • http://www.uptodate.com/home

PROGNOSIS • Good, with preventive methods • Prognosis is poor in the presence of progressive scarring and foreign-body granuloma formation.

COMPLICATIONS • Scarring (occasionally keloidal) • Foreign-body granuloma formation • Disfiguring postinflammatory hyperpigmentation (use sunscreens; can treat with hydroquinone 4% cream, Retin A, clinical peels) • Impetiginization of inflamed skin • Epidermal (erythema, crusting, burns with scarring) and pigmentary changes

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with laser

REFERENCES 1. Bridgeman-Shah S. The medical and surgical therapy of pseudofolliculitis barbae. Dermatol Ther. 2004;17(2):158–163. 2. Perry PK, Cook-Bolden FE, Rahman Z, et al. Defining pseudofolliculitis barbae in 2001: a review of the literature and current trends. J Am Acad Dermatol. 2002;46(2)(Suppl):S113–S119. 3. Quarles FN, Brody H, Johnson BA, et al. Pseudofolliculitis barbae. Dermatol Ther. 2007;20(3):133–136. 4. Xia Y, Cho S, Howard RS, et al. Topical eflornithine hydrochloride improves the effectiveness of standard laser hair removal for treating pseudofolliculitis barbae: a randomized, double-blinded, placebo-controlled trial. J Am Acad Dermatol. 2012;67(4):694–699. 5. Weaver SM III, Sagaral EC. Treatment of pseudofolliculitis barbae using the long-pulse Nd:YAG laser on skin types V and VI. Dermatol Surg. 2003;29(12):1187–1191.

ADDITIONAL READING • Cook-Bolden FE, Barba A, Halder R, et al. Twice-daily application of benzoyl peroxide 5%/ clindamycin 1% gel versus vehicle in the treatment of pseudofolliculitis barbae. Cutis. 2004;73(6)(Suppl):18–24. • Daniel A, Gustafson CJ, Zupkosky PJ, et al. Shave frequency and regimen variation effects on the management of pseudofolliculitis barbae. J Drugs Dermatol. 2013;12(4):410–418. • Kindred C, Oresajo CO, Yatskayer M, et al. Comparative evaluation of men’s depilatory composition versus razor in black men. Cutis. 2011;88(2):98–103. • Kundu RV, Patterson S. Dermatologic conditions in skin of color: part II. Disorders occurring predominately in skin of color. Am Fam Physician. 2013;87(12):859–865.

SEE ALSO Folliculitis; Impetigo

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CODES ICD10 • L73.1 Pseudofolliculitis barbae • B35.0 Tinea barbae and tinea capitis • L73.8 Other specified follicular disorders

CLINICAL PEARLS • Electrolysis is not recommended as a treatment. It is expensive, painful, and often unsuccessful. • Combination of laser therapy with eflornithine is more effective than laser alone. • Use Bump Fighter razor from American Safety Razor Company (http://www.asrco.com/). • Men may prefer the convenience of the Bump Fighter razor over depilatory products. • The aversive smell of sulfur could be a problem with some depilatory products. • Have patient test for skin sensitivity with a small (coin-sized) amount of the depilatory on the bearded area or forearm.

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PSEUDOGOUT (CALCIUM PYROPHOSPHATE DIHYDRATE) Caitlyn M. Rerucha, MD BASICS DESCRIPTION • Autoinflammatory disease triggered by calcium pyrophosphate dihydrate (CPPD) crystal deposition in the joints • One of many diseases associated with pathologic deposition of crystal, mineralization, and ossification – CPPD crystal deposition = chondrocalcinosis, pseudogout – Monosodium urate crystal deposition = gout – Hydroxyapatite deposition associated with ankylosing spondylitis, osteoarthritis, and vascular calcification • Suspect pseudogout in arthritis cases with a pattern of joint involvement not usually affected by degenerative joint disease (e.g., metacarpophalangeal joints, wrists) • Clinical presentation is broad: – Asymptomatic CPPD (incidentally identified on radiograph by chondrocalcinosis with or without additional findings of osteoarthritis) – Acute CPPD arthritis (acute onset, self-limiting, synovitis) – Chronic CPPD crystal inflammatory arthritis (1)[C] • Chronic CPPD crystal deposition may cause a progressive degenerative arthritis in numerous joints: – Primarily affects the elderly – Usually involves large joints • Symptom onset is usually insidious. • Definitive diagnosis requires the identification of CPPD crystals in synovial fluid. • System(s) affected: endocrine/metabolic; musculoskeletal • Synonyms: pseudogout; CPPD; pyrophosphate arthropathy; chondrocalcinosis —when calcification visibly seen within tissues on imaging

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EPIDEMIOLOGY Prevalence • Predominant age: 80% of patients >60 years • Predominant sex: male > female 1.4:1 • Prevalence varies on method of identification (chondrocalcinosis on radiograph vs. CPPD crystals in synovial fluid) • Chondrocalcinosis is present in 1:10 adults age 60 to 75 years and 1:3 by >80 years; however, only a small percentage develop arthropathy. • 20–43% prevalence of CPPD cyrstals in synovial fluid of osteoarthritic joints at time of joint replacement

ETIOLOGY AND PATHOPHYSIOLOGY • Arthropathy results from an acute autoinflammatory reaction to CPPD crystals in the synovial cavity. • CPPD crystal deposition occurs in three general stages: – CPPD crystals first develop in the pericellular matrix of the articular cartilage via overproduction of anionic pyrophosphate (PPi). – PPi binds calcium to form CPPD crystals that are released from cartilage surface and elicit an inflammatory response. Neutrophils engulf CPPD crystals, inducing the formation of extracellular traps. – Increased deposition of CPPD crystals in and around cartilage causes inflammation and damage. Cartilage degeneration is accelerated through mechanical wear and tear of the joint (2)[C].

Genetics Uncommonly seen in familial pattern with autosomal dominant inheritance (100,000 WBCs/mL, 22% prevalence • Wet prep with polarized microscopy may demonstrate small numbers of crystals. False-negative rate is high.

ALERT Rhomboid-shaped weakly positively birefringent crystals in the fluid and within neutrophils is pathognomonic. In contrast, gout crystals are needleshaped and negatively birefringent. • Obtain the following metabolic studies in patients 50,000/mL

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• Treat with appropriate antibiotics pending culture results.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring Reevaluate response to therapy 48 to 72 hours after beginning treatment; reexamine in 1 week then as needed.

DIET No known relationship to diet

PATIENT EDUCATION • Rest affected joint. • Symptoms usually resolve in 7 to 10 days.

PROGNOSIS • Acute attack usually resolves in 10 days; prognosis for resolution of acute attack is excellent. • Patients may experience progressive joint damage and functional limitation.

COMPLICATIONS • Recurrent acute attacks • Osteoarthritis

Geriatric Considerations Elderly patients treated with NSAIDs require careful monitoring and are at higher risk for GI bleeding and acute renal insufficiency. No loading dose for colchicine due to high rates of renal insufficiency in elderly patients.

REFERENCES 1. Zhang W, Doherty M, Bardin T, et al. European League Against Rheumatism recommendations for calcium pyrophosphate deposition. Part I: terminology and diagnosis. Ann Rheum Dis. 2011;70(4):563–570. 2. Rosenthal AK, Ryan LM. Nonpharmacologic and pharmacologic

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management of CPP crystal arthritis and BCP arthropathy and periarticular syndromes. Rheum Dis Clin North Am. 2014;40(2):343–356. 3. Zhang W, Doherty M, Pascual E, et al. EULAR recommendations for calcium pyrophosphate deposition. Part II: management. Ann Rheum Dis. 2011;70(4):571–575. 4. Pascart T, Richette P, Flipo RM. Treatment of nongout joint deposition diseases: an update. Arthritis. 2014;2014:375202. 5. Finckh A, Mc Carthy GM, Madigan A, et al. Methotrexate in chronicrecurrent calcium pyrophosphate deposition disease: no significant effect in a randomized crossover trial. Arthritis Res Ther. 2014;16(5):458.

ADDITIONAL READING • Bruges-Armas J, Bettencourt BF, Couto AR, et al. Effectiveness and safety of infliximab in two cases of severe chondrocalcinosis: nine years of follow-up. Case Rep Rheumatol. 2014;2014:536856. • Daoussis D, Antonopoulos I, Andonopoulos AP. ACTH as a treatment for acute crystal-induced arthritis: update on clinical evidence and mechanisms of action. Semin Arthritis Rheum. 2014;43(5):648–653. • Demertzis JL, Rubin DA. MR imaging assessment of inflammatory, crystalline-induced, and infectious arthritides. Magn Reson Imaging Clin N Am. 2011;19(2):339–363. • Macmullan P, McCarthy G. Treatment and management of pseudogout: insights for the clinician. Ther Adv Musculoskelet Dis. 2012;4(2):121–131. • Richette P, Bardin T, Doherty M. An update on the epidemiology of calcium pyrophosphate dihydrate crystal deposition disease. Rheumatology (Oxford). 2009;48(7):711–715. • Sattui SE, Singh JA, Gaffo AL. Comorbidities in patients with crystal diseases and hyperuricemia. Rheum Dis Clin North Am. 2014;40(2):251–278.

CODES ICD10 • M11.20 Other chondrocalcinosis, unspecified site

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• M11.269 Other chondrocalcinosis, unspecified knee • M11.29 Other chondrocalcinosis, multiple sites

CLINICAL PEARLS • Suspect CPPD if arthritis case doesn’t follow a pattern typical of degenerative joint disease (e.g., metacarpophalangeal joints, wrists). • Perform arthrocentesis to confirm diagnosis. • If septic arthritis is considered, treat presumptively with antibiotics until culture results are available. • NSAID therapy is the preferred treatment for acute flare. • Oral steroids are useful if NSAIDs are contraindicated. • Intra-articular steroids can be used if septic arthritis has been excluded.

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PSORIASIS Edwin A. Farnell, IV, MD • Michael O. Needham, MD • Rebecca Matz, MD BASICS DESCRIPTION • A chronic, multisystem inflammatory disorder most commonly characterized by cutaneous erythematous papules and plaques with silvery scale. A complex genetic and immune-mediated disorder with flares related to systemic, psychological, infectious, and environmental factors. Skin disease with multiple different phenotypic variations and degrees of severity • Clinical phenotypes – Plaque (vulgaris): most common variant (>80% of cases); well-demarcated, red plaques with thick, silvery scale; symmetrically distributed most commonly on the scalp, extensor surfaces of extremities, and trunk – Guttate: 350 treatments – Systemic therapies Methotrexate: blocks DNA synthesis and inhibits proliferation and migration of T cells; start 7.5 to 15 mg/week IV, PO, IM, or SC, then increase 2.5 mg every 2 to 3 weeks, up to 25 mg; contraindicated in pregnancy; supplement with folic acid 1 to 5 mg/day to protect against side effects : hepatotoxicity, pulmonary toxicity, bone marrow suppression; baseline chest x-ray, monitor LFTs, renal function, CBC, testing for latent tuberculosis (TB); consider liver biopsy when cumulative dose reaches 1 to 1.5 g; avoid alcohol and medications that interfere with folic acid metabolism, including Bactrim, NSAIDS,

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sulfamethoxazole, or hepatotoxic agents (e.g., retinoids). Cyclosporine: inhibits T-cell activation; start 2.5 mg/kg/day; if insufficient response after 4 weeks, increase by 0.5 mg/kg/day; additional dosage increases every 2 weeks (max dose: 5 mg/kg/day pregnancy Category C; side effects: renal toxicity and hypertension, limit use to 6 months to 1 year: Monitor renal function, with Mg2+ and K+, CBC, lipids, and BP. Acitretin (Soriatane): systemic retinoid; onset ranges from 3 to 6 months; start at 10 to 25 mg/day given with the main meal; effective for pustular psoriasis and as a maintenance therapy after stabilization with other agents; sometimes combined with UVB/PUVA; pregnancy Category X: pregnancy test before starting; two forms of contraception 1 month before, during, and for at least 3 years after treatment; avoid alcohol (may convert acitretin to etretinate); side effects: alopecia, xerosis, cheilitis, hepatotoxicity, hyperlipidemia, cataracts; monitor LFTs, renal function, lipid profile, CBC, regular eye exams. – Biologics: general guidelines: Screen for latent TB at baseline and yearly, hepatitis panel at baseline, avoid live vaccines; monitor CBC with differential, signs/symptoms of infections, heart failure, malignancy, druginduced lupus, inflammatory bowel disease, demyelinating disorder. Some concern for “biologic fatigue” phenomenon, or loss of PASI 75 over time, likely due to antidrug antibodies. Each has been shown to be effective at 24 weeks with an NNT between 1 and 3. All should be considered effective first-line treatments (5)[A]. Pregnancy Category B TNF-α inhibitors: etanercept (Enbrel): Begin at 50 mg SC twice a week for 3 months then maintenance of 50 mg/week. Adalimumab (Humira): Dosing starts at 80 mg SC for 1 week, then 40 mg SC every other week. Infliximab (Remicade): 5 mg/kg IV at weeks 0, 2, and 6; maintenance doses of 5 mg/kg every 8 weeks thereafter; adjust interval, as needed; anaphylaxis-like infusion reaction occurs in 20% of BSA, psoriatic arthritis, severe extremity involvement, particularly hands and feet

SURGERY/OTHER PROCEDURES Psoriasis and psoriatic medications can affect wound healing postoperatively; methotrexate: Monitor for postoperative infections; hold cyclosporine for 1 week before and after; some surgeons may prefer to hold therapy with biologics for up to 1 month before and after surgery.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS Generalized pustular psoriasis/erythrodermic psoriasis: Rule out sepsis; restoration of barrier function of skin with cleaning and bandaging; intensive topical corticosteroid therapy, phototherapy, systemic therapy, particularly medications with a quick onset such as oral cyclosporine; management of electrolytes

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Measure BSA involvement to determine if therapy is working; change therapy or add agent if no improvement is seen.

DIET Well-balanced diet and exercise to limit cardiovascular risk factors and decrease risk of associated conditions, including obesity, metabolic syndrome, diabetes,

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and atherosclerosis

PATIENT EDUCATION National Psoriasis Foundation: www.psoriasis.org; 800-723-9166

PROGNOSIS Guttate form may be self-limited and remit after 4 months; chronic plaque type is lifelong, with intermittent spontaneous remissions and exacerbations; erythrodermic and generalized pustular forms may be severe and persistent.

COMPLICATIONS Psoriatic arthritis, generalized pustular psoriasis, erythrodermic psoriasis

REFERENCES 1. Menter A, Korman NJ, Elmets CA, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 6. Guidelines of care for the treatment of psoriasis and psoriatic arthritis: case-based presentations and evidence-based conclusions. J Am Acad Dermatol. 2011;65(1):137–174. 2. Villaseñor-Park J, Wheeler D, Grandinetti L. Psoriasis: evolving treatment for a complex disease. Cleve Clin J Med. 2012;79(6):413–423. 3. Mason AR, Mason J, Cork M, et al. Topical treatments for chronic plaque psoriasis. Cochrane Database Syst Rev. 2013;(3):CD005028. 4. Hendricks AG, Keijsers RR, de Jong EM, et al. Efficacy and safety of combinations of first-line topical treatments in chronic plaque psoriasis: a systematic literature review. J Eur Acad Dermatol Venereol. 2013;27(8):931– 951. 5. Nast A, Jacobs A, Rosumeck S, et al. Efficacy and safety of systemic longterm treatments for moderate-to-severe psoriasis: a systematic review and meta-analysis. J Invest Dermatol 2015;135(11):2641–2684.

ADDITIONAL READING Galván-Banqueri M, Marín Gil R, Santos Ramos B, et al. Biologic treatments for moderate-to-severe psoriasis: indirect comparison. J Clin Pharm Ther. 2013;38(2):121–130.

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SEE ALSO Arthritis, Psoriatic

CODES ICD10 • L40.9 Psoriasis, unspecified • L40.50 Arthropathic psoriasis, unspecified • L42 Pityriasis rosea

CLINICAL PEARLS Chronic lifelong inflammatory skin condition with remissions and exacerbations; set realistic expectations with patient. Disease burden not limited to skin. If one medication does not work, use/combine with another agent.

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PSYCHOSIS Alan J. Anderson, DO • Bernadette M. Stevenson, MD, PhD BASICS DESCRIPTION Syndrome seen with schizophrenia, schizoaffective disorder, mood disorder, substance use, medical problems, delirium, and dementia; symptoms include the following: • Positive symptoms: hallucinations and delusions (fixed false and often paranoid beliefs created as the patient loses the ability to correct errors in thinking) • Negative symptoms: anhedonia, poverty of speech, lack of motivation, social withdrawal, affective blunting • Disorganized speech/behavior • Cognition: decreased working memory, difficulty with attention, poor and slow information processing

EPIDEMIOLOGY Prevalence • Schizophrenia: peak onset 18 to 25 years in men; women peak onset 25 to 35 years – 1% of the U.S. population; similar percentage worldwide • Delusional disorder: 0.03% of population • Bipolar type I: 1% of population • Prevalence in major depression not known

ETIOLOGY AND PATHOPHYSIOLOGY • Neurodevelopmental predisposition plus 1st/3rd trimester in utero insult (e.g., 1st trimester infection or 3rd trimester birth hypoxia) leads to exaggerated neuronal apoptosis in late adolescence with subsequent thalamic sensory overload. Increased dopaminergic mesolimbic transmission may contribute to delusions and hallucinations in schizophrenia. Dopamine deficiency in

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mesocortical pathways may contribute to frontal lobe hypoactivity often associated with apathy and withdrawal in schizophrenia. Glutamate, neurosteroids, inflammation, and neurodevelopmental abnormalities are active areas of research. • Postulated stress-diathesis model: Individuals biologically at risk develop psychosis when under stress.

Genetics Schizophrenia: 50% concordance for monozygotic twins, little or no shared environmental effect; multiple candidate genes involved

RISK FACTORS Substance abuse (particularly cannabis or synthetic cannabinoids), family history of psychosis, lower socioeconomic status (SES)

GENERAL PREVENTION Community interventions for early detection and treatment of prodromal symptoms show promise. Research currently exploring use of omega-3 fatty acids/fish oil and anti-inflammatories which may prevent prodromal progression to schizophrenia.

COMMONLY ASSOCIATED CONDITIONS • Serious mental illness is associated with metabolic syndrome, autonomic dysfunction, and sudden cardiac death. • Cancer mortality: particularly breast and lung cancer • Substance abuse disorders, including nicotine dependence

DIAGNOSIS First, rule out delirium: Psychosis should not have fluctuating consciousness/reduced clarity of awareness.

HISTORY • Delusions (fixed false beliefs): persecutory (being monitored), bizarre (involving impossible states), somatic (fixed belief in nonexistent serious illness), referential (getting messages from TV, radio, or thoughts

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inserted/deleted by others), grandiose (belief that one has special powers) • Hallucinations: auditory, visual, tactile • Bipolar illness, depression, and dementia are all associated with psychosis, so screen for symptoms of depression, mania, and memory loss. • Screen for toxidromes of drugs of abuse. • Screen for history of epileptiform activity. • Suicidality: higher risk with comorbid depression/mania, previous suicide attempts, drug abuse, agitation/akathisia, poor compliance

PHYSICAL EXAM • Mental status exam: disorganized idea sequencing and/or error correction, not incorrect thought content, is the conditio sine qua non of schizophrenia. Patients often have negative symptoms (e.g., social withdrawal, lack of initiative, poverty of thought) and disorganized behavior. • Attention to neurologic focalities, antipsychotic-induced parkinsonism, tardive dyskinesia, and akathisia • May rarely present with catatonia: extreme excitement/lack of movement; posturing, mutism, grimacing, waxy flexibility

DIFFERENTIAL DIAGNOSIS • Schizophrenia: positive symptoms (psychosis) and negative symptoms (flat affect), prodrome of social withdrawal, cognitive impairment; schizophreniform disorder: psychotic/prodromal symptoms in 6 mg rarely more effective and higher risk of

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parkinsonism; higher risk of prolactinemia/parkinsonism due to D2 blockade – Paliperidone: Start 3 to 6 mg/day target dose 6 to 12 mg/day; titrate over 1 to 2 weeks. Higher risk of prolactinemia/parkinsonism than others; excreted unchanged in urine, ideal for hepatic impairment – Ziprasidone: Start 20 to 40 mg PO BID, with target dose of 100 to 200 mg/day in divided doses over 2 weeks; prolongs QTc; less likely to cause weight gain than other atypicals; higher risk of akathisia/parkinsonism. Requires meal for optimal absorption; often activating at lower doses – Aripiprazole: Start 10 to 15 mg/day, may increase up to 30 mg/day over a week or 2; less weight gain but higher rates of akathisia/parkinsonism – Asenapine: Start 5 mg at bedtime or BID sublingually, increase to 10 mg BID if needed over a week or 2; less weight gain than some, higher rates of akathisia/parkinsonism; sedation, orthostatic hypotension, numb tongue, nausea, bad taste – Lurasidone: Start 20 to 40 mg once daily with food (at least 350 calories), increase up to max of 160 mg at bedtime if needed over 2 to 4 weeks. Less weight gain than some but higher rates of akathisia/parkinsonism; not antihistaminic but α-blocking sedation and serotonergic nausea – Iloperidone: Start 1 mg BID, may increase by 2 mg BID each day, but slower can be better due to significant orthostasis. Increase to max 12 mg BID; little akathisia/parkinsonism, less weight gain but slower efficacy due to long titration, orthostasis, sedation – Brexpiprazole: Start 1 mg qd for first 4 days, 2 mg qd days 5 to 7, can dose up to 4 mg/day based on response and tolerability. Lower rates of akathisia/parkinsonism than aripiprazole but higher rates than others; less weight gain than others – Cariprazine: Start at 1.5 mg qd, can be increased to 3 mg qd on day 2, dosed up to 6 mg daily based on tolerability and response. In 6-week study, similar to placebo in changes of fasting glucose, cholesterol, triglycerides and showed 0.8 to 1.0 kg weight increase.

Geriatric Considerations Increased risk of death compared to placebo when antipsychotics are used in the elderly with dementia 3[B]

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Second Line • Clozapine: more effective for reducing symptoms, preventing relapse, decreasing tardive dyskinesia, and decreasing suicidality than other antipsychotics but second line given risk of fatal agranulocytosis. Single national registry (clozapine REMS) for all patients on clozapine, updated guidelines in 2015 requiring CBC to monitor absolute neutrophil count (ANC) weekly for first 6 months, then every 2 weeks for 6 months, and then every 4 weeks. More weight gain, hyperlipidemia, hyperglycemia, seizures, myocarditis, pulmonary embolus, and sedation but low rate of parkinsonism, tardive dyskinesia; useful in treatment-refractory psychosis and in Parkinson disease psychosis • Despite association with more weight gain than other antipsychotics, clozapine and olanzapine do not appear to increase risk of cardiac and allcause mortality (2,3)[B]. • Long-acting preparations: available for 2 typicals (haloperidol and fluphenazine) and 4 atypicals (risperidone, paliperidone, olanzapine, aripiprazole; olanzapine requires registration due to rare delirium syndrome). Test tolerability with oral medication first. Long-acting antipsychotics promote compliance. • Long-acting haloperidol, paliperidone, olanzapine, aripiprazole administered every 4 weeks; aripiprazole has formulation with better oral equivalence conversion; paliperidone also has every 3-month injection, long-acting risperidone and fluphenazine administered every 2 weeks.

ISSUES FOR REFERRAL Encourage contact with advocacy groups for families and patients (National Alliance for the Mentally Ill).

ADDITIONAL THERAPIES Cognitive-behavioral therapy (CBT) is an effective adjuvant to antipsychotics (1)[B].

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Admission criteria/initial stabilization: at risk for harm to self or others;

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extreme functional impairment; unable to care for self; new-onset psychosis • Discharge criteria: no longer a danger to self or others and adequate outpatient treatment in place

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Close follow-up for inpatient discharge (high risk for suicide), use CBT, exercise, teach smoking cessation

PATIENT EDUCATION National Alliance on Mental Illness: www.nami.org/

PROGNOSIS Schizophrenia: Fluctuating course, 70% first-episode psychosis patients improve in 3 to 4 months; 7% will die of suicide; 20–40% will attempt suicide.

REFERENCES 1. National Institute for Health and Care Excellence. Psychosis and schizophrenia in adults: prevention and management. http://www.nice.org.uk/guidance/cg178. Accessed September 27, 2016. 2. Tiihonen J, Lönnqvist J, Wahlbeck K, et al. 11-Year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study). Lancet. 2009;374(9690):620–627. 3. Strom BL, Eng SM, Faich G, et al. Comparative mortality associated with ziprasidone and olanzapine in real-world use among 18,154 patients with schizophrenia: the Ziprasidone Observational Study of Cardiac Outcomes (ZODIAC). Am J Psychiatry. 2011;168(2):193–201.

ADDITIONAL READING • McEvoy JP, Lieberman JA, Stroup TS, et al. Effectiveness of clozapine versus olanzapine, quetiapine, and risperidone in patients with chronic schizophrenia who did not respond to prior atypical antipsychotic treatment. Am J Psychiatry. 2006;163(4):600–610.

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• van Iersel MB, Zuidema SU, Koopmans RT, et al. Antipsychotics for behavioural and psychological problems in elderly people with dementia: a systematic review of adverse events. Drugs Aging. 2005;22(10):845–858.

SEE ALSO Delirium; Schizophrenia

CODES ICD10 • F29 Unsp psychosis not due to a substance or known physiol cond • F20.9 Schizophrenia, unspecified • F39 Unspecified mood [affective] disorder

CLINICAL PEARLS • Antipsychotics are the mainstay of treatment; evidence corroborates decreased all-cause mortality in patients who are adherent to these medications. • Clozapine and long-acting preparations may increase adherence, whereas newer atypicals quetiapine, lurasidone, aripiprazole, olanzapine-fluoxetine combination) may help with depressive symptoms in psychosis.

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PULMONARY ARTERIAL HYPERTENSION J. Todd Vassalli, MD • David Navel, MD BASICS DESCRIPTION • Pulmonary arterial hypertension (PAH) is a category of pulmonary hypertension (PH) characterized by abnormalities in the small pulmonary arteries (precapillary PH) that produce increased pulmonary arterial pressure (PAP) and vascular resistance, eventually resulting in right-sided heart failure. PAH is a progressive disorder associated with increased mortality. – Previously, PH was classified as primary PH (without cause, now idiopathic pulmonary arterial hypertension [IPAH]) or secondary PH (with cause or associated condition); now, it is clear that some types of secondary PH closely match primary PH (IPAH) in their histology, natural history, and response to treatment. Therefore, WHO classifies PH into five groups based on mechanism, with PAH as group 1 in this classification. • PAH is diagnosed by right-heart catheterization and defined by: – Mean PAP ≥25 mm Hg at rest – Pulmonary capillary wedge pressure ≤15 mm Hg (to exclude PH owing to left heart disease; i.e., group 2 PH) – Mild or absent chronic lung disease or other causes of hypoxemia (excludes PH owing to lung disease or hypoxemia; i.e., group 3 PH) – Absent venous thromboembolic disease (excludes chronic thromboembolic PH; i.e., group 4 PH) – Absent systemic disorder (like sarcoidosis), hematologic disorders (like myeloproliferative disease), and metabolic disorders (like glycogen storage disease). Purpose is to exclude group 5 PH. • PAH is divided into following main categories: – Idiopathic: sporadic, with no family history or risk factors – Heritable: IPAH with mutations or familial cases with or without mutations – Drug or toxin induced: mostly associated with anorectics (e.g., fenfluramine), rapeseed oil, L-tryptophan, and illicit drugs such as

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methamphetamine and cocaine – Associated: connective tissue diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis, scleroderma), HIV infection, portal hypertension, congenital heart disease, schistosomiasis (chronic hemolytic anemia added to group 5 PH—unclear/multifactorial mechanisms (1) – Pulmonary veno-occlusive disease (PVOD) and/or pulmonary capillary hemangiomatosis (PCH) and persistent pulmonary hypertension of the newborn (PPHN) are classified as separate categories due to more differences than similarities with PAH. PVOD and/or PCH: rare cause of PH characterized by extensive diffuse occlusion of the pulmonary veins (unlike PAH which involves the small muscular pulmonary arterioles) PPHN: 2 per 1,000 live births; maternal SSRI use may correlate. • System(s) affected: pulmonary, cardiovascular

EPIDEMIOLOGY • Age: can occur at any age; mean age 37 years • Sex (IPAH): female > male (~4:1)

Incidence • Overall PAH: 5 to 52 cases/million • IPAH: low, ~2 to 6 per million • Drug-induced PAH: 1/25,000 with >3 months of anorectic use • HIV associated: 0.5/100 • Portal hypertension associated: 1 to 6/100 • Scleroderma associated: 6–60%

Prevalence • PAH: ~15 to 50 cases per million • IPAH: ~6 cases per million

ETIOLOGY AND PATHOPHYSIOLOGY • Pulmonary: Inflammation, vasoconstriction, endothelial dysfunction, and remodeling of pulmonary arteries produced by increased cell proliferation and reduced rates of apoptosis lead to obstruction. • Cardiovascular: right ventricular hypertrophy (RVH), eventually leading to

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right-sided heart failure • IPAH: by definition, unknown. True IPAH is mostly sporadic or sometimes familial in nature. • Pulmonary arteriolar hyperactivity and vasoconstriction, occult thromboembolism, or autoimmune (high frequency of antinuclear antibodies)

Genetics • 75% of heritable pulmonary arterial hypertension (HPAH) cases and 25% of IPAH cases have mutations in BMPR2 (autosomal dominant). • Mutations in ALK1 and endoglin (autosomal dominant) also are associated with PAH.

RISK FACTORS • Female sex • Previous anorectic drug use • Recent acute pulmonary embolism • First-degree relatives of patient with familial PAH

COMMONLY ASSOCIATED CONDITIONS See associated PAH, earlier discussed.

DIAGNOSIS Symptoms of PAH are nonspecific, which can lead to missed or delayed diagnosis of this serious disease.

HISTORY Dyspnea, weakness, syncope, dizziness, chest pain, palpitations, lower extremity edema

PHYSICAL EXAM • Pulmonary component of S2 (at apex in >90% of patients) • Right ventricular (RV) lift • Early systolic click of pulmonary valve • Pansystolic murmur of tricuspid regurgitation • Diastolic murmur of pulmonic insufficiency (Graham-Steell murmur)

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• RV S3 or S4 • Edema as jugular vein distention, ascites, hepatomegaly, or peripheral edema

DIFFERENTIAL DIAGNOSIS Other causes of dyspnea: • Pulmonary parenchymal disease such as chronic obstructive pulmonary disease • Pulmonary vascular disease such as pulmonary thromboembolism • Cardiac disease such as cardiomyopathy • Other disorders of respiratory function such as sleep apnea

DIAGNOSTIC TESTS & INTERPRETATION • ECG: RVH and right axis deviation • Pulmonary function testing and/or arterial blood gas: arterial hypoxemia, reduced diffusion capacity, hypocapnia • Ventilation–perfusion ratio (V/Q) scan: must rule out proximal pulmonary artery emboli and chronic thromboembolic PH (CTEPH) • Exercise test: reduced maximal O2 consumption, high-minute ventilation, low anaerobic threshold, increased PO2 alveolar–arterial gradient; correlation to severity of disease with 6-minute walk test (6MWD) • Antinuclear antibody positive (up to 40% of patients) • LFTs to evaluate for portopulmonary HTN, a complication of chronic liver disease • HIV test, thyroid function tests, sickle cell disease screening • Elevated brain natriuretic peptide (BNP) and N-terminal-proBNP may be useful for early detection of PAH in young, otherwise healthy patients with mild symptoms. It can also be used to assess disease severity and prognosis. • Chest radiograph – Prominent central pulmonary arteries with peripheral hypovascularity of pulmonary arterial branches – RV enlargement is a late finding. • Echo Doppler – Should be performed with suspicion of PAH; recent studies show some inaccuracy compared with right-sided heart catheterization. – Most commonly used screening tool

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Estimates mean PAP and assesses cardiac structure and function, excludes congenital anomalies Echo suggests, but does not diagnose, PAH. Invasive hemodynamic evaluation confirms PAH diagnosis. • Right atrial and ventricular enlargement; tricuspid regurgitation • Important to rule out underlying cardiac disease such as atrial septal defect with secondary PH or mitral stenosis • Cardiac magnetic resonance is not commonly used.

Diagnostic Procedures/Other • Pulmonary angiography – Should be done if V/Q scan suggests CTEPH – Use caution; can lead to hemodynamic collapse; use low osmolar agents, subselective angiograms. • Right-sided cardiac catheterization (gold standard for diagnosis of PAH) – Essential first step to confirm diagnosis and determine severity and prognosis by measuring pulmonary arterial pressures and hemodynamics – Rule out underlying cardiac disease (e.g., left-sided heart disease) and response to vasodilator therapy. • Lung biopsy: not recommended unless primary pulmonary parenchymal disease exists • 6MWD: classifies severity of PAH and estimates prognosis

TREATMENT • Treat underlying diseases/conditions that may cause PAH to relieve symptoms and improve quality of life and survival. • Reasonable goals of therapy include the following: – Modified NYHA FC I or II – Echocardiography/CMR of normal/near-normal RV size and function – Hemodynamic parameters showing normalization of the RV function (RAP 2.5 to 3.0 L/min/m2 – 6MWD of >380 to 440 m – Cardiopulmonary exercise testing, including peak oxygen consumption of

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>15 mL/min/kg and EqCO2 60 mmHg (3)[C]

MEDICATION • Acute vasodilator test (performed during cardiac catheterization) for all PAH patients who are potential candidates for long-term oral calcium channel blocker (CCB) therapy (3)[C] – Screens for pulmonary vasoreactivity/responsiveness using inhaled nitrous oxide; epoprostenol (IV) or adenosine (IV): Positive response may be a prognostic indicator. – Contraindicated in right-sided heart failure or hemodynamic instability • Chronic vasodilator therapy – If IPAH with positive response to acute vasodilator test (a fall in mean PAP of ≥10 mm Hg and to a value 2,500 m) – Drug toxicity (salicylates, opiates) – Embolism (thrombus, fat, air, amniotic fluid) – Neurogenic (after head trauma/surgery) – Reexpansion (after pneumothorax/thoracentesis)

Genetics Multifactorial

RISK FACTORS • Cardiogenic: HTN, valvular disease, hyperlipidemia, atherosclerosis, diabetes mellitus, obesity, excessive alcohol intake, physical inactivity, dietary choices, and smoking • Noncardiogenic: sepsis, aspiration, pneumonia, trauma, inhaled toxins, DIC

GENERAL PREVENTION Early detection and treatment of risk factors, including high blood pressure, diabetes, alcohol intake, obesity, and tobacco abuse (1)[A]

COMMONLY ASSOCIATED CONDITIONS See “Etiology and Pathophysiology.”

DIAGNOSIS HISTORY • Past medical history – Underlying comorbidities, including prior heart failure or prior myocardial infarction (MI) – Recent trauma – Drug (illicit opiate, cocaine) or alcohol abuse – Dietary or medication noncompliance – Recent weight gain or increasing edema – Recent use of negative inotropic agents – Recent use of NSAIDs (increase water retention)

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• Symptoms – Fever or other symptoms of infection – Progressive dyspnea – Orthopnea and paroxysmal nocturnal dyspnea – Cough – Fatigue and generalized weakness – Pink frothy sputum – Chest pain

PHYSICAL EXAM • Vital signs: tachypnea, tachycardia, and hypoxemia. Patients may be hypotensive or hypertensive. • General: respiratory distress, diaphoresis • HEENT (head, eyes, ears, nose, throat): frothy oral secretions, cyanosis • Cardiac: S3 or S4, jugular venous distension, murmurs suggestive of valvular disease • Pulmonary: rales, crackles, or wheezing • Extremities: edema, cyanosis, mottled skin

DIFFERENTIAL DIAGNOSIS • COPD • Pneumonia • Pulmonary embolism • Asthma/reactive airway disease • Pneumothorax • Cardiac tamponade • Asphyxiant or toxic gas exposure • Inhalational burns

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • CBC/differential to screen for anemia or infection • Chemistry panel to screen for acute kidney injury, hyponatremia (associated with severe heart failure), or electrolyte disturbances leading to dysrhythmias • Troponin may be elevated from recent infarction causing acute heart failure or

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from myocardial ischemia secondary to elevated ventricular strain. Elevated cardiac enzymes carry a strongly negative prognosis in heart failure. • In settings of clinical uncertainty, B-type natriuretic peptide (BNP), or Nterminal pro-BNP, can add to clinical judgment in patients with symptoms suggestive of heart failure (1,2)[A]. BNP >500 pg/mL suggests heart failure, and BNP 95 which is +2. PE unlikely if 0 to 2 and PE likely if >3.

HISTORY • Determine if the presentation is provoked or idiopathic. Approximately 30% of cases develop without identifiable risk factor. • Presence of risk factors and family history • Bleeding risk (previous anticoagulation, history of bleeding, recent interventions/surgeries, liver disease) • Sudden onset dyspnea (>85%), chest pain (>50%), cough (20%), syncope (14%), hemoptysis (7%).

PHYSICAL EXAM • Dyspnea, syncope, hemoptysis, tachycardia, tachypnea, accentuated S2. Pleuritic chest pain, pleural friction rub, rales (1) • Signs of DVT: leg swelling, tenderness, visible collateral veins (1) • Signs of RV failure: jugular vein distention, third or fourth sound, systolic murmur at left sternal edge, hepatomegaly (1)

ALERT • Massive PE: mortality rate exceeding 20%. Hemodynamic instability with sustained hypotension, pulselessness, or persistent bradycardia, cardiogenic

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shock, acute manifesting RV failure (1) • Submassive PE: hemodynamically stable. Mortality rate of 5–25%. No systemic hypotension but there is either RV dysfunction or myocardial necrosis (1,3). – RV dysfunction: RV dilation or systolic dysfunction on echocardiography, RV dilation on CT, elevation of brain natriuretic peptide (BNP) or Nterminal pro-BNP (500 pg/mL), or consistent ECG changes • Low-risk PE: acute and absence of clinical markers of adverse prognosis

DIFFERENTIAL DIAGNOSIS • Pulmonary: pneumonia, bronchitis, pneumothorax, pneumonitis, chronic obstructive pulmonary disease (COPD) exacerbation, pulmonary edema, pneumothorax • Cardiac/vascular: myocardial infarction, pericarditis, congestive heart failure (CHF), aortic dissection • Musculoskeletal: rib fracture(s), musculoskeletal chest wall pain

DIAGNOSTIC TESTS & INTERPRETATION • D-dimer ELISA: In patients with low pretest probability, it can rule out PE if it is negative (high negative predictive value [NPV]) (1)[A]. It is not diagnostic if positive (low positive predictive value [PPV]) and it is not helpful if pretest probability is intermediate or high (1)[B]. • CBC, creatinine, aPTT and PT, ABG: In young patients with idiopathic, recurrent, or significant family history of VTE, consider testing for hypercoagulable tests. – Do not test for protein C, S, factor VIII, or antithrombin in the acute setting or while on treatment, as may be falsely abnormal. – Patients with intermediate or high pretest probability and low probability with elevated D-dimer need further diagnostic testing. • Chest x-ray (CXR): Westermark sign (lack of vessels in an area distal to the embolus), Hampton hump (wedge-shaped opacity with base in pleura), Fleischner sign (enlarged pulmonary arteries), atelectasis, pleural effusion, pulmonary infarct, hemidiaphragm elevation (1) • ECG: right heart strain, nonspecific rhythm abnormalities, S1Q3T3 • CT pulmonary angiography: sensitivity 96–100%, specificity 86–89%; NPV

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99.8%. If normal, it safely excludes PE if low or intermediate clinical probability (1)[A]. • Ventilation/perfusion scintigraphy (V/Q scan): safe with few allergic reactions. Use if CT angiography is not available or contraindicated. A highprobability V/Q scan makes the diagnosis of PE; normal V/Q scan excludes PE (1)[B]. • Pulmonary angiography: gold standard but invasive and technically difficult: 2% morbidity and 90%, specificity approximately 95%. It confirms the diagnosis of PE in patients with clinical suspicion (1)[B]. • CT venography: can be done at the same time as CT angiography; increases diagnostic yield (1)

ALERT If your preclinical probability is intermediate or high and the patient has a low bleeding risk, start treatment while waiting for the diagnostic results (3)[C]. Follow-Up Tests & Special Considerations Elevated troponin I or T and elevated BNP are markers for higher risk patients.

TREATMENT MEDICATION • If clinical suspicion is high and no contraindications, start treatment immediately. • Start LMWH, fondaparinux, UFH, as initial therapy for first 5 to 10 days. VKA can be started the 1st day and must overlap with parenteral treatment for minimum of 5 days, until international normalized ratio (INR) is 2 to 3 for 24 hours. • Following 5 to 10 days of parenteral therapy, dabigatran or edoxaban are also approved (1).

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• An oral option for initial and long-term treatment is rivaroxaban or apixaban (1). • Patients with massive PE with low bleeding risk: Consider systemic thrombolytics if no contraindications. Also in patients 40, recurrent VTE, upper extremity DVT (not related to catheter or lines), bilateral lower extremity DVT, intra-abdominal DVT, resistance to treatment. • In patients with prolonged baseline aPTT, adjust heparin dose with anti-Xa levels (therapeutic range 0.3 to 0.7).

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PULMONARY FIBROSIS Azfar S. Syed, DO • Zachary Prather, MD BASICS DESCRIPTION • Characterized by fibrosis of the lung parenchyma • Chest CT shows reticular pattern and honeycombing, with subpleural and lower lobe predominance. • Lung biopsy shows “usual interstitial pneumonia” pattern. • Classified based on etiology – Idiopathic – Nonidiopathic

EPIDEMIOLOGY Incidence • Incidence of IPF is 7 to 16/100,000 person-years. • Idiopathic pulmonary fibrosis (IPF) is more common in men. • Most patients with IPF are >60 years. • Incidence of nonidiopathic pulmonary fibrosis is unknown.

Prevalence • Prevalence of IPF is 2 to 39 cases/100,000 people. • Prevalence of nonidiopathic pulmonary fibrosis is unknown.

ETIOLOGY AND PATHOPHYSIOLOGY • Postulated that microinjury to alveolar epithelial cells causes release of cytokines that activates fibroblasts, which in turn leads to excess production of extracellular matrix • Causes of the nonidiopathic form include: – Occupational exposure – Environmental exposure – Drugs – Systemic connective tissue diseases

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– Granulomatous diseases

Genetics • 90%

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient should follow-up with a pulmonologist.

Patient Monitoring Disease progression can be monitored by periodic PFTs and HRCT.

DIET No specific dietary requirements

PATIENT EDUCATION • Patients should be counseled extensively regarding the prognosis of this diagnosis and given as much support as possible. Information about support groups in the local community and online may be helpful. • American Lung Association: http://www.lung.org/lung-health-anddiseases/lung-disease-lookup/pulmonary-fibrosis/ • Pulmonary Fibrosis Foundation: http://www.pulmonaryfibrosis.org/ which includes information about active pulmonary fibrosis clinical trials

PROGNOSIS • Median survival time was thought to be 2 to 3 years from time of diagnosis. However, recent data from clinical trials suggest that this may be an underestimate. • Some patients may deteriorate quickly, whereas others can remain stable for an extended period of time. Acute exacerbations carry a high mortality, and

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ICU treatment (mechanical ventilation) is mostly unsuccessful. • A higher extent of fibrosis increases the risk of death, whereas a higher percentage-predicted diffusing capacity of lung for carbon monoxide reduced the risk of death.

COMPLICATIONS • Respiratory failure • Infection • Pulmonary hypertension • Rib fractures secondary to prolonged coughing (especially in elderly patients with decreased bone density)

REFERENCES 1. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med. 2011;183(6):788– 824. 2. Lynch DA, Godwin JD, Safrin S, et al. High-resolution computed tomography in idiopathic pulmonary fibrosis: diagnosis and prognosis. Am J Respir Crit Care Med. 2005;172(4):488–493. 3. Rverson CJ, Cottin V, Brown KK, et al. Acute exacerbation of idiopathic pulmonary fibrosis: shifting the paradigm. Eur Respir J. 2015:46(2):512–520. 4. King TE Jr, Bradford WZ, Castro-Bernardini S, et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2083–2092. 5. Richeldi L, du Bois RM, Raghu G, et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med. 2014;370(22):2071–2082. 6. Rogliani P, Calzetta L, Cavalli F, et al. Pirfenidone, nintedanib, and Nacetylcysteine for treatment of idiopathic pulmonary fibrosis: a systematic review and meta-analysis. Pulm Pharmacol Ther. 2016;40:95–103. 7. Rafii R, Juarez MM, Albertson TE, et al. A review of current and novel therapies for idiopathic pulmonary fibrosis. J Thorac Dis. 2013;5(1):48–73.

ADDITIONAL READING

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• Baddini-Martinez J, Baldi BG, Costa CH, et al. Update on diagnosis and treatment of idiopathic pulmonary fibrosis. J Bras Pneumol. 2015;41(5):454– 466. • Castriotta RJ, Eldadah BA, Foster WM, et al. Workshop on idiopathic pulmonary fibrosis in older adults. Chest. 2010;138(3):693–703. • Covvey JR, Mancl EE. Recent evidence for pharmacological treatment of idiopathic pulmonary fibrosis. Ann Pharmacother. 2014;48(12):1611–1619. • Coward WR, Saini G, Jenkins G. The pathogenesis of idiopathic pulmonary fibrosis. Ther Adv Respir Dis. 2010;4(6):367–388. • Hoo ZH, Whyte MK. Idiopathic pulmonary fibrosis. Thorax. 2012;67(8):742– 746. • Hutchinson J, Fogarty A, Hubbard R, et al. Global incidence and mortality of idiopathic pulmonary fibrosis: a systematic review. Eur Respir J. 2015;46(3):795–806. • Kakugawa T, Sakamoto N, Sato S, et al. Risk factors for an acute exacerbation of idiopathic pulmonary fibrosis. Respir Res. 2016;17(1):79. • Lee JS, McLaughlin S, Collard HR. Comprehensive care of the patient with idiopathic pulmonary fibrosis. Curr Opin Pulm Med. 2011;17(5):348–354. • Ryu JH, Moua T, Daniels CE, et al. Idiopathic pulmonary fibrosis: evolving concepts. Mayo Clin Proc. 2014;89(8):1130–1142.

CODES ICD10 • J84.10 Pulmonary fibrosis, unspecified • J84.112 Idiopathic pulmonary fibrosis

CLINICAL PEARLS • Pulmonary fibrosis can usually be diagnosed based on characteristic chest CT findings, which include a reticular pattern, traction bronchiectasis, and honeycombing with a peripheral and basilar predominance. • There are idiopathic and nonidiopathic forms of pulmonary fibrosis. • Treatment options for pulmonary fibrosis are very limited and, at best, serve to

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slow the progression of disease.

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PYELONEPHRITIS Katelin M. Lisenby, PharmD, BCPS • Dana G. Carroll, PharmD, BCPS, CDE, CGP • Catherine Scarbrough, MD, MSc, FAAFP BASICS DESCRIPTION • Acute pyelonephritis is a syndrome caused by an infection of the renal parenchyma and renal pelvis, often producing localized flank/back pain combined with systemic symptoms, such as fever, chills, and nausea. It has a wide spectrum of presentation, from mild illness to septic shock. • Chronic pyelonephritis is the result of progressive inflammation of the renal interstitium and tubules, due to recurrent infection, vesicoureteral reflux, or both. • Pyelonephritis is considered uncomplicated if the infection is caused by a typical pathogen in an immunocompetent patient who has normal urinary tract anatomy and renal function. • System(s) affected: renal; urologic • Synonym: acute upper urinary tract infection (UTI)

Geriatric Considerations • May present as altered mental status; absence of fever is common in this age group. • Elderly patients with diabetes and pyelonephritis are at higher risk of bacteremia, longer hospitalization, and mortality. • The high prevalence of asymptomatic bacteriuria in the elderly makes the use of urine dipstick less reliable for diagnosing UTI in this population (1)[A].

Pregnancy Considerations • Most common medical complication requiring hospitalization • Affects 1–2% of all pregnancies. Morbidity does not differ between trimesters. • Urine culture as test of cure 1 to 2 weeks after therapy

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Pediatric Considerations • UTI is present in ~5% of patients age 2 months to 2 years with fever and no apparent source on history and physical exam. • Treatment (oral or IV; inpatient or outpatient) should be based on the clinical situation and patient toxicity.

EPIDEMIOLOGY Incidence Community-acquired acute pyelonephritis: 28/10,000/year

Prevalence Adult cases: 250,000/year, with 200,000 hospitalizations

ETIOLOGY AND PATHOPHYSIOLOGY • Escherichia coli (>80%) • Other gram-negative pathogens: Proteus, Klebsiella, Serratia, Clostridium, Pseudomonas, and Enterobacter • Enterococcus • Staphylococcus: Staphylococcus epidermis, Staphylococcus saprophyticus (number 2 cause in young women), and Staphylococcus aureus • Candida

RISK FACTORS • Underlying urinary tract abnormalities • Indwelling catheter/recent urinary tract instrumentation • Nephrolithiasis • Immunocompromise, including diabetes • Elderly, institutionalized patients (particularly women) • Prostatic enlargement • Childhood UTI • Acute pyelonephritis within the prior year • Frequency of recent sexual intercourse; spermicide use; new sex partner within the prior year • Stress incontinence in the previous 30 days • Pregnancy • Hospital-acquired infection

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• Symptoms >7 days at time of presentation

COMMONLY ASSOCIATED CONDITIONS • Indwelling catheters • Renal calculi • Benign prostatic hyperplasia

DIAGNOSIS HISTORY • In adults – Fever – Flank pain – Nausea ± vomiting – Malaise, anorexia – Myalgia – Dysuria, urinary frequency, urgency – Suprapubic discomfort – Mental status changes (elderly) • In infants and children – Fever – Irritability and poor feeding – GI symptoms

PHYSICAL EXAM • In adults – Fever: ≥38°C (100.4°F) – Costovertebral angle tenderness – Presentation ranges from no physical findings to septic shock. – Mental status changes common in the elderly – A pelvic exam may be necessary in female patients to exclude pelvic inflammatory disease. • In infants and children – Sepsis – Fever

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– Poor skin perfusion – Inadequate weight gain/weight loss – Jaundice to gray skin color

DIFFERENTIAL DIAGNOSIS • Obstructive uropathy • Acute bacterial pneumonia (lower lobe) • Cholecystitis • Acute pancreatitis • Appendicitis • Perforated viscus; aortic dissection • Pelvic inflammatory disease; ectopic pregnancy • Kidney stone • Diverticulitis

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Urinalysis: pyuria ± leukocyte casts, hematuria, nitrites (sensitivity 35–85%; specificity 92–100%), and mild proteinuria • Urine leukocyte esterase positive (sensitivity 74–96%; specificity 94–98%) • Urine Gram stain; urine culture (>100,000 colony-forming units/mL or >100 colony forming units/mL + symptoms) and sensitivities • CBC, BUN, Cr, GFR, and pregnancy test (if indicated) • C-reactive protein levels have been shown to correlate with prolonged hospitalization and recurrence; serum albumin 7, GFR 20% E. coli strains are resistant to ampicillin and TMP-SMX in community-acquired infections.

First Line • Adults – Oral (initial outpatient treatment) Ciprofloxacin: 500 mg q12h for 7 days Ciprofloxacin XR: 1,000 mg/day for 7 days Levofloxacin: 750 mg/day for 5 days – Trimethoprim-sulfamethoxazole (TMP-SMX) (160/800 mg): 1 tab q12h for 14 days provided uropathogen known to be susceptible ± ceftriaxone 1 g initial IV dose given IV (assuming normal creatinine clearance [CrCl]) Ciprofloxacin: 400 mg q12h Levofloxacin: 750 mg/day Cefotaxime: 1 g q8–12h up to 2 g q4h Ceftriaxone: 1 to 2 g/day Cefepime: 1 to 2 g q12h Gentamicin: 5 to 7 mg/kg of body weight daily Ampicillin: 2 g q6h ± gentamicin for Enterococcus – Severe illness: IV therapy until afebrile 24 to 48 hours and tolerating oral hydration and medications, then oral agents to complete up to a 2-week

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course • Pediatric – Oral: cefdinir: 14 mg/kg/day for 10 to 14 days; ceftibuten 9 mg/kg/day for 10 to 14 days; cefixime 8 mg/kg/day for 10 to 14 days – IV (general indication for IV therapy is age 80% heritability • Multiple gestation—200 fold increased risk if monozygotic twin diagnosed and 20 fold increased risk if dizygotic twin diagnosed • Breast feeding protective versus bottle feeding risk increased • Postnatal macrolide use (i.e., erythromycin, azithromycin)—erythromycin agonist of motilin which might cause continuous contraction of the pyloric muscle (2)[B],(3)[C] • A recent surveillance study of a population-based birth defects registry identified association between pyloric stenosis and the use of fluoxetine in the 1st trimester, even after adjustment for maternal age and smoking. The adjusted odds ratio was 9.8 (95% CI 1.5–62) (4)[B].

COMMONLY ASSOCIATED CONDITIONS Associated anomalies present in ∼4–7% of infants with pyloric stenosis. • Hiatal and inguinal hernias (most commonly) • Other anomalies include the following: – Congenital heart disease – Esophageal atresia – Tracheoesophageal fistula – Renal abnormalities – Turner syndrome and trisomy 18 – Cornelia de Lange syndrome – Smith-Lemli-Opitz syndrome • A common proposed genetic link between breast cancer, endometriosis, and

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pyloric stenosis has been observed in families.

DIAGNOSIS HISTORY • Nonbilious projectile vomiting after feeding, increasing in frequency and severity • Emesis may become blood-tinged from vomiting-induced gastric irritation. • Hunger due to inadequate nutrition • Decrease in bowel movements • Weight loss

PHYSICAL EXAM • Firm, mobile (“olivelike”) mass palpable in the right upper quadrant (historically 70–90% of the time) • However, this finding has decreased in occurence to about 13% due to earlier diagnosis with US (3)[C] • Epigastric distention • Visible gastric peristalsis after feeding • Late signs: dehydration, weight loss • Rarely, jaundice when starvation leads to decreased glucuronyl transferase activity resulting in indirect hyperbilirubinemia

DIFFERENTIAL DIAGNOSIS • Inexperienced or inappropriate feeding • GERD • Gastritis • Congenital adrenal hyperplasia, salt-losing • Pylorospasm • Gastric volvulus • Antral or gastric web

DIAGNOSTIC TESTS & INTERPRETATION Metabolic disturbances are late findings and are uncommon in present era of early diagnosis and intervention.

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• If prolonged vomiting, then check electrolytes for the following: – Hypokalemia – Hypochloremia – Metabolic alkalosis • Elevated unconjugated bilirubin level (rare) • Paradoxical aciduria: The kidney tubules excrete hydrogen to preserve potassium in face of hypokalemic alkalosis. • Abdominal US is the study of choice. – US shows thickened and elongated pyloric muscle and redundant mucosa. • Upper GI series reveals strong gastric contractions; elongated, narrow pyloric canal (string sign); and parallel lines of barium in the narrow channel (doubletract sign or railroad track sign).

Test Interpretation Concentric hypertrophy of pyloric muscle

TREATMENT SURGERY/OTHER PROCEDURES • Ramstedt pyloromyotomy is curative. The entire length of hypertrophied muscle is divided, with preservation of the underlying mucosa. • Surgical approaches include open (traditional right upper quadrant transverse) incision, more contemporary circumumbilical incision, and laparoscopic techniques. • A recent review concluded that the laparoscopic approach results in less postoperative pain and can be performed with no increase in operative time or complications (5)[A]. • Conservative approach – Conservative management of infantile hypertrophic pyloric stenosis with atropine can be effective in approximately six out of seven cases but has a lower success rate and longer duration of therapy than surgery (6)[B]. – Atropine therapy may be considered as an alternative to pyloromyotomy for patients unsuitable or at high risk for surgery and in areas of the world where surgery on small infants is unavailable or unsafe (6)[B].

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ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Prompt treatment to avoid dehydration and malnutrition • Correct acid–base and electrolyte disturbances. Surgery should be delayed until alkalosis is corrected. • Patients need pre- and postop apnea monitoring. They have a tendency toward apnea to compensate with respiratory acidosis for their metabolic alkalosis. • IV fluids to correct dehydration and metabolic abnormalities. For optimal resusication in infants, use D5 1/2NS with 20 meq of KCl (3)[C].

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Routine pediatric health maintenance • Postoperative monitoring, including monitoring for pain, emesis, apnea • If significant emesis present after 1 to 2 weeks, then upper GI studies needed to rule out incomplete pyloromyotomy or duodenal leak (3)[C]

DIET • No preoperative feeding • Initiate feeding 4 hours after surgery with adlib feedings thereafter (7)[A].

PROGNOSIS Surgery is curative.

COMPLICATIONS • No long-term morbidity • Incomplete pyloromyotomy • Mucosal perforation • Wound infections • Delayed feeding due to postoperative vomiting • Serosal tear • Subcutaneous emphysema • 4.6–12% complication rate (3)[C]

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REFERENCES 1. Feenstra B, Geller F, Carstensen L, et al. Plasma lipids, genetic variants near APOA1, and the risk of infantile hypertrophic pyloric stenosis. JAMA. 2013;310(7):714–721. 2. Krogh C, Fischer TK, Skotte L, et al. Familial aggregation and heritability of pyloric stenosis. JAMA. 2010;303(23):2393–2399. 3. Peters B, Oomen MW, Bakx R, et al. Advances in infantile hypertrophic pyloric stenosis. Expert Rev Gastroenterol Hepatol. 2014;8(5):533–541. 4. Bakker MK, De Walle HE, Wilffert B, et al. Fluoxetine and infantile hypertrophic pylorus stenosis: a signal from a birth defects-drug exposure surveillance study. Pharmacoepidemiol Drug Saf. 2010;19(8):808–813. 5. Oomen MW, Hoekstra LT, Bakx R, et al. Open versus laparoscopic pyloromyotomy for hypertrophic pyloric stenosis: a systematic review and meta-analysis focusing on major complications. Surg Endosc. 2012;26(8):2104–2110. 6. Mercer AE, Phillips R. Question 2: can a conservative approach to the treatment of hypertophic pyloric stenosis with atropine be considered a real alternative to surgical pyloromyotomy? Arch Dis Child. 2013;98(6):474–477. 7. Graham KA, Laituri CA, Markel TA, et al. A review of postoperative feeding regimens in infantile hypertrophic pyloric stenosis. J Pediatr Surg. 2013;48(10):2175–2179.

ADDITIONAL READING • Ein SH, Masiakos PT, Ein A. The ins and outs of pyloromyotomy: what we have learned in 35 years. Pediatr Surg Int. 2014;30(5):467–480. • Everett KV, Capon F, Georgoula C, et al. Linkage of monogenic infantile hypertrophic pyloric stenosis to chromosome 16q24. Eur J Hum Genet. 2008;16(9):1151–1154. • Everett KV, Chioza BA, Georgoula C, et al. Genome-wide high-density SNPbased linkage analysis of infantile hypertrophic pyloric stenosis identifies loci on chromosomes 11q14–q22 and Xq23. Am J Hum Genet. 2008;82(3):756– 762. • Georgoula C, Gardiner M. Pyloric stenosis a 100 years after Ramstedt. Arch

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Dis Child. 2012;97(8):741–745. • National Birth Defects Prevention Network. Selected birth defects data from population-based birth defects surveillance programs in the United States, 2003–2007. Birth Defects Res A Clin Mol Teratol. 2010;88(12):1062–1174. • Owen RP, Almond SL, Humphrey GM. Atropine sulphate: rescue therapy for pyloric stenosis [published online ahead of print August 2, 2012]. BMJ Case Rep. • Sommerfield T, Chalmers J, Youngson G, et al. The changing epidemiology of infantile hypertrophic pyloric stenosis in Scotland. Arch Dis Child. 2008;93(12):1007–1011. • Wyrick DL, Smith SD, Dassinger MS. Surgeon as educator: bedside ultrasound in hypertrophic pyloric stenosis. J Surg Educ. 2014;71(6):896–898.

CODES ICD10 Q40.0 Congenital hypertrophic pyloric stenosis

CLINICAL PEARLS • Pyloric stenosis is the most common condition requiring surgical intervention in the 1st year of life. • The condition classically presents between 1 and 5 months of life, with projectile vomiting after feeds and a firm, mobile mass in the right upper quadrant. • Abdominal US is the study of choice. • Surgery (laparoscopic Ramstedt pyloromyotomy is the preferred method) is curative.

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RABIES Alan M. Ehrlich, MD BASICS DESCRIPTION • A rapidly progressive CNS infection caused by a ribonucleic acid (RNA) rhabdovirus affecting mammals, including humans • Generally considered to be 100% fatal once symptoms develop • System(s) affected: nervous • Synonym(s): hydrophobia (inability to swallow water)

EPIDEMIOLOGY Incidence • Most cases are in developing countries. • Estimated 55,000 deaths worldwide per year • Typically only 1 to 3 cases per year in the United States, with 1/3 of those being due to exposure outside of the United States • Predominant age: any • Predominant sex: male = female

ETIOLOGY AND PATHOPHYSIOLOGY Lyssavirus, an RNA virus in the family Rhabdoviridae • Rabies virus is a neurotropic virus present in saliva of infected animals. • Transmission occurs via bites from infected animals or when saliva from an infected animal comes in contact with an open wound or mucous membranes. • Bats are most common reservoir in the United States.

RISK FACTORS • Professions or activities with exposure to potentially infected (wild or domestic) animals (e.g., animal handlers, lab workers, veterinarians, cave explorers) • Most U.S. cases are associated with bat exposure. • Internationally, rabies is widespread in both domestic and feral dogs.

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• Human-to-human transmission has occurred through transplantation of cornea, solid organs, and other tissues. • Travel to countries where canine rabies is endemic.

GENERAL PREVENTION • Preexposure vaccination for high-risk groups (veterinarians, animal handlers, and certain laboratory workers) • Consider preexposure vaccination for travelers to areas (such as North Africa) that have increased risk of rabies from domestic animals. • Immunization of dogs and cats • Contact animal control and avoid approaching or handling wild (or domestic) animals exhibiting strange behaviors. • Avoid wild and unknown domestic animals. • Seek treatment promptly if bitten, scratched, or in contact with saliva from potentially infected animal. • Prevent infection by prompt postexposure treatment. • Consider postexposure prophylaxis for individuals in direct contact with bats, unless it is known that an exposure did not occur. • Hospital contacts of patients infected with rabies do not require postexposure prophylaxis unless there has been exposure through mucous membranes or an open wound (including a bite) to saliva, CSF, or brain tissue from the infect patient.

DIAGNOSIS HISTORY • History of animal exposure • Most patients do not recall exposure. • Five stages (may overlap) – Incubation period: time between bite and first symptoms: usually 10 days to 1 year (average of 20 to 60 days). Incubation is shortest in patients with extensive bites in the head or trunk. – Prodrome: lasts 1 to 14 days; symptoms include pain or paresthesia at bite site and nonspecific flulike symptoms, including fever and headache.

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– Acute neurologic period: lasts 2 to 10 days. CNS symptoms dominate; generally 1 of 2 forms: (i) furious rabies: brief (~5 minute) episodes of hyperactivity with hydrophobia, aerophobia, hyperventilation, hypersalivation, and autonomic instability; (ii) paralytic rabies: Paralysis dominates; may be ascending (as in Guillain-Barré syndrome) or may affect ≥1 limbs differentially – Coma: lasts hours to days; may evolve over several days following acute neurologic period; may be sudden, with respiratory arrest – Death: usually occurs within 3 weeks of onset as result of complications

PHYSICAL EXAM Findings range from normal exam to severe neurologic findings, including paralysis and coma, depending on the stage of rabies at the time of presentation.

DIFFERENTIAL DIAGNOSIS • Any rapidly progressive encephalitis; important to exclude treatable causes of encephalitis, especially herpes • Transverse myelitis

DIAGNOSTIC TESTS & INTERPRETATION Initial Tests (lab, imaging) • Lumbar puncture. WBC count is normal or shows moderate pleocytosis; protein normal or moderately elevated • Skin biopsy to detect rabies antigen in hair follicles – Available through state and federal reference labs • Rabies antibody titer of serum and CSF • Skin biopsy from nape of neck for direct fluorescent antibody examination • Viral isolation from saliva or CSF • Corneal smear stains are positive by immunofluorescence in 50% of patients. • Hyponatremia is common. • Head CT scan: normal or nonspecific findings consistent with encephalitis • MRI can help rule out other forms of encephalitis. Follow-Up Tests & Special Considerations Submit brain of the biting animal for testing if possible.

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Test Interpretation Encephalitis may be found on brain biopsy. Other abnormal findings (e.g., brainstem, midbrain, cerebellum) often found only postmortem.

TREATMENT Thorough wound cleansing with soap and water is first line of treatment. Irrigate wound with virucidal agent, such as povidone-iodine, if available.

GENERAL MEASURES • Evaluate risk based on exposure and consult public health officials about the need for rabies prophylaxis. • In the United States, raccoons, skunks, bats, foxes, and coyotes are the animals most likely to be infected. Any carnivore can carry the disease. • Before initiating antirabies treatment, consider: – Type of exposure (bite or nonbite) – Epidemiology of rabies in species involved – Circumstances surrounding exposure (provoked vs. unprovoked bite) – Vaccination status of offending animal

MEDICATION ALERT • Immunosuppression alters immunity after vaccination. Immunosuppressive drugs should be avoided during postexposure prophylaxis if possible. If postexposure prophylaxis is given to an immunosuppressed patient, check serum samples for the presence of rabies virus–neutralizing antibody to assess response to vaccination (1)[C]. • Clean wounds thoroughly, regardless of postexposure prophylaxis status. • Assess need for postexposure prophylaxis based on circumstances of possible exposure. • Increased risk: – Bites involving skin puncture are high risk; saliva exposure is a risk only if it comes in contact with an open wound or mucous membranes. – Wild or domestic animals unavailable for quarantine

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– Bat exposure – Hybrid animals of wild and domestic species (e.g., wolf-dog) – Unprovoked attack (Feeding a wild animal is considered a provoked attack.) • Management: – Bites from cats, dogs, and ferrets that can be watched for 10 days do not require prophylaxis unless animal shows signs of illness. – Skunks, foxes, bats, raccoons, and most carnivores are high risk, and prophylaxis should begin promptly unless animal can be captured and euthanized for pathologic evaluation. – For rodents or livestock, consult local public health authorities before initiating prophylaxis. • Postexposure prophylaxis (2)[B] – Passive vaccination: rabies immunoglobulin (RIG, HyperRAB) 20 IU/kg administered once. Infiltrate RIG around the wound if possible. Administer remaining RIG IM. Do not administer RIG using the same syringe or into the same anatomic site as vaccine. – Active vaccination: rabies vaccine, human diploid cell vaccine (HDCV) or rabies vaccine adsorbed (RVA) or purified chick embryo cell vaccine IM in the deltoid. Give the first dose, 1 mL, as soon as possible after exposure. The day of the first dose is designated day 0. Give additional 1mL doses on days 3, 7, and 14. If immunocompromised, give fifth dose on day 28. For children, use the anterolateral aspect of the thigh and avoid the gluteal area. • For previously vaccinated patients, administer an initial 1-mL IM dose of vaccine immediately and an additional 1-mL dose 3 days later. RIG is not necessary in these patients (2)[B]. • Preexposure vaccination: for people in high-risk groups, such as veterinarians, animal handlers, certain laboratory workers, and those spending time in foreign countries where rabies is enzootic (3)[B]: – Primary preexposure: three IM 1-mL injections of HDCV or RVA in deltoid area on days 0, 7, and 21, or 28 – Preexposure boosters: For people at risk of exposure to rabies, test serum every 2 years. Administer preexposure booster of 1-mL IM if immunity is

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waning. If titer cannot be obtained, a booster can be administered instead. • Contraindications: none for postexposure treatment

Pregnancy Considerations • Pregnancy is not a contraindication to postexposure prophylaxis. • Rabies vaccination is not associated with a higher incidence of spontaneous abortion, premature births, or fetal abnormalities.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS Clinical rabies • Comfort care and sedation for all patients. • Milwaukee protocol: experimental treatment using ketamine, midazolam, and amantadine (originally included ribavirin but no longer recommended) (1,4) [C]. One patient who did not receive pre- or postexposure prophylaxis recovered from clinical rabies in 2004 after being treated with medically induced coma and amantadine l (1)[C]. • Control cerebral artery vasospasm (with an agent such as nimodipine) (4,5) [C]. • Fludrocortisone and hypertonic saline if needed to maintain normal sodium level (5)[C]

ONGOING CARE FOLLOW-UP RECOMMENDATIONS After primary vaccination, serologic testing is necessary only if the patient has a disease or takes immunosuppresive medication.

PATIENT EDUCATION Use screens over ventilation areas in the roof to secure from bats. Avoid exposure to wild mammalian species known to carry rabies and report potential exposures immediately.

PROGNOSIS • No postexposure failures in the United States since the 1970s.

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• If untreated, rabies has the highest case fatality rate of any infectious disease; generally considered to be 100% fatal once symptoms develop. • There have only been a small number of cases of successful recovery from rabies. Almost all received some form of pre- or postexposure immunization.

COMPLICATIONS 0.6% of people develop mild serum sickness reaction following HDCV boosters. Mild local and systemic reactions are common following vaccination. Do not interrupt immunization series with mild reactions.

REFERENCES 1. Willoughby RE Jr, Tieves KS, Hoffman GM, et al. Survival after treatment of rabies with induction of coma. N Engl J Med. 2005;352(24):2508–2514. 2. Rupprecht CE, Briggs D, Brown CM, et al. Use of a reduced (4-dose) vaccine schedule for postexposure prophylaxis to prevent human rabies: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2010;59(RR-2):1–9. 3. Manning SE, Rupprecht CE, Fishbein D, et al. Human rabies prevention— United States, 2008: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2008;57(RR-3):1–28. 4. Aramburo A, Willoughby RE, Bollen AW, et al. Failure of the Milwaukee protocol in a child with rabies. Clin Infect Dis. 2011;53(6):572–574. 5. Hu WT, Willoughby RE Jr, Dhonau H, et al. Long-term follow-up after treatment of rabies by induction of coma. N Engl J Med. 2007;357(9):945– 946.

ADDITIONAL READING • Centers for Disease Control and Prevention. http://www.cdc.gov/rabies/ • Centers for Disease Control and Prevention. Recovery of a patient from clinical rabies—California, 2011. MMWR Morb Mortal Wkly Rep. 2012;61(4):61–65. • Crowcroft NS, Thampi N. The prevention and management of rabies. BMJ. 2015;350:g7827. • De Serres G, Skowronski DM, Mimault P, et al. Bats in the bedroom, bats in

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the belfry: reanalysis of the rationale for rabies postexposure prophylaxis. Clin Infect Dis. 2009;48(11):1493–1499. • Eckerle I, Rosenberger KD, Zwahlen M, et al. Serologic vaccination response after solid organ transplantation: a systematic review. PLoS One. 2013;8(2):e56974. • Hemachudha T, Ugolini G, Wacharapluesadee S, et al. Human rabies: neuropathogenesis, diagnosis, and management. Lancet Neurol. 2013;12(5):498–513. • Vora NM, Basavaraju SV, Feldman KA, et al. Raccoon rabies virus variant transmission through solid organ transplantation. JAMA. 2013;310(4):398– 407.

SEE ALSO Bites, Animal and Human

CODES ICD10 • A82.9 Rabies, unspecified • Z20.3 Contact with and (suspected) exposure to rabies

CLINICAL PEARLS • Rabies is rare in the United States but more common in other areas of the world. • Seek immediate treatment if exposed to scratch, bite, or saliva of potentially infected animal (e.g., feral dog, bat, fox, raccoon, or other wild mammals). • Postexposure prophylaxis consists of three steps: local wound cleansing, passive immunization with rabies immunoglobulin, and active immunization with HDCV. • Consider postexposure prophylaxis for those reporting direct contact with bats, unless it can be verified that an exposure did not occur.

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RAPE CRISIS SYNDROME Ravin V. Patel, MD • Dustin Creech, MD BASICS DESCRIPTION • Definitions (legal definitions may vary from state to state) – Sexual contact: intentional touching of a person’s intimate parts (including thighs) or the clothing covering such areas, if it is construed as being for the purpose of sexual gratification – Sexual conduct: vaginal intercourse between a male and female, or anal intercourse, fellatio, or cunnilingus between persons, regardless of sex – Rape (which is a legal term, physician should use the phrase alleged sexual assault): any sexual penetration, however slight, using force or coercion against the person’s will – Sexual imposition: similar to rape but without penetration or the use of force (i.e., nonconsensual sexual contact, stalking) – Gross sexual imposition: nonconsensual sexual contact with the use of force – Corruption of a minor: sexual conduct by an individual age ≥18 years with an individual male – For males 69% of male victims were first raped before age 18 years. 41% of male victims were raped before age 12 years.

INCIDENCE • In the United States, approximately 1.5 million women and 834,700 men are sexually assaulted annually (1). • Estimated that only a fraction of sexual assaults are reported to law enforcement. • 18% of American women will be sexually assaulted during their lifetime (2). – Between 20% and 25% of females will experience rape/attempted rape during their college years. • 2–3% of American men will be sexually assaulted during their lifetime. • Most rape victims either know or have some acquaintance with their attacker.

RISK FACTORS • Chronologic age of adolescent and young adults 16 to 24 years incur sexual assault. Children living in household of sexual assault are increase risk of maltreatment and lifelong poor health. • Previous history of victimization (sexually or physically) • Alcohol consumption is estimated to be involved in 1/2 of sexual assault. • Illicit drug may also contribute to sexual assault.

GENERAL PREVENTION • The public health approach should include both prevention and avoidance of vulnerability factors and implementation of protective factors. • Females may benefit from assertiveness training and self-defense training. • U.S. Preventive Services Task Force found insufficient evidence to support

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general screening in all their patient (no evidence of harm in screening), but physician should discuss sexual assault and family violence with their patient in nonjudgement manner.

DIAGNOSIS • In adults – History of sexual penetration – Sexual contact/conduct without consent and/or with the use of force • In children – Actual observation/suspicion of sexual penetration, sexual contact, or sexual conduct – Signs include evidence of the use of force and/or evidence of sexual contact (e.g., presence of semen and/or blood).

HISTORY • Avoid questioning that implies the patient is at fault. • Record answers in patient’s own words insofar as possible. Include date, approximate time, and general location as best as possible. Document physical abuse other than sexual. Describe all types of sexual contact, whether actual/attempted. Take history of alcohol and/or drug use before or after alleged incident; note that some states require specific forms for documenting history. • Document time of last activity that could possibly alter specimens (e.g., bath, shower, douche). • Thorough gynecologic history is mandatory, including last menstrual period, last consenting sexual contact, contraceptive practice, and prior gynecologic surgery (3)[C].

PHYSICAL EXAM • Use of drawings and/or photographs is encouraged; note that some states require specific forms for documenting physical exam. • Document all signs of trauma/unusual marks. • Document mental status/emotional state. • Use UV light (Wood lamp) to detect seminal stains on clothing/skin.

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• Obtaining the patient’s consent at each step of examination helps the patient regain a sense of control.

ALERT • A forensic kit or “rape kit” contains swabs that are collected from the vagina and rectum, and instructions are given with the kit regarding proper collection. • Many states and emergency departments across the country are using a Sexual Assault Nurse Examiner (SANE) when available. This has led to more consistent and more accurate collection of evidence in alleged rape cases. • Complete genital–rectal exam, including evidence of trauma, secretions, or discharge. – Use of a nonlubricated, water-moistened speculum is mandatory because commonly used lubricants may destroy evidence. – Testing and/or specimen collection, as indicated, and in compliance with state requirements (4)

DIFFERENTIAL DIAGNOSIS Consenting sex among adults

DIAGNOSTIC TESTS & INTERPRETATION • In females, obtain a serum or urine pregnancy test. • Record results of wet mount, screening for vaginitis, but also note the presence/absence of sperm and, if present, whether it is motile/immotile. • Drug/alcohol testing as indicated by history and/or physical findings

TREATMENT GENERAL MEASURES • Providing health care to victims of sexual assault/abuse requires special sensitivity and privacy. • All such cases must be reported immediately to the appropriate law enforcement agency. • With the victim’s permission, enlist the help of personnel from local support

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agencies (e.g., rape crisis center). When available, use of in-house social services is extremely helpful to victim and family. • SANE programs have been shown to be beneficial, especially in large cities and metropolitan areas with multiple emergency departments of varying capability and staff training/experience. • Give sedation and tetanus prophylaxis when indicated. • Discuss possible pregnancy and pregnancy termination with the victim. If hospital policy precludes such as discussion, then information about this option should be offered to the victim via follow-up mechanisms. • Discuss suspected HIV and hepatitis B exposure and testing with the victim in accordance with hospital, regional, and state policies/protocols. The initial HIV test should be completed within 7 days of the suspected exposure.

MEDICATION First Line • Controversy exists regarding empiric antibiotic prophylaxis for victims of sexual assault. However, the Centers for Disease Control and Prevention (CDC) recommends empiric antibiotic prophylaxis of potential sexually transmitted infections (specifically, gonorrhea, chlamydia, trichomoniasis, and potentially syphilis), as many patients will not return for a follow-up visit and many patients prefer immediate treatment (5)[C]. • Cultures are not required before initiating treatment but can be considered as part of routine evidence collection. • Gonorrhea: ceftriaxone 250 mg IM once. Note: Be aware that drug resistance is on the rise in several major cities. Quinolones are no longer recommended for treatment of gonorrhea. • Chlamydia: azithromycin 1 g PO single dose, or doxycycline 100 mg PO BID for 7 days, or erythromycin base 500 mg PO QID for 7 days, or erythromycin ethylsuccinate 800 mg PO QID for 7 days • Syphilis: benzathine penicillin G 2 to 4 million units IM once, or doxycycline 100 mg PO BID for 14 days. Some suggest ceftriaxone 1 g/day, either IM/IV, for 8 to 10 days, but treatment failures have been reported in several geographic areas. • Trichomoniasis and bacterial vaginosis, if present (if cultures/wet mount were

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collected): metronidazole 2 g PO once, or metronidazole 500 mg PO BID for 7 days (consider single dose to maximize compliance), or metronidazole gel 0.75% 1 full applicator (5 g) intravaginally every day for 5 days; or clindamycin cream 2% 1 full applicator (5 g) intravaginally at bedtime for 7 days (considered less efficacious than PO metronidazole) • If pregnancy prophylaxis is indicated, use levonorgestrel 1.5 mg once (Plan B, progestin-only), efficacious for up to 5 days after the incident. – Levonorgestrel alone has proved more effective than the Yuzpe regimen, a method of emergency contraception. – Alternatively, ethinyl estradiol/levonorgestrel (Yuzpe) 100 μg/0.5 mg once and repeated in 12 hours can be used. – Alternatively, ulipristal acetate (Ella) 30 μg once can be used. – Alternatively, a copper intrauterine device can be inserted up to 5 days after the earliest predicted date of ovulation in that cycle (6)[C]. • HIV: Currently, there is a low likelihood of HIV transmittance, but the CDC still recommends postexposure prophylaxis (PEP) for victims of sexual assault. Regimen is PEP for 3 to 7 days, with short-term follow-up for further counseling, with a specialist familiar with PEP regimens. – Most effective if started within 4 hours and could reduce transmission by as much as 80%; unlikely to be beneficial if started after 72 hours. • Hepatitis B: if prevalent in area or assailant known to be high risk: hepatitis B immunoglobulin 0.06 mL/kg IM, single dose, and initiate 3-dose hepatitis B virus immunization series. No treatment if the victim has had a complete hepatitis B vaccine series, with documented levels of immunity (7)[C].

Second Line Pregnancy Considerations Conduct baseline pregnancy test; discuss pregnancy prevention and termination with patient.

Pediatric Considerations Assure the child that she or he is a good person and was not the cause of the incident.

ADMISSION, INPATIENT, AND NURSING

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CONSIDERATIONS • Contact appropriate social services agency. • Most adult victims can be treated as outpatients, unless associated trauma (physical/mental) requires admission. • Most pediatric sexual assault/abuse victims will require admission/outside placement until appropriate social agency can evaluate home environment (8) [C].

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Patient should be seen in 7 to 10 days for follow-up care, including pregnancy testing and counseling. • Close exam for vaginitis and treatment if necessary. • Follow-up test for gonorrhea should occur in 1 to 2 weeks. • Follow-up testing for syphilis, HIV, and hepatitis B should occur at 6 weeks, 3 months, and 6 months. • Provide telephone numbers of counseling agency(ies) that can provide counseling/legal services to the patient. • Strongly consider SANE, if available (9)[C].

PATIENT EDUCATION • Local rape crisis support organizations • National Sexual Violence Resource Center, 123 Enola Drive, Enola, PA 17025; (877) 739-3895; www.nsvrc.org • National Domestic Violence Hotline at (800) 799-SAFE(7233) or TTY (800) 787-3224 or www.thehotline.org

PROGNOSIS • Acute phase (usually 1 to 3 weeks following rape): shaking, pain, wound healing, mood swings, appetite loss, crying. Also feelings of grief, shame, anger, fear, revenge, or guilt • Late/chronic phase (also called “reorganization”): Female victim may develop

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fear of intercourse, fear of men, anxiety or increase discomfort during Pap smears, nightmares, sleep disorders, daytime flashbacks, fear of being alone, loss of self-esteem, anxiety, depression, posttraumatic stress syndrome, and somatic complaints (e.g., nonspecific abdominal pain). • Recovery may be prolonged. Patients who are able to talk about their feelings seem to have a faster recovery. It is unclear if pharmaco- or psychotherapy results in better outcomes.

COMPLICATIONS Sequelae include the following: • Trauma (physical and or mental) • STIs, including HIV • Unwanted pregnancy (with the possibility of abortion) – The rape-related pregnancy rate in the United States is 5% per rape among victims of reproductive age, resulting in >32,000 unwanted pregnancies each year. – Adolescents are at highest risk of pregnancy. • Medical: chronic pain, fibromyalgia, headaches, irritable bowel syndrome, sexual dysfunction • Psychological: anxiety, depression, posttraumatic stress disorder, eating disorder, substance abuse

REFERENCES 1. Cronholm PF, Fogarty CT, Ambuel B, et al. Intimate partner violence. Am Fam Physician. 2011;83(10):1165–1172. 2. Tjaden P, Thoennes N. Extent, Nature, and Consequences of Rape Victimization: Findings from the National Violence Against Women Survey. Washington, DC: National Institute of Justice and the Centers for Disease Control and Prevention; 2006. 3. Linden JA. Clinical practice. Care of the adult patient after sexual assault. N Engl J Med. 2011;365(9):834–841. 4. U.S. Department of Justice, Office on Violence Against Women. A National Protocol for Sexual Assault Medical Forensic Examinations (Adults/Adolescents). 2nd ed. Washington, DC: U.S. Department of Justice;

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2013. 5. Workowski KA, Berman S; for the Centers for Disease Control and Prevention. Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep. 2010;59(RR-12):1–110. 6. Cheng L, Che Y, Gülmezoglu AM. Interventions for emergency contraception. Cochrane Database Syst Rev. 2012;(8):CD001324. 7. Mast EE, Weinbaum CM, Fiore AE, et al. A comprehensive immunization strategy to eliminate transmission of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices (ACIP) part II: immunization of adults. MMWR Recomm Rep. 2006;55(RR-16):1–33; quiz CE1–CE4. 8. DeVore HK, Sachs CJ. Sexual assault. Emerg Med Clin North Am. 2011;29(3):605–620. 9. ACOG educational bulletin. Sexual assault. Number 242, November 1997 (replaces no. 172, September 1992). American College of Obstetricians and Gynecologists. Int J Gynaecol Obstet. 1998;60(3):297–304.

ADDITIONAL READING • Centers for Disease Control and Prevention. Sexual Violence: Facts at a Glance. Atlanta, GA: Centers for Disease Control and Prevention; 2012. • National Consensus Guidelines of Identifying and Responding to Domestic Violence. San Franscisco, CA: Family Voilence Prevention Fund; 2002.

SEE ALSO Chlamydia Infection (Sexually Transmitted); Gonococcal Infections; Hepatitis B; Hepatitis C; HIV/AIDS; Posttraumatic Stress Disorder; Syphilis

CODES ICD10 • T74.21XA Adult sexual abuse, confirmed, initial encounter • T74.22XA Child sexual abuse, confirmed, initial encounter

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• Z04.41 Encounter for exam and obs following alleged adult rape

CLINICAL PEARLS • Rape is a legal term, and the examining physician is encouraged to use terminology such as alleged rape or alleged sexual conduct. • Marital rape is a federal offense in all 50 states and the District of Columbia; in some states, also applies to unmarried cohabiting couples. • Because “consent defense” is common, documentation of evidence supporting the use of force or the administration of drugs/alcohol is imperative. • Use of a protocol is encouraged to assure every victim a uniform, comprehensive evaluation, regardless of the expertise of the examiner. The protocol must ensure that all evidence is properly collected and labeled, chain of custody is maintained, and the evidence is sent to the most appropriate forensic laboratory. • All medical records must be well documented and legible. • All medical personnel must be willing and able to testify on behalf of the patient. The views expressed in this chapter are those of the author and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the U.S. government. Opinions, interpretations, conclusions, and recommendations herein are those of the author and are not necessarily endorsed by the U.S. Army.

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RAYNAUD PHENOMENON Herbert L. Muncie, Jr., MD • Kelsey E. Phelps, MD BASICS DESCRIPTION • Idiopathic intermittent episodes of vasoconstriction of digital arteries, precapillary arterioles, and cutaneous arteriovenous shunts in response to cold, emotional stress, or blunt trauma – A triphasic color change of the fingers (occasionally the toes, rarely nipples) is the principal physical manifestation. The initial color is white from extreme pallor, then blue from cyanosis, and finally with warming and vasodilatation the skin appears red. Thumbs are rarely involved. – Swelling, throbbing, and paresthesias are associated symptoms. – Primary 80% of patients have primary disease. Episodes are bilateral and nonprogressive. Diagnosis confirmed if after 2 years of symptoms, no underlying connective tissue disease develops. – Secondary Progressive and asymmetric Vascular spasm is more frequent and more severe over time. Ulceration is rare; gangrene does not develop; 13% progress to digital fat pad atrophy and ischemic changes of the fingertips. Typically associated with an underlying connective tissue disorder • System(s) affected: hematologic, lymphatic, immunologic, musculoskeletal, dermatologic, exocrine

Pregnancy Considerations • Raynaud phenomenon can appear as breast pain in lactating women (1). • Positive breast milk bacterial culture distinguishes mastitis from Raynaud phenomenon.

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Geriatric Considerations Initial appearance of Raynaud phenomenon after age 40 years often indicates underlying connective tissue disease.

Pediatric Considerations Associated with systemic lupus erythematosus (SLE) and scleroderma

EPIDEMIOLOGY Incidence • Primary – Predominant age: 14 years; ~1/4 begin >40 years – Predominant sex: female > male (4:1) • Secondary – Predominant age: >40 years – Predominant sex: no gender predilection

Prevalence • Primary: 3–12.5% of men; 6–20% of women (based on clinical history) • Secondary: ~1% of population

ETIOLOGY AND PATHOPHYSIOLOGY Unknown. Dysregulation of vascular control mechanisms leads to imbalance between vasodilation and vasoconstriction. There is a reduced endothelindependent vasodilation activity and an increased vasoconstriction in peripheral vessels by overproduction of endothelin-1. 5-HT2 serotonin receptors may be involved in secondary Raynaud phenomenon. Platelet and blood viscosity abnormalities in secondary contribute to ischemic pathology.

Genetics Some studies suggest dominant inheritance pattern. ~1/4 of primary patients have a first-degree relative with Raynaud phenomenon.

RISK FACTORS • Existing autoimmune or connective tissue disorder • End-stage renal disease with hemodialysis may increase risk if a steal phenomenon associated with the arterial-venous shunt develops.

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• Primary and secondary disease associated with elevated homocysteine levels. • Smoking is not associated with increased risk of Raynaud phenomenon but may worsen symptoms.

GENERAL PREVENTION • Avoid cold exposure. • Tobacco cessation • No relationship has been established between Raynaud phenomenon and vibratory tool use.

COMMONLY ASSOCIATED CONDITIONS Secondary Raynaud • Scleroderma; SLE; polymyositis • Sjögren syndrome; occlusive vascular disease • Cryoglobulinemia

DIAGNOSIS HISTORY • Primary – Symmetric attacks involving fingers – Family history of connective tissue disorder – Absence of tissue necrosis, ulceration, or gangrene – If after ≥2 years of symptoms, no abnormal clinical or laboratory signs have developed, secondary disease is highly unlikely. • Secondary – Onset typically after 40 years of age – Asymmetric episodes more intense and painful – Arthritis, myalgias, fever, dry eyes and/or mouth, rash, or cardiopulmonary symptoms – History of medication and/or recreational drug use – Exposure to toxic agents – Repetitive trauma

PHYSICAL EXAM

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Pallor (whiteness) of fingertips with cold exposure, then cyanosis (blue), then redness and pain with warming • Ischemic attacks evidenced by demarcated or cyanotic skin limited to digits; usually starts on one digit and spreads symmetrically to remaining fingers of both hands.The thumb is typically spared. • May rarely involve other peripheral tissues (e.g., tongue) (2). • Beau lines: transverse linear depressions in nail plate on most or all fingernails that occurs after exposure to cold or any insult that disrupts normal nail growth. • Livedo reticularis: mottling of the skin of the arms and legs; benign and reverses with warming • Primary – Normal physical exam – Nail bed capillaries have normal appearance: Place 1 drop of grade B immersion oil on skin at base of fingernail and view capillaries with handheld ophthalmoscope at 10 to 40 diopters. • Secondary – Skin changes, arthritis, and abnormal lung findings suggest connective tissue disease, – Ischemic skin lesions: ulceration of finger pads (autoamputation in severe, prolonged cases) – Nail bed capillary distortion including giant loops, avascular areas, and increased tortuosity – Abnormal Allen test: conducted by having the patient open and close his or her hand several times and then squeezing his or her hand tightly into a fist. The examiner sequentially occludes the ulnar and radial arteries while the patient opens his or her hand to reveal the return of color as a measure of circulation.

DIFFERENTIAL DIAGNOSIS • Thromboangiitis obliterans (Buerger disease): primarily affects men; smoking-related • Rheumatoid arthritis (RA) • Progressive systemic sclerosis (scleroderma): Raynaud phenomenon precedes other symptoms.

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• SLE • Carpal tunnel syndrome; thoracic outlet syndrome • Hypothyroidism • CREST syndrome (calcinosis cutis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasias) • Cryoglobulinemia; Waldenström macroglobulinemia • Acrocyanosis • Polycythemia • Occupational (e.g., especially from vibrating tools, masonry work, exposure to polyvinyl chloride) • Drug-induced (e.g., clonidine, ergotamine, methysergide, amphetamines, bromocriptine, bleomycin, vinblastine, cisplatin, cyclosporine)

DIAGNOSTIC TESTS & INTERPRETATION Provocative test (e.g., ice water immersion) unnecessary • Primary – Antinuclear antibody: negative – ESR: normal • Secondary – Tests for secondary causes (e.g., CBC, ESR) – Positive autoantibody has low positive predictive value for connective tissue disease (30%). – Antibodies to specific autoantigens (e.g., scleroderma with anticentromere or antitopoisomerase antibodies) – Videocapillaroscopy is gold standard (200 times magnification). Follow-Up Tests & Special Considerations Periodic assessments for a connective tissue disorder

Diagnostic Procedures/Other Diagnosis is determined by history and physical exam.

TREATMENT Assess using a Raynaud Condition Score.

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GENERAL MEASURES • Dress warmly, wear gloves, and avoid cold temperatures. • During attacks, rotate the arms in a windmill pattern or placing the hands under warm water or in a warm body fold to alleviate symptoms. • Tobacco cessation • Avoid β-blockers, amphetamines, ergot alkaloids, and sumatriptan. • Temperature-related biofeedback may help patients increase hand temperature. 1-year follow-up is no better than control. • Finger guards to protect ulcerated fingertips

MEDICATION First Line • Calcium channel blockers (CCBs). Nifedipine is the best studied and most frequently used. • Nifedipine: 30 to 180 mg/day (sustained-release form); seasonal (winter) use is effective with up to 75% of patients experiencing improvement. • Is compatible with breastfeeding • Contraindications: allergy to drug, pregnancy, CHF • Precautions: may cause headache, dizziness, lightheadedness, edema, or hypotension • Significant possible interactions – Increases serum level of digoxin

Second Line • Amlodipine (5 to 10 mg/day) and nicardipine are effective and may have fewer adverse effects. • No data exist to support switching CCB if initial drug is ineffective. • Small studies support benefit from losartan and fluoxetine. • Phosphodiesterase type-5 inhibitors (sildenafil, vardenafil) may reduce symptoms without increasing blood flow. • Parenteral iloprost, a prostacyclin, in low doses (0.5 ng/kg/min over 6 hours), has improved ulcerations with severe Raynaud phenomenon when CCBs failed. Oral prostacyclin has not proven useful. • Nitroglycerin patches may be helpful, but use is limited by the incidence of severe headache. Nitroglycerin gel has shown promise as a topical therapy.

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• Prazosin (1 to 2 mg TID) is the only well-studied α1-adrenergic receptor blocker with modest effect, but adverse effects may outweigh any benefit. • ACE inhibitors are no longer recommended.

ISSUES FOR REFERRAL If an underlying disease is suspected, consider rheumatology consultation for evaluation and treatment.

ADDITIONAL THERAPIES • Botulinum toxin has shown some effect in reducing vasospastic episodes, frequency of attacks, rest pain, and helping to promote digital ulcer healing (3) [C]. • Aspirin • Digital or wrist block with lidocaine or bupivacaine (without epinephrine) for pain control • Short-term anticoagulation with heparin if persistent critical ischemia, evidence of large-artery occlusive disease, or both

SURGERY/OTHER PROCEDURES Surgical intervention is rarely indicated or used for Raynaud phenomenon. Effect of cervical sympathectomy is transient; symptoms return in 1 to 2 years. Digital fat grafting is a novel modality that has shown improved symptomatology and evidence of measurably increased perfusion in several cases; further study is needed (4)[C].

COMPLEMENTARY & ALTERNATIVE MEDICINE • Ginkgo biloba may reduce the frequency of attacks. • Well-designed studies have not been done yet (5)[B]. • Fish oil supplements may increase digital systolic pressure and time to onset of symptoms after exposure to cold; not proven in controlled trials • Vitamin D supplementation led to improvement in self-reported symptoms in vitamin D–deficient patients with Raynaud phenomenon (6)[B]. • Evening primrose oil reduced severity of attacks in one study. • Oral arginine is no better than placebo. • Biofeedback is not helpful.

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ONGOING CARE FOLLOW-UP RECOMMENDATIONS Avoid exposure to cold; reassess for secondary causes.

Patient Monitoring Manage fingertip ulcers and rapidly treat infection.

DIET No special diet.

PATIENT EDUCATION • Tobacco cessation. • Avoid triggers (e.g., trauma, vibration, cold). • Dress warmly; wear gloves. • Warm hands when experiencing vasospasm.

PROGNOSIS • Attacks may last from several minutes to a few hours. • 2/3 of attacks resolve spontaneously. • ~13% of Raynaud patients develop a secondary disorder, typically connective tissue diseases.

COMPLICATIONS • Primary: very rare • Secondary: gangrene, autoamputation of fingertips

REFERENCES 1. Barrett ME, Heller MM, Stone HF, et al. Raynaud phenomenon of the nipple in breastfeeding mothers: an underdiagnosed cause of nipple pain. JAMA Dermatol. 2013;149(3):300–306. 2. Lioger B, Diot E. Raynaud’s phenomenon of the tongue: uncommon presentation of a classical sign. QJM. 2013;106(6):583–584. 3. Neumeister MW, Webb KN, Romanelli M. Minimally invasive treatment of Raynaud phenomenon: the role of botulinum type A. Hand Clin.

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2014;30(1):17–24. 4. Bank J, Fuller SM, Henry GI, et al. Fat grafting to the hand in patients with Raynaud phenomenon: a novel therapeutic modality. Plast Reconstr Surg. 2014;133(5):1109–1118. 5. Bredie SJ, Jong MC. No significant effect of Ginkgo biloba special extract EGb 761 in the treatment of primary Raynaud phenomenon: a randomized controlled trial. J Cardiovasc Pharmacol. 2012;59(3):215–221. 6. Hélou J, Moutran R, Maatouk I, et al. Raynaud’s phenomenon and vitamin D. Rheumatol Int. 2013;33(3):751–755.

ADDITIONAL READING • Herrick AL. Contemporary management of Raynaud’s phenomenon and digital ischaemic complications. Curr Opin Rheumatol. 2011;23(6):555–561. • Huisstede BM, Hoogvliet P, Paulis WD, et al. Effectiveness of interventions for secondary Raynaud’s phenomenon: a systematic review. Arch Phys Med Rehabil. 2011;92(7):1166–1180. • Malenfant D, Catton M, Pope JE. The efficacy of complementary and alternative medicine in the treatment of Raynaud’s phenomenon: a literature review and meta-analysis. Rheumatology (Oxford). 2009;48(7):791–795. • Maverakis E, Patel F, Kronenberg DG, et al. International consensus criteria for the diagnosis of Raynaud’s phenomenon. J Autoimmun. 2014;48–49:60– 65.

SEE ALSO Algorithm: Raynaud Phenomenon

CODES ICD10 • I73.00 Raynaud’s syndrome without gangrene • I73.01 Raynaud’s syndrome with gangrene

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CLINICAL PEARLS • The diagnosis of Raynaud phenomenon is based on clinical symptoms. • Provocative testing is not recommended. • Initial presentation of Raynaud phenomenon after age 40 years suggests underlying (secondary) disease. • Raynaud phenomenon is a cause of breast pain in lactating women. • Primary Raynaud phenomenon is symmetric; secondary Raynaud phenomenon is asymmetric. • Primary Raynaud phenomenon is treated with handwarming and avoiding cold exposure. • Digital ulcers are not normal and always merit a workup for secondary disease.

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REACTIVE ARTHRITIS (REITER SYNDROME) Douglas W. MacPherson, MD, MSc–CTM, FRCPC BASICS Reiter syndrome is a seronegative, multisystem, inflammatory disorder classically involving joints, the eye, and the lower genitourinary (GU) tract. Axial joint (e.g., spine, sacroiliac joints) and dermatologic manifestations are common (1)[C].

DESCRIPTION The classic triad include arthritis, conjunctivitis/iritis, and either urethritis or cervicitis (“can’t see; can’t pee; can’t bend my knee”). • The epidemiology is similar to other reactive arthritides, characterized by sterile joint inflammation associated with infections originating at nonarticular sites. A fourth feature (dermatologic involvement) may include buccal ulceration, balanitis, or a psoriaform skin eruption. (Having only two features does not rule out the diagnosis.) • Two forms of Reiter syndrome: – Sexually transmitted: Symptoms emerge 7 to 14 days after exposure to Chlamydia trachomatis and other sexually acquired pathogens. – Postenteric infection (including traveler’s diarrhea) • In individuals with new or frequent sexual partners, the triggering infection is likely sexually transmitted (rather than enteric). • In individuals with a history of recent enteric illness, the triggering event is more likely to be a bacterial enteric infection than sexually transmitted. • System(s) affected: musculoskeletal, renal/urologic, dermatologic/exocrine • Synonym(s): idiopathic blennorrheal arthritis; arthritis urethritica; urethrooculosynovial syndrome; Fiessinger-Leroy-Reiter disease; reactive arthritis

Pediatric Considerations Juvenile rheumatoid arthritis has many of the same clinical features as Reiter syndrome.

Pregnancy Considerations

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No special considerations; usual drug precautions

EPIDEMIOLOGY Incidence • Predominant age: 20 to 40 years • Predominant sex: male > female • 0.24–1.5% incidence after epidemics of bacterial dysentery • Complicates 1–2% of nongonococcal urethritis cases

ETIOLOGY AND PATHOPHYSIOLOGY • The pathophysiology of all the seronegative reactive arthritis syndromes and the immunologic role of infectious diseases as precipitants for clinical illness are incompletely understood. • Avoiding precipitant infections and early management of multiorgan inflammation is important. Antibiotic treatment following onset of syndrome does not appear to benefit inflammatory joint, eye, or urinary tract symptoms. • C. trachomatis is the most common sexually transmitted infection associated with Reiter syndrome. • Dysentery-associated Reiter syndrome follows infection with Shigella, Salmonella, Yersinia, and Campylobacter spp. Enteric-associated Reiter syndrome is more common in women, children, and the elderly than the postvenereal form.

Genetics HLA-B27 tissue antigen present in 60–80% of patients, suggesting a genetic predisposition.

RISK FACTORS • New or high-risk sexual contacts 7 to 14 days before the onset of clinical presentation; the primary infection may be subclinical and undiagnosed. • Food poisoning or bacterial dysentery

GENERAL PREVENTION • The immune-response characteristics of this syndrome make specific avoidance of infectious precipitants the most important general precaution (and potentially the most difficult to achieve).

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• Safe sexual practices; proper food and water hygiene

COMMONLY ASSOCIATED CONDITIONS • Enteric disease – Shigellosis; Salmonellosis; Campylobacteriosis – Enteric infection with Yersinia spp. • Urogenital infection – Chlamydia urethritis/cervicitis (2)[C] – Mycoplasma or Ureaplasma spp. • HIV/AIDS

DIAGNOSIS • Based on clinical presentation with joint, eye, and GU inflammation (“classic triad”) and negative serologic testing for rheumatoid factor • Classic symptoms not always present at the same time • HLA-B27 testing is not required for diagnosis.

HISTORY The presence of the clinical syndrome plus • Diarrhea, dysentery, urethritis, or genital discharge and appropriate exposure history • Exposure risks, including travel or migration history and potential infectious exposure • Arthritis associated with urethritis for >1 month (84% sensitive; 98% specific for diagnosis) • Urethritis occurs 1 to 15 days after sexual exposure. • Reiter syndrome onset within 10 to 30 days of either enteric infection or STI • Mean duration of symptoms is 19 weeks.

PHYSICAL EXAM • Musculoskeletal – Asymmetric arthritis (especially knees, ankles, and metatarsophalangeal joints) – Enthesopathy (inflammation at tendinous insertion into bone, such as

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plantar fasciitis, digital periostitis, and Achilles tendinitis) – Spondyloarthropathy (spine and sacroiliac joint involvement) • Urogenital tract – Urethritis; prostatitis; cystitis (rare) – Balanitis – Cervicitis: usually asymptomatic • Eye – Conjunctivitis of one or both eyes – Occasionally, scleritis, keratitis, and corneal ulceration – Rarely, uveitis and iritis • Skin – Mucocutaneous lesions (small, painless superficial ulcers on oral mucosa, tongue, or glans penis) – Keratoderma blennorrhagica (hyperkeratotic skin lesions of palms and soles and around nails—can be mistaken for psoriasis) • Cardiovascular: occasionally, pericarditis, murmur, conduction defects, and aortic incompetence • Nervous system: rarely, peripheral neuropathy, cranial neuropathy, meningoencephalitis, and neuropsychiatric changes • Constitutional – Fever, malaise, anorexia, and weight loss – Patient can appear seriously ill (e.g., fever, rigors, tachycardia, and exquisitely tender joints).

DIFFERENTIAL DIAGNOSIS • Rheumatoid arthritis (RA) • Ankylosing spondylitis • Arthritis associated with inflammatory bowel disease • Psoriatic arthritis • Juvenile RA • Bacterial arthritis, including gonococcal

DIAGNOSTIC TESTS & INTERPRETATION • Blood – Negative rheumatoid factor

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– Leukocyte count: 10,000 to 20,000 cells/mm3 – Neutrophil predominance – Elevated ESR and/or CRP – Moderate normochromic anemia – Hypergammaglobulinemia • Synovial fluid – Leukocyte count: 1,000 to 8,000 cells/mm3 – Bacterial culture negative • Supportive tests – Cultures, antigens, or PCR positive for Chlamydia trachomatis or stool test positive for Salmonella, Shigella, Yersinia, or Campylobacter species – HIV serology positive (acute retroviral syndrome) – HLA-B27-positive (not required for diagnosis) – Drugs that may alter lab results: Antibiotics may affect isolation of the bacterial pathogens. • X-ray – Periosteal proliferation, thickening – Articular bony spurs; erosions at articular margins – Residual joint destruction – Syndesmophytes (spine); sacroiliitis

Diagnostic Procedures/Other HLA-B27 histocompatibility antigen: positive result in 60–80% of cases in non– HIV-related Reiter syndrome; HLA testing is not required or recommended for diagnosis. Rheumatoid factor is negative. • Screen for STI if clinically indicated. • Screening for enteric infections is rarely useful and generally not indicated.

Test Interpretation • Seronegative spondyloarthropathy (similar to ankylosing spondylitis, enteric arthritis, and psoriatic arthritis) • Villous formation within joints; hyperemia, and inflammation • Prostatitis and seminal vesiculitis • Skin biopsy similar to psoriasis

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TREATMENT GENERAL MEASURES Treatment is determined by symptoms. • Conjunctivitis does not require specific treatment. • Iritis requires treatment. • Mucocutaneous lesions do not require treatment. • Physical therapy (PT) aids recovery. • Arthritis may become prominent and disabling during the acute phase.

MEDICATION First Line • Symptomatic management: NSAIDs, including indomethacin, naproxen, and others; intra-articular or systemic corticosteroids for refractory arthritis and enteritis – Contraindications GI bleeding Peptic ulcer, gastritis, or ulcerative colitis Renal insufficiency • Specific treatment of isolated microorganism (3)[A]: – C. trachomatis: doxycycline 100 mg PO BID for 7 to 14 days (Note: All STIs should be treated whether associated with Reiter syndrome or not.) – Salmonella, Shigella, Yersinia, and Campylobacter infections: ciprofloxacin 500 mg PO BID for 5 to 10 days (Note: Emerging antimicrobial resistance may limit the effectiveness of ciprofloxacin. Antibiotic treatment does not reduce GI symptoms or duration of infection or prevent carrier state.) – Trials of antibiotic treatment for reactive arthritis have produced mixed results, rendering the efficacy of antibiotics uncertain. • GI upset: antacids • Iritis: intraocular steroids • Keratitis: topical steroids

Second Line • Aspirin or other NSAIDs

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• Sulfasalazine is promising but not approved by the FDA for this indication. • Methotrexate or azathioprine in severe cases (experimental, not approved or known to be effective); immunosuppressive therapy is relatively contraindicated in HIV-related Reiter syndrome. • Consultation with specialist is recommended, particularly when considering immunomodulatory agents such as sulfasalazine, methotrexate, or azathioprine or for treatment with anti-TNF medications (etanercept and infliximab) which have shown benefit in isolated case reports. • Role of antibiotics under investigation—currently unproven effectiveness in seronegative arthritides. • No published evidence supports the beneficial effect of antibiotics on the long-term outcome in patients with Reiter syndrome.

ISSUES FOR REFERRAL Joint and eye complications; complex cases—consider reconsultation with rheumatology; ophthalmology

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Based on severity of disease and associated complications • Inpatient care may be needed during acute phase.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Activity modification until joint inflammation subsides

Patient Monitoring Monitor clinical response to anti-inflammatory drugs. Observe for complications, particularly with sulfasalazine and immunosuppressive drugs.

PATIENT EDUCATION • Educate on risk factors for exposure and recurrence. • Home physical therapy • Arthritis Foundation, 1314 Spring Street NW, Atlanta, GA 30309, 404-872-

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7100 • National Institute of Arthritis and Musculoskeletal and Skin Diseases: http://www.niams.nih.gov/

PROGNOSIS Prognosis is poor in cases involving the heel, eye, or heart.

COMPLICATIONS • Chronic or recurrent disease in 5–50% of patients • Ankylosing spondylitis develops in 30–50% of patients who test positive for HLA-B27 antigen. • Urethral strictures • Cataracts and blindness • Aortic root necrosis

REFERENCES 1. Selmi C, Gershwin ME. Diagnosis and classification of reactive arthritis. Autoimmun Rev. 2014;13(4–5):546–549. 2. Zeidler H, Hudson AP. New insights into Chlamydia and arthritis. Promise of a cure? Ann Rheum Dis. 2014;73(4):637–644. 3. Barber CE, Kim J, Inman RD, et al. Antibiotics for treatment of reactive arthritis: a systematic review and metaanalysis. J Rheumatol. 2013;40(6):916–928.

ADDITIONAL READING • Carter JD, Inman RD. Chlamydia-induced reactive arthritis: hidden in plain sight? Best Pract Res Clin Rheumatol. 2011;25(3):359–374. • Contini C, Grilli A, Badia L, et al. Detection of Chlamydophila pneumoniae in patients with arthritis: significance and diagnostic value. Rheumatol Int. 2011;31(10):1307–1313. • Curry JA, Riddle MS, Gormley RP, et al. The epidemiology of infectious gastroenteritis related reactive arthritis in U.S. military personnel: a casecontrol study. BMC Infect Dis. 2010;10:266. • Kim PS, Klausmeier TL, Orr DP. Reactive arthritis: a review. J Adolesc

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Health. 2009;44(4):309–315. • Mathew AJ, Ravindran V. Infections and arthritis. Best Pract Res Clin Rheumatol. 2014;28(6):935–959. • National Guideline Clearinghouse. British Association of Sexual Health and HIV (BASHH) United Kingdom national guideline on management of sexually acquired reactive arthritis. 2009:13596. http://www.bashh.org/BASHH/Guidelines/Guidelines/BASHH/Guidelines/Guidelines.aspx Accessed August 21, 2015. • Porter CK, Thura N, Riddle MS. Quantifying the incidence and burden of postinfectious enteric sequelae. Mil Med. 2013;178(4):452–469. • Wilson G, Folzenlogen DD. Spondyloarthropathies: new directions in etiopathogenesis, diagnosis and treatment. Mo Med. 2012;109(1):69–74.

SEE ALSO Ankylosing Spondylitis; Arthritis, Psoriatic; Behçet Syndrome

CODES ICD10 • M02.30 Reiter’s disease, unspecified site • M02.39 Reiter’s disease, multiple sites

CLINICAL PEARLS • Diagnosis of Reiter syndrome is based on the clinical presentation of the classic triad of joint, eye, and GU inflammation and negative serologic testing for rheumatoid factor (signs and symptoms may not all be present at the same time). • Screen for STI (including HIV) if sexually acquired. Enteric studies are rarely clinically indicated. • Refer patients with a chronic or recurrent course or those who have clinical complications.

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REFRACTIVE ERRORS Robert M. Kershner, MD, MS, FACS BASICS DESCRIPTION • Refraction is the bending of a wave of light as it passes through the optical system of the eye. The degree of bending is dependent on the index of refraction through the air, cornea, and lens and is described quantitatively by Snell law. A refractive error refers to the inability of the eye to produce a focused image on the fovea or central part of the retina. • Emmetropia: When light rays are in perfect focus, the image being viewed is seen clearly. • Ametropia: any refractive error of the eye that prevents normal focusing of the image • Hyperopia: When the cornea of the eye is too flat or the eye is too short, light rays fall in focus behind the retina, and the individual is “farsighted.” • Myopia: When the cornea is too steep or the length of the eyeball is too long, the focal point for light rays lies short of the retina, and the individual is “nearsighted.” • Presbyopia: The natural tendency of the crystalline lens to harden/become sclerotic with age, limiting the focusing of the eye on near objects (accommodation). By the age of 40 years, most people do not have enough room within the eye to allow normal excursion of the lens and accommodation; viewing of near objects is blurred, and reading glasses are required. • Astigmatism: When the cornea is steeper in one meridian more than the other or the globe is not round (i.e., is oval or almond shaped), visual blurriness occurs due to the absence of a single point of focus. • Anisometropia: an unequal refractive error between the two eyes • System(s) affected: nervous

Geriatric Considerations Presbyopia occurs after the age of 40 years.

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Pediatric Considerations Refractive errors can be detected early in life.

EPIDEMIOLOGY • Predominant age: Refractive errors may be present at birth and can increase in magnitude with age until the eye is fully developed. Often they are not detected until puberty. • Predominant gender: male = female • Individuals >40 years of age are more likely to experience presbyopia/the normal loss of accommodation that occurs with age, necessitating the use of reading glasses for close work.

Prevalence Of the general U.S. population, 70% have some form of ametropia.

ETIOLOGY AND PATHOPHYSIOLOGY • Developmental (most common) • Ocular trauma • Iatrogenic (e.g., post refractive surgery or cataract removal)

Genetics Inherited

GENERAL PREVENTION No exercises; optical lenses can correct the refractive error.

COMMONLY ASSOCIATED CONDITIONS • Patients with diabetes mellitus have fluctuating myopia as a result of poorly controlled blood glucose and concomitant swelling of the crystalline lens. • Those who have a pathologic steepening of the cornea due to structural weakness (keratoconus) may have increasing myopia and astigmatism throughout life.

DIAGNOSIS HISTORY

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• Difficulty seeing objects at a distance • Difficulty focusing on near objects • Difficulty reading • Squinting • Headaches (from squinting) • In children: – Rubbing of the eyes – Sitting close to TV/computer screen – Problems in sports, particularly declining performance – Declining grades – Preference for front-row seating – Covering of an eye while reading

PHYSICAL EXAM Snellen eye chart (developed by Dr. Hermann Snellen in 1862) • Test each eye separately. • The smallest row of letters that the patient can read determines visual acuity in the uncovered eye. • The standard convention is visual acuity measured at 20 feet with a Snellen chart. A person with “normal” acuity will see letters clearly at 20 feet as recorded 20/20 (6/6 in meters). A person with 20/200 vision would be considered legally blind and able only to see a letter at 20 feet that a person with normal vision could see clearly at 200 feet.

DIAGNOSTIC TESTS & INTERPRETATION • Pinhole vision test: To distinguish a refractive error from an organic cause of visual blurring, have the patient look through a pinhole in a card without a corrective lens. • Patients with a pure refractive error have improved vision because the pinhole blocks nonparallel and unfocused rays of light. • There are no lab tests for measuring visual acuity. • A number of digital imaging systems exist for measuring refractive error. – Ultrasound or Laser Interferometry can determine the length of the eye (AScan or Laser Biometry). – Autorefractors can measure myopia, hyperopia, and astigmatism using a

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projected light into the eye and measuring the quality of its image upon its return. – Corneal topography or Orbscan quantitatively and qualitatively measures the amount of curvature on the surface of the cornea that affects the bending and focusing of light on the retina. – Wavefront corneal analysis measures the reflected rays of light as they pass into and out of the entire optical system (cornea, lens, and retina). • Most corneal and refractive imaging techniques are reserved for individuals who are contemplating refractive surgical correction (intraocular lenses or excimer laser surgery “LASIK”). Follow-Up Tests & Special Considerations Corneal and refractive imaging are used to monitor changing refractive errors postsurgically and to follow pathologic changes such as in keratoconus.

Diagnostic Procedures/Other • Methods – Objective streak retinoscopy may be used to measure the degree of refractive error in spherocylinder correction for the proper spectacle/contact lens. – Antimuscarinic agents, such as cyclopentolate (Cyclogyl) or tropicamide (Mydriacyl), applied topically paralyze the ciliary body, preventing accommodation. Cycloplegic refraction can then be performed. – α-Adrenergic agents, such as phenylephrine (Neo-Synephrine), can be used concomitantly to stimulate and dilate the pupillary dilator muscle, making measurements easier. They have no effect on cycloplegia. • Age-related testing – Newborns should be examined for general eye health; ophthalmologic evaluation is indicated for any problems discovered. – Vision screening should occur at each well-child visit. – Visual acuity testing and motility testing should be performed at ~3 to 5 years of age or at any time that a malposition of the eyes, squinting, or difficulty following objects is observed. – Visual acuity must be performed by age 5 years or prior to the child entering school to screen for and pick up refractive errors early before they

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lead to amblyopia. – Visual acuity should be retested prior to obtaining a driver’s license, at age 40 years, and every 2 to 4 years until age 65 years, after which age evaluations are recommended every 1 to 2 years.

DIFFERENTIAL DIAGNOSIS • Corneal disease • Cataract • Retinal abnormalities • Diseases of the optic nerve • Neuromuscular disorders • Neurologic impairment

TREATMENT GENERAL MEASURES • Spectacle lenses (glasses) • Soft/hard contact lenses • Surgery

MEDICATION Precaution: Antimuscarinic agents may induce acute glaucoma via acute-angle closure in susceptible individuals. The elderly and those with high hyperopia or a history of angle closure should not be tested with these agents.

First Line No medical treatment for refractive error exists.

Second Line Cycloplegia is sometimes used to “fog/blur” the better seeing eye in cases of amblyopia.

ISSUES FOR REFERRAL Any individual who fails a basic screening visual acuity test should be promptly referred to an eye care professional for evaluation. Children do not outgrow refractive errors. Left untreated, refractive errors can lead to permanent visual

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loss.

ADDITIONAL THERAPIES Eye exercises and visual training may improve hand-to-eye coordination and visual awareness but do not treat refractive error.

SURGERY/OTHER PROCEDURES • Astigmatic keratotomy with a surgical diamond blade has been performed either as an isolated procedure or as a part of the cataract surgical procedure to effectively flatten the steep corneal meridian (1,2)[C]. • Manual astigmatic keratotomy is being superseded by the femtosecond laser whereby the surgeon applies the laser to perform the limbal corneal relaxing incisions (LRIs) instead of the surgical diamond blade (3)[C]. • Laser-assisted in-situ keratomileusis (LASIK) was approved by the FDA in 1997. A superficial corneal flap is created with a mechanical keratome/femtosecond laser, under which the excimer laser removes a small amount of tissue corresponding to the correction of refractive error, thus reshaping the cornea. LASIK can be used for all refractive errors but not in all patients. Healing is rapid because reepithelialization is not required. Surgery is reserved for those with a stable refractive error and a cornea that is thick enough to allow safe removal of tissue. The procedure is permanent. • Implantable contact lens (ICL): A thin plastic lens is permanently implanted either in the anterior chamber and anchored to the iris (FDA approved in 2005, VERISYSE) or in the posterior chamber (Visian ICL, FDA approved in 2006) between the iris and the human crystalline lens. All refractive errors can be corrected. Risks include damage to the natural lens during surgery, cataract formation, and intraocular inflammation/infection. • Excimer laser photorefractive keratectomy: The laser photoablates corneal tissue from the central visual axis, flattening it. Following the procedure, the cornea must reepithelialize. Healing takes several months, during which there is a mild haze and blurring of vision; FDA approved in October 1995. • Other modifications: – LASIK (laser in-situ keratomileusis), which involves removing of the superficial epithelium before laser application (Epi-LASIK). – IntraLASIK is a femtosecond laser that is used to create the flap as an

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alternative to a mechanical keratome. – Custom ablation: uses the information from a wavefront map of the cornea and eye to tailor the ablation to remove higher orders of refractive errors • Older methods now superseded by LASIK: – Radial keratotomy: With topical anesthesia, a surgical keratome is used to incise multiple (4 to 8) radial incisions into the peripheral cornea to a depth of ≥85%. The incisions cause gaping and thus flatten the central, optical zone of the cornea. Radial keratotomy is safe and effective, corrects nearsightedness and astigmatism, but has been replaced by excimer laser surgery for its improved accuracy and stability of correction. – Photorefractive keratectomy: Surface corneal tissue is removed with the excimer laser to reshape the cornea, correcting nearsightedness, farsightedness, or astigmatism. Risks and disadvantages include pain, keratitis, and potential scarring. Healing requires 3 months with topical antibiotics and steroids, with associated risks of glaucoma, cataract, chronic inflammation, and scarring. • Several scleral expansion procedures have been under investigation to attempt to increase the space within the ciliary body by surgical means to restore lens movement and accommodation. The results have been unsatisfactory. • Bifocal intraocular lenses (several types have been approved by the FDA: AcrySof IQ ReSTOR, ReZOOM-AMO, TECNIS-AMO) are implanted in the posterior chamber. They increase the depth of field to allow viewing objects both at near and at distance. Side effects include decreased contrast, glare, ghosting of images, and problems with night vision. • Accommodative intraocular lenses (Crystalens): first FDA-approved intraocular lens; several others under clinical investigation. The accommodative intraocular lens moves in response to ciliary body movement to allow focusing at different focal lengths. Side effects are minimal. Present lenses have limited range of focus.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring

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• Exams recommended when starting school, entering college, with any change in vision quality, and at the age of onset of presbyopia (the need for reading glasses) • Individuals with any of the known risks of eye disease or conditions that could affect the eyes (e.g., diabetes, thyroid disease, hypertension, macular degeneration) need annual ocular examinations. • Family history of eye diseases/refractive errors necessitates annual reexam.

DIET Although refractive error is unaffected by diet, diet has been shown to be important for retinal health. Diets high in fats, cholesterol, along with cigarette smoking or diabetes can lead to an increased risk of age-related macular degeneration (AMD), a potentially blinding disease of the retina. Diets high in vegetables, low in meats, and high in antioxidants (e.g., lutein, β-carotene, vitamins A, C, and E, zinc, and omega-3 fatty acids) have been shown to be protective for retinal degeneration. The age-related eye disease study (AREDS) formulation, which has been proven effective in numerous clinical trials, includes a specific daily amount of 500-mg vitamin C, 400 IU of vitamin E, 15 mg of β-carotene (often labeled as the equivalent of 25,000-IU vitamin A), 80 mg of zinc as zinc oxide, and 2 mg of copper as cupric oxide to prevent copper deficiency anemia and is taken with meals in two equally divided doses in the morning and evening. This therapy has been superseded by the AREDS2 formulation, which eliminated vitamin E due to its associated increased risk of lung cancer in smokers and replacing β-carotene with lutein and zeaxanthin.

PATIENT EDUCATION • All patients should have their eyes examined when starting school and periodically thereafter. • The options of eyeglasses, contact lenses, and permanent surgical correction of refractive errors can be considered. • Encourage aggressive control of diabetes mellitus and annual exams by an ophthalmologist. These individuals are at increased risk of blindness from their disease and should not undergo refractive corrective surgery.

PROGNOSIS

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• Good, if discovered early and corrected appropriately. • It is not unusual for refractive errors to be temporarily worsened during pregnancy because of hormonal changes in tear function and corneal swelling. • It is common that refractive errors worsen as a child ages until complete adult growth has been achieved (this is around age 18 to 20 years for girls and 20 to 25 years for boys). This is a common source of concern for parents. Reassurance that refractive change is often seen with growth spurts, especially at puberty, is advised. • Any refractive change that is increasing/worsening each year should prompt further investigation by an ophthalmologist.

COMPLICATIONS • Amblyopia or permanent loss of vision that is not correctable with glasses or contact lenses • Poor school performance • Inability to pass a drivers license examination

REFERENCES 1. Kershner RM. Keratolenticuloplasty. In: Gills JP, Martin RG, Thornton SP, et al, eds. Surgical Treatment of Astigmatism. Thorofare, NJ: Slack; 1994:143– 155. 2. Grabow HB. Intraocular correction of refractive errors. In: Kershner RM, ed. Refractive Keratotomy for Cataract Surgery and the Correction of Astigmatism. Thorofare, NJ: Slack; 1994:141. 3. Abbey A, Ide T, Kymionis GD, et al. Femtosecond laser-assisted astigmatic keratotomy in naturally occurring high astigmatism. Br J Ophthalmol. 2009;93(12):1566–1569.

ADDITIONAL READING • American Academy of Ophthalmology. Policy Statement: Frequency of Ocular Exams. San Francisco, CA: American Academy of Ophthalmology; 2009. • American Academy of Ophthalmology, American Academy of Pediatrics, American Association for Pediatric Ophthalmology and Strabismus. Joint

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Policy Statement: Vision Screening for Infants and Children. San Francisco, CA: American Academy of Ophthalmology; 2007. http://www.aao.org/clinical-statement/vision-screening-infants-children-2013. • Fax-on-Demand service of American Academy of Ophthalmology for policy statement and patient education materials: (908) 935-2761. • National Eye Institute. Facts About Refractive Errors. Bethesda, MD: National Eye Institute; 2009. http://www.nei.nih.gov/health/errors/errors/.asp.

CODES ICD10 • H52.7 Unspecified disorder of refraction • H52.00 Hypermetropia, unspecified eye • H52.10 Myopia, unspecified eye

CLINICAL PEARLS • Vision screening should occur at each well-child visit. • Visual acuity testing should be performed at ~3.5 years of age or at any time that the physician or parent is concerned about the child’s eye movements, ability to see, or track objects. • Children never grow out of a refractive error. All suspected refractive errors should be referred to the appropriate eye care professional for evaluation to prevent permanent loss of vision from amblyopia.

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RENAL TUBULAR ACIDOSIS Jason Kurland, MD BASICS DESCRIPTION • Renal tubular acidosis (RTA) is composed of a group of disorders characterized by an inability of the kidney to resorb bicarbonate/secrete hydrogen ions, resulting in normal anion gap metabolic acidosis. Renal function (glomerular filtration rate [GFR]) must be normal or near normal. • Several types have been identified: – Type I (distal) RTA: inability of the distal tubule to acidify the urine due to impaired hydrogen ion secretion, increased back leak of secreted hydrogen ions, or impaired sodium reabsorption (interfering with the generation of negative luminal charge required for hydrogen/potassium secretion). Urine pH >5.5. – Type II (proximal) RTA: defect of the proximal tubule in bicarbonate (HCO3) reabsorption. Proximal tubular HCO3 reabsorption is absent; plasma HCO3 concentration stabilizes at 12 to 18 mEq/L due to compensatory distal HCO3 reabsorption. Urine pH 5.5) despite metabolic acidosis in type I; also in type II if HCO3 above reabsorptive threshold (12 to 18 mEq/L) • Urine culture: Rule out UTI with urea-splitting organism (may elevate pH) and chronic infection. • Urine anion gap (UAG; urine [Na+ + K+] − Cl- on a random specimen): reflects unmeasured urine anions, so inversely related to urine NH4+ (or acid) excretion. Positive UAG in an acidemic patient indicates impaired renal acid excretion. Urine Na+ >25 mEq/L required for accurate interpretation of UAG. Results tend to be – Negative in HCO3 losses due to diarrhea, UTI caused by urea-splitting organisms, and other extrarenal causes of nonanion gap metabolic acidosis – Variable in type II RTA – Positive in type I RTA (7), type IV RTA – Positive in impaired acid excretion due to renal failure • Urine calcium – High in type I – Typically normal in type II • Drugs that may alter lab results – Diuretics – Sodium bicarbonate (and other alkali) – Cholestyramine

Initial Tests (lab, imaging)

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Serum electrolytes; consider urinalysis, urine culture.

Diagnostic Procedures/Other • Helpful to measure urine pH on fresh sample with pH meter for increased accuracy instead of dipstick. Pour film of oil over urine to avoid loss of CO2 if pH cannot be measured quickly. • Urine NH4+ excretion (anion gap only provides a qualitative estimate) • Urinary acidification (impaired in type I RTA) can be assessed by oral administration of furosemide and fludrocortisone; patients with type I RTA unable to reduce urine pH to 15% during HCO3 infusion (type II RTA) (1)

Test Interpretation • Nephrocalcinosis • Nephrolithiasis • Rickets • Osteomalacia, osteopenia • Findings of an underlying disease causing RTA

TREATMENT MEDICATION First Line • Provide oral alkali to raise serum HCO3 to normal. Start at a low dose and increase until HCO3 is normal. Give as sodium bicarbonate (7.7 mEq NaHCO3/650 mg tab), sodium citrate (oral solution, 1 mEq HCO3 equivalent/mL), sodium/potassium citrate (oral solution), or potassium citrate (tablet, powder, or oral solution: 2 mEq K/mL, 2 mEq HCO3/mL), depending on need for potassium. • Type I RTA: Typical doses 1 to 2 mEq/kg/day (in adults), 3 to 4 mEq/kg/day (in children) PO alkali divided 3 to 4 times per day (require much higher doses if HCO3 wasting is present). May require K+ supplementation • Type II RTA: Typical doses 10 to 15 mEq/kg/day alkali, divided 4 to 6 times

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per day. Very difficult to restore plasma HCO3 to normal, as renal HCO3 losses increase once plasma HCO3 is corrected above resorptive threshold. Exogenous HCO3 increases K+ losses, requiring supplemental K+. Often need supplemental PO4 and vitamin D due to proximal PO4 losses. May add thiazide diuretic to induce mild hypovolemia, which increases proximal Na+/HCO3− reabsorption • Type IV RTA: Avoid inciting medications; restrict dietary K+. May augment K+ excretion with loop diuretic, thiazide diuretic, or Kayexalate. Correcting hyperkalemia increases activity of the urea cycle, augmenting renal ammoniagenesis and adding substrate for renal acid excretion. If necessary, 1 to 5 mEq/kg/day alkali divided 2 to 3 times per day. If mineralocorticoid deficiency, fludrocortisone: 0.1 to 0.3 mg/day • Precautions – Sodium-containing compounds will increase urinary calcium excretion, potentially increasing the risk of nephrolithiasis. – Mineralocorticoids and sodium-based alkali may lead to hypertension and/or edema. – Aluminum-containing medications (antacids, sucralfate) should be avoided if solutions containing citric acid are prescribed because citric acid increases aluminum absorption. – Sodium bicarbonate may cause flatulence because CO2 is formed, whereas citrate is metabolized to HCO3 in the liver, avoiding gas production.

Second Line Thiazide diuretics may be used as adjunctive therapy in type II RTA (after maximal alkali replacement) but are likely to further increase urinary K+ losses.

SURGERY/OTHER PROCEDURES If distal RTA is due to obstructive uropathy, surgical intervention may be required.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS Generally managed as outpatient; inpatient if acidosis severe, patient unreliable,

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emesis persistent, or infant with severe failure to thrive

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Electrolytes 1 to 2 weeks following initiation of therapy, monthly until serum HCO3 corrected to desired range, then as clinically indicated • Monitor underlying disease as indicated. • Poor compliance common due to 3 to 6 times per day alkali dosing schedule

DIET Varies based on serum K+ level and volume status

PATIENT EDUCATION • National Kidney & Urologic Diseases Information Clearinghouse, Box NKUDIC, Bethesda, MD 20893, 301-468-6345: http://www.kidney.niddk.nih.gov/ • National Kidney Foundation: https://www.kidney.org/

PROGNOSIS • Depends on associated disease; otherwise, good with therapy • Transient forms of all types of RTA may occur.

COMPLICATIONS • Nephrocalcinosis, nephrolithiasis (type I) • Hypercalciuria (type I) • Hypokalemia (type I, type II if given bicarbonate) • Hyperkalemia (type IV, some causes of type I) • Osteomalacia (type II due to phosphate wasting), osteopenia (due to buffering of acid in bone)

REFERENCES 1. Reddy P. Clinical approach to renal tubular acidosis in adult patients. Int J Clin Pract. 2011;65(3):350–360.

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2. Liamis G, Milionis HJ, Elisaf M. Pharmacologically-induced metabolic acidosis: a review. Drug Saf. 2010;33(5):371–391. 3. Heering PJ, Kurschat C, Vo DT, et al. Aldosterone resistance in kidney transplantation is in part induced by a down-regulation of mineralocorticoid receptor expression. Clin Transplant. 2004;18(2):186–192. 4. Batlle D, Haque SK. Genetic causes and mechanisms of distal renal tubular acidosis. Nephrol Dial Transplant. 2012;27(10):3691–3704. 5. Casaletto JJ. Differential diagnosis of metabolic acidosis. Emerg Med Clin North Am. 2005;23(3):771–787. 6. Lolekha PH, Vanavanan S, Teerakarnjana N, et al. Reference ranges of electrolyte and anion gap on the Beckman E4A, Beckman Synchron CX5, Nova CRT, and Nova Stat Profile Ultra. Clin Chim Acta. 2001;307(1–2):87– 93. 7. Goswami RP, Mondal S, Karmakar PS, et al. Type 3 renal tubular acidosis. Indian J Nephrol. 2012;22(6):466–468. 8. Walsh SB, Shirley DG, Wrong OM, et al. Urinary acidification assessed by simultaneous furosemide and fludrocortisone treatment: an alternative to ammonium chloride. Kidney Int. 2007;71(12):1310–1316.

CODES ICD10 N25.89 Oth disorders resulting from impaired renal tubular function

CLINICAL PEARLS • Consider RTA in cases of normal anion gap metabolic acidosis with normal/near-normal renal function. • Type I RTA: urine pH >5.5 in setting of acidemia; positive urine anion gap; acidemia can be severe. • Type II RTA: urine pH 65 years old (1,3)[C] – Patients with hemoglobinopathies, atherosclerotic lesions, and prosthetic valves, grafts, or joints or any immunosuppressed state (1,3)[C],(4)[A] • Chronic carriage of nontyphoidal Salmonella – 4 to 6 weeks of antimicrobial therapy – Prophylactic therapy in immunocompromised patients (4)[A]

GENERAL MEASURES • Hydration and electrolyte replacement • Hand washing and barrier precautions for inpatients • Avoid antimotility drugs in patients with fever or dysentery. Antimotility drugs may increase contact time of the enteropathogen in the gut mucosa (1) [C].

MEDICATION First Line • Gastroenteritis, uncomplicated: No specific medications are necessary. Supportive care (1)[A] • Gastroenteritis, complicated (due to illness severity or host risk factors such as immunocompromise) – Adults (treat for 14 days if immunocompromised) Levofloxacin (or other fluoroquinolone) 500 mg/day PO for 7 to 10 days (1)[C]; or Trimethoprim-sulfamethoxazole: 160/800 mg PO BID for 7 to 10 days or Amoxicillin: 500 mg PO TID for 7 to 10 days or Ceftriaxone: 1 to 2 g/day IV for 7 to 10 days or Azithromycin: 500 mg/day PO for 7 days (1)[C] – Children Ceftriaxone: 100 mg/kg/day IV or IM in 2 equally divided doses for 7 to 10 days (1)[C]; or Azithromycin: 20 mg/kg/day PO daily for 7 days (1)[C] – HIV patients Increased duration of antimicrobial therapy and/or zidovudine may decrease relapse (4)[C].

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• Bacteremia: Due to resistance trends, treat life-threatening infections in adults with a fluoroquinolone and a 3rd-generation cephalosporin until susceptibilities are determined (4)[A]. – Adults Ciprofloxacin (or other fluoroquinolone): 400 mg IV BID for 10 to 14 days; plus Ceftriaxone: 1 to 2 g/day IV for 10 to 14 days; or Cefotaxime: 2 g IV q8h for 10 to 14 days – Children Ampicillin: 200 mg/kg/day in 4 divided doses for 10 to 14 days; or Trimethoprim-sulfamethoxazole: 8 to 12 mg/kg/day of trimethoprim component in 2 divided doses for 10 to 14 days; or Ceftriaxone: 50 to 75 mg/kg/day (max 1 g) once per day for 10 to 14 days • Localized infection (e.g., septic arthritis, osteomyelitis, cholangitis, and pneumonia) – Same treatment as for bacteremia – In sustained bacteremia, prolonged local infection, or immunocompromised patients, give antibiotics PO for 4 to 6 weeks (4)[A]. • Chronic carrier state (shedding >1 year duration) – Amoxicillin: 1 g PO TID for 12 weeks; or – Trimethoprim-sulfamethoxazole 160 mg/800 mg PO BID for 12 weeks; or – Ciprofloxacin: 500 mg PO BID for 4 weeks, or – Levofloxacin 500 mg/day for 4 weeks; or – Norfloxacin 400 mg PO BID for 4 weeks if gallstones are present.

ALERT Antimicrobial resistance • Strains resistant to ampicillin, chloramphenicol, and trimethoprimsulfamethoxazole have been reported (6)[B]. • Fluoroquinolone resistance is increasing, perhaps due to increasing use in livestock (6)[B]. • Extended-spectrum cephalosporin resistance has been reported with increasing frequency (6)[B].

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Second Line • Aztreonam is an alternative agent that may be useful in patients with multiple allergies or organisms with unusual resistance patterns (4)[A]. • Fluoroquinolones are now routinely given to children for 5 to 7 days in areas of the world where multidrug-resistant Salmonella typhi is common (4)[A].

SURGERY/OTHER PROCEDURES • Surgical excision and drainage for infected tissue sites, followed by a minimum of 2 weeks of antibiotic therapy (4)[A] • If biliary tract disease is present, a preoperative 10- to 14-day course of parenteral antibiotics is recommended prior to cholecystectomy.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Patient Monitoring • Asymptomatic shedding of Salmonella may occur for weeks after infection. Follow-up fecal cultures are generally not indicated for patients with uncomplicated gastroenteritis. Requirements may differ during a Salmonella outbreak (4)[A]. • Criteria may vary by state and local regulations. Some public health departments require negative stool cultures for health workers and food handlers prior to returning to work. Shedding may last 4 to 8 weeks (4)[A]. • Serotyping of isolates can be performed at public health laboratories.

DIET Easily digestible foods (1)[C]

PATIENT EDUCATION • Meticulous hand hygiene; caution handling raw meat, poultry, and eggs • Fruits and vegetables should be thoroughly washed prior to consumption. • Thoroughly cooking meats eliminates Salmonella. • Caution when handling animals with high fecal carriage rates • www.cdc.gov/salmonella/general/prevention.html

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PROGNOSIS • Most cases of Salmonella gastroenteritis are self-limited and have an excellent prognosis. • Increased mortality is seen in the young (65 years), and immunocompromised (1–3). • Increased mortality is seen with bacteremia and other invasive infections (2,5). • Mortality is increased in multidrug-resistant strains (5).

COMPLICATIONS Toxic megacolon, hypovolemic shock, metastatic abscess formation, endocarditis, infectious endarteritis, meningitis, septic arthritis, reactive arthritis, osteomyelitis, pneumonia, appendicitis, cholecystitis (1,3,4)

REFERENCES 1. DuPont HL. Clinical practice. Bacterial diarrhea. N Engl J Med. 2009;361(16):1560–1569. 2. Ao TT, Feasey NA, Gordon MA, et al. Global burden of invasive nontyphoidal Salmonella disease, 2010. Emerg Infect Dis. 2015;21(6). 3. Crum-Cianflone NF. Salmonellosis and the gastrointestinal tract: more than just peanut butter. Curr Gastroenterol Rep. 2008;10(4):424–431. 4. Hohmann EL. Nontyphoidal salmonellosis. Clin Infect Dis. 2001;32(2):263– 269. 5. Onwuezobe IA, Oshun PO, Odigwe CC. Antimicrobials for treating symptomatic non-typhoidal Salmonella infection. Cochrane Database Syst Rev. 2012;(11):CD001167. 6. Crump JA, Medalla FM, Joyce KW, et al. Antimicrobial resistance among invasive nontyphoidal Salmonella enterica isolates in the United States: National Antimicrobial Resistance Monitoring System, 1996 to 2007. Antimicrob Agents Chemother. 2011;55(3):1148–1154.

ADDITIONAL READING • Chen HM, Wang Y, Su LH, et al. Nontyphoid Salmonella infection:

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microbiology, clinical features, and antimicrobial therapy. Pediatr Neonatol. 2013;54(3):147–152. • Guerrant RL, Van Gilder T, Steiner TS, et al. Practice guidelines for the management of infectious diarrhea. Clin Infect Dis. 2001;32(3):331–351. • Hurley D, McCusker MP, Fanning S, et al. Salmonella–host interactions— modulation of the host innate immune system. Front Immunol. 2014;5:481. • Lee MB, Greig JD. A review of nosocomial Salmonella outbreaks: infection control interventions found effective. Public Health. 2013;127(3):199–206. • Odey F, Okomo U, Oyo-Ita A. Vaccines for preventing invasive salmonella infections in people with sickle cell disease. Cochrane Database Syst Rev. 2015;(6):CD006975.

SEE ALSO Gastroenteritis; Typhoid Fever

CODES ICD10 • A02.9 Salmonella infection, unspecified • A02.0 Salmonella enteritis • A02.1 Salmonella sepsis

CLINICAL PEARLS • Nontyphoidal Salmonella infection is typically a foodborne infection associated with a self-limited gastroenteritis. • Clinical syndromes include gastroenteritis, bacteremia, endovascular infection, localized infection outside the GI tract, and a chronic carrier state. • Those at greatest risk of complications from Salmonella infection include the young, the elderly, and immunocompromised patients. • Uncomplicated gastroenteritis in healthy patients can be treated with supportive care. • Antibiotics should be used in infants, the elderly, immunocompromised

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patients, and for invasive infections such as bacteremia outside the GI tract.

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SARCOIDOSIS Donnah Mathews, MD, FACP BASICS DESCRIPTION • Sarcoidosis is a noninfectious, multisystem, granulomatous disease of unknown cause, commonly affecting young and middle-aged adults. – Frequently presents with hilar adenopathy, pulmonary infiltrates, ocular or skin lesions – In ~50% of cases, it is diagnosed in asymptomatic patients with abnormal chest x-rays (CXRs). – Almost any organ may be involved. • System(s) affected: primarily pulmonary but also cardiovascular, gastrointestinal, hematologic/lymphatic, endocrine, renal, neurologic, dermatologic, ophthalmologic, musculoskeletal • Synonym(s): Löfgren syndrome (erythema nodosum [EN], hilar adenopathy, fever, arthralgias); Heerfordt syndrome (uveitis, parotid enlargement, facial palsy, fever); Besnier-Boeck disease; Boeck sarcoid; Schaumann disease (1,2,3,4)[C]

EPIDEMIOLOGY Incidence Estimated 6/100 person-years (4,5)[C]

Prevalence • Estimated 10 to 20/100,000 persons • Usually occurs in younger persons, peak age 20 to 39 years • Rare in children (3,4)[C],(5)[B]

ETIOLOGY AND PATHOPHYSIOLOGY • Despite extensive research, mostly unknown • Thought to be due to exaggerated cell-mediated immune response to unknown antigen(s)

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• In the lungs, the initial lesion is CD4+ T-cell alveolitis, causing noncaseating granulomata, which may resolve or may undergo fibrosis. • “Immune paradox” with affected organs showing an intense immune response and yet anergy exists elsewhere (1,6)[C]

Genetics • Reports of familial clustering, with genetic linkage to a section within MHC on short arm of chromosome 6 • 3 to 4 times more common in African Americans • Although worldwide in distribution, increased prevalence in Scandinavians, Japanese, African Americans, and women (5)[B] • In Northern Europe, 5 to 40 cases/100,000 persons. In Black Americans, 35 cases/100,000 persons. In Caucasian Americans, 11 cases/100,000 persons (4) [C]

RISK FACTORS Exact etiology and pathogenesis remain unknown.

GENERAL PREVENTION None

COMMONLY ASSOCIATED CONDITIONS None

DIAGNOSIS HISTORY • Patients may be asymptomatic. • Patients may have nonspecific complaints, such as the following: – Nonproductive cough – Shortness of breath – Fever – Night sweats – Weight loss – General fatigue – Eye pain

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– Chest pain/palpitations – Skin lesions – Polyarthritis – Renal calculi – Facial droop due to Bell palsy – Encephalopathy, seizures, hydrocephalus (rare) – Patients >70 years old more likely to have systemic symptoms (6)[C]

PHYSICAL EXAM • Many patients have a normal physical exam. • Lungs may reveal wheezing/fine interstitial crackles in advanced disease. • ~30% of patients have extrapulmonary manifestations (2)[C], which may include the following: – Uveitis – Other eye findings: conjunctival nodules, lacrimal gland enlargement, cataracts, glaucoma, papilledema – Cranial nerve palsies – Salivary gland swelling – Lymphadenopathy – Arrhythmias – Hepatosplenomegaly – Polyarthritis – Rashes (7)[B] Maculopapular of nares, eyelids, forehead, base of neck at hairline, and previous trauma sites Waxy nodular of face, trunk, and extensor surfaces of extremities Plaques (lupus pernio) of nose, cheeks, chin, and ears EN (component of Löfgren syndrome) Atypical lesions

DIFFERENTIAL DIAGNOSIS • Sarcoidosis is a diagnosis of exclusion. • Infectious granulomatous disease, such as tuberculosis and fungal infections • Hypersensitivity pneumonitis • Lymphoma

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• Other malignancies associated with lymphadenopathy • Berylliosis (1)[B]

DIAGNOSTIC TESTS & INTERPRETATION No definitive test for diagnosis, but diagnosis is suggested by the following: • Clinical and radiographic manifestations • Exclusion of other diagnoses • Histopathologic detection of noncaseating granulomas

Initial Tests (lab, imaging) • CBC: Anemia/leukopenia ± eosinophilia can be seen. • Hypergammaglobulinemia can exist. • LFTs: Abnormal liver function and increased alkaline phosphatase can be encountered with hepatic involvement. • Calcium: Hypercalciuria occurs in up to 10% of patients, with hypercalcemia less frequent. • Serum ACE inhibitors elevated in >75% of patients but is not diagnostic or exclusionary – Drugs may alter lab results: Prednisone will lower serum ACE and normalize gallium scan. ACE inhibitors will lower serum ACE level. – Disorders may alter lab results: Hyperthyroidism and diabetes will increase serum ACE level. • CXR or CT scan may reveal granulomas/hilar adenopathy. Routine CXRs are staged using Scadding classification. – Stage 0 = normal – Stage 1 = bilateral hilar adenopathy alone – Stage 2 = bilateral hilar adenopathy + parenchymal infiltrates – Stage 3 = parenchymal infiltrates alone (primarily upper lobes) – Stage 4 = pulmonary fibrosis (8)[C] • Chest CT scan may enhance appreciation of lymph nodes. • High-resolution chest CT scan may reveal peribronchial disease. • Gallium scan will be positive in areas of acute disease/inflammation but is not specific. • Positron emission tomography (PET) scan can indicate areas of disease activity in lungs, lymph nodes, and other areas of the body but does not

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differentiate between malignancy and sarcoidosis. • Cardiac PET scan may detect cardiac sarcoidosis (3,4,8)[C]

Diagnostic Procedures/Other • Pulmonary function tests (PFTs) may reveal restrictive pattern with decreased carbon monoxide diffusing capacity (DLCO). • Characteristically in active disease, bronchioalveolar lavage fluid has an increased CD4-to-CD8 ratio. • Ophthalmologic examination may reveal uveitis, retinal vasculitis, or conjunctivitis. • ECG • Tuberculin skin test • Biopsy of lesions should reveal noncaseating granulomas. • If lungs are affected, bronchoscopy with biopsy of central and peripheral airways is helpful. Endobronchial US (EBUS)–guided transbronchial needle aspiration may potentially have a better diagnostic yield (8)[A]. • Kveim test (ongoing research): Suspension of sterilized splenic cells from a patient with sarcoidosis is injected in an intradermal skin test to evoke a sarcoid granulomatous response over 3 weeks, similar to a tuberculin skin test.

ALERT If signs indicate Löfgren syndrome (acute sarcoid with bilateral hilar lymphadenopathy, EN, and diffuse arthritis/arthralgias), it is not necessary to perform a biopsy because prognosis is good with observation alone, and biopsy would not change management.

Test Interpretation Noncaseating epithelioid granulomas without evidence of fungal/mycobacterial infection

TREATMENT • Many patients undergo spontaneous remission. It is difficult to assess disease activity and severity, however, making it challenging to develop guidelines. • No treatment may be necessary in asymptomatic individuals, but treatment

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may be needed for specific indications, such as cardiac, CNS, renal, or ocular involvement. • No treatment is indicated for asymptomatic patients with stage I to III radiographic changes with normal/mildly abnormal lung function, although close follow-up is recommended. • Treatment of pulmonary and skin manifestations is done on the basis of impairment. The symptoms that necessitate systemic therapy remain controversial. – Worsening pulmonary symptoms – Deteriorating lung function – Worsening radiographic findings (9)[B]

MEDICATION Systemic therapy is clearly indicated for hypercalcemia, cardiac disease, neurologic disease, and eye disease not responding to topical therapy. Most patients with pulmonary sarcoidosis do not require treatment with medications, as many are asymptomatic or have a spontaneous remission.

First Line • There is no FDA-approved treatment specifically for sarcoidosis. • Systemic corticosteroids in the symptomatic individual (dyspnea, cough, hemoptysis) or in the individual with worsening lung function or radiographic findings – The optimal dose of glucocorticoids is not known. – Usually prednisone initially, 0.3 to 0.6 mg/kg ideal body weight (20 to 40 mg/day) for 4 to 6 weeks – If stable, taper by 5 mg/week to 10 to 20 mg/day over the next 6 weeks. – If no relapse, 10 to 20 mg/day for 8 to 12 months – Relapse is common. – Higher doses (80 to 100 mg/day) may be warranted in patients with acute respiratory failure, cardiac, neurologic, or ocular disease. • In patients with skin disease, topical steroids may be effective. • Inhaled steroids (budesonide 800 to 1,600 μg BID) may be of some clinical benefit in early disease with mild pulmonary symptoms. – Contraindications: patients with known problems with corticosteroids

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– Precautions: careful monitoring in patients with diabetes mellitus and/or hypertension – Significant possible interactions: Refer to the manufacturer’s profile of each drug (1,4,9)[C].

Second Line • All alternative agents to glucocorticoids carry substantial risk for toxicity, including myelosuppression, hepatotoxicity, and opportunistic infection. • Methotrexate: initially 7.5 mg/week, increasing gradually to 10 to 15 mg/week • Azathioprine: generally a supplement to prednisone in an attempt to lower steroid doses • Leflunomide: 20 mg/day • Use of immunosuppressants, such as methotrexate or azathioprine, will require regular monitoring of CBC and LFTs. • Antimalarial agents, such as chloroquine or hydroxychloroquine • Tumor necrosis factor antagonists, such as infliximab, have been useful in refractory cases (4,9)[C].

ISSUES FOR REFERRAL May be followed by a pulmonologist, with referrals to other specialists as dictated by involvement of other organ systems. If requiring a second-line therapy, should be followed by a specialist.

SURGERY/OTHER PROCEDURES Lung transplantation in severe, refractory cases; long-term outcomes are unknown.

COMPLEMENTARY & ALTERNATIVE MEDICINE None known to be effective

ONGOING CARE FOLLOW-UP RECOMMENDATIONS There is limited data on indications for the specific tests and optimal frequency of monitoring of disease activity. Suggestions follow.

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Patient Monitoring • Patients on prednisone for symptoms should be seen q1–2mo while on therapy. • Patients not requiring therapy should be seen regularly (q3mo) for at least the first 2 years after diagnosis, obtaining a thorough history and physical exam, laboratory testing tailored to sites of disease activity, PFTs, and ambulatory pulse oximetry. • If active disease – Every 6 to 12 months, obtain ophthalmologic exam if on hydroxychloroquine. – Annually, CBC, creatinine, calcium, LFTs, ECG, 25-hydroxy vitamin D and 1,25 dihydroxy vitamin D, CXR, ophthalmologic examination • Other testing per individual patient’s symptoms, including HRCT, echocardiogram, Holter monitoring, urinalysis (UA), thyroid-stimulating hormone (TSH), bone density, MRI of brain • The serum ACE level is used by some physicians to follow the disease activity. In patients with an initially elevated ACE level, it should fall toward normal while on the therapy or when the disease resolves. • If inactive disease, follow annually with history and physical exam, PFTs, ambulatory pulse oximetry, CBC, creatinine, calcium, liver enzymes, 1,25 dihydroxy vitamin D, ECG, ophthalmologic exam.

DIET No special diet

PATIENT EDUCATION • The American Lung Association: www.lungusa.org/lung-disease/sarcoidosis/? gclid=CPX6zuipm6MCFQxW2godISFepQ • Sarcoidosis by Medline Plus: www.nlm.nih.gov/medlineplus/sarcoidosis.html

PROGNOSIS • 50% of patients will have spontaneous resolution within 2 years. • 25% of patients will have significant fibrosis, but no further worsening of the disease after 2 years. • 25% of patients (higher in some populations, including African Americans)

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will have chronic disease. • Patients on corticosteroids for >6 months have a greater chance of having chronic disease. • Overall death rate: 2 months of age. In children 6 months: 7.5 mg/kg BID for 10 days; adults: 250 mg BID for 10 days • Oral cephalosporins: Many are effective, but first-generation cephalosporins are less expensive: – Cephalexin 25 to 50 mg/kg/day divided every 12 hours for 10 days; max 500 mg every 12 hours (1)[A] – Cefadroxil 30 mg/kg/day divided BID; max 500 mg BID for 10 days (1) • Clindamycin 20 mg/kg/day divided TID for 10 days (4)[B] • Tetracyclines and sulfonamides should not be used.

ALERT Avoid aspirin in children due to risk of Reye syndrome.

ISSUES FOR REFERRAL Peritonsillar abscess; shock symptoms: hypotension, disseminated intravascular coagulation (DIC), cardiac, liver, renal dysfunction

SURGERY/OTHER PROCEDURES • Tonsillectomy is recommended with recurrent bouts of pharyngitis (≥6 positive strep cultures in 1 year). • While children still may get streptococcal pharyngitis (“strep throat”) after a tonsillectomy, the procedure reduces the frequency and severity of infections.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS Follow-up throat culture is not needed unless the patient is symptomatic.

Patient Monitoring GAS is uniformly susceptible to penicillin, treatment failures are typically due to:

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• Poor adherence to recommended antibiotic therapy • β-Lactamase oral flora hydrolyzing penicillin • GAS carrier state and concurrent viral rash (requires no treatment) • Repeat exposure to carriers in family: Streptococci persist on nonrinsed toothbrushes and orthodontic appliances for up to 15 days. • Recurrent GAS pharyngitis after a recent oral antibiotic course can be retreated with the same agent, an alternative oral agent, or IM penicillin G.

DIET No special diet

PATIENT EDUCATION • A brief delay in initiating treatment awaiting culture results does not increase the risk of rheumatic fever. • Complete the entire course of antibiotics. • Children should not return to school/daycare until they have received >24 hours of antibiotic therapy. • Can spread person to person: attend to personal hygiene (wash hands, don‘t share utensils) • “Recurring strep throat: When is tonsillectomy useful?” (http://www.mayoclinic.org/diseases-conditions/strep-throat/expertanswers/recurring-strep-throat/faq-20058360)

PROGNOSIS • Symptoms are shortened by 12 to 24 hours with penicillin. • Recurrent attacks are possible (different erythrogenic toxins).

COMPLICATIONS • Suppurative – Sinusitis – Otitis media/mastoiditis – Cervical adenitis – Peritonsillar abscess/retropharyngeal abscess – Pneumonia – Bacteremia with metastatic infectious foci: meningitis, brain abscess, osteomyelitis, septic arthritis, endocarditis, intracranial venous sinus

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thrombosis, necrotizing fasciitis • Nonsuppurative – Rheumatic fever: Therapy prevents rheumatic fever when started as long as 10 days after onset of acute GAS infection. – Glomerulonephritis: due to nephritogenic strain of Streptococcus; prevention even after adequate treatment of GAS is less certain – Streptococcal toxic shock syndrome: fever; hypotension; DIC; and cardiac, liver, and/or kidney dysfunction related to other toxin-mediated sequelae – Cellulitis – Weeks to months later, may develop transverse grooves in nail plates and hair loss (telogen effluvium)

REFERENCES 1. Choby BA. Diagnosis and treatment of streptococcal pharyngitis. Am Fam Physician. 2009;79(5):383–390. 2. Shulman ST, Bisno AL, Clegg HW, et al. Clinical practice guideline for the diagnosis and management of group A streptococcal pharyngitis: 2012 update by the Infectious Diseases Society of America. Clin Infect Dis. 2012;55(10):1279–1282. 3. University of Michigan Health System. Pharyngitis. Ann Arbor, MI: University of Michigan Health System; 2013. National Guideline Clearinghouse Guideline Summary NGC-9967. 4. Gerber MA, Baltimore RS, Eaton CB, et al. Prevention of rheumatic fever and diagnosis and treatment of acute streptococcal pharyngitis: a scientific statement from the American Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Young, the Interdisciplinary Council on Functional Genomics and Translational Biology, and the Interdisciplinary Council on Quality of Care and Outcomes Research: endorsed by the American Academy of Pediatrics. Circulation. 2009;119(11):1541–1551. 5. van Driel ML, De Sutter AI, Keber N, et al. Different antibiotic treatments for group A streptococcal pharyngitis. Cochrane Database Syst Rev. 2013; (4):CD004406. 6. Lennon DR, Farrell E, Martin DR, et al. Once-daily amoxicillin versus twice-

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daily penicillin V in group A beta-haemolytic streptococcal pharyngitis. Arch Dis Child. 2008;93(6):474–478.

SEE ALSO • Pharyngitis • Algorithm: Pharyngitis

CODES ICD10 • A38.9 Scarlet fever, uncomplicated • J02.0 Streptococcal pharyngitis • A38.0 Scarlet fever with otitis media

CLINICAL PEARLS • Consider scarlet fever in the differential diagnosis of children with fever and an exanthematous rash. • Key clinical findings include strawberry tongue, circumoral pallor, and a coarse sandpaper rash. • Desquamation (7 to 10 days after symptom onset) may last for several weeks following acute illness in scarlet fever. • Throat culture remains the diagnostic test of choice to document streptococcal illness. • Penicillin is the drug of choice for treatment.

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SCHIZOPHRENIA Margarita Abi Zeid Daou, MD • Jeffrey Stovall, MD BASICS Schizophrenia is a persistent and severe psychiatric condition characterized by neurocognitive decline and impairment in reality testing.

DESCRIPTION • Major psychiatric disorder characterized by prodrome, active, and residual psychotic symptoms involving disturbances in appearance, speech, behavior, perception, and thought that last for at least 6 months. • DSM-5 eliminated subcategories of schizophrenia (1). • System(s) affected: central nervous system (CNS)

EPIDEMIOLOGY Incidence • 7.7 to 43/100,000 • Predominant sex: male-to-female ratio = 1.4:1.0 • Age of onset: typically 45 years

Prevalence • Lifetime (1%): highest prevalence in lower socioeconomic classes and urban settings (2-fold higher risk) • 1.1% of the population >18 years old; similar rates in all countries

ETIOLOGY AND PATHOPHYSIOLOGY • Stems from a complex interaction between genetic and environmental factors; higher incidence if prenatal infection or hypoxia, winter births, firstgeneration immigrants, advanced paternal age, drug use, and genetic (velocardiofacial) syndromes • Overstimulation of mesolimbic dopamine D2 receptors, deficient prefrontal dopamine, and aberrant prefrontal glutamate (NMDA) activity results in perceptual disturbances, disordered thought process, and cognitive

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impairments.

Genetics If first-degree biologic relative has schizophrenia, risk is 8–10%; a 10-fold increase

GENERAL PREVENTION • Currently, no known preventive measures decrease the incidence of schizophrenia. • Interventions to improve long-term outcome and associated comorbid conditions are employed during management.

COMMONLY ASSOCIATED CONDITIONS • Nicotine dependence (>50%) (1) and substance use disorders are common and lead to significant long-term medical and social complications (2). • Metabolic syndrome, diabetes mellitus, obesity, and certain infectious diseases, including HIV, hepatitis B, and hepatitis C all occur in higher-thanexpected rates in individuals with schizophrenia.

DIAGNOSIS Focus on identifying an insidious social and functional decline per history with the onset of ≥2 of the following characteristic symptoms on mental status exam: • Delusions (fixed, false beliefs) • Hallucinations (auditory > visual disturbances) • Disorganized thought (derailed or incoherent speech) • Grossly disorganized/catatonic behavior (hyper- or hypoactive movements that are often repetitive) • Negative symptoms (affective flattening, avolition, asociality, alogia, anhedonia) (1)

PHYSICAL EXAM No physical findings characterize the illness; however, chronic treatment with neuroleptic agents may result in parkinsonism, tardive dyskinesia, and other extrapyramidal symptoms.

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DIFFERENTIAL DIAGNOSIS • Psychotic disorder due to another medical condition – Disorientation, in particular, indicates delirium – Possible medical illnesses include porphyria, TBI, infection, tumor, metabolic, endocrine, and intoxication, including withdrawal states and disorders that affect the CNS (i.e., epilepsy, Huntington disease, Wilson disease, lupus cerebritis, anti-NMDA limbic encephalitis, metachromatic leukodystrophy). • Substance-induced psychosis: secondary to substance use/abuse, such as cocaine, hallucinogens (amphetamines, LSD, phencyclidine), cannabis (including synthetic), bath salts, alcohol, or prescribed medications including steroids, anticholinergics, and opiates • Personality disorders (paranoid, schizotypal, schizoid, borderline personality disorder) • Mood disorders: bipolar disorder, major depressive disorders with psychotic features or catatonia • Other thought disorders: delusional disorder, schizoaffective disorder • Posttraumatic stress disorder • Cultural belief system • Autism spectrum disorder or neurodevelopmental disorders

DIAGNOSTIC TESTS & INTERPRETATION • No tests are available to indicate schizophrenia. • Imaging (MRI), EEG, LP, and laboratory tests may be needed to rule out other causes and may be used as clinical presentation warrants.

Initial Tests (lab, imaging) These are needed to rule out a medical etiology of psychotic symptoms and when starting antipsychotic medications; these may include the following: • CBC, blood chemistries • Thyroid-stimulating hormone (TSH) • Blood glucose level, preferably fasting • Hemoglobin A1C, fasting lipid panel • Vitamin levels (thiamine, vitamin D, vitamin B12) • Drug/alcohol screen of blood and urine

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• Urinalysis, urine pregnancy test • Rapid plasma reagin (RPR), HIV • Heavy-metal exposure: lead, mercury • Ceruloplasmin, urine porphobilinogen as indicated • ECG, for baseline QTc Follow-Up Tests & Special Considerations Clinical and laboratory tests for routine monitoring, at least yearly, if using antipsychotic medications (3)[A] • Blood pressure, weight, and waist circumference • CBC, blood chemistries • Fasting blood glucose level, hemoglobin A1C • Lipid panel, TSH • Pregnancy test and prolactin level, if indicated • ECG, monitoring for QTc prolongation

Diagnostic Procedures/Other Neuropsychologic testing: not a routine part of assessment but can help assess cognitive level to predict functioning and need for assistance

Test Interpretation No diagnostic pathologic findings; however, ventriculomegaly is frequently seen on MRI with whole brain grey matter loss and white matter loss in medial temporal lobe structures preferentially (4)[A].

TREATMENT MEDICATION First Line • Two classes of antipsychotic medications: typical and atypical. First-line treatment is with an atypical antipsychotic given lower potential for extrapyramidal side effects. – Atypical (2nd generation) Risperidone, olanzapine, ziprasidone, aripiprazole, quetiapine, paliperidone, iloperidone, asenapine, lurasidone, clozapine,

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brexpiprazole, cariprazine – Typical (1st generation) Haloperidol, chlorpromazine, fluphenazine, trifluoperazine, perphenazine, thioridazine, thiothixene, loxapine • Medication choice is based on clinical and subjective response and side effect profile (3)[A]. • Sensitivity to extrapyramidal adverse effects: atypicals • For least risk of tardive dyskinesia: quetiapine, clozapine • For least risk of metabolic syndrome: aripiprazole, ziprasidone, lurasidone • For poor compliance/high risk of relapse: injectable form of long-acting antipsychotic such as haloperidol, fluphenazine, risperidone, olanzapine, aripiprazole, or paliperidone • Usual oral daily dose (initial dose may be lower) – Chlorpromazine: 200 mg BID – Aripiprazole: 10 to 30 mg/day – Asenapine: 5 mg BID (sublingual) – Fluphenazine: 5 mg BID – Haloperidol: 5 mg BID – Lurasidone: 40 to 80 mg/day (with meal) – Olanzapine: 15 to 30 mg/day – Paliperidone: 3 to 12 mg/day – Perphenazine: 24 mg/day divided BID or TID – Quetiapine: 200 to 300 mg BID – Risperidone: 3 mg/day – Ziprasidone: 60 to 80 mg BID (with meal) – Cariprazine: 1.5 to 6 mg/day – Brexpiprazole: 2 to 4 mg/day – Clozapine: 200 mg BID Start 12.5 mg/day and increase daily by 25 mg until dose of 300 mg/day split into BID dosing; do not exceed 900 mg/day. Effective in treatment of refractory or suicidal patients (3)[A] Serious risk of agranulocytosis mandates registration with National Clozapine Registry and monitoring regular periodic CBC with differential (weekly to once monthly).

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Significant risk of seizure at higher doses Side effects can include myocarditis, DVT, sialorrhea, tachycardia, and weight gain.

ALERT All antipsychotics are associated with weight gain and carry the risk of metabolic SE and tardive dyskinesia. • Managing adverse effects of antipsychotics – Dystonic reaction (especially of head and neck): Give diphenhydramine 25 to 50 mg IM or benztropine 1 to 2 mg IM. – Akathisia (restlessness): propranolol 20 to 30 mg BID or lorazepam 0.5 to 1 mg BID – Parkinsonism: trihexyphenidyl 2 mg BID (may be increased to 15 mg/day if needed) or benztropine 0.5 BID (1 to 4 mg/day); amantadine 100 mg daily (up to 300 mg daily) – Neuroleptic malignant syndrome: hyperthermia, autonomic dysfunction, and extrapyramidal symptoms; requires hospitalization and supportive management (IVF and cessation of offending neuroleptic) • Geriatric considerations: All antipsychotics carry a black box warning for increased mortality risk in elderly patients with dementia. • Adjunctive treatments – Benzodiazepines May be effective adjuncts to antipsychotics during acute phase of illness Useful for the treatment of catatonia Withdrawal reactions with psychosis or seizures; risk for dependence and cognitive impairment – Mood stabilizers (valproic acid, lithium, lamotrigine, carbamazepine): may be effective adjuncts for those with agitated/violent behavior (3,5)[A] – Antidepressants: if prominent symptoms of depression are present – Metformin: helps minimize risk of metabolic SE with use of AP (6)[A]

ISSUES FOR REFERRAL • Consider in cases of suicidality, coexistence of an addiction, difficulty in engagement, or poor self-care.

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• Patients with schizophrenia should receive multidisciplinary care from both a primary care physician and a psychiatrist. • Family members often benefit from referral to family advocacy organizations such as NAMI (7)[A].

ADDITIONAL THERAPIES • Family patient education and psychotherapy: These include specific treatments to reduce the impact of psychotic symptoms and to enhance social functioning. Cognitive-behavioral therapy has been shown to be effective for specific symptoms of schizophrenia (8)[C]. • Cognitive remediation is a new approach for cognitive retraining and psychosocial recovery. • Vocational support programs have shown success in returning individuals to work.

COMPLEMENTARY & ALTERNATIVE MEDICINE Omega-3 fatty acids may improve cognitive symptoms, but evidence remains inconclusive (9).

SURGERY/OTHER PROCEDURES • Electroconvulsive therapy (ECT) should be considered early for patients presenting with catatonic features when response to benzodiazepines is insufficient (3)[B]. • Surgical interventions are not available.

ADMISSION, INPATIENT, AND NURSING CONSIDERATIONS • Initial stabilization focuses on maintaining a safe environment and reducing acute psychotic symptoms and agitation through the initiation of pharmacologic treatment. • The decision to admit is usually based on the patient’s risk of self-harm or harm to others and the inability to care for self as governed by local legal statute. • Monitor for safety concerns and establish a safe and supportive environment. • Discharge criteria based on the patient’s ability to remain safe in the community. It reflects a combination of suicide risk, level of psychotic

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symptoms, support systems, and the availability of appropriate outpatient services.

ONGOING CARE FOLLOW-UP RECOMMENDATIONS • Long-term symptom management and rehabilitation depend on engagement in ongoing pharmacologic and psychosocial treatment. • Monitoring is based on evaluation of symptoms (including safety and psychotic symptoms), looking for the emergence of comorbidities, medication side effects, and prevention of complications.

DIET • Newer atypical antipsychotics confer a higher risk of metabolic side effects such as diabetes, hypercholesterolemia, and weight gain. • Although there are no specific dietary requirements, attention should be paid to the high risk of development of obesity and metabolic syndrome in individuals with schizophrenia.

PATIENT EDUCATION • National Institute of Mental Health: Schizophrenia, at www.nimh.nih.gov/health/topics/schizophrenia/index.shtml • Helping a Family Member with Schizophrenia: www.aafp.org/afp/20070615/1830ph.html • National Alliance on Mental Illness (NAMI): www.NAMI.org

PROGNOSIS • Typical course is one of remissions and exacerbations. Although uncommon, there are known cases of complete remission and of refractory illness. • Negative symptoms are often most difficult to treat. • About 20% attempt suicide. 5–6% die of suicide (1). • Decreased life span related to comorbidities (coronary artery disease, pulmonary disease, or substance use disorders) and suboptimal care; guarded prognosis

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COMPLICATIONS • Side effects from antipsychotic medications including tardive dyskinesia, orthostatic hypotension, QTc prolongation, and metabolic syndrome • Self-inflicted trauma and suicide • Combative behavior toward others (only 5% of crimes are caused by mental illness including psychosis) (10) • Comorbid addictions, including nicotine (11)[A]

REFERENCES 1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, 5th ed. Arlington, VA: American Psychiatric Association; 2013. 2. Fagerström K, Aubin HJ. Management of smoking cessation in patients with psychiatric disorders. Curr Med Res Opin. 2009;25(2):511–518. 3. Hasan A, Falkai P, Wobrock T, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of schizophrenia, part 1: update 2012 on the acute treatment of schizophrenia and the management of treatment resistance. World J Biol Psychiatry. 2012;13(5):318–378. 4. Shenton ME, Dickey CC, Frumin M, et al. A review of MRI findings in schizophrenia. Schizophr Res. 2001;49(1–2):1–52. 5. Essali A, Al-Haj Haasan N, Li C, et al. Clozapine versus typical neuroleptic medication for schizophrenia. Cochrane Database Syst Rev. 2009; (1):CD000059. 6. Mizuno Y, Suzuki T, Nakagawa A, et al. Pharmacological strategies to counteract antipsychotic-induced weight gain and metabolic adverse effects in schizophrenia: a systematic review and meta-analysis. Schizophr Bull. 2014;40(6):1385–1403. 7. Mojtabai R, Nicholson RA, Carpenter BN. Role of psychosocial treatments in management of schizophrenia: a meta-analytic review of controlled outcome studies. Schizophr Bull. 1998;24(4):569–587. 8. Grant PM, Huh GA, Perivoliotis D, et al. Randomized trial to evaluate the efficacy of cognitive therapy for low-functioning patients with

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schizophrenia. Arch Gen Psychiatry. 2012;69(2):121–127. 9. Knöchel C, Voss M, Grüter F, et al. Omega 3 fatty acids: novel neurotherapeutic targets for cognitive dysfunction in mood disorders and schizophrenia? Curr Neuropsychopharmacol. 2015;13(5):663–680. 10. Fazel S, Grann M. The population impact of severe mental illness on violent crime. Am J Psychiatry. 2006;163(8):1397–1403. 11. Saha S, Chant D, McGrath J. A systematic review of mortality in schizophrenia: is the differential mortality gap worsening over time? Arch Gen Psychiatry. 2007;64(10):1123–1131.

ADDITIONAL READING Saks E. The Center Cannot Hold: My Journey Through Madness. New York, NY: Hyperion; 2007.

SEE ALSO Algorithm: Delirium

CODES ICD10 • F20.9 Schizophrenia, unspecified • F20.0 Paranoid schizophrenia • F20.1 Disorganized schizophrenia

CLINICAL PEARLS • A debilitating chronic mental illness that affects all cultures • Schizophrenia is characterized by positive symptoms, including hallucinations such as voices that converse with/about the patient, delusions