Textbook of Peripheral Neuropathy[NewMedicalBooks]

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Textbook of Peripheral Neuropathy

EDITOR

Peter D. Donofrio, MD Professor of Neurology Chief of the Neuromuscular Section Vanderbilt University Medical Center Nashville, Tennessee

New York

Visit our website at www.demosmedpub.com ISBN: 978-1-936287-10-9 e-book ISBN: 978-1-617050-34-3 Acquisitions Editor: Beth Barry Compositor: Manila Typesetting Company © 2012 Demos Medical Publishing, LLC. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without the prior written permission of the publisher. Medicine is an ever-changing science. Research and clinical experience are continually expanding our knowledge, in particular our understanding of proper treatment and drug therapy. The authors, editors, and publisher have made every effort to ensure that all information in this book is in accordance with the state of knowledge at the time of production of the book. Nevertheless, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, express or implied, with respect to the contents of the publication. Every reader should examine carefully the package inserts accompanying each drug and should carefully check whether the dosage schedules mentioned therein or the contraindications stated by the manufacturer differ from the statements made in this book. Such examination is particularly important with drugs that are either rarely used or have been newly released on the market. Library of Congress Cataloging-in-Publication Data Textbook of peripheral neuropathy / editor, Peter D. Donofrio. p. ; cm. Includes bibliographical references and index. ISBN 978-1-936287-10-9 – ISBN 978-1-61705-034-3 (e-book) I. Donofrio, Peter D. [DNLM: 1. Mononeuropathies. 2. Polyneuropathies. WL 500] 616.85’6–dc23 2012002506 Special discounts on bulk quantities of Demos Medical Publishing books are available to corporations, professional associations, pharmaceutical companies, health care organizations, and other qualifying groups. For details, please contact: Special Sales Department Demos Medical Publishing, LLC 11 West 42nd Street, 15th Floor New York, NY 10036 Phone: 800-532-8663 or 212-683-0072 Fax: 212-941-7842 E-mail: [email protected] Printed in the United States of America by Bradford & Bigelow. 12  13  14  15  /  5  4  3  2  1

Contents

Preface   v Contributors   vii 1. Clinical Approach to the Patient With Peripheral Neuropathy   1 Peter D. Donofrio 2. Entrapment Neuropathies of the Upper Extremity   9 Kevin R. Scott, Kishori Somyreddy, and Milind J. Kothari 3. Common Mononeuropathies of the Lower Extremities   27 Peter D. Donofrio 4. Approach to the Evaluation of Mononeuropathy Multiplex   41 Suraj Ashok Muley and Gareth J. Parry 5. Diabetic Neuropathy   57 Jennifer A. Tracy and P. James B. Dyck 6. Nutritional and Alcoholic Neuropathies   69 Russell L. Chin, Jennifer Langsdorf, Naomi Feuer, and Bridget Carey 7. Occupational, Biologic, and Environmental Toxic Neuropathies   87 James W. Albers 8. Inherited Peripheral Neuropathies (Charcot-Marie-Tooth Disease)   107 Jun Li 9. Role of Electrodiagnosis in the Evaluation of Peripheral Neuropathies   117 Mark B. Bromberg and Alexander A. Brownell 1 0. Brachial and Lumbosacral Plexopathies   131 Mohammad Alsharabati and Kerry H. Levin 1 1. Disorders of Spinal Nerve Roots   149 Diane W. Braza, David deDianous, P. Andrew Nelson, and Timothy R. Dillingham 1 2. Guillain-Barré Syndrome   167 Alexander J. Menze and Ted M. Burns 13. Chronic Inflammatory Demyelinating Polyradiculoneuropathy, Multifocal Motor Neuropathy, and Related Disorders   187 Christina M. Ulane and Thomas H. Brannagan 1 4. Medication-Related Neuropathy   203 Peter D. Donofrio

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iv  Contents

1 5. Paraproteinemic Neuropathy: Distinguishing the Ominous From the Ordinary   217 Charlene Hoffman-Snyder and Benn E. Smith 1 6. Neuropathies Due to Amyloidosis   227 John C. Kincaid 1 7. Paraneoplastic Neuropathies   233 Sindhu Ramchandren and Richard A. Lewis 8. Vasculitic Neuropathies   245 1 Richard Rosenbaum and Andrew Rose-Innes 9. Infectious Neuropathies   259 1 Marcos R.G. de Freitas and Fernando de Mendonça Cardoso 2 0. Sensory Neuronopathies or Ganglionopathies   273 Thierry Kuntzer and Andreas J. Steck 2 1. Porphyric Neuropathies   289 Elias Abou-Zeid and Peter D. Donofrio 2 2. Neuropathies Secondary to Systemic Diseases   309 James Wallace Teener 2 3. Neuropathies Associated With HIV Infection and Antiretroviral Therapy   323 Kathryn J. Elliott and David M. Simpson 2 4. Peripheral Neuropathies in Childhood   339 Hugh J. McMillan and H. Royden Jones 2 5. Bolton’s Critical Illness Polyneuropathy   363 Douglas W. Zochodne 2 6. Focal Cranial Neuropathies   375 Craig G. Carroll 2 7. Multiple Cranial Neuropathy   407 Craig G. Carroll and William W. Campbell 2 8. Autonomic Peripheral Neuropathy   421 Roy Freeman 2 9. Laboratory Evaluation of Peripheral Neuropathies   439 Lenay Santana-Gould and John England Index   457

Preface

pearls and key points to make consultation of the textbook quick and rewarding. The textbook begins with a chapter discussing the clinical presentations of different types of neuropathy, followed by chapters on mononeuropathies in the upper and lower extremities, mononeuritis multiplex, and many chapters addressing diffuse and symmetric polyneuropathies. Interspersed are chapters on brachial and lumbosacral plexopathies and spinal root disorders, conditions that are typically asymmetric, but can have manifestations that can mimic diffuse or focal neuropathies, and, when present in a patient with a polyneuropathy, can complicate the diagnosis and evaluation. I would like to thank all of the authors who have contributed to the textbook with their expertise and time. I also express appreciation to my many mentors in neurology and neuromuscular disorders and, finally, the many patients whose patience and confidence in me as a clinician lead to an interest in peripheral neuropathy and its many manifestations.

Clinicians in many areas of medicine are consulted by patients who have symptoms and signs of a peripheral neuropathy. Those health care providers include neurologists, family physicians, internists, endocrinologists, rheumatologists, orthopedic surgeons, neurosurgeons, medical students, neurology residents, nurse practitioners, and physician assistants. Patients with neuropathy may have a single nerve lesion such as carpal tunnel syndrome or an ulnar palsy, or a diabetic or alcoholic lengthdependent polyneuropathy. In most instances, those presentations are not difficult to recognize. Conversely, the patient may present with a rarer form of polyneuropathy, an unusual proximal or cranial mononeuropathy, or a mononeuritis multiplex. Length-dependent polyneuropathies have a long differential diagnosis, often prompting the clinician to review the topic quickly from a source which is easy to peruse and understand. The goal of this textbook is to overview the large array of peripheral neuropathies in a format where the suspected condition can be easily found and reviewed and a plan of evaluation and treatment can be constructed quickly. To this end the chapters are replete with tables and figures, and many chapters conclude with a list of clinical

Peter D. Donofrio

v

Contributors

Elias Abou-Zeid, MD Clinical Fellow Neuro-EMG Division Vanderbilt University Medical Center Nashville, Tennessee

Alexander A. Brownell, MD, PhD Research Assistant Clinical Neurosciences Center University of Utah Salt Lake City, Utah

James W. Albers, MD, PhD Emeritus Professor of Neurology University of Michigan Health System Ann Arbor, Michigan

Ted M. Burns, MD Associate Professor Department of Neurology University of Virginia Charlottesville, Virginia

Mohammad Alsharabati, MD Associate staff, Neuromuscular Center Neurological Institute, Cleveland Clinic Cleveland, Ohio

William W. Campbell, MD, MSHA Professor Department of Neurology Uniformed Services University of Health Sciences Bethesda, Maryland

Thomas H. Brannagan III, MD Associate Professor of Clinical Neurology Director, Peripheral Neuropathy Center Neurological Institute College of Physicians and Surgeons Columbia University New York, New York

Bridget Carey Assistant Professor of Neurology Department of Neurology Peripheral Neuropathy Center Weill Cornell Medical College New York, New York

Diane W. Braza, MD Interim Chair and Associate Professor Physical Medicine and Rehabilitation PM&R Residency Director Medical College of Wisconsin Milwaukee, Wisconsin

LCDR Craig G. Carroll, DO Head of Neurology Naval Medical Center Portsmouth Suffolk, Virginia Russell L. Chin, MD Associate Professor of Clinical Neurology Clinical Neurology, Peripheral Neuropathy Center Weill Cornell Medical College New York, New York

Mark B. Bromberg, MD, PhD Professor Department of Neurology Clinical Neurosciences Center University of Utah Salt Lake City, Utah

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viii  Contributors

David de Dianous, MD Assistant Professor Physical Medicine and Rehabilitation SpineCare Center Medical College of Wisconsin Milwaukee, Wisconsin

Roy Freeman, MD Professor Department of Neurology Beth Israel Deaconess Medical Center Harvard Medical School Boston, Massachusetts

Marcos R.G. de Freitas, MD, PhD Federal Fluminense University and Antonio Pedro Hospital Niterói, RJ, Brazil

Charlene Hoffman-Snyder, DNP, FNP-BC Assistant Professor Department of Neurology Mayo Clinic College of Medicine Scottsdale, Arizona

Fernando de Mendonça Cardoso, MD Service of Neurology Antonio Pedro Hospital Niterói, RJ, Brazil

H. Royden Jones, MD Clinical Professor of Neurology Children’s Hospital Boston Harvard Medical School Boston and Department of Neurology Lahey Clinic Burlington, Massachusetts

Timothy R. Dillingham, MD Professor and Chairman Department of Physical Medicine and Rehabilitation University of Pennsylvania Perelman School of Medicine Philadelphia, Pennsylvania Peter D. Donofrio, MD Professor of Neurology Chief of the Neuromuscular Section Vanderbilt University Medical Center Nashville, Tennessee P. James B. Dyck, MD Professor Department of Neurology Mayo Clinic Rochester, Minnesota Kathryn J. Elliott, MD, JD, MSc Assistant Professor of Neurology Mount Sinai School of Medicine New York, New York John England, MD Grace Benson Professor and Chairman Department of Neurology Louisiana State University Health Sciences Center New Orleans, Louisiana Naomi Feuer, MD Fellow, Clinical Neurophysiology Peripheral Neuropathy Center Weill Cornell Medical College New York, New York

John C. Kincaid, MD Professor of Neurology Cellular and Integrative Physiology Physical Medicine and Rehabilitation Indiana University School of Medicine Indianapolis, Indiana Milind J. Kothari, DO Professor and Vice Chair of Neurology The Pennsylvania State University College of Medicine Milton S. Hershey Medical Center Hershey, Pennsylvania Thierry Kuntzer, MD Professor Department of Clinical Neurosciences Lausanne University Hospital (CHUV) Lausanne, Switzerland Jennifer Langsdorf, MD Assistant Professor of Neurology Department of Neurology Peripheral Neuropathy Center Weill Cornell Medical College New York, New York Kerry Levin, MD Chairman, Department of Neurology Director, Neuromuscular Center Neurological Institute Cleveland Clinic Cleveland, Ohio

Contributors  ix

Richard A. Lewis Professor and Associate Chair of Neurology Co-Director, Neuromuscular Program Wayne State University Detroit Medical Center Detroit, Michigan Jun Li, MD, PhD Associate Professor of Neurology Director of Vanderbilt CMT Clinic Center for Human Genetics Research Vanderbilt University School of Medicine Nashville, Tennessee Hugh J. McMillan, MD, MSc Assistant Professor Division of Neurology Children’s Hospital of Eastern Ontario University of Ottawa Ottawa, Ontario, Canada Alexander J. Menze, MD Staff Neurologist United States Air Force Malcolm Grow Medical Center Andrews Air Force Base, Maryland Suraj Ashok Muley, MD Director, Neuromuscular Division Barrow Neurological Institute Phoenix, Arizona P. Andrew Nelson, MD Assistant Professor Physical Medicine and Rehabilitation SpineCare Center Medical College of Wisconsin Milwaukee, Wisconsin Gareth J. Parry, MD Professor Department of Neurology Director, Clinical Neuroscience Research Unit University of Minnesota Minneapolis, Minneapolis Sindhu Ramchandren, MD, MS Assistant Professor Department of Neurology Wayne State University Detroit Medical Center Detroit, Michigan Andrew Rose-Innes, MD The Neurology Division East The Oregon Clinic Portland, Oregon

Richard Rosenbaum, MD The Neurology Division East The Oregon Clinic Portland, Oregon Lenay Santana-Gould, MD Assistant Professor Department of Neurology Louisiana State University Health Sciences Center New Orleans, Louisiana Kevin R. Scott, MD Assistant Professor Director, Clinical Neurophysiology/Neuromuscular Program Department of Neurology The Pennsylvania State University College of Medicine Milton S. Hershey Medical Center Hershey, Pennsylvania David M. Simpson, MD Professor of Neurology Director, Neuro-AIDS Program Director, Clinical Neurophysiology Laboratories Director, Neuromuscular Division Mount Sinai School of Medicine New York, New York Benn E. Smith, MD Associate Professor Department of Neurology Mayo Clinic College of Medicine Scottsdale, Arizona Kishori Somyreddy, MD The Pennsylvania State University College of Medicine Milton S. Hershey Medical Center Hershey, Pennsylvania Andreas J. Steck, MD Professor Departments of Neurology and Biomedicine University Hospital Basel Basel, Switzerland Jennifer A. Tracy, MD Department of Neurology Mayo Clinic Rochester, Minnesota Christina M. Ulane, MD, PhD Internal Medicine/Neurology Resident Columbia University Medical Center New York, New York

x  Contributors

James Wallace Teener Clinical Associate Professor Department of Neurology University of Michigan Health System Ann Arbor, Michigan

Douglas W. Zochodne, MD Professor Department of Clinical Neurosciences Director, Neuromuscular Clinic (adult) The Hotchkiss Brain Institute University of Calgary Calgary, Alberta, Canada

Peter D. Donofrio

1

Clinical Approach to the Patient With Peripheral Neuropathy

INTRODUCTION

history review, physical examination, electrodiagnostic testing, and laboratory testing reveals a cause in 76% of patients (3). When one considers the many systemic disorders, medications, and chemotherapeutic agents that can cause a polyneuropathy, the number of conditions that give rise to a polyneuropathy exceeds one hundred. Knowledge of the motor and sensory peripheral neuro­anatomy is necessary to help predict the fiber types affected in a diffuse polyneuropathy. Table 1.1 lists peripheral nerve fiber types and the functions they subserve.

Peripheral neuropathy is a commonly encountered disorder presenting to primary care physicians and neurologists in the community. Peripheral neuropathy can be subdivided into 3 types, mononeuropathy, mononeuropathy multiplex or mononeuritis multiplex, and polyneuropathy, based on the involvement of a single nerve, multiple single nerves, or many nerves, respectively, in a symmetric length-dependent fashion. Mononeuropathies are usually caused by injury to a single nerve, usually a large nerve in the upper arm or forearm or in the thigh or shin region. Mononeuropathies can also affect cranial nerves, such as the trigeminal and facial nerves or the large nerves in the shoulder or pelvic region. The mechanism of injury is usually compression, but mononeuropathies can arise from a vasculitis or focal ischemia. Two chapters in this textbook will focus on mononeuropathies in the upper and lower limbs. The term mononeuritis multiplex applies to a condition in which 2 or more mononeuropathies arise, usually in close temporal evolution. They are frequently heralded by pain followed by the acute or subacute presentation of sensory loss and weakness in the distribution of several single nerves. Mononeuritis multiplex is often secondary to a connective tissue disorder, an infection, an underlying vasculitis, or other conditions such as HIV, diabetes, leprosy, ischemia, sarcoidosis, granulomatous disease, or a paraneoplastic phenomenon. Its presentation implies a sense of urgency to determine the cause of the condition and to treat the underlying mechanism of the disease.

Common Presentation The clinical presentation of the most common polyneuropathies follows a sensory and motor length-dependent pattern that makes the diagnosis relatively easy once the history has been elicited and the examination performed. Table 1.2 lists common symptoms and signs of patients who present to physicians for a polyneuropathy. Patients often relate the onset of their illness to the development of numbness and paresthesia of the toes and soles of the feet, and over time, the symptoms advance proximally to affect the entire foot and ankle. Other descriptors include lack of feeling, woody sensation, jabbing pain, electric shocks, sharp pains, and ice pick pain. Often, the first motor symptom is gait instability, particularly when walking in the dark or maintaining balance when the eyes are closed. Patients may relate their concern over the recent onset of tripping when walking on area rugs, doorsills, stairs, and curbs. As the disease advances, patients commonly develop a footdrop and frequent falls. Cramps are common, particularly in the distal legs. Peripheral neuropathy is one of the illnesses that can produce restless legs syndrome. When the process progresses to the knees, patients often begin to experience sensory symptoms and weakness of the hands. Those with neuropathic pain usually complain that the pain is worse at night and is a frequent cause of insomnia. A small percentage of patients with neuropathy complain of allodynia, pain caused by stimuli that do not

Clinical Presentation and Etiologies The prevalence of polyneuropathy is approximately 2.4% of the population in midlife but rises to 8% in individuals older than 55 years (1,2). Polyneuropathy is a syndrome rather than a specific disease, and a careful 1

2  Textbook of Peripheral Neuropathy

Table 1.1  Peripheral Nerve Function by Fiber Type Function Motor strength Deep tendon or muscle stretch reflexes

Joint position strength Vibration perception Pain (pinprick) Cold perception Light touch

Autonomic function

normally cause pain. A good example would be brushing of the skin by human touch or cloth. Patients may complain of problems with fine finger movements such as winding a watch or clock, playing the piano, writing, typing, or gripping jar lids. Atrophy in the hands and feet is common when the polyneuropathy is severe or

Type of Nerve Fiber Alpha motor neurons—large myelinated fibers Alpha motor neurons—large myelinated fibers Gamma motor neurons—large myelinated fibers Large myelinated sensory fibers Large myelinated sensory fibers Large myelinated sensory fibers Small myelinated sensory fibers Small unmyelinated sensory fibers Small myelinated sensory fibers Small unmyelinated sensory fibers Large myelinated sensory fibers Small myelinated sensory fibers Small unmyelinated sensory fibers Small unmyelinated fibers

long-standing. Somatic neuropathies of the sensory and motor nerves are frequently accompanied by involvement of the autonomic fibers. Patients with autonomic neuropathy may complain of dry mouth or eyes. They may have difficulty adjusting to changes in light as autonomic dysfunction affects the ability of the iris to

Table 1.2  Features Commonly Observed in Sensory and Motor Polyneuropathy Symptoms Early Features   Distal numbness and tingling   Distal neuropathic pain   Gait imbalance   Toe weakness Latter Features   Progression of numbness and tingling to proximal body parts   Prominent neuropathic pain   Tripping easily   Worsening of gait  Frequent falls Signs Early Signs   Distal sensory loss to cold, pinprick, and/or vibration  Reduced or lost ankle reflex  Romberg sign   Impaired tandem walking   Toe extensor weakness Latter Features   Distal loss of cold, pinprick, vibration, and joint position sense   Areflexia at ankles and knees  Footdrop   Inability to toe-and-heel walk

CHAPTER 1: Clinical Approach to the Patient With Peripheral Neuropathy   3

dilate or constrict quickly. Other autonomic symptoms include reduced or absent sweating, poor heat and cold tolerance, urinary and bowel incontinence, and erectile dysfunction or dry vaginal mucosa. One of the most common and disabling symptoms is dizziness or lightheadedness during changes of position, which is a good clue to orthostasis, and the lack of an appropriate pulse rise during change of position. Autonomic dysfunction can be detected on physical examination by the appearance of dry mouth and eyes, lack of sweating in the axilla and groin, change in skin color of the hands and feet, and orthostatic changes in blood pressure and pulse. Other observations are ulceration of the skin especially in distal limbs, poor healing, tissue resorption, neuropathic joints (Charcot joints), and mutilation. These often result from recurrent injury to skin and joints that represent a combination of insensitivity to pain and autonomic d­ysfunction. Neurologic Examination The neurologic examination in most neuropathies shows a distal gradient sensory loss from the toes to the more proximal legs and as the disease advances from the fingertips to the wrists and forearms. This pattern is commonly called a stocking-and-glove loss of sensation, yet, anatomically, the sensory loss is gradual and in a gradient pattern, not abrupt as might be construed when envisioning the distribution of a glove and stocking. The findings are relatively symmetric, and any major asymmetry suggests a superimposed process such as a radiculopathy of a single or multiple roots, a plexopathy, a spinal cord process, or a brainstem or cerebral cortex lesion. If the large sensory fibers are primarily affected, there is loss of vibration and joint position sense. If small fibers are affected, the small myelinated and un­ myelinated fiber functions of pain, pinprick, and cold perception will be lost in a gradient fashion. Light touch is carried by both large and small fibers. In most neuropathies, there is involvement of both large and small fibers. If a neuropathy is early and mild and affects only sensory fibers, the neurologic examination results may be normal. In a severe sensory polyneuropathy or dorsal root ganglionopathy, the examiner may find hypesthesia of the top of the scalp and in the trigeminal distribution. Hyperesthesia is rare in most polyneuropathies. In the setting of a severe sensory neuropathy or sensory neuronopathy, patients may develop involuntary movements of the fingers and hands called pseudoathetosis. This is a physiologic response to deafferentation of the sensory fibers to the spinal cord. When conducting the sensory examination, it is often more discerning to examine the patient from distal sites of anesthesia or hypesthesia, such as the toes and fingertips, toward areas predicted to be normal. Thus, one would examine from the fingertips to the elbows and from the toes to the knees. Early or mild sensory neuropathies can be difficult to assess and differentiate from other causes of pain and sensory symptoms and signs in the distal

legs, such as tarsal tunnel syndrome, plantar fasciitis, vascular disease of the legs, and adverse effects of medications. The examiner must keep in mind the subjectivity of the sensory examination and the effect of age and cooperation on responses. Each patient is different, and some may not understand the intent of the examination. A prolonged examination of the 5 major modalities of sensation may not be more productive than a careful examination performed over 2 minutes that demarcates patterns of sensory loss of small and large fibers. Repeated testing of the same parts of the body may confuse both the examiner and patient. The examiner must keep in mind the range of perception that varies among patients and the variation of sensation in different parts of the body. For instance, light touch is perceived with less pressure over hairy than glabrous skin, the latter between the fingers and on the fingertips (4). The same applies to testing over the soles of the feet and on callous hands. Cold perception is greater over the face and lateral chest and abdomen than over the extremities. Joint position sense is less precise at the toes than at the fingertips. As patients age, their appreciation of vibration and joint position sense becomes less precise, and many neurologists consider the loss of ankle reflexes and moderate loss of vibration to be normal in patients older than 80 years. The equipment used to perform the neurologic examination may influence the examiner’s interpretation of the results. A heavy reflex hammer is necessary to properly assess deep tendon or muscle stretch reflexes, particularly at the ankles. The absence of an ankle reflex when elicited by a light, short-length tomahawk hammer does not confirm areflexia. Vibration perception should be tested using a tuning fork of 128 or 64 Hz. Assessing perception using a 256- and 512-Hz reflex hammer may miss vibratory loss in the distal hands and feet necessary to help establish the diagnosis of a polyneuropathy. At the bedside, it is convenient to compare the vibratory loss of the patient to the examiner (ie, finger to finger and toe to toe). Strength is lost in a similar pattern to the sensory examination but usually arises later in the evolution of the illness. Initially, weakness usually affects the extensor muscles of the toes more than the flexor muscles. In early motor involvement, the examiner may not find objective weakness, and the patient’s only motor dysfunction may be the inability to walk on his or her heels. The patient may complain of hearing a slapping of his or her feet when walking, suggestive of early ankle dorsiflexion weakness. If the patient’s gait appears to be more ataxic and out of proportion to what would be predicted by the degree of weakness and sensory loss to cold and vibration, this might be explained by proprioceptive loss in the toes and ankles. Neurologists describe this phenomenon as a sensory gait ataxia, which is usually accompanied on examination by a positive Romberg sign. As the disease advances, patients will often develop a

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footdrop from weakness of the anterior tibial muscles. Often, the footdrop develops on one side first, suggesting a common peroneal mononeuropathy at the fibular head. This is often not found electrodiagnostically. For unclear reasons, the footdrop presents on one side, often followed within months by a footdrop on the other side. Patients who have bilateral footdrop will have difficulty clearing both feet when walking, and their gait is described as steppage in quality. As the motor involvement progresses, patients develop hand weakness. This often manifests as atrophy of the intrinsic hand muscles and weakness of spreading and opposition of the fingers. Over time, patients may complain of dropping objects and difficulty writing, typing, using a key, removing a jar lid, playing the piano, or performing other activities requiring fine motor skills. In inherited neuropathies and long-standing neuropathies, it is common to find high-arched feet, hammer toes, and pronounced distal more than proximal atrophy, giving rise to the term inverted champagne bottle legs. In a typical neuropathy, reflexes are diminished or lost in a pattern predicable when one considers the distalto-proximal gradient evolution of the process. Ankle reflexes tend to be lost first, followed by the knee, brach­ ioradialis, and lastly, the biceps brachii and triceps. In early neuropathy, ankle and knee reflexes can be lost when muscle bulk and strength are preserved. Deep tendon reflexes are more objective and repeatable than the sensory examination, so abnormalities in a patient with patchy sensory loss or an uninterpretable sensory examination could be consistent with peripheral nerve disease. Reflexes can also be diffusely absent in healthy patients. This is often the case in large muscular men, such as professional and college athletes. Many neurologists feel that ankle reflexes can be lost in healthy individuals older than 65 years. If autonomic involvement is present, the examiner may observe the distal extremities to be cold or too warm or show erythematous or blanching color changes, shiny skin, loss of hair over the feet and distal shins, dystrophic nails, lack of sweating in the axilla and groin region, and dry mouth, eyes, and mucosa. In its severest manifestation, autonomic neuropathy, usually in the setting of profound sensory loss, may manifest as skin ulceration, poor healing, neuropathic arthropathy, painless burns, and skin ulcers and fissures on the soles of the feet. Bladder and bowel sphincter involvement is rare in a distal neuropathy but may occur in more severe forms of neuropathy, as in advanced diabetic neuropathy. Palpation of the peripheral nerves is a lost art but one that can give a clue to the etiology of a neuropathy. Enlarged ulnar and peroneal nerves raise the possibility of an inherited neuropathy such as the hypertrophic neuropathies of Charcot-Marie-Tooth disease (type I) and Degerine-Sottas disease (hereditary motor-sensory neuropathy type III). Nerve enlargement is also seen in leprosy and amyloidosis. In leprosy, nerve enlargement

and thickening can be observed in the sensory branches of the radial nerve and in the greater auricular nerve. Not all neuropathies fit the pattern of weakness in the distal muscles or distal more than proximal weakness. Some of the inflammatory neuropathies cause weakness that affects proximal muscles or proximal more than distal involvement. This is commonly attributed to a polyradicular component to the neuropathy affecting the mid cervical roots (C5 through C7) and the upper lumbar roots (L1 through L4). Proximal more than distal weakness is noted in a small percentage of patients with G­uillain-Barré syndrome (GBS) and is commonly observed in chronic inflammatory demyelinating polyneuropathy (CIDP) and other chronic inflammatory polyneuropathies (5). If a neuropathy is acute or subacute and worsens rapidly over days to weeks, or if major fluctuations take place over the same period, this raises the possibility of a demyelinating polyradiculoneuropathy such as GBS or CIDP or recurrent toxin exposure.

Search for Clues to Diagnosis When first evaluating a patient with a polyneuropathy, it is good practice to ask specific questions about previous diseases, viral illnesses, lifestyle, and work and occupational exposure that may render a clue to the diagnosis. Initial questions should be asked about diabetes, alcohol abuse, vitamin deficiencies, and dietary habits. Other questions should address the use of overthe-counter drugs, zinc consumption, gastric bypass surgery, and medications prescribed in the past (especially those used long term). If no clues arise after those questions, one should enquire about HIV infection, a family history of neuropathy, foot deformities in the family, amyloidosis, a history of thyroid disease, chronic renal and liver disease, malignancy, previous treatment with chemotherapeutic agents, connective tissue disorders, recreational use of substances, and exposure to heavy metals, industrial agents, herbicides, and pesticides. Many etiologies have been found for the diffuse length-dependent polyneuropathies, and it is not uncommon to find more than one in the same patient, such as diabetes, alcohol abuse, and vitamin B12 deficiency. At other times, an initially considered cause may not materialize, as in the patient with a polyneuropathy who has received B12 injection for years, yet further inquiry does not substantiate the deficiency. Not uncommonly, the diagnosis is presumptive, as in the situation where a polyneuropathy is apparent from history and examination and one elicits a history of cancer and chemotherapy, yet the names of the specific chemotherapeutic agents cannot be determined despite attempts to locate the past medical records. Another frequent occurrence is patients’ association of the onset of their symptoms to exposure to an agent they perceive to be a toxin at their place of employment or home. It may be impossible to link a cause and effect without identification of the toxin, the amount of exposure, and whether others at

CHAPTER 1: Clinical Approach to the Patient With Peripheral Neuropathy   5

work developed identical symptoms. Surgery and falls are other conditions to which patients often relate their neuropathy.

Etiologists for Polyneuropathy Table 1.3 lists etiologies for polyneuropathy classified by categories of pathophysiology. The causes of polyneuropathy span a spectrum of disorders from endocrine, toxic, nutritional, and metabolic disorders to granulomatous diseases, connective tissue disorders, vasculitis, genetic causes, inflammatory diseases, and paraneoplastic diseases. As is the case in any classification, some disorders are more difficult to categorize and others so rare as to minimize the need to place them in a broad table. The term neuronopathy, when applied to the peripheral nervous system, refers to diseases at the level of the anterior horn cell or, more commonly, at the dorsal root ganglion. In a dorsal root ganglionopathy, the sensory loss can be profound and often does not conform to the stockingand-glove pattern of sensory loss normally observed in a distal dying-back neuropathy. Sensory lost can be distal and proximal and may lead to impressive loss of vibration and joint position sense in the toes, ankles, and knees and sensory loss in a radicular pattern. In some patients, the sensory loss is asymmetric. Patients with profound dorsal root ganglionopathies may manifest choreoathetotic movements of the hands and feet, reflecting the deafferentation that can occur in dorsal root dysfunction. Dorsal root ganglionopathies are seen in carcinomas, usually of the lung, in Sjögren syndrome, in pyridoxine toxicity, and in other rare conditions. It is important to distinguish a dorsal root ganglionopathy from a distal length-dependent sensory neuropathy, as the recovery from a dorsal root ganglion-

opathy is often poor, leaving the patient with significant disability. Rarely, polyneuropathies can be purely motor in manifestation. They may occur in patients who are treated with dapsone, an antimicrobial drug used to treat leprosy and several dermatologic disorders (6). Pure motor neuropathy can be associated with lymphoma, lead poisoning, and porphyria. In many instances, what is initially perceived to be a motor neuropathy is later diagnosed as motor neuron disease, particularly progressive muscular atrophy or amyotrophic lateral sclerosis.

Evaluation of Polyneuropathies Once a polyneuropathy is diagnosed and an etiology is determined, patients inquire about the reversibility of their condition and its prognosis. In approximately 15% of patients, a neuropathy will be found that has potential for improvement with treatment. Often, the improvement is partial, as in the case of subacute combined degeneration from B12 deficiency. The regeneration of the peripheral nerve begins at the proximal stump of the nerve, and regrowth of the axon and myelin is slow and variable and depends on the integrity of the nerve basement membrane, Schwann cells, nerve sheath, and abnormalities of the surrounding tissue, particularly fibrosis. Recovery is much more likely if the degree of motor and sensory axon loss is mild and the amount of proximal involvement is minimal. The chances for improvement are limited if a patient has a severe axon loss sensory or motor neuropathy, as the axon growth must arise from the anterior horn cell or dorsal root ganglion, grow the length of the peripheral nerve, and

Table 1.3 Etiologies for Polyneuropathies Endocrine: diabetes mellitus, hypothyroidism, hyperthyroidism Alcohol abuse Nutritional deficiencies: B1, B2, B6, B12, folic acid, and gastric bypass surgery Vitamin excess: pyridoxine Metabolic: uremia, liver disease, porphyria Granulomatous-sarcoidosis Connective tissue disorders: systemic lupus erythematosus, rheumatoid arthritis, Sjögren syndrome, polyarteritis nodosa, scleroderma Vasculitis Amyloidosis: secondary and familial Genetic: Charcot-Marie-Tooth disease and other inherited neuropathies Inflammatory: GBS, CIDP, plasma cell dyscrasias, HIV infection, Lyme disease, leprosy Toxic: industrial, therapeutic, medications, antiretroviral agents, chemotherapeutic agents, heavy metal poisoning, zinc toxicity Paraneoplastic: carcinoma, lymphoma, leukemia Abbreviations: CIDP, chronic inflammatory demyelinating polyneuropathy; GBS, Guillain-Barré syndrome.

6  Textbook of Peripheral Neuropathy

reinnervate the muscle or sensory effector. The prognosis for recovery is much better if the primary pathologic process is demyelinating and further demyelination can be aborted. Even in the setting of prominent proximal and distal demyelination, recovery can occur over weeks if only remyelination is necessary and good axon structure is in place. It is common for patients with an acquired demyelinating polyneuropathy to make a complete recovery, as is the case in GBS.

Conditions Mimicking Polyneuropathy Other neurologic conditions can give rise to symptoms and signs suggestive of a polyneuropathy. Patients with posterior column disease often have symptoms of numbness and tingling in the feet, and the differentiation from a distal polyneuropathy can be difficult. In this situation, posterior column functions such as joint position sense and vibration should be abnormal, whereas temperature and pain are normal. Often, there are other features of a myelopathy that lead the examiner to favor posterior column disease over a polyneuropathy, such as increased tone, hyperreflexia, a Romberg sign, and Babinski signs. Lumbosacral spinal stenosis can also present with symptoms highly suggestive of a polyneuropathy. Those patients have a loss of ankle reflexes and sensory loss in a distribution below the knees similar to what would be expected in a distal sensory neuropathy (ie, loss of sensation in the L5, S1, and S2 root dermatomes). In lumbosacral spinal stenosis, nerve conduction studies and needle examination almost always differentiate the neuropathy from the polyradiculopathy. Furthermore, the presence of low back pain, sphincter involvement, erectile dysfunction, and spinal claudication would favor spinal stenosis over a polyneuropathy. Tabes dorsalis is not a polyneuropathy, but many of its symptoms and signs suggest the diagnosis of a severe polyneuropathy. Patients with tabes dorsalis usually have severe lancinating pain in the legs, complaints of numbness and tingling, subjective weakness in the legs, absent ankle and knee reflexes, poor balance, and markedly diminished to absent joint position sense and vibration in the toes and ankles and sometimes in the knees. Results of nerve conduction studies are usually normal in tabes dorsalis as the pathology resides in the dorsal root entry zone (7). It is this pathology that explains the absent soleus H reflexes in the setting of normal motor and sensory nerve conduction studies (7). Electrodiagnosis has become critically important in the evaluation of polyneuropathies. It represents an extension of the neurologic examination, and its results usually complement the impressions generated from a neurologic history and examination. Nerve conduction studies and electromyography are necessary and justifiable in most patients with polyneuropathy to help establish if a neuropathy is present and to determine whether the motor or sensory fibers are involved and whether the process is

axon loss, demyelinating, or both. Additionally, they are useful in documenting the distribution of involvement (diffuse, focal, or multifocal) and in determining whether the neuropathy documented by the nerve conduction studies parallels the clinical examination results. The characteristics of the motor and sensory results can render important clues to the etiology. The results can be used to guide the diagnostic evaluation of the patient and limit the number of studies needed to establish the diagnosis (8). One example is the presence of uniform demyelinating features in patients with Charcot-Marie-Tooth type IA as opposed to multifocal demyelinating features in patients with CIDP or neuropathies associated with paraproteinemias. The presence of uniform demyelination would direct the clinician to genetic testing of the neuropathy rather than a complicated assessment of an acquired multifocal demyelinating condition. The needle examination can help determine the age and chronicity of the neuropathy primarily through the analysis of recruitment and the morphology of the motor unit action potentials. Electrodiagnostic testing can also be used to exclude disorders that mimic or complicate a neuropathy, such as a polyradiculopathy, anterior horn cell disorder, mononeuritis multiplex, myelopathy, or neuromuscular junction abnormality. Not all patients with neuropathy require peripheral electrodiagnosis. This is often the case in patients with the classic presentation of a mild diabetic neuropathy or in patients with a small-fiber neuropathy. Because of the importance of electrodiagnosis in the evaluation of a diffuse neuropathy, an entire chapter has been devoted to this topic. England and colleagues (9) reported their findings from a consensus process used to define a distal symmetric polyneuropathy for clinical research. The study was conducted by members of 3 organizations who frequently evaluate patients with a polyneuropathy. The authors determined that a single specific symptom such as foot numbness had a low sensitivity but a high specificity for the presence of a polyneuropathy (9). Multiple neuropathic symptoms were more accurate than single symptoms and should carry more weight in determining the presence of a neuropathy. Signs are better predictors of polyneuropathy than symptoms and should be given stronger consideration. As would be expected, multiple signs are a better predictor of a polyneuropathy. Somewhat surprising was the conclusion that simple examinations are as accurate in diagnosing polyneuropathy as complex scoring systems. The final conclusion was that the combination of neuropathic symptoms, signs, and abnormal electrodiagnostic study results imparts the strongest accuracy for determining the presence of a polyneuropathy (9).

References 1. Martyn CN, Hughes RAC. Epidemiology of peripheral neuropathy. J Neurol Neurosurg Psychiatry. 1997;62:310–318. 2. England JD, Asbury AK. Peripheral neuropathy. Lancet. 2004;363:2151–2161.

CHAPTER 1: Clinical Approach to the Patient With Peripheral Neuropathy   7 3. Dyck PJ, Oviatt KF, Lambert EH. Intensive evaluation of referred unclassified neuropathies yields improved diagnosis. Ann Neurol. 1981;10:222–226. 4. Bradley WG. Clinical features of peripheral nerve disease. Disorders of Peripheral Nerves. Oxford, UK: Blackwell Scientific Publications; 1974:Chapter 3. 5. Winer JB, Hughes RAC, Osmond C. A prospective study of acute idiopathic neuropathy. I. Clinical features and their prognostic value. J Neurol Neurosurg Psychiatry. 1988;51:605–612. 6. Gutmann L, Martin JD, Welton W. Dapsone motor neuropathy. Neurology. 1976;26:514–516.

7. Donofrio PD, Walker FO. Tabes dorsalis: electrodiagnostic features. J Neurol Neurosurg Psychiatry. 1988;51:1097–1099. 8. Donofrio PD, Albers JW. AAEM minimonograph #34: polyneuropathy: classification by nerve conduction studies and electromyography. Muscle Nerve. 1990;13:889–903. 9. England JD, Gronseth GS, Franklin G, et al. Distal symmetric polyneuropathy: a definition for clinical research. Report of the American Academy of Neurology, the American Association of Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2005;64:199–207.

2

Kevin R. Scott, Kishori Somyreddy, and Milind J. Kothari

Entrapment Neuropathies of the Upper Extremity

INTRODUCTION

muscle, providing branches to innervate this muscle, as well as the flexor carpi radialis (FCR), palmaris longus, and flexor digitorum superficialis (FDS) muscles of the forearm. Posteriorly, the median nerve gives off the anterior interosseous nerve (AIN), which innervates the flexor pollicis longus (FPL), flexor digitorum profundus to digits 2 and 3 (FDP II/III), and the pronator quadratus (PQ) muscles. The AIN provides no cutaneous sensory

Focal entrapment mononeuropathies of the upper and lower extremities are usually encountered in clinical practice. Upper extremity neuropathies are more prevalent than those of the lower extremity. In this chapter, common entrapments of the upper extremities will be discussed and correlated with their electrodiagnostic findings.

COMMON MONONEUROPATHIES OF THE UPPER EXTREMITY Median Neuropathy The median nerve can be entrapped at various levels, the most common site being at the wrist. This neuropathy is the most common of all entrapment neuropathies affecting the upper extremity.

Median nerve

Anatomy The median nerve is formed by a combination of the medial and lateral cords of the brachial plexus (1). Figure 2.1 diagrams the course of the median nerve. The lateral cord is made up of fibers of C6 through C7 and supplies median sensory fibers to the thenar eminence, thumb, and index and middle fingers, as well as most motor fibers to the proximal median-innervated forearm muscles. The medial cord is composed of fibers of C8 through T1 and supplies most motor fibers to the distal median-innervated muscles of the forearm and hand, as well as sensory fibers to the lateral half of the ring finger. After the medial and lateral cords join, the median nerve courses distally in the upper arm, along the medial side of the humerus. No muscular branches are given off during its course through the proximal arm. The nerve enters the region of the antecubital fossa, where it lies medial to the biceps tendon and brachial artery. As it passes into the forearm, the median nerve travels between the 2 heads of the pronator teres (PT)

Pronator teres

Flexorcarpi radialis

Flexor digitorum sublimis Flexor pollicis longus Flexor digitorum profundus Pronator quadratus Abductor pollicis brevis Opponens pollicis Superfic head of flexor pollicisb brevis 1st & 2nd lumbricals

Palmaris longus Flexor digitorum profundus Anterior interosseous nerve Cutaneous innervation

Post.

Ant.

Figure 2.1 Anatomical Course and Cutaneous Innervation of the Median Nerve. Reprinted from Haymaker W, Woodhall B, Peripheral Nerve Injuries, 2nd ed. Philadelphia: WB Saunders, 1953 (4). 9

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Table 2.1  Muscle and Nerve Abbreviations • • • • • • • • • • • • • •

Abductor pollicis brevis (APB) Anterior interosseous nerve (AIN) Extensor digitorum communis (EDC) Extensor indicis proprius (EIP) First dorsal interosseous (FDI) Flexor carpi radialis (FCR) Flexor digitorum profundus (FDP) Flexor digitorum superficialis (FDS) Flexor pollicis brevis (FPB) Flexor pollicis longus (FPL) Opponens pollicis (OP) Palmaris longus (PL) Pronator quadratus (PQ) Pronator teres (PT)

innervation but does supply sensation to the interosseous membrane and wrist joint (1–3). In the distal forearm, but proximal to the wrist, the median nerve gives off the palmar sensory cutaneous nerve, which provides sensation over the thenar eminence. The median nerve, along with the 9 flexor tendons of the hand, continues through the carpal tunnel, which is formed by the transverse carpal ligament and carpal bones. After passing into the palm, the nerve divides into sensory and motor trunks. The sensory trunk divides further, providing digital sensory nerves to innervate the first 3 fingers and lateral portion of the fourth (ring finger). The motor trunk gives off the recurrent thenar branch, which supplies the muscles of the thenar eminence including the opponens pollicis, abductor pollicis brevis (APB), and the superficial portion of the flexor pollicis brevis muscles, before continuing distally and supplying the first and second lumbricals (1–3).

Clinical Features of Median Nerve Dysfunction A. Median neuropathy at the wrist (carpal tunnel syndrome) This is the most common entrapment neuropathy affecting the upper extremity. Patients present with a variety of signs and symptoms, including weakness and sensory disturbances (Table 2.2). The most common complaint is that of pain and paresthesias. Pain usually localizes to the wrist and fingers but may radiate to the forearm, arm, or even the shoulder (5). Some patients report a diffuse aching sensation involving the entire arm. Sensory disturbances usually involve the lateral 3 fingers; however, it is not uncommon for patients to report paresthesias involving the entire hand, including regions supplied by the ulnar nerve (1). It is important to note that sensation over the thenar eminence will be spared in carpal tunnel syndrome (CTS), as this region is supplied by the palmar cutaneous branch, which arises proximal to the carpal tunnel. Patients often report an increase in symptoms when the wrist is held in a flexed or extended posture (typing, driving, holding a telephone, reading a newspaper). A hallmark of CTS is nocturnal paresthesias. Patients frequently awaken from sleep to shake their hands. This is likely due to nerve ischemia resulting from the persistent flexed or extended posture of the wrist. In general, sensory fibers are involved earlier than motor fibers (1). Later, there may be frank weakness of thumb abduction and opposition with atrophy over the thenar eminence. Activities requiring fine motor dexterity may be impaired (buttoning shirts, writing, dropping utensils, and opening jars). Provocative testing (Tinel and Phalen) may be helpful. The clinician must be aware of sensitivity and specificity issues. In CTS, a Tinel sign may be present in roughly half of cases. Of importance, healthy people may exhibit false-positive Tinel sign.

Table 2.2  Clinical Features of Median Neuropathy at the Wrist (Carpal Tunnel Syndrome) Symptoms 1. Nocturnal paresthesias that awaken patients from sleep 2. Pain and paresthesias resulting from prolonged wrist flexion or extension (eg, typing, driving, holding a telephone, reading the newspaper) 3. Impaired finger dexterity (eg, buttoning shirts, writing, dropping utensils, opening jars) 4. Symptoms exacerbated by repetitive forceful use of the hand 5. Pain is localized to the wrist and fingers, but may radiate to the forearm, arm, or even the shoulder. Signs 1. Sensory disturbance of digits 1-3 with involvement of lateral aspect of digit 4 2. Sparing of sensation over the thenar eminence or thumb 3. Weakness of thumb abduction 4. Atrophy of the thenar eminence 5. Paresthesias that are reproduced with Phalen maneuver (wrist held passively flexed for at least 1 minute) 6. Tinel sign when tapping over the median nerve at the wrist resulting in paresthesias of the median-innervated fingers

CHAPTER 2: Entrapment Neuropathies of the Upper Extremity   11

Table 2.3  Differential Diagnosis of Carpal Tunnel Syndrome Proximal median neuropathy secondary to compression at Ligament of Struthers PT Sublimis bridge of the FDS muscle Brachial plexopathy Cervical radiculopathy Central nervous system lesions Stroke Demyelinating disease Cervical cord lesions (syrinx, intraaxial lesions) Abbreviations: FDS, flexor digitorum superficialis; PT, pronator teres.

differential diagnosis of carpal tunnel syndrome. Other peripheral or central nervous system lesions can produce symptoms that may mimic CTS (Table 2.3). In evaluating a patient with CTS, a clinician should consider the possibility of a proximal median nerve lesion, a lesion affecting the brachial plexus, a cervical radiculopathy, or even stroke. One’s neurological examination should be helpful in excluding these conditions. For example, patients may have weakness involving the proximal muscles (eg, wrist flexion and pronation) and reflex abnormalities, implying the lesion to be proximal to the wrist or the coexistence of a second peripheral nervous system or central nervous system process. There are many conditions that can lead to the development of CTS (Table 2.4) (1). CTS may be the result of repetitive-use injuries or wrist trauma. Inflammatory or infectious causes include connective tissue disease, sarcoidosis, Lyme infection, tuberculosis, or compression resulting from a septic joint. Metabolic causes such as diabetes, hypothyroidism, or acromegaly lead to weight gain and/or tissue edema that predisposes to compression within the tunnel. Less common causes include t­umors (eg, lipoma, schwannoma, neurofibroma, ganglion cysts) vs congenital disorders such as anomalous muscles, a congenitally small carpal tunnel, or a persistent median artery (1). electrophysiology in carpal tunnel syndrome. When performing electrodiagnostic studies, limb temperature must be controlled and adequately maintained at or above 32°C. The pathophysiology of CTS is usually that of demyelination, which may be associated with secondary axonal degeneration (1). In patients with typical CTS, the median distal motor and sensory latencies are prolonged, whereas the results of ulnar studies are normal (Table 2.5). In early or mild cases of CTS, the sensory nerve conduction studies may show the only ab-

normalities. However, there is a small group (10%-25%) of patients in whom these routine nerve conduction study results are normal (1). In this group, comparison studies (discussed below) should be performed in

Table 2.4  Potential Causes of Median Neuropathy at the Wrist (Carpal Tunnel Syndrome) A. Inflammatory/infectious 1. Connective tissue disease (eg, rheumatoid arthritis, lupus, Raynaud disease, scleroderma) 2. Sarcoidosis 3. Lyme disease 4. Tuberculosis 5. Leprosy 6. Complications of septic arthritis 7. Gout or pseudogout 8. Paget disease B. Traumatic/overuse 1. Repetitive-use injuries 2. Wrist or hand trauma 3. Degenerative arthritis 4. Tenosynovitis C. Metabolic/endocrine 1. Diabetes mellitus 2. Hypothyroidism 3. Pregnancy 4. Acromegaly 5. Obesity 6. Renal failure and hemodialysis D. Congenital 1. Congenitally small carpal tunnel 2. Anomalous muscles 3. Persistent median artery 4. Hereditary neuropathy with liability to pressure palsies E. Local tumors 1. Lipoma 2. Ganglion cysts 3. Schwannoma 4. Neurofibroma F. Drugs/toxic 1. Alcohol use 2. Tobacco use G. Others 1. Multiple myeloma 2. Amyloidosis Source: Ref. 1.

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Table 2.5  Expected Electrodiagnostic Findings in Carpal Tunnel Syndrome Amplitude

Distal Latency

Conduction

Median Sensory Motor

Normal to reduced Normal to reduced

Prolonged Prolonged

Sloweda Slowedb

Ulnar Sensory Motor

Normal Normal

Normal Normal

Normal Normal

Radial Sensory Motor

Normal Normal

Normal Normal

Normal Normal

a

Conduction velocity slowed across the wrist. Conduction velocity may be slowed across the wrist. With significant axon loss, conduction velocities through the forearm segment can be reduced as well.

b

Table 2.6  Electrodiagnostic Evaluation of Median Neuropathies A. Nerve conduction studies 1. Median nerve studies a. Median motor study stimulating at the wrist and below elbow sites while recording from the APB muscle b. Median F-wave responses (optional) c. Median sensory study stimulating at the wrist while recording from the first digit 2. Ulnar nerve studies a. Ulnar motor study, stimulating at the wrist, below elbow, and above elbow sites, while recording from the ADM muscle b. Ulnar F-wave responses (optional) c. Ulnar sensory study stimulating at the wrist while recording from the fifth digit 3. Radial nerve studies a. Radial sensory study stimulating forearm, recording from snuffbox 4. Median-ulnar comparison studies (indicated only if the median nerve studies are equivocal or if one suspects CTS in the setting of normal median nerve study results) a. Median second lumbrical vs ulnar interosseous motor study stimulating wrist while recording palm b. Median-ulnar mixed palmar sensory studies stimulating palm while recording wrist c. Median-ulnar digit 4 sensory studies stimulating wrist and recording fourth digit d. Median-radial sensory studies recording thumb B. Electromyography 1. Routine a. APB b. Two proximal median nerve-innervated muscles (eg, PT, FCR, FPL) c. Two proximal C6 through C7–innervated muscles (eg, PT, FCR, EDC) d. If the APB is abnormal, at least 1 nonmedian nerve/C8-innervated muscle (eg, EIP, FDI) Abbreviations: ADM, abductor digiti minimi; APB, abductor pollicis brevis; CTS, carpal tunnel syndrome; EIP, extensor indicis proprius; FCR, flexor carpi radialis; FDI, first dorsal interosseous; FPL, flexor pollicis longus. Source: Ref. 1.

CHAPTER 2: Entrapment Neuropathies of the Upper Extremity   13

an attempt to demonstrate abnormalities of the median nerve (5–8). Suggested routine nerve conduction studies evaluating for CTS should include the following: (1) median motor study—stimulating at the wrist and elbow, while recording from the APB muscle; (2) ulnar motor study— stimulating at the wrist, below the elbow, and above elbow sites, while recording from the abductor digiti minimi (ADM) muscle; (3) ulnar and median F-wave responses are optional because of low sensitivity and specificity for CTS; (4) median sensory study—stimulating at the wrist, while recording from the index finger; (5) ulnar sensory study—stimulating at the wrist, while recording from the fifth digit; and (6) radial sensory study—stimulating at the forearm, while recording from the snuffbox (to e­xclude a generalized polyneuropathy) (1,7). If routine nerve conduction study results are normal, comparison short-latency studies should be considered. (Comparison studies can also be performed on the contralateral nerves.) Comparison studies evaluate for compression by comparing median nerve function to ulnar nerve function and are more sensitive because they record over very short nerve segments. Three frequently used comparison studies are the following: (1) median vs ulnar palm-to-wrist mixed-nerve latencies; (2) median vs ulnar wrist-to-digit 4 sensory latencies; and (3) median (second lumbrical) vs ulnar (interosseous) distal motor latencies. In each case, identical distances are used between the stimulating and recording electrodes for the median and ulnar nerves. The results of these sensitive comparison studies are considered abnormal if differences between the median and ulnar latencies exceed 0.4 to 0.5 millisecond (1). Other studies, used less frequently in most laboratories include the following: (1) inching studies across the wrist; (2) comparative median vs radial sensory studies recording from the thumb; (3) comparative median vs ulnar F-wave minimal latency differences; (4) wrist-to-palm vs wrist-to-digit 2 sensory latency (1). Needle examination should be performed in each patient being evaluated for CTS. The APB muscle and a proximal C6 through C7 muscle (eg, extensor digitorum communis [EDC], PT, FCR) should be sampled to exclude a C6 through C7 radiculopathy. If the APB muscle is abnormal, another lower trunk/C8 through T1 muscle (eg, first dorsal interosseous [FDI], extensor indicis proprius [EIP]) should be examined to exclude a C8 through T1 radiculopathy, lower trunk brachial plexopathy, or polyneuropathy. In addition, one should consider studying at least 2 proximal median nerveinnervated muscles (eg, FCR, PT, FPL) to exclude a proxi­ mal median neuropathy in the forearm (1). other diagnostic tests. Magnetic resonance imaging can be helpful in diagnosing CTS. This imaging modality is usually reserved for situations where the clinical picture is confusing, for example, when nerve conduction study results are equivocal or contradictory or in

cases of trauma or when there is suspicion of a mass lesion (eg, tumor). Plain films are generally low yield. High-resolution ultrasonography (US) has received increased attention in the evaluation of CTS. Recent studies have shown that patients with CTS have an increased cross-sectional area of the median nerve vs controls. Currently, US can be a valuable adjunct but is not yet accurate enough to replace nerve conduction studies for diagnosis of CTS (9). treatment.

The conservative management of CTS involves withdrawal of provoking factors, use of a neutral wrist splint, and local corticosteroid injections (10). If this approach fails, surgical decompression may be necessary. Surgery usually provides benefit in 85% to 90% of patients (11). Surgeons may use an open or an endoscopic approach. Both approaches have similar efficacy in properly selected patients (12). B. Proximal median neuropathy Proximal median neuropathies (Table 2.7) are distinctly uncommon compared with entrapment at the wrist (CTS). The most common sites of entrapment are the following: (1) the ligament of Struthers; (2) the lacertus fibrosus; (3) the heads of the PT muscle; (4) the sublimis bridge of the FDS muscle; and (5) the AIN. In addition, proximal median neuropathies have been described secondary to compression from casting, trauma, and venipuncture; compressive mass lesions such as soft tissue tumors or hematomas; or anomalous anatomical structures such as an accessory head of the FPL (Gantzer muscle). Less common causes of extrinsic compression of the median nerve such as chronic compartment syndrome, partial rupture of the distal biceps insertion, and synovial osteochondromatosis at the elbow have also Table 2.7  Potential Causes of Proximal Median Nerve Entrapment Entrapment at Ligament of Struthers Lacertus fibrosis (bicipital aponeurosis) PT Sublimis bridge of the FDS muscle Casting Trauma Venipuncture Compressive soft tissue tumors or hematomas Anomalous anatomical variants, for example, accessory head of the FPL muscle (Gantzer muscle) Compartment syndrome Partial rupture of the distal biceps insertion Synovial osteochondromatosis at the elbow Surgically created arteriovenous fistulas Hereditary neuropathy with liability to pressure palsies

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been reported and arteriovenous fistulas created for renal dialysis (13). ligament of struthers entrapment.

Entrapment at the ligament of Struthers is uncommon but may occur when the median nerve becomes entrapped by a tendinous band running from the medial epicondyle to a bony spur on the distal medial humerus. The prevalence of such a supracondylar bone spur, which is easily seen on plain films, is approximately 1% to 2% of the population. Patients present with symptoms of pain in the volar forearm and paresthesias in the median-innervated digits. These symptoms are exacerbated by supination of the forearm and/or extension of the elbow. At times, a bony spur may be palpated at the distal humerus. Patients will also demonstrate weakness of proximal median-innervated muscles including the PT. Sensory loss may be noted in the median distribution, including the thenar eminence (13).

pronator syndrome. Pronator syndrome refers to compression of the median nerve as it passes between the 2 heads of the PT muscle or under the proximal edge of the FDS arch. It is rare in comparison to CTS. Symptoms usually have an insidious onset and may be confused with CTS. Numbness or tingling can occur in the median sensory distribution of the hand; however, unlike CTS, sensory symptoms include the proximal palm and thenar eminence. In contrast to patients with CTS, who usually report nocturnal paresthesias, patients with pronator syndrome experience symptoms primarily during the day secondary to repetitive activities involving grasping and forearm pronation. Patients may experience pain and tenderness over the PT. The sole finding of increased pain on provocative testing is unreliable. A Tinel sign at the PT may be present in about 50% of cases (13,14). A thorough electrodiagnostic study is helpful in these patients. The median sensory study result is usually abnormal. The median motor study may show slowing of forearm conduction velocity. There may be a drop in the motor amplitude proximally as compared to the distal site. If there is focal demyelination at the ligament of Struthers, one may find conduction block or temporal dispersion between the antecubital fossa and the axilla. If there is focal demyelination in the vicinity of the antecubital fossa, conduction block or temporal dispersion may be seen between the antecubital fossa and the wrist. Needle examination will demonstrate abnormalities in medianinnervated muscles involving the wrist and forearm. When testing for a proximal median neuropathy, at least 2 proximal muscles should be examined. It is important to remember that in a lesion at the level of the PT, the PT muscle itself may be spared (1). Magnetic resonance imaging may be useful to visualize the nerve (15). Highresolution ultrasound has become an attractive adjunct to electrodiagnostic studies and may provide additional information for making the diagnosis. In addition, US may be effective as a preoperative planning tool (16).

treatment. Conservative treatment that includes avoidance of aggravating activities, rest, and anti-inflammatory medications is frequently successful in alleviating symptoms. Corticosteroids have also been shown to be efficacious (13). Surgical evaluation should be considered for refractory cases. Surgery may involve exploration of the median nerve throughout its proximal course with the release at all compressive sites (ie, the ligament of Struthers [if it is present], the lacertus fibrosis (bicipital aponeurosis), the fascia of the PT, and the fascia of the FDS) (17).

C. Anterior interosseous neuropathy The AIN is the largest branch of the median nerve and originates just distal to the PT in the forearm. The nerve has no cutaneous sensory fibers; thus patients will not experience sensory complaints clinically. The nerve supplies 3 muscles. These are the FPL, the flexor digitorum profundus (digits 2 and 3), and the PQ. To test the PQ muscle, the elbow should be flexed to avoid activating the PT. Involvement of the AIN is tested by having the patient perform the “OK” sign. Patients with AIN injury will be unable to flex the distal phalanges of the thumb and forefinger. Instead of forming a circular “OK” sign, these patients maintain an extended position at the distal interphalangeal joints and form a pincer-type grasp (3). Electrodiagnostic testing will usually demonstrate normal nerve conduction study results. The needle examination should demonstrate abnormalities in those muscles supplied by the AIN and is critical in making the diagnosis. Patients may present with AIN (Table 2.8) as a manifestation of trauma, compressive lesions, or an autoimmune brachial plexopathy (18). Treatment is typically conservative; however, surgical exploration may be considered in cases not showing improvement in 4 to 6 months. Clinicians must maintain a high level of suspicion for the diagnosis of AIN, as results of nerve conduction studies are normal and the 3 muscles affected are not often tested in patients with forearm pain and hand weakness. Table 2.8  Potential Causes of the Anterior Interosseous Neuropathy A. Noncompressive - As part of autoimmune-mediated brachial plexitis (Parsonage-Turner syndrome) B. Trauma - Rupture of the FPL tendon, which may occur in patients with rheumatoid arthritis - Fractures of the forearm and distal humerus C. Compressive - Fibrous bands - Enlarged bursae - Tumors - Aberrant or thrombosed vessels - Aberrant muscles

CHAPTER 2: Entrapment Neuropathies of the Upper Extremity   15

Ulnar Neuropathy Anatomy The ulnar nerve is derived from the C8 through T1 nerve roots. Nearly all ulnar nerve fibers travel through the lower trunk and medial cord of the brachial plexus. Figure 2.2 diagrams the course of the ulnar nerve. The ulnar nerve does not give off any branches during its descent through the upper arm until it reaches the elbow. At the elbow, muscular branches to the flexor carpi ulnaris (FCU) and FDP to digits 4 and 5 (FDP IV/V) arise. Some literature states that the branch to the FCU can arise above the elbow. The ulnar nerve then descends to the wrist. Proximal to the wrist, the

Table 2.9  Potential Causes of Ulnar Neuropathy at the Elbow A. Old fracture with joint deformity B. Recent elbow trauma without fracture C. Habitual leaning on elbow D. Occupational repetitive flexion/extension E. Congenital variations of HUA architecture 1. Absent HUA with nerve prolapse 2. Hypertrophy of retinaculum 3. Anconeus epitrochlearis muscle F. Diabetes mellitus G. Hereditary neuropathy with liability to pressure palsies H. Rheumatoid arthritis I. Iatrogenic 1. Malpositioning during surgery 2. Nerve infarction during transposition Abbreviation: HUA, humeroulnar aponeurotic arcade.

Ulnar n.

dorsal ulnar cutaneous sensory branch exits to provide sensation over the dorsal and medial surface of the hand. Just before entering the Guyon canal, the ulnar nerve gives off the palmar cutaneous sensory branch, which provides sensation to the hypothenar area. Next, the ulnar nerve enters the Guyon canal and provides sensation to the volar fifth and medial fourth digits as well as motor innervation to the hypothenar muscles, palmar and dorsal interossei, third and fourth lumbricals, adductor pollicis, and deep head of the flexor pollicis brevis muscles (1,2).

Med.cut.n.of arm Med.cut.n.of forearm

Flexor carpi ulnaris

Cutaneous distribution

Flexor carpi digitorum profundus

Clinical Features of Ulnar Nerve Dysfunction

Adductor pollicis

Palmaris brevis 34

Post.

Ant.

Abductor Opponens

Flexor

Digiti quinti

2

1 3

3rd & 4th lumbricals Palmer & dorsal interossei

Figure 2.2 Anatomical Course and Cutaneous Innervation of the Ulnar Nerve. Reprinted from Haymaker W, Woodhall B, Peripheral Nerve Injuries, 2nd ed. Philadelphia: WB Saunders, 1953 (4).

A. Ulnar neuropathy at the elbow Ulnar nerve entrapment at the elbow (Table 2.9) is the second most common entrapment syndrome of the upper extremity after CTS. Typical symptoms include numbness and tingling in digits 4 and 5. Some patients may report elbow pain that radiates into the ulnar aspect of the hand. In some cases, only sensory symptoms are present (19). Impaired sensation of the volar fingertips is the most common sensory deficit. Sensory loss over the ulnar palm is less frequent (19). Deep tendon reflexes are usually preserved with ulnar neuropathies. An early sign may be an inability to adduct the fifth digit (Wartenberg sign). In more severe cases, there will be weakness of handgrip with atrophy of the intrinsic hand muscles. With weakness of the adductor pollicis, patients compensate by flexing the FPL muscle, resulting in Froment sign. Weakness of the FDI muscle is more frequent (84%) then weakness of the abductor digiti quinti muscle (76%) (20). Weakness of the flexor digitorum profundus and FCU muscle occurs in 56% and 20% of patients, respectively (20). In severe cases, clawing of digits 4 and 5 can

16  Textbook of Peripheral Neuropathy

develop owing to an imbalance between intrinsic and extrinsic muscles controlling the hand. This results in hyperextension of the metacarpophalangeal joints (secondary to weakness of the lumbricals) with flexion of the proximal interphalangeal and distal interphalangeal joints (secondary to relative sparing of the FDP III/IV muscles) resulting in the “claw” or “Benedictine” hand (21). There are a variety of provocative maneuvers that may increase the diagnostic yield of one’s clinical examination. These include a Tinel sign at the elbow, sustained manual pressure over the cubital tunnel, sustained elbow flexion, and flexion combined with manual pressure. Combined flexion with manual pressure over the cubital tunnel has been reported to have the highest sensitivity (91%) (22). The differential diagnosis of a suspected ulnar neuropathy at the elbow includes a lower trunk or medial cord brachial plexopathy, a C8 through T1 radiculopathy, or an ulnar neuropathy at locations proximal or distal to the elbow. electrophysiology.

As with other mononeuropathies, the goal of electrodiagnostic testing should be to localize the abnormality to the ulnar nerve in the arm, forearm, or hand. The ulnar motor study result should demonstrate evidence of focal demyelination at the elbow characterized by either focal slowing or conduction block. When performing the ulnar motor study, it is important to understand that elbow position is crucial. The flexed elbow position should be used and is more sensitive than the

extended position (23,24). Inching studies across the elbow segment can be useful in confirming and more precisely localizing focal demyelination (25). Ulnar motor studies, recording from the FDI muscle, may be more sensitive than motor studies recording from the abductor digiti quinti muscle (26). As a result, it can be useful to record from the FDI if an ulnar lesion is suspected and not found on recording from the ADM muscle. Additionally, it is important to keep in mind that some ulnar lesions affect only the axon and do not produce focal slowing in the elbow region. Evaluation of the ulnar nerve should involve nerve conduction studies followed by a needle electromyogram. Table 2.10 outlines a reasonable electrodiagnostic approach. If routine nerve conduction studies do not localize the lesion, it may be helpful to consider additional techniques. These include the following: (1) repeating the ulnar motor study recording from the FDI muscle; (2) inching (ulnar motor) studies across the elbow segment; (3) sensory or mixed-nerve studies across the elbow; (4) comparing dorsal ulnar cutaneous sensory amplitudes between the affected and asymptomatic limbs; and (5) comparing the medial antebrachial cutaneous sensory response between affected and asymptomatic sides if there is reason to suspect a brachial plexopathy. In most cases, the lesion is at the elbow; however, lesions at the wrist or more proximal locations (brachial plexus or root) should be excluded by the electrodiagnostic study. Because the dorsal ulnar cutaneous sensory nerve

Table 2.10  Electrodiagnostic Evaluation of Ulnar Neuropathy at the Elbow A. Nerve conduction studies 1. Ulnar nerve studies A. Ulnar motor study, stimulating at the wrist, below elbow, and above elbow sites, while recording from the ADM muscle and/or FDI B. Ulnar F-wave responses C. Ulnar sensory study stimulating at the wrist while recording from the fifth digit 2. Median nerve studies A. Median motor study stimulating at the wrist and below elbow sites while recording from the APB muscle B. Median F-wave responses C. Median sensory study stimulating at the wrist while recording from the second digit B. Electromyography 1. Routine a. At least 1 ulnar-innervated muscle distal to the wrist (eg, FDI, ADM) b. Two ulnar-innervated muscles of the forearm (eg, FDP, FCU) 2. If the result of testing of any of the routine muscles is abnormal, then additional needle examination should include a. At least 2 non-ulnar, lower trunk, C8 through T1 muscles (eg, APB, FPL, EIP) b. C8 and T1 paraspinal muscles Abbreviations: FCU, flexor carpi ulnaris; FDP, flexor digitorum profundus. Source: Ref. 1.

CHAPTER 2: Entrapment Neuropathies of the Upper Extremity   17

arises proximal to the wrist, it should be involved (reduced amplitude relative to the unaffected limb) in lesions at the elbow but spared in ulnar nerve lesions at the wrist. other diagnostic tests.

Radiographs of the involved extremity can be useful to rule out bony deformities as a cause of nerve entrapment at the elbow or the wrist. Anteroposterior, lateral, and epicondylar tunnel views of the elbow are helpful in excluding arthritis, posttraumatic changes, and abnormal carrying angle (eg, cubitus valgus). Cervical spine radiographs, including outlet views and transaxillary views, are helpful in evaluating for thoracic outlet syndrome secondary to a cervical rib. Magnetic resonance imaging is indicated if there is suspicion of a C8 radiculopathy. Ultrasound of the cubital tunnel can help compare the size of the ulnar nerve relative to normal values, as a correlation between reduced nerve diameter and progressive ulnar neuropathy at the elbow has been demonstrated (27). treatment.

The treatment of patients with ulnar neuropathy at the elbow is conservative initially. Nonoperative management should include avoidance of pressure on the elbow and/or prolonged elbow flexion and utilization of an elbow splint. In some patients, steroid injections into the cubital tunnel can be helpful. Occupational therapy emphasizing correct ergonomics at work and rest can also aid recovery. In those patients with significant or progressive neurological deficits, surgical evaluation is warranted. There are a number of procedures used depending on the patient’s presentation. In one study, there was no statistically significant difference between simple decompression and anterior subcutaneous and submuscular transposition of the ulnar nerve for cubital tunnel

syndrome; however, a trend toward improved clinical outcomes was seen after transposition as opposed to simple decompression (28). B. Ulnar neuropathy at the wrist Ulnar nerve entrapment at the wrist is uncommon relative to compression at the elbow. Entrapment at the wrist can be difficult to diagnose; therefore, it is important to understand the anatomical course of the ulnar nerve. The site of entrapment typically is within the Guyon canal. Five clinical syndromes have been described secondary to entrapment here (Table 2.11). Patients can present with sensory and/or motor involvement confined to the distal ulnar nerve distribution. They may have sensory loss, paresthesias, or pain in the region supplied by the distal ulnar sensory branch. The region supplied by the dorsal ulnar cutaneous sensory branch (located over the dorsomedial aspect of the hand) should be spared. Motor deficits should be limited to the intrinsic muscles of the hand, with sparing of the proximal ulnar-innervated muscles. Examination may demonstrate weakness, atrophy, or fasciculations in the intrinsic hand muscles. A Tinel sign may be present over the Guyon canal (29,30). The electrophysiology of this entrapment at the wrist is complex. Table 2.12 outlines a reasonable protocol to consider when testing for ulnar nerve entrapment at the wrist. Table 2.13 summarizes the typical electrodiagnostic findings that one may see in each of the various syndromes. Magnetic resonance imaging may be useful in detecting structural lesions leading to nerve injury. A variety of different causes have been described; however, ganglion cysts and traumatic wrist injuries (to include occupational repetitive neuritis) account for most cases (29,30). Other causes to consider include ulnar artery disease, aberrant muscles, tumors, osteoarthritis, rheumatoid arthritis, joint dislocations, and activities involving

Table 2.11  Clinical Syndromes Produced by Ulnar Nerve Compression at the Wrist A. Combined motor and sensory syndrome (type 1)—A lesion at the proximal portion of the canal may involve both motor and sensory divisions. Weakness of all ulnar-innervated hand muscles and loss of sensation over the palmar fifth and medial fourth fingers occurs. Cutaneous sensation over the hypothenar and dorsomedial surfaces of the hand should be spared. B. Pure sensory syndrome (type 2)—Clinically, there is loss of sensation over the palmar surface of the fifth and medial fourth fingers. Sensation is spared over the hypothenar eminence. Motor fibers are not affected. There is no weakness associated with this lesion. C. Pure motor syndromes 1. Lesion affecting the deep palmar and hypothenar motor branches (type 3)—This lesion affects the motor trunk proximal to the takeoff of the hypothenar branches. As a result, all ulnar-innervated muscles of the hand are involved. Because the sensory branch is not affected, sensation is spared. 2. Lesion affecting the deep palmar motor branch only (type 4)—Clinically, there is weakness of lumbricals 1 and 2 as well as the ulnar-innervated muscles of the thenar eminence. This type of lesion spares the muscles of the hypothenar eminence. 3. Lesion affecting only the distal deep palmar motor branch (type 5)—This type of lesion occurs just proximal to the branches innervating the adductor pollicis and FDI muscles, resulting in weakness of these muscles. Source: Refs. 1, 28.

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Table 2.12  Electrodiagnostic Evaluation of Ulnar Neuropathy at the Wrist A. Nerve conduction studies 1. Ulnar nerve studies a. Ulnar motor study stimulating at the wrist, below elbow, and above elbow sites, while recording from the ADM muscle b. Ulnar motor study (bilateral) stimulating at the wrist, while recording from the FDI muscle c. Ulnar F-wave responses d. Ulnar sensory study stimulating at the wrist, recording from digit 5 e. Dorsal ulnar cutaneous sensory study stimulating forearm while recording from the dorsolateral hand 2. Median nerve studies a. Median motor study stimulating at the wrist and elbow sites while recording from the APB muscle b. Median F-wave responses c. Median sensory study stimulating wrist while recording second digit 3. Ulnar-median comparison studies a. Lumbrical (second)-interosseous (first palmar) comparison study B. Electromyography 1. Routine a. One deep palmar motor muscle (eg, FDI) b. One hypothenar branch muscle (eg, ADM) c. Two forearm muscles (eg, FCU, FDP) 2. If the result of testing of any of the routine muscles is abnormal, then additional needle examination should include a. At least 2 nonulnar lower trunk, C8 through T1 muscles (eg, APB, FPL, EIP) b. C8 and T1 paraspinal muscles Source: Ref. 1.

Table 2.13  Nerve Conduction Study Findings in Ulnar Neuropathy at the Wrist A. Combined motor and sensory syndrome (type 1)—Reduced ulnar sensory and motor amplitudes with prolonged motor distal latencies. EMG shows denervation of all intrinsic hand muscles. B. Pure sensory syndrome (type 2)—Decreased ulnar sensory amplitude. Ulnar motor study result will be normal. EMG is normal. C. Pure motor syndromes 1. Lesion affecting the deep palmar and hypothenar motor branches (type 3)—Ulnar sensory response is normal. Ulnar motor amplitude recorded at the ADM and FDI is decreased with prolonged distal latency. EMG shows denervation of all intrinsic hand muscles. 2. Lesion affecting the deep palmar motor branch only (type 4)—Ulnar sensory response is normal. Ulnar motor amplitude is decreased with prolonged distal latency when recording from the FDI muscle, whereas it is normal to the ADM muscle. EMG shows denervation of the FDI muscle with sparing of the hypothenar muscles. 3. Lesion affecting only the distal deep palmar motor branch (type 5)—Ulnar sensory response is normal. Ulnar motor amplitude is decreased with prolonged distal latency when recording from the FDI muscle, whereas it is normal to the ADM muscle. EMG shows denervation of the FDI muscle with sparing of the hypothenar muscles. Abbreviation: EMG, electromyogram. Source: Ref. 29.

CHAPTER 2: Entrapment Neuropathies of the Upper Extremity   19

prolonged wrist extension (32). Handlebar palsy, described in bicycle and motorcycle riders, usually results in an isolated deep motor branch lesion (33). In cases where a structural lesion is identified, surgical removal is recommended. In unusual or severe cases, surgical exploration may be considered even if imaging studies fail to identify a structural lesion.

Radial Neuropathy Focal neuropathies of the radial nerve occur less often than those involving the median and ulnar nerves. The main trunk of the radial nerve may be injured at the axilla or upper third of the arm, the spiral groove of the humerus, or the elbow (21). Anatomy The radial nerve receives fibers from all 3 trunks of the brachial plexus and the C5 throughT1 roots. The posterior divisions of the upper, middle, and lower trunks unite to form the posterior cord, which subsequently gives off the radial nerve. The radial nerve exits the lateral wall of the axilla and travels distally through the proximal arm just medial to the humerus. Figure 2.3 diagrams the course of the median nerve. Proximally, 3 sensory nerves—the posterior cutaneous nerve of the arm, the lower lateral cutaneous nerve of the arm, and the posterior cutaneous nerve of the forearm—arise from the radial nerve providing sensation over the posterolateral portions of the arm, as well as a small strip along the middle posterior aspect of the forearm. Muscular branches are then given to the long, lateral, and medial triceps muscles, as well as the anconeus muscle. Moving distally, the radial nerve wraps around the humerus, traveling in the spiral groove, before giving off additional branches to the supinator, long head of the extensor carpi radialis, and brachioradialis muscles. A few centimeters distal to the lateral epicondyle, the radial nerve divides into the superficial radial sensory nerve and the posterior interosseous nerve. The superficial radial sensory nerve travels distally along the radius providing sensation over the dorsolateral hand and proximal portions of the dorsal aspect of the thumb and index, middle, and ring fingers. The posterior interosseous nerve travels through the supinator muscle passing under the arcade of Frohse. The posterior interosseous nerve supplies muscular branches to the short head of the extensor carpi radialis, extensor digitorum communis, extensor carpi ulnaris, abductor pollicis longus, EIP, extensor pollicis longus, and extensor pollicis brevis muscles (1,2,21,34). A. Radial neuropathy at the axilla This entrapment results from prolonged compression of the nerve as it courses through the axilla. A common presentation is the patient who uses crutches incorrectly, resulting in prolonged pressure to the axillary region. Because the lesion occurs proximal to muscular

Radial n.

C5

Post cut n. of arm Lower lat.cut.n.of arm Post cut n. of forearm Triceps Post.interosseous n.

Triceps & anconeus Brachioradials Extensor carpi radialis longus Extensor carpi radialis brevis Supinator Extensor digitorum Extensor digit quinti Extensor carpi ulnaris Abductor pollicis longus Extensor pollicis longus & brevis

Cutaneous innervation

Extensor indicis

Dorsal digital n’s. Ant.

Post.

Figure 2.3 Anatomical Course and Cutaneous Innervation of the Radial Nerve. Reprinted from Haymaker W, Woodhall B, Peripheral Nerve Injuries, 2nd ed. Philadelphia: WB Saunders, 1953 (4). branches supplying the triceps muscle group, the clinical presentation is similar to radial neuropathy at the spiral groove; however, the triceps muscle is also weak. Additionally, sensory disturbance extending into the posterior arm and forearm due to compression of the posterior cutaneous sensory nerves of the forearm and arm is commonly seen. Triceps and brachioradialis reflexes may be reduced (1,21). B. Radial neuropathy at the spiral groove This is the most common site of radial nerve injury and occurs in patients who have draped their arm over a chair or bench during deep sleep or intoxication (“Saturday night palsy”). It has also been reported after strenuous muscular effort, fracture of the humerus, or infarction from vasculitis (1). Patients with this particular entrapment typically present with wrist and finger drop, in combination with decreased sensation over the posterolateral hand in the distribution of the superficial radial sensory nerve. Patients could have weakness of

20  Textbook of Peripheral Neuropathy

supination and/or elbow flexion (mild) depending on the degree of supinator and brachioradialis involvement; however, elbow extension (triceps muscle) will be spared (1,21). C. Posterior interosseous neuropathy In this condition, patients also present with wrist drop; however, there are several distinct features of this particular entrapment that distinguish it from lesions at the spiral groove. With a posterior interosseous neuropathy (PIN), entrapment usually occurs at the arcade of Frohse. In a PIN, there is sparing of radial-innervated muscles proximal to the takeoff of the posterior interosseous nerve (triceps, anconeus, brachioradialis, and long head of the extensor carpi radialis muscles). When the patient extends the wrist, he or she may do so weakly, and with radial deviation. This occurs because the extensor carpi ulnaris is weak but the extensor carpi radialis is preserved. These patients typically do not experience cutaneous sensory deficits. Patients, however, may complain of forearm pain, which results from dysfunction of the deep sensory fibers of the posterior interosseous nerve that supply the interosseous membrane and joint capsule (1,2,21). D. Superficial radial sensory neuropathy In the forearm, the superficial radial sensory nerve travels subcutaneously next to the radius. Its superficial location makes it susceptible to compression. Sensory disturbances occur over the dorsolateral surface of the hand and the proximal dorsal portions of the fingers. Various objects such as tight fitting bands, watches, bracelets, or handcuffs may lead to a superficial radial neuropathy. As this is a pure sensory neuropathy, these patients do not develop weakness (1,2). Differential Diagnosis of Wrist Drop The differential diagnosis of a wrist drop should include the various radial nerve lesions discussed above (Table 2.14). In addition, more proximal lesions such as a posterior cord brachial plexopathy, a C7 through C8 radiculopathy, or even a central lesion should be con­ sidered. A careful clinical examination can usually localize the lesion causing wrist drop.

Electrophysiology The electrodiagnostic study should identify the presence of a radial neuropathy and properly localize the level of dysfunction. A radial motor study should be performed and compared with the contralateral side. A protocol outlining a reasonable electrodiagnostic approach to evaluating radial neuropathy is outlined in Table 2.15. Needle examination should focus on localizing the lesion. Typically, one should examine at least 2 PIN-innervated muscles (eg, EIP, extensor carpi ulnaris, extensor digitorum communis muscles); 2 radial-innervated muscles that are proximal to the PIN but distal to the spiral groove (eg, long head of extensor carpi radialis, brachioradialis); 2 nonradial nerve, C7-innervated muscles (eg, PT, FPL, FCR, cervical paraspinal muscles); 1 radial-innervated muscle proximal to the spiral groove (eg, triceps muscle); and 1 nonradial, posterior cordinnervated muscle (eg, deltoid) (1). Table 2.16 summarizes the different electrophysiologic abnormalities that may be encountered. Imaging Studies Visualization of the superficial radial nerve can be achieved by using high-resolution sonography. Occasionally, plain radiographs of the elbow region or the humeral area are indicated to determine if any mass or bony lesions (eg, fractures, osteophytes, callus formations) are compressing the nerve. Magnetic resonance imaging is helpful for evaluating soft tissue lesions and provides more direct imaging of the nerve. Treatment Therapy is dependent on the site and cause of the lesion. When the lesion is due to external compression at the spiral groove, removing the source of the compression and conservative management are indicated. Physical therapy and wrist splinting can assist in reestablishing functional use of the hand. If the lesion is due to a humeral fracture, the fracture must be carefully reduced to avoid further injury (35). This may require external fixation. If no recovery is noted within several months, then exploration with possible surgical reanastomosis may be indicated. With posterior interosseous neurop-

Table 2.14  Potential Causes of Radial Neuropathy A. Traumatic causes 1. Fractures (eg, humerus, radius, ulna) 2. Penetrating or blunt trauma without fracture or subluxation 3. Slashing or gunshot wounds B. Nontraumatic causes 1. External compression 2. Idiopathic 3. Lead intoxication 4. Hereditary neuropathy with liability to pressure palsies

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Table 2.15  Electrodiagnostic Evaluation of Radial Neuropathy) A. Nerve conduction studies 1. Radial nerve studies a. Radial motor study stimulating at the forearm and elbow, below spiral groove, and above spiral groove sites while recording from EIP muscle. Bilateral studies are necessary if abnormal or if conduction block is not present. b. Superficial radial sensory study—Stimulate at the forearm while recording over the extensor tendons of the thumb. Bilateral studies are recommended. 2. Median nerve studies a. Median motor study stimulating at the wrist and below elbow sites while recording from the APB muscle b. Median sensory study stimulating at the wrist while recording from the index finger c. Median F-wave responses 3. Ulnar nerve studies a. Ulnar motor study, stimulating at the wrist, below elbow, and above elbow sites, while recording from the ADM muscle b. Ulnar F-wave responses c. Ulnar sensory study stimulating at the wrist while recording from the fifth digit B. Electromyography 1. At least 2 PIN-innervated muscles (eg, EIP, extensor carpi ulnaris, EDC) 2. At least 2 radial-innervated muscles proximal to the PIN but distal to the spiral groove (eg, brachioradialis, long head of ECR) 3. At least 1 radial-innervated muscle proximal to the spiral groove (eg, triceps) 4. At least 1 nonradial, posterior cord-innervated muscle (eg, deltoid) 5. At least 2 nonradial C7-innervated muscles (eg, FCR, PT, FPL, cervical paraspinal muscles) Abbreviations: ECR, extensor carpi radialis; PIN, posterior interosseous neuropathy. Source: Ref. 1. Table 2.16  Electrodiagnostic Findings in Radial Neuropathy A. Posterior interosseous neuropathy 1. Nerve conduction studies—Superficial radial sensory response is normal. Radial motor study may show lowamplitude response (if axonal) or conduction block at the elbow (if demyelinating). 2. EMG—Denervation in the EIP, extensor digitorum communis, and extensor carpi ulnaris muscles B. Radial neuropathy at the spiral groove 1. Nerve conduction studies—Superficial radial sensory response is low (if axonal). Radial motor study may show lowamplitude response (if axonal) or conduction block at the spiral groove (if demyelinating). 2. EMG—Denervation as in PIN plus long head of ECR, brachioradialis, and supinator muscles C. Radial neuropathy at the axilla 1. Nerve conduction studies—Superficial radial sensory response is low (if axonal). Radial motor study may show lowamplitude response (if axonal). 2. EMG—Denervation as in spiral groove, plus triceps muscle D. Posterior cord brachial plexopathy 1. Nerve conduction studies—Superficial radial sensory response is low (if axonal). Radial motor study may show lowamplitude response (if axonal). 2. EMG—Denervation as in axilla, plus deltoid, and latissimus dorsi muscles E. C7 Radiculopathy 1. Nerve conduction studies—Radial motor study may show low-amplitude response (if axonal). 2. EMG—Denervation as in axilla, plus FCR and cervical paraspinal muscles, but sparing the brachioradialis and supinator muscles Source: Ref. 1.

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athies, repetitive supination of the forearm should be avoided. In distal radial sensory nerve lesions, management is typically conservative.

OTHER FOCAL MONONEUROPATHIES OF THE UPPER EXTREMITY Suprascapular Neuropathy Suprascapular neuropathy is an uncommon cause of shoulder pain and weakness and may be overlooked (Table 2.17). The suprascapular nerve is vulnerable to compression at the suprascapular notch as it travels under the transverse scapular ligament. Less frequently, the nerve can be entrapped distally at the spinoglenoid notch. Shoulder pain is typically deep and boring and occurs along the superior aspect of the scapula, with radiation into the shoulder. The pain may be exacerbated by adduction of the extended arm (1,2,36). Patients may demonstrate weakness of shoulder abduction (supraspinatus) and external rotation (infraspinatus). Atrophy may be present in severe cases. If the nerve is entrapped distally at the spinoglenoid notch, the deficit will be limited to the infraspinatus muscle. In such a case, pain is usually absent, as the deep sensory fibers to the shoulder joint arise proximal to the l­esion (1). Various conditions that may mimic this entrapment syndrome include the following: subacromial impingement syndrome, C5 through C6 radiculopathy, upper trunk brachial plexopathy, rotator cuff injury, and other orthopedic conditions of the shoulder. In rare cases, a focal suprascapular neuropathy may be the primary manifestation of a more diffuse autoimmune-mediated brachial plexopathy (neuralgic amyotrophy) (1,36). Electrodiagnostic studies should identify involvement of suprascapular-innervated muscles and exclude other causes. Results of routine nerve conduction studies of the upper extremity should be normal. Motor studies of the suprascapular nerve can be performed, but they require careful technique and are not commonly performed. Compound muscle action potentials

may be recorded using a monopolar needle electrode placed in the spinatus muscles while stimulating over the Erb point (1). Needle examination is very useful and will help identify abnormalities limited to the spinatus muscles, thus supporting the diagnosis of suprascapular neuropathy. Magnetic resonance imaging of the shoulder is usually recommended to exclude a ganglion cyst causing compression of the nerve (36). Treatment In the absence of a space-occupying lesion, treatment is conservative and includes rest, physical therapy, and nonsteroidal antiinflammatory drugs. Nerve entrapment at the suprascapular notch that does not respond to conservative management can benefit from transverse scapular ligament release (37). Extrinsic nerve compression at the spinoglenoid notch, secondary to ganglion cyst impingement, includes a period of nonoperative therapy. Patients who fail conservative management should undergo surgical cyst excision or decompression (38).

Axillary Neuropathy The axillary nerve originates from the posterior cord of the brachial plexus. Axillary nerve injury (Table 2.18) typically occurs in the setting of trauma (dislocation of the shoulder or fracture of the humerus). The most common site of injury is just proximal to the quadrilateral space, defined as the anatomical space formed by the humerus, teres major, teres minor, and long head of the triceps muscles (34). Nontraumatic causes include brachial neuritis and quadrilateral space syndrome. Clinically, patients have a well-demarcated “patch” of numbness along the lateral aspect of the shoulder with weakness of shoulder abduction (deltoid) and external rotation (teres minor). The differential diagnosis is sim­ ilar to that of a suprascapular neuropathy. Results of routine nerve conduction studies are again normal. Motor study of the axillary nerve can be performed, but it requires careful technique and can be painful. Axillary motor studies are rarely performed, as the needle examination is more sensitive. With axillary nerve injury, ab-

Table 2.17  Differential Diagnosis of Suprascapular Neuropathies Entrapment - Suprascapular notch - Spinoglenoid notch Subacromial impingement syndrome C5 through C6 radiculopathy Upper trunk brachial plexopathy Rotator cuff injury Other orthopedic conditions of the shoulder Autoimmune-mediated brachial plexopathy (neuralgic amyotrophy)

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Table 2.18  Axillary Neuropathy Differential Diagnosis - Trauma (eg, dislocation of the shoulder, fracture of the humerus) - Quadrilateral space syndrome - Subacromial impingement syndrome - C5 through C6 radiculopathy - Upper trunk brachial plexopathy - Rotator cuff injury - Other orthopedic conditions of the shoulder - Autoimmune-mediated brachial plexopathy (neuralgic amyotrophy) Clinical Features - Sensory deficit (patchy) along the lateral aspect of the shoulder - Weakness of shoulder abduction (deltoid) - Weakness of external rotation (teres minor) - Normal strength of other C5/6-innervated muscles (eg, biceps, brachioradialis, spinatus) - Normal sensation over the C5/6 dermatome as well as the radial, median, and ulnar nerve territories

normalities in the result of needle examination should be seen only in the deltoid and teres minor muscles. All other C5/6-innervated muscles (eg, supraspinatus, infraspinatus, brachioradialis, biceps brachii) should be normal (1).

Long Thoracic Neuropathy The long thoracic nerve (LTN) arises directly from the C5, C6, and C7 nerve roots proximal to the brachial plexus. The nerve supplies the serratus anterior muscle exclusively. Table 2.19 summarizes the most common causes and findings in patients with LTN. Patients will exhibit scapular winging with their arms outstretched. In patients with neuralgic amyotrophy, the serratus

anterior can be weak owing to dysfunction of nerve fibers emanating from the brachial plexus and coursing through the LTN. Dysfunction of the LTN can also result from traumatic injuries that cause widespread damage to multiple cervical nerve roots. Another cause is inadequate intraoperative positioning of a surgical patient with longstanding compression of the neck and shoulder regions while sedated. Onset can sometimes be traced to a single traumatic event, or winging can develop more slowly owing to repetitive heavy lifting or overhead movements. The common pathway of injury seems to be physical compression of the nerve by the fibers of the middle scalene muscle. Isolated cases of long thoracic neuropathy are rare. For this reason, electrodiagnostic studies in suspected LTN should be performed

Table 2.19 Long Thoracic Neuropathies Differential Diagnosis - Trauma - Autoimmune-mediated brachial plexopathy (neuralgic amyotrophy) - Radiculopathies involving levels C5 through C7 - Upper +/– middle trunk brachial plexopathy—compressive - Repetitive heavy overhead lifting - Other orthopedic conditions of the shoulder - Compression by scalene muscles Clinical Features - Scapular winging - Scapular pain - Normal strength of other C5 through C7–innervated muscles (eg, biceps, spinatus, triceps) - Normal sensation over the C5 through C7 dermatomes as well as the radial, median, and ulnar nerve territories - Normal biceps and triceps reflexes

24  Textbook of Peripheral Neuropathy

Table 2.20  Musculocutaneous Neuropathy Differential Diagnosis - Trauma Dislocation of the shoulder Fracture of the humerus - C5 through C6 radiculopathy - Upper trunk or lateral cord brachial plexopathy - Other orthopedic conditions of the shoulder and arm - Autoimmune-mediated brachial plexopathy (neuralgic amyotrophy) Clinical Features - Sensory deficit along the lateral aspect of the volar forearm - Weakness of elbow flexion (biceps) - Absent bicep deep tendon reflex - Normal strength of other C5/6-innervated muscles (eg, brachioradialis, spinatus) - Normal sensation over the C5/6 dermatome as well as the radial, median, and ulnar nerve territories

and expanded to exclude a more widespread process. Decompression and microneurolysis of the LTN has been shown to be an effective solution for scapular winging caused by nerve injury (39).

Musculocutaneous Neuropathy The musculocutaneous nerve arises from the lateral cord of the brachial plexus and contains fibers primarily from the C5 and C6 nerve roots. Isolated musculocutaneous neuropathies are rare; however, when they are seen, they are most commonly the result of widespread trauma to the shoulder and arm. Patients will have weakness of elbow flexion, sensory loss over the lateral forearm (lateral antebrachial cutaneous nerve), and an absent biceps reflex. Table 2.20 summarizes the most common causes and findings in patients with musculocutaneous neuropathies. Electrodiagnostic testing should localize the lesion to this nerve, thus excluding a brachial plexopathy or cervical radiculopathy. The lateral antebrachial cutaneous sensory study should demonstrate reduced or absent amplitude when compared

to the contralateral side. Motor study of the musculocutaneous nerve can be performed, but careful technical skill is required to ensure accuracy of the result. Needle examination should demonstrate abnormalities in the biceps, brachialis, and coracobrachialis muscles (1).

Spinal Accessory Neuropathy Isolated lesions of this nerve occur in the region of the posterior cervical triangle and most commonly result in isolated weakness of the trapezius muscle. If the lesion is more proximal, however, there may be weakness of the sternocleidomastoid muscle as well. Stretch injuries may occur, but usually, this neuropathy is seen as a complication of head and neck surgical procedures. Patients may have shoulder drop due to weakness of the trapezius muscle. Table 2.20 summarizes the more common causes and findings in patients with spinal accessory neuropathies. The needle examination provides the greatest utility with this type of entrapment syndrome. Results of routine nerve conduction studies of the upper extremity should be normal. A careful needle examina-

Table 2.21  Spinal Accessory Neuropathy Differential Diagnosis - Traction injuries - Head/neck surgical procedures in the region of the posterior cervical triangle - Upper trunk brachial plexopathy Clinical Features - Weakness of the trapezius muscle - Weakness (less common) of sternocleidomastoid muscle with proximal lesions - Shoulder drop - Normal strength and sensation otherwise

CHAPTER 2: Entrapment Neuropathies of the Upper Extremity   25

tion should isolate any abnormalities to the trapezius and possibly the sternocleidomastoid muscles, thus excluding a brachial plexus injury.

References 1. Preston DC, Shapiro BE. Electromyography and Neuromuscular Disorders: Clinical-Electrophysiologic Correlations. 2nd ed. Philadelphia, PA: Elsevier, Butterworth-Heinemann; 2005. 2. Ellis H, Standring S, Gray HD. Gray’s Anatomy: The Anatomical Basis of Clinical Practice. St. Louis, MO: Elsevier, Churchill Livingstone; 2005. 3. Gross PT, Tolomeo EA. Proximal median neuropathies. Neurol Clin. 1999;17(3):425–445. 4. Haymaker W, Woodhall B. Peripheral Nerve Injuries: Principles of Diagnosis. 2nd ed. Philadelphia, PA: W.B. Saunders; 1953. 5. Preston DC. Distal median neuropathies. Neurol Clin. 1999;17(3):407–424. 6. Preston DC, Logigian EL. Lumbrical and interossei recording in carpal tunnel syndrome. Muscle Nerve. 1992;15: 1253–1257. 7. American Association of Electrodiagnostic Medicine. Practice parameter for electrodiagnostic studies in carpal tunnel syndrome: summary statement. Muscle Nerve. 2002;25: 918–922. 8. Preston DC, Ross MH, Kothari MJ, et al. The median-ulnar latency difference studies are comparable in mild carpal tunnel syndrome. Muscle Nerve. 1994;17:1469–1471. 9. Moran L, Perez M, Esteban A, Bellon J, Arranz B, del Cerro M. Sonographic measurement of cross-sectional area of the median nerve in the diagnosis of carpal tunnel syndrome: correlation with nerve conduction studies. J Clin Ultrasound. 2009;37(3):125–31. 10. Scott KR, Kothari MJ. Non-surgical treatment of carpal tunnel syndrome. In: Rose BD, ed. UpToDate. Wellesley, MA; Wolters Kluwer Health, 2005. 11. Clarke AM, Stanley D. Prediction of the outcome 24 hours after carpal tunnel decompression. J Hand Surg (Br). 1993;18:180–181. 12. Mondelli M, Morana P, Ballerini M, Rossi S, Gianni F. Mononeuropathies of the radial nerve: clinical and neurographic findings in 91 consecutive cases. J Electromyogr Kinesiol. 2005;15:377–383. 13. Dang AC, Rodner CM. Unusual compression neuropathies of the forearm, part 2: median nerve. J Hand Surg Am. 2009;34:(10):1915–1920. 14. Gross PT, Tolomeo EA. Proximal median neuropathies. Neurol Clin. 1999;17(3):425–445. 15. Fricker R, Fuhr P, Pippert H, et al. Acute median nerve compression at the distal forearm caused by a thrombosed aneurysm of an epineural vessel: case report. Neurosurgery. 1996;38(1):194–196. 16. Ginn SD, Cartwright MS, Chloros GD, et al. Ultrasound in the diagnosis of a median neuropathy in the forearm: case report. J Brachial Plex Peripher Nerve Inj. 2007;2:23. 17. Trumble TE, Budoff JE. Hand Surgery Update IV. Rosemont, IL: American Society for Surgery of the Hand; 2007. 18. Rennels GD, Ochoa J. Neuralgic amyotrophy manifesting as anterior interosseous nerve palsy. Muscle Nerve. 1980;3: 160–164.

19. Bradshaw DY, Shefner JM. Ulnar neuropathy at the elbow. Neurol Clin. 1999;17(3):447–461. 20. Stewart JD. The variable clinical manifestations of ulnar neuropathies at the elbow. J Neurol Neurosurg Psychiatry. 1987;50:252–258. 21. Carlson N, Logigian EL. Radial neuropathy. Neurol Clin. 1999;17(3):499–523. 22. Novak CB, Lee GW, MacKinnon SE, et al. Provocative testing for cubital tunnel syndrome. J Hand Surg. 1994;19A:817–820. 23. Kothari MJ, Preston DC. Comparison of the flexed and e­xtended elbow positions in localizing ulnar neuropathy at the elbow. Muscle Nerve. 1995;18:336–340. 24. AANEM. Practice parameter for electrodiagnostic studies in ulnar neuropathy at the elbow. In: Guidelines in Electrodiagnostic Medicine. Rochester, MN: American Association of Electrodiagnostic Medicine. http://www.aanem.org/ documents/UlnarNeur.pdf. 25. Campbell WW, Pridgeon RM, Sahni SK. Short segment incremental studies in the evaluation of ulnar neuropathy at the elbow. Muscle Nerve. 1992;15:1050–1054. 26. Kothari MJ, Heistand M, Rutkove SB. Three ulnar nerve conduction studies in patients with ulnar neuropathy at the elbow. Arch Phys Med Rehab. 1998;79:87–89. 27. Elhassan B, Steinmann SP. Entrapment neuropathy of the ulnar nerve. J Am Acad Orthop Surg. 2007;15:672–681. 28. Macadam RA, Gandhi R, Bezuhly M, Lefaivre KA. J Hand Surg. 2008;23(8):1314.e1–1314.e12. 29. Wu JS, Morris JD, Hogan GR. Ulnar neuropathy at the wrist. Case report and review of the literature. Arch Phys Med Rehab. 1985;66:785–788. 30. Kothari MJ. Ulnar neuropathy at the wrist. Neurol Clin. 1999;17(3):463–476. 31. Shea JD, McClain EJ. Ulnar-nerve compression syndrome at and below the wrist. J Bone Joint Surg. 1969;51A:1095– 1103. 32. Murata K, Shih JT, Tsai TM. Causes of ulnar tunnel syndrome: a retrospective study of 31 subjects. J Hand Surg (Am). 2003;28(4):647–651. 33. Capitani D, Beer S. Handlebar palsy—a compression syndrome of the deep terminal (motor) branch of the ulnar nerve in biking. J Neurol. 2002;249(10):1441–1445. 34. Wheeless CR. Wheeless’ Textbook of Orthopaedics. 2009. http://www.wheelessonline.com/ortho. 35. Bumbasirevic M, Lesic A, Bumbasirevic V, Cobeljic G, Milosevic I, Atkinson HD. The management of humeral shaft fractures with associated radial nerve palsy: a review of 117 cases. Arch Orthop Trauma Surg. 2009;August 11. 36. Goslin KL, Krivickas LS. Proximal neuropathies of the upper extremity. Neurol Clin. 1999;17(3):525–548. 37. Romeo AA, Rotenberg DD, Bach BR. Suprascapular neuropathy. J Am Acad Orthop Surg. 1999;7:358–67. 38. Piatt BE, Hawkins RJ, Fritz RC, Ho CP, Wolf E, Schickendantz M. Clinical evaluation and treatment of spinoglenoid notch ganglion cysts. J Shoulder Elbow Surg. 2002;11: 600–4. 39. Disa JJ, Wang B, Dellon AL. Correction of scapular winging by supraclavicular neurolysis of the long thoracic nerve. J Reconstr Microsurg. 2001; 17(2):79–84.

3

Peter D. Donofrio

Common Mononeuropathies of the Lower Extremities

Introduction

Clinically, patients with iliohypogastric neuropathy complain of pain and sensory loss in the groin and the suprapubic area. Etiologies for iliohypogastric mono­ neuropathy include trauma from pelvic and gynecologic surgery (1,2), herniorrhaphy (3), and laparoscopy (4).

A mononeuropathy by definition affects a single nerve, usually in the upper or lower extremity, but can involve nerves in the chest, abdomen, and cranial distribution. Mononeuropathies are more common in the upper limb, as described in the previous chapter. Neverthe­ less, mononeuropathies of the lower extremity are fre­ quent enough presentations to physicians in primary care, neurology, neurosurgery, and physiatry to require knowledge of their manifestations. As is true of any pe­ ripheral nerve process, the diagnosis of a specific neu­ ropathy is not difficult if the clinician has a good grasp of neuroanatomy. Most mononeuropathies of the legs cause pain and impairment of gait, so they lead to sig­ nificant disability for the patient. This chapter will dis­ cuss in detail only common mononeuropathies and will make brief mention of less common affectations. Injuries to the proximal lower extremity include the rare and difficult to diagnose, iliohypogastric, ilioingui­ nal, and the genitofemoral neuropathies, and the more common, lateral femoral cutaneous, femoral, and obtu­ rator neuropathies. Distal mononeuropathies of the legs include the less common sural and saphenous neuropa­ thies and the more common peroneal, sciatic, deep pero­ neal, and superficial peroneal. This chapter will not review the topics of tarsal tunnel syndrome or mononeuropathies of the foot interdigital nerves.

Ilioinguinal Nerve The ilioinguinal nerve comes off the anterior ramus of the L1 root at the point where the iliohypogastric nerve begins. Its muscular branches also innervate the internal oblique and transverse muscles. It eventually courses along the inguinal ligament within the inguinal canal and penetrates the external spermatic fascia. Sensory branches innervate the anterior abdominal wall, the penis, the upper part of the scrotum, the upper thigh medial to the femoral triangle, and a strip of skin over­ lying the inguinal ligament. Patients with this condition commonly complain of pain in the groin area and ra­ diation of the pain to the proximal inner surface of the groin. The ilioinguinal nerve can be injured during an inguinal herniorrhaphy or as a result of adhesions de­ veloping during the healing process (5). Other condi­ tions that give rise to ilioinguinal mononeuropathy are pelvic and gynecologic surgery (1,6), mesh entrapment herniorrhaphy (7), laparoscopy (4), nephrectomy (6), pregnancy (6), and removal of bone from the inner table of the iliac crest (8).

Genitofemoral Nerve

Iliohypogastric Nerve

The genitofemoral nerve begins from the undivided rami of the L1 and L2 roots. It penetrates the iliopsoas muscle and follows the common and external iliac arter­ ies. At the level of the inguinal ligament, it divides into the genital and femoral branches. The genital branch en­ ters the deep inguinal ring and terminates in the cremas­ teric muscle and the skin of the scrotum and the adjacent thigh. The femoral branch descends below the middle of the inguinal ligament and supplies sensation over the

The iliohypogastric nerve arises from the anterior pri­ mary ramus of the L1 root. After traversing the psoas major muscle, it reaches the iliac crest and terminates in the pubis. Muscular branches innervate the internal oblique muscle and transverse muscle of the abdominal wall. Sensory branches are the lateral cutaneous to the upper and lateral aspect of the gluteal region and the an­ terior cutaneous branch to the anterior abdominal wall. 27

28  Textbook of Peripheral Neuropathy

femoral triangle (upper anterior thigh). The clinical pre­ sentation of a genitofemoral mononeuropathy is usually neuropathic pain and sensory loss over the medial and inferior region of the groin and the upper anterior me­ dial thigh. Causes of genitofemoral mononeuropathies are pelvic and gynecologic surgery and endoscopic herniorrhaphies (1,2,9). In some patients, no cause is found (10).

Lateral Femoral Cutaneous Nerve This sensory nerve is created by the union of fibers from the undivided rami of L2 and L3. Similar to the nerves discussed above, it penetrates the iliopsoas major mus­ cle, moves to the latter region of the inguinal ligament, and passes between the 2 prongs where the inguinal ligament attaches to the iliac bone. It divides into the an­ terior branch, which innervates the skin over the lateral aspect of the anterior thigh as far down as the knee, and the posterior branch, which innervates the lateral region of the upper two thirds of the thigh as well as the lateral aspect of the buttock below the greater trochanter. Injury to the lateral femoral cutaneous nerve is not uncommon, and its frequency relates to its propensity to be entrapped when the nerve passes between the 2 prongs where the inguinal ligament attaches to the iliac bone. Injury is seen in patients who wear tight clothing

Table 3.1 Lateral Femoral Cutaneous Mononeuropathy Etiologies Cardiac catheterization of femoral artery (29,64) Diabetes (12) Femoral acetabular impingement (65) Hemangiomatosis (65) Iliac bone graft harvesting (66) Ilioinguinal/Iliohypogastric nerve block (1) Intramuscular injection (67) Kidney transplantation (68) Laparoscopic radical prostatectomy and cystectomy (69) Lipoma (70) Low-cut tight trousers (11) Lumbar spine surgery (71) Migrating opiate pump (72) Military body armor (73) Obesity (12) Pelvic and abdominal surgery (13,74,75) Pelvic mass (76) Pregnancy (77) Prolonged lateral positioning (78) Prone positioning after surgery (79,80) Strenuous exercise (80) Surgical lithotomy positioning (27) Total hip arthroplasty (81)

2 3 4 Iliacus

Femoral n.

Quadriceps: Rectus femoris Vastus lateralis

Pectineus Sartorius

Vastus medialis Vastus intermedius

Medial cutaneous n. of thigh Intermediate cutaneous n. of thigh Saphenous n. Infrapatellar branch Terminal branch

Cutaneous distribution from anterior aspect

Cutaneous distribution from medial aspect

Figure 3.1 The Course and Distribution of the Femoral Nerve. The motor course and innervations are shown in black, and the cutaneous innervations are shown in gray. Reprinted from Haymaker W, Woodhall B. Peripheral Nerve Injuries, Principles of Diagnosis. 2nd ed. Philadelphia, PA: WB Saunders Co.; 1953. (11), are diabetic (12), are obese (12), or have sustained trauma to the lateral inguinal ligament area (13). A lat­ eral femoral cutaneous neuropathy can also be seen in conditions that cause chronic tilting of the pelvis and fractures of the anterior portion of the ilium. Patients with a lateral femoral cutaneous neuropathy or meralgia paresthetica, as it is commonly called, present with par­ esthesia, numbness, and burning pain in the sensory dis­ tribution described above. Table 3.1 lists disorders that can produce a lateral femoral cutaneous neuropathy.

Femoral Nerve Roots L2, L3, and L4 give rise to the femoral nerve. Af­ ter passing through the iliopsoas muscle, it descends

CHAPTER 3: Common Mononeuropathies of the Lower Extremities   29

under the inguinal ligament, just lateral to the femoral artery, and enters the thigh, where it gives off the sa­ phenous nerve, which renders sensation from the ante­ rior and medial aspect of the thigh and the medial shin to the inner aspect of the foot. The motor fibers of the femoral nerve innervate the iliacus muscle in the abdo­ men, the sartorius and pectineus muscles in the upper thigh, and the muscles of the anterior thigh, called the quadriceps muscles or muscle group. The latter consists of the vastus medialis, intermedialis, and lateralis, and the rectus femoris. The femoral nerve gives rise to the anterior cutaneous branches of the front of the thigh. Figure 3.1 shows the origin, path, and innervations of the femoral nerve. The motor dysfunction produced by femoral nerve injuries depends on the location of the nerve injury. Lesions in the abdomen can cause profound weakness of hip flexion, whereas lesions at the level of the ingui­ nal ligament will spare hip flexion but affect knee exten­ sion. Patients with femoral nerve injuries typically have difficulty extending the knee when sitting and when the knee is held at 90º to the direction of the femur. Once extension is initiated actively or passively, the patient is often able to fully extend the leg and lock the leg in full extension. This locking of the knee allows patients with femoral neuropathy to walk straight-legged. Be­ cause of this select weakness of the quadriceps muscle group, patients often have an easier time climbing stairs than descending. In the latter situation, the instability of the knee may result in a collapse of the knee and loss of balance. Patients with femoral neuropathy often have

Table 3.2 Manifestations of Femoral and Obturator Mononeuropathies Femoral Motor (weakness) Hip flexor (high pelvic pathology) Knee extension Internal rotation of hip in knee flexion Adduction and internal rotation of hip Absent knee reflex Sensory loss and pain Lower anterior thigh Medial shin Obturator Motor (weakness) Adduction of thigh Flexion of knee Medial rotation of hip Flexion of hip (minor contribution) Sensory loss and pain Medial thigh (may be difficult to discern)

Table 3.3 Femoral Mononeuropathy: Etiologies Abdominal pelvic surgery (14,82) Amyloidosis (83) Blunt trauma (84) Coronary angiography (15) Femoral acetabular impingement (65) Femoral nerve block (85) Hydatid cyst (86) Iatrogenic (87,88) Ilioinguinal/Iliohypogastric nerve block (89) Laparoscopic surgery (90) Lithotomy positioning (91) Lymphomatous compression (92) Pelvic extraperitoneal hematoma (93) Postpartum (94) Psoas muscle hematoma (95) Renal failure (96) Renal transplantation (97) Retroperitoneal hematoma (16) Rhabdomyolysis (98) Total hip arthroplasty (99) Urologic surgery (100,101) Vasculitis (102)

profound atrophy of the quadriceps muscle group, loss of knee reflex, and loss or impaired sensation over the anterior and medial aspect of the thigh and the medial region of the shin to the foot. Most commonly, the femo­ ral nerve is injured partially and below the branch to the iliopsoas muscle. Table 3.2 lists the most common clini­ cal manifestations of a femoral mononeuropathy (and obturator mononeuropathy). Etiologies for femoral neuropathy include injury from abdominal surgery (14), abdominal retractors used during surgery, vaginal hysterectomies, gunshot wounds, femoral artery catheterizations (15), retroperi­ toneal and groin hematomas (16), and pelvic fractures. A list of causes for a femoral neuropathy can be found in Table 3.3.

Saphenous Nerve The saphenous nerve is the termination of the femoral nerve and is populated by sensory fibers that compose the infrapatellar branch and the descending branch of the nerve subserving sensation over the medial aspect of the shin. Injuries of the saphenous nerve can arise from direct trauma causing angulatory and torsional forces (17,18), surgery for varicose veins, harvesting of super­ ficial veins, lacerations, stretch injuries (19), popliteal aneurysm repair (20), arthroscopic meniscal repair (21), and bypass surgery in the femoral-popliteal region (22).

30  Textbook of Peripheral Neuropathy

Clinically, patients have sensory loss and pain over the medial aspect of the shin.

Obturator Nerve The obturator nerve is created by a union of roots L2, L3, and L4. Like other nerves arising from the lumbar roots, it penetrates the iliopsoas muscle and descends into the obturator foramen, where it divides into the an­ terior and posterior branches before descending into the medial aspect of the thigh. The obturator nerve does not give off branches in the pelvis. Its motor fibers innervate the adductor longus, brevis, and magnus; the gracilis; the obturator externus; and the pectineus muscle on oc­ casion. The nerve gives sensation to the medial aspect of the thigh. The motor fibers primarily function to adduct the thigh but also assist in flexion of the knee, medial L2

2

3

Lateral cutaneous n. of thigh

4

Obturator n.

Posterior Anterior

branch

Posterior branch

Anterior branch

Obturator externus Adductors: longus magnus brevis

Table 3.4 Obturator Mononeuropathy: Etiologies Acetabular labral cyst (103) Aneurysm of hypogastric artery (104) Caesarian section (105) Collagen injection (106) Diabetes (24) Femoral artery angioplasty (24,29) Forceps delivery (30) High-performance athletics (107) Hip arthroplasty (24) Idiopathic (24) Laparoscopic radical prostatectomy and cystectomy (69) Laparoscopic retroperitoneal surgery (26) Laparoscopic tubal occlusion (108) Lipomatosis infiltration (31) Lithotomy positioning (27) Local anesthesia (25) Metastatic disease to obturator canal (24) Myositis ossificans (24) Obturator hernia (109) Pelvic lymphadenectomy (110) Pelvic surgery (2,23,24) Pelvic trauma (24) Postpartum (111) Retroperitoneal hematoma (28) Ruptured abdominal aneurysm (112) Synovial cyst (113) Total hip arthroplasty (24) Total knee arthroplasty (24) Vaginal tapes (114)

Gracilis Cutaneous branch

Field of Lat.cut. n. of high

Cut.field of obturation n.

Figure 3.2 The Course and Distribution of the Obturator Nerve and the Lateral Femoral Cutaneous Nerve of the Thigh. The black innervations are motor from the obturator nerve, and the white innervations are sensory to the lateral femoral cutaneous nerve. The stippled area is the sensory innervation from the obturator nerve. Reprinted from Haymaker W, Woodhall B. Peripheral Nerve Injuries, Principles of Diagnosis. 2nd ed. Philadelphia, PA: WB Saunders Co.; 1953.

rotation of the tibia, flexing of the hip, and thigh outward rotation. The origin, pathway, and motor and sensory in­ nervation of the obturator nerve are shown in Figure 3.2. The major clinical findings of an obturator mononeu­ ropathy are listed in Table 3.2. Table 3.4 lists many of the etiologies for an obtura­ tor mononeuropathy. More common causes of this rare mononeuropathy include pelvic and gynecologic surgery (2,23,24), local anesthesia (25), laparoscopic surgery (26), lithotomy positioning (27), pelvic trauma (24), hematoma (28), and cardiac catheterization (29). Other causes are pel­ vic fractures (24), osteitis pubis, nerve trauma during for­ ceps delivery (30), and neoplastic infiltration of the nerve (31). The nerve is not traumatized frequently, because its inner location is a protection from outside trauma. The clinical manifestation of an obturator neuropathy is pain over the medial thigh and involuntary abduction of the thigh during walking. The degree of adduction weakness is not as severe as one would predict since the adductor magnus and the adductor longus assist in

CHAPTER 3: Common Mononeuropathies of the Lower Extremities   31

Sciatic n.

Hamstring muscles :

Adductor magnus

Semimembranosus Semitendinosus Biceps femoris (long head) Biceps femoris (short head) Tribial n. Posterior tribial n.

Distribution of planter n’s.

Common peroneal n.

Gastrocnemius Plantaris Soleus Popliteus Tibialis posterior Flexor digitorum longus Flexor hallucis longus

Post tibial n. Med calcanean n.

Lat.plantar n. Med plantar n.

Cutaneous distribution Plant digital n’s.

Sural n.

Figure 3.3 The Course and Distribution of the Sciatic Nerve and Its Branches to the Tibial, Posterior Tibial, and Sural Nerves. The motor course and innervations are shown in black, and the sural nerve cutaneous innervations are displayed in a stippled area. Reprinted from Haymaker W, Woodhall B. Peripheral Nerve Injuries, Principles of Diagnosis. 2nd ed. Philadelphia, PA: WB Saunders Co.; 1953. this movement and both receive innervation from other proximal nerves (the adductor magnus from the sciatic nerve and the adductor longus sometimes from the fem­ oral nerve). Loss of sensation is also not a severe as one might envision because of overlap of sensory innerva­ tion from other nerves in the region.

Sciatic Nerve The sciatic nerve is the largest and longest nerve in the human body. Its origin, pathway, divisions, and motor

and sensory innervations are shown in Figure 3.3. The sciatic nerve receives its origin from nerve roots L4, L5, S1, S2, and S3. The nerve in the pelvis and upper thigh appears to be a single nerve, but is composed of 2 large nerves, the tibial and common peroneal, and the smaller nerve to the hamstrings. In some patients, the nerve to the hamstrings arises separately from the nerve roots L4 through S3. The 3 nerves are encased by a firm sheath. Once it leaves the pelvis via the sciatic notch, the sciatic nerve proceeds under the pyriformis and gluteus maxi­ mus muscles, midway between the greater trochanter and the ischial tuberosity. After giving off its branches to the hamstring muscles in the upper posterior thigh and part of the adductor magnus, the nerve branches into the common peroneal and the tibial at a variable location above the popliteal fossa. The nerve to the hamstrings innervates the adductor magnus, the semimembrano­ sus, the semitendinosus, and the long head of the biceps femoris muscle. Once the sciatic nerve divides into the common peroneal and the tibial nerve, the common pero­ neal gives off its branch to the short head of the biceps femoris muscle. This arises above the popliteal fossa. The sciatic nerve can be injured by many mechanisms, including gunshot and knife wounds (32). Other causes include fractures of the pelvis and femur and posterior dislocations of the hip (32), medially placed medication injections into or near the nerve (33,34), a fall in the sit­ ting position, compression of the sciatic nerve against the hard edge of a chair in thin patients, and compres­ sion by a tight pyriformis muscle. Almost regardless of the cause, the peroneal divi­ sion of the sciatic nerve is affected more than the tibial fibers. This is explained by the more superficial relation­ ship of the peroneal fibers, which are less protected from trauma, and the tighter fascicule architecture of the pero­ neal fibers compared with the looser composition of the tibial fibers. There is less connective tissue and fat in the peroneal fibers to cushion external trauma and pressure. Patients with sciatic mononeuropathies may initially

Table 3.5  Manifestations of Sciatic Mononeuropathy Motor (weakness) Hip flexion (if lesion above branches to hamstrings) Hip adduction Ankle dorsiflexion and plantar flexion Foot eversion and inversion Toe extension and flexion Loss of ankle reflex Sensory loss and pain Posterior lateral shin Lateral malleolus region Sole of foot

32  Textbook of Peripheral Neuropathy

Table 3.6 Sciatic Mononeuropathy: Etiologies Choristoma (115) Endometriosis (116) External compression (32) Femur fracture (32) Gunshot wound (32) Hematoma from anticoagulation (117) Hip arthroplasty (32) Hip fracture/dislocation (32) Idiopathic (32) Infarction (32) Intramuscular injection (34) Lipomatosis infiltration (118) Neurilemmoma (119) Trauma (120) Tumors (120) Uterine compression (121)

appear to manifest a common peroneal palsy because of the foot drop, but closer examination reveals involve­ ment of the tibial fibers below the knees and weakness of the hamstrings, even if the latter muscles show only mild weakness. The hamstrings may be strong if those muscles are innervated by a nerve to the hamstrings that arises directly from roots L5 and S1 and not as a branch of the sciatic nerve. In a sciatic neuropathy, the preserved function of the sartorius and gracilis produces some flex­ ion at the knee. In a sciatic neuropathy, sensation is di­ minished or lost below the knees except over the medial aspect where the skin is innervated by the saphenous nerve (branch of the femoral nerve). Sciatic mononeu­ ropathies can be difficult to differentiate from an L5, S1, and S2 radiculopathy. Table 3.5 lists the most common clinical manifestations of a sciatic mononeuropathy, and Table 3.6, etiologies for the same mononeuropathy.

Sural Nerve The sural nerve carries only sensory fibers and arises from anastomotic branches contributed by the common peroneal and tibial nerves. It gives sensation over the posterior-lateral shin and the lateral foot. It can be in­ jured by trauma (19,35) or surgery, or during diagnostic biopsy, prolonged dancing (36), high-intensity athletics (37), an os perineum fracture (38), solitary osteochon­ droma (39), and a Baker cyst (40).

Common Peroneal Nerve The common peroneal nerve begins above the popliteal fossa, courses down the back of the leg, and moves to the lateral aspect of the popliteal fossa, where it winds

and crosses the neck of the fibula. At that point, the nerve divides into the superficial and the deep pero­ neal nerves. The superficial peroneal nerve courses laterally down the shin, where it gives sensation to the anterior and lateral aspect of the shin and the dorsum of the foot except for the web space between digits 1 and 2. The superficial peroneal nerve also innervates the peroneal longus and brevis muscles. Figures 3.4 and 3.5 show the origin, pathway, and innervations of the common peroneal nerve and the deep and superfi­ cial peroneal nerves. The common peroneal nerve is the most commonly in­ jured nerve in the lower extremity, and this relates to its superficial position as it crosses the fibular head. It can be traumatized by gunshot wounds, stretching from a strong inversion of the foot, fibular fractures, tightly applied plaster casts, and tight boots worn for prolonged periods. Excessive and prolonged pressure from leg crossing par­ ticularly in patients with preexisting polyneuropathies (diabetes, alcohol abuse, vitamin deficiencies, inherited neuropathies) is a frequent cause of a common peroneal palsy at the fibular head. Other etiologies include pro­ longed squatting and long periods of lying on one side of the body, especially in thin patients (41). Patients with common peroneal palsies have weakness or cannot dorsiflex or evert the foot. They demonstrate a foot drop when walking, and their gait is often accompa­ nied by a slap of the foot, the sound made when the heel strikes the ground and the unopposed plantar flexors cause the foot to strike the ground firmly in the presence of weak dorsiflexors of the foot. The foot tends to invert when the patient is observed walking. At rest, the foot hangs down

Table 3.7  Manifestations of Common, Deep, and Superficial Mononeuropathies Common Peroneal Nerve Motor (weakness) Weakness of foot dorsiflexion and eversion Weakness of extension of toes Foot drop noted on walking Sensory loss and pain Anterior and lateral shin, sparing the lateral foot Deep Peroneal Nerve Motor (weakness) Weakness of foot dorsiflexion and extension of toes Sensory loss and pain Web space between digits 1 and 2 Superficial Peroneal Nerve Motor (weakness) Foot eversion Sensory loss and pain Lower anterior and lateral shin

CHAPTER 3: Common Mononeuropathies of the Lower Extremities   33

Table 3.8 Common Peroneal

Common peroneal n.

Mononeuropathy: Etiologies Childbirth (normal) (122) Chronic lymphatic leukemia (123) Compartment syndrome (124) Crohn disease (125) Dancing (36) Fibular bone tumors (126) Ganglion (127) Hyperthyroidism (128) Intermittent pneumatic compression (129) Intraneural mucoid pseudocyst (130) Intraneural perineurinoma (131) Ischemia (46) Knee dislocation (132,133) Liver transplantation (134) Orthopedic surgery (135) Plaster cast (136) Postcardiac surgery (137) Prolonged squatting (41) Rheumatoid arthritis (138) Sports injury (139) Tacrolimus (140) Weight loss (141)

and is inverted. Patients with common peroneal palsies cannot extend the toes. Sensory loss is present over the an­ terior lateral regions of the shin and the dorsum of the foot. This sensory loss is often subtle and may not be detected in all patients. Sometimes, the sensory loss may come as a surprise to the patient who does not volunteer sensory symptoms in the leg. Other patients complain of pain and numbness over the anterior and lateral aspect of the shin. The most common clinical features of a common, deep peroneal and superficial peroneal mononeuropathy are shown in Table 3.7. Table 3.8 lists common and rare etiolo­ gies for a common peroneal palsy.

Deep Peroneal Nerve The deep peroneal nerve begins below the fibular head and descends down the anterior part of the shin. It ducks under the superior extensor retinaculum and gives sensation over the lateral aspect of the great toe and the medial aspect of the second toe. Sensory loss in deep peroneal nerve palsies is minimal and requires detailed testing of sensation of the toes and web spaces. Thus, the deep peroneal nerve communicates little sen­ sation from the lower extremities, as most of the sen­ sation is carried by the superficial peroneal nerve. The deep peroneal nerve innervates the following muscles: tibialis anterior, extensor hallucis longus, extensor digi­ torum longus, peroneal tertius, first dorsal interosseous

Deep peroneal n.

Superficial

Tibialis anterior

peroneal n.

(cut)

Extensor digitorum longus Extensor hallucis longus

Peroneus tertius Extensor digitorum brevis

Cutaneous distribution

Ist. dorsal interosseous

Dorsal digital cutaneous n.

Figure 3.4 The Course and Distribution of the Deep Peroneal Nerve. The black innervations are motor from the deep peroneal nerve, and the stippled area is the distal cutaneous innervation. Reprinted from Haymaker W, Woodhall B. Peripheral Nerve Injuries, Principles of Diagnosis. 2nd ed. Philadelphia, PA: WB Saunders Co.; 1953. muscle, and the extensor digitorum brevis. Figure 3.4 shows the course of the deep peroneal nerve after it leaves the common peroneal nerve.

Table 3.9  Deep Peroneal Mononeuropathy: Etiologies Aneurysm (142) Bone tumors (126) Compartment syndrome (43) Compression (143,144) Dancing (36) Decompression sickness (145) External ankle frame fixator (146) Fibula bone exostosis (147) Hypothyroidism (148) Intraneural ganglion (149) Neurofibroma (150) Postsurgical (151) Schwannoma (152) Synovial cyst (142) Total hip arthroplasty (153) Trauma (42)

34  Textbook of Peripheral Neuropathy

The deep peroneal nerve can be impaired by direct trauma (42), tibial fractures, gunshot wounds, and pres­ sure from a compartment syndrome (43). Causes of a deep peroneal mononeuropathy are listed in Table 3.9.

Superficial Peroneal Nerve Patients with superficial peroneal palsies often complain of burning pain and numbness in the distribution of the nerve. Motor involvement is difficult to assess clinically, as the peroneal tertius and longus muscles, when weak, are not easy to detect. Figure 3.5 shows the course of the superficial peroneal nerve after its origin from the common peroneal nerve. Table 3.10 shows common and uncommon etiologies for a superficial peroneal monon­

Common peroneal n.

Lateral cutaneous n. of calf

Table 3.10 Superficial Peroneal Mononeuropathy: Etiologies Angiotrophic lymphoma (154) Ankle inversion sprain (155) Compartment syndrome (43) Dancing (36) Entrapment (19) Fibrolipoma (156) Intraneural ganglion (157) Intraneural lipoma (158) Leprosy (159) Lipoma (160) Necrotizing vasculitis (161) Nerve herniation through fascial defect (162) Schwannoma (163)

europathy. The most common causes are entrapment and ankle inversion sprains (19,44).

Tibial Nerve Deep peroneal n (cut)

Cutaneous distribution

Superficial peroneal n.

Peroneus brevis

The tibial nerve begins in the lower one third of the poste­ rior thigh from the bifurcation of the sciatic nerve into the common peroneal and the tibial nerve. It descends into the posterior fossa, where it becomes the posterior tibial at the upper level of the soleus muscle. Tibial nerve mo­ tor fibers innervate the medial and lateral gastrocnemius muscles, the plantaris, soleus, popliteus, and the poste­ rior tibial muscle. Anastomotic branches from the poste­ rior tibial nerve contribute to the formation of the sural nerve.

Posterior Tibial Nerve Medial cutaneous branch Anterior

Lateral cutaneous branch

Lateral

Figure 3.5 The Course and Distribution of the Superficial Peroneal Nerve. The motor course and innervations are shown in black, and the cutaneous innervation is displayed in the stippled area. Note the origin of the lateral cutaneous nerve of the calf above the fibular head and its differing cutaneous distribution from the lateral and medial cutaneous branch. Reprinted from Haymaker W, Woodhall B. Peripheral Nerve Injuries, Principles of Diagnosis. 2nd ed. Philadelphia, PA: WB Saunders Co.; 1953.

The posterior tibial nerve is an extension of the tibial nerve, descends posteriorly in the shin, and passes un­ der the flexor retinaculum, which is behind and poste­ rior to the medial malleolus. In the posterior shin, the posterior tibial nerve innervates the soleus, the tibialis posterior, the flexor digitorum longus, and the flexor hallucis longus muscles. It is notable that the posterior tibial and the soleus muscle can be innervated by the tib­ ial or posterior tibial nerves, depending on the location of the branch origin. The posterior tibial nerve ends by dividing into the medial or lateral plantar nerves. Those nerves, respectively, give sensation to the anterior two thirds of the medial and lateral foot and many intrinsic foot muscles. Tibial or posterior tibial mononeuropathies are much less common than peroneal lesions. Patients with tibial or posterior tibial neuropathies typically have less dramatic complaints than those with a common or deep peroneal mononeuropathy, and the deficits depend on whether the location of the nerve injury is in the tibial or poste­

CHAPTER 3: Common Mononeuropathies of the Lower Extremities   35

rior tibial nerve. Patients may complain only of loss of spring in their steps, difficulty walking on their toes, or sensory symptoms on the soles of their feet. The degree of sensory loss will depend on whether there is coexis­ tent involvement of the sural nerve. The tibial nerve can be injured by surgery in the popliteal fossa, Baker cyst (45), knife and gunshot wounds in the popliteal fossa and posterior shin, ischemia (46), neurilemmoma (47), compression (48), nerve sheath tumors (49), synovial cysts (49), tendinous arches (49), hypertrophic nerve tis­ sue (50,51), and a granulomatous arteritis (52).

thy can have severe pain in the posterior shin and soles. Femoral neuropathy primarily causes hip weakness and impaired knee extension. Common peroneal palsies re­ sult in a foot drop and weakness of foot eversion and must be differentiated from an L5 radiculopathy and a partial sciatic neuropathy. Many etiologies exist for mononeuropathies of the lower extremities. The most common are compressive, posttraumatic, postsurgical, nerve blocks, intramuscular injections, and hematoma compression, and most become obvious when the pres­ ent or past history of the patient is considered.

Superior Gluteal Nerve

References

The superior gluteal nerve receives its innervation from the posterior aspect of the plexus, roots L4, L5, and S1. The nerve exits the pelvis via the greater sciatic foramen and then reenters the pelvis by passing over the pyriformis muscle and moves laterally to innervate the gluteus medius and minimus muscles. These 2 muscles are important in abducting and rotating the thigh medi­ ally. The superior gluteal nerve also innervates the ten­ sor fascia lata muscle. A mononeuropathy of the superior gluteal nerve produces lateral rotation of the leg at rest. When walking, the patient bends toward the affected side and the pelvis drops. A superior gluteal neuropathy can be caused by hypertrophy of the pyriformis muscle (53), hereditary multiple exostoses (54), entrapment by the pyriformis muscle tendons (55), intramuscular injec­ tions (56), total hip arthroplasty (57), and prolonged lat­ eral decubitus positioning during surgery (58).

  1. Bohrer JC, Walters MD, Park A, Polston D, Barber MD. Pelvic nerve injury following gynecologic surgery: a pro­ spective cohort study. Am J Obstet Gynecol. 2009;201:531– 537.   2. Cardosi RJ, Cox CS, Hoffman MS. Postoperative neu­ ropathies after major pelvic surgery. Obstet Gynecol. 2002; 100:240–244.   3. Vuilleumier H, Hubner M, Demartines N. Neuropathy after herniorrhaphy: indication for surgical treatment and outcome. World J Surg. 2009;33:841–845.   4. Choi PD, Nath R, Mackinnon SE. Iatrogenic injury to the ilioinguinal and iliohypogastric nerves in the groin: a case report, diagnosis, and management. Ann Plast Surg. 1996;37:60–65.   5. Arcocha Aguirrezabal J, Irimia Sieira P, Soto O. [Ilioingui­ nal neuropathy: usefulness of conduction studies]. Neurologia. 2004;19:24–26.   6. Benini A. [Ilioinguinal and genito-femoral neuralgia. Causes, clinical aspects, therapy]. Schweiz Rundsch Med Prax. 1992;81:1114–1120.   7. Miller JP, Acar F, Kaimaktchiev VB, Gultekin SH, Burchiel KJ. Pathology of ilioinguinal neuropathy produced by mesh entrapment: case report and literature review. Hernia. 2008;12:213–216.   8. Swenson MR, Rothrock JF. Ilioinguinal neuropathy after iliac crest biopsy. Mayo Clin Proc. 1986;61:604.   9. Walter J, Reichart R, Vonderlind C, Kuhn SA, Kalff R. [Neuralgia of the genitofemoral nerve after hernioplasty. Therapy by peripheral nerve stimulation]. Chirurg. 2009; 80:741–744. 10. ter Meulen BC, Peters EW, Wijsmuller A, Kropman RF, Mosch A, Tavy DL. Acute scrotal pain from idio­ pathic ilioinguinal neuropathy: diagnosis and treatment with EMG-guided nerve block. Clin Neurol Neurosurg. 2007;109:535–537. 11. Moucharafieh R, Wehbe J, Maalouf G. Meralgia paresthet­ ica: a result of tight new trendy low cut trousers (‘taille basse’). Int J Surg. 2008;6:164–168. 12. Parisi TJ, Mandrekar J, Dyck PJ, Klein CJ. Meralgia par­ esthetica: relation to obesity, advanced age, and diabetes mellitus. Neurology. 2011;77:1538–1542. 13. Heidenreich W, Lorenzoni E. [Injury of the lateral cuta­ neous nerve of the thigh. A rare complication following gynecologic surgery]. Geburtshilfe Frauenheilkd. 1983;43: 766–768. 14. Bradshaw AD, Advincula AP. Postoperative neuropathy in gynecologic surgery. Obstet Gynecol Clin North Am. 2010;37:451–459.

Inferior Gluteal Nerve The inferior gluteal nerve is composed of contributions from roots L5, S1, and S2 arising from the posterior sur­ face of the plexus. The nerve leaves the pelvis through the greater sciatic notch and innervates the gluteus max­ imus muscle through multiple branches. Injury to the inferior gluteal nerve produces atrophy and sagging of the muscle, loss of definition of the gluteal fold, severe weakness of hip extension, and weakness when arising from a sitting position and climbing stairs. The inferior gluteal nerve can be injured by endometriosis surround­ ing and compressing the nerve (59), hereditary multiple exostoses (54), hematoma of the pyramidal muscle (60), recurrent colorectal carcinoma (61), hypertrophy of the piriformis muscle (62), and intragluteal muscle injec­ tions (63).

Summary Mononeuropathies affecting the lower extremities are less common than median and ulnar nerve lesions but, when present, cause significant disability because of neu­ ropathic pain or the impairment of gait or balance. The most severe disability is produced by a sciatic mononeu­ ropathy, as knee flexion and all strength below the knee is affected. Furthermore, patients with sciatic neuropa­

36  Textbook of Peripheral Neuropathy 15. Barcin C, Kursaklioglu H, Kose S, Isik E. Transient femoral nerve palsy after diagnostic coronary angiography. Anadolu Kardiyol Derg. 2009;9:248–249. 16. Merrick HW, Zeiss J, Woldenberg LS. Percutaneous decom­ pression for femoral neuropathy secondary to heparininduced retroperitoneal hematoma: case report and review of the literature. Am Surg. 1991;57:706–711. 17. Pendergrass TL, Moore JH. Saphenous neuropathy fol­ lowing medial knee trauma. J Orthop Sports Phys Ther. 2004;34:328–334. 18. Lippitt AB. Neuropathy of the saphenous nerve as a cause of knee pain. Bull Hosp Jt Dis. 1993;52:31–33. 19. Beltran LS, Bencardino J, Ghazikhanian V, Beltran J. En­ trapment neuropathies III: lower limb. Semin Musculoskelet Radiol. 2010;14:501–511. 20. Shenoy AM, Wiesman J. Saphenous mononeuropathy after popliteal vein aneurysm repair. Neurologist. 2010;16:47–49. 21. Austin KS. Complications of arthroscopic meniscal repair. Clin Sports Med. 1996;15:613–619. 22. Senegor M. Iatrogenic saphenous neuralgia: successful therapy with neuroma resection. Neurosurgery. 1991;28: 295–298. 23. Huang MI, Debernardo RL, Rodgers M, Hart DJ. Endome­ trial stromal sarcoma metastasis to the lumbar spine and sphenoid bone. Rare Tumors. 2011;3:e27. 24. Sorenson EJ, Chen JJ, Daube JR. Obturator neuropathy: causes and outcome. Muscle Nerve. 2002;25:605–607. 25. Park AJ, Fisch JM, Walters MD. Transient obturator neu­ ropathy due to local anesthesia during transobturator sling placement. Int Urogynecol J Pelvic Floor Dysfunct. 2009;20:247–249. 26. Holub Z. Obturator neuropathy after laparoscopic retro­ peritoneal surgery. Int J Gynaecol Obstet. 2006;95:165–166. 27. Warner MA, Warner DO, Harper CM, Schroeder DR, Max­ son PM. Lower extremity neuropathies associated with lithotomy positions. Anesthesiology. 2000;93:938–942. 28. Lazaro RP, Brinker RA, Weiss JJ, Olejniczak S. Femoral and obturator neuropathy secondary to retroperitoneal hemorrhage: the value of the CT scan. Comput Tomogr. 1981;5:221–224. 29. Kent KC, Moscucci M, Gallagher SG, DiMattia ST, Skill­ man JJ. Neuropathy after cardiac catheterization: inci­ dence, clinical patterns, and long-term outcome. J Vasc Surg. 1994;19:1008–1013; discussion 1013–1004. 30. Warfield CA. Obturator neuropathy after forceps delivery. Obstet Gynecol. 1984;64:47S–48S. 31. Nardone R, Venturi A, Ladurner G, Golaszewski S, Psenner K, Tezzon F. Obturator mononeuropathy caused by lipomatosis of the nerve: a case report. Muscle Nerve. 2008;38:1046–1048. 32. Yuen EC, Olney RK, So YT. Sciatic neuropathy: clinical and prognostic features in 73 patients. Neurology. 1994;44: 1669–1674. 33. Ramtahal J, Ramlakhan S, Singh K. Sciatic nerve injury fol­ lowing intramuscular injection: a case report and review of the literature. J Neurosci Nurs. 2006;38:238–240. 34. Clark K, Williams PE Jr, Willis W, McGavran WL III. In­ jection injury of the sciatic nerve. Clin Neurosurg. 1970;17: 111–125. 35. Toy BJ. Conservative treatment of bilateral sural nerve entrapment in an ice hockey player. J Athl Train. 1996; 31:68–70.

36. Kennedy JG, Baxter DE. Nerve disorders in dancers. Clin Sports Med. 2008;27:329–334. 37. Fabre T, Montero C, Gaujard E, Gervais-Dellion F, Du­ randeau A. Chronic calf pain in athletes due to sural nerve entrapment. A report of 18 cases. Am J Sports Med. 2000;28:679–682. 38. Perlman MD. Os peroneum fracture with sural nerve en­ trapment neuritis. J Foot Surg. 1990;29:119–121. 39. Montgomery PQ, Goddard NJ, Kemp HB. Solitary osteo­ chondroma causing sural nerve entrapment neuropathy. J R Soc Med. 1989;82:761. 40. Nakano KK. Entrapment neuropathy from Baker’s cyst. JAMA. 1978;239:135. 41. Yilmaz E, Karakurt L, Serin E, Guzel H. [Peroneal nerve palsy due to rare reasons: a report of three cases]. Acta Orthop Traumatol Turc. 2004;38:75–78. 42. Jones HR Jr, Felice KJ, Gross PT. Pediatric peroneal mono­ neuropathy: a clinical and electromyographic study. Muscle Nerve. 1993;16:1167–1173. 43. Lorei MP, Hershman EB. Peripheral nerve injuries in athletes. Treatment and prevention. Sports Med. 1993;16: 130–147. 44. Johnston EC, Howell SJ. Tension neuropathy of the super­ ficial peroneal nerve: associated conditions and results of release. Foot Ankle Int. 1999;20:576–582. 45. Lee JH, Jun JB, Lee HS, et al. Posterior tibial neuropathy by a Baker’s cyst: case report. Korean J Intern Med. 2000; 15:96–98. 46. Sprowson AP, Rankin K, Shand JE, Ferrier G. Common peroneal and posterior tibial ischemic nerve damage, a rare cause. Foot Ankle Surg. 2010;16:e16–17. 47. Boya H, Ozcan O, Oztekin HH. Tarsal tunnel syndrome associated with a neurilemmoma in posterior tibial nerve: a case report. Foot (Edinb). 2008;18:174–177. 48. Tacconi P, Manca D, Tamburini G, Cannas A, Giagheddu M. Bed footboard peroneal and tibial neuropathy. A fur­ ther unusual type of Saturday night palsy. J Peripher Nerv Syst. 2004;9:54–56. 49. Oh SJ, Meyer RD. Entrapment neuropathies of the tibial (posterior tibial) nerve. Neurol Clin. 1999;17:593–615, vii. 50. Mitsumoto H, Levin KH, Wilbourn AJ, Chou SM. Hyper­ trophic mononeuritis clinically presenting with painful legs and moving toes. Muscle Nerve. 1990;13:215–221. 51. Iyer VG, Garretson HD, Byrd RP, Reiss SJ. Localized hy­ pertrophic mononeuropathy involving the tibial nerve. Neurosurgery. 1988;23:218–221. 52. Augereau B, Orcel L, Apoil A. [Tarsal tunnel syndrome caused by granulomatous arteritis of an artery supplying the posterior tibial nerve. Apropos of a case]. J Chir (Paris). 1984;121:23–24. 53. Diop M, Parratte B, Tatu L, Vuillier F, Faure A, Monnier G. Anatomical bases of superior gluteal nerve entrapment syndrome in the suprapiriformis foramen. Surg Radiol Anat. 2002;24:155–159. 54. Paik NJ, Han TR, Lim SJ. Multiple peripheral nerve com­ pressions related to malignantly transformed hereditary multiple exostoses. Muscle Nerve. 2000;23:1290–1294. 55. Rask MR. Superior gluteal nerve entrapment syndrome. Muscle Nerve. 1980;3:304–307. 56. Kaufman MD. Isolated superior gluteal neuropathy due to intramuscular injection. N C Med J. 1988;49:85–86.

CHAPTER 3: Common Mononeuropathies of the Lower Extremities   37 57. Eskelinen A, Helenius I, Remes V, Ylinen P, Tallroth K, Paavilainen T. Cementless total hip arthroplasty in pa­ tients with high congenital hip dislocation. J Bone Joint Surg Am. 2006;88:80–91. 58. Donofrio PD, Bird SJ, Assimos DG, Mathes DD. Iatro­ genic superior gluteal mononeuropathy. Muscle Nerve. 1998;21:1794–1796. 59. Hettler A, Bohm J, Pretzsch M, von Salis-Soglio G. [Ex­ tragenital endometriosis leading to piriformis syndrome]. Nervenarzt. 2006;77:474–477. 60. Augustin P, Daluzeau N, Dujardin M, Clement O, Denis P. [Hematoma of the pyramidal muscle. A complication of anti­ coagulant treatment]. Rev Neurol (Paris). 1984;140:443–445. 61. LaBan MM, Meerschaert JR, Taylor RS. Electromyographic evidence of inferior gluteal nerve compromise: an early representation of recurrent colorectal carcinoma. Arch Phys Med Rehabil. 1982;63:33–35. 62. Mondelli M, Martelli G, Greco G, Ferrari F. Mononeuropa­ thies of inferior and superior gluteal nerves due to hyper­ trophy of piriformis muscle in a basketball player. Muscle Nerve. 2008;38:1660–1662. 63. Obach J, Aragones JM, Ruano D. The infrapiriformis fora­ men syndrome resulting from intragluteal injection. J Neurol Sci. 1983;58:135–142. 64. Butler R, Webster MW. Meralgia paresthetica: an unusual complication of cardiac catheterization via the femoral ar­ tery. Catheter Cardiovasc Interv. 2002;56:69–71. 65. Ahmed A. Meralgia paresthetica and femoral acetabu­ lar impingement: a possible association. J Clin Med Res. 2010;2:274–276. 66. Yamamoto T, Nagira K, Kurosaka M. Meralgia paresthet­ ica occurring 40 years after iliac bone graft harvesting: case report. Neurosurgery. 2001;49:1455–1457. 67. Schnatz P, Wax JR, Steinfeld JD, Ingardia CJ. Meralgia par­ esthetica: an unusual complication of post-cesarean anal­ gesia. J Clin Anesth. 1999;11:416–418. 68. Nikoobakht M, Mahboobi A, Saraji A, et al. Pelvic nerve neuropathy after kidney transplantation. Transplant Proc. 2007;39:1108–1110. 69. Manny TB, Gorbachinsky I, Hemal AK. Lower extremity neuropathy after robot assisted laparoscopic radical pros­ tatectomy and radical cystectomy. Can J Urol. 2010;17:5390– 5393. 70. Rau CS, Hsieh CH, Liu YW, Wang LY, Cheng MH. Mer­ algia paresthetica secondary to lipoma. J Neurosurg Spine. 2010;12:103–105. 71. Gupta A, Muzumdar D, Ramani PS. Meralgia paraesthet­ ica following lumbar spine surgery: a study in 110 consec­ utive surgically treated cases. Neurol India. 2004;52:64–66. 72. Windsor RE, Thampi S. Migrating opiate pump: atypical [corrected] cause of meralgia paresthetica. Pain Physician. 2003;6:495–497. 73. Fargo MV, Konitzer LN. Meralgia paresthetica due to body armor wear in U.S. soldiers serving in Iraq: a case report and review of the literature. Mil Med. 2007;172:663–665. 74. Kavanagh D, Connolly S, Fleming F, Hill AD, McDermott EW, O’Higgens NJ. Meralgia paraesthetica following open appendicectomy. Ir Med J. 2005;98:183–185. 75. Jablecki CK. Postoperative lateral femoral cutaneous neu­ ropathy. Muscle Nerve. 1999;22:1129–1131. 76. Suber DA, Massey EW. Pelvic mass presenting as meralgia paresthetica. Obstet Gynecol. 1979;53:257–258.

77. Ferra Verdera M, Ribera Leclerc H, Garrido Pastor JP. [2 cases of paresthetic meralgia of the femoral cutaneous nerve]. Rev Esp Anestesiol Reanim. 2003;50:154–156. 78. Stephenson LL, Webb NA, Smithers CJ, Sager SL, Seefelder C. Lateral femoral cutaneous neuropathy following lat­ eral positioning on a bean bag. J Clin Anesth. 2009;21: 383–384. 79. Cho KT, Lee HJ. Prone position-related meralgia paresthet­ ica after lumbar spinal surgery: a case report and review of the literature. J Korean Neurosurg Soc. 2008;44:392–395. 80. Kho KH, Blijham PJ, Zwarts MJ. Meralgia paresthetica af­ ter strenuous exercise. Muscle Nerve. 2005;31:761–763. 81. Bhargava T, Goytia RN, Jones LC, Hungerford MW. Lateral femoral cutaneous nerve impairment after direct anterior ap­ proach for total hip arthroplasty. Orthopedics. 2010;33:472. 82. Walsh C, Walsh A. Postoperative femoral neuropathy. Surg Gynecol Obstet. 1992;174:255–263. 83. Kang EH, Lee EB, Im CH, et al. A case of femoral com­ pressive neuropathy in AL amyloidosis. J Korean Med Sci. 2005;20:524–527. 84. D’Amelio LF, Musser DJ, Rhodes M. Bilateral femoral nerve neuropathy following blunt trauma. Case report. J Neurosurg. 1990;73:630–632. 85. Brull R, McCartney CJ, Chan VW, El-Beheiry H. Neurolog­ ical complications after regional anesthesia: contemporary estimates of risk. Anesth Analg. 2007;104:965–974. 86. Jellad A, Boudokhane S, Ezzine S, Ben Salah Z, Golli M. Femoral neuropathy caused by compressive iliopsoas hy­ datid cyst: a case report and review of the literature. Joint Bone Spine. 2010;77:371–372. 87. Al-Ajmi A, Rousseff RT, Khuraibet AJ. Iatrogenic femoral neuropathy: two cases and literature update. J Clin Neuromuscul Dis. 2010;12:66–75. 88. Parke L, Horrobin DF. Iatrogenic femoral neuropathy. Br Med J. 1976;1:262–263. 89. Shivashanmugam T, Kundra P, Sudhakar S. Iliac compart­ ment block following ilioinguinal iliohypogastric nerve block. Paediatr Anaesth. 2006;16:1084–1086. 90. Seid AS, Amos E. Entrapment neuropathy in laparoscopic herniorrhaphy. Surg Endosc. 1994;8:1050–1053. 91. Wilson M, Ramage L, Yoong W, Swinhoe J. Femoral neu­ ropathy after vaginal surgery: a complication of the litho­ tomy position. J Obstet Gynaecol. 2011;31:90–91. 92. Tokunaga M, Kawano F, Watanabe S, Koga Y, Hashimoto Y, Uchino M. [A case of femoral nerve palsy with malig­ nant lymphoma]. No To Shinkei. 2000;52:723–727. 93. Cingel V, Kokavec M, Trnka J. [Paresis of the femoral nerve in pelvic extraperitoneal hematoma– case reports and literature review]. Acta Chir Orthop Traumatol Cech. 2005;72:250–253. 94. Pham LH, Bulich LA, Datta S. Bilateral postpartum femo­ ral neuropathy. Anesth Analg. 1995;80:1036–1037. 95. Marquardt G, Barduzal Angles S, Leheta F, Seifert V. Spontaneous haematoma of the iliac psoas muscle: a case report and review of the literature. Arch Orthop Trauma Surg. 2002;122:109–111. 96. Brouns R, De Deyn PP. Neurological complications in re­ nal failure: a review. Clin Neurol Neurosurg. 2004;107:1–16. 97. Meech PR. Femoral neuropathy following renal transplan­ tation. Aust N Z J Surg. 1990;60:117–119. 98. Ng YS, Li HS, Chan CW. Bilateral femoral nerve compres­ sion and compartment syndrome resulting from influenza

38  Textbook of Peripheral Neuropathy A-induced rhabdomyolysis: a case report. J Orthop Surg (Hong Kong). 2008;16:117–121.   99. Simmons C Jr, Izant TH, Rothman RH, Booth RE Jr, Balderston RA. Femoral neuropathy following total hip arthroplasty. Anatomic study, case reports, and literature review. J Arthroplasty. 1991;6 Suppl:S57–66. 100. Pastor Guzman JM, Pastor Navarro H, Donate Moreno MJ, et al. [Femoral neuropathy in urological surgery]. Actas Urol Esp. 2007;31:885–894. 101. Hernandez Castrillo A, de Diego Rodriguez E, Rado Ve­ lazquez MA, Lanzas Prieto JM, Galindo Palazuelos M, Terrazas Hontanon JM. [Bilateral femoral neuropathy af­ ter prostatectomy. Case report and bibliographic review]. Arch Esp Urol. 2008;61:929–932. 102. Genc H, Balaban O, Karagoz A, Erdem HR. Femoral neu­ ropathy in a patient with rheumatoid arthritis. Yonsei Med J. 2007;48:891–893. 103. Yukata K, Arai K, Yoshizumi Y, Tamano K, Imada K, Na­ kaima N. Obturator neuropathy caused by an acetabu­ lar labral cyst: MRI findings. Am J Roentgenol. 2005;184: S112–114. 104. Kleiner JB, Thorne RP. Obturator neuropathy caused by an aneurysm of the hypogastric artery. A case report. J Bone Joint Surg Am. 1989;71:1408–1409. 105. Hakoiwa S, Hoshi T, Tanaka M, Mishima H. [Case of bilat­ eral obturator neuropathy after caesarean section]. Masui. 2011;60:721–723. 106. Dimachkie MM, Ohanian S, Groves MD, Vriesendorp FJ. Peripheral nerve injury after brief lithotomy for transure­ thral collagen injection. Urology. 2000;56:669. 107. Siwinski D. [Neuropathy of the obturator nerve as a source of pain in soccer players]. Chir Narzadow Ruchu Ortop Pol. 2005;70:201–204. 108. Jirsch JD, Chalk CH. Obturator neuropathy complicat­ ing elective laparoscopic tubal occlusion. Muscle Nerve. 2007;36:104–106. 109. Mondelli M, Giannini F, Guazzi G, Corbelli P. Obtura­ tor neuropathy due to obturator hernia. Muscle Nerve. 2002;26:291–292. 110. Rafii A, Querleu D. Laparoscopic obturator nerve neuroly­ sis after pelvic lymphadenectomy. J Minim Invasive Gynecol. 2006;13:17–19. 111. Nogajski JH, Shnier RC, Zagami AS. Postpartum obturator neuropathy. Neurology. 2004;63:2450–2451. 112. Fletcher HS, Frankel J. Ruptured abdominal aneurysms presenting with unilateral peripheral neuropathy. Surgery. 1976;79:120–121. 113. Stuplich M, Hottinger AF, Stoupis C, Sturzenegger M. Combined femoral and obturator neuropathy caused by synovial cyst of the hip. Muscle Nerve. 2005;32:552–554. 114. Corona R, De Cicco C, Schonman R, Verguts J, Ussia A, Koninckx PR. Tension-free Vaginal Tapes and Pelvic Nerve Neuropathy. J Minim Invasive Gynecol. 2008;15: 262–267. 115. Maher CO, Spinner RJ, Giannini C, Scheithauer BW, Crum BA. Neuromuscular choristoma of the sciatic nerve. Case report. J Neurosurg. 2002;96:1123–1126. 116. Dognon L, Himmi A, Avigdor S, et al. [Catamenial sciatic pain due to endometriosis of the sciatic nerve. Review of the literature, apropos of a case]. J Gynecol Obstet Biol Reprod (Paris). 1994;23:386–390. 117. Lopez Dominguez JM, Rodriguez Arce A, Pamies Andreu E, Gil Neciga E. [Compression neuropathy of the sciatic

nerve during anticoagulant treatment]. Med Clin (Barc). 1993;101:557. 118. Fandridis EM, Kiriako AS, Spyridonos SG, Delibasis GE, Bourlos DN, Gerostathopoulos NE. Lipomatosis of the sciatic nerve: report of a case and review of the literature. Microsurgery. 2009;29:66–71. 119. Prusick VR, Herkowitz HN, Davidson DD, Stambough JL, Rothman RH. Sciatica from a sciatic neurilemmoma. A case report and review of the literature. J Bone Joint Surg Am. 1986;68:1456–1457. 120. Srinivasan J, Ryan MM, Escolar DM, Darras B, Jones HR. Pediatric sciatic neuropathies: a 30-year prospective study. Neurology. 2011;76:976–980. 121. Sheth D, Gutmann L, Blumenthal DT, Mullett M, Boden­ steiner JB. Compressive sciatic neuropathy due to uterine abnormality. Muscle Nerve. 1994;17:1486–1488. 122. Sahai-Srivastava S, Amezcua L. Compressive neuropathies complicating normal childbirth: case report and literature review. Birth. 2007;34:173–175. 123. Escolar E, Garcia-Vela J, Aladro Y, Martinez-Menendez B, Martin A. [Mononeuropathy in chronic lymphatic leukae­ mia]. Rev Neurol. 2007;45:233–235. 124. Godeiro-Junior CO, Oliveira AS, Felicio AC, Barros N, Gabbai AA. Peroneal nerve palsy due to compartment syndrome after facial plastic surgery. Arq Neuropsiquiatr. 2007;65:826–829. 125. Malas FU, Ozcakar L, Firat F, Kuyumcu ME, Ates O, Sivri B. Drop foot in Crohn’s disease: reported nadir incidence of peroneal neuropathy. Inflamm Bowel Dis. 2007;13:1586–1587. 126. Abdel MP, Papagelopoulos PJ, Morrey ME, Wenger DE, Rose PS, Sim FH. Surgical management of 121 benign proximal fibula tumors. Clin Orthop Relat Res. 2010;468:3056–3062. 127. Agrawal A, Shetty BK, Makannavar JH, Shetty L, Shetty RK. Ganglion: an uncommon cause of compressive per­ oneal neuropathy. Neurol India. 2007;55:424–425. 128. Ijichi S, Niina K, Tara M, et al. Mononeuropathy associ­ ated with hyperthyroidism. J Neurol Neurosurg Psychiatry. 1990;53:1109–1110. 129. Fukuda H. Bilateral peroneal nerve palsy caused by inter­ mittent pneumatic compression. Intern Med. 2006;45:93–94. 130. Chick G, Alnot JY, Silbermann-Hoffman O. Intraneural mucoid pseudocysts. A report of ten cases. J Bone Joint Surg Br. 2001;83:1020–1022. 131. Heilbrun ME, Tsuruda JS, Townsend JJ, Heilbrun MP. In­ traneural perineurinoma of the common peroneal nerve. Case report and review of the literature. J Neurosurg. 2001;94:811–815. 132. Niall DM, Nutton RW, Keating JF. Palsy of the common peroneal nerve after traumatic dislocation of the knee. J Bone Joint Surg Br. 2005;87:664–667. 133. Gruber H, Peer S, Meirer R, Bodner G. Peroneal nerve palsy associated with knee luxation: evaluation by sono­ graphy—initial experiences. Am J Roentgenol. 2005;185: 1119–1125. 134. Singhal A, Varma M, Goyal N, Vij V, Wadhawan M, Gupta S. Peroneal neuropathy following liver transplantation: possible predisposing factors and outcome. Exp Clin Transplant. 2009;7:252–255. 135. Montgomery AS, Birch R, Malone A. Entrapment of a dis­ placed common peroneal nerve following knee ligament reconstruction. J Bone Joint Surg Br. 2005;87:861–862. 136. Aprile I, Caliandro P, La Torre G, et al. Multicenter study of peroneal mononeuropathy: clinical, neurophysiologic,

CHAPTER 3: Common Mononeuropathies of the Lower Extremities   39 and quality of life assessment. J Peripher Nerv Syst. 2005; 10:259–268. 137. Durmaz B, Atamaz F, On A. Bilateral common peroneal nerve palsy following cardiac surgery. Anadolu Kardiyol Derg. 2008;8:313–314. 138. Armstrong DJ, McCarron MT, Wright GD. Successful treatment of rheumatoid vasculitis-associated foot-drop with infliximab. J Rheumatol. 2005;32:759; author reply 759–760. 139. Krivickas LS, Wilbourn AJ. Peripheral nerve injuries in athletes: a case series of over 200 injuries. Semin Neurol. 2000;20:225–232. 140. Jain A, Mathew PJ, Modi M, Mangal K. Unilateral com­ mon peroneal nerve palsy following renal transplantation: a case report of tacrolimus neurotoxicity. J Postgrad Med. 2011;57:126–128. 141. Papagianni A, Oulis P, Zambelis T, Kokotis P, Koulouris GC, Karandreas N. Clinical and neurophysiological study of per­ oneal nerve mononeuropathy after substantial weight loss in patients suffering from major depressive and schizophrenic disorder: suggestions on patients’ management. J Brachial Plex Peripher Nerve Inj. 2008;3:24. 142. Kim JY, Ihn YK, Kim JS, Chun KA, Sung MS, Cho KH. Non-traumatic peroneal nerve palsy: MRI findings. Clin Radiol. 2007;62:58–64. 143. Reed SC, Wright CS. Compression of the deep branch of the peroneal nerve by the extensor hallucis brevis muscle: a variation of the anterior tarsal tunnel syndrome. Can J Surg. 1995;38:545–546. 144. Jones HR Jr. Compressive neuropathy in childhood: a re­ port of 14 cases. Muscle Nerve. 1986;9:720–723. 145. Sander HW. Mononeuropathy of the medial branch of the deep peroneal nerve in a scuba diver. J Peripher Nerv Syst. 1999;4:134–137. 146. Lui TH, Chan LK. Deep peroneal nerve injury following external fixation of the ankle: case report and anatomic study. Foot Ankle Int. 2011;32:S550–555. 147. Lucchetta M, Liotta GA, Briani C, et al. Ultrasound diag­ nosis of peroneal nerve variant in a child with compressive mononeuropathy. J Pediatr Surg. 2011;46:405–407. 148. Yasuoka T, Yokota T, Tsukagoshi H. [Deep peroneal nerve palsy associated with hypothyroidism]. No To Shinkei. 1993;45:563–566. 149. Bischoff J, Kortmann KB, Engelhardt M. [Intraneural gan­ glion of the peroneal nerve. A case report]. Z Orthop Unfall. 2010;148:589–593.

150. Chang LR, Shieh SJ. Neurofibroma derived from the deep peroneal nerve: a case report. Kaohsiung J Med Sci. 2006;22:290–296. 151. Kayal R, Katirji B. Atypical deep peroneal neuropathy in the setting of an accessory deep peroneal nerve. Muscle Nerve. 2009;40:313–315. 152. Mahitchi E, Van Linthoudt D. [Schwannoma of the deep peroneal nerve. An unusual presentation in rheumatol­ ogy]. Praxis (Bern 1994). 2007;96:69–72. 153. Ahmad I, Patil S. Isolated deep peroneal (fibular) nerve palsy in association with primary total hip arthroplasty. Clin Anat. 2007;20:703–704. 154. Vital C, Heraud A, Vital A, Coquet M, Julien M, Maupetit J. Acute mononeuropathy with angiotrophic lymphoma. Acta Neuropathol. 1989;78:105–107. 155. O’Neill PJ, Parks BG, Walsh R, Simmons LM, Miller SD. Excursion and strain of the superficial peroneal nerve dur­ ing inversion ankle sprain. J Bone Joint Surg Am. 2007;89: 979–986. 156. Akisue T, Matsumoto K, Yamamoto T, et al. Neural fi­ brolipoma of the superficial peroneal nerve in the ankle: a case report with immunohistochemical analysis. Pathol Int. 2002;52:730–733. 157. Stamatis ED, Manidakis NE, Patouras PP. Intraneural gan­ glion of the superficial peroneal nerve: a case report. J Foot Ankle Surg. 2010;49:400.e1–4. 158. Sabapathy SR, Langer V, Bhatnagar A. Intraneural lipoma associated with a branch of the superficial peroneal nerve. J Foot Ankle Surg. 2008;47:576–578. 159. de Freitas MR, Nascimento OJ, Hahn MD. Isolated super­ ficial peroneal nerve lesion in pure neural leprosy: case re­ port. Arq Neuropsiquiatr. 2004;62:535–539. 160. Terrence Jose Jerome J. Superficial peroneal nerve lipoma. Rom J Morphol Embryol. 2009;50:137–139. 161. Vincent D, Gombert B, Vital A, Vital C. A case of mono­ neuropathy multiplex with type II cryoglobulinemia, ne­ crotizing vasculitis and low grade B cell lymphoma. Clin Neuropathol. 2007;26:28–31. 162. Yang LJ, Gala VC, McGillicuddy JE. Superficial peroneal nerve syndrome: an unusual nerve entrapment. Case re­ port. J Neurosurg. 2006;104:820–823. 163. Traistaru R, Enachescu V, Manuc D, Gruia C, Ghilusi M. Multiple right schwannoma. Rom J Morphol Embryol. 2008;49:235–239.

Suraj Ashok Muley and Gareth J. Parry

4

Approach to the Evaluation of Mononeuropathy Multiplex

Introduction and Description of the Type of Neuropathy

nerves can be responsible (Table 4.1). Furthermore, multiple mechanisms may be involved in the same patient. The clinical picture can vary depending on the pathogenesis, although there is significant overlap.

Mononeuropathy multiplex (MM) is a syndrome that is characterized by multifocal involvement of individual peripheral nerves by a wide variety of disease processes. The term mononeuritis multiplex has also been use to describe the same syndrome, but mononeuropathy multiplex is more appropriate since it does not imply a singular inflammatory mechanism. The disease may start in a single peripheral nerve, with sequential involvement of other nerves, or involvement of multiple nerves at onset may occur. The latter pattern probably indicates a disease process that is more rapid in its evolution. As the disease becomes advanced, confluent involvement of multiple nerves can result in a clinical picture of a symmetric neuropathy, although in most instances, subtle signs of multifocality persist (1). Sensory and motor axonal involvement is the most common presentation, but in rare instances, isolated sensory or motor involvement can be seen at onset, with subsequent involvement of both types of axons. In some disorders, the disease process can remain restricted to either the sensory or the motor axons.

Vascular Ischemia of peripheral nerves, usually because of microangiopathy, is the most common pathogenic mechanism. Vasculitis can be either systemic or restricted to the peripheral nervous system (PNS); nonsystemic vasculitic neuropathy (NSVN) is the most common cause of ischemia (1–3). The pattern of peripheral nerve involvement is dictated by the luminal size of the blood vessels involved. Systemic vasculitis can occur in the context of connective tissue disease, infection, cancer, diabetes, graft versus host disease, and drug toxicity. Rarely, ischemia can be secondary to red cell sickling, as seen with sickle cell disease. Intraneural hemorrhage that occurs in idiopathic thrombocytopenic purpura (ITP) and hemophilia can also result in MM.

Inflammatory

Pathogenesis and Pathophysiology

Autoimmune Vasculitis is commonly related to autoimmunity, as has been described above in the vascular category. Inflammatory neuropathies such as multifocal motor neuropathy (MMN) with conduction block (CB) and Lewis-Sumner syndrome (LSS) are related to autoimmunity against putative myelin-based antigens. Perineuritis has been described in patients with Wartenberg migratory sensory neuritis, a rare, purely sensory disorder.

The term mononeuropathy multiplex does not imply a single pathogenetic mechanism but rather is a description of the clinical phenotype. Autoimmunity is a common underlying theme, but a wide range of pathogenetic mechanisms, including ischemia, hemorrhage, tumor cell infiltration, infection, inflammation, and mechanical compression of

Infectious Infection with agents such as HIV, hepatitis B or C virus, Borrelia burgdorferi, and leprosy can present with MM, and the pathogenesis may be related to direct infection as in leprosy or a vasculitic mechanism such as in hepatitis B and perhaps also in hepatitis C and Lyme disease.

KEY POINT MM can become confluent and present with a clinical picture of symmetric neuropathy, although subtle clinical and electrophysiological signs of multifocality remain.

41

42  Textbook of Peripheral Neuropathy

Table 4.1  Pathogenetic Mechanisms in Mononeuropathy Multiplex Pathophysiology Vascular

Inflammatory

Pathogenesis Vasculitis

Red blood sickling Intraneural hemorrhage

Etiology Systemic vasculitides Vasculitis restricted to PNS Connective tissue disease related Infectious (hepatitis B/C, HIV, Lyme disease) Diabetes Paraneoplastic Drug induced Sickle cell anemia ITP Hemophilia

Autoimmune Infection Granulomatous

Vascular (see above), MMN, LSS Lyme disease, hepatitis B/C, HIV, leprosy Sarcoidosis, leprosy, Wegener granulomatosis

Entrapment Malignancy

HNPP, diabetes Intraneural metastases Paraneoplastic

Leukemia, lymphoma Lung cancer, lymphoma, etc

Abbreviations: HNPP, hereditary neuropathy with liability to pressure palsy; ITP, idiopathic thrombocytopenic purpura; LSS, Lewis-Sumner syndrome; MMN, multifocal motor neuropathy; PNS, peripheral nervous system.

Granulomatous Granulomatous inflammation causing MM is seen in sarcoidosis. Granulomas can also be seen in leprosy and Wegener granulomatosis (WG).

Entrapment Mechanical compression of nerves at multiple entrapment sites can result in multiple compressive neuropathies and MM; this is commonly seen in hereditary neuropathy with liability to pressure palsy (HNPP) and in patients with diabetes in whom multiple entrapment neuropathies are common.

Malignancy In the context of cancer, MM can result from direct invasion of nerves or from a paraneoplastic vasculitic disorder with secondary nerve ischemia. Infiltration of nerves is seen with hematological malignancies such as lymphoma or leukemia. Paraneoplastic vascultis has been most commonly described with lung cancer but can occur in the context of other malignancies.

Axonal Versus Demyelinating MM can also be classified based on whether the primary pathology is axonal degeneration or segmental demyelination. Electrodiagnosis is critical in making this distinction. In the latter stages of the disease process, axonal degeneration tends to be the predominant pathology, even though the primary mechanism may

have been demyelinating. The diagnostic approach should therefore include differentiation between the primary and predominant pathology. MM secondary to nerve ischemia, infection, and cancer tends to primarily cause axonal degeneration. Mechanical compression and autoimmunity to myelin components (eg, MMN and LSS) typically result in a primarily demyelinating neuropathy.

Clinical Approach to Diagnosis Sensory and motor involvement in a peripheral nerve rather than a dermatomal or myotomal distribution is the characteristic presentation, but predominantly sensory or motor involvement can be seen, depending on the nerve involved and the pathological process; for example, MMN is purely motor, while Wartenberg migrant sensory neuritis (WMSN) is a purely sensory disorder. A segmental pattern of involvement raises the possibility of disorders affecting the dorsal root ganglion (DRG) or the anterior horn cell rather than peripheral nerves. The clinical presentation of patients with MM can offer important clues regarding the pathogenesis and perhaps the etiology of the underlying disorder. Hyperacute onset of symptoms, to the extent that patients may remember the precise moment of onset of symptoms even after significant time lapse, suggests nerve ischemia commonly seen with vasculitis. Severe pain at initial presentation is also commonly seen with nerve ischemia but can also be seen with intraneural metastases, hemorrhage, and perineuritis.

CHAPTER 4: Approach to the Evaluation of Mononeuropathy Multiplex   43

KEY POINT Ischemia of the peripheral nerve, commonly related to vasculitis, presents with hyperacute painful focal neuropathy. Differential involvement of fascicles within a nerve commonly seen with nerve ischemia but also with inflammatory injury in neuralgic amyotrophy can result in sparing of some muscles supplied by the same nerve, with severe involvement of others. Differential fascicular involvement at onset has also been described with MMN (4), although absence of pain and the slower evolution help in differentiation.

KEY POINT Fascicular sparing is commonly seen with nerve ischemia but can also be seen in inflammatory disorders such as neuralgic amyotrophy and MMN. In disorders that are primarily axonal, muscle atrophy tends to occur early in the disease process, and the severity of weakness is proportional to the degree of atrophy. In the initial stages of demyelinating disorders such as MMN and LSS, there is relative preservation of muscle bulk despite severe weakness since weakness is related to CB rather than to a loss of axons, and the trophic influence of nerve on muscle is preserved.

KEY POINT Severe muscle weakness with preservation of mus­cle bulk strongly suggests demyelination. This can be confirmed electrophysiologically; nerve conduction study

results can show CB, and needle examination results show reduced recruitment, with a paucity of changes related to axonal degeneration. Laboratory testing should be based on the suspected pathogenetic mechanism and whether the process is thought to be primarily axonal or demyelinating (Table 4.2). Electrodiagnostic testing can assist in making this differentiation but can also offer clues to the pathogenesis (see below). Nerve biopsy is also an important component of diagnosis, especially in axonal MM, when the diagnosis is not obvious with laboratory and electrodiagnostic testing. Tissue histology is the only definitive diagnostic test for sarcoidosis but can also be very important in diagnosis of vasculitis, leprosy, perineuritis, and intraneural metastases. Diabetic amyotrophy and neuralgic amyotrophy are painful motor-predominant focal disorders that can present with mononeuropathy as the initial manifestation. Rarely, inflammatory neuropathies such as chronic inflam­ matory demyelinating polyneuropathy and G­uillain-Barré syndrome can also present in a multifocal pattern. These disorders can therefore resemble MM, especially at initial presentation. As the disease evolves, the clinical picture becomes that of a symmetric radiculoneuropathy or plexopathy, and the initial resemblance to MM is superficial. These neuropathies will not be further discussed in this chapter.

KEY POINT Disorders affecting the brachial plexus, lumbosacral plexus, and nerve roots can present with striking multifocality, resulting in a clinical picture that resembles MM.

Table 4.2  Laboratory Testing for Mononeuropathy Multiplex Axonal Vascular

Inflammatory Malignancy Demyelinating Inherited Acquired

CBC, urine analysis, liver enzymes, creatinine, ESR, CRP, complement levels, cryoglobulin, p- & c-ANCA Anti-ENA antibodies Fasting plasma glucose Sickle cell test, bleeding time, PT, PTT Hepatitis B/C serology, HIV screen, Lyme serology, serology and skin biopsy for leprosy Nerve biopsy ACE level, tissue biopsy, ESR, CRP Nerve biopsy, ESR, CSF analysis, MRI with gadolinium and PET (consider: anti-Hu; imaging studies of chest, abdomen, pelvis)

Gene test for PMP22 gene deletion, mutation Anti-GM1 antibody, CSF analysis

Abbreviations: ACE, angiotensin-converting enzyme; anti-ENA, antibodies to extractable nuclear antigen; c-ANCA, cytoplasmic antineutrophil cytoplasmic antibody; CBC, complete blood count; CRP, C-reactive protein; CSF, cerebrospinal fluid; ESR, erythrocyte sedimentation rate; p-ANCA, perinuclear antineutrophil cytoplasmic antibody; PMP, peripheral myelin protein; PT, prothrombin time; PTT, partial thromboplastin time.

44  Textbook of Peripheral Neuropathy

Electrodiagnosis Electrodiagnostic testing in the form of nerve conduction studies (NCSs) and electromyography (EMG) is an essential component of the initial diagnostic workup. The first step is to eliminate disorders of the nerve root, DRG, anterior horn cell, or plexus that can clinically mimic MM. Once the diagnosis of MM is established, the next step is to determine whether the primary process is axonal or demyelinating and to look for other clues to the pathophysiology. In diseases affecting the motor neuron and/or ventral roots, denervation is in a myotomal rather than a peripheral nerve pattern. The sensory nerve action potential (SNAP) is affected in disorders of the DRG and their peripheral axons; motor axons are spared. Lastly, in disorders of the brachial or lumbosacral plexus, sensory and motor involvement is confined to a specific component of the plexus. These distinctions can generally be made through electrodiagnostic testing, although in some cases, it can be difficult. Also, electrodiagnostic findings need to be interpreted in the context of the clinical picture, with particular attention to preexisting conditions and the duration of symptoms prior to the study. In axonal disorders, there is reduction in the amplitude of the SNAP in the distribution of the peripheral nerve involved with relative preservation of conduction velocities. The compound muscle action potential (CMAP) amplitude may also be reduced, although in chronic disorders, the CMAP amplitude is often relatively preserved owing to terminal collateral sprouting or remaining motor axons reinnervating many muscle fibers. In demyelinating disorders, there is conduction slowing that is disproportionate to the reduction in the CMAP amplitude, and there may be segmental temporal dispersion of the CMAP or CB. Conduction slowing and CB that are restricted to or accentuated at compressive sites can be seen in entrapment neuropathies associated with HNPP or diabetes. Segmental amplitude decrement in the CMAP response between distal and proximal sites of stimulation can be seen in both axonal and demyelinating disorders, but there are significant differences. In patients with nerve ischemia, noncontinuity (or pseudo) CB is seen when motor NCSs are done very early in the disease process, before axons distal to the site of transection have lost their capacity to conduct electrical impulses (5,6). If initial NCSs done within 2 to 3 weeks from the onset of symptoms show segmental amplitude decrement between proximal and distal sites of stimulation, the study should be repeated a few weeks later. If the segmental amplitude decrement is due to noncontinuity block, the amplitude decrement will be eliminated owing to decline in the distal amplitude (Figure 4.1). Demyelinating CB is sometimes seen at entrapment sites in HNPP but is rare in other entrapment neuropathies. In MMN and LSS, CB tends to occur at nonentrapment sites (Figure 4.2) and can remain localized for long periods, with only

Figure 4.1 Noncontinuity (pseudo) conduction block. minimal reduction in the distal CMAP amplitude even after significant time lapse.

KEY POINT Conduction block seen on NCS results can be either demyelinating or related to axonal noncontinuity. Demyelinating CB persists for weeks or months, while noncontinuity CB resolves over 7 to 14 days because of reduction of the distal CMAP amplitude secondary to wallerian degeneration. The presence of demyelinating CB is suggestive of an inflammatory demyelinating neuropathy, and noncontinuity block is highly suggestive of nerve ischemia. Fascicular sparing (FS) is a result of differential involvement of fascicles within a nerve, as has been discussed previously. This may be clinically covert but can be uncovered by electrodiagnostic testing. Some muscles in the distribution of a specific nerve may be denervated while others are spared, for example, patients may have complete denervation of flexor pollicis longus with sparing of the pronator quadratus muscle in anterior interosseous neuropathy. Lastly, NCSs can aid in selecting the optimal nerve bi­ opsy site; nerves that are moderately involved have a greater diagnostic yield than nerves that are severely affected or nerves that appear electrophysiologically normal.

Treatment The mainstay of management is treatment of the primary condition. This is discussed below with individual diseases. In axonal forms of MM, early diagnosis and institution of treatment are important since once axonal degeneration becomes severe, recovery is slow and incomplete. Symptomatic treatment of neuropathic pain with antidepressants, antiepileptic and antiarrhythmic drugs, and narcotic analgesics is also important.

CHAPTER 4: Approach to the Evaluation of Mononeuropathy Multiplex   45

Figure 4.2 Conduction block related to focal demyelination. Diseases I. Vasculitides A. Systemic Vasculitis clinical manifestations. Even though multisystem involvement usually dominates the clinical picture, MM is the most common neurological manifestation of these disorders and may be the presenting feature. Polyarteritis nodosa (PAN) is a necrotizing angiitis that presents with weight loss, fever, asthenia, renal failure, musculoskeletal and cutaneous manifestations, hypertension, gastrointestinal tract involvement, and cardiac failure. Churg-Strauss syndrome (CSS) is a systemic vasculitis similar to PAN but occurs in the context of asthma and allergic rhinitis and is accompanied by eosinophilia. PAN is commonly related to hepatitis B and rarely with other infections (7). MM can also be seen with WG but tends to occur later in the disease course than in the other vasculitides (8).

Figure 4.3 Transmural and perivascular infiltration of lymphocytes related to vasculitis. pathogenesis and pathophysiology. The precise etiology of the various vasculitides remains unclear. Hepatitis B virus is found to be associated with PAN in a significant proportion of patients (9,10). Hepatitis C virus (HCV) and HIV have also been associated with PAN (11,12). Drug-induced vasculitic MM has also been described with amphetamine, cocaine, and minocycline (13–15). Rheological factors have also been proposed in PAN. Antineutrophil cytoplasmic antibodies (ANCAs) play a pathogenetic role in CSS and WG (16). The pathological hallmark is transmural lymphocytic infiltration and fibrinoid necrosis of the vessel wall of small- and mediumsized blood vessels (Figure 4.3). This results in secondary nerve ischemia with axonal degeneration in a multifocal distribution that results in MM (8,17,18) (Figure 4.4). Pathological demonstration of vessel wall inflammation is important in diagnosis and classification of the various vasculitides. In PAN, there is involvement of

Figure 4.4 A: Normal nerve fascicle. B: Severe focal reduction in nerve fiber density related to ischemia.

46  Textbook of Peripheral Neuropathy

m­edium and small-sized arteries without involvement of  arterioles, venules, and capillaries. In CSS, eosinophilic granulomatous inflammation of the respiratory tract and necrotizing vasculitis of small- and mediumsized vessels is seen. WG is characterized by granulomatous inflammation of the respiratory tract with necrotizing vasculitis of medium- and small-sized blood vessels and necrotizing glomerulonephritis (19). diagnostic evaluation. Initial laboratory workup is aimed at determining whether there is systemic involvement and should include complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, liver enzyme level, creatinine level, urine analysis, and ANCA profile. In roughly two thirds of patients with CSS, there is elevation of antibodies to myeloperoxidase (p-ANCA), and most patients with WG have antibodies to proteinase 3 (c-ANCA). Biopsy of a clinically involved nerve can be useful in diagnosis, although since the disease process is patchy, an unaffected part of the nerve is sometimes biopsied inadvertently. If the definitive diagnostic findings of fibrinoid necrosis of the vascular media and transmural inflammation are not seen, presence of perivascular inflammation, asymmetric fiber loss, hemosiderin, immune deposits, neovascularization, perineurial damage, and endoneurial hemorrhage can provide supportive diagnostic evidence in the appropriate clinical context (20). electrophysiology. Nerve conduction studies should be done as early as possible since CB secondary to nerve ischemia is seen early in the disease process and, unlike CB related to demyelination, can resolve over weeks as there is wallerian degeneration of the distal axons (Figure 4.1). The presence of a noncontinuity CB in the appropriate clinical context is highly suggestive of nerve ischemia and is an important step in the diagnostic evaluation (5,6). treatment.

Immunosuppressants in the form of prednisone and cyclophosphamide are the mainstay of treatment (21,22). Treatment with prednisone should be initiated as early as possible after diagnosis. In most cases, cyclophosphamide treatment for several months is necessary and enables reduction of the dose of prednisone and induction of a remission. Other immunosuppressive agents that have been used include azathioprine, methotrexate, intravenous immunoglobulin (IVIg), mycophenolate mofetil, plasma exchange, and rituximab.

KEY POINT PAN is commonly related to hepatitis B infection. B. Vasculitis Restricted to the PNS clinical manifestations. MM seen in NSVN is similar to that seen with systemic vasculitis except for lack of systemic involvement in NSVN (1,2,23). The prognosis

for NSVN is better than that for systemic vasculitis, with low mortality (2,23). pathogenesis and pathophysiology.

The etiology of NSVN remains unclear. The pathological changes on nerve biopsy are similar to those seen with systemic vasculitis, with the exception that there is no systemic involvement. This suggests that the pathogenesis of the 2 disorders may also be similar (20).

diagnostic evaluation. The initial diagnostic workup should include laboratory testing to rule out systemic vasculitis. Mild elevation of ESR is seen in approximately 50% of patients, and low titers of antinuclear antibodies can also be seen (2,24). Markedly elevated ESRs, leukocytosis, rheumatoid factor, and ANCA antibodies suggest the possibility of systemic vasculitis (24). electrophysiology. Electrophysiological findings are similar to those seen with systemic vasculitis. treatment. Immunosuppressant in the form of prednisone is the mainstay of treatment. Cyclophosphamide may be used in cases that do not respond to prednisone alone or as steroid-sparing agents (22). There is suggestion that using a combination of prednisone and cyclophosphamide as initial treatment is more effective than delaying treatment with cyclophosphamide (23). Other immunosuppressive agents can also be used as with systemic vasculitis.

KEY POINT The clinical presentation of vasculitis restricted to the PNS is similar to systemic vasculitis except for the lack of systemic involvement. C. Vasculitis Secondary to Connective Tissue Disorders clinical manifestations. Vasculitic MM can occur in the context of connective tissues diseases such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), scleroderma, and rarely, Sjögren syndrome (SS) (25–30). MM can be the initial manifestation of rheumatic diseases and can bring the underlying disease to light (26). SLE causes vasculitis of small-sized and medium-sized vessels (30) that presents with visceral vasculitis and ulcerated ischemic cutaneous lesions in addition to MM. Systemic rheumatoid vasculitis in patients with RA presents with MM or a symmetric neuropathy (28,29). Patients with scleroderma, especially those with a combination of CREST (calcinosis, Raynaud’s phenomenon, esophageal dysfunction, sclerodactyly, telangiectasias) syndrome and SS, are at increased risk of developing MM (25). MM is extremely rare with isolated SS (27), but when it occurs, it is similar to that seen with systemic vasculitis; sensory neuronopathy related to DRG involvement is more common and presents with multifocal sensory loss that can be confused with MM.

CHAPTER 4: Approach to the Evaluation of Mononeuropathy Multiplex   47 pathogenesis and pathophysiology.

The pathogenesi­s of MM is related to vasculitis affecting small- and m­edium-sized blood vessels (29,30). The pathophysiology is similar to that seen with systemic vasculitis, although there is a greater likelihood the multifocality will be covert because of clinical confluence of multiple small focal l­esions.

diagnostic evaluation. In patients with MM in whom other etiologies are ruled out, workup for connective tissue disease should be done even in the absence of clinical indications of the same (26). Laboratory workup should include antibodies to extractable nuclear antigen and complement levels. electrophysiology. Electrodiagnostic features are similar to those seen with the systemic vasculitides. treatment.

Treatment of the underlying connective tissue disease may lead to improvement or stabilization of the MM. Immunosuppressants are the mainstay of treatment, and treatment should be coordinated with rheumatology. D. Diabetic Mononeuritis Multiplex clinical manifestations. Polyneuropathy is common in patients with diabetes. Asymmetric neuropathies can occur with diabetes and are commonly a result of multiple entrapment neuropathies. Occasionally vasculitic MM that evolves in a subacute fashion can also occur (31–33) and is probably part of the diabetic amyotrophy spectrum. Unlike entrapment neuropathy, the onset of vasculitic MM tends to be acute and painful, with rapid evolution to nadir in only a few days. Sequential involvement of nerves occurs at a slower pace than with the systemic vasculitides (33). pathogenesis and pathophysiology.

Unlike diabetic polyneuropathy, which is related to the severity and duration of hyperglycemia, diabetic MM is related to an immune-mediated vasculopathy. Accordingly, a significant proportion of patients with diabetic MM may not have long-standing diabetes or an accompanying polyneuropathy (32). Perivascular lymphocytic infiltration of small-caliber blood vessels with secondary nerve ischemia is the underlying pathogenesis (33).

diagnostic evaluation.

Vasculitic MM related to diabetes is relatively rare (33), and workup to rule out other potential etiologies is always in order. The diagnosis is based on nerve biopsy changes and elimination of other etiologies. Conversely, in patients with MM where no other cause is found, screening for diabetes with fasting blood glucose level and a glucose tolerance test may be beneficial.

electrophysiology.

The electrophysiological features are similar to those seen with systemic vasculitis. An

accompanying polyneuropathy and superimposed en­ trap­­ment neuropathies are commonly seen and make diagnosis of MM difficult (32). treatment. Immunotherapy may be effective in disease stabilization. Medications that have been used include prednisone, pulsed methylprednisolone, IVIg, and chlo­ rambucil (33).

KEY POINT Diabetic MM is related to vasculitis and has pathophysiological similarities to diabetic amyotrophy. Differentiation from entrapment neuropathy is important since immunosuppressive treatments can be beneficial.

II. Hematologic Disorders A. Sickle Cell Disease

clinical manifestations.

In patients with sickle cell anemia, large-vessel occlusion with secondary organ ischemia commonly occurs, especially during sickle cell crises. MM can occur during sickle cell crises but is less common and probably related to occlusion of smallercaliber vessels (34,35).

pathogenesis and pathophysiology.

The pathogenesis is presumably related to nerve ischemia secondary to red cell sickling and vasocclusion.

diagnostic evaluation. In most states in the US, newborns are screened for sickle cell disease. Also, systemic manifestations of this disease generally make the diagnosis obvious in most cases, but pain related to sickle cell crisis can easily mask symptoms of MM and make diagnosis difficult. Hemoglobin solubility and sodium metabisulfite test is used in screening. Hemoglobin electrophoresis and genetic testing can establish a definitive diagnosis. electrophysiology. Nerve conduction studies show noncontinuity CB and multifocal axonal neuropathy similar to that seen with neuropathy related to the systemic vasculitides. treatment.

Treatment of the sickle cell crisis leads to stabilization of the MM. Axonal degeneration that has already occurred can improve over time through neural repair mechanisms. B. Other Hematological Disorders Several case reports have been published on ITP presenting with MM (36–38). Hemophilia commonly causes hematoma in the iliopsoas muscle, resulting in a femoral neuropathy; other mononeuropathies and MM can also occur and are thought to be related to the severity of hemophilia (39).

clinical manifestations.

48  Textbook of Peripheral Neuropathy pathogenesis and pathophysiology.

The pathogenesis of MM in ITP is thought to be related to intraneural hemorrhage (36). In hemophilia, MM relates to external compression from hematomas; intraneural hemorrhage has been proposed but remains controversial (39).

diagnostic evaluation. In patients with ITP, bleeding time is prolonged, but PT and PTT are normal. Thrombocytopenia is seen on routine CBC, and platelet antibodies may be detected. In hemophilia, bleeding time and PT are normal, but PTT is prolonged. Factor assays and genetic tests can be used to make a definitive diagnosis. electrophysiology.

A multifocal axonal neuropathy is seen on electrophysiological testing. It is unclear whether CB is seen. treatment. The mainstay of management is treatment of the primary condition that can result in stabilization of the MM.

III. Malignancy clinical manifestations.

Neuropathy related to cancer can be a result of direct mechanical compression from solid tumors, leptomeningeal infiltration, intraneural infiltration or through a paraneoplastic process (40–46). MM related to cancer is a result of either direct intraneural metastases or a paraneoplastic immune-mediated mechanism. Pain is a prominent feature of both MM related to intraneural metastases and vasculitis. MM due to paraneoplastic vasculitis evolves more rapidly. Intraneural metastasis is rare but can occur with synovial sarcoma, carcinoid (47–49), and hematological malignancies such as acute leukemia or lymphoma (43,44,50,51). Neurolymphomatosis is a form of B cell lymphoma that arises from systemic or central nervous system lymphoma and affects peripheral nerves and nerve roots (52) and presents with painful MM (53). Paraneoplastic MM is commonly a result of focal vasculitis (40,45) but rarely may be related to other autoimmune mechanisms, with presence of antineuronal antibodies (41). Paraneoplastic vasculitic neuropathy (PVN) commonly occurs in patients with small cell lung cancer and lymphoma but also other cancers (40,42,45,46,54). The primary process is axonal degeneration and affects both sensory and motor axons. Radiation plexopathy can also be seen in patients with cancer, but pain is less prominent, and the clinical presentation is of a plexopathy rather than MM.

pathogenesis and pathophysiology.

MM in malignancy may result from direct infiltration of tumor cells usually seen with leukemia and lymphoma or from a PVN (53,55). PVN is similar to the neuropathy seen with the systemic vasculitides and can rarely be associated with neuronal antibodies (41).

diagnostic evaluation. In patients with known cancer who develop MM, the first consideration should be given to metastatic disease. MM can be the harbinger of a relapse in leukemia and lymphoma. MRI scans with gadolinium, PET scans (56,57), and nerve biopsy to look for intraneural tumor metastases can all be part of the initial diagnostic workup. If metastatic disease is ruled out, a PVN must be considered, and nerve biopsy can be useful in diagnosis. Elevated ESR and cerebrospinal fluid (CSF) protein levels are commonly seen with PVN and can offer further support to the diagnosis (42). electrophysiology.

Nerve conduction studies show a multifocal axonal neuropathy in patients with intraneural metastases. In patients with a vasculitic neuropathy, noncontinuity CBs and a multifocal axonal neuropathy are typically seen, similar to the systemic vasculitides.

treatment. The mainstay of management is treatment of the underlying malignancy (42,46). Immunosuppressive treatments for vasculitis can be considered if there is indication that the underlying malignancy is quiescent and that the process is purely immune mediated (45).

KEY POINT MM in malignancy can be related to a paraneoplastic vasculitic neuropathy or direct infiltration of the nerves.

IV. Infections A. Lyme Disease

clinical manifestations.

Neuropathy can occur in both acute and chronic Borrelia infection. Polyradiculoneuritis and cranial neuropathy are the common peripheral nerve complications of Lyme disease, although MM can also occur with both acute and chronic infection (58–62).

pathogenesis and pathophysiology.

The pathogenesis of MM in Lyme infection is not entirely clear, and both direct infection and a parainfectious mechanism have been proposed (61). Pathological findings that have been described include vasculitis of the vasa nervorum (60), perineuritis (63), and endoneurial inflammation (62). Multifocal axonal degeneration because of a vasculopathy is the most likely underlying mechanism.

diagnostic evaluation. Serological tests include the enzyme-linked immunosorbent assay (ELISA) for initial screening and Western blot for confirmation. When MM occurs in the context of acute Lyme infection with the characteristic rash, erythema chronicum migrans, the diagnosis is obvious. Analysis of CSF shows a lymphocytic pleocytosis with elevated protein and normal

CHAPTER 4: Approach to the Evaluation of Mononeuropathy Multiplex   49

glucose levels. In chronic Lyme infection, the diagnosis is made based on history of acute Lyme infection and serological testing. electrophysiology. In MM, NCSs show evidence of a multifocal axonal neuropathy. In cases of radiculoneuritis, prolongation of F wave latencies and other signs of demyelination may be seen early in the disease process. Electromyography shows changes consistent with active and chronic denervation in a radicular pattern (64). treatment.

Treatment of the infection with ceftriaxone for 2 to 4 weeks in both the acute and chronic cases is the mainstay of treatment. Despite pathologic evidence for an immune-mediated process, there is no evidence that immunosuppressive treatments are effective. B. HIV Infection

clinical manifestations.

MM can occur in early stages of HIV infection with high CD4 counts and rarely in the advanced stage with low CD4 counts (65). MM in advanced AIDS is commonly related to cytomegalovirus (CMV) infection and presents with an acute rapidly progressive neuropathy (66,67). MM in the early stages of HIV infection tends to be less severe (65,68). pathogenesis and pathophysiology.

In CMV-related MM, there is infection of endothelial cells of endoneurial capillaries and inflammatory infiltrates around blood vessels. Nerve histology shows multifocal necrotic endoneurial lesions with neutrophillic infiltration; polymorphonuclear reaction may be related to tissue necrosis or to release of cytokines by CMV-infected cells (66). MM that occurs in the early stages of HIV infection is probably immune mediated. Necrotizing vasculitis has also been described in HIV-related MM (12,69–71), and virus-like particles have been found in Schwann cell cytoplasm (71), suggesting viral neurotropism as the inciting factor. Lastly, hepatitis C–related vasculitic neuropathy should also be considered because of the possibility of coinfection.

diagnostic evaluation.

Serological testing for initial diagnosis of HIV infection includes screening with an enzyme immunoassay and confirmation with a Western blot. In patients with CMV-related MM, signs of retinitis, gastroenteritis, or pneumonia secondary to CMV can make the diagnosis obvious. CSF polymerase chain reaction for CMV and demonstration of virus in nerve tissue can also aid in diagnosis. In immune-mediated MM, nerve biopsy can be important in diagnosis and shows necrotizing vasculitis with secondary multifocal axonal degeneration.

electrophysiology. Nerve conduction studies and EMG

show findings related to a multifocal axonal neuropathy, similar to that seen with systemic vasculitides.

treatment. In CMV-related MM, aggressive treatment of the infection with ganciclovir or foscarnet is important and may lead to stabilization, but prognosis is poor (65,67). Immunosuppression can be beneficial in patients with vasculitic MM (12,65,70,72).

C. Hepatitis Infection

clinical manifestations. Hepatitis B and C virus infections can cause MM. Hepatitis B virus is a common cause of PAN, as discussed above (73,74). Hepatitis C virus with or without cryoglobulinemia can also cause MM (11,75,76). There is suggestion that MM may be more common in patients without cryoglobulinemia and that polyneuropathy is more common with cryoglobulinemia (76). The clinical features vary depending on the size of the blood vessels involved (77). pathogenesis and pathophysiology.

The pathogenesis is related to vasculitis involving small and m­edium-sized epineurial blood vessels, with resulting nerve ischemia and multifocal axonal degeneration (74,75). In HCV infection, the disease mechanism is similar in patients with or without cryoglobulinemia (76). Viral RNA has been demonstrated in nerve tissue of patients with HCV (78) and may be the trigger for the immune cascade that i­nvolves various chemokines and cytokines (79). AntiGM1 and antisulfatide antibodies have also been seen in these p­atients (80), but their significance remains unclear.

diagnostic evaluation.

Hepatitis B serology consisting of hepatitis B surface antigen, hepatitis B core antibody (antiHBc), and hepatitis B surface (anti-HBs) antibody is useful in making the diagnosis. Anti-HCV antibody is a useful screening test for hepatitis C infection. Recombinant i­mmunoblot assay and qualitative and quantitative HCVRNA polymerase chain reaction can be useful in further diagnosis. Serum cryoglobulins are seen in approximately half of patients with chronic hepatitis C infection.

electrophysiology. Nerve conduction studies and EMG show a multifocal axonal neuropathy similar to that seen with the systemic vasculitides. treatment. In hepatitis B–related PAN, MM is treated with a combination of plasma exchange and antiviral agents (9). In MM related to HCV, treatment with interferon a (75) is effective; whether ribavirin used in conjunction is beneficial remains unclear (81). Immunosuppressive agents such as prednisone, plasma exchange, and rituximab should also be considered (11,82,83).

D. Leprosy

clinical manifestations.

Leprosy is endemic in South America, Asia, and Africa but is uncommon in the United States, mostly being seen in immigrants from endemic areas. Skin and peripheral nerve involvement are

50  Textbook of Peripheral Neuropathy

common in leprosy. The clinical manifestation depends on whether the disease is paucibacillary or multibacillary (84). Involvement of peripheral nerves at entrapment sites and of dermal nerves underlying skin lesions is common and can lead to MM. Ulnar neuropathy is common, but median, peroneal, tibial, and facial nerves can also be involved (84-86). The neuropathy tends to be sensory predominant at onset, with involvement of cutaneous nerves (loss of temperature and pain sensation); evolution to large-fiber sensory loss and motor involvement can occur with progression. Nerve hypertrophy is seen, especially in pure neuritic forms of the disease. pathogenesis and pathophysiology.

Peripheral nerve involvement can occur directly through site of entry or through hematogenous spread. The type of disease that evolves depends on the effectiveness of cellmediated immunity and balance between T-helper (type 1) and T-suppressor (type 2) cells. In paucibacillary cases, cell-mediated immunity is effective, while in multibacillary cases, it is deficient. Accordingly, in multibacillary cases, bacilli are seen in fibroblasts, macrophages, endothelial cells, and Schwann cells, and in paucibacillary cases, a hypertrophic reaction in the perineurium leading to fibrosis is typical. Lymphocytic vasculitis of the vasa nervorum also occurs but does not lead to ischemia. These pathological reactions lead to axonal degeneration and segmental demyelination (84).

diagnostic evaluation.

The diagnosis of leprosy, especially the paucibacillary cases, can be difficult and elusive. The World Health Organization expert committee on leprosy has designated diagnostic criteria as 1 or more hypopigmented or reddish spots with definite sensory loss (Figure 4.5), thickened peripheral nerves, or acid-fast bacilli seen on skin smears or biopsies (87). Serological tests, fluorescent antibody absorption test, and PGL-1 ELISA are also useful in diagnosis but are more sensitive in multibacillary cases. Bacteria can be identified with dermal scrapings or skin biopsy, especially in multibacillary cases. The lepromin skin test (not available in the United States) can be useful in classification of the type of leprosy and is an assessment of the patient’s cell-mediated immunity; the test result is strongly positive in paucibacillary cases. Nerve biopsy and fine needle aspiration can be useful in diagnosis in the pure neuritic form, where there are no skin lesions (84,88). electrophysiology. Nerve conduction studies show evidence of a multifocal neuropathy with features of axonal degeneration and segmental demyelination. Conduction slowing is typically seen at sites of entrapment and in hypertrophic nerves (84,89). There has been recent interest in using sonography looking at crosssectional nerve area as a diagnostic tool (86). treatment. The WHO-recommended multidrug regimen of dapsone, rifampicin, and clofazimine has been used

Figure 4.5 Hypopigmented and reddish skin lesions with decreased sensation in a patient with leprosy. since 1982 and is very effective (84,90,91). The recommended duration of treatment is 24 months in multibacillary cases and 6 months in paucibacillary cases, although there is some evidence that shorter duration of treatment in multibacillary cases may be sufficient (90). In patients with a very high initial bacterial load, treatment until slit skin smears become negative may be a useful strategy in decreasing relapse rate compared to the 24-month regimen (92). Steroids may also be of benefit in cases presenting with new weakness or sensory loss (93–95).

V. Inflammatory Disorders A. Sarcoidosis

clinical manifestations.

Peripheral nerve sarcoidosis can present with sensorimotor polyneuropathy, MM, and inflammatory neuropathy (96–100). Systemic symptoms such as weight loss, arthralgia, fatigue, malaise, fever, and involvement of other organs such as the skin, lungs, lymph nodes, and eyes is common. The neuropathy tends to be sensory predominant with an acute painful onset (99).

pathogenesis and pathophysiology.

Nerve biopsy speci­ men shows epineurial noncaseating granulomas, peri­ neuritis, multinucleated giant cells, microvasculitis, and necrotizing vasculitis (Figure 4.6). The inflammatory infiltrate is made up of macrophages and CD4+ T cells (97,100). Axonal degeneration is thought to extend from the root to the distal nerve and is related either to compression of nerve fibers by granuloma or from ischemia related to vasculitis (97,99,100).

diagnostic evaluation.

In the appropriate clinical context, the diagnosis of sarcoidosis is made based on histological evidence of noncaseating granulomas in affected tissue and elimination of other granulomatous disease processes. Serum angiotensin converting enzyme level can be elevated is some patients (97), but absence of elevation does not rule out the diagnosis. Gallium 67 scan, bronchoalveolar lavage lymphocyte count, and CD4+/CD8+ ratio can provide supportive evidence in

CHAPTER 4: Approach to the Evaluation of Mononeuropathy Multiplex   51 treatment.

Even though the disease can evolve for years, it is generally self-limited. Immunosuppressive agents may be considered is severe cases, but their efficacy remains unclear.

KEY POINT WMSN is a relatively benign disorder of cutaneous sensory nerves that presents with multifocal numbness. It is thought to be related to perineuritis. It should be differentiated from vasculitic neuropathy and sensory ganglionopathy, which may have a similar clinical presentation.

Figure 4.6 Blue arrow: Noncaseating granuloma. Black arrows: Compact granuloma with giant cell in a patient with sarcoidosis. diagnosis. Neuroimaging studies showing enlargement and T2 enhancement of nerve roots, plexus, and limb nerves can also be useful (99). electrophysiology. A multifocal axonal neuropathy or radiculoneuropathy is commonly seen on electrophysiological testing (96,98). Conduction blocks that improve with treatment, suggesting and element of focal demyelination have also been described (101). treatment. Steroids are the mainstay of treatment and can lead to stabilization of the neuropathy (97,99).

B. Sensory Perineuritis

clinical manifestations.

Wartenberg’s migrant sensory neuritis is an inflammatory condition that affects cutaneous nerves and presents with multifocal pain and numbness (102–105). It usually involves limb nerves, but torso nerves and the trigeminal nerve can also be involved (105). Pain is typically brought on by maneuvers that stretch the affected nerve. The disease evolves over several years, and eventual stabilization is common (105). Motor involvement is not seen even after long-term follow-up, but evolution to distal symmetric sensory neuropathy has been described (105).

VI. Diabetic Neuropathy Diabetes can present with MM through a vasculitic mechanism that has been discussed above. Entrapment neuropathies such as median neuropathy at the wrist, ulnar neuropathy at the elbow and peroneal neuropathy at the fibular head are common with diabetes and can result in a picture of MM (106).

VII. Demyelinating Neuropathies A. Hereditary Neuropathy With Liability to Pressure Palsies clinical manifestations. Hereditary neuropathy with liability to pressure palsies is an autosomal dominant, inherited demyelinating neuropathy related to deletion (85%) or mutation in the peripheral myelin protein 22 (PMP22) gene that results in focal myelin thickening (tomacula) and proneness of nerves to pressure, resulting in multiple entrapment neuropathies (107). This often results in a clinical picture of MM, although other phenotypes have been described (108). Patients may have recurrent acute episodes or a more chronically evolving multifocal disorder. pathogenesis and pathophysiology.

Deletion or mutation in the PMP22 gene leads to thickening of myelin surrounding nerve fibers and formation of tomaculae,

pathogenesis and pathophysiology. The pathogenesis is probably autoimmune, and nerve biopsies have shown inflammation of the perineurium, axonal degeneration, and immunoglobulin G deposition (103,104) (Figure 4.7). diagnostic evaluation.

The diagnosis is typically made based on the clinical picture and electrodiagnostic and nerve biopsy findings. Differentiation from a vasculitic neuropathy and sensory neuronopathy are important because management strategies are different.

electrophysiology.

Nerve conduction studies show reduction in the amplitude of SNAPs of affected nerves with conduction slowing (103,105).

Figure 4.7 Inflammatory infiltrate in the perineurium in patient with multifocal sensory neuropathy.

52  Textbook of Peripheral Neuropathy

also been described (118). The immune attack causes demyelinative CB leading to motor (MMN) or sensorimotor (LSS) symptoms.

which increase their liability to pressure palsies (109,110) (Figure 4.8).

diagnostic evaluation. The diagnosis of MMN and LSS should be considered in all patients who present with MM. Electrodiagnostic testing (see below) is useful for initial evaluation and can reveal CB. In MMN, the clinical picture can be confused with motor neuron disease, and careful clinical examination that indicates weakness in a peripheral nerve rather than segmental distribution is important in diagnosis (especially in patients in whom CB is not seen, as discussed below). Anti-GM1 antibodies are seen in some patients with MMN and can be useful in diagnosis (119), especially in patients without overt CB. Elevation of CSF protein level is seen in patients with LSS, but GM-1 antibodies are typically absent (116).

diagnostic evaluation.

electrophysiology.

Figure 4.8 Focal myelin thickening (tomacula) in single teased nerve fiber in a patient with HNPP.

Electrodiagnostic testing is useful in initial evaluation (see below). Definitive diagnosis is made through genetic testing for PMP22 gene deletions. Nerve biopsy is rarely necessary but shows sausage like swellings in the myelin sheath or tomaculae.

electrophysiology.

Conduction slowing at sites of entrapment is the electrophysiological hallmark of these neuropathies, although a generalized demyelinating neuropathy can also be seen and may dominate the clinical picture (107,108,111–113). Acquired demyelinating neuropathies can sometimes lead to a similar electrophysiological picture and can lead to misdiagnosis.

treatment.

Avoidance of prolonged external pressure on nerves and use of splints can prevent pressure palsies.

KEY POINT In patients with multiple compressive neuropathies and electrophysiological evidence of conduction slowing at sites of entrapment, the diagnosis of HNPP should be considered. B. Multifocal Motor Neuropathy and Lewis-Sumner Syndrome clinical manifestations. MMN is characterized by multifocal weakness in the distribution individual peripheral nerves, without sensory symptoms, that results in a clinical picture of a purely motor MM (114). In LSS, additionally, sensory axons are involved, resulting in sensorimotor MM (115). Some patients with LSS can develop a confluent pattern that resembles CIDP, although in most patients, the disease remains multifocal (116). pathogenesis and pathophysiology. MMN and LSS are inflammatory neuropathies presumably related to an autoimmune attack on myelin components of peripheral nerve (117). MMN secondary to TNF blockers has

The electrophysiological hallmark is the presence of demyelinative CB in motor (MMN) or sensory and motor (LSS) axons that persists and remains localized for long periods of time (114,115) (Figure 4.2). In some patients with MMN, CB may not be demonstrable, and the picture is that of a multifocal axonal neuropathy sparing sensory axons (120,121).

treatment. IVIg is efficacious in the treatment of MMN and LSS, although patients with LSS may also respond to steroids (116,122). Other immunosuppressive treatments may also be used (117).

KEY POINT When CB is seen at nonentrapment sites, the diagnosis of MMN or LSS should be considered. In MMN, CB exclusively affects the motor axons, and the SNAP response is preserved with stimulation proximal to the CB.

References 1. Kissel JT, Slivka AP, Warmolts JR, Mendell JR. The clinical spectrum of necrotizing angiopathy of the peripheral nervous system. Ann Neurol. 1985;18(2):251–257. 2. Davies L, Spies JM, Pollard JD, McLeod JG. Vasculitis confined to peripheral nerves. Brain. 1996;119(pt 5):1441–1448. 3. Said G, Lacroix-Ciaudo C, Fujimura H, Blas C, Faux N. The peripheral neuropathy of necrotizing arteritis: a clinicopathological study. Ann Neurol. 1988;23(5):461–465. 4. Slee M, Selvan A, Donaghy M. Multifocal motor neuropathy: the diagnostic spectrum and response to treatment. Neurology. 2007;69(17):1680–1687. 5. Ropert A, Metral S. Conduction block in neuropathies with necrotizing vasculitis. Muscle Nerve. 1990;13(2):102–105. 6. McCluskey L, Feinberg D, Cantor C, Bird S. “Pseudoconduction block” in vasculitic neuropathy. Muscle Nerve. 1999;22(10):1361–1366.

CHAPTER 4: Approach to the Evaluation of Mononeuropathy Multiplex   53 7. Lhote F, Cohen P, Guillevin L. Polyarteritis nodosa, microscopic polyangiitis and Churg-Strauss syndrome. Lupus. 1998;7(4):238–258. 8. Cattaneo L, Chierici E, Pavone L, et al. Peripheral neuropathy in Wegener’s granulomatosis, Churg-Strauss syndrome and microscopic polyangiitis. J Neurol Neurosurg Psychiatry. 2007;78(10):1119–1123. 9. Guillevin L, Mahr A, Callard P, et al. Hepatitis B virusassociated polyarteritis nodosa: clinical characteristics, outcome, and impact of treatment in 115 patients. Medicine (Baltimore). 2005;84(5):313–322. 10. Cacoub P, Terrier B. Hepatitis B-related autoimmune manifestations. Rheum Dis Clin North Am. 2009;35(1):125–137. 11. Cacoub P, Maisonobe T, Thibault V, et al. Systemic vasculitis in patients with hepatitis C. J Rheumatol. 2001;28(1):109–118. 12. Bradley WG, Verma A. Painful vasculitic neuropathy in HIV-1 infection: relief of pain with prednisone therapy. Neurology. 1996;47(6):1446–1451. 13. Stafford CR, Bogdanoff BM, Green L, Spector HB. Mono­ neuropathy multiplex as a complication of amphetamine angiitis. Neurology. 1975;25(6):570–572. 14. Orriols R, Munoz X, Ferrer J, Huget P, Morell F. Cocaineinduced Churg-Strauss vasculitis. Eur Respir J. 1996;9(1): 175–177. 15. Ogawa N, Kawai H, Yamakawa I, Sanada M, Sugimoto T, Maeda K. Case of minocycline-induced vasculitic neuropathy. Rinsho Shinkeigaku. 2010;50(5):301–305. 16. Mouthon L. Causes and mechanisms of systemic vasculitides. Rev Prat. 2008;58(5):487–491. 17. Bouche P, Leger JM, Travers MA, Cathala HP, Castaigne P. Peripheral neuropathy in systemic vasculitis: clinical and electrophysiologic study of 22 patients. Neurology. 1986;36(12):1598–1602. 18. Nishino H, Rubino FA, DeRemee RA, Swanson JW, Parisi JE. Neurological involvement in Wegener’s granulomatosis: an analysis of 324 consecutive patients at the Mayo Clinic. Ann Neurol. 1993;33(1):4–9. 19. Jennette JC, Falk RJ. The role of pathology in the diagnosis of systemic vasculitis. Clin Exp Rheumatol. 2007;25(1 suppl 44):S52–S56. 20. Collins MP, Periquet-Collins I. Nonsystemic vasculi­ tic neuropathy: update on diagnosis, classification, patho­ genesis, and treatment. Front Neurol Neurosci. 2009;26: 26–66. 21. Hawke SH, Davies L, Pamphlett R, Guo YP, Pollard JD, McLeod JG. Vasculitic neuropathy. A clinical and pathological study. Brain. 1991;114(pt 5):2175–2190. 22. Gorson KC. Therapy for vasculitic neuropathies. Curr Treat Options Neurol. 2006;8(2):105–117. 23. Collins MP, Periquet MI, Mendell JR, Sahenk Z, Nagaraja HN, Kissel JT. Nonsystemic vasculitic neuropathy: insights from a clinical cohort. Neurology. 2003;61(5):623–630. 24. Collins MP, Periquet MI. Isolated vasculitis of the peripheral nervous system. Clin Exp Rheumatol. 2008;26(3 suppl 49):S118–S130. 25. Oddis CV, Eisenbeis CH Jr, Reidbord HE, Steen VD, Medsger TA Jr. Vasculitis in systemic sclerosis: association with Sjogren’s syndrome and the CREST syndrome variant. J Rheumatol. 1987;14(5):942–948. 26. Hellmann DB, Laing TJ, Petri M, Whiting-O’Keefe Q, Parry GJ. Mononeuritis multiplex: the yield of evaluations for occult rheumatic diseases. Medicine (Baltimore). 1988;67(3):145–153.

27. Andonopoulos AP, Lagos G, Drosos AA, Moutsopoulos HM. Neurologic involvement in primary Sjogren’s syndrome: a preliminary report. J Autoimmun. 1989;2(4):485–488. 28. Puechal X, Said G, Hilliquin P, et al. Peripheral neuropathy with necrotizing vasculitis in rheumatoid arthritis. A clinicopathologic and prognostic study of thirty-two patients. Arthritis Rheum. 1995;38(11):1618–1629. 29. Genta MS, Genta RM, Gabay C. Systemic rheumatoid vasculitis: a review. Semin Arthritis Rheum. 2006;36(2):88–98. 30. Ramos-Casals M, Nardi N, Lagrutta M, et al. Vasculitis in systemic lupus erythematosus: prevalence and clinical characteristics in 670 patients. Medicine (Baltimore). 2006;85(2):95–104. 31. Raff MC, Sangalang V, Asbury AK. Ischemic mononeuropathy multiplex in association with diabetes mellitus. Neurology. 1968;18(3):284. 32. Fraser DM, Campbell IW, Ewing DJ, Clarke BF. Mononeuropathy in diabetes mellitus. Diabetes. 1979;28(2):96–101. 33. Kelkar P, Parry GJ. Mononeuritis multiplex in diabetes mellitus: evidence for underlying immune pathogenesis. J Neurol Neurosurg Psychiatry. 2003;74(6):803–806. 34. Shields RW Jr, Harris JW, Clark M. Mononeuropathy in sickle cell anemia: anatomical and pathophysiological basis for its rarity. Muscle Nerve. 1991;14(4):370–374. 35. Roohi F, Gowda RM, Goel N, Kula RW. Mononeuropathy multiplex in sickle cell disease: a complication in need of recognition. J Clin Neuromuscul Dis. 2001;3(2):63–69. 36. Greenberg MK, Sonoda T. Mononeuropathy multiplex complicating idiopathic thrombocytopenic purpura. Neurology. 1991;41(9):1517–1518. 37. Yalcin A, Avcu F, Cetin T, Yesilova Z, Beyan C, Kaptan K. Mononeuropathy multiplex in the course of idiopathic thrombocytopenic purpura. A case report. Acta Haematol. 1998;100(4):211–212. 38. Ijichi T, Muranishi M, Shimura K, et al. Idiopathic thrombocytopenic purpura and mononeuropathy multiplex. Acta Haematol. 2003;110(1):33–35. 39. Chang C, Shen M. Mononeuropathy multiplex in hemophilia: an electrophysiologic assessment. Eur Neurol. 1998;40(1):15–18. 40. Johnson PC, Rolak LA, Hamilton RH, Laguna JF. Paraneoplastic vasculitis of nerve: a remote effect of cancer. Ann Neurol. 1979;5(5):437–444. 41. Liang BC, Albers JW, Sima AA, Nostrant TT. Paraneoplastic pseudo-obstruction, mononeuropathy  multi­plex, and sensory neuronopathy. Muscle Nerve. 1994;17(1):91–96. 42. Oh SJ. Paraneoplastic vasculitis of the peripheral nervous system. Neurol Clin. 1997;15(4):849–863. 43. Walk D, Handelsman A, Beckmann E, Kozloff M, Shapiro C. Mononeuropathy multiplex due to infiltration of lymphoma in hematologic remission. Muscle Nerve. 1998;21(6):823–826. 44. Pages M, Girard-Herpe M, Rousset T, Pages AM. NonHodgkin’s malignant lymphoma of the peripheral nervous system: clinicopathological correlations in ten patients. Rev Neurol (Paris). 2005;161(8-9):823–828. 45. Fain O, Hamidou M, Cacoub P, et al. Vasculitides associated with malignancies: analysis of sixty patients. Arthritis Rheum. 2007;57(8):1473–1480. 46. Solans-Laque R, Bosch-Gil JA, Perez-Bocanegra C, SelvaO’Callaghan A, Simeon-Aznar CP, Vilardell-Tarres M. Paraneoplastic vasculitis in patients with solid tumors: report of 15 cases. J Rheumatol. 2008;35(2):294–304.

54  Textbook of Peripheral Neuropathy 47. Grisold W, Piza-Katzer H, Jahn R, Herczeg E. Intraneural nerve metastasis with multiple mononeuropathies. J Peripher Nerv Syst. 2000;5(3):163–167. 48. Cantone G, Rath SA, Richter HP. Intraneural metastasis in a peripheral nerve. Acta Neurochir (Wien). 2000;142(6):719–720. 49. Matsumine A, Kusuzaki K, Hirata H, Fukutome K, Maeda M, Uchida A. Intraneural metastasis of a synovial sarcoma to a peripheral nerve. J Bone Joint Surg Br. 2005;87(11):1553–1555. 50. Lekos A, Katirji MB, Cohen ML, Weisman R Jr, Harik SI. Mononeuritis multiplex. A harbinger of acute leukemia in relapse. Arch Neurol. 1994;51(6):618–622. 51. Levin N, Soffer D, Grissaru S, Aizikovich N, Gomori JM, Siegal T. Primary T-cell CNS lymphoma presenting with leptomeningeal spread and neurolymphomatosis. J Neurooncol. 2008;90(1):77–83. 52. Baehring J, Cooper D. Neurolymphomatosis. J Neurooncol. 2004;68(3):243-244. 53. Baehring JM, Damek D, Martin EC, Betensky RA, Hochberg FH. Neurolymphomatosis. Neuro Oncol. 2003;5(2):104–115. 54. Ashok Muley S, Brown K, Parry GJ. Paraneoplastic vasculitic neuropathy related to carcinoid tumor. J Neurol. 2008;255(7):1085–1087. 55. Billstrom R, Lundquist A. Acute myelomonocytic leukaemia with infiltrative peripheral neuropathy. J Intern Med. 1992;232(2):193–194. 56. Rosso SM, de Bruin HG, Wu KL, van den Bent MJ. Diagnosis of neurolymphomatosis with FDG PET. Neurology. 2006;67(4):722–723. 57. Kim JH, Jang JH, Koh SB. A case of neurolymphomatosis involving cranial nerves: MRI and fusion PET-CT findings. J Neuroonol. 2006;80:209–210. 58. Pachner AR, Steere AC. The triad of neurologic manifestations of Lyme disease: meningitis, cranial neuritis, and radiculoneuritis. Neurology. 1985;35(1):47–53. 59. Meier C, Grahmann F, Engelhardt A, Dumas M. Peripheral nerve disorders in Lyme-Borreliosis. Nerve biopsy studies from eight cases. Acta Neuropathol. 1989;79(3):271–278. 60. Tezzon F, Corradini C, Huber R, et al. Vasculitic mononeuritis multiplex in patient with Lyme disease. Ital J Neurol Sci. 1991;12(2):229–232. 61. Logigian EL. Peripheral nervous system Lyme borreliosis. Semin Neurol. 1997;17(1):25–30. 62. Jalladeau E, Pradat PF, Maisonobe T, Leger JM. Multiple mononeuropathy and inflammatory syndrome manifested in Lyme disease. Rev Neurol (Paris). 2001;157(10):1290–1292. 63. Elamin M, Alderazi Y, Mullins G, Farrell MA, O’Connell S, Counihan TJ. Perineuritis in acute lyme neuroborreliosis. Muscle Nerve. 2009;39(6):851–854. 64. Muley SA, Parry GJ. Antibiotic responsive demyelinating neuropathy related to Lyme disease. Neurology. 2009;72(20):1786–1787. 65. Robinson-Papp J, Simpson DM. Neuromuscular diseases associated with HIV-1 infection. Muscle Nerve. 2009;40(6):1043–1053. 66. Said G, Lacroix C, Chemouilli P, et al. Cytomegalovirus neuropathy in acquired immunodeficiency syndrome: a clinical and pathological study. Ann Neurol. 1991;29(2):139–146. 67. Roullet E, Assuerus V, Gozlan J, et al. Cytomegalovirus multifocal neuropathy in AIDS: analysis of 15 consecutive cases. Neurology. 1994;44(11):2174–2182. 68. Wulff EA, Wang AK, Simpson DM. HIV-associated peripheral neuropathy: epidemiology, pathophysiology and treatment. Drugs. 2000;59(6):1251–1260.

69. Dalakas MC, Pezeshkpour GH. Neuromuscular diseases associated with human immunodeficiency virus infection. Ann Neurol. 1988;23(suppl):S38–S48. 70. Brannagan TH III. Retroviral-associated vasculitis of the nervous system. Neurol Clin. 1997;15(4):927–944. 71. Mahadevan A, Gayathri N, Taly AB, Santosh V, Yasha TC, Shankar SK. Vasculitic neuropathy in HIV infection: a c­linicopathological study. Neurol India. 2001;49(3):277–283. 72. Lipkin WI, Parry G, Kiprov D, Abrams D. Inflammatory neuropathy in homosexual men with lymphadenopathy. Neurology. 1985;35(10):1479–1483. 73. Henegar C, Pagnoux C, Puechal X, et al. A paradigm of diagnostic criteria for polyarteritis nodosa: analysis of a series of 949 patients with vasculitides. Arthritis Rheum. 2008;58(5):1528–1538. 74. 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. 75. Khella SL, Frost S, Hermann GA, et al. Hepatitis C infection, cryoglobulinemia, and vasculitic neuropathy. Treatment with interferon alfa: case report and literature review. Neurology. 1995;45(3 pt 1):407–411. 76. Nemni R, Sanvito L, Quattrini A, Santuccio G, Camerlingo M, Canal N. Peripheral neuropathy in hepatitis C virus infection with and without cryoglobulinaemia. J Neurol Neurosurg Psychiatry. 2003;74(9):1267–1271. 77. Taieb G, Maisonobe T, Musset L, Cacoub P, Leger JM, Bouche P. Cryoglobulinemic peripheral neuropathy in hepatitis C virus infection: clinical and anatomical correlations of 22 cases. Rev Neurol (Paris). 2010;166(5):509–514. 78. De Martino L, Sampaolo S, Tucci C, et al. Viral RNA in nerve tissues of patients with hepatitis C infection and peripheral neuropathy. Muscle Nerve. 2003;27(1):102–104. 79. Saadoun D, Bieche I, Authier FJ, et al. Role of matrix metalloproteinases, proinflammatory cytokines, and oxidative stress-derived molecules in hepatitis C virus-associated mixed cryoglobulinemia vasculitis neuropathy. Arthritis Rheum. 2007;56(4):1315–1324. 80. Alpa M, Ferrero B, Cavallo R, et al. Anti-neuronal antibodies in patients with HCV-related mixed cryoglobulinemia. Autoimmun Rev. 2008;8(1):56–58. 81. Brok J, Gluud LL, Gluud C. Meta-analysis: ribavirin plus interferon vs. interferon monotherapy for chronic hepatitic C - an updated Cochrane review. Aliment Pharmacol Ther. 2010;32(7):840–850. 82. Bryce AH, Dispenzieri A, Kyle RA, et al. Response to rituximab in patients with type II cryoglobulinemia. Clin Lymphoma Myeloma. 2006;7(2):140–144. 83. Cavallo R, Roccatello D, Menegatti E, Naretto C, Napoli F, Baldovino S. Rituximab in cryoglobulinemic peripheral neuropathy. J Neurol. 2009;256(7):1076–1082. 84. Panezai S, Saleh FG. Leprosy and peripheral neuropathy. J Clin Neuromuscul Dis. 2004;5(3):138–145. 85. van Brakel WH, Nicholls PG, Das L, et al. The INFIR Cohort Study: investigating prediction, detection and pathogenesis of neuropathy and reactions in leprosy. Methods and baseline results of a cohort of multibacillary leprosy patients in north India. Lepr Rev. 2005;76(1):14–34. 86. Elias J Jr, Nogueira-Barbosa MH, Feltrin LT, et al. Role of ulnar nerve sonography in leprosy neuropathy with electrophysiologic correlation. J Ultrasound Med. 2009;28(9):1201–1209.

CHAPTER 4: Approach to the Evaluation of Mononeuropathy Multiplex   55 87. Ustianowski AP, Lockwood DN. Leprosy: current diagnostic and treatment approaches. Curr Opin Infect Dis. 2003;16(5):421–427. 88. Jayaseelan E, Shariff S, Rout P. Cytodiagnosis of primary neuritic leprosy. Int J Lepr Other Mycobact Dis. 1999; 67(4):429–434. 89. McLeod JG, Hargrave JC, Walsh JC, Booth GC, Gye RS, Barron A. Nerve conduction studies in leprosy. Int J Lepr Other Mycobact Dis. 1975;43(1):21–31. 90. Lockwood DN, Kumar B. Treatment of leprosy. BMJ. 2004;328(7454):1447–1448. 91. Nations SP, Barohn RJ. Peripheral Neuropathy Due to Leprosy. Curr Treat Options Neurol. 2002;4(3):189–196. 92. Girdhar BK, Girdhar A, Kumar A. Relapses in multibacillary leprosy patients: effect of length of therapy. Lepr Rev. 2000;71(2):144–153. 93. Britton WJ. The management of leprosy reversal reactions. Lepr Rev. 1998;69(3):225–234. 94. Garbino JA, Virmond Mda C, Ura S, Salgado MH, Naafs B. A randomized clinical trial of oral steroids for ulnar neuropathy in type 1 and type 2 leprosy reactions. Arq Neuropsiquiatr. 2008;66(4):861–867. 95. Jardim MR, Illarramendi X, Nascimento OJ, et al. Pure neural leprosy: steroids prevent neuropathy progression. Arq Neuropsiquiatr. 2007;65(4A):969–973. 96. Zuniga G, Ropper AH, Frank J. Sarcoid peripheral neuropathy. Neurology. 1991;41(10):1558–1561. 97. Said G, Lacroix C, Plante-Bordeneuve V, et al. Nerve granulomas and vasculitis in sarcoid peripheral neuropathy: a clinicopathological study of 11 patients. Brain. 2002;125(pt 2):264–275. 98. Zivkovic SA, Lacomis D. Sarcoid neuropathy: case report and review of the literature. J Clin Neuromuscul Dis. 2004;5(4):184–189. 99. Burns TM, Dyck PJ, Aksamit AJ, Dyck PJ. The natural history and long-term outcome of 57 limb sarcoidosis neuropathy cases. J Neurol Sci. 2006;244(1-2):77–87. 100. Vital A, Lagueny A, Ferrer X, Louiset P, Canron MH, Vital C. Sarcoid neuropathy: clinico-pathological study of 4 new cases and review of the literature. Clin Neuropathol. 2008;27(2):96–105. 101. Sawai S, Misawa S, Kobayashi M, et al. Multifocal conduction blocks in sarcoid peripheral neuropathy. Intern Med. 2010;49(5):471–474. 102. Sprofkin BE. Cheiralgia paresthetica—Wartenberg’s disease. Neurology. 1954;4(11):857–862. 103. Laterre C, Ghilain S, Tassin S, Guerit JM. Wartenberg’s disseminated sensory neuropathy. Rev Neurol (Paris). 1988;144(5):358–364. 104. Nicolle MW, Barron JR, Watson BV, Hammond RR, Miller TA. Wartenberg’s migrant sensory neuritis. Muscle Nerve. 2001;24(3):438–443. 105. Stork AC, van der Meulen MF, van der Pol WL, Vrancken AF, Franssen H, Notermans NC. Wartenberg’s migrant sensory neuritis: a prospective follow-up study. J Neurol. 2010;257(8):1344–1348.

106. Said G. Diabetic neuropathy—a review. Nat Clin Pract Neurol. 2007;3(6):331–340. 107. Mouton P, Tardieu S, Gouider R, et al. Spectrum of clinical and electrophysiologic features in HNPP patients with the 17p11.2 deletion. Neurology. 1999;52(7):1440–1446. 108. Kumar N, Muley S, Pakiam A, Parry GJ. Phenotypic Variability Leads to Under-recognition of HNPP. J Clin Neuromuscul Dis. 2002;3(3):106–112. 109. Gabreels-Festen A, Wetering RV. Human nerve pathology caused by different mutational mechanisms of the PMP22 gene. Ann N Y Acad Sci. 1999;883:336–343. 110. Vital A, Vital C, Latour P, et al. Peripheral nerve biopsy study in 19 cases with 17p11.2 deletion. J Neuropathol Exp Neurol. 2004;63(11):1167–1172. 111. Verhagen WI, Gabreels-Festen AA, van Wensen PJ, et al. Hereditary neuropathy with liability to pressure palsies: a clinical, electroneurophysiological and morphological study. J Neurol Sci. 1993;116(2):176–184. 112. Amato AA, Gronseth GS, Callerame KJ, Kagan-Hallet KS, Bryan WW, Barohn RJ. Tomaculous neuropathy: a clinical and electrophysiological study in patients with and without 1.5-Mb deletions in chromosome 17p11.2. Muscle Nerve. 1996;19(1):16–22. 113. Pareyson D, Scaioli V, Taroni F, et al. Phenotypic heterogeneity in hereditary neuropathy with liability to pressure palsies associated with chromosome 17p11.2-12 deletion. Neurology. 1996;46(4):1133–1137. 114. Parry GJ, Clarke S. Multifocal acquired demyelinating neuropathy masquerading as motor neuron disease. Muscle Nerve. 1988;11(2):103–107. 115. Lewis RA, Sumner AJ, Brown MJ, Asbury AK. Multifocal demyelinating neuropathy with persistent conduction block. Neurology. 1982;32(9):958–964. 116. Saperstein DS, Amato AA, Wolfe GI, et al. Multifocal acquired demyelinating sensory and motor neuropathy: the Lewis-Sumner syndrome. Muscle Nerve. 1999;22(5): 560–566. 117. Muley SA, Parry GJ. Inflammatory demyelinating neuropathies. Curr Treat Options Neurol. 2009;11(3):221–227. 118. Lozeron P, Denier C, Lacroix C, Adams D. Long-term course of demyelinating neuropathies occurring during tumor necrosis factor-alpha-blocker therapy. Arch Neurol. 2009;66(4):490–497. 119. Pestronk A, Cornblath DR, Ilyas AA, et al. A treatable multifocal motor neuropathy with antibodies to GM1 ganglioside. Ann Neurol. 1988;24(1):73–78. 120. Pakiam AS, Parry GJ. Multifocal motor neuropathy without overt conduction block. Muscle Nerve. 1998;21(2): 243–245. 121. Katz JS, Barohn RJ, Kojan S, et al. Axonal multifocal motor neuropathy without conduction block or other features of demyelination. Neurology. 2002;58(4):615–620. 122. Leger JM, Chassande B, Musset L, Meininger V, Bouche P, Baumann N. Intravenous immunoglobulin therapy in multifocal motor neuropathy: a double-blind, placebocontrolled study. Brain. 2001;124(pt 1):145–153.

Jennifer A. Tracy and P. James B. Dyck

5

Diabetic Neuropathy

INTRODUCTION AND DESCRIPTION OF THE TYPE OF NEUROPATHY

While diabetic polyneuropathy is the most common pattern of neuropathy observed in diabetic patients, other types include diabetic lumbosacral radiculoplexus neuropathy (DLRPN), thoracic radiculopathies, autonomic neuropathy, cranial neuropathies, “insulin neuritis,” and mononeuropathies (such as carpal tunnel syndrome). “Diabetic chronic inflammatory demyelinating polyneuropathy (CIDP)” and, in recent years, the entity of glucose intolerance neuropathy have been described. Each of these entities will be reviewed individually, as the clinical presentations and mechanisms may be distinct.

Diabetic neuropathies are common in the general population and varied in their manifestations, and they have different underlying mechanisms, including metabolic, inflammatory, ischemic, and compressive. They are not a single disease but many, and the subtype needs to be correctly identified to know how to best treat them. They range from carpal tunnel syndrome or mild length-dependent peripheral neuropathies to severe diabetic lumbosacral radiculoplexus neuropathies causing marked disability. Identification of these types of neuropathy is important and may directly alter patient management, resulting in attempts to gain tighter glucose control measures for some patients, immunotherapy in other selected patients, and in all patients the need for proper education to avoid worsening of the underlying neuropathy and to protect against secondary injuries, such as ulcerations and amputations.

Diabetic Sensorimotor Polyneuropathy Diabetic sensorimotor polyneuropathy (DPN) is the most well-recognized neuropathic syndrome in diabetic patients. The presentation is usually insidious, with a length-dependent pattern of loss of sensation to both large-fiber (vibration, touch, and proprioception) and small-fiber (pain, temperature) modalities. The feet are generally affected first, and given the length-dependent aspect, the hands generally become affected later in the course of the disease, generally by the time the lower extremity neuropathic symptoms/signs reach the level of the knees. Recently, DPN that shows length-dependent sensory loss has been termed typical DPN, whereas DPN that is a painful and small-fiber neuropathy without other findings have been termed atypical DPN (2). Weakness is uncommon in DPN and, when present at all, is a minor feature. Dyck et al (1), in a communitybased study of diabetic patients, found that only 6% of type 1 diabetic patients and 1% of type 2 diabetic patients had a severe enough neuropathy that they were unable to walk on their heels. Motor deficits can occur, but significant motor deficits should prompt a search for other causes of neuropathy. Although DPN is very common (about half of diabetic patients will develop it), most cases of DPN are so mild that it is asymptomatic and identified only on baseline testing. Early or preferential upper extremity involvement should raise

CLINICAL MANIFESTATIONS The clinical manifestations of diabetic neuropathy are varied. In a large cohort of diabetic patients followed longitudinally (the Rochester Diabetic Neuropathy Study), Dyck et al (1) found that 66% of insulin-dependent diabetic patients (type 1 diabetes mellitus) had some type of neuropathy (54% polyneuropathy, 22% asymptomatic carpal tunnel syndrome, 11% symptomatic carpal tunnel syndrome, 7% autonomic neuropathy, 3% other types) and 59% of non–insulin-dependent diabetic patients (type 2 diabetes mellitus) had neuropathy (45% polyneuropathy, 29% asymptomatic carpal tunnel syndrome, 6% symptomatic carpal tunnel syndrome, 5% autonomic neuropathy, 3% other types). This study highlighted the frequency and importance of careful neurologic evaluation in these patients. Furthermore, it highlighted that not all neuropathies are the same and that perhaps more important than how frequent neuropathy occurs in diabetes mellitus is how severe it is; severe neuropathies occurred uncommonly. 57

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consideration of a superimposed neuropathic phenomenon, such as carpal tunnel syndrome or ulnar neuropathy at the elbow (3). Diabetic sensorimotor polyneuropathy is not an early diabetic phenomenon; it is more common with more prolonged exposures to hyperglycemia, and the presence of DPN is correlated with the presence of other microvascular complications of diabetes, such as diabetic retinopathy and nephropathy (4). In serial testing of summated nerve conduction attributes, subclinical worsening has been observed even before meeting standard criteria for DPN, again suggesting an insidious process (5).

Neuropathy With Impaired Glucose Tolerance This is an entity that has received increased attention in recent years. While classical DPN is associated with prolonged hyperglycemic exposure and other evidence of microvascular damage, the neuropathy of impaired glucose tolerance is present in prediabetic subjects and in people with a shorter duration of hyperglycemic exposure. Impaired glucose tolerance is typically assessed by the use of a 2-hour oral glucose tolerance test. In healthy subjects, at 2 hours after test initiation, blood sugar should be less than 140 mg/dL. The criterion for impaired glucose tolerance is a 2-hour blood sugar level from 140 mg/dL to 199 mg/dL, and a 2-hour blood sugar level at 200 mg/dL or higher is consistent with diabetes. A number of authors have noted an increased rate of abnormal glucose tolerance test results in patients with otherwise idiopathic peripheral neuropathy. Singleton et al (6) prospectively tested 107 patients with idiopathic neuropathy with glucose tolerance tests and found that 13 had diabetes mellitus and 36 had impaired glucose tolerance, which they note is almost 3 times the prevalence among previously published control patients. Sumner et al (7) had glucose tolerance tests performed on 73 patients with idiopathic peripheral neuropathy and found that 56% had abnormal results (26 with impaired glucose tolerance and 15 with diabetes mellitus); they reported that the patients with impaired glucose tolerance had a predominant small-fiber neuropathy. HoffmanSnyder et al (8) retrospectively reviewed records of patients with chronic idiopathic axonal neuropathy who had an oral glucose tolerance test performed and found that 62% had abnormalities on the oral glucose tolerance test (OGTT) consistent with either impaired glucose tolerance (38 patients) or diabetes mellitus (24 patients). The presentation of neuropathy associated with glucose intolerance is generally small-fiber predominant, with prominent pain complaints (6). Sumner et al (7) also showed that the neuropathy of impaired glucose tolerance affected small nerve fibers predominantly and also that it was less severe than diabetic neuropathy (by criteria of sural nerve conduction studies [NCSs] and distal intraepidermal nerve fiber density). However there may be some variation; Hoffman-Snyder et al (8)

found similar rates of each subtype of glucose metabolism in the 3 subtypes of their patients (sensorimotor, pure sensory, small fiber). The results of the association of impaired glucose tolerance and neuropathy are intriguing but have some methodological issues. The patients in the studies were taken from neurologic practices with idiopathic smallfiber neuropathies and were not population based. Furthermore, the controls were taken from previously published data. With the epidemic of obesity occurring in Western populations, it is unclear to the authors whether these results definitely establish a causal relation between small-fiber neuropathies and impaired glucose tolerance. A population-based study of impared glucose tolerance (IGT) and peripheral neuropathy has just been published and found that there is not an increased frequency of peripheral neuropathy in the IGT group compared to the normal blood sugar group. However, people who initially were diagnosed as having new-onset diabetes mellitus were found to have an increased frequency of peripheral neuropathy (9).

Diabetic Lumbosacral Radiculoplexus Neuropathy Diabetic lumbosacral radiculoplexus neuropathy is a relatively uncommon entity but has been found to occur in approximately 1% of diabetic patients (1). It has been described as diabetic amyotrophy (10), proximal diabetic neuropathy (11), and several other terms, making evalua­ tion of the literature more complex. A series by Dyck et al (12) prospectively evaluated the clinical features, electrophysiologic and other studies, and nerve pathology of 33 patients with DLRPN. The median age of this group was 65 years; in general, they had mild diabetes mellitus, and nearly all (except for 1) had type 2 diabetes with a low rate of microvascular complications such as retinopathy or nephropathy. When compared with the Rochester Diabetic Neuropathy Study cohort, a community-based study of diabetic patients, the patients with DLRPN had significantly lower hemoglobin A1c and body mass index and significantly less retinopathy and cardiovascular disease. The typical presentation is subacute onset of severe unilateral lower extremity pain, followed by weakness and sensory loss. This form of diabetic neuropathy probably produces the greatest morbidity. The pain is aching, burning, and lancinating. Contact allodynia (touch causing a painful response) is very common. Likewise, weakness is profound, and most patients require the use of gait-assistive devices. The weakness involves both proximal and distal segments, so patients have difficulty getting out of chairs and frequently have footdrop. While most patients have unilateral symptoms, in the Dyck et al (4) cohort, all but 1 patient eventually developed bilateral involvement. One half of the patients had some degree of autonomic involvement, such as orthostatic hypotension or problems with gastrointestinal motility. By the time of the follow-up telephone interview (median of 25.9 months

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after symptom onset), 2 of 31 patients reported that they were back to normal, while weakness, distal predominant, was the major long-term complaint. Approximately one half of the cohort required a wheelchair at the time of initial evaluation, but only 3 were still using wheelchairs at the follow-up interview, and 12 needed no gait assists at all. Diabetic lumbosacral radiculoplexus neuropathy often occurs in conjunction with diabetic thoracic radiculopathies and with diabetic cervical radiculoplexus neuropathies. Together, the lumbosacral, thoracic, and cervical syndromes are termed diabetic radiculoplexus neuropathies. These types of neuropathy are clinically and pathologically distinct from DPN.

Diabetic Autonomic Neuropathy There is a clear relationship between the development of DPN and the development of autonomic neuropathy. Autonomic neuropathies in diabetes can be mild or severe and can include but are not limited to symptoms/ signs such as orthostatic hypotension, erectile dysfunction, and gastroparesis. Painful DPN is associated with greater autonomic dysfunction than painless DPN (13). A study of 702 diabetic patients from the Joslin Clinic assessing orthostatic hypotension found a prevalence of 12% in males and 13% in females, and the authors noted that the amount of systolic blood pressure decrease was associated with age, postprandial blood glucose, supine diastolic blood pressure, and the presence of retinopathy (14). Gastric emptying has been found to be slowed in approximately 30% to 50% of patients with long-term type 1 or type 2 diabetes, although there is not always a clear relationship between gastrointestinal symptoms and degree of slowing (15). Erectile dysfunction occurs more frequently in diabetes mellitus. A study of 312 Iranian patients with diabetes mellitus (mean age, 55.2 years; mean duration of diabetes, 7.6 years) reported a 34% prevalence of moderate to complete erectile dysfunction; they note a higher risk in patients with comorbidities of depression and cardiovascular disease (16). The severity of erectile dysfunction is noted to be associated with higher hemoglobin A1c levels (17). An association has been found between the presence of urinary incontinence and insulin-requiring diabetes mellitus in women aged 50 to 90 years in a large population-based study (18). In another populationbased study, Jackson et al (19) found that among postmenopausal women aged 55–75 years, those with diabetes mellitus reported more severe incontinence, difficulty controlling urination, inability to completely empty the bladder, and being unaware of leakage when compared with nondiabetic subjects. They also reported that severe incontinence was associated with diabetes duration, peripheral neuropathy, and retinopathy. In autonomic testing in 16 patients with diabetic neuropathy, abnormal sweating was found in 100% and an abnormal Valsalva ratio in 64% (20). Low et al (21) found autonomic dysfunction in 54% of type 1 diabetic

subjects and 73% of type 2 diabetic subjects, although the autonomic failure was usually mild. Another study of 73 patients with diabetic neuropathy found that 58% had postganglionic sympathetic failure in the foot, 55% had cardiovagal failure, and only 26% had orthostatic hypotension, making the argument for more extensive autonomic testing in these patients to identify the presence of a diabetic autonomic neuropathy (DAN) (22). Results of a thermoregulatory sweat test in 51 patients suspected to have a diabetic neuropathy showed a clearly abnormal sweat pattern in 94% (23). There has been some concern about the possible role of autonomic neuropathy as a factor in the development of sudden cardiac death in these patients. Suarez et al (24) reviewed cases of sudden cardiac death in diabetic patients and found a correlation with atherosclerotic heart disease, nephropathy, and, to a lesser extent, the pres­ ence of autonomic neuropathy; the authors’ conclusions were that autonomic neuropathy is unlikely to be the primary cause in these cases of sudden cardiac death. In most cases, DAN probably is part of a more generalized DPN. Other forms of diabetic neuropathy can also have significant coexisting autonomic features; the most common is likely DLRPN (as noted above).

Chronic Inflammatory Demyelinating Polyneuropathy in Diabetes Mellitus Because diabetes mellitus is a common disorder, cases of CIDP will occur in patients who are diabetic. The question has been raised of whether there is an increased occurrence of CIDP in diabetic patients. Sharma et al (25), among others (26), have suggested that CIDP is more common in patients with diabetes mellitus than in those without. This association is somewhat difficult to ascertain, however, given that diabetic neuropathy often will have some demyelinating features (like CIDP). In order to address this question, Laughlin et al (27) along with one of the authors (P.J.B.D.) studied the incidence and prevalence of CIDP in Olmsted County, Minnesota, and its association with diabetes mellitus. No association was found between diabetes mellitus and CIDP. Chio et al (28) also did not find an association between diabetes mellitus and CIDP in an Italian population. Consequently, it seems likely that diabetes mellitus is not a major risk factor for developing CIDP, and if an association exists, it is very small. Chronic inflammatory demyelinating polyneuropathy generally presents as a motor-predominant neuropathy with both proximal and distal weakness on clinical examination. Its presentation is usually progressive (unlike acute demyelinating polyradiculoneuropathy, it progresses over at least an 8-week period) but in some cases can be relapsing-remitting. In general, deep tendon reflexes are markedly reduced to absent. Some degree of sensory loss is usually present, with predominant involvement of large-fiber modalities and with negative sensory findings more common than positive

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sensory symptoms. Nerve conduction studies usually show characteristic demyelinating features, and cerebrospinal fluid analysis usually shows increased protein levels without CSF pleocytosis. In some cases, magnetic resonance imaging of the spine may show enlarged nerve roots consistent with the hypertrophic changes of repeated demyelination/remyelination. The mechanism of CIDP is felt to be immune-mediated demyelination. There are a number of different published diagnostic criteria for the diagnosis of CIDP, with varying weight on clinical, electrophysiologic, and other factors (29–32). Gorson et al (33) studied clinical and electrophysiologic features of 14 cases with coexisting diabetes mellitus and CIDP and compared them to nondiabetic patients with CIDP. They found that the diabetic patients with CIDP were older and more commonly had imbalance. They also found that electrophysiologically, patients with diabetes mellitus and CIDP had decreased ulnar motor responses, more commonly had an absent sural response, and that nerve biopsies of patients with diabetic CIDP were more likely to have predominant axonal loss. Of interest, they also reported that patients with CIDP with diabetes had less improvement in strength after treatment with immunomodulatory agents (suggesting that some of the neuropathy was due to an underlying DPN). Garces-Sanchez et al (34) recently studied a cohort of patients with diabetes mellitus who had lower limb weakness without pain, with the thought that if diabetic CIDP existed, it was more likely to occur within this group. The questions were whether the patients’ disease was diabetic CIDP, a painless form of DLRPN, or a different entity. Twenty-three patients with the painless, lower-limb motor-predominant neuropathy were identified and underwent detailed evaluation including nerve biopsy. The electrophysiologic findings were those of an axonal lumbosacral radiculoplexus neuropathy, and the pathologic findings were those of ischemic injury from microvasculitis (and not inflammatory demyelination, as would be expected in CIDP). Consequently, they concluded that the painless, lower limb, motor neuropathy in diabetes is a form of DLRPN and not diabetic CIDP.

Mononeuropathies in Diabetes Mellitus Compressive mononeuropathies occur commonly in diabetic patients. This includes median neuropathy at the wrist, which can present with paresthesias, numbness, and/or pain in the first 3 fingers and lateral fourth finger; in severe cases, weakness in median-innervated muscles of the hand, such as in thumb abduction, can occur. A positive Tinel or Phalen sign can be helpful diagnostically. Ulnar neuropathy at the elbow can present with paresthesias, numbness, and/or pain in the fifth and medial fourth finger and medial hand and forearm, with weakness in ulnar-innervated muscles, including interossei, hypothenar muscles, flexor carpi ulnaris, and flexor digitorum profundus (digits 4 and 5). Peroneal neuropathy at the fibular head can present with par-

esthesias, numbness, and/or pain at the lateral calf and dorsal foot, and with weakness of foot dorsiflexion and/ or eversion. Stevens et al (35) reviewed medical information of patients with carpal tunnel syndrome for predisposing conditions and found a standardized morbidity ratio (the ratio between observed cases and the expected cases in a population) of 2.3 for diabetes mellitus Diabetes mellitus is also a significant risk factor for the development of bilateral carpal tunnel syndrome (36). In cases of upper extremity neuropathic symptoms/ signs in diabetic patients, these commonly represent mononeuropathies rather than upward extension of a DPN. Clues to the presence of mononeuropathy as the cause should include asymmetry and relatively mild DPN or the absence of evidence of DPN in the lower extremities (3).

Other Neuropathies There are multiple neuropathic manifestations of diabetes mellitus; we have focused on the more commonly encountered subtypes above. Other neuropathies that can occur in the context of diabetes mellitus include cranial neuropathies, thoracic radiculopathies, and cervical radiculoplexus neuropathies, which should be considered, based upon the clinical context. Watanabe et al (37) found a 0.97% incidence of cranial neuropathies in diabetic patients as compared to a 0.13% incidence in control subjects; however, clearly, the incidence is overall quite low. One study that reviewed diabetic patients with oculomotor palsies found that 50% had involvement of the sixth cranial nerve, 43.3% had involvement of the third cranial nerve, and 7.7% had involvement of the fourth cranial nerve (38). Thoracic radiculopathies can present as exquisitely painful sensory symptoms in a dermatomal distribution, often with associated contact allodynia. Neurologic examination may reveal either decreased sensation or cutaneous hypersensitivity in the affected thoracic dermatome. If there is associated abdominal wall weakness, focal, asymmetric outpouching of the abdomen may be seen at that level (39,40). Needle electromyography (EMG) may be helpful in diagnosis (41); a thermoregulatory sweat test can also be useful in showing localized sweat loss in a dermatomal distribution (23). Cervical radiculoplexus neuropathy has been described in diabetic patients, and the etiology may be similar to that of DLRPN, given its subacute onset, asymmetry, and severe associated pain. In the Dyck et al (12) study of lumbosacral radiculoplexus neuropathy, the authors noted that of their 33 patients, 3 also had bilateral asymmetric cervical radiculoplexus neuropathy. Katz et al (42) reviewed 60 patients with DLRPN and found that 9 also had upper extremity involvement (unilateral in 5, bilateral and asymmetric in 4). The upper extremity findings followed a course similar to DLRPN with subacute pain and weakness, followed by gradual improvement with or without immunomodulatory

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therapy in the 7 patients for whom they had long-term follow-up. Both the diabetic thoracic radiculopathies and the diabetic cervical radiculoplexus neuropathies are best categorized as DLRPN. Insulin neuritis has been reported in the literature as a syndrome of an acute-onset painful neuropathy (43,44). The data on this entity are limited, primarily to case reports of patients who generally developed painpredominant neuropathies in the context of rapid control of blood sugars with the use of insulin. The mechanism of this is unknown, with some investigators implicating local ischemia to the endoneurium (45). However, information on pathophysiology is sparse. Santillan et al (46) reported a case of a patient who developed bilateral brachial plexopathies in the context of diabetic ketoacidosis. There are other individual reports of severe neuropathies occurring in the context of diabetic ketoacidosis (47,48), although most of the neurologic findings associated with diabetic ketoacidosis tend to be central in origin.

DIFFERENTIAL DIAGNOSIS The differential diagnosis for diabetic neuropathies is broad, and it should not be assumed that all neuropathies in a diabetic patient are secondary to diabetes mellitus. The differential will vary depending on the clinical phenotype of diabetic neuropathy. In cases of diabetic sensorimotor peripheral polyneuropathy, the differential is broad and can include inflammatory causes (including neuropathies associated with rheumatoid arthritis, Sjögren syndrome, and other rheumatological illness); infectious causes (eg, Lyme disease); metabolic causes (B12 deficiency, copper deficiency); toxic causes (heavy metals, medication associated); infiltrative processes (eg, amyloid, malignancy), and monoclonal protein– associated neuropathies, among others. Autonomic neuropathy can have many different causes, although diabetes is one of the most common. Neuropathies with predominant autonomic symptoms/signs include amyloidosis, hereditary sensory and autonomic neuropathies, inflammatory or paraneoplastic neuropathies. Autonomic dysfunction can also occur in the context of other neurologic diseases, such as Parkinson disease or multiple-system atrophy. There are other conditions that can mimic focal neuropathies of diabetes mellitus, such as DLRPN. A nondiabetic lumbosacral radiculoplexus neuropathy can occur with clinical features and pathologic findings similar to that of DLRPN (49). Other considerations include focal infiltrative processes; malignant invasion should be considered, as should amyloidosis. A focal form of CIDP should also be in the differential, although generally, these are not pain predominant.

PATHOGENESIS AND PATHOPHYSIOLOGY The mechanisms of diabetic neuropathies vary based on the subtype. The most common form, DPN, is likely

multifactorial and may be related to both microvascular and metabolic effects. As previously noted, its occurrence is correlated with the presence of other diabetes-related microvascular disease, such as retinopathy and nephropathy (1). Sural nerve biopsies in patients with diabetic neuropathy showed increased endothelial nuclei and abnormally increased microvessel thickness, related to basement membrane reduplication (50); a study of nerves in streptozocin-induced diabetic rats showed increased microvessel area (51). Dyck et al (52) evaluated sural nerves of 32 patients with DPN, 4 diabetic patients without peripheral neuropathy, and 47 healthy controls with routine pathologic studies, teased fiber evaluation, and morphometry and found that in those with DPN, the pathologic changes were most consistent with a primary process of fiber loss with secondary changes of demyelination/remyelination. The distribution of fiber loss was both diffuse and multifocal, which raised the possibility of an ischemic etiology. Another study evaluating lower limb nerve pathology (proximal to distal) in subjects with DPN showed that even in mild cases, fiber loss and increased variability of myelinated fiber density was present in proximal as well as distal nerves, in a pattern suggestive of ischemic injury (53). However, there are likely also separate metabolic factors that influence its development. One study of sural nerve biopsies in diabetic patients showed increased mean endoneurial glucose, fructose, and sorbitol levels in diabetic patients and found that nerve sorbitol levels were inversely related to the numbers of myelinated fibers (54). Another study has also shown increased endoneurial glucose, fructose, and sorbitol levels in the endoneurium of diabetic patients (55). There is concern that the development of advanced glycation end-products, resulting from binding of sugars to many different types of proteins, may result in both microvascular damage and direct effects on intracellular enzymes and on axonal transport (56). Misur et al (57) studied nerves of type 2 diabetic patients with distal symmetric peripheral neuropathy and proximal peripheral neuropathy and compared them to controls; they found marked advanced glycation end-product immunoreactivity in the diabetic nerves but not in the control nerves. In addition, they reported increased perineurial thickening, narrowed microvessel lumens, and decreased preserved axons in the diabetic nerves compared with controls. The presence of these morphologic changes was also significantly correlated with the intensity of advanced glycation endproduct immunoreactivity. It is felt that increased glycemic exposure activates the polyol pathway, resulting in production of advanced glycation end-products, which in turn cause decreased glutathione and upregulated nuclear factor kappa B and increased tumor necrosis factor alpha, resulting in damage to nerve from oxidative stress and the presence of proinflammatory cytokines (58). Low et al (20) performed histologic studies on autopsied greater splanchnic nerves in patients with diabetic

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neuropathy and compared them to controls; they found decreased fiber density and changes of demyelination in the diabetic patients. They also did a histologic evaluation of the sural nerves in 2 diabetic patients with autonomic dysfunction and found primarily changes of active axonal degeneration in small myelinated and in unmyelinated nerve fibers. Full-thickness gastric biopsy in 2 patients with diabetic gastroparesis showed normal findings in 1 patient, with short-duration diabetes mellitus, and in the other patient showed increased fibrosis, decreased nerve fibers, and a decrease in myenteric plexus neurons. The authors conclude that the mechanisms of gastroparesis in diabetic patients are likely heterogeneous (59). Dyck et al (11) examined 33 distal whole sensory nerve biopsies of patients with DLRPN and found the follow-

ing: 2 cases with necrotizing vasculitis, 13 cases in which inflammatory cells were infiltrating vessel walls (suggestive of microvasculitis) (Figure 5.1), and all cases showing an abnormal degree of inflammation (small or greater collections of inflammatory cells). Ischemic injury was also seen. Focal or multifocal fiber loss was observed in 19 nerves (Figure 5.2), 24 had perineurial thickening, 21 had neovascularization, and 12 showed injury neuroma (Figure 5.2). Teased fiber analysis showed that axonal degeneration was the predominant pathologic change, with a mildly increased rate of demyelination. The conclusion of the authors was that the most likely mechanism for the nerve damage was ischemia secondary to microvasculitis. The authors compared these nerves to those from DPN patients and found much less ischemic injury and inflammatory changes in DPN nerves.

Figure 5.1 Serial skip paraffin sections of a microvessel above (upper), at (middle), and below (lower) a region of microvasculitis in the sural nerve of a patient with diabetic lumbosacral radiculoplexus neuropathy. The sections in the left column are stained with hematoxylin-eosin, the sections in the middle column are reacted with antihuman smooth muscle actin (Dako), and the sections on the right column are reacted with leukocytes (CD45). The smooth muscle of the tunica media in the region of microvasculitis (middle) is separated by mononuclear cells, fragmented and decreased in amount. The changes are those of a focal microvasculitis. Reprinted from Sinnreich M, Taylor BV, Dyck PJB. Diabetic neuropathies —classification, clinical features, and pathophysiological basis. The Neurologist. 2005;11(2):63–79, Figure 4, p.74.

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Figure 5.2 Transverse epoxy sections ( p-phenylenediamine) of distal sural nerves from patients with diabetic lumbosacral radiculoplexus neuropathy illustrating the dramatic focal fiber loss characteristic of the disorder (A) and the abortive microfascicular nerve regeneration (B, as identified by the arrow). Note that the abortive regeneration (injury neuroma) is made up of multiple regenerating fascicles and that they are situated adjacent to a fascicle devoid of myelinated fibers. Most of the fibers in the right fascicle in the lower panel are actively degenerating. As discussed in the text, these changes are indicative of ischemic injury that we attribute to a microscopic vasculitis. Reprinted from Dyck PJB, Norell JE, Dyck PJ. Microvasculitis and ischemia in diabetic lumbosacral radiculoplexus neuropathy. Neurology. 1999;53:2113–2121, Figure 1, p.2118. DIAGNOSTIC EVALUATION The most important part of the diagnostic evaluation is a complete history and physical examination. This should include the length of time the patient has had diabetes, whether it is type 1 or 2, the adequacy of blood sugar management, and the presence of other diabetic complications such as retinopathy and nephropathy. One should ensure that the time course and clinical presentation of the patient’s neuropathy is consistent with one of the previously mentioned subtypes. The presence of coexisting medical illnesses that may be associated with neuropathy should be ascertained, as well as whether the patient is taking medications with a potential side effect of neurop-

athy. Nutritional deficiencies, alcohol consumption, and family history should be carefully assessed. A full neurologic examination should be carried out. In typical diabetic polyneuropathy, a length-dependent pattern of reduced sensation to large (proprioception, vibration, light touch) and small (temperature, pain) fiber modalities can be demonstrated. Reduced deep tendon reflexes, usually distally, are common. Weakness is less common in diabetic polyneuropathy but, when present, is usually distal. Diabetic lumbosacral radiculoplexus neuropathy is typically characterized by asymmetric lower limb weakness (both proximal and distal), numbness, and pain (often contact allodynia, making examination difficult). Some degree of autonomic dysfunction can be assessed during the clinical examination, particularly with orthostatic blood pressures. Patients may also have either isolated cranial neuropathies or thoracic radiculopathies, with decreased sensation or hyperesthesia in a thoracic dermatomal distribution. All patients with suspected diabetic neuropathy should have routine blood work to rule out other possible causes of neuropathy. This workup will vary depending on the patient but will usually include a complete blood count, electrolyte count, kidney and liver function tests, and vitamin B12 and methylmalonic acid levels. In some patients, particularly if they have associated sicca symptoms (dry eyes, dry mouth), arthralgias, or other findings suggestive of rheumatological disease, antinuclear antibodies and antibodies to extractible nuclear antigens as well as rheumatoid factor should be checked. Quantitative sensory testing can be helpful in the assessment and follow-up of patients suspected to have diabetic neuropathy, particularly when the findings on physical examination are mild or equivocal. These should include assessment of vibratory detection threshold, cooling detection threshold, and heat-pain detection threshold (as in Computer-Assisted Sensory Examination System IV [CASE IV]) (60,61). All (or almost all) patients should have NCSs and EMG performed. These can be helpful both in confirming the diagnosis of peripheral neuropathy, as other conditions, including local foot disease, can cause painful distal symptoms. Autonomic reflex screen and thermoregulatory sweat testing can be considered and may be particularly useful in patients with normal NCS/EMG results when small-fiber neuropathy features are predominant. In selected patients, particularly those with a DLRPN phenotype, cerebrospinal fluid evaluation is warranted to assess for elevated protein and also to exclude alternative causes for an asymmetric neuropathy, such as infectious etiologies or malignancy (especially lymphoma). Nerve biopsy is rarely required in diabetic neuropathy cases unless there are atypical features to suggest vasculitis or another inflammatory or neoplastic etiology. Nerve biopsy can be helpful with the DLRPN phenotype. Also, if etiologies other than diabetes are being considered (vasculitis, amyloidosis, etc) then nerve biopsy should be considered.

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ELECTROPHYSIOLOGY The electrophysiology of diabetic neuropathies varies depending on subtype. In DPN, a frequent pattern is decreased sensory and motor amplitudes on nerve conduction studies, with somewhat (or mildly) slowed conduction velocities. Dyck et al (62) reviewed patients with diabetic polyneuropathy, diabetes without neuropathy, and controls and found that reductions in nerve conduction velocities were the most frequent abnormality found in patients with diabetic neuropathy. Claus et al (63) similarly found that motor and sensory nerve conduction velocities were the most sensitive indicators for DPN. Lamontagne et al (64) evaluated several nerve conduction study and electromyographic parameters and found that sensory nerve conduction abnormalities were the most sensitive indicator of diabetic neuropathy, followed by the presence of fibrillations. The medial plantar sensory response has been reported to be an early indicator of diabetic nerve dysfunction (65). The nerve conduction abnormalities are generally symmetric, with one study of nerve conduction studies (median and ulnar motor and sensory, peroneal and tibial motor, and sural) in diabetic patients showing symmetry, with the exception of the median sensory amplitudes (66). In contrast, patients with DLRPN will frequently have an NCS/EMG result that appears to show a diffuse sensorimotor peripheral neuropathy with superimposed lumbosacral radiculopathies. We believe that these findings are generally due to the extent of the DLRPN rather than 2 separate pathologic processes occurring. In most cases of DLPRN, diabetes mellitus is mild and has not been present for a long time; thus, complications of longstanding diabetes mellitus, such as DPN, would not be expected. Diabetic lumbosacral radiculoplexus neuropathy is due to ischemic injury with microvasculitis that occurs most profoundly in the lumbosacral segments.

TREATMENT The treatment of diabetic neuropathies is complex, and management is dependent upon the specific subtype of diabetic neuropathy. Diabetic polyneuropathy has been given much attention because of its relative frequency, and strategies for its management focus both on improving the underlying mechanism and on symptomatic treatment. Because DPN is related to length and severity of hyperglycemic exposure, attention has been given to trying to improve DPN, prevent its progression, or delay/ halt its onset through intensive control of blood sugar. The Diabetes Control and Complications Trial Research Group reported on 1441 patients with insulin-dependent diabetes and randomized them into either a conventional insulin regimen or an intensive insulin regimen, which consisted of at least 3 insulin injections and/or continuous insulin with an increased glucose monitoring regimen. They found that subjects treated more in-

tensively had lower rates of neuropathy. At the 5-year mark, there was 64% less development of confirmed clinical neuropathy in the intensively treated patients, the prevalence of abnormal nerve conduction test results was lowered by 44%, and abnormal autonomic testing was lowered by 53% in the patients receiving intensive insulin treatment (67,68). This trial has led to greater focus on the prevention of DPN through more intensive glucose control. A recent article by Albers et al (69) reviewed long-term prevalence of neuropathy in 1186 of the subjects in that previous trial and noted that within 5 years after trial completion, there was no longer a significant difference in the hemoglobin A1c levels between the intensively and conventionally treated groups. Despite this, 13 to 14 years after the Diabetes Control and Complications Trial closed, there was still a significant difference in the prevalence of neuropathy between the 2 groups (25% in the intensively treated group and 35% in the conventionally treated group), which would indicate a long-term benefit of the intensive insulin treatment many years earlier. However, another study of patients with diabetes, hemoglobin A1c concentrations greater than 7.5%, and cardiovascular disease (or 2 or more cardiovascular risk factors), with random assignment to either intensive (target hemoglobin A1c of less than 6.0%) or standard (target hemoglobin A1c of 7.0%-7.9%) therapy, was stopped prematurely because of a higher mortality in the intensive-therapy group. The authors caution that careful consideration of the increased risk of total and cardiovascular disease–related mortality versus the microvascular disease benefits should be taken into account (70). Pop-Busui et al (71) reviewed the patients in this trial to see if the baseline presence of cardiac autonomic neuropathy was associated with differences in mortality outcome with intensive or conventional treatment; while baseline cardiac autonomic neuropathy was associated with increased mortality, there was no difference in mortality among these patients, whether treated with intensive or conventional treatment. Other strategies for treatment of DPN have included the use of antioxidant agents such as alpha lipoic acid, aldose reductase inhibitors, and recombinant human nerve growth factor, among others. In the SYDNEY trial, patients with DPN were treated with either intravenous (IV) alpha lipoic acid or placebo, and the treated group showed a significant improvement in positive neuropathic symptoms and in the Neuropathy Impairment Score (NIS) (72). However, the ALADIN III trial, which treated patients DPN with IV alpha lipoic acid (600 mg IV daily for 3 weeks) followed by an oral form (600 mg orally 3 times a day for 6 months), IV alpha lipoic acid (600 mg IV daily for 3 weeks) followed by an oral placebo, or IV placebo followed by oral placebo, did not show any difference after 7 months in either the Total Symptom Score or the NIS (73). Unlike the SYDNEY trial, in which patients were given treatments 5 days a week, for a total of 14 treatments, the ALADIN III trial,

CHAPTER 5: Diabetic Neuropathy  65

which was a longer-term study, did not show a benefit of alpha lipoic acid. Aldose reductase inhibitors have been studied to try to improve DPN. One study of sural nerve biopsies in diabetic patients examined repeated nerve biopsies of 6 diabetic patients after they were treated with sorbinil (an aldose reductase inhibitor) for a year and found decreases in endoneurial sorbitol and fructose levels (54). The results of studies on the effect of aldose reductase inhibitors on clinical and electrophysiologic outcomes, however, are mixed, with one study of ponalrestat for 52 weeks in patients with DPN showing no significant differences in motor and sensory conduction velocities, vibration thresholds, or symptom scores (74). A study of tolrestat for 52 weeks in patients with DPN showed significant improvements in motor nerve conduction velocities and in paresthesias, but concordant improvement at 24 weeks was maintained in only 28% of the patients at the 52-week evaluation (75). A large study of 549 patients with DPN, treated with either ranirestat or placebo, showed an improvement in summed motor nerve conduction velocities at week 12; there was no significant improvement in summed sensory nerve conduction velocities from baseline (76). Recombinant human growth factor has been considered as a treatment agent. A study of 250 patients with DPN treated with recombinant human growth factor or placebo for 6 months found a trend toward NIS in the lower limbs (NIS-LL) improvement in the treated group (77). A larger study of recombinant human nerve growth factor versus placebo in 1019 patients with DPN, over a 48-week period, failed to show any significant change in NIS(LL) from baseline (78). While insulin and/or oral antihyperglycemic agents may not be typically used in cases of glucose intolerance, strategies to lower blood sugar and increase muscle tissue sensitivity to glucose may provide benefit to those patients suspected of having a neuropathy of impaired glucose tolerance. Smith et al (79) provided 32 patients with impaired glucose tolerance with diet and exercise counseling, and they found a significant improvement in intraepidermal nerve fiber density on skin biopsy and decreased complaints of pain. This change was also associated with significant improvements in glucose, cholesterol, and weight. These findings may suggest that early lifestyle intervention may be the most important variable in treating and reducing neuropathy progression when dealing with these small-fiber neuropathies. The treatment of DAN is primarily symptomatic. Orthostatic hypotension is a common concern. It is important to evaluate the patient’s medication list, to attempt to eliminate offending agents that may be exacerbating orthostasis. It is important to emphasize proper hydration. The use of compression stockings and/or abdominal binders should be discussed with the patient, as a nonmedication strategy for increasing blood pressure. When necessary, the use of fludrocortisone to expand intravascular fluid volume or midodrine to cause increased blood vessel constriction may be helpful symp-

tomatic agents. The risk of increased blood pressure should be taken into account, however, particularly as diabetic patients have an increased risk of cardiovascular disease as well as other macrovascular complications of their disease. The presence of supine hypertension should be carefully evaluated, and treatment of patients with both supine hypertension and orthostatic hypotension increases the complexity of medication choice. Supine hypertension may be decreased by raising the head of the patient’s bed at night and may be limited by avoiding evening doses of midodrine. Singer et al (80) have found significant improvement in neurogenic orthostatic hypotension without worsening supine hypertension with the use of pyridostigmine. While the changes of DPN are likely due to metabolic effects on the nerve and nerve vasculature, the mechanism of disease in DLRPN is most likely microvasculitis, which changes the anticipated treatment strategy. Several attempts have been made to employ immunosuppressive therapy in these patients. Pascoe et al (81) reviewed degrees of improvement in patients with DLRPN who were treated with immunosuppressive agents (steroids, IV immunoglobulin, and plasma exchange) versus no treatment and did not find a statistically significant difference between the 2 groups (9 of 12 treated patients improved; 17 of 29 untreated patients improved). Dyck et al (82) performed a placebo-controlled, double-blind trial on 75 patients with DLRPN randomized to either placebo or IV methylprednisolone (1 gram 3 times a week, with tapering over 12 weeks). The parameters studied were the NIS, NIS-LL, and the Neuropathy Symptoms and Change score, with the primary outcome being time to improvement of the NIS-LL by 4 points. There was no statistically significant difference in the primary end point of this study. However, those patients in the treatment arm reported significantly greater improvement of symptoms, especially pain and positive sensory symptoms. It is unclear if treatment earlier in the course of the disease would have produced a better response. Tamburin et al (83) treated 4 patients with refractory DLRPN (unresponsive to symptomatic pain medications and corticosteroids) with IV immunoglobulin (0.4  g/kg daily for 5 days) and found that 4 of 5 patients had improved pain response, and there was significant improvement in MRC (Medical Research Council) score for the lower limbs at 1 month. Two patients in their study required repeated IVIG for recurrent pain symptoms. Given the significant and persistent neuropathic symptoms and signs in many of these patients, the authors feel that immunomodulatory treatment (especially IV methylprednisolone) should still be considered in these patients, particularly if they are actively worsening at the time of evaluation. Further studies with earlier immunomodulatory treatment and with other immunomodulatory agents (eg, IV immunoglobulin) would be helpful in coming to a consensus on the best treatment strategies for these patients.

66  Textbook of Peripheral Neuropathy

Conclusions Diabetic neuropathies occur commonly and are varied in their manifestations. While the neuropathies described above are associated with diabetes, there is evidence for varying mechanisms (metabolic, vascular, and inflammatory) as being a predominant feature for each type. The diagnosis should be made carefully, as not all neuropathies that occur in diabetic patients are secondary to diabetes, and alternative etiologies should be carefully ruled out. A full history and neurologic examination, particularly with concern for other disease entities and/or toxins (including medications), as well as related testing should be undertaken. Depending on the type of diabetic neuropathy, appropriate therapy should be initiated, whether it is tighter glycemic control, symptomatic management, or immunotherapy. In all cases, education of the patient regarding reducing the risk of secondary injuries to areas affected by neuropathy should take place.

CLINICAL PEARLS AND KEY POINTS 1. Diabetic neuropathy is not a single phenotype; there are multiple types of diabetic neuropathy, each of which likely has a different pathogenesis. 2. Diabetic polyneuropathy is the most common type of diabetic neuropathy; it is distal predominant and symmetric and involves sensory more than motor fibers. Severe weakness is uncommon in DPN. 3. The best evidence for management/ prevention of development of DPN is tight glucose control. However, there is concern about increased mortality in diabetic patients with tight glucose control, and risks and benefits of this strategy have to be carefully considered. 4. Some types of diabetic neuropathy (eg, DLRPN, DCRPN) likely have an immune-mediated pathogenesis, and immunotherapy should be considered in affected patients. 5. All patients with diabetic neuropathies should have careful education for prevention of secondary injuries such as ulcerations.

REFERENCES 1. Dyck PJ, Kratz KM, Karnes JL, et al. The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology. 1993;43(4):817–824. 2. Tesfaye S, Boulton AJ, Dyck PJ, et al. Diabetic neuropathies: update on definitions, diagnostic criteria and estimation of severity (the Toronto Expert Group Meeting 2009). Diabetes Care. 2010;33(10):2285–2293.

3. Tracy JA, Dyck PJB, Harper CM, et al. Hand symptomatology in diabetes usually due to mononeuropathy, not polyneuropathy. Ann Neurol. 2005;58(suppl 9):S36. 4. Dyck PJ, Davies JL, Wilson DM, et al. Risk factors for severity of diabetic polyneuropathy. Intensive longitudinal assessment of the Rochester Diabetic Neuropathy Study cohort. Diabetes Care. 1999;22(9):1479–1486. 5. Dyck PJ, O’Brien PC, Litchy WJ, et al. Monotonicity of nerve tests in diabetes. Subclinical nerve dysfunction precedes diagnosis of polyneuropathy. Diabetes Care. 2005;28(9): 2192–2200. 6. Singleton JR, Smith AG, Bromberg MB. Increased prevalence of impaired glucose tolerance in patients with painful sensory neuropathy. Diabetes Care. 2001;24(8),1448–1453. 7. Sumner CJ, Sheth S, Griffin JW, et al. The spectrum of neuropathy in diabetes and impaired glucose tolerance. Neurology. 2003;60(1):108–111. 8. Hoffman-Snyder C, Smith BE, Ross MA, et al. Value of the oral glucose tolerance test in the evaluation of chronic idiopathic axonal polyneuropathy. Arch Neurol. 2006;63(8): 1075–1079. 9. Dyck PJ, Clark VM, Overland CJ, et al. Impared glycemic and diabetic polyneuropathy. The OC IG survey. Diabetes Care. 2012;35:584–591. 10. Garland H. Diabetic amyotrophy. Br Med J. 1955;2:1287–1296. 11. Williams IR, Mayer RF. Subacute proximal diabetic neuropathy. Neurology. 1976;26:108–116. 12. Dyck PJB, Norell JE, Dyck PJ. Microvasculitis and ischemia in diabetic lumbosacral radiculoplexus neuropathy. Neurology. 1999;53(9):2113–2121. 13. Gandhi RA, Marques JL, Selvarajah D, et al. Painful diabetic neuropathy is associated with greater autonomic dysfunction than painless diabetic neuropathy. Diabetes Care. 2010;33(7):1585–1590. 14. Krolewski AS, Warram JH, Cupples A, et al. Hypertension, orthostatic hypotension and the microvascular complications of diabetes. J Chronic Dis. 1985;38(4):319–326. 15. Horowitz M, O’Donovan D, Jones KL, et al. Gastric emptying in diabetes: clinical significance and treatment. Diabet Med. 2002;19(3):177–194. 16. Shiri R, Ansari M, Falah Hassani K. Association between comorbidity and erectile dysfunction in patients with diabetes. Int J Impot Res. 2006;18(4):348–353. 17. Rhoden EL, Ribeiro EP, Riedner CE, et al. Glycosylated haemoglobin levels and the severity of erectile function in diabetic men. BJU Int. 2005;95(4):615–617. 18. Lewis CM, Schrader R, Many A, et al. Diabetes and urinary incontinence in 50- to 90-year-old women: a crosssectional population-based study. Am J Obstet Gynecol. 2005;193(6):2154–2158. 19. Jackson SL, Scholes D, Boyko EJ, et al. Urinary incontinence and diabetes in postmenopausal women. Diabetes Care. 2005;28(7):1730–1738. 20. Low PA, Walsh JC, Huang CY, et al. The sympathetic nervous system in diabetic neuropathy. A clinical and pathological study. Brain. 1975;98(3):341–356. 21. Low PA, Benrud-Larson LM, Sletten DM, et al. Autonomic symptoms and diabetic neuropathy: a population-based study. Diabetes Care. 2004;27(12):2942–2947. 22. Low PA, Zimmerman BR, Dyck PJ. Comparison of distal sympathetic with vagal function in diabetic neuropathy. Muscle Nerve. 1986;9(7):592–596.

CHAPTER 5: Diabetic Neuropathy  67 23. Fealey RD, Low PA, Thomas JE. Thermoregulatory sweating abnormalities in diabetes mellitus. Mayo Clin Proc. 1989;64(6):617–628. 24. Suarez GA, Clark VM, Norell JE, et al. Sudden cardiac death in diabetes mellitus: risk factors in the Rochester Diabetic Neuropathy Study. J Neurol Neurosurg Psychiatry. 2005;76(2):240–245. 25. Sharma KR, Cross J, Farronay O, et al. Demyelinating neu­ ropathy in diabetes mellitus. Arch Neurol. 2002;59(5):758–765. 26. Krendel DA, Costigan DA, Hopkins LC. Successful treatment of neuropathies in patients with diabetes mellitus. Arch Neurol. 1995;52(11):1053–1061. 27. Laughlin RS, Dyck PJ, Melton LJ III, et al. Incidence and prevalence of CIDP and the association of diabetes mellitus. Neurology. 2009;73(1):39–45. 28. Chio A, Plano F, Calvo A, et al. Comorbidity between CIDP and diabetes mellitus: only a matter of chance? Eur J Neurol. 2009;16(6):752–754. 29. Barohn RJ, Kissel JT, Warmolts JR, et al. Chronic inflammatory demyelinating polyradiculoneuropathy: clinical characteristics, course, and recommendations for diagnostic criteria. Arch Neurol. 1989;46:878–884. 30. Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Report from an Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. Neurology. 1991;41(5):617–618. 31. Saperstein DS, Katz JS, Amato AA, et al. Clinical spectrum of chronic acquired demyelinating polyneuropathies. Muscle Nerve. 2001;24(3)(3):311–324. 32. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society. J Peripher Nerv Syst. 2005;10(3):220–228. 33. Gorson KC, Ropper AH, Adelman LS, et al. Influence of diabetes mellitus on chronic inflammatory demyelinating polyneuropathy. Muscle Nerve. 2000;23(1):37–43. 34. Garces-Sanchez M, Laughlin RS, Dyck PJ, et al. Painless d­iabetic motor neuropathy: a variant of diabetic lumbosacral radiculoplexus neuropathy? Ann Neurol. 2011;PMID: 21425185. 35. Stevens JC, Beard CM, O’Fallon WM, et al. Conditions associated with carpal tunnel syndrome. Mayo Clin Proc. 1992;67(6):541–548. 36. Becker J, Nora DB, Gomes I, et al. An evaluation of gender, obesity, age and diabetes mellitus as risk factors for carpal tunnel syndrome. Clin Neurophysiol. 2002;113(9): 1429–1434. 37. Watanabe K, Hagura R, Akanuma Y, et al. Characteristics of cranial nerve palsies in diabetic patients. Diabetes Res Clin Pract. 1990;10(1):19–27. 38. Trigler L, Siatkowski RM, Oster AS, et al. Retinopathy in patients with diabetic ophthalmoplegia. Ophthalmology. 2003;110(8):1545–1550. 39. Parry GJ, Floberg J. Diabetic truncal neuropathy presenting as abdominal hernia. Neurology. 1989;39(11):1488–1490. 40. Chiu HK, Trence DL. Diabetic neuropathy, the great masquerader: truncal neuropathy manifesting as abdominal pseudohernia. Endocr Pract. 2006;12(3):281–283. 41. Massey EW. Diabetic truncal mononeuropathy: electromyographic evaluation. Acta Diabetol Lat. 1980;17(3-4): 269–272.

42. Katz JS, Saperstein DS, Wolfe G, et al. Cervicobrachial involvement in diabetic radiculoplexopathy. Muscle Nerve. 2001;24(6):794–798. 43. Wilson JL, Sokol DK, Smith LH, et al. Acute painful neuropathy (insulin neuritis) in a boy following rapid glycemic control for type 1 diabetes mellitus. J Child Neurol. 2003;18(5):365–367. 44. Llewelyn JG, Thomas PK, Fonseca V, et al. Acute painful diabetic neuropathy precipitated by strict glycaemic control. Acta Neuropathol (Berl). 1986;72(2):157–163. 45. Tesfaye S, Malik R, Harris N, et al. Arterio-venous shunting and proliferating new vessels in acute painful neuropathy of rapid glycaemic control (insulin neuritis). Diabetologia. 1996;39(3):329–335. 46. Santillan CE, Katirji B. Brachial plexopathy in diabetic ketoacidosis. Muscle Nerve. 2000;23(2):271–273. 47. Bonfanti R, Bognetti E, Meschi F, et al. Disseminated intravascular coagulation and severe peripheral neuropathy complicating ketoacidosis in a newly diagnosed diabetic child. Acta Diabetol. 1994;31(3):173–174. 48. Atkin SL, Coady AM, Horton D, et al. Multiple cerebral haematomata and peripheral nerve palsies associated with a case of juvenile diabetic ketoacidosis. Diabet Med. 1995;12(3):267–270. 49. Dyck PJB, Norell JE, Dyck PJ. Non-diabetic lumbosacral radiculoplexus neuropathy. Natural history, outcome and comparison with the diabetic variety. Brain. 2001;124(Pt 6): 1197–1207. 50. Yasuda H, Dyck PJ. Abnormalities of endoneurial microvessels and sural nerve pathology in diabetic neuropathy. Neurology. 1987;37:20–28. 51. Benstead TJ, Sangalang VE. Nerve microvessel changes in diabetes are prevented by aldose reductase inhibition. Can J Neurol Sci. 1995;22(3):192–197. 52. Dyck PJ, Lais A, Karnes JL, et al. Fiber loss is primary and multifocal in sural nerves in diabetic polyneuropathy. Ann Neurol. 1986;19(5):425–439. 53. Dyck PJ, Karnes JL, O’Brien PC, et al. The spatial distribution of fiber loss in diabetic polyneuropathy suggests ischemia. Ann Neurol. 1986;19(5):440–449. 54. Dyck PJ, Zimmerman BR, Vilen TH, et al. Nerve glucose, fructose, sorbitol, myo-inositol, and fiber degeneration and regeneration in diabetic neuropathy. N Engl J Med. 1988;319(9):542–548. 55. Cameron NE, Eaton SE, Cotter MA, et al. Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy. Diabetologia. 2001;44(11):1973–1988. 56. Harati Y. Diabetic neuropathies: unanswered questions. Neurol Clin. 2007;25(1):303–317. 57. Misur I, Zarkovic K, Barada A, et al. Advanced glycation end products in peripheral nerve in type 2 diabetes with neuropathy. Acta Diabetol. 2004;41(4):158–166. 58. Sugimoto K, Yasujima M, Yagihashi S. Role of advanced glycation end products in diabetic neuropathy. Curr Pharm Des. 2008;14(10):953–961. 59. Pasricha PJ, Pehlivanov ND, Gomez G, et al. Changes in the gastric enteric nervous system and muscle: a case report on two patients with diabetic gastroparesis. BMC Gastroenterology. 2008;8:21. 60. Dyck PJ, Zimmerman IR, O’Brien PC, et al. Introduction of automated systems to evaluate touch-pressure, vibration, and thermal cutaneous sensation in man. Ann Neurol. 1978;4:502–510.

68  Textbook of Peripheral Neuropathy 61. Dyck PJ, Zimmerman IR, Gillen DA, et al. Cool, warm, and heat-pain detection thresholds: testing methods and inferences about anatomic distribution of receptors. Neurology. 1993;43:1500–1508. 62. Dyck PJ, Karnes JL, Daube J, et al. Clinical and neuropathological criteria for the diagnosis and staging of diabetic neuropathy. Brain. 1985;108(Pt 4):861–880. 63. Claus D, Mustafa C, Vogel W, et al. Assessment of diabetic neuropathy: definition of norm and discrimination of a­bnormal nerve function. Muscle Nerve. 1993;16(7):757–768. 64. LaMontagne A, Buchthal F. Electrophysiological studies in diabetic neuropathy. J Neuro Neurosurg Psychiatry. 1970;33(4):442–452. 65. Reeves ML, Seigler DE, Ayyar DR, et al. Medial plantar sensory response. Sensitive indicator of peripheral nerve dysfunction in patients with diabetes mellitus. Am J Med. 1984;76(5):842–846. 66. Perkins BA, Ngo M, Bril V. Symmetry of nerve conduction studies in different stages of diabetic polyneuropathy. Muscle Nerve. 2002;25(2):212–217. 67. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993; 329:977–986. 68. The Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Intern Med. 1995;122(8):561–568. 69. Albers JW, Herman WH, Pop-Busui R, et al. Effect of prior intensive insulin treatment during the Diabetes Control and Complications Trial (DCCT) on peripheral neuropathy in type 1 diabetes during the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. Diabetes Care. 2010;33(5):1090–1096. 70. Ismail-Beigi F, Craven T, Banerji MA, et al. Effect of intensive treatment of hyperglycaemia on microvascular outcomes in type 2 diabetes: an analysis of the ACCORD randomised trial. Lancet. 2010;376(9739):419–430. 71. Pop-Busui R, Evans GW, Gerstein HC, et al. Effects of cardiac autonomic dysfunction on mortality risk in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Diabetes Care. 2010;33(7):1578–1584.

72. Ametov AS, Barinov A, Dyck PJ, et al. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid. The Sydney Trial. Diabetes Care. 2003;26(3):770–776. 73. Ziegler D, Hanefeld M, Ruhnau KJ, et al. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a 7-month multicenter randomized controlled trial (ALADIN III Study). ALADIN III Study Group. Alpha-Lipoic Acid in Diabetic Neuropathy. Diabetes Care. 1999;22(8):1296–1301. 74. Krentz AJ, Honigsberger L, Ellis SH, et al. A 12-month randomized controlled study of the aldose reductase inhibitor ponalrestat in patients with chronic symptomatic diabetic neuropathy. Diabet Med. 1992;9(5):463–468. 75. Boulton AJ, Levin S, Comstock J. A multicentre trial of the  aldose-reductase inhibitor, tolrestat, in patients with symptomatic diabetic neuropathy. Diabetologia. 1990;33(7): 431–437. 76. Bril V, Hirose T, Tomioka S, et al. Ranirestat for the management of diabetic sensorimotor polyneuropathy. Diabetes Care. 2009;32(7):1256–1260. 77. Apfel SC, Kessler JA, Adornato BT, et al. Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy. Neurology. 1998;51(3):695–702. 78. Apfel SC, Schwartz S, Adornato BT, et al. Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy. A randomized controlled trial. JAMA. 2000;284:2215–2221. 79. Smith AG, Russell J, Feldman EL, et al. Lifestyle intervention for pre-diabetic neuropathy. Diabetes Care. 2006; 29(6):1294–1299. 80. Singer W, Sandroni P, Opfer-Gehrking TL, et al. Pyridostigmine treatment trial in neurogenic orthostatic hypotension. Arch Neurol. 2006;63(4):513–518. 81. Pascoe MK, Low PA, Windebank AJ, et al. Subacute Dia­ betic  Proximal Neuropathy. Mayo Clin Proc. 1997;72(12): 1123–1132. 82. Dyck PJB, O’Brien P, Bosch EP, et al. The multi-center, double-blind controlled trial of IV methylprednisolone in diabetic lumbosacral radiculoplexus neuropathy. Neurology. 2006;66(5 suppl 2):A191. 83. Tamburin S, Zanette G. Intravenous immunoglobulin for the treatment of diabetic lumbosacral radiculoplexus neuropathy. Pain Med. 2009;10(8):1476–1480.

Russell L. Chin, Jennifer Langsdorf, Naomi Feuer, and Bridget Carey

6

Nutritional and Alcoholic Neuropathies

INTRODUCTION

The typical features of neuropathies associated with specific nutritional derangements will be considered individually and are summarized in Table 6.2. It is likely that multiple vitamin deficiencies, rather than an isolated deficiency, may be the cause of most presentations.

Peripheral neuropathy is a well-known complication of nutritional deficiencies. Historically, this has been observed in the malnourished state that develops in the setting of famine, war, or poverty, where access to a varied, healthy diet is limited. In the developed world, however, malnutrition is more likely to be encountered in the setting of eating disorders or alcohol abuse or following gastric surgery for weight loss or malignancy. In addition, a nutritionally deficient state may result from prolonged vomiting (eg, hyperemesis gravidarum), parenteral nutrition, or certain medications (eg, isoniazid or penicillamine, which act as antagonists to B6).

Vitamin B1 (Thiamine) Thiamine is synthesized in bacteria, fungi, and plants. Humans are unable to synthesize thiamine and must obtain it from their diet. As a result, a deficiency state can develop within 1 to 3 months of a daily intake of less than 0.2 mg. The most readily available dietary sources of thiamine are cereal grains, legumes, nuts, and yeast. Beef and pork also contain thiamine (2). Thiamine pyrophosphate, the metabolically active form of thiamine, is essential for the metabolism of glucose. As a result, thiamine requirement may increase with diets high in carbohydrates. Thiamine is a cofactor for 4 enzymes: pyruvate dehydrogenase, a-ketoglutarate dehydrogenase, transketolase, and branched-chain aketoacid dehydrogenase. It is absorbed primarily in the duodenum and proximal jejunum. At high concentrations, it is absorbed via passive diffusion, while at low concentrations, it is absorbed via active transport. The peripheral neuropathy associated with thiamine deficiency (TD) results from dysfunction and subsequent degeneration of peripheral nerve axons (3).

NUTRITIONAL NEUROPATHIES General Considerations When screening for nutritional neuropathies, it is important to consider all the possible reasons for a malnourished state (Table 6.1). A careful review of the patient’s dietary habits, medications, and gastrointestinal history is imperative. The clinical and electrodiagnostic features of most nutritional neuropathies are similar to those of cryptogenic polyneuropathies with distal extremity sensory or sensorimotor symptoms and generic, length-dependent axonal findings. There are notable exceptions, however, with a sensory neuronopathy or ganglionopathy seen with B6 toxicity, myelopathy with B12 and copper deficiencies, and a spinocerebellar syndrome with vitamin E deficiency. A history of sudden onset of symptoms in the hands or hands and feet may also indicate a myelopathy due to B12 deficiency. The presence of visual complaints (optic neuropathy, retinopathy, night blindness) or cognitive disturbances should also alert one to the possibility of a nutritional deficit (1). Repletion of the deficiency may arrest neuropathy progression; however, recovery may be protracted and partial depending on the amount of preexisting d­amage.

Etiology/Pathogenesis Causes of TD include an inadequate diet or poor nutritional status due to alcoholism or protracted vomiting (eg, eating disorders, hyperemesis gravidarum). Alcohol has a direct role in decreasing thiamine absorption in the small intestine and reducing hepatic thiamine storage (4). Gastrointestinal disorders that result in mal­absorption, such as bariatric surgery, inflammatory bowel disease, gastritis, pancreatitis, and prolonged diarrhea, are also associated with TD (5). Thiamine is easily destroyed in alkaline conditions (pH > 8); therefore, conditions that alter the pH of the gastrointestinal tract can also contribute to TD. Other causes include 69

70  Textbook of Peripheral Neuropathy

Table 6.1  Mechanisms of Nutritional Deficiencies Inadequate Intake Limited access (due to poverty, famine) Unbalanced or limited diet (fad diet, alcohol abuse) Eating disorders (anorexia nervosa, bulimia) Excessive vomiting (hyperemesis gravidarum) Malabsorption Gastric/intestinal wall damage or infiltration (pernicious anemia, inflammatory bowel disease, celiac disease) Bacterial overgrowth Pancreatic insufficiency Physically altered intestine (due to surgical resection or bypass) Drugs/Supplements •  H2 blockers, proton pump inhibitors (B12 deficiency) •  Nitrous oxide (B12 deficiency) •  Isoniazid, hydralazine, penicillamine, desoxypyridoxine, oral contraceptives (B6 deficiency) •  5-fluorouracil (niacin deficiency) •  Chloramphenicol (B12 deficiency) •  Clioquinol, an antifungal and antiprotozoal agent (copper deficiency) •  Excess zinc, found in cold remedies or denture creams (copper deficiency) •  Excess iron (copper deficiency) Genetic Conditions Menkes disease Hartnup disease

hemodialysis and ingestion of raw fish and shellfish, which contain thiaminases (6). Clinical Features Thiamine deficiency is implicated in several clinical syndromes, including the following: (1) WernickeKorsakoff encephalitis; (2) “wet” beriberi, in which the primary symptom is congestive heart failure; (3) “dry” beriberi, in which the primary symptom is peripheral neuropathy; and (4) infantile beriberi. The polyneuropathy associated with TD is typically symmetric, with motor and sensory deficits affecting the lower more than the upper limbs. The neuropathy can rarely present like Guillain-Barré syndrome with fulminant sensorimotor decline; however, respiratory or bulbar involvement is rare (7). The onset and progression of neuropathy symptoms is variable. The typical presentation of dry beriberi involves sensory symptoms in the lower more than upper

distal extremities with burning dysesthesias (mediated by small sensory fibers) and impaired discriminatory touch and joint position sense (mediated by large sensory fibers). Involvement of motor nerve fibers can result in muscle wasting in foot and hand muscles. Fasciculations and cramps may be reported. Motor tasks such as stair climbing and standing on one leg may become progressively difficult. A distal, symmetric, length-dependent sensorimotor neuropathy is the most common phenotype; however, in severe disease, autonomic symptoms of orthostatic hypotension, urinary retention, and/or gastroparesis may be seen. Vagus nerve involvement may precipitate autonomic cardiac dysfunction with symptoms of tachycardia, palpitations, vocal hoarseness, and dysphagia (1). Cranial nerve involvement may occur with resulting retrobulbar optic neuritis, facial weakness, or dysarthria. Diagnostic Evaluation Serum thiamine level may poorly reflect the body’s actual thiamine stores and will quickly normalize with dietary supplementation. Measurement of erythrocyte transketolase activity can accurately reflect levels of body thiamine. If the concentration is less than 0.017 U/ dL, a deficiency state is present. Erythrocyte transketolase activity will also rapidly normalize following dietary supplementation (8,9). Therapy In patients with suspected beriberi or Wernicke encephalopathy, prompt parenteral thiamine replacement is necessary. A common regimen is 100 mg intravenously (IV) 3 times per day for several days with long-term maintenance of 50 to 100 mg/d orally. Higher doses may be acutely required in patients with Wernicke encephalopathy in the setting of alcoholism (2).

Vitamin B3 (Niacin) Niacin (also known as nicotinic acid or vitamin B3) is found in meat and poultry/eggs, salmon, dairy products, peanuts, lentils, whole grains, green leafy vegetables, brewer’s yeast, coffee, and tea. Niacin can also be formed by the metabolism of tryptophan, with 60 g of tryptophan equivalent to 1 mg of niacin. Deficiency and the resulting condition, called pellagra, are rare in the United States, as bread has been enriched with high-vitamin yeast since the 1930s (10). Pellagra, however, can still sometimes be found in Africa, the Caribbean, China, and India (11). Etiology/Pathogenesis Niacin deficiency is mainly found in places where corn is the main dietary staple and there is a concurrent protein deficiency. The niacin contained in corn is released only if the corn is processed using specific methods to increase its bioavailability, such as soaking it in a calcium oxide solution. Niacin deficiency may result for reasons other than inadequate ingestion. Normally, ingested tryptophan is

Function

Meat, poultry/ eggs, salmon, dairy products, whole grains, legumes (lentils), peanuts, brewer’s yeast, coffee/tea

B3 (niacin)

Clinical/Neurologic Manifestation

Recurrent vomiting, 1. Beriberi, severe alcoholism, dieting, gastric deficiency; dry, surgery neuropathic; wet, Body stores can be depleted in cardiac disease with 6-8 weeks peripheral edema; infantile 2. Wernicke encephalopathy: ocular changes, ataxia, and mental confusion (classic triad) 3. “Burning foot” syndrome: acute/ subacute predomi­ nantly sensory axonal, length-dependant PN 4. Optic neuropathy

Causes of Deficiency

Biologically active Severe malnutrition, carcinoid Pellagra: dementia, as nicotinamide, tumor, prolonged intake of photosensitive which is used to isoniazid or 5-fluorouracil, dermatitis, diarrhea form coenzymes Hartnup disease Less common: NAD and NADP, encephalopathy, critical for oxidationseizures, myoclonus of reduction reactions face/shoulders, cranial that produce cellular neuropathy, cerebellar energy ataxia, paratonia of Regulates cholesterol limbs or PN

Enriched whole- Cofactor required by 4 grain products, enzymes (including yeast, legumes, transketolase) nuts, organ Responsible for meats carbohydrate metabolism

B1 (thiamine)

Food Sources

Diagnosis

Urinary excretion of methylated niacin metabolites (eg, N-methylnicotinamide); low levels indicate deficiency

Serum or urinary level Erythrocyte transketolase activity TPP effect: measurement of enhancement of enzymatic activity from added thiamine pyrophosphate (TPP)

Table 6.2  Summary of Nutrients, Neurologic Manifestations, Diagnosis, and Treatment

14–16 mg/d

1–1.5 mg/d

RDA

(continued on next page)

40–250 mg of nicotinamide per day IM/orally

50–100 mg/d IV/IM/ orally PN may have limited potential for full recovery

Treatment

CHAPTER 6: Nutritional and Alcoholic Neuropathies  71

Function

Meat, eggs, dairy products, fortified cereals

B12 (cobalamin)

Toxicity

B6 (pyridoxine)

Precursor to active coenzymes (methylcobalamin and adenosylco­ balamin)

Meat, fish, eggs, Cofactor for enzymes dairy products, involved in amino legumes, nuts acid metabolism and synthesis of d-aminolevulinic acid Role in neuronal excitability?

Deficiency

B6 (pyridoxine)

Food Sources

Clinical/Neurologic Manifestation RDA

Low plasma pyridoxal 2 mg/d phosphate level with elevated homocysteine and cysathioprine levels Urinary xanthurenic acid after tryptophan loading (>50 mg/d is abnormal) Anemia (microcytic, hypochromic)

Diagnosis

Low serum cobalamin 3–6 μg/d (nL = 250–1100 pg/mL) Elevated methylmalonic acid, homocystein (intermediary metabolites) Macrocytic anemia Intrinsic factor and parietal cell antibodies (pernicious anemia) Schilling test (rarely used)

Pure sensory Elevated plasma pyridoxal neuronopathy/ level ganglionopathy (painful, burning paresthesias, lengthdependent or non–length-dependent pattern) Described in patients taking 200–2000 mg/d

Inadequate intake (vegan 1. Subacute combined diet); in severe deficiency, degeneration of cord can take 2–5 years before (with pathologic deficiency develops reflexes, distal Malabsorption (secondary predominantly largeto gastric surgery, ileal fiber sensory loss, resection, inflammatory positive Romberg and bowel disease) Lhermitte sign, visual H2 blockers, proton pump impairment) inhibitors, chloramphenicol, 2. Distal sensory axonal nitrous oxide (laughing gas) polyneuropathy +/Pernicious anemia (with myelopathy antibodies against intrinsic 3. Demyelinating factor) polyneuropathy (rare)

Hypervitaminosis

Medications (isoniazid, Burning feet, painful hydralazine, penicillamine, paresthesias, desoxypyridoxine, oral sensorimotor contraceptives), alcoholism, polyneuropathy GI disease Cutaneous changes (may Increased metabolic demand look like pellagra) with (pregnancy, post– glossitis, conjunctivitis, abdominal surgery) dermatitis, cheilosis Infantile seizures

Causes of Deficiency

Table 6.2  Summary of Nutrients, Neurologic Manifestations, Diagnosis, and Treatment  (continued)

Cyanocobalamin: 1 mg IM daily for 1 week, then weekly for 1 month, then monthly Oral: 500–1000 µg daily orally (only 1% absorbed by passive diffusion)

Limit supplementation to 40 kg/m2) or for those with a BMI of 35 to 39.9 kg/m2 with accompanying comorbidities (such as hypertension, sleep apnea, hyperlipidemia, or type II diabetes mellitus). Reversal of the metabolic syndrome of hypertension and elevated lipid and glucose levels is also anticipated following successful weight loss (79). Bariatric procedures can be divided into restrictive and bypass procedures, with the latter associated with a higher incidence of nutritional deficiencies. Restrictive procedures, such as gastric banding (Lap-Band®) and the less-commonly performed vertical banded gastroplasty procedure, are less invasive but may also be less effective for weight loss than bypass procedures. With bypass procedures, a small stomach pouch (with a volume of 15–30 mL) is fashioned, and malabsorption is achieved via bypass of the small intestine. The most common bypass procedure is the Roux-en-Y gastric bypass (RYGB). Biliopancreatic diversion with or without duodenal switch is a more extreme bypass procedure. It is reserved for the “super” obese (BMI > 50 kg/m2) and results in limited nutrient exposure to the distal ileum. Jejunoileal bypass procedures resulted in intolerable side effects and have been mostly abandoned.

CHAPTER 6: Nutritional and Alcoholic Neuropathies  81

With RYGB, patients are expected to lose 50% to 70% of their excess weight within 12 to 18 months. Loss of 60% to 80% of excess weight is expected over a 2-year period in patients with biliopancreatic diversion. Neurologic complications following bariatric surgery (BS) are reported in 0.08% to 16% of patients, according to a review of 18 surgical series reported between 1976 and 2004 (79). A 4% neurologic complication rate was reported in a single prospective study. In a review of 96 patients (described in 50 case reports), the most common presentations were peripheral neuropathy (62%) and encephalopathy (31%) (79). Others have found that peripheral neuropathy and acute polyradiculoneuropathy account for 51% of post–bariatric surgery neurologic complications (80). On average, the neuropathy developed 3.7 years after surgery (80). Risk factors for post–bariatric surgery peripheral neuropathy include increased hemoglobin A1c and triglyceride levels prior to surgery (81). Prolonged nausea and vomiting, rapid weight loss, poor follow-up at a nutritional clinic, reduced serum albumin and transferrin levels, postsurgical complications, and jejunoileal bypass are also risk factors for neurologic complications (82). Etiology/Pathogenesis Nutritional deficiencies are suspected to play an important role in the pathogenesis of post–bariatric surgery peripheral neuropathy, particularly the sensory-predominant polyneuropathies (82). Deficiencies may result from reduced dietary intake, reduced gastric acid, inadequate intrinsic factor secretion, or lack of nutrient exposure to the duodenum (83). Neuropathy has been linked to specific deficiencies of thiamine, B12, vitamin A, and copper. Focal neuropathies are less clearly related to specific deficiencies than polyneuropathy (81,84). Some patients lack clear evidence of malnutrition, suggesting that other disease mechanisms may be involved. The association with rapid weight loss and cachexia and the finding of prominent axonal degeneration and perivascular inflammation by sural nerve biopsy raise the possibility of inflammatory mechanisms (82). Clinical Features The most common presentations are polyneuropathy or mononeuropathies (79,82). The polyneuropathy is predominantly sensory, with prickling sensations or “dead”-type numbness in the feet and hands. Weakness is rare. Pain is described as aching, stabbing, or burning. Autonomic symptoms (such as lightheadedness, urinary incontinence, impotence, and constipation) may also be reported (82). Mononeuropathies have been described involving the median, ulnar, peroneal, and lateral femoral cutaneous nerves (79,82). Radiculoplexus neuropathy with acute asymmetric pain followed by weakness in the lower limbs or upper limbs is a rarer presentation. Those with mononeuropathy or radiculoplexus neuropathy were found to be more likely to have diabetes mellitus (82).

Some neurologic complications have been linked to specific deficiencies: 1. Vitamin B1 (thiamine): An acute, painful peripheral neuropathy or polyradiculoneuropathy reminiscent of Guillain-Barré syndrome (80), subacute large-fiber polyneuropathy, and painful small fiber with burning feet have been reported. Wernicke encephalopathy may follow persistent vomiting and rapid weight loss post–bariatric surgery (85–87). Symptoms of TD typically present within months of surgery, but some have been reported as long as 20 years following surgery (2). Cognitive symptoms often improve to a greater extent than motor or sensory symptoms following parenteral thiamine therapy (85). The deficiency may occur despite dietetic supervision and multivitamin supplementation (86). 2. B12: Myeloneuropathy and sensory more than motor neuropathy have been reported (80). 3. Vitamin A: Night blindness, xerophthalmia, Bitot spots, and anemia have been described following biliopancreatic diversion (88). 4. Copper: A copper deficiency myelopathy, clinically similar to subacute combined degeneration, with prominent sensory ataxia due to dorsal column dysfunction was described in 13 patients. Four of these patients had a history of gastric surgery, including 1 patient who had intestinal bypass for obesity (51). This patient had reduced copper and ceruloplasmin levels and a normal zinc level. All 13 patients had varying degrees of axonal neuropathy; however, the peripheral nervous system involvement was not the predominant reason for the sensory ataxia. Improvement of sensory symptoms was reported following parenteral copper administration (89). Iron deficiency is the most commonly identified mineral deficiency and is seen in nearly 50% of patients who have undergone gastric bypass surgery. It is believed to be caused by bone demineralization from impaired calcium absorption, often with concurrent vitamin D deficiency and secondary hyperparathyroidism. The significance of riboflavin, niacin, pyridoxine, vitamin C, and vitamin E deficiency is less well established. Other Gastric Surgery Gastric surgery for duodenal ulcers or malignancies may also result in neurologic complications due to TD (9,90), vitamin E deficiency (41), or copper deficiency (51). Thiamine deficiency following gastrectomy has been described to be identical to beriberi neuropathy, with a similar spectrum of clinicopathologic features and substantial recovery, particularly of motor function, following supplementation (4,9). Therapy Intensive preoperative and postoperative dietary counseling with a nutritionist has been shown to reduce, but

82  Textbook of Peripheral Neuropathy

not eliminate, the incidence of post–bariatric surgery peripheral neuropathy (81). Clinicians should be alert to nutritional deficiencies of thiamine, B12, vitamin C, iron, and zinc that precede surgery, particularly in those who have been dieting. The most common postsurgery deficiencies reported by meta-analysis are thiamine, B12, and folate (84). Calcium, zinc, selenium, vitamin A, and 25-hydroxyvitamin D deficiencies have also been reported. There are a variety of regimens recommended for prophylaxis against neurologic complications. A standard regimen includes the following: (1) multivitamin containing folate 400 μg, thiamine 1.2 mg, B12 (dose dependent on serum levels), 1 to 2 times daily; (2) calcium citrate (1200–2000 mg/d); (3) vitamin D (400–800 U/d); and (4) elemental iron (40–65 mg/d, particularly for menstruating women). Some recommend additional thiamine and B12 (1 mg IM monthly or 500 μg intranasally weekly) to supplement the relatively small doses found in a multivitamin (84). The B12 RDA is 2.4 μg; however, 30% of patients taking this amount of B12 in their daily multivitamin formulation developed B12 deficiency within 1 year of bariatric surgery (91). Patients taking 1 mg IM of B12 every 3 months or 500 μg intranasally weekly had B12 deficiency rates of 3.6% at 1 year and 2.3% at 2 years. Copper (RDA, 900 μg/d) is not listed in current recommendations. If biliopancreatic diversion +/– duodenal switch has been performed, fat-soluble vitamins should be supplemented, including the following: vitamin A (5000– 10 000 IU daily), vitamin E (400 IU daily), and vitamin K (1 mg/d). If RYGB has been performed, the following laboratory studies should be performed every 3 to 6 months for the first year: CBC, comprehensive metabolic panel, iron studies, lipid profile, calcium, vitamin D, alkaline phosphatase, parathyroid hormone (optional), thiamine, B12, and RBC folate. (It is unclear if copper levels should be routinely checked.) If the patient has had a biliopancreatic diversion, these tests should be performed every 3 to 6 months in perpetuity. Albumin, prealbumin, fat-soluble vitamin levels, zinc and selenium levels, and a metabolic bone evaluation should also be checked regularly in patients with biliopancreatic diversion (92). In the acute setting, thiamine should be replaced IV. One recommended regimen is 500 mg IV 3 times a day for 2 to 3 days, followed by 50 to 100 mg 3 times a day orally as long as the patient has gastrointestinal complaints (84). When adequate supplementation of identified deficiencies is without benefit, bypass reversal may be necessary (80,92–94).

CONCLUSION Historically, peripheral neuropathy related to nutritional deficiencies has been reported in settings of socio-

economic deprivation or alcoholism. In the 21st century, given rising obesity rates in the developed world, neuropathy should also be considered in the setting of intentional malabsorption due to bariatric surgery. The water-soluble B vitamins (B1, B3, B6 and B12), folate, vitamin E, and copper are particularly important for optimal functioning of the peripheral nervous system. Deficiencies of these and other nutrients are believed to play a role in the development of ALN or post–gastric surgery neuropathy. There is evidence, however, that suggests that other mechanisms may be involved, such as a directly toxic effect of ethanol or its metabolites or an immune-mediated process in some cases of neuropathy following bariatric surgery. Nutritional neuropathies typically present with sensory or sensorimotor symptoms in a distal, lengthdependent pattern, with mostly axonal electrodiagnostic findings. Notable exceptions, however, include the sensory neuronopathy or ganglionopathy seen with B6 toxicity, myelopathy with B12 and copper deficiencies, and a spinocerebellar syndrome with vitamin E deficiency. Early detection and correction of the nutritional deficits and underlying risk factors is crucial as the prognosis depends on the duration of symptoms and degree and extent of axonal nerve damage.

References 1. Saperstein D, Barohn R. Neuropathy associated with nutritional and vitamin deficiencies. In: Dyck PJ, Thomas PK, eds. Peripheral Neuropathy. Philadelphia, PA: Elsevier Saunders; 2005:2051–2062. 2. Kumar N. Neurologic presentations of nutritional deficiencies. Neurol Clin. 2010;28:107–170. 3. McCormick DB, Greene HL. Vitamins. In: Burtis CA, Ashwood ER, eds. Tietz Textbook of Clinical Chemistry. Philadelphia, PA: WB Saunders; 1999:999–1028. 4. Koike H, Iijima M, Sugiura M, et al. Alcoholic neuropathy is clinicopathologically distinct from thiamine-deficient neuropathy. Ann Neurol. 2003;54:19–29. 5. Sekiyama S, Takagi S, Kondo Y. Peripheral neuropathy due to thiamine deficiency after inappropriate diet and total gastrectomy. Tokai J Exp Clin Med. 2005;30(3):137–140. 6. Murata K. Actions of two types of thiaminase on thiamin and its analogues. Ann NY Acad Sci. 1982;378:146–156. 7. Koike H, Ito S, Morozumi S, et al. Rapidly developing weakness mimicking Guillain-Barré syndrome in beriberi neuropathy: two case reports. Nutrition. 2008;24: 776–780. 8. Shields RW. Alcoholic and nutritional polyneuropathies. In: Brown WF, Bolton CF, Aminoff MJ, eds. Neuromuscular Function and Disease. Vol 2. Philadelphia, PA: WB Saunders; 2002:1109–1125. 9. Koike H, Misu K, Hattori N, et al. Postgastrectomy polyneuropathy with thiamine deficiency. J Neurol Neurosurg Psychiatry. 2001;71:357–362. 10. Park YK, Sempos CT, Barton CN, Vanderveen JE, Yetley EA. Effectiveness of food fortification in the United States: the case of pellagra. Am J Public Health. 2000; 90:727–738.

CHAPTER 6: Nutritional and Alcoholic Neuropathies  83 11. Jacob RA, Swendseid, ME, McKee RW, Fu CS, Clemens RA. Biochemical markers for assessment of niacin status in young men: urinary and blood levels of niacin metabolites. J Nutr. 1989;119:591–98. 12. Shah GM, Shah RG, Veillette H, Kirkland JB, Pasieka JL, Warner RR. Biochemical assessment of niacin deficiency among carcinoid cancer patients. Am J Gastroenterol. 2005;100:2307–2314. 13. Stevens HP, Ostelere LS, Begent RH, Dooley JS, Rustin MH. Pellagra secondary to 5-fluorouracil. Br J Dermatol. 1993;128:578–80. 14. Ishii N, Nishihara Y. Pellagra encephalopathy among tuberculous patients: its relation to isoniazid therapy. J Neurol Neurosurg Psychiatry. 1985;48:628–634. 15. Seow HF, Bröer S, Bröer A, et al. Hartnup disorder is caused by mutations in the gene encoding the neutral amino acid transporter SLC6A19. Nat Genetics. 2004;36:1003–1007. 16. Kirkland JB. Niacin and carcinogenesis. Nutr Cancer. 2003;46:110–118. 17. Ishii N, Nishihara Y. Pellagra among chronic alcoholics: clinical and pathological study of 20 necropsy cases. J Neurol Neurosurg Psychiatry. 1981;44:209–215. 18. Perry TA, Weerasuriya A, Mouton PR, Holloway HW, Greig NH. Pyridoxine-induced toxicity in rats: a stereological quantification of the sensory neuropathy. Exp Neurol. 2004;190:133–144. 19. Schaumberg H, Kaplan J, Windebank A, et al. Sensory neuropathy from pyridoxine abuse: a new megavitamin syndrome. N Eng J Med. 1983;309(8):445–448. 20. Savage DG, Lindenbaum J. Neurologic complications of a­cquired cobalamin deficiency; clinical aspects. Bailliere Clin Haematol. 1995;8:657–677. 21. Carmel, R. Current concepts in cobalamin deficiency. Annu Rev Med. 2000;51:357–375. 22. Carmel R. How I treat cobalamin (vitamin B12) deficiency. Blood. 2008;112:2214–2221. 23. Dali-Youcef N, Andres E. An update on cobalamin deficiency in adults. Q J Med. 2009;102:17–28. 24. Hemmer B, Glocker FX, Schumacher M, Deuschl G, Lucking CH. Subacute combined degeneration: clinical electrophysiological, and magnetic resonance imaging findings. J Neurol Neurosurg Psychiatry. 1998;65:822–827. 25. Metz J. Cobalamin deficiency and the pathogenesis of nervous system disease. Annu Rev Nutr. 1992;12:59–79. 26. Weir D, Scott J. The biochemical basis of the neuropathy in cobalamin deficiency. Bailliere’s Clin Haematol. 1995;8(3): 479–497. 27. McCombe PA, Mcleod JG. The peripheral neuropathy of vitamin B12 deficiency. J Neurol Sci, 1984; 66:117–126. 28. Saperstein D, Wolfe G, Gronseth G, et al. Challenges in the identification of cobalamin-deficiency polyneuropathy. Arch Neurol. 2003;60:1296–1301. 29. Cox-Klazinga M, Endtz LJ. Peripheral nerve involvement in pernicious anemia. J Neurol Sci. 1980;45:367–371. 30. Fine EJ, Soria E, Paroski MW, et al. The neurophysiological profile of vitamin B12 deficiency. Muscle Nerve. 1990;13: 158–164. 31. Puntambekar P, Basha M, Zak I, Madhavan R. Rare sensory and autonomic disturbances associated with vitamin B12 d­eficiency. J Neurol Sci. 2009;287:285–287. 32. Vasconcelos OM, Poehm EH, McCarter RJ, et al. Potential outcome factors in subacute combined degeneration. J Gen Intern Med. 2006;21:1063–1068.

33. Satya-Murti S, Howerd L, Krohel G, Wolf B. The spectrum of neurologic disorder from vitamin E deficiency. Neurology. 1986;36:917–921. 34. Sokol RJ. Vitamin E deficiency and neurologic disease. Ann Rev Nutr. 1988;8:351–73. 35. Food and Nutrition Board, Institute of Medicine. Niacin. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press; 1998. 36. Ouahchi K, et al. Ataxia with isolated vitamin E deficiency is caused by mutations in the a-tocopherol transfer protein. Nat Genetics. 1995;9:141–145. 37. Harding AE, Muller DPR, Thomas PK, Willison HJ. Spinocerebellar degeneration secondary to chronic intestinal mal­ absorption: a vitamin E deficiency syndrome. Ann Neurol. 1982;12:419–424. 38. Rosenblum JL, Keating JP, Prensky AL, Nelson JS. A progressive neurologic syndrome in children with chronic liver disease. N Engl J Med. 1981;304:503–508. 39. Muñoz SJ, Heubi JE, Balistreri WF, Maddrey WC. Vitamin E deficiency in primary biliary cirrhosis: gastrointestinal malabsorption, frequency and relationship to other lipidsoluble vitamins. Hepatology. 1989;9(4):525–531. 40. Werlin Sl, Harb JM, Swick H, Blank E. Neuromuscular dysfunction and ultrastructural pathology in children with chronic cholestasis and vitamin E deficiency. Ann Neurol. 1983;13:291–296. 41. Ueda N, Suzuki Y, Takahashi T, Rino Y, Takanashi Y. Treatment of neurological complication due to post-gastrectomy vitamin E deficiency. No To Shinkei. 2005;57:145–148. 42. Rino Y, Suzuki Y, Kuroiwa Y, et al. Vitamin E malabsorption and neurological consequences after gastrectomy for gastric cancer. Hepatogastroenterology. 2007;54(78): 1858–1861. 43. Sokol RJ, Heubi JE, Iannaccone ST, Bove KE, Balistreri WF. Vitamin E deficiency with normal serum vitamin E concentrations in children with chronic cholestasis. N Engl J Med. 1984;310:1209–1212. 44. Yokota T, Shiojiri T, Gotoda T. Freidreich-like ataxia with retinitis pigmentosa caused by the His101 Gln mutation of the a-tocopherol transfer protein gene. Ann Neurol. 1997;41:826–832. 45. Traber MG, Sokol RJ, Ringel SP, Neville HE, Thellman CA, Kayden HJ. Lack of tocopherol in peripheral nerves of vitamin E-deficient patients with peripheral neuropathy. N Engl J Med. 1987;317:262–265. 46. Kumar N. Copper deficiency myelopathy (human swayback). Mayo Clin Proc. 2006;81:1371–1384. 47. Brown EA, Muller BR, Sampson B, Curtis JR. Urinary iron loss in nephrotic syndrome—an usual cause of iron deficiency with a note on urinary copper losses. Postgrad Med J. 1984;60:125–128. 48. Tateishi J. Subacute myelo-optico-neuropathy: clioquinol intoxication in humans and animals. Neuropathology. 2000;20:S20–24. 49. Danks DM, Campbell PE, Stevens BJ, Mayne V, Cartwright E. Menke’s kinky hair syndrome: an inherited defect in copper absorption with widespread effects. Pediatrics. 1972;50:188–201. 50. Kaler SG, Buist NR, Holmes CS, Goldstein DS, Miller RC, Gahl WA. Early copper therapy in classic Menkes disease patients with a novel splicing mutation. Ann Neurol. 1995;38:921–928.

84  Textbook of Peripheral Neuropathy 51. Kumar N, Gross JB, Ahlskog JE. Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration. Neurology. 2004;63:33–39. 52. Naismith RT, Shepherd JB, Weihl CC, et al. Acute and b­ilateral blindness due to optic neuropathy associated with copper deficiency. Arch Neurol. 2009;66:1025–1027. 53. Uauy R, Olivares M, Gonzalez M. Essentiality of copper in humans. Am J Clin Nutr. 1998;67(5 Suppl):952S–959S. 54. Goodman BP, Bosch EP, Ross MA, Hoffman-Snyder C, Dodick DD, Smith BE. Clinical and electrodiagnostic findings in copper deficiency myeloneuropathy. J Neurol Neurosurg Psychiatry. 2009;80:524–527. 55. Prodan CI, Holland NR, Wisdom PJ, Burstein SA, Bottomley SS. CNS demyelination associated with copper deficiency and hyperzinemia. Neurology. 2002;59:1453–1456. 56. Champe PC, Harvey RA. Nutrition. In: Biochemistry. 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1987:325– 326. 57. Reynolds EH. Benefits and risks of folic acid to the nervous system. J Neurol Neurosurg Psychiatry. 2002;72:567–571. 58. Moreiras GV, Murphy MM, Scott JM. Cobalamin, folic acid and homocysteine. Nutr Rev. 2009;67:S69–S72. 59. Reynolds EH. Folic acid, ageing, depression, and dementia. Br Med J. 2002;324:1512–1514. 60. Fehling C, Jagerstad M, Lindstrand K, et al. Folate deficiency and neurological disease. Arch Neurol. 1974;30:263–265. 61. Manzoor M, Runcie J. Folate-responsive neuropathy: report of 10 cases. Br Med J. 1976;1:1176–1178. 62. Botez MI, Peyronnard J, Bachevalier J, Charron L. Polyneuropathy and folate deficiency. Arch Neurol. 1978;35: 581–584. 63. Huertas R, Del Cura MI. Deficiency neuropathy in wartime: the “paraesthetic-causalgic syndrome” described by Manuel Peraita during the Spanish Civil War. J Hist Neurosci. 2010; 19:173–181. 64. Nightingale LM, Paviour DC. Nutritional optic and peripheral neuropathy: a case report. Cases J. 2009;2:7762. 65. Thomas PK, Plant GT, Baxter P, Bates C, Santiago Luis R. An epidemic of optic neuropathy and painful sensory neuropathy in Cuba: clinical aspects. J Neurol. 1995; 242:629–638. 66. Rowland LP, Gordon PH. Hereditary and acquired spastic paraplegia. In: Rowland LP, ed. Merritt’s Neurology. Philadelphia, PA: Lippincott Williams & Wilkins; 2005:856–857. 67. Plant GT, Mtanda AT, Arden GB, Johnson GJ. An epidemic of optic neuropathy in Tanzania: Characterization of the visual disorder and associated peripheral neuropathy. J Neurol Sci. 1997;145:127–140. 68. Koike H, Sobue G. Alcoholic neuropathy. Curr Opin Neurol. 2006;19:481–486. 69. Zambelis T, Karandreas N, Tzavellas E, et al. Large and small fiber neuropathy in chronic alcohol-dependent subjects. J Peripher Nerv Syst. 2005;10:375–381. 70. Behse F, Buchthal F. Alcoholic neuropathy: clinical, electrophysiological, and biopsy findings. Ann Neurol. 1977;2:95–110. 71. Strauss MB. The etiology of alcoholic polyneuritis. Am J Med Sci. 1935;189:378–382. 72. Victor M, Adams RD. On the etiology of the alcoholic neurologic diseases. With special references to the role of nutrition. Am J Clin Nutr. 1961;9:379–397. 73. Montforte R, Estruch R, Valls-Solé J, et al. Autonomic and peripheral neuropathies in patients with chronic alcohol-

ism: a dose-related toxic effect of alcohol. Arch Neurol. 1995;52:45–51. 74. Vittadini G, Buonocore M, Colli G, et al. Alcoholic polyneuropathy: a clinical and epidemiological study. Alcohol Alcohol. 2001;36:393–400. 75. Paparrigopoulos T, Tzavellas E, Karaiskos D, et al. A­lcoholic optic neuropathy: another complication of alcohol abuse. J Neuropsychiatry Clin Neurosci. 2008;20:368–369. 76. Wöhrle JC, Spengos K, Steinke W, et al. Alcohol-related acute axonal polyneuropathy. A differential diagnosis of Guillain-Barré syndrome. Arch Neurol. 1998;55: 1329–1334. 77. Ammendola A, Tata MR, Aurilio C, et al. Peripheral neuropathy in chronic alcoholism: a retrospective crosssectional study in 76 patients. Alcohol Alcohol. 2001;36: 271–275. 78. Gane E, Bergman R, Hutchinson D. Resolution of alcoholic neuropathy following liver transplantation. Liver Transpl. 2004;10:1545–1548. 79. Koffman BM, Greenfield LJ, Ali II, et al. Neurologic complications after surgery for obesity. Muscle Nerve. 2006;33:166– 176. 80. Juhasz-Pocsine K, Rudnicki SA, Archer RL, et al. Neurologic complications of gastric bypass surgery for morbid obesity. Neurology. 2007;68:1843–1850. 81. Thaisetthawatkul P, Collazo-Clavell ML, Sarr MG, Norell JE, Dyck PJB. Good nutritional control may prevent polyneuropathy after bariatric surgery. Muscle Nerve. 2010;42:709– 714. 82. Thaisetthawatkul P, Collazo-Clavell ML, Sarr MG, Norell JE, Dyck PJB. A controlled study of peripheral neuropathy after bariatric surgery. Neurology. 2004;63: 1462–1470. 83. Mason ME, Jalagani H, Vink AJ. Metabolic complications of bariatric surgery: diagnosis and management issues. Gastroenterol Clin North Am. 2005;34:25–33. 84. Rudnicki SA. Prevention and treatment of peripheral neuropathy after bariatric surgery. Curr Treat Options Neurol. 2010;12:29–36. 85. Cirignotta F, Manconi M, Mondini S, Buzzi G, Ambrosetto P. Wernicke-Korsakoff encephalopathy and polyneuropathy after gastroplasty for morbid obesity. Arch Neurol. 2000;57:1356–1359. 86. Chaves LCL, Faintuch J, Kahwage S, Alencar FA. A cluster of polyneuropathy and Wernicke-Korsakoff syndrome in a bariatric unit. Obesity Surgery. 2002;12:328–334. 87. Aashaim ET. Wernicke encephalopathy after bariatric surgery: a systematic review. Ann Surg. 2008;248:714–720. 88. Hatzifotis M, Dola K, Newbury L, et al. Symptomatic vitamin A deficiency following biliopancreatic diversion. Obes Surg. 2003;13:655–657. 89. Kumar N, McEvoy KM, Ahlskog JE. Myelopathy due to copper deficiency following gastrointestinal surgery. Arch Neurol. 2003;60:1782–1785. 90. Nakagawa H, Yoneda M, Maeda A, Umehara F, Kuriyama M. [Thiamine deficiency polyneuropathy after gastrectomy associated with high level of serum vascular endothelial growth factor (VEGF). A case report.] Rinsho Shinkeigaku. 2004;44:91–95. 91. Provenzale D, Reinhold RB, Golner B, et al. Evidence for diminished B12 absorption after gastric bypass: oral supplementation does not prevent low plasma B12 levels in bypass patients. J Am Coll Nutr. 1992;11(1):29–35.

CHAPTER 6: Nutritional and Alcoholic Neuropathies  85 92. Mechanick JL, Kushner RF, Sugerman HJ, et al. American Association of Clinical Endocrinologists, The Obesity Society, and American Society for Metabolic & Bariatric Surgery Medical Guidelines for Clinical Practice for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient. Surg Obes Relat Dis. 2008;4(5 Suppl):S109–S184. 93. Aasheim ET, Hofsø D, Hjelmesaeth J, et al. Peripheral neuropathy and severe malnutrition following duodenal switch. Obes Surg. 2008;19:1640–1643.

94. Vyas ID, Purohit MG, Bearn AR. Reversible peripheral neuropathy following jejuno-ileal bypass surgery for morbid obesity. J R Coll Surg Edinb. 1979;24:278–279. 95. Chaudhry V, Umapathi T, Ravich WJ. Neuromuscular disease and disorders of the alimentary system. Muscle Nerve. 2002;25:768–784.

James W. Albers

7

Occupational, Biologic, and Environmental Toxic Neuropathies

INTRODUCTION

in soil grouting, in water proofing, as a flocculator in water treatment and municipal water systems, and as a byproduct in some foods. The acrylamide monomer is neurotoxic, but the polymer, polyacrylamide, is not (3,4). Acrylamide is of historic interest as an animal model of “dying-back” neuropathy. Although an uncommon cause of clinically evident neuropathy, acrylamide is among a select group of neurotoxicants that produce neurofilamentous axonal masses demonstrable on nerve biopsy, a finding pathognomonic for the giant axonal neuropathies. In experimental acrylamide neuropathy, action potential propagation fails in the distal nerve terminals (5), and there is axonal degeneration distal to the neurofilamentous swellings (6). The largest myelinated sensory neurons are preferentially involved (7,8). Accumulation of neurofilaments reflects impaired retrograde transport (6,9–13), although the mechanism whereby acrylamide produces axonal degeneration is unknown (14). Acrylamide intoxication has been associated with hyperhydrosis. This possibly is related to the degeneration of the unmyelinated postganglionic sudomotor sympathetic efferent nerve fibers observed in mouse models of acrylamide neuropathy, although anhidrosis would be more characteristic of dysautonomia (15). Alternatively, there may be a direct effect on the skin, as acrylamide produces aggregation of intermediate filaments in cultured human skin fibroblasts (16).

Our understanding of the neuropathologic mechanisms of neuropathy derives, in large part, from the study of neurotoxicants. Although toxic substances are a potential cause of neuropathy, the diagnosis of “toxic-metabolic” neuropathy is probably overused, especially when no specific cause is apparent. Clinically important toxic neuropathies due to occupational, biologic, or environmental exposures are uncommon relative to other causes, aside from those associated with medications. Industrial exposures are typically chronic, low level, and occurring during a manufacturing process, or acute, high level, and associated with an industrial accident. Rarely is exposure information available through industrial hygiene air monitoring or biologic sampling programs. Environmental exposures are usually inadvertent, without known contact with the substance. Fortunately, knowing the cause of a neuropathy is not a prerequisite for making a correct neurologic diagnosis, and the cause must be determined after the correct clinical diagnosis is established. In this chapter, several toxic neuropathies are described, based on a classification using electrophysiologic features. These features—motor or sensory predominant, conduction slowing or no conduction slowing—focus the differential diagnosis and suggest additional testing to help identify a final diagnosis and establish the cause of the neuropathy. Several of the tables presented in this chapter have been modified from previous publications (1,2) and reflect important competing diagnoses, not just those due to toxins or toxicants. Few toxic neuropathies have unique features, but, on occasion, systemic clues suggest their identity. Familiarity with these clues increases the likelihood they will be recognized when present.

Clinical Manifestations Acrylamide neuropathy presents with complaints of distal numbness and weakness, clumsiness, and sometimes, hyperhydrosis. The neuropathy is characterized by stockingglove sensory loss and weakness, unsteady gait, and loss of ankle reflexes (17). The initial descriptions appeared shortly after acrylamide was commercially manufactured (18). These reports of occupationally exposed workers also described ataxia attributed to cerebellar involvement because unsteadiness seemed disproportionate to sensory loss (17). Other reports described hyperhydrosis of

SELECTED EXAMPLES Acrylamide Acrylamide is a vinyl monomer, and potential occupational or environmental exposures result from its use 87

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the palms and soles in association with impaired vibration and joint position sensations (sometimes absent below the ankles), positive Romberg sign, truncal and gait ataxia, distal weakness, and areflexia (19). The early and marked loss of vibration sensation has been attributed to involvement of fibers in Pacinian corpuscles. Such severe sensory loss could produce unsteadiness sufficient to be confused with cerebellar ataxia. It is unclear whether hyperhydrosis reflects an irritant effect or autonomic dysfunction (20). Removal from exposure before substantial neuropathy develops results in the complete recovery (18,21). Electrophysiology Early reports described normal motor nerve conduction velocity in the arms, with borderline-reduced velocity (between 80% and 90% of the lower limit of normal) in the legs and evidence of denervation (fibrillation potentials) in leg muscles (19). Some workers diagnosed

with acrylamide neurotoxicity showed low-amplitude sensory and motor responses with modest conduction slowing (17,22,23). Asymptomatic acrylamide-exposed workers showed low sensory amplitudes and neurogenic changes on needle electromyography (EMG), changes said to precede clinically evident acrylamide neuropathy (24). Differential Diagnosis Acrylamide is among a large number of toxins that cause sensorimotor neuropathies. Although some reports of acrylamide neuropathy can be characterized as a sensorimotor neuropathy with little conduction slowing, others emphasize motor greater than sensory involvement and conduction slowing, albeit modest and possibly attributable to loss of the largest myelinated motor fibers. Therefore, acrylamide is included both among the sensorimotor neuropathies having no conduction slowing (Table 7.1) and among the neuropathies having con-

Table 7.1  Mixed Sensory and Motor Neuropathy With No Conduction Slowing Hereditary/familial Giant axonal dystrophy Friedreich ataxia Myotonic dystrophy Infectious HIV Leprosy Inflammatory (autoimmune) Churg-Strauss Connective tissue disorders Gout Necrotizing angiopathy Periarteritis Rheumatoid arthritis Sarcoidosis Systemic lupus erythematosus Metabolic Acromegaly Hypothyroidism

Toxic Acrylamide Amitriptyline Arsenic (chronic) Carbon monoxide Chloroquine Colchicine (neuromyopathy) Ethambutol Ethyl alcohol Ethylene oxide Elemental mercury Gold Hydralazine Isoniazid Lithium Metronidazole Nitrofurantoin Nitrous oxide (myeloneuropathy) Paclitaxel Perhexiline Phenytoin Vincristine

Neoplastic (paraneoplastic) Amyloidosis Carcinoma Lymphoma Monoclonal gammopathy (MGUS) Multiple myeloma Nutritional Critical illness neuropathy Vitamin deficiency (eg, folate, B12, thiamine, postgastrectomy) Whipple disease Abbreviation: MGUS, monoclonal gammopathy of unknown significance. Source: Donofrio and Albers (1) and Albers and Berent (2).

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duction slowing (Table 7.2). The presence or absence of conduction slowing may reflect the timing of evaluation vis-à-vis the onset of neuropathy as other neurotoxicants, including arsenic, have electrodiagnostic characteristics that depend on the timing of evaluation. Several other giant axonal axonopathies appear in Table 7.2, including n-hexane, methyl n-butyl ketone, and carbon disulfide. In this context, the association of neuropathy and hyperhydrosis distinguishes acrylamide from other potential causes. Additional Diagnostic Evaluation The primary additional diagnostic test in the evaluation of suspected acrylamide neuropathy is a nerve biopsy showing focal axonal swellings containing masses of neurofilaments. This neuropathology is not specific for acrylamide, but it is associated with a relatively small number of conditions producing a giant neurofilamentous axonopathy, thereby greatly reducing the number of possible diagnostic considerations. Treatment The only treatment for acrylamide neuropathy is removal from exposure.

Arsenic Arsenic is a metalloid, present in inorganic (toxic) and organic (nontoxic) forms. Occupational exposures include smelting, mining, tanning, and numerous manufacturing processes (25). Environmental exposures

include groundwater contamination, combustion fumes of contaminated fossil fuels and arsenate-treated wood, contact with arsenic-containing pesticides and herbicides, and iatrogenic medicinal exposure, including folk and herbal medicines (26–29). Arsenic is best known as a homicidal or suicidal agent, despite its long history of medicinal applications (the difference between medicine and poison is intent) (30–32). Arsenic is a general protoplasmic poison that interferes with cellular energy metabolism and disrupts protein and enzyme activity (28). The neuropathology is characterized by axonal d­egeneration with preferential involvement of largediameter nerve fibers (31). Clinical Manifestations Acute arsenic neuropathy usually follows a single massive exposure, after which neuropathy appears within 5 to 10 days. Initial symptoms include paresthesias and burning pain, distal numbness and tingling, muscle aches, and distal weakness. The neuropathy progresses over weeks despite no additional exposure (coasting). In some cases, the neuropathy results in flaccid paralysis with bifacial weakness, respiratory failure, profound sensory loss, and areflexia, with a temporal course resembling the Guillain-Barré syndrome (GBS) (33). Arsenic neuropathy is one part of a generalized multi­ s­ystem illness, with cardiovascular (cardiomyopathy and dysrhythmia); gastrointestinal (abdominal pain, nausea, vomiting, diarrhea, hepatitis, and hepatomegaly); hematologic (bone marrow failure with basophilic

Table 7.2  Motor or Motor More Than Sensory Neuropathy With Conduction Slowing Hereditary/familial HMSN (type I, III) Hereditary tomaculous Infectious HIV Inflammatory (autoimmune) Castleman disease Chronic inflammatory demyelinating Diphtheria GBS Monoclonal gammopathy (MGUS) Systemic lupus erythematosus Swine flu vaccine Vasculitis (confluent mononeuritis)

Toxic Acrylamide Arsenic (shortly after acute exposure) Amiodarone Carbon disulfide Ara-C Disulfiram Methyl n-butyl ketone n-Hexane Saxitoxin (sodium channel blocker) Suramin

Neoplastic (paraneoplastic) Monoclonal gammopathy (MGUS) Multiple myeloma Osteosclerotic myeloma Abbreviations: Ara-C, cytosine arabinoside; GBS, Guillain-Barré syndrome; HMSN, hereditary motor-sensory neuropathy. Source: Donofrio and Albers (1) and Albers and Berent (2).

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stippling); renal (acute tubular necrosis); and dermatologic (hyperpigmentation, desquamation, keratosis, and Mees lines) involvement. Some systemic features, such as gastrointestinal symptoms, antedate the onset of neuropathy and may be mistaken for an antecedent illness associated with GBS. Features suggestive of a toxic etiology, such as Mees lines (Figure 7.1), are not apparent initially and appear only later, usually when the diagnosis is no longer in question (34). Chronic arsenic intoxication produces signs similar to those of acute intoxication but having more insidious onset. A neuropathy due to chronic arsenic intoxication is rarely recognized, however, and there are no convincing reports of symptomatic chronic arsenic neuropathy in the United States or Canada (35). Patients who survive acute arsenic intoxication experience substantial or complete neurologic recovery over months to years, depending on the degree and extent of denervation, age, and the presence of underlying conditions. In the United States, arsenic is best known for it use as an intentional poison, either as a homicidal or suicidal agent. In some parts of the world, most notably Bangladesh and West Bengal, subacute onset or chronic arsenic neuropathy commonly reflects exposure to drinking water contaminated with arsenic from geologic, mining, or other industrial sources or ingestion of arsenic-containing homeopathic medicines (36–38). Electrophysiology Evaluations performed soon after the onset of neuropathy often fulfill criteria suggestive of an acquired demyelinating neuropathy (39). Motor studies show reduced amplitudes, increased temporal dispersion and/ or partial conduction block (Figure 7.2), slowed conduction velocities, prolonged distal latencies, and absent F responses. Results of sensory studies may be normal or show reduced amplitude, especially involving the sural nerve, not the “normal sural–absent median” sensory

Figure 7.1 Mees lines in the fingernails of a patient with arsenic intoxication following single acute exposure. Reprinted from Albers and Bromberg (40) with permission of Lippincott Williams & Wilkins.

Figure 7.2 Ulnar motor responses (surface recording from the abductor digiti minimi muscle) recorded from patient with acute arsenic neuropathy 12 days after the onset of neuropathic symptoms; stimulation of the ulnar nerve at the wrist (A), below elbow (B), above elbow (C), axilla (D), and Erb point (E). Reprinted from Donofrio et al. (39) with permission of John Wiley & Sons, Inc.

pattern frequently observed in GBS (41). Initial needle EMG abnormalities include only reduced motor unit recruitment. Within several weeks, the initial results are replaced by findings more characteristic of a severe dying-back sensorimotor neuropathy, often with absent motor and sensory responses and evidence of denervation (fibrillation potentials) and reinnervation (largeamplitude, polyphasic motor units). Differential Diagnosis The differential diagnosis for a sensorimotor or motor greater than sensory neuropathy characterized by motor conduction slowing is shown in Table 7.2. The clinical presentation is consistent with GBS, and that diagnosis would most often be the correct diagnosis, although the finding of low amplitude or absent sural sensory responses should be recognized as atypical of GBS. Additional Diagnostic Evaluation Evidence of cerebrospinal fluid (CSF) albuminocellular dissociation is characteristic of GBS but not specific for that disorder, and patients with acute arsenic neuropathy may have elevated CSF protein levels in the range of 150 to 300 mg/dL. A urine “heavy metal screen” (which includes arsenic even though arsenic is a metalloid, not a heavy metal) is often requested when GBS is suspected. Arsenic is rapidly excreted in the urine, and a 24-hour urine collection reliably establishes exposure but not intoxication. Indiscriminant urine arsenic screening is not appropriate for patients with chronic neuropathy. Nontoxic organic arsenic salts are widespread (eg, shellfish and bottom-feeding fin fish) and can cause alarmingly elevated urine arsenic levels b­ecause routine analyses do not distinguish organic a­rsenic from inorganic a­rsenic. Arsenic is rapidly cleared from the blood, and s­erum levels are helpful only when collected within hours to a few days of acute ingestion (28,42).

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Other l­aboratory a­bnormalities reflecting systemic toxicity i­nclude abnormal liver function and renal study results, pancytopenia, and basophilic stippling of red blood cells, a nonspecific but important indicator of some toxic exposure. When arsenic neuropathy is first considered late in the course of the illness (eg, such as when Mees lines are discovered), the amount of arsenic present in hair or nails can be measured, as arsenic binds to keratin (43). Treatment The most important treatment is removal from exposure. Although most cases involve a single, massive exposure, recurrent homicidal poisonings have included reexposure of an individual who survived presumed GBS (44). Removal from exposure is possible for ongoing environmental or occupational arsenic exposures, once the diagnosis is established and the source identified. Treatment of acute arsenic poisoning includes, depending on the timing, gastric lavage, hemodialysis, and chelation. It is questionable whether hemodialysis or chelation influences neurologic progression or recovery as irreversible damage likely occurs before neurologic signs appear. Anecdotal experience suggests that therapeutic plasma exchange does not influence the course of arsenic neuropathy. Supportive care includes monitoring and management of respiratory and cardiac function and prevention or treatment of infection, circulatory failure, and thromboembolism.

Botulinum Toxin Botulinum toxin, considered the most potent poison known, is produced by the spores of Clostridium botulinum maintained in an anaerobic environment. Of the 7 types of botulism, 3 (A, B, and E) produce human disease (45,46). This environmental toxin inhibits acetylcholine release from presynaptic terminals of motor and autonomic axons, interfering with neuromuscular transmission and autonomic function. The initial weakness reflects impaired neuromuscular transmission, not neuropathy, but the irreversible neuromuscular blockade functionally denervates skeletal muscle, and the axon terminal degenerates, producing a severe motor neuropathy (45). In the intestine, botulinum toxin is dissociated from its protective proteins, absorbed into the bloodstream, and transported to cholinergic axon terminals, where it is taken into the terminal by calciumdependent, receptor-mediated endocytosis (45,47–49). There are few more striking examples of the similarity between poisons and medications than botulinum toxin, given its extensive medicinal and cosmetic uses. Small amounts of Types A and F are injected into skeletal muscles to produce localized “chemodenervation” to control conditions characterized by muscle overactivity (eg, blepharospasm, hemifacial spasm, and dystonia). The most widespread application is cosmetic, involving partial denervation of facial muscles that contribute to wrinkles.

Clinical Manifestations About 12 to 72 hours after botulinum intoxication, the initial neuromuscular blockade manifests as diplopia, dysarthria, dysphagia, respiratory distress, and weakness. Examination shows dilated, poorly reactive pupils and skeletal muscle weakness with varying degrees of external ophthalmoplegia, facial and bulbar diplegia, respiratory insufficiency, and flaccid quadriparesis (46). Involvement is not always uniform, and some patients with near-total paralysis retain unexpected function of some muscles, such as those resulting in movement of a distal limb and a preserved ankle reflex. When the characteristic eye findings are absent or diffuse paresthesias are prominent, the diagnosis of botulism may not be considered. At times, there is a history of ingesting or tasting some food thought to have gone bad (eg, sampling food that smelled unusual from a canning jar). Recovery is slow, beginning about 6 weeks after onset, although full recovery is usually achieved via axonal sprouting and regeneration of distal axons. Electrophysiology Sensory responses are normal, despite occasional sensory symptoms. Motor responses show low-amplitude responses with normal conduction in proximal and distal segments. Evaluation of neuromuscular transmission produces variable results, depending on the timing after onset and the degree of paralysis. The most characteristic findings include a decremental response to repetitive motor nerve stimulation at low rates (3 Hz), less decrement at higher rates (eg, 20 Hz), and facilitation at even higher rates (eg, 50 Hz) or after volitional activation (although typically less than seen in Lambert-Eaton myasthenic syndrome). Single-fiber EMG shows markedly increased jitter and prominent blocking. A needle EMG study performed within days of onset shows only decreased recruitment, whereas studies performed after the first week show profuse fibrillation potentials, reflecting the distal site of pathology at the terminal axon. The combined findings are those of a presynaptic defect of neuromuscular transmission in the setting of extensive skeletal muscle denervation. The findings are sufficiently characteristic that the diagnosis of botulinum intoxication often is unsuspected until the EMG evaluation is performed. Differential Diagnosis Conditions producing a rapid-onset quadriparesis with facial weakness and respiratory insufficiency include disorders of neuromuscular transmission (eg, myasthenia gravis or Lambert-Eaton myasthenia syndrome); inflammatory neuropathies (eg, GBS or possibly Miller Fisher syndrome), and some myopathies (polymyositis or acute quadriplegic myopathy). Hyporeflexia is atypical of myasthenia and uncommon in myopathies other than the most severe. The presence of dilated, poorly reactive pupils is a cardinal feature that should strongly suggest the diagnosis of botulism. Other considerations are listed in Table 7.3, where botulism is included among

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Table 7.3  Motor or Motor More Than Sensory Neuropathy (Or Motor Neuronopathy) With No Conduction Slowing Hereditary/familial Hereditary (HMSN type II, V) Hereditary neuropathy with liability to pressure palsya Kennedy syndromea Motor neuron diseasea Porphyria (AIP, corproporphyria, variegate) Infectious Coxsackie virusa Botulism (presynaptic NMJ blockade) Poliomyelitisa West Nile virusa

Toxic Cimetidine Dapsonea Doxorubicin Lead (possibly)a Nitrofurantoin (after initial sensory) OP esters (OPIDN) Tick paralysis Vincristine (after initial sensory)

Inflammatory (autoimmune) Axonal GBS Lewis-Sumner varianta MMN* Metabolic Critical illness neuropathy Hyperinsulin/hypoglycemia Neoplastic (paraneoplastic) Lymphoma Abbreviations: AIP, acute intermittent porphyria; MMN, multifocal motor neuropathy; NMJ, neuromuscular junction; OP, organophosphorus; OPIDN, organophosphorus-induced delayed neuropathy. a The weakness characterized by these conditions is usually asymmetric. Source: Donofrio and Albers (1) and Albers and Berent (2).

the axonal motor or motor more than sensory neuropathies (despite being a neuromuscular junction disorder). Additional Diagnostic Evaluation Results of routine laboratory studies are usually normal, including creatine kinase, aside from an occasionally elevated white blood count. Anti-GQ1b antibody titers associated with Miller Fisher syndrome are not elevated. The CSF is unremarkable, without the albuminocellular dissociation seen with GBS. Edrophonium (short-acting acetylcholinesterase [AChE] inhibitor) does not produce improvement. The diagnosis of botulism is verified by bioassay confirming the presence of botulinum toxin. The contents of contaminated food can be examined to document the source of exposure. Treatment Initial symptomatic treatment is supportive and usually requires intubation to protect the airway and to support respiration. Once the diagnosis is established, treatment includes administration of trivalent equine botulism antitoxin (A, B, and E).

Carbon Disulfide Carbon disulfide is used in the production of matches, viscose rayon fiber, cellophane, plywood, vulcanized rubber,

and pesticides, where it is absorbed by inhalation or contact with the skin (50,51). Reports exist of neuropathy developing after long-term occupational exposure to carbon disulfide, but clinically evident neuropathy is uncommon (50,52). Most often, neuropathy has been reported in the context of many years (at least 10 years in one study) of ongoing occupational exposure (53). The neuropathology of carbon disulfide neuropathy is characterized by axonal degeneration with paranodal and internodal giant axonal swellings, similar to several other toxic neuropathies discussed in this chapter (54,55). Disulfiram, a medication used to induce ethanol abstinence, is metabolized to carbon sulfide and produces neuropathy in some patients, compelling support that carbon disulfide is a peripheral neurotoxicant. Like most toxic neuropathies, improvement follows removal from ongoing or recurrent exposure, although it may be slow and incomplete (54). Clinical Manifestations The neuropathy associated with occupational exposure to carbon disulfide (and to disulfiram) is length dependent and involves motor more than sensory fibers. Signs include distal weakness, mild sensory impairment involving large- and small-fiber sensory modalities, and absent reflexes in the legs (54,56–58). Carbon disulfide neuropathy is frequently described in the context of

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extrapyramidal features such as bradykinesia, resting tremor, and impaired gait (51,59–61). Extrapyramidal signs and parkinsonism have also been associated with disulfiram use (62,63). In the appropriate setting, the combination of coexisting extrapyramidal signs and neuropathy may reflect excessive exposure to carbon disulfide. Experimental models of carbon disulfide neuropathy display axonal degeneration with paranodal and internodal swellings due to accumulation of neurofilaments, similar to neuropathology associated with n-hexane, acrylamide, and disulfiram (55,64). Electrophysiology Carbon disulfide neuropathy is characterized by motor more than sensory abnormalities and a degree of motor conduction slowing atypical of pure axonal loss disorders, suggesting either loss of large myelinated fibers or acquired demyelination (65). Differential Diagnosis Conditions associated with neuropathies having motor more than sensory involvement and some degree of conduction slowing are shown in Table 7.2. Additional Diagnostic Evaluation No laboratory findings are specific for carbon disulfide intoxication, although the evaluation should likely include investigation for an acquired inflammatory neuropathy, such as associated with a monoclonal gammopathy. In the event that the diagnosis remains unclear, sural nerve biopsy may reveal distended axonal swellings characteristic of a neurofilamentous axono­pathy (66,67). Such results are not diagnostic of carbon disulfide neuropathy, but they are uncommon and sufficiently distinct to exclude most competing disorders such as inflammatory neuropathy or vasculitis. Treatment The only treatment for carbon disulfide neuropathy is removal from exposure.

n-Hexane n-Hexane is one of many 6-member carbon chain ring molecules having different substitution groups, of which n-hexane is the unsubstituted molecule. It is found in many types of industrial and household glues, and exposure occurs in association with footwear assembly, refinery work, and many construction jobs. It is one of small number of solvents that produce a clinically significant neuropathy (68). The neuropathy was initially reported after occupational exposures to n-hexane (69,70), but most often it results from intentional abuse (glue “sniffing” or “huffing”) (71,72). The neurotoxic potential of n-hexane was supported when accumulations of neurofilaments were identified in the nerves of n-hexane–intoxicated animals (73). The neurofilament accumulations are thought to reflect abnormalities of fast and slow axonal transport mechanisms (74). Methyl n-butyl ketone is another common substituted hexacar-

bon that also produces a length-dependent neuropathy. n-Hexane and methyl n-butyl ketone both undergo oxidative metabolism to 2,5-hexanedione, the neurotoxic moiety (75–77). Clinical Manifestations n-Hexane produces a classic dying-back neuropathy that presents with distal numbness, painful dysesthesias, sensory loss, and weakness. The rate of progression depends on the dose and whether exposure continues. In some instances, the neuropathy progresses rapidly over weeks to a few months. Ultimately, there is stockingglove-distribution sensory loss to all modalities, flaccid weakness, and absent reflexes (ankles and sometimes knees). Motor signs predominate, but occasional descriptions refer to distal sensory loss without weakness. Despite cessation of exposure, weakness progresses for weeks to months (coasting), typical of many toxic neuropathies. Thereafter, the neuropathy stabilizes and then improves, and even severe n-hexane neuropathy is reversible if exposure is terminated. Electrophysiology The electrophysiology of n-hexane neuropathy depends on the severity of neuropathy and the rate of progression. Asymptomatic workers having chronic, low-level occupational exposure to n-hexane may show low sensory amplitudes and normal or slightly reduced motor conduction velocities (69,78,79). In contrast, acute n-hexane neuropathy shows electrodiagnostic features suggesting nonuniform conduction slowing once thought to be pathognomonic of inflammatory nerve disease (78,80–82). Early in the course, sensory responses usually show reduced amplitude, but a sural response can often be recorded despite quite-severe neuropathy. Nevertheless, motor abnormalities predominate, with low-amplitude responses showing abnormal temporal dispersion, reduced conduction velocities (often in the range of 30 to 40 m/s), prolonged distal latencies, and prolonged or unobtainable F responses. The needle EMG examination shows decreased recruitment and fibrillation potentials in distal extremity muscles. After removal from exposure, serial evaluations show progressive improvement with resolution over about 12 months (Figure 7.3) (71,72). Differential Diagnosis The differential diagnosis for a motor greater than sensory neuropathy with conduction slowing is shown in Table 7.2. The list includes n-hexane, together with several other toxicants discussed in this chapter. Absent the history of n-hexane or other exposure, an important consideration is GBS or one of the chronic forms of inflammatory neuropathy, including those associated with HIV infections and monoclonal gammopathy or other dysproteinemia (eg, Castleman disease or osteosclerotic myeloma). When pain is a prominent feature, a confluent mononeuritis multiplex associated with systemic or isolated nervous system vasculitis should be considered (83).

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Figure 7.3 Sequential motor response amplitudes of patient with n-hexane neuropathy demonstrating progressive improvement after termination of exposure. Abbreviations: MMW, median motor stimulating at wrist; UMW, ulnar motor stimulating at wrist. Reprinted from Smith and Albers JW (71) with permission of John Wiley & Sons, Inc. Additional Diagnostic Evaluation Routine laboratory results are unremarkable. The CSF protein may be slightly elevated, reducing the liklihood of an inflammatory neuropathy such as GBS or chronic inflammatory demyelinating polyneuropathy. Sural nerve biopsy showing loss of large myelinated fibers and axonal swellings (Figure 7.4) supports the impression of a toxic etiology (9,81,84). After an acute exposure to n-hexane, its metabolite, 2,5-hexanedione, can be demonstrated in the urine for a few days. Treatment The only treatment for n-hexane neuropathy is removal from exposure and supportive care, including control of pain, when painful dysesthesias are prominent.

reprocessing of lead-containing products, demolition of lead-painted structures, manufacturing paint pigments, and repair of automobile radiators (93). Our understanding of lead neuropathy reflects case reports published before electrophysiologic evaluations were widely used. Despite reports dating to antiquity linking lead (plumbism) to illness, few physicians ever identify a patient with lead neuropathy. Between 1949 and 1989, fewer than 10 cases of lead neuropathy were identified among 3,500,000 new patient evaluations at the Mayo Clinic (31). This placed lead neuropathy among the rarest of neurologic disorders, and Wilbourn (94) declared lead neuropathy almost extinct as of the 1980s. The rarity of lead neuropathy has limited clinical investigations, and neither the lesion responsible for lead neuropathy nor its mechanism is known (94). Some descriptions of lead neuropathy resemble those of porphyric neuropathy, including abnormal porphyrin excretion, leading some to propose that lead neuropathy represents lead-induced porphyric neuropathy (39,95). There are similarities between lead neuropathy and motor neuron disease (96,97), an association supported by a few case-control studies but not by subsequent studies (98). Animal models of lead intoxication confirm that it has peripheral toxicity in some species, but the models generally produced disorders dissimilar to that reported in humans. For example, lead intoxication in the rat produces a neuropathy characterized by prominent demyelination, something not recognized in humans (99). Clinical Manifestations Lead is a systemic poison. Acute lead intoxication causes abdominal cramping, constipation, and anorexia. Chronic intoxication results in weight loss, constipation, renal insufficiency, anemia, gingival lead lines, and occasionally, neuropathy (101,102). Classic lead neuropathy is said to produce asymmetric weakness of wrist and finger extensor muscles, perhaps sparing the brachioradialis muscle (94,103,104). However, even the classic

Lead Lead is a nonferrous toxic metal that is absorbed across respiratory and gastrointestinal membranes (85). Lead intoxication causes encephalopathy in children and possibly neuropathy in adults. Lead exposure increased dramatically with the development of metallurgy, and bone lead levels increased several orders of magnitude relative to prehistoric samples (86). Current environmental exposures in the United States have decreased relative to the mid-20th century, primarily because of the ban on leaded gasoline (87,88). Opportunities for excessive exposure still result from consumption of illicit whiskey made in lead-lined stills (89), lead-containing candy, powdered food coloring, herbal medications, or food contaminated by glaze pigments in ceramic dishes (90–92). Occupational sources include smelting,

Figure 7.4 Sural nerve biopsy of patient with n-hexane neuropathy demonstrating loss of large myelinated fibers and axonal swellings. Reprinted from Albers (100) with permission of Lippincott Williams & Wilkins.

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picture of a motor neuropathy is in doubt, as descriptions exist of a distal sensorimotor neuropathy with autonomic involvement (102) or of a sensory neuropathy, based on cross-sectional observations of lead-exposed workers (95). Electrophysiology The diagnostic test most likely to distinguish between the items included in the differential diagnosis of possible lead neuropathy is the electrophysiology evaluation. Unfortunately, credible descriptions of lead neuropathy are lacking. Despite the confusing results involving subclinical neuropathy among lead-exposed workers, electrophysiologic evaluations remain the gold standard for confirming the presence of clinically suspected neuropathy. The evaluation should be directed at identifying characteristics feature to suggest alternative disorders. For example, nerve conduction study evidence of partial conduction block might suggest a diagnosis of multi­ focal motor neuropathy, or characteristic needle EMG evidence of a myopathic recruitment pattern may suggest the need for additional investigation of inclusion body myositis. Differential Diagnosis Disorders associated with motor or motor more than sensory involvement and no conduction slowing are listed in Table 7.3. Those characterized by asymmetry are identified and include multifocal motor neuropathy, dapsone neuropathy, and many types of motor neuron disease. In addition, there are conditions unrelated to neuropathy that produce findings similar to those ascribed to lead, such as inclusion body myositis and various forms of compressive neuropathy, radiculopathy, or plexopathy. None presents as a lengthdependent neuropathy, and most are atypical of a toxic neuropathy, the exception being neuropathy associated with dapsone. Additional Diagnostic Evaluation The blood lead level reflects recent exposure and is the primary screening test for lead exposure. Lead disrupts heme synthesis, producing a microcytic, hypochromic anemia with basophilic stippling and abnormal excretion of heme precursors (105,106). However, anemia in association with lead levels less than 80 µg/dL should not be attributed to lead until other causes are excluded (107). The free erythrocyte porphyrins in the blood reflect chronic lead exposure. Lead has a long biologic half-life, with most of the total body burden found in bone (108). Urine and hair lead levels can be measured, but neither is widely used. Lead can be identified on abdominal or bone x-rays, and in vitro x-ray fluorescence has been used to estimate bone lead levels (109). An increase in urine lead excretion after chelation challenge represents a possible surrogate of body stores, but this mobilization test has limited utility (110). Laboratory evaluations directed at identifying competing diagnosis, such as Kennedy syndrome, may be relevant.

Treatment Chelation protocols exist for the treatment of lead encephalopathy and symptomatic lead poisoning without encephalopathy. Their effectiveness is limited by the large stores of lead in bone, and application to lead neuropathy is unknown.

Elemental Mercury Mercury is used in the chloralkali industry, in metal plating, and in tanning processes. It is still found in thermometers, electromechanical switches, and other electrical equipment. It is a component of dental amalgams and has had use as an antiseptic and purgative medication (31,111). Mercury toxicity depends on its oxidation state (31). Reports of elemental mercury toxicity are uncommon, and few neurologists will ever see a patient with mercury intoxication. Signs of chronic intoxication include poorly defined and controversial behavioral changes, postural tremor, and neuropathy (112,113). Elemental mercury is poorly absorbed by the gastrointestinal tract, whereas mercury vapor is readily absorbed after inhalation. Mercury is oxidized in blood and tissues and excreted in the bile and urine (114). Mercury combines with sulfhydryl groups in enzymes and structural proteins, but the mechanism by which mercury damages tissue is unclear (31). Clinical Manifestations Acute exposure to high-level mercury vapor produces an erosive bronchitis, interstitial pneumonitis with pulmonary edema, and renal insufficiency (115,116). Neurologic symptoms develop shortly thereafter in the form of increased excitability, postural tremor, and perioral numbness (113,115). The adverse effects associated with sublethal exposure resolve spontaneously (52). Chronic elemental mercury vapor exposure is characterized by the insidious onset of stocking-distribution sensory loss, Romberg sign, absent ankle reflexes, and a postural tremor of the outstretched hands, arguably the most sensitive clinical indicator of overexposure (116,117). Motor involvement, if present, is mild. Some evaluations of mercury-exposed workers show a higher-than-expected frequency of other signs, including some suggestive of mild parkinsonism (117,118). The signs of mercury toxicity generally resolve after removal from exposure, although there may be residual tremor (117). Electrophysiology The electrophysiologic findings include low-amplitude sensory responses and normal or borderline-lowamplitude motor responses; distal latencies are slightly prolonged, but conduction velocities are normal. The EMG needle examination may show chronic neurogenic changes, most notable in the intrinsic foot muscles. Evidence of mild neuropathy has been identified among chloralkali workers exposed to elemental mercury and having markedly elevated urinary mercury excretion, with 28% of workers having levels above 850 µg/L

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showing clinical evidence of neuropathy, compared with a 10% remaining workers (117,118). Differential Diagnosis The differential diagnosis related to a mild sensorimotor neuropathy of the axonal type is extensive (Table 7.1), although the history and routine evaluations usually exclude many of the items on the list. The presence of neuropathy and a postural tremor suggest the possibility of elemental mercury intoxication, a suspicion sometimes supported by a history of occupational exposure. Diagnostic Evaluation Elemental mercury is nephrotoxic, and laboratory testing may show impaired renal function. The diagnosis of mercury intoxication requires confirmation by elevated urinary mercury excretion (119), preferably based on a 24-hour urine excretion corrected for creatine. Spot urine mercury measures are less reliable than 24-hour or firstmorning-void determinations. An area of uncertainty is the level of urine mercury excretion associated with neurotoxicity. Much of our understanding of elemental mercury toxicity is derived from study of mercuryexposed workers, and chloralkali workers, for example, show urinary mercury levels hundreds of times higher than in the general population (118). In the early 1980s, such workers were removed from mercury vapor exposure only when routine sampling showed urine mercury levels exceeding 500 µg/L, a level in the range associated with abnormal postural tremor (120). Diagnostic chelation challenge has been proposed to estimate body burden but discredited as a useful biomarker of past mercury exposure (121). Serum mercury concentrations also are poor indicators of body burden, and hair is not a reliable tissue to document elemental mercury exposure, because the measure probably reflects mercury absorption from the atmosphere, not the blood (111). Treatment The primary treatment for elemental mercury intoxication is removal from ongoing excessive exposure. Chelation therapy is not generally considered necessary or effective.

Organophosphorus Compounds Industrial and commercial applications of organophosphorus (OP) compounds include use in insecticides, hydraulic fluids, lubricants, fuel additives, plasticizers, and flame retardants. Organophosphorus insecticides are used in suicide attempts (122,123), and OP compounds have been used in warfare and acts of bioterrorism. Organophosphorus insecticides inhibit AChE at cholinergic nerve endings, producing cholinergic toxicity with muscarinic overactivity and acute neuromuscular blockade (124). The “irreversible” inactivation of AChE produced by OP insecticides is actually slowly reversible, as AChE can be reactivated. Massive exposure to some OPs produces OP-induced delayed

neuropathy (OPIDN), a consequence of inhibition and aging (molecular rearrangement) of neuropathy target esterase (125,126). Organophosphorus-induced delayed neuropathy due to OP insecticide poisoning follows a severe cholinergic syndrome requiring respiratory support. Some other OP compounds, including those that do not inhibit AChE, also may produce OPIDN as the neuropathy is not related to the anticholinesterase effect (127). For example, tri-ortho-cresyl phosphate (TOCP) produced a outbreak of OPIDN in the 1930s after it was added to Jamaican ginger extract (“Jake”) as a plasticizer to circumvent prohibition regulations (128). Jake was sold as a medicinal tonic but also consumed for its alcohol content. Shortly after the addition of TOCP, thousands of those who consumed Jake developed OPIDN (Jake paralysis). Similarly, TOCP was suspected in an outbreak of OPIDN in the 1970s, attributed to the use of contaminated cooking oil that had been transported in containers previously used to store mineral oils (129). In contrast to the established effects of massive OP exposure, it is unlikely that low-level OP exposure produces adverse neurologic effects. Clinical Manifestations A massive OP insecticide exposure results in cholinergic stimulation of muscarinic and nicotinic receptors. Muscarinic effects include miosis, increased secretions, sweating, gastric hyperactivity, and bradycardia, whereas nicotinic effects include fasciculations and skeletal muscle weakness. Patients who ultimately developed OPIDN require intubation and intensive care unit support during the cholinergic phase. During initial recovery from the cholinergic phase, some patients deteriorate (intermediate syndrome) and experience weakness of cranial, respiratory, neck flexor, and proximal limb muscles, a distribution of weakness similar to that of myasthenia gravis (130). Still other patients develop OPIDN during or after recovery from the life-threatening cholinergic effects (131). Organophosphorus-induced delayed neuropathy is characterized by subacute onset of dysesthesias but few sensory signs, rapidly developing distal weakness, and reduced or absent ankle reflexes but normal or brisk reflexes elsewhere. Over about 6 months, the flaccid weakness is replaced by spasticity and hyperactive reflexes, reflecting pyramidal tract motor involvement unmasked by the resolving neuropathy. Organophosphorus-induced delayed neuropathy associated with TOCP presents similarly, minus the initial cholinergic syndrome. Electrophysiology Patients evaluated during the cholinergic crises of an OP insecticide poisoning show repetitive discharges to a single depolarizing stimulus, presumably due to recurrent depolarization of the postsynaptic endplate (132). Depending on the magnitude of neuromuscular blockade, motor amplitudes may be low and show a

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decremental response to repetitive stimulation at high rates but not at rates of 2 to 3 Hz, an observation difficult to reconcile with conventional understanding of neuromuscular physiology (130,133). These acute cholinergic effects resolve over days to weeks. The abnormalities of OPIDN include low-amplitude motor responses without substantial conduction slowing and needle EMG evidence of fibrillation potentials, decreased recruitment, and large-amplitude motor units in distal muscles (131,133,134). Despite reports of a sensory involvement (135), a prospective study of workers having substantial exposure to an OP insecticide during the manufacturing process (as evidenced by significant inhibition of plasma butyrylcholinesterase activity) found no evidence of a clinical or subclinical sensory neuropathy (136). Differential Diagnosis The differential diagnosis appropriate for an acute OP poisoning is not the focus of this section, although the initial clinical presentation of cholinergic overactivity and diffuse paralysis with respiratory insufficiency suggest the diagnosis. In the absence of cholinergic overactivity, additional explanations for an acute quadriparesis with respiratory failure include GBS, acute intermittent porphyria, diphtheria, tick paralysis, myasthenia gravis, botulinum intoxication, hypophosphatemia, and acute inflammatory myositis. Onset of recurrent weakness within weeks of recovery from a life-threatening OPinduced cholinergic syndrome requiring intensive support suggests the diagnosis of OPIDN (137). Identification of OPIDN due to an OP compound that does not produce cholinergic toxicity is more challenging but likely would occur in the setting of a combined central and peripheral motor syndrome. Nevertheless, some conditions producing a motor or motor greater than sensory neuropathy without substantial motor conduction slowing are listed in Table 7.3. Diagnostic Evaluation The AChE inhibition caused by an acute OP insecticide poisoning is documented by depressed activity of plasma butyrylcholinesterase and red blood cell AChE, whose activity is closely related to the physiologic effects and is used to assess toxicity. Symptoms usually develop in association with at least a 70% or greater decrease from baseline cholinesterase activity, recognizing that baseline levels are available only in some occupational settings (138). Metabolites of some OP insecticides can be measured in the urine to document the magnitude of exposure. There are no other specific laboratory abnormalities associated with OPIDN. Treatment Treatment of the acute cholinergic syndrome is not the focus of this chapter. However, gastric lavage of a recently ingested OP and supportive care are required in severe poisonings. Atropine reduces the adverse muscarinic effects, and pralidoxime reactivates the phospho-

rylated cholinesterase at the neuromuscular junction, reducing skeletal muscle weakness (139–141). There is no specific treatment for OPIDN.

Carbamates Carbamate insecticides are reversible AChE inhibitors similar to the OP compounds. Carbamate pesticides differ structurally from OP pesticides, but they do inhibit AChE. Acetylcholinesterase inhibition produced by carbamate insecticides is transient and rapidly reversible, resolving in hours. Unlike OP insecticides, carbamate insecticides are considered unlikely to initiate a neuropathy similar to OPIDN. However, there is a report of a patient who, after ingesting a carbamate pesticide producing a severe cholinergic toxicity, initially recovered only to develop acute limb weakness and loss of knee and ankle reflexes due to an axonal sensorimotor neuropathy (127). Another report associated an outbreak of nausea, vomiting, dizziness, fasciculations, and blurred vision to food adulterated with a carbamate insecticide (142).

Thallium Thallium is included among the neurotoxic heavy metals and metalloids. It has a variety of industrial and medicinal applications. Reports of industrial or environmental thallium intoxication include inhalation and dermal exposures to contaminated dust from pyrite burners, during zinc and lead smelting processes and the manufacture of cadmium, and related to handling thalliumcontaining materials (143,144). Medical applications include treatment of venereal diseases, tuberculosis, and ringworm (31,145), and use of thallium isotopes in diagnostic imaging (143). Thallium is a systemic poison used in insecticides, in rodent poisons, and as a homicidal agent (143,145). Criminal use as a homicidal agent was a leading source of exposure (146), and a 1972 US ban on thallium for use as a rodent poison was intended to limit its availability (147). Thallium is readily absorbed across respiratory, gastrointestinal, and dermal membranes; thallium salts are water soluble, with distribution throughout the body prior to elimination in the stool and urine (145,148). The widespread distribution contributes to a multisystem disorder, of which a painful neuropathy is one part (56,149,150). Rapid-onset alopecia is an important hallmark of thallium poisoning (151). Other system features include nephropathy, anemia, hepatotoxicity, renal failure, dermatitis, and Mees lines (31,94,145,151). The elimination half-time is as long as 30 days, depending on the rate of ingestion (143). Thallium enters cells through potassium channels (148). The mechanism by which it exerts it neurotoxicity is thought to involve impaired oxidative phosphorylation (148) and perhaps the sodium/potassium-ATPase system (31,148).

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Clinical Manifestations Thallium neuropathy has several features atypical for most neuropathies, including painful dysesthesias developing hours to days after ingestion, characterized by stinging pain beginning in feet and progressing to midthigh level (149,152). Pain at times involves areas not usually affected by neuropathy, such as the joints, back, and chest (94). Clinical signs include stockingglove-distribution sensory loss showing a disproportionate impairment of pin-pain sensation and preserved reflexes. The painful onset, impaired pin-pain sensation, and preserved reflexes support a predominant involvement of small nerve fibers. Consistent with this impression, some patients have dysautonomia with abdominal pain, constipation, urinary retention, anhidrosis, and signs of cardiovascular autonomic neuropathy (153-155). Occasionally, patients develop distal weakness, including progressive quadriparesis with respiratory failure, although hyperpathia may make manual muscle testing difficult to interpret (148,156). Patients who survive the initial illness have a good prognosis (157). Electrophysiology Thallium neuropathy is characterized by sensory and motor abnormalities with low-amplitude responses but

normal conduction and needle EMG evidence of partial denervation of intrinsic foot muscles, sometimes apparent when the sural response is normal (152). Serial studies show progressive loss of sensory and motor amplitudes with preserved conduction velocity and profuse fibrillation potentials in muscles distal to the knee, indicative of a profound distal axonopathy. Thallium is of historic interest to electromyographers because Kaeser and Lambert used thallium to produce a “pure” axonal neuropathy in their pioneering descriptions of axonal loss lesions (94,158). Differential Diagnosis Many neuropathies present subacutely with painful dysesthesias, including GBS and several toxic neuropathies, including arsenic neuropathy. Neuropathies characterized by predominant or exclusive sensory symptoms and signs, however, are listed in Table 7.4. Most of the neuropathies listed show large-fiber involvement, and predominant signs of impaired pin-pain sensation that persists well into the course of the neuropathy, frequently with preserved reflexes, result in thallium being included among the group of neuropathies having prominent small-fiber involvement (eg, amyloidosis, diabetes mellitus, ethanol, Fabry disease, HIV associated,

Table 7.4  Sensory Neuropathy or Neuronopathy With No Conduction Slowing Hereditary/familial Amyloidosisa Fabry diseasea Friedreich ataxia Kennedy syndrome Sensory autonomic neuropathya Tangier diseasea Infectious HIV associateda Leprosy

Toxic Cisplatin Ethyl alcohola Metronidazole Pyridoxine Styrene (possibly) Thalidomide Thalliuma Vacor Zinc (myeloneuropathy)

Inflammatory (autoimmune) Fisher variant of GBS Idiopathic sensory ganglionitis Sjogren syndrome Metabolic Diabetes mellitusa Metabolic syndromea Neoplastic (paraneoplastic) Small cell tumors Other malignancies Nutritional Vitamin deficiency a

The sensory neuropathy produced by these conditions may be small fiber predominant.

Source: Donofrio and Albers (1) and Albers and Berent (2).

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Tangier disease). Preserved reflexes also would suggest localization to the spinal cord, a possibility addressed by investigating for a sensory level on the trunk, bladder or bowel dysfunction, and atavistic reflexes. Additional Diagnostic Evaluation Routine laboratory investigations may show evidence of systemic poisoning with nonspecific anemia, nephrop­athy, and hepatotoxicity. Toxicologic evaluation documenting elevated levels of thallium excretion is necessary to establish exposure and estimate the potential dose. Thallium levels can be measured in s­erum, 24-hour urine excretion, and hair. The results of sural nerve biopsy are not specific for thallium poisoning, showing loss of axons and degeneration of myelin sheaths along some axons into a series of ovoids (axon bodies) (152). Treatment Treatment includes removal from exposure, diuresis, and general medical support.

Trichloroethylene Trichloroethylene (TCE) is a chlorinated hydrocarbon that has had widespread occupational and medicinal applications, both as an industrial solvent and an inhalation anesthetic. Trichloroethylene and similar solvents became the source of controversy because of the alleged association with the syndrome of chronic toxic encephalopathy. The most characteristic adverse ef-

fect of TCE exposure, however, was development of a cranial mononeuropathy multiplex (159–161). The association of TCE with a cranial mononeuropathy multi­ plex originated during its use as a general anesthetic (162). The mechanism was ultimately thought to reflect a decomposition product (dichloroacetylene) resulting from reaction between the TCE and soda lime in the anesthesia system, perhaps enhancing the effects of TCE or reactivating a latent viral infection (159,160, 162–164). Avoiding these anesthetic conditions supposedly eliminated the problem (159). This explanation, however, does not account for the occasional occurrence of an identical syndrome in the setting of occupational exposure to TCE (159). A postmortem examination of a patient who had developed a cranial mononeuropathy multiplex attributed to an industrial TCE exposure showed neuropathology abnormalities confined to the brain stem, involving especially the nuclei and tracts of the trigeminal nerve, particularly the sensory divisions (159). Clinical Presentation Clinical features include subacute onset of numbness of the face, mouth, and oral pharynx plus weakness of jaw muscles, a distribution reflecting trigeminal involvement. Some cases have had involvement of cranial nerves II, III, IV, V, VI, and VII with various combinations of constricted visual fields, impaired eye movements, impaired facial sensation, bifacial weakness, and impaired taste perception over the anterior tongue (164).

Table 7.5  Multifocal Cranial Mononeuropathy or Mononeuropathy Multiplex Hereditary/familial Familial facial and ocular motor palsies Porphyria Infectious Leprosy Lyme disease Varicella zoster and herpes simplex (reactivation)

Toxic TCE Vascular Cavernous sinus syndrome Traumatic

Inflammatory (autoimmune) Multifocal variant of CIDP Sarcoidosis Vasculitis (eg, periarteritis nodosa) Metabolic Diabetes mellitus Neoplastic (paraneoplastic) Meningeal infiltration (carcinomatosis) Nutritional Vitamin deficiency (Wernicke syndrome) Abbreviations: CIDP, chronic inflammatory demyelinating polyneuropathy; TCE, trichloroethylene.

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Limb strength, sensation, and reflexes remain intact, and slow recovery progresses over months to years. Electrophysiology Facial nerve conduction studies show prolonged latencies and a temporally dispersed motor response (amplitudes not reported) (164). Some studies of subjects having chronic, low-level occupational or environmental TCE (and other solvent) exposure identified prolonged R1 latencies on blink reflex studies (165). More recently, studies performed on workers who had at least 10 years of occupational solvent exposure also found that the mean R1 latency of the exposed worker group was slightly but significantly prolonged compared to historical control values, although the latency was not associated with duration of solvent exposure and the small differences were of no known importance (166). Only after blink reflex latencies obtained from a larger referent group became available (167) were the reported “abnormalities” found to be statistically unremarkable, casting doubt on the use of R1 latency as a biologic marker of TCE exposure.

Differential Diagnosis The differential diagnosis for a cranial mononeuropathy multiplex is not extensive (Table 7.5), and several items listed are more likely to cause a generalized mononeuritis multiplex, not one limited to the cranial nerves. However, if bifacial weakness predominates, myasthenia gravis is another consideration, in addition to Lyme disease, porphyria, and sarcoidosis. The presence of additional signs, such as trigeminal-distribution sensory loss, excludes the possibility of a neuromuscular junction disorder. A cranial mononeuropathy multiplex also occurs in association with diabetes mellitus and some infiltrative brain stem disorders. Reactivation of latent herpes simplex virus or varicella zoster virus is a known infectious cause of multiple cranial mononeuropathies. Additional Diagnostic Evaluation The evaluation of the disorders listed in the differential diagnosis may include laboratory evidence of an underlying vasculitis or identify an autoantibody for a specific disorder. There are no laboratory tests specific for TCE intoxication.

CLINiCAL PEARLS AND KEY POINTS • When diagnosing a specific toxic neuropathy, the diagnosis and characterization of the neuropathy is established independently from determining it cause. • Acrylamide monomer is among a select group of neurotoxicants that produce a giant axonal neuropathy characterized by impaired axonal transport and accumulation of neurofilamentous axonal masses. Suggestive feature: anhidrosis. • Acute arsenic neuropathy resembles GBS with nerve conduction slowing prior to loss of recordable motor or sensory responses. Suggestive features: pancytopenia with basophilic stippling, Mees lines, and dermatitis. • Botulinum toxin–induced blockade of neuromuscular transmission produces a rapid-onset quadriparesis with facial weakness, respiratory insufficiency, and hyporeflexia. Suggestive feature: poorly reactive dilated pupils and EMG evidence of a presynaptic defect of neuromuscular transmission in the setting of extensive skeletal muscle denervation. • Carbon disulfide produces a motor more than sensory giant axonal neuropathy characterized by accumulation of neurofilaments. Suggestive feature: extrapyramidal signs. • Acute n-hexane neuropathy is another giant axonal neuropathy that resembles GBS. Suggestive features: rapid onset, diffuse weakness, conduction slowing, and increased CSF protein. • The classic description of lead neuropathy is that of a pure motor disorder with asymmetric weakness, including wrist drop. Lead neuropathy is incredibly rare, and few patients thought to have lead neuropathy have been evaluated using modern electrophysiologic techniques. • Elemental mercury produces a distal sensory or sensorimotor neuropathy. Suggestive feature: accentuated postural tremor, the most characteristic feature of intoxication. • Organophosphorus insecticides inactivate AChE, thereby producing miosis, increased secretions and sweating, gastric hyperactivity, fasciculations, and skeletal muscle weakness. Some OPs produce delayed neurotoxicity (OPIDN), a motor system disorder characterized by flaccid weakness that is replaced by spasticity and hyperactive reflexes as the neuropathy resolves. • Thallium intoxication results in a systemic poisoning presenting as a gastrointestinal illness prior to onset of a small-fiber neuropathy characterized by severe pain at onset, early preservation of reflexes, stocking-glove impairment of pain and light touch sensations, and sometimes, dysautonomia with anhidrosis. Cardinal feature: alopecia. • Trichloroethylene is thought to produce a cranial mononeuritis with prominent trigeminal nerve involvement, possibly due to reactivation of a latent viral infection.

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Treatment There is no specific treatment for the cranial mononeuritis attributed to TCE, although antiviral treatment is likely indicated, given the uncertain cause and the possibility that the association represents reactivation of a latent viral infection.

SUMMARY The evaluation of a suspected toxic neuropathy occurring in the presence of an industrial or environmental exposure is simplified when conventional methods are used to establish the presence of a neuropathy and its predominant pathophysiology. Most toxic neuropathies are symmetrical and length dependent, presenting with stocking- or stocking-glove-distribution sensory loss or weakness involving the large sensory or motor axons. The underlying pathophysiology of any neuropathy is investigated using nerve conduction studies and needle EMG, and the anatomic diagnosis of neuropathy is established independently of determining its cause. Additional medical and laboratory investigations are used to identify systemic disorders associated with neuropathy or pursue systemic signs associated with specific toxins. Individual responses to neurotoxic exposure differ somewhat, but the differences typically involve the exposure required to produce the neuropathy, not the type of neuropathy. As an exception to this general rule, the response to a chronic, low-level exposure to a given neurotoxicant may differ from the response to acute, high-level exposure.

References 1. Donofrio PD, Albers JW. Polyneuropathy: classification by nerve conduction studies and electromyography. Muscle Nerve. 1990;13:889–903. 2. Industrial and environmental agents. In: Albers JW, Berent S, eds. Neurobehavioral Toxicology. Neurological and Neuropsychological Perspectives. Vol II. Peripheral Nervous System. London, United Kingdom, and New York, NY: Taylor & Francis; 2005:329–427. 3. Smith EA, Oehme FW. Acrylamide and polyacrylamide: a review of production, use, environmental fate and neurotoxicity. Rev Environ Health. 1991;9:215–228. 4. Mulloy KB. Two case reports of neurological disease in coal mine preparation plant workers. Am J Ind Med. 1996;30:56–61. 5. Sumner AJ, Asbury AK. Physiological studies of the dyingback phenomenon: muscle stretch afferents in acrylamide neuropathy. Brain. 1975;98:91–100. 6. Gupta RP, Abou-Donia MB. Acrylamide and carbon di­ sulfide treatments increase the rate of rat brain tubulin polymerization. Mol Chem Neuropathol. 1997;30:223–237. 7. Tandrup T, Braendgaard H. Number and volume of rat dorsal root ganglion cells in acrylamide intoxication. J Neurocytol. 1994;23:242–248. 8. Ko MH, Chen WP, Lin-Shiau SY, et al. Age-dependent acrylamide neurotoxicity in mice: morphology, physiology, and function. Exp Neurol. 1999;158:37–46. 9. Sayre LM, Autilio-Gambetti L, Gambetti P. Pathogenesis of experimental giant neurofilamentous axonopathies:

a unified hypothesis based on chemical modification of neurofilaments. Brain Res 1985;357:69–83. 10. Le Quesne PM. Clinical and morphological findings in acrylamide toxicity. Neurotoxicology. 1985;6:17–24. 11. Moretto A, Sabri MI. Progressive deficits in retrograde axon transport precede degeneration of motor axons in acrylamide neuropathy. Brain Res. 1988;440:18–24. 12. Gold BG, Griffin JW, Price DL. Somatofugal axonal atrophy precedes development of axonal degeneration in acrylamide neuropathy. Arch Toxicol. 1992;66:57–66. 13. Harris CH, Gulati AK, Friedman MA, et al. Toxic neurofilamentous axonopathies and fast axonal transport. V. Reduced bidirectional vesicle transport in cultured neurons by acrylamide and glycidamide. J Toxicol Environ Health. 1994;42:343–356. 14. Edwards PM, Sporel-Ozakat E, Gispen WH. Neurotoxic acrylamide and neurotrophic melanocortin peptides—can contrasting actions provide clues about modes of action? Neuropathol Appl Neurobiol. 1991;17:91–104. 15. Navarro X, Verdu E, Guerrero J, et al. Abnormalities of sympathetic sudomotor function in experimental acrylamide neuropathy. J Neurol Sci. 1993;114:56–61. 16. Durham HD, Pena SD, Carpenter S. The neurotoxins 2,5hexanedione and acrylamide promote aggregation of intermediate filaments in cultured fibroblasts. Muscle Nerve. 1983;6:631–637. 17. Garland TO, Patterson MWH. Six cases of acrylamide poisoning. Br Med J. 1967;4:134–138. 18. Gold BG, Schaumburg HH. Acrylamide. In: Spencer PS, Schaumburg HH, eds. Experimental and Clinical Neurotoxicology. New York: Oxford University Press; 2000: 124–132. 19. Davenport JG, Farrell DF, Sumi M. “Giant axonal neuropathy” caused by industrial chemicals: neurofilamentous axonal masses in man. Neurology. 1976;26:919–923. 20. LeQuesne PM. Clinical and morphological findings in acrylamide toxicity. Neurotoxicology. 1985;6:17–24. 21. Hagmar L, Tornqvist M, Nordander C, et al. Health effects of occupational exposure to acrylamide using hemoglobin adducts as biomarkers of internal dose. Scand J Work Environ Health. 2001;27:219–226. 22. Fullerton PM. Electrophysiological and histological observations on peripheral nerves in acrylamide poisoning in man. J Neurol Neurosurg Psychiatry. 1969;32: 186–192. 23. Aminoff MJ. Electrophysiologic recognition of certain occupation-related neurotoxic disorders. Neurol Clin. 1985; 3:687–697. 24. He FS, Zhang SL, Wang HL, et al. Neurological and electroneuromyographic assessment of the adverse effects of acrylamide on occupationally exposed workers. Scand J Work Environ Health. 1989;15:125–129. 25. Feldman RG, Niles CA, Kelly Hayes M, et al. Peripheral neuropathy in arsenic smelter workers. Neurology. 1979;29:939–944. 26. Kreiss K, Zack MM, Landrigan PJ, et al. Neurologic evalua­ tion of a population exposed to arsenic in Alaskan well water. Arch Environ Health. 1983;38:116–121. 27. Mukherjee SC, Rahman MM, Chowdhury UK, et al. Neuropathy in arsenic toxicity from groundwater arsenic contamination in West Bengal, India. J Environ Sci Health Part A—Toxic/Hazardous Subst Environ Eng. 2003;38(1): 165–183.

102  Textbook of Peripheral Neuropathy 28. Albers JW, Garabrant DH. Arsenic poisoning. In: Lynn DJ, Newton HB, eds. The 5-Minute Neurology Consult. Philadelphia, PA: Lippincott Williams & Wilkins; 2004:70–71. 29. Tay CH, Seah CS. Arsenic poisoning from anti-asthmatic herbal preparations. Med J Aust. 1975;2:424–428. 30. Gallagher RE. Arsenic—new life for an old potion. N Engl J Med. 1998;339:1389–1391. 31. Windebank AJ. Metal neuropathy. In: Dyck PJ, Thomas PK, Griffin JW, Low PA, Poduslo JF, eds. Peripheral Neuropathy. Philadelphia: WB Saunders; 1993:1549–1570. 32. Chhuttani PN, Chawla LS, Sharma TD. Arsenical neuropathy. Neurology. 1967;17:269–274. 33. Greenberg SA. Acute demyelinating polyneuropathy with arsenic ingestion. Muscle Nerve. 1996;19:1611–1613. 34. London Z, Albers JW. Toxic neuropathies associated with pharmaceutical and industrial agents. Neurol Clin. 2007;25(1):257–276. 35. Herkovitz S, Scelsa SN, Schaumburg HH. The toxic neuropathies: industrial, occupational, and environmental agents. Peripheral Neuropathies in Clinical Practice. London, United Kingdom: Oxford University Press; 2010:301–310. 36. Chakraborti D, Mukherjee SC, Saha KC, et al. Arsenic toxicity from homeopathic treatment. J Toxicol—Clin Toxicol. 2003;41(7):963–967. 37. Mukherjee SC, Rahman MM, Chowdhury UK, et al. Neuropathy in arsenic toxicity from groundwater arsenic contamination in West Bengal, India. J Environ Sci Health Part A—Toxic/Hazardous Subst Environ Eng. 2003;38(1):165–183. 38. Rahman MM, Chowdhury UK, Mukherjee SC, et al. Chronic arsenic toxicity in Bangladesh and West Bengal, India—a review and commentary. J Toxicol—Clin Toxicol. 2001;39(7):683–700. 39. Donofrio PD, Wilbourn AJ, Albers JW, et al. Acute arsenic intoxication presenting as Guillain-Barré–like syndrome. Muscle Nerve. 1987;10:114–120. 40. Albers, JW, Bromberg MB. Neuromuscular emergencies. In: Schwartz GR, ed. Principles and Practice of Emergency Medicine. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1992:1564. 41. Bromberg MB, Albers JW. Patterns of sensory nerve conduction abnormalities in demyelinating and axonal peripheral nerve disorders. Muscle Nerve. 1993;16:262–266. 42. Valenzuela OL, Borja-Aburto VH, Garcia-Vargas GG, et al. Urinary trivalent methylated arsenic species in a population chronically exposed to inorganic arsenic. Environ Health Perspect. 2005;113(3):250–254. 43. Hindmarsh JT. Caveats in hair analysis in chronic arsenic poisoning. Clin Biochem. 2002;35:1–11. 44. Poklis A, Saady JJ. Arsenic poisoning: acute or chronic? Suicide or murder? Am J Forensic Med Pathol. 1990;11:226–232. 45. Goetz CG, Meisel E. Biological neurotoxins. Neurol Clin. 2000;18:719–740. 46. Arnon SS, Schechter R, Inglesby TV, et al. Botulinum toxin as a biological weapon: medical and public health management. JAMA. 2001;285:1059–1070. 47. Shapiro RL, Hatheway C, Swerdlow DL. Botulism in the United States: a clinical and epidemiologic review. Ann Intern Med. 1998;129:221–228. 48. Montecucco C, Schiavo G. Structure and function of tetanus and botulinum neurotoxins. Q Rev Biophys. 1995;28:423–472. 49. Maselli RA, Bakshi N. AAEM case report 16. Botulism. American Association of Electrodiagnostic Medicine. Muscle Nerve. 2000;23:1137–1144.

50. Allen N. Solvents and other industrial organic compounds. In: Vinken PJ, Bruyn GW, eds. Handbook of Clinical Neurology. Amsterdam, Netherlands: Elsevier/North Holland Biomedical Press; 1979:361–389. 51. Seppalainen AM, Haltia M. Carbon disulfide. In: Spencer PS, Schaumburg HH, eds. Experimental and Clinical Neurotoxicology. Baltimore, MD: Williams & Wilkins; 1980:356–373. 52. Albers JW, Bromberg MB. Chemically induced toxic neuropathy. In: Rosenberg NL, ed. Occupational and Environmental Neurology. Boston, MA: Butterworth-Heinemann; 1995:175–233. 53. Aaserud O, Hommeren OJ, Tvedt B, et al. Carbon di­ sulfide exposure and neurotoxic sequelae among viscose rayon workers. Am J Ind Med. 1990;18:25–37. 54. Schaumburg HH, Spencer PS. Human toxic neuropathy due to industrial agents. In: Dyck PJ, Thomas PK, Lambert EH, Bunge R, eds. Peripheral Neuropathy. Philadelphia, PA: WB Saunders; 1984:2115–2132. 55. Gottfried MR, Graham DG, Morgan M, et al. The morphology of carbon disulfide neurotoxicity. Neurotoxicology. 1985;6:89–96. 56. Albers JW, Wald JJ. Industrial and environmental toxic neuropathy. In: Brown WF, Bolton CF, Aminoff MJ, eds. Clinical Neurophysiology and Neuromuscular Diseases. Philadelphia, PA: WB Saunders; 2002:1143–1168. 57. Bradley WG, Hewer RL. Peripheral neuropathy due to disulfiram. Br Med J. 1966;2:449. 58. Frisoni GB, Di Monda V. Disulfiram neuropathy: a review (1971–1988) and report of a case. Alcohol Alcohol. 1989;24: 429–437. 59. Vigliani EC. Carbon disulfide poisoning in viscose rayon factories. Br J Ind Med. 1954;11:235–244. 60. Peters HA, Levine RL, Matthews CG, et al. Carbon di­ sulfide-induced neuropsychiatric changes in grain storage workers. Am J Ind Med. 1982;3:373–391. 61. Peters HA, Levine RL, Matthews CG, et al. Extrapyramidal and other neurologic manifestations associated with carbon disulfide fumigant exposure. Arch Neurol. 1988;45: 537–540. 62. Vaccari A, Saba PL, Ruiu S, et al. Disulfiram and diethyl­ dithiocarbamate intoxication affects the storage and release of striatal dopamine. Toxicol Appl Pharmacol. 1996; 139(1):102–108. 63. Laplane D, Attal N, Sauron B, et al. Lesions of basal ganglia due to disulfiram neurotoxicity. J Neurol Neurosurg Psychiatry. 1992;55(10):925–929. 64. Bilbao JM, Briggs SJ, Gray TA. Filamentous axonopathy in disulfiram neuropathy. Ultrastruct Pathol. 1984;7: 295–300. 65. Chu CC, Huang CC, Chen RS, et al. Polyneuropathy induced by carbon disulphide in viscose rayon workers. Occup Environ Med. 1995;52:404–407. 66. Ansbacher LE, Bosch EP, Cancilla PA. Disulfiram neuropathy: a neurofilamentous distal axonopathy. Neurology. 1982;32:424–428. 67. Johnson BL, Boyd J, Burg JR, et al. Effects on the peripheral nervous system of workers’ exposure to carbon disulfide. Neurotoxicology. 1983;4:53–66. 68. Korobkin R, Asbury AK, Sumner AJ, et al. Glue-sniffing neuropathy. Arch Neurol. 1975;32:158–162. 69. Chang CM, Yu CW, Fong KY, et al. n-Hexane neuropathy in offset printers. J Neurol, Neurosurg Psychiatry. 1993; 56:538–542.

CHAPTER 7: Occupational, Biologic, and Environmental Toxic Neuropathies   103 70. Herskowitz A, Ishii N, Schaumburg HH. n-Hexane neuropathy: a syndrome occurring as a result of industrial exposure. N Engl J Med. 1971;285:82–85. 71. Smith AG, Albers JW. n-Hexane neuropathy due to rubber cement sniffing. Muscle Nerve. 1997;20:1445–1450. 72. Lalloo M, Cosnett JE, Moosa A. Benzine-sniffing neuropathy. S Afr Med J. 1981;59:522–524. 73. Cavanagh JB. Solvent neurotoxicity. Br J Ind Med. 1985;42:433–434. 74. Graham DG, Anthony DC, Szakal-Quin G, et al. Covalent crosslinking of neurofilaments in the pathogenesis of n-hexane neuropathy. Neurotoxicology. 1985;6:55–63. 75. Allen N, Mendell JR, Billmaier DJ, et al. Toxic polyneuropathy due to methyl n-butyl ketone: an industrial outbreak. Arch Neurol. 1975;32:209–218. 76. Governa M, Calisti R, Coppa G, et al. Urinary excretion of 2,5-hexanedione and peripheral polyneuropathies workers exposed to hexane. J Toxicol Environ Health. 1987;20:219–228. 77. Couri D, Milks MM. Hexacarbon neuropathy: tracking a toxin. Neurotoxicology. 1985;6:65–71. 78. Ruff RL, Petito CK, Acheson LS. Neuropathy associated with chronic low level exposure to n-hexane. Clin Toxicol. 1981;18:515–519. 79. Paulson GW, Waylonis GW. Polyneuropathy due to n-hexane. Arch Inter Med. 1976;136:880–882. 80. Kuwabara S, Nakajima M, Tsuboi Y, et al. Multifocal conduction block in n-hexane neuropathy. Muscle Nerve. 1993;16:1416–1417. 81. Scelsi R, Poggi P, Fera L, et al. Toxic polyneuropathy due to n-hexane. J Neurol Sci. 1980;47:7–19. 82. Pastore C, Izura V, Marhuenda D, Prieto MJ, Roel J, Cardona A. Partial conduction blocks in N-hexane neuropathy. Muscle Nerve. 2002 Jul;26:132–135. 83. Albers JW, Kelly JJ Jr. Acquired inflammatory demyelin­ ating polyneuropathies; clinical and electrodiagnostic features. Muscle Nerve. 1989;12:435–451. 84. Yokoyama K, Feldman RG, Sax DS, et al. Relation of distribution of conduction velocities to nerve biopsy findings in n-hexane poisoning. Muscle Nerve. 1990;13:314–320. 85. Fischbein A. Environmental and occupational lead exposure. Environ Occup Med. 1983;57:433–447. 86. Grandjean P. Widening perspectives of lead toxicity. A review of health effects of lead exposure in adults. Environ Res. 1978;17:303–321. 87. Tavolato B, Licandro AC, Argentiero V. Lead polyneuropathy of nonindustrial origin. Eur J Neurol. 1980;19:273–276. 88. Wu PB, Kingery WS, Date ES. An EMG case report of lead neuropathy 19 years after a shotgun injury. Muscle Nerve. 1995;18:326–329. 89. Ellis T, Lacy R. Illicit alcohol (moonshine) consumption in West Alabama revisited. South Med J. 1998;91:858–860. 90. Anonymous. Lead poisoning associated with imported candy and powdered food coloring—California and Michigan. Morbidity Mortality Weekly Rep. 1998;47:1041–1043. 91. Ibrahim AS, Latif AH. Adult lead poisoning from a herbal medicine. Saudi Med J. 2002;23:591–593. 92. Phan TG, Estell J, Duggin G, et al. Lead poisoning from drinking Kombucha tea brewed in a ceramic pot. Medical Journal of Aust. 1998;169:644–646. 93. Conradi S, Ronnevi LO, Norris FH. Motor neuron disease and toxic metals. Adv Neurol. 1982;36:201–231. 94. Wilbourn AJ. Metal neuropathies. AAEE 31st Annual Meeting, Course B1: Toxic Neuropathies. Kansas City, MO:

American Association of Electrodiagnostic Medicine; 1984:13–25. 95. Rubens O, Logina I, Kravale I, et al. Peripheral neuropathy in chronic occupational inorganic lead exposure: a clinical and electrophysiological study. J Neurol Neurosurg Psychiatry. 2001;71:200–204. 96. Campbell AMG, Williams ER, Barltrop D. Motor neurone disease and exposure to lead. J Neurol Neurosurg Psychiatry. 1970;33:877–885. 97. Roelofs-Iverson RA, Mulder DW, Elveback LR. ALS and heavy metals: a pilot case-control study. Neurology. 1984;34:393–395. 98. Armon C, Kurland LT, Daube JR, et al. Epidemiologic correlates of sporadic amyotrophic lateral sclerosis. Neurology. 1991;41:1077–1084. 99. Ehle AL. Lead neuropathy and electrophysiological studies in low level lead exposure: a critical review. Neurotoxicology. 1986;7:203–216. 100. Albers, JW. Toxic neuropathies. In: Bleecker ML, ed. C­ontinuum; Lifelong Learning in Neurology. Vol 5: Neurotoxicology. Baltimore, MD: Lippincott Williams & Wilkins; 1999:33. 101. Feldman RG, Hayes MK, Younes R, et al. Lead neuropathy in adults and children. Arch Neurol. 1977;34:481–488. 102. Kumar N. Neurotoxic metals. In: Schaumburg HH, ed. American Academy of Neurology Education Program Syllabus: Neurotoxicology. Minneapolis, MN: American Academy of Neurology; 2010:6–22. 103. Aub JC, Fairhall LT, Minot AS, et al. Lead poisoning. Medicine. 1925;4:1–250. 104. Beritic T. Lead neuropathy. Crit Rev Toxicol. 1984;12: 149–213. 105. Moore MR, McColl KEL, Rimington C, Goldberg SA. Disorders of Porphyrin Metabolism. New York, NY: Plenum, 1987. 106. Baloh RW. Laboratory diagnosis of increased lead absorption. Arch Environ Health. 1974;28:198–208. 107. Froom P, Kristal-Boneh E, Benbassat J, et al. Lead exposure in battery-factory workers is not associated with anemia. J Occup Environ Med. 1999;41:120–123. 108. Conradi S, Ronnevi LO, Nise G, et al. Long-time penicillamine treatment in amyotrophic lateral sclerosis with parallel determination of lead in blood, plasma and urine. Acta Neurologica Scandinavica. 1982;65:203–211. 109. Landrigan PJ, Todd AC. Lead poisoning. West J Med. 1994;161:153–159. 110. Whitaker JA, Austin W, Nelson JD. Edathamil calcium disodium (versenate) diagnostic test for lead poisoning. Pediatrics. 1962;(82)29:384–388. 111. Clarkson TW, Friberg L, Nordberg GF, Sager PR. Mercury. Biological Monitoring of Toxic Metals. New York, NY: Plenum Press; 1988:199–246. 112. Hanninen H. Behavioral effects of occupational exposure to mercury and lead. Acta Neurologica Scandinavia Suppl. 1982;66:167–175. 113. Bromberg MB. Peripheral neurotoxic disorders. Neurol Clin. 2000;18:681–694. 114. Chang LW. Mercury. In: Spencer P, Schaumburg HH, eds. Experimental and Clinical Neurotoxicology. Baltimore, MD: Williams & Wilkens; 1980:508–526. 115. Berlin M. Mercury. In: Friberg L, Nordberg GF, Vouk VB, eds. Handbook on the Toxicology of Metal. New York, NY: Elsevier; 1986:387–445.

104  Textbook of Peripheral Neuropathy 116. Feldman RG. Neurological manifestations of mercury intoxication. Acta Neurologica Scandinavica. 1982;66(Suppl 92):201–209. 117. Albers JW, Kallenbach LR, Fine LJ, et al. Neurological abnormalities associated with remote occupational elemental mercury exposure. Ann Neurol. 1988;24:651–659. 118. Albers JW, Cavender GF, Levine SP, et al. Asymptomatic sensorimotor polyneuropathy in workers exposed to elemental mercury. Neurology. 1982;32:1168–1174. 119. Windebank AJ, McCall JT, Dyck PJ. Metal neuropathy. In: Dyck PJ, Thomas PK, Lambert EH, Bunge R, eds. Peripheral Neuropathy. Philadelphia, PA: WB Saunders; 1984:2133–2161. 120. World Health Organization. International Programme on Chemical Safety, Environmental Health Criteria 1: Mercury. Geneva, Switzerland: World Health Organization; 1976. 121. Frumkin H, Manning CC, Williams PL, et al. Diagnostic chelation challenge with DMSA: a biomarker of long-term mercury exposure? Environ Health Perspect. 2001;109:167–171. 122. Malik GM, Mubarik M, Romshoo GJ. Organophosphorus poisoning in the Kashmir Valley, 1994 to 1997 (letter). N Engl J Med. 1998;338:1078. 123. Jayaratnam J. Acute pesticide poisoning: a major global health problem. World Healthstate Q. 1990;43:139–144. 124. Kropp TJ, Richardson RJ. Relative inhibitory potencies of chlorpyrifos oxon, chlorpyrifos methyl oxon, and mipafox for acetylcholinesterase versus neuropathy target esterase. J Toxicol Environ Health. 2003;66:1145–1157. 125. Richardson RJ. Assessment of the neurotoxic potential of chlorpyrifos relative to other organophosphorus compounds: a critical review of the literature. J Toxicol Environ Health. 1995;44:135–165. 126. Lotti M. The pathogenesis of organophosphate polyneuropathy. Crit Rev Toxicol. 1991;21:465–487. 127. Dickoff DJ, Gerber O, Turovsky Z. Delayed neurotoxicity after ingestion of carbamate pesticide. Neurology. 1987;37:1229–1231. 128. Morgan JP, Penovich P. Jamaica ginger paralysis. Arch Neurol. 1978;35:530–532. 129. Senanayake N, Jeyaratnam J. Toxic polyneuropathy due to gingili oil contaminated with tri-cresyl phosphate affecting adolescent girls in Sri Lanka. Lancet. 1981;1:88–89. 130. Senanayake N, Karalliedde L. Neurotoxic effects of organophosphorus insecticides. N Engl J Med. 1987;316: 761–763. 131. Senanayake N, Johnson MK. Acute polyneuropathy after poisoning by a new organophosphate insecticide. N Engl J Med. 1982;306:155–157. 132. Gutmann L, Besser R. Organophosphate intoxication: pharmacologic, neurophysiologic, clinical, and therapeutic considerations. Semin Neurol. 1990;10:46–51. 133. Wadia RS, Chitra S, Amin RB, et al. Electrophysiological studies in acute organophosphate poisoning. J Neurol Neurosurg Psychiatry. 1987;50:1442–1448. 134. LeQuesne PM. Neuropsychological investigations of subclinical and minimal toxic neuropathies. Muscle Nerve. 1978;1:392–395. 135. Kaplan JG, Rosenberg NL, Pack D, et al. Sensory neuropathy associated with Dursban (chlorpyrifos) exposure. Neurology. 1993;43:2193–2196. 136. Albers JW, Garabrant DH, Schweitzer SJ, et al. The effects of occupational exposure to chlorpyrifos on the peripheral

nervous system: a prospective cohort study. Occup Environ Med. 2004;61:201–211. 137. Moretto A, Lotti M. Poisoning by organophosphorus insecticides and sensory neuropathy. J Neurol Neurosurg Psychiatry. 1998;64:463–468. 138. Osterloh J, Lotti M, Pond SM. Toxicologic studies in a fatal overdose of 2,4-D, MCPP, and chlorpyrifos. J Analytical Pharmacol. 1983;7:125–129. 139. Sidell FR. Clinical effects of organophosphorus cholines­ terase inhibitors. J Appl Toxicol. 1994;14:111–113. 140. Koller WC, Klawans HL. Organophosphorous intoxication. In: Vinken PJ, Bruyn GW, eds. Handbook of Clinical Neurology. Vol 37. Amsterdam, Netherlands: North Holland Publishing Co; 1979:541–562. 141. Wills JH. Toxicity of anticholinesterases and treatment of poisoning. In: Karczman AG, ed. Anticholinesterase Agents. Vol. I, International Encyclopedia of Pharmacology and Therapeutics, Section 13. Oxford, United Kingdom: Pergamon Press, 1970:355–471. 142. Hirsch GH, Mori BT, Morgan GB, et al. Report of illnesses caused by aldicarb-contaminated cucumbers. Food Addit Contam. 1988;5(2):155–160. 143. Moore D, House I, Dixon A. Thallium poisoning. Diagnosis may be elusive but alopecia is the clue. Br Med J. 1993;306:1527–1529. 144. Hirata M, Taoda K, Ono-Ogasawara M, et al. A probable case of chronic occupational thallium poisoning in a glass factory. Ind Health. 1998;36:300–303. 145. Bank WJ. Thallium. In: Spencer PS, Schaumburg HH, eds. Experimental and Clinical Neurotoxicology. Baltimore, MD: Williams and Wilkins; 1980:570–577. 146. Rusyniak DE, Furbee RB, Kirk MA. Thallium and arsenic poisoning in a small midwestern town. Ann Emerg Med. 2002;39:307–311. 147. Desenclos JC, Wilder MH, Coppenger GW, et al. Thallium poisoning: an outbreak in Florida, 1988. South Med J. 1992;85:1203–1206. 148. Cavanagh JB. Neurotoxic effects of metal and their interaction. In: Galli CL, Manzo L, Spencer PS, eds. Recent Advances in Nervous System Toxicology. NATO ASI Series. New York, NY: Plenum Press; 1984:177–202. 149. Kubis N, Talamon C, Smadja D, et al. Peripheral neuropathy caused by thallium poisoning. Rev Neurologique (Paris). 1997;153:599–601. 150. Meggs WJ, Hoffman RS, Shih RD, et al. Thallium poisoning from maliciously contaminated food. J Toxicol—Clin Toxicol. 1994;32:723–730. 151. Feldman J, Levisohn DR. Acute alopecia: clue to thallium toxicity. Pediatr Dermatol. 1993;10:29–31. 152. Dumitru D, Kalantri A. Electrophysiologic investigation of thallium poisoning. Muscle Nerve. 1990;13: 433–437. 153. Kalantri A, Kurtz E. Electrodiagnosis in thallium toxicity: a case report (abstract). Muscle Nerve. 1988;11:968A. 154. Herrero F, Fernandez E, Gomez J, et al. Thallium poisoning presenting with abdominal colic, paresthesia, and irritability. J Toxicol Sci. 1995;33:261–264. 155. Nordentoft T, Andersen EB, Mogensen PH. Initial sensorimotor and delayed autonomic neuropathy in acute thallium poisoning. Neurotoxicology. 1998;19:421–426. 156. Andersen O. Clinical evidence and therapeutic indications in neurotoxicology, exemplified by thallotoxicosis. Acta Neurologica Scandinavia Suppl. 1984;70:185–192.

CHAPTER 7: Occupational, Biologic, and Environmental Toxic Neuropathies   105 157. Vergauwe PL, Knockaert DC, Van Tittelboom TJ. Near fatal subacute thallium poisoning necessitating prolonged mechanical ventilation. Am J Emerg Med. 1990;8:548–550. 158. Kaeser HE, Lambert EH. Nerve function studies in experimental polyneuritis (Proc 1st Int Congr Electromyography, Pavia). Electroencephalogy Clin Neurophysiol. 1962;Suppl 22:29–35. 159. Buxton PH, Hayward M. Polyneuritis cranialis associated with industrial trichloroethylene poisoning. J Neurol Neurosurg Psychiatry. 1967;30:511–518. 160. Feldman RG, Mayer RM, Taub A. Evidence for peripheral neurotoxic effect of trichloroethylene. Neurology. 1970;20:599–606. 161. Feldman RG. Facial nerve latency studies in man: effects of trichloroethylene intoxication. Electromyography. 1970;Nr. 1:93–100. 162. Humphrey JH, McClelland M. Cranial-nerve palsies with herpes following general anaesthesia. Br Med J. 1944;4:315–318.

163. Selby G. Diseases of the fifth cranial nerve. In: Dyck PJ, Thomas PK, Lambert EH, Bunge R, eds. Peripheral Neuropathy. Philadelphia: WB Saunders; 1984:1224–1299. 164. Feldman RG, White RF, Currie JN, et al. Long-term followup after single toxic exposure to trichloroethylene. Am J Ind Med. 1985;8:119–126. 165. Feldman RG, Niles C, Proctor SP, et al. Blink reflex measurement of effects of trichloroethylene exposure on the trigeminal nerve. Muscle Nerve. 1992;15:490–495. 166. Albers JW, Wald JJ, Trask CL, et al. Evaluation of blink reflex results obtained from workers previously diagnosed with solvent-induced toxic encephalopathy. J Occup Environ Med. 2001;43:713–722. 167. de Tommaso M, Sciruicchio V, Spinelli A, et al. Features of the blink reflex in individuals at risk for Huntington’s disease. Muscle Nerve. 2001;24:1520–1525.

8

Jun Li

Inherited Peripheral Neuropathies (Charcot-Marie-Tooth Disease)*

INTRODUCTION

the patient has a neuropathy with X-linked inheritance; and CMT4 if the neuropathy is recessively inherited. Furthermore, cases of CMT1, CMT2, and CMT4 will be further subdivided based on time sequence when the genetic abnormalities or linkages were initially discovered. For instance, chromosome 17p11.2 duplication was first identified to cause a CMT1. Subsequently, mutations in the MPZ gene were found to cause another subtype of CMT1. Thus, they were classified as CMT1A and CMT1B. However, the classification of CMT remains confusing in some aspects and will certainly require further revisions as new genetic forms of the neuropathies are identified. Due to its unique phenotypic features, hereditary neuropathy with liability to pressure palsies (HNPP) stands alone as a separate group. Recently, mutations in the SH3TC2 gene were found to be associated with carpal tunnel syndrome (2). While additional work has to be done to confirm the causal relationship, this mutation could be an additional member to be listed in the group of neuropathies with susceptibility to mechanical stress. In addition, it should be clarified that genetic causes for DejerineSottas disease (DSD) are heterogeneous, including autosomal dominant mutations in PMP22, MPZ, and EGR2. Pathologic changes also range from severe dysmyelination to predominantly axonal loss. Thus, DSD is no longer listed as a subtype of CMT; rather, it is defined clinically as early onset by 2 years of age, delayed motor milestones, and severe motor/sensory and skeletal deficits.

Mutations in human genes may affect peripheral nerves, and the neuropathies that result are collectively called Charcot-Marie-Tooth disease (CMT), a term that refers to 3 investigators who described them in the late 1800s. As CMT diseases affect approximately 1 in 2500 people, they are among the most common inherited neurologic disorders. Most cases of CMT are inherited in an autosomal dominant mode. The remaining patients may have X-linked and autosomal recessive inheritances. A small portion of these patients may have the disease caused by de novo mutations that begin as a new mutation in a given patient. Most patients have a “typical” CMT phenotype that is characterized by distal weakness, sensory loss, foot deformities (pes cavus and hammer toes), and absent reflexes. Over the past several decades, remarkable progress has been made toward understanding the genetic causes and pathogenic mechanisms of many types of CMT. In this chapter, we will review the clinical, electrodiagnostic, genetic, and pathologic features of CMT.

CLASSIFICATION Inherited neuropathies were first classified by Dyck and Lambert (1) into 2 subtypes based on their electrophysiologic and pathologic features. Hereditary motor and sensory neuropathy type I (CMT type I [CMT1]) refers to dominantly inherited demyelinating/dysmyelinating neuropathies, whereas type II (CMT2) refers to dominantly inherited axonal neuropathies. With the advance of molecular genetics, many genetic mutations have been identified to cause CMT. The classification has had to be expanded (Table 8.1). In this chapter, we will classify CMT into the following: CMT1 if the patient has an autosomal dominantly inherited demyelinating/dysmyelinating neuropathy; CMT2 if the neuropathy is dominantly inherited axonal type; X-linked CMT (CMTX) if

Demyelinating/Dysmyelinating CMT With Autosomal Dominant Inheritance Charcot-Marie-Tooth disease type IA is the most common form of CMT, with a prevalence of 1:5000, and accounts for about 50% of all patients with CMT. Clinical features in patients with CMT1A have been considered as the prototypic phenotype, which is often shared by

* This material was supported in part by grants from the NIH (R01NS066927-01) and MDA115087.

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108  Textbook of Peripheral Neuropathy

Table 8.1  Classification of Charcot-Marie-Tooth Disease Type

Locus/Gene

Prominent Phenotype

CMT1: CMT1A CMT1B CMT1C CMT1D CMT1F

17p11.2/PMP22 duplication 1q21-23/MPZ 16p12-13/SIMPLE/LITAF 10q21-22/EGR2 8p21/NEFL

prototype of CMT1 may present as an axonal neuropathy almost indistinguishable from CMT1A severe dysmyelination with cranial nerve involvement lacks demyelination/dysmyelination, but CV is in the range of CMT1

CMT with nerve susceptibility to mechanical stress: HNPP 17p11.2/PMP22 deletion focal sensory loss and weakness; tomacula Others? CMTX: CMTX1

X chromosome/GJB1

intermediate range of CV

CMT2: CMT2A CMT2B CMT2C CMT2D CMT2E CMT2F CMT2G CMT2L

1p36/MFN2 3q21/RAB7 12q23/TRPV4 7p15/GARS 8p21/NEFL 7q/HSP27 12q12-13/unknown 12q24/HSP27

early and late onset; optic atrophy/hearing loss prominent sensory loss and foot ulcers vocal cord paralysis; skeletal deformities motor deficits in upper limbs lacks demyelination/dysmyelination, but CV is in the range of CMT1 classical CMT2 or distal SMA

CMT4: CMT4A CMT4B1 CMT4B2 CMT4C CMT4D CMT4E CMT4F CMT4H CMT4J

8q13/GDAP1 11q22/MTMR2 11p15/MTMR13 5q32/SH3TC2(KIAA1985) 8q24/NDRG1 10q21/EGR2 19q13/PRX 12q11/FGD4 6q21/FIG4

rapidly progressive asymmetric weakness

AR CMT2A

1q21/LMNA

proximal muscle weakness; muscular dystrophy; cardiomyopathy

DI-CMT: DI-CMTA DI-CMTB DI-CMTC

10q24 19q12/DNM2 1p34/YARS

Inherited brachial plexopathy: HNPP 17p11.2/PMP22 deletion HNA 17q25/SEPT9

classical CMT2 or distal SMA

demyelination or axonal; vocal cord paralysis myelin folding myelin folding severe; hearing loss; CNS involvement severe dysmyelination or amyelination myelin folding—tomacula

no pain/unilateral arm weakness severe pain/arm weakness & atrophy

Abbreviations: CMT, Charcot-Marie-Tooth disease; CNS, central nervous system; CV, conduction velocity; HNA, hereditary neuralgic amyotrophy; HNPP, hereditary neuropathy with liability to pressure palsies; SMA, spinal muscular atrophy.

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most patients in this group (3,4). Most patients with CMT1A (85%) become symptomatic in their first 2 decades of life. They are slow runners in childhood and often called “clumsy kids” by their peers. Foot deformities, such as high-arched feet or hammer toes, usually develop early and often become conspicuous in their teenage years. Many of them receive surgical corrections. These deformities are typically companied by ankle weakness and result in foot tripping or ankle sprain. These motor problems often prevent the patients from practicing sports. The ankle weakness often requires orthotics for ankle support as adults. Variable degrees of hand weakness occur but typically lagging about 10 years behind the development of foot weakness. In contrast, sensory symptoms are much more insidious and typically not the main complaint of the patients. Sensory loss involves both large (vibration and proprioception) and small (pain and temperature) modalities. The combination of weak ankles and decreased proprioception leads to problems with balance. Because of preserved strength in proximal muscles, most patients remain ambulatory throughout their life. Occasionally, patients may develop a severe phenotype in infancy, while others develop minimal disability throughout life. Since phenotypic variability can occur even within the same generation of the same family, it is not yet possible to precisely predict the final outcome of an affected individual. While patients with CMT1B have phenotypes similar to those in patients with CMT1A, they tend to cluster in two groups, the early- and late-onset groups. Patients in the early-onset group often manifest severe sensory and motor defects resembling the phenotype of DSD. The late-onset group clinically manifests more closely to CMT1A (5–7). Interestingly, phenotypic presentation in patients with CMT1C is usually indistinguishable from that in CMT1A (8). Finally, phenotypes in CMT1E with point mutations of the PMP22 gene may vary from a severe DSD to a mild form of pressure palsies similar to those in HNPP. There are other subtypes of CMT1 that are rare and will not be discussed further. On physical examination, in addition to the sensory loss and foot deformities, most patients have absent deep tendon reflexes. Muscle weakness and atrophy are typically detectable in the distal muscles. Postural tremor may occur in some patients with CMT1A. When a postural tremor is observed in patients with CMT1A, the term Roussey-Levy syndrome is often applied to these patients. Adie pupil is often seen in patients with CMT1B. Genetics Charcot-Marie-Tooth disease type IA was first shown to be caused by a duplication of a DNA segment on chromosome 17p11.2 containing the gene encoding peripheral myelin protein 22kD (PMP22) (9,10). Peripheral myelin protein 22kD is primarily expressed in the compact myelin of the peripheral nervous system. Its molec-

ular function is still largely unknown. There are about 80% of patients with CMT1 who have this mutation. Interestingly, a heterozygous deletion of exactly the same chromosome 17p11.2 region causes an entirely different disorder, HNPP, that will be discussed below (11). Missense or nonsense mutations in PMP22, although rare, have all been reported to cause different subtypes of CMT. A missense mutation may produce a mutant protein and result in a severe and early-onset dysmyelinating neuropathy like DSD. In contrast, a nonsense mutation in the gene may create a premature stop codon to prevent full expression of PMP22. A patient with a premature stop codon would manifest an HNPP phenotype (12,13). Charcot-Marie-Tooth disease type IB is caused by missense mutations in a myelin protein gene, on chromosome 1, encoding myelin protein zero (MPZ) (14). Myelin protein zero is a major myelin protein and accounts for approximately 50% of all myelin proteins. Myelin protein zero is a member of the immunoglobulin superfamily, has a single transmembrane domain, and is necessary for the adhesion of myelin wraps on the peripheral nerve axons (15). Charcot-Marie-Tooth disease type IC involves mutations in a gene encoding SIMPLE/LITAF. Missense mutations in the early growth response 2 (EGR2, also called krox20), on chromosome 10, cause CMT1D (16). Early growth response 2 is a transcription factor involved in the transcriptional regulations of genes encoding myelin proteins, such as PMP22 or MPZ, in the myelinating Schwann cell. Nerve Conduction Testing Nerve conduction studies (NCSs) have been an indispensable tool in characterizing CMT. They were used initially to differentiate CMT1 from CMT2, with the first type showing slowed conduction velocities and the second type showing reduced amplitude of sensory/motor responses. Interestingly, most patients with CMT1 have uniformly slowed conduction velocities, whereas acquired demyelinating neuropathies show nonuniform slowing (17). Thus, conduction velocity changes have been used, along with family pedigrees, to distinguish between inherited and acquired neuropathies. However, this approach has had to be qualified. Patients with CMT1A and 1B do have uniformly slowed conduction velocities of about 20 m/s (although values as high as 38 m/s have been used as a “cutoff” value). However, nonuniform slowing can be seen in patients with HNPP and with missense mutations in PMP22, MPZ, EGR2 and Cx32 (18). This issue is particularly important when one deals with patients with CMT who do not have a clear family history of neuropathy. These patients could be readily misdiagnosed as having an acquired demyelinating neuropathy, such as chronic inflammatory demyelinating polyneuropathy (CIDP). The use of conduction velocities to distinguish between demyelinating and axonal neuropathies is important. Similar to patients with CMT2, all subtypes of

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CMT1 have secondary axonal loss, in addition to demyelination/dysmyelination. Thus, reduction in compound muscle action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes is found in most patients with CMT1 (4). However, conduction velocities in patients with CMT2 are not decreased or are minimally slowed. The distinction between demyelinating and axonal features of nerve conduction becomes difficult when dealing with a subset of patients with conduction velocities in the intermediate range (30–40 m/s). This is typified by CMTX1 that is caused by mutations in the connexin32 gene. Conduction velocities in patients with CMTX1 are faster than those in most patients with CMT1A, often with prominent reductions in motor and sensory amplitudes. Temporal dispersion and conduction block have also been observed in patients with CMTX1 (19). Some women with CMTX1, probably through inactivation of their mutant X chromosome, have normal conduction velocities, although many have values similar to those of their male counterparts.

Pathology Onion bulbs are the most characteristic feature in the nerves of patients with CMT1. They are formed by concentric lamellar processes of Schwann cells that circle around the axon but fail to form compact myelin. In the innermost layers of the onion bulb, one of the Schwann cells successfully establishes a one-to-one relationship with the axon and forms compact myelin with reduced thickness. In cases of DSD, dysmyelination and onion bulbs are severe (Figure 8.1). Onion bulbs occur in many forms of CMT1 and are generally less frequent in children than in adults. In adults, the presence of onion bulbs may dominate the pathology (20). As exemplified by nerves of patients with CMT1A, segmental demyelination has been observed. It has been hypothesized that onion bulbs are formed by Schwann cells following repeated segmental demyelination and remyelination (21,22). Direct evidence for this mechanism is still lacking in CMT. Interestingly, a systematic analysis of dermal myelinated nerve fibers in a cohort of patients with CMT1A shows no segmental demyelination while internodal length is shortened (23).

Figure 8.1 A. Sciatic nerve section from control autopsy stained with toluidine blue contains numerous myelinated nerve fibers. B. In contrast, a semithin section from the tibial nerve of a patient with axonal form of MPZ mutation, also stained with toluidine blue, showed a reduced density of myelinated nerve fibers with many regenerating clusters (arrowheads). These features are consistent with the axonal type of neuropathy. C. A semithin section from a sural nerve biopsy of a patient with CMT1B showed numerous onion bulbs (arrowheads) with severely reduced density of myelinated nerve fibers. These features are typical for CMT1. D. Human skin biopsy was taken from a patient with CMT1A and triple-stained with antibodies against axonal marker PGP9.5 (green) and myelin marker MBP (myelin basic protein, red). Internodes with nodal gaps were clearly visible. This minimally invasive technique permitted us to observe internodal length, segmental demyelination, and molecular architecture changes on the myelinated nerve fibers. Abbreviation: CMT, Charcot-Marie-Tooth disease. All figures are adapted from our previous publications (Li et al [6]; Bai et al [7]; Saporta et al [23]) with permission.

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Thus, a developmental defect of internodal elongation has been speculated to explain this finding. Like its clinical presentation, CMT1C is also indistinguishable pathologically from CMT1A. Axonal loss is almost an inevitable feature in patients with CMT1 and may affect both small- and largediameter myelinated fibers. The lost axons are typically replaced by a large amount of collagen fibers. The degree of axonal loss, rather than the slowing of conduction velocities, correlates with permanent disabilities in these patients. Some myelinated fibers have relatively thickened myelin sheaths, resulting in lowered mean gratios (axon diameter compared to total diameter of the nerve fiber). Focal, sausagelike thickenings of the myelin sheath (tomacula) may be present in various types of CMT1. However, none of them has tomacula present to the extent seen in HNPP. Immunologic electron microscopic analysis of sural nerve biopsies from patients with CMT1A demonstrates increased PMP22 labeling compared to controls (24). These changes were replicated using human skin biopsies (25,26). Interestingly, this study shows that the levels of PMP22 in subjects with CMT1A, but not in those with HNPP or controls, were highly variable. This finding suggests that the extra copy of PMP22 in CMT1A results in disruption of the tightly regulated expression of PMP22 (23).

X-Linked Charcot-Marie-Tooth Disease The second most common form of CMT, encompassing between 10% and 16% of cases, is caused by missense mutations in the connexin 32kd (Cx32) gene located on the X chromosome (27). Cx32, localized in the uncompacted myelin of the paranodal loops and SchmidtLanterman incisures, presumably functions as a gap junction protein, permitting the passage of small molecules and ions between adjacent loops of the paranode or incisures (28). Currently, over 200 different mutations of Cx32 have been identified. Because they have a single X chromosome, men tend to develop CMTX more severely than their female counterparts. Women, probably because of X-inactivation of the abnormal chromosome, usually have milder disease, although most are affected to some degree (see below). Patients with CMTX usually develop symptoms in their late teenage years or young adulthood. Wasting of calf muscles is often more pronounced in patients with CMTX than in those with CMT1A. Interestingly, despite the more than 200 different mutations described, few, if any, appear to have severe Dejerine-Sottas or congenital hypomyelination phenotypes. As with patients with CMT1A, abnormalities are usually slowly progressive, are limited to the distal legs and hands, and do not shorten the lifespan. Occasionally, female patients have presented in adulthood with a CIDP-like neuropathy (29). Conduction velocities in patients with CMTX1 usually fall in the intermediate range and are often nonuni-

form or asymmetric. Moreover, the wave forms of motor responses tend to be dispersed and may show conduction block. These features closely resemble the NCSs in acquired demyelinating diseases, such as CIDP. Thus, caution should be taken to avoid erroneous diagnosis. Nerve pathology tests of patients with Cx32 mutations reveal axonal loss of myelinated nerve fibers. Demyelination is suggested by abnormally thin myelin ensheathing large-caliber axons. Teased fiber analysis reveals frequent widening at the nodal gap, paranodal retractions, and, less frequently, segmental demyelination. Onion bulbs are infrequent (30). Taken together, these pathologic changes differ from those in nerves of patients with CMT1A, CMT1B, CMT1C, or HNPP.

Inherited Neuropathies With Nerve Susceptibility to Mechanical Stresses Hereditary neuropathy with liability to pressure palsies is caused by a deletion of the same region of chromosome 17p11.2 that is duplicated in CMT1A. This DNA segment contains the PMP22 gene. It is the heterozygous deletion of PMP22 responsible for the disease, not the other genes in chromosome 17p11.2, suggesting that PMP22 is particularly dosage sensitive (12,13). Patients with HNPP present with a variety of reversible focal sensory and motor deficits that are usually developed when peripheral nerves are challenged by mechanical stresses, including stretching, compression, or repetitive movement of the affected limbs (31). Strenuous physical activities could even result in limb paralysis with concomitant massive axonal damages (32). Neurologic examination may reveal minimal abnormalities or significant sensory loss, weakness, or muscle atrophy in hands or feet. These abnormalities become particularly conspicuous in elderly patients when symmetric axonal loss develops in limbs. Occasionally, a brachial plexopathy may be the presenting symptom. However, HNPP is a distinct disorder from hereditary neuralgic plexopathy (see later in chapter) and shows no or minimal pain during the episode of plexopathy. Tomacula are pathologic hallmarks of HNPP and have been identified in at least 1 patient prior to the development of clinical symptoms (20). The tomacula are formed by excessive myelin folding, predominantly in the paranodal regions (33). The axon encased by the tomacula is often deformed (34). While segmental demyelination and remyelination have been described in nerve biopsies from patients with HNPP, these are usually much less prominent, comparing with those in CMT1A. This is consistent with mildly reduced conduction velocities found in patients with HNPP (35). Immunologic electron microscopic studies of sural nerve or skin biopsies have demonstrated the predicted underexpression of PMP22 (24,26). Electrophysiologic findings in patients with HNPP are quite unique. Nerve conduction studies show accentuated slowing in motor distal latencies at the sites

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susceptible to mechanical pressure, such as the median nerve at the wrist and the peroneal nerve at the ankle. In addition, focal slowing of conduction velocities is almost always seen at sites subject to compression, such as the ulnar nerve across the elbow and the peroneal nerve across the fibular head. In contrast, conduction velocities in other nerve segments are usually normal or minimally slowed (35). In our experience, 80% of patients fulfilling these electrophysiologic features have a positive finding in their DNA testing for HNPP deletion. In the remaining 20% of patients, it would be caused by another, yet-to-be-discovered, genetic etiology. Interestingly, mutations in the SH3TC2 gene are associated with carpal tunnel syndrome (2). One would expect to see more genetic causes discovered in the future that are responsible for neuropathies with mechanical susceptibilities.

Axonal CMT With Autosomal Dominant Inheritanc­e Charcot-Marie-Tooth disease type II makes up a third of cases of autosomal dominant CMT. In general, the clinical phenotype of patients with CMT2 is similar to that of patients with CMT1. The patients have distal weakness, atrophy, sensory loss, and foot deformities. Compared to those with CMT1, patients with CMT2 may be more likely to maintain their deep tendon reflexes. However, it is impossible to accurately clinically distinguish patients with CMT1 from those with CMT2 without electrodiagnostic testing. It is even more difficult to differentiate subtypes of CMT2 purely based on clinical presentation. Table 8.1 lists some clinical features that are relatively prominent in each subtype of CMT2, but these are not completely unique. Nerve conduction study is very helpful to distinguish CMT1 from CMT2. Reduced CMAP and SNAP amplitudes with normal or mildly slow conduction velocities are hallmarks of CMT2 (18). With needle electromyography, changes of active denervation and reinnervation are common. The electrophysiologic features are consistent with pathologic findings from sural nerve biopsies that demonstrate axonal loss and regenerating nerve fiber clusters without evidence of demyelination. While pathologic findings in CMT2 are clearly different from those in CMT1, these findings are insufficient to allow one to differentiate different subtypes of CMT2. Genetic studies have demonstrated that CMT2 is a group of very heterogeneous disorders, like CMT1. Eight subtypes of CMT2 (CMT2A-L) have been identified by linkage analysis. Charcot-Marie-Tooth disease type IIA is caused by mutations in the mitofusin-2 gene (MFN2) on chromosome 1p36 (36). It is the most common form of CMT2 and accounts for about 20% of all cases of CMT2. The encoding protein of MFN2 functions as a regulator to control mitochondrial fusion. Charcot-Marie-Tooth disease type IIB is a predominantly sensory polyneu-

ropathy. The causal mutations have been mapped to chromosome 3q13 encoding a gene called RAB7 (37). Charcot-Marie-Tooth disease type IIC is a rare disorder in which patients have paresis of vocal cords, motor more than sensory deficits, and skeletal deformities, in addition to other characteristics of CMT2. The causal mutations have been identified recently in a cation channel transient receptor potential vanilloid-4 (TRPV4) gene on chromosome 12q24 (38,39). The detail functions of this nonspecific ion channel remain to be determined. Charcot-Marie-Tooth disease type IID is caused by mutations in the glycyl-tRNA synthetase (GARS) gene on chromosome 7p15 (40). Most of these patients present with a motor axonal polyneuropathy and are often regarded as a distal spinal muscular dystrophy (41). While this protein is essential for protein translations in all cell types, it is still a mystery how mutations in the gene affect the nervous system specifically. Similar clinical phenotype with motor nerves predominantly involved may be seen in patients with Charcot-Marie-Tooth disease type IIF (mutations in heat shock protein-27) (42) and Charcot-Marie-Tooth disease type IIL (mutations in heat shock protein-22) (43). Charcot-Marie-Tooth disease type IIE was linked to mutations in the neurofilament light (NEFL) gene on chromosome 8p21 (44). Interestingly, while neurofilament light expresses in axons, patients with CMT2E show significantly slowed conduction velocities. The mechanism of this is not well understood. Patients with this mutation tend to develop early onset and severe phenotype.

CMT4 With Autosomal Recessive Inheritance Charcot-Marie-Tooth disease type IV, the group of autosomal recessively inherited neuropathies, is also a heterogeneous group of disorders. Cases of CMT4 are rare and usually severe in their clinical deficits, with significant proximal muscle weakness. Many patients may have systemic symptoms, such as cataracts and skeletal deformities. These key clinical features of each CMT4 subtype are listed in the Table 8.1. In many aspects, these recessive CMTs, including CMT4A to 4H, are clinically similar to Dejerine-Sottas syndrome. Based on electrophysiologic features, CMT4 can also be separated into demyelinating and axonal forms. Due to frequent absence of sensory/motor responses in the distal limbs, recording from the proximal muscles is often required to differentiate the demyelinating form from the axonal form. There are several subtypes of CMT4 that have unique clinical or pathophysiologic features worthwhile to be discussed here briefly. Charcot-Marie-Tooth disease types IVb1 and b2 are caused by recessive mutations in the MTMR2 and MTMR13 genes, respectively. The genes encode phosphatases with specificity toward 5’ phosphate on the inositol ring of phosphatidylinositol3,5-diphosphate (PI3,5P2), thereby regulating the concentration of PI3,5P2. Patients with CMT4B1 or CMT4B2

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usually present with severe, early-onset sensory loss and weakness. Pathologic studies show focally folded myelin sheaths in their nerve biopsies. The folded myelin loops run longitudinally along the axis of the myelinated a­xons and often drag axolemma with the myelin loops to form many small axonal pockets out of the main proper of a­xons (45). In contrast, myelin membrane in the tomacula of patients with HNPP tends to wrap concentrically. Interestingly, a related phosphatase, FIG4, is also involved in regulating the level of PI3,5P2. Its mutations cause CMT4J. Myelin folding is not prominent in these patients. Instead, loss of function of FIG4 results in a rapidly progressive asymmetric weakness and denervation. The patients do not complain of sensory symptoms, while sensory abnormalities are conspicuous by physical examination and NCSs. Thus, clinically, this presentation resembles motor neuron disease (46,47). However, patients with early onset could present a phenotype like CMT1, an issue to be determined in the future. Another severe form of recessive CMT, Charcot-MarieTooth disease type IVF, was initially defined in a large Lebanese family in which mutations have been found in the periaxin (PRX) gene on chromosome 19. Conduction velocities in patients with PRX mutations are markedly slowed, and onion bulbs are present in sural nerve biopsies (48). PRX, expressed in Schwann cells, encodes proteins that contain PDZ domains that usually interact with other PDZ-domain-bearing proteins in intracellular signal transduction pathways. Binding partners for PRX in Schwann cells have not yet been identified, nor have the signal transduction pathways involving PRX been delineated. Interestingly, PRX mutations also result in myelin folding that is almost identical to the tomacula seen in patients with HNPP. Finally, there are a few axonal forms of autosomal recessive CMTs, including mutations in lamin A/C nuclearenvelope proteins (LMNA) and ganglioside induced differentiation-associated protein-1 (GDAP1) genes. Patients with these CMTs usually have severe disabilities with early onset (Table 8.1). Giant axonal neuropathy is a rare autosomal recessive disorder presenting in childhood and progressing to death by the end of the third decade. The genetic cause of the disease has been demonstrated to be mutations in a cytoskeletal gene termed gigaxonin (49). The name of the disorder comes from the characteristic pathologic abnormalities that result from the general disorganization of intermediate filaments in nerve axons. Because of disorganized intermediate filaments, many patients, although not all, may have characteristically kinky hair. Nerve conduction studies reveal severe reductions in CMAP and SNAP amplitudes.

HEREDITARY BRACHIAL PLEXOPATHY Brachial plexopathy can be caused by genetic mutations. There are at least 2 types of brachial plexopathies that

are genetically defined. First, a subset of patients with HNPP mutation may present with brachial plexopathy. The sensory and motor deficits are often reversible within a variable length of time. An important clinical feature of this condition is that patients usually do not experience pain during the episode. In addition, the patients often have other clinical features of HNPP, such as focal slowing of conduction velocities at the sites susceptible to mechanical stress or tomacula in nerve biopsies. Another inherited brachial plexopathy is often called hereditary neuralgic amyotrophy (HNA). Hereditary neuralgic amyotrophy has been linked to chromosome 17q25, containing the SEPT9 gene. This autosomal dominant disorder presents with episodes of pain, weakness, and sensory loss in the upper extremities. Almost invariably, the onset of weakness is preceded by pain in the affected arm. Recovery usually occurs, beginning several weeks to months after the onset of symptoms, but often leaves significant muscle atrophy in the affected limbs. Attacks may subsequently occur in the same or opposite arm. Several dysmorphic features, including short stature, hypotelorisms, epicanthal folds, and cleft palate, have been associated with HNA but do not appear to be invariant. Nerve conduction studies have shown axonal loss, demyelinating changes, or asymmetrically reduced CMAPs and SNAPs. Muscle denervation due to axonal damages can also be revealed by needle electromyography (50,51).

DIAGNOSIS The initial step in diagnosis is to ensure that the patient has a peripheral nerve disorder. Clinically, most patients with CMT usually have symptoms of weakness and sensory loss in the distal limbs. In general, CMTs are chronic, with symptoms extending back into childhood, although some can have their onset in adulthood. The neurologic examination typically shows weakness of foot dorsiflexion and eversion, out of proportion to plantar flexion and inversion weakness. Muscle wasting in feet and hands is frequent, as are foot abnormalities such as pes cavus. Scoliosis is also frequent. Reflexes are often, but not always, decreased. Other causes of peripheral neuropathy, such as diabetes mellitus, monoclonal gammopathy, renal disease, medications, and alcohol abuse need to be excluded. Obtaining a careful pedigree is critical in the diagnosis of inherited neuropathies, not only to determine that there is an inherited neuropathy but also to determine who is at risk for developing the neuropathy. Careful pedigrees require going back at least 3 generations. Male-to-male transmission is the most reliable way to confirm autosomal dominant inheritance. Caution must be taken in interpreting negative pedigrees. Even dominantly inherited diseases can start in a particular patient, so their parents might have no signs of neuropathy. In recessive disorders, family histories will usually be negative for signs of neuropathy.

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The next step is to use NCSs to characterize the patterns of the neuropathy. This is essential to determine whether patients are likely to have demyelination/dysmyelinating neuropathy or axonal neuropathy. We would emphasize the importance of evaluating nerve conductions in proximal muscles when the recording from the distal muscles is nonresponsive. This will allow one to gain information about the conduction velocities, which is obviously critical in differentiating demyelination/dysmyelinating type from the axonal type of CMT. Sural nerve biopsies are rarely helpful in diagnosing inherited neuropathies, although they may be invaluable for research investigating pathogenic mechanisms of CMT. Data from clinical interview and electrodiagnostic testing should then be carefully considered in order to guide the genetic testing, which is the only way to yield a definitive diagnosis. Genetic testing has therefore become an important tool in the diagnosis of CMT. While there are batteries of DNA tests available commercially, they involve testing a large set of candidate genes and are very expensive. There are a few algorithms that have been published to guide the selection of genetic test (52–54). We believe that a simplified approach should allow one to reach the diagnosis in more than 50% of patients with CMT. First, if a patient has uniform slowing of conduction velocities of around 20 m/s and an autosomal dominant inheritance, we recommend doing a PMP22 duplication test. Based on the prevalence of CMT1A, this step should allow one to diagnose nearly half of all patients with CMT. If the result of this test is negative, a LITAF/ SIMPLE gene test would be the next step since CMT1C with mutations in SIMPLE have a presentation identical to CMT1A. If a patient has an intermediate range of conduction velocities and an X-linked inheritance, there is a great chance that the Cx32 test result will be positive. This step would allow one to diagnose about 15% of patients with CMT. If a patient has an NCS result showing axonal neuropathy, prediction of an accurate diagnosis will be more difficult. However, since CMT2A is the most common form of CMT2A, it is reasonable to obtain a mitofusin-2 gene test first. Together, these 3 simple steps would diagnose more than 50% of patients with CMT. The remaining patients will likely have rare forms of CMT. The clinicians can either obtain guidance from the published algorithms or refer the patients to physicians who specialize in CMT. There remain about 20% to 30% of patients with inherited neuropathies who carry unknown genetic causes. Their diagnosis may be clarified by referring them to a research laboratory where new genetic mutations can be investigated. Genetic counseling is an important part of the treatment of patients. Many patients are not well informed about the complicated genetics underlying CMT. There may be concerns about who is at risk in the family and what options are available to parents.

MANAGEMENT There are no specific cures for inherited neuropathies, although there are clinical trials ongoing to test medications for treating CMT. Most patients will require some form of physical or occupational therapy. Orthotics or ankle bracing is the cornerstone of foot care and, if done well, can help patients ambulate independently throughout their lives. In severely affected patients, surgical interventions might be needed to correct foot deformities. Difficulties with fine movements of the fingers are common in patients with CMT. In these cases, occupational therapy can help with techniques to aid in buttoning, zippering, and other hand movements requiring dexterity. Certain subtypes of CMT may require special management due to their unique pathophysiologic characteristics. This is typified by HNPP that exhibits susceptibility to mechanical stress. Our studies suggest that nerve dysfunction can not only be provoked by compression but also evoked by repetitive use of the affected limbs or stretching. Extraneous physical activities can even induce limb paralysis. The patients thus should be advised to take precaution in activities that might stress the peripheral nerves. Pain is rarely an initial symptom of patients with CMT, probably because the mutations affect genes encoding proteins primarily expressed in the myelinated nerve fibers, not in the nonmyelinated nerve fibers that convey the signals of pain. However, in our experience, most patients with CMT suffer from pain during the course of their diseases. The pain often appears from joints or ligaments, rather than any typical neuropathic pain. Nonsteroids might be partially helpful. In addition, the pain may also be improved by strengthening weak ankles, correcting foot deformities, or using custom-made shoes to restore the balance of gait. Diseased peripheral nerves in patients with CMT appear particularly sensitive to the side effect of medications. In general, medications that have clear neurotoxic effects, such as vincristine or cis-platinum, should be avoided if medically possible because they are likely to exacerbate the existing neuropathy. There have been reports of severe weakness developed in patients with CMT who were given vincristine. For other medications, the situation is less clear. The Charcot-Marie-Tooth Association publishes a list of medications that may exacerbate CMT on their Web site. The degree of risk varies with the individual medication, and in some cases, the risk may be small compared to the medical need. Good judgment by the physician on the risk/benefit ratio of a given medication can probably serve as a useful guide for the use of these medicines.

SUMMARY With advances in medical genetics and molecular biology, the clinical spectrum of inherited neuropathies has been drastically expanded. After the new genera-

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tion of rapid whole-genome exon sequencers becomes available, discovery of new mutations causal of CMT is expected to accelerate dramatically. Thus far, there have been at least 36 genes known to cause inherited neuropathies, and more than 53 distinct loci have been identified. Genetic testing for over 10 forms of CMT is now available, which significantly facilitates accurate diagnosis in patients with CMT. This large repertoire of human mutations of CMT behaves like “a natural library of genetic models.” It will undoubtedly teach us how mutated proteins cause demyelination, axonal degeneration, and alterations of Schwann cell–axonal signaling, which should, in turn, advance our understanding of the basis of neurologic diseases. Moreover, increased understanding of the molecular mechanisms underlying these pathways will provide targets for future therapeutic intervention.

References   1. Dyck PJ, Lambert EH. Lower motor and primary sensory neuron diseases with peroneal muscular atrophy. I. Neurologic, genetic, and electrophysiologic findings in hereditary polyneuropathies. Arch Neurol. 1968;18:603–618.   2. Lupski JR, Reid JG, Gonzaga-Jauregui C, et al. Wholegenome sequencing in a patient with Charcot-Marie-Tooth neuropathy. N Engl J Med. 2010;362:1181–1191.   3. Thomas PK, Marques W Jr, Davis MB, et al. The phenotypic manifestations of chromosome 17p11.2 duplication. Brain. 1997;120( Pt 3):465–478.   4. Krajewski KM, Lewis RA, Fuerst DR, et al. Neurological dysfunction and axonal degeneration in Charcot-MarieTooth disease type 1A. Brain. 2000;123( Pt 7):1516–1527.   5. Shy ME, Jani A, Krajewski K, et al. Phenotypic clustering in MPZ mutations. Brain. 2004;127:371–384.   6. Li J, Bai YH, Anokova E, et al. Major myelin protein gene (P0) mutation causes a novel form of axonal degeneration. J Comp Neurol. 2006;498:252–265.   7. Bai YH, Ianokova E, Pu Q, et al. R69C mutation in P0 gene alters myelination and ion channel subtypes. Arch Neurol. 2006;63:1787–1794.   8. Street VA, Bennett CL, Goldy JD, et al. Mutation of a putative protein degradation gene LITAF/SIMPLE in CharcotMarie-Tooth disease 1C. Neurology. 2003;60:22–26.   9. Lupski JR, Oca-Luna RM, Slaugenhaupt S, et al. DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell. 1991;66:219–232. 10. Raeymaekers P, Timmerman V, Nelis E, et al. Estimation of the size of the chromosome 17p11.2 duplication in Charcot-Marie-Tooth neuropathy type 1a (CMT1a). HMSN Collaborative Research Group. J Med Genet. 1992;29: 5–11. 11. Chance PF, Alderson MK, Leppig KA, et al. DNA deletion associated with hereditary neuropathy with liability to pressure palsies. Cell. 1993;72:143–151. 12. Nicholson GA, Valentijn LJ, Cherryson AK, et al. A frame shift mutation in the PMP22 gene in hereditary neuropathy with liability to pressure palsies. Nat Genet. 1994;6: 263–266. 13. Li J, Ghandour K, Radovanovic D, et al. Stoichiometric alteration of PMP22 protein determines the phenotype of HNPP. Arch Neurol. 2007;64:974–978.

14. Hayasaka K, Takada G, Ionasescu VV. Mutation of the myelin P0 gene in Charcot-Marie-Tooth neuropathy type 1B. Hum Mol Genet. 1993;2:1369–1372. 15. Martini R, Mohajeri MH, Kasper S, Giese KP, Schachner M. Mice doubly deficient in the genes for P0 and myelin basic protein show that both proteins contribute to the formation of the major dense line in peripheral nerve myelin. J Neurosci. 1995;15:4488–4495. 16. Warner LE, Mancias P, Butler IJ, et al. Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies. Nat Genet. 1998;18:382–384. 17. Lewis RA, Sumner AJ. The electrodiagnostic distinctions between chronic familial and acquired demyelinative neuropathies. Neurology. 1982;32:592–596. 18. Lewis RA, Sumner AJ, Shy ME. Electrophysiological features of inherited demyelinating neuropathies: a reappraisal in the era of molecular diagnosis. Muscle Nerve. 2000;23:1472–1487. 19. Gutierrez A, England JD, Sumner AJ, et al. Unusual electrophysiological findings in X-linked dominant CharcotMarie-Tooth disease. Muscle Nerve. 2000;23:182–188. 20. Gabreels-Festen A, Wetering RV. Human nerve pathology caused by different mutational mechanisms of the PMP22 gene. Ann N Y Acad Sci. 1999;883:336–343. 21. Webster HD, Schroder JM, Asbury AK, Adams RD. The role of Schwann cells in the formation of “onion bulbs” found in chronic neuropathies. J Neuropathol Exp Neurol. 1967;26: 276–299. 22. Hall SM. The response of the (myelinating) Schwann cell population to multiple episodes of demyelination. J Neurocytol. 1983;12:1–12. 23. Saporta MA, Katona I, Lewis RA, Masse S, Shy ME, Li J. Shortened internodal length of dermal myelinated nerve fibres in Charcot-Marie-Tooth disease type 1A. Brain. 2009;132:3263–3273. 24. Vallat JM, Sindou P, Preux PM, et al. Ultrastructural PMP22 expression in inherited demyelinating neuropathies. Ann Neurol. 1996;39:813–817. 25. Li J, Bai Y, Ghandour K, et al. Skin biopsies in myelinrelated neuropathies: bringing molecular pathology to the bedside. Brain. 2005;128:1168–1177. 26. Katona I, Wu X, Feely SM, et al. PMP22 expression in dermal nerve myelin from patients with CMT1A. Brain. 2009;132:1734–1740. 27. Bergoffen J, Scherer SS, Wang S, et al. Connexin mutations in X-linked Charcot-Marie-Tooth disease. Science. 1993;262:2039–2042. 28. Balice-Gordon RJ, Bone LJ, Scherer SS. Functional gap junctions in the Schwann cell myelin sheath. J Cell Biol. 1998;142:1095–1104. 29. Tabaraud F, Lagrange E, Sindou P, Vandenberghe A, Levy N, Vallat JM. Demyelinating X-linked Charcot-Marie-Tooth disease: unusual electrophysiological findings. Muscle Nerve. 1999;22:1442–1447. 30. Hahn AF, Ainsworth PJ, Bolton CF, Bilbao JM, Vallat JM. Pathological findings in the x-linked form of Charcot-MarieTooth disease: a morphometric and ultrastructural analysis. Acta Neuropathol. 2001;101:129–139. 31. Li J, Krajewski K, Lewis RA, Shy ME. Loss-of-function phenotype of hereditary neuropathy with liability to pressure palsies. Muscle Nerve. 2004;29:205–210. 32. Horowitz SH, Spollen LE, Yu W. Hereditary neuropathy with liability to pressure palsy: fulminant development

116  Textbook of Peripheral Neuropathy with axonal loss during military training. J Neurol Neurosurg Psychiatry. 2004;75:1629–1631. 33. Madrid R, Bradley G. The pathology of neuropathies with focal thickening of the myelin sheath (tomaculous neuropathy): studies on the formation of the abnormal myelin sheath. J Neurol Sci. 1975;25:415–448. 34. Bai Y, Zhang X, Katona I, et al. Conduction block in PMP22 deficiency. J Neurosci. 2010;30:600–608. 35. Li J, Krajewski K, Shy ME, Lewis RA. Hereditary neuropathy with liability to pressure palsy: the electrophysiology fits the name. Neurology. 2002;58:1769–1773. 36. Zuchner S, Mersiyanova IV, Muglia M, et al. Mutations in the mitochondrial GTPase mitofusin 2 cause CharcotMarie-Tooth neuropathy type 2A. Nat Genet. 2004;36: 449–451. 37. Verhoeven K, De JP, Coen K. et al. Mutations in the small GTP-ase late endosomal protein RAB7 cause CharcotMarie-Tooth type 2B neuropathy. Am J Hum Genet. 2003;72: 722–727. 38. Deng HX, Klein CJ, Yan J, et al. Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4. Nat Genet. 2010;42:165–169. 39. Landoure G, Zdebik AA, Martinez TL, et al. Mutations in TRPV4 cause Charcot-Marie-Tooth disease type 2C. Nat Genet. 2010;42:170–174. 40. AntonelliS A, Ellsworth RE, Sambuughin N, et al. Glycyl tRNA synthetase mutations in Charcot-Marie-Tooth disease type 2D and distal spinal muscular atrophy type V. Am J Hum Genet. 2003;72:1293–1299. 41. Sivakumar K, Kyriakides T, Puls I, et al. Phenotypic spectrum of disorders associated with glycyl-tRNA synthetase mutations. Brain. 2005;128:2304–2314. 42. Evgrafov OV, Mersiyanova I, Irobi J, et al. Mutant small heat-shock protein 27 causes axonal Charcot-Marie-Tooth disease and distal hereditary motor neuropathy. Nat Genet. 2004;36:602–606. 43. Irobi J, Van IK, Seeman P, et al. Hot-spot residue in small heat-shock protein 22 causes distal motor neuropathy. Nat Genet. 2004;36:597–601.

44. Mersiyanova IV, Ismailov SM, Polyakov AV, et al. Screening for mutations in the peripheral myelin genes PMP22, MPZ and Cx32 (GJB1) in Russian Charcot-Marie-Tooth neuropathy patients. Hum Mutat. 2000;15:340–347. 45. Bolis A, Zordan P, Coviello S, Bolino A. Myotubularinrelated (MTMR) phospholipid phosphatase proteins in the peripheral nervous system. Mol Neurobiol. 2007;35:308–316. 46. Chow CY, Zhang Y, Dowling JJ, et al. Mutation of FIG4 causes neurodegeneration in the pale tremor mouse and patients with CMT4J. Nature. 2007;448:68–72. 47. Zhang X, Chow CY, Sahenk Z, Shy ME, Meisler MH, Li J. Mutation of FIG4 causes a rapidly progressive, asymmetric neuronal degeneration. Brain. 2008;131:1990–2001. 48. Boerkoel CF, Takashima H, Stankiewicz P, et al. Periaxin mutations cause recessive Dejerine-Sottas neuropathy. Am J Hum Genet. 2001;68:325–333. 49. Bomont P, Cavalier L, Blondeau F, et al. The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family, is mutated in giant axonal neuropathy. Nat Genet. 2000;26:370–374. 50. Chance PF, Lensch MW, Lipe H, Brown RH Sr, Brown RH Jr, Bird TD. Hereditary neuralgic amyotrophy and hereditary neuropathy with liability to pressure palsies: two distinct genetic disorders. Neurology. 1994;44:2253–2257. 51. Kuhlenbaumer G, Hannibal MC, Nelis E, et al. Mutations in SEPT9 cause hereditary neuralgic amyotrophy. Nat Genet. 2005;37:1044–1046. 52. England JD, Gronseth GS, Franklin G, et al. Practice parame­ ter: evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence-based review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology. 2009;72:185–192. 53. Patzko A, Shy me. Update on Charcot-Marie-Tooth disease. Curr Neurol Neurosci Rep. 2011;11:78–88. 54. Reilly MM, Shy ME. Diagnosis and new treatments in genetic neuropathies. J Neurol Neurosurg Psychiatry. 2009;80: 1304–1314.

Mark B. Bromberg and Alexander A. Brownell

9

Role of Electrodiagnosis in the Evaluation of Peripheral Neuropathies

Abstract

Anatomy

This chapter considers the role of electrodiagnosis in the evaluation of peripheral neuropathies. Electrodiagnostic testing permits an assessment and estimate of underlying nerve pathology in terms of distribution and extent of involvement, type of nerve damage, and time course. These data supplement clinical information, leading to a more full characterization of the neuropathy, formulation of a sound differential diagnosis, and selection of rational tests. In this chapter, we first discuss principles of nerve conduction and needle electromygraphy studies. We then apply them to a range of neuropathies illustrating the distinguishing and diagnostic features. Also included are sections on planning studies and interpreting outside studies.

A nerve (whole nerve) consists of individual nerve fibers of many types bundled together. They can be divided by function into somatic and autonomic fibers and, within each type, into motor and sensory fibers. They can also be divided by size because nerve fibers consist of axons of varying diameters that are insulated by myelin, thick and tightly wrapped for myelinated fibers and thin and loosely wrapped for unmyelinated fibers. The functional and electrodiagnostic implication of different nerve fiber diameters and their degree of myelination is variation in nerve fiber conduction velocities. Myelinated fibers have faster velocities due to saltatory conduction (30–60 m/s), while unmyelinated fibers conduct relatively slowly (1 millisecond), resulting in less phase cancellation and a larger SNAP amplitude (6). While muscle fiber action potentials also lengthen in duration, the effect on CMAP amplitude is negligible. For both, the lower nerve temperature slows conduction (increases distal latency and slows conduction velocity). To stimulate a nerve, 2 electrodes, cathode and anode, are applied to the skin over the nerve, and with activation, current flows from the anode to the cathode. The goal is to activate all axons to record a maximal SNAP or CMAP response. Axons are depolarized beneath the cathode and hyperpolarized beneath the anode. It is important to place the cathode along the nerve closest to the recording site, for if the anode is placed between the cathode and the recording site, 2 issues occur. The first is that measured distances between recording and stimulating electrodes can be approximately 3 to 4 cm greater (distance between the electrodes) if there is confusion about the electrode poles, leading to artificially longer distal latencies or slowed conduction velocities. The other is the phenomenon of anodal block that can cause partial conduction block along the nerve due to hyperpolarization of some axons under the anode, leading to artificially lower CMAP amplitudes. Nerve conduction studies yield 2 types of metrics that can help distinguish between pathology affecting axons or myelin (Figure 9.2). One is the amplitude of the evoked response, and the other is the set of measures of timing. The amplitude of the SNAP and CMAP is roughly proportional to the number of axons conducting between the stimulating and recording electrodes. With progressive axonal loss, CMAP amplitude will drop more slowly than SNAP amplitude owing to the effects of collateral reinnervation of motor nerves (to be discussed later). The timing measures generally reflect activity of the fastest myelinated fibers and include distal latency (conduction over set or standardized distances), F wave latency (conduction over whole length of motor nerves), and conduction velocity (over segments of nerve). The duration of the CMAP waveform provides an estimate of more slowly conducting myelinated fibers.

Basic mechanics of needle EMG In needle EMG, an electrode is inserted into muscle, and electrical activity from muscle fibers is recorded to assess the integrity of muscle fibers and their architecture within the muscle (7). The electrical motor unit

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Figure 9.1 Effects of temporal dispersion on the waveforms of sensory (top set) and motor (lower set) nerve responses. Stimulation sites for both top and bottom sets of waveforms: A1, wrist; A2, below elbow; A3, above elbow; A4, axilla; A5, Erb point. Top set: sensory nerve action potential (SNAP). Bottom set: compound motor nerve action potential (CMAP). Insets to the right of waveforms show mechanism of phase cancellation in the summation of nerve fiber action potentials to form SNAP and muscle fiber action potentialsto form CMAP. Solid-line waveforms indicate fastest fiber action potentials, and dashed-line waveforms indicate slowest fiber action potentials; waveform to right of arrow represents summation of all action potentials. recorded by the EMG needle is called the motor unit action potential (MUAP) and represents only a portion of the anatomic motor unit as the electrical uptake area of the electrode is less than 1.5 mm in diameter. Thus, the MUAP includes only about 7 to 15 fibers of the anatomic motor unit. During voluntary activation of the muscle,

the number of active motor units increases from zero at rest to larger numbers with increasing voluntary activation of the muscle. Most routine EMG studies are performed at low levels of activation so that individual MUAPs can be observed. Accordingly, during low levels of activation, the needle electrode will record at a given

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Figure 9.2 A: Nerve conduction waveform metrics, applicable to both CMAP and sensory SNAP. These include distal latency, negative peak duration, negative peak amplitude, and area. B and C: Relative preservation of CMAP amplitude with proximal stimulation; method of calculating segmental conduction velocity. D, E, and F: Rapid loss of SNAP amplitude with proximal stimulation. site in the muscle from 3 to 5 MUAPs close to the needle. The waveform of the MUAPs will vary with slight needle movement based on the proximity of the needle tip to muscle fibers within the anatomic motor unit (8). Needle EMG studies are performed in 2 stages, with the goals of determining whether there is axonal loss, the degree of loss, and the chronicity of the process (Figure 9.3). The first stage is assessment for the presence of abnormal spontaneous muscle fiber activity when the muscle is at rest, and the second is assessment of MUAPs during voluntary activation of the muscle. The presence of abnormal spontaneous activity in the form of positive waves and fibrillation potentials (the different waveforms are of equal clinical significance) indicates denervation and, in the context of a peripheral neuro­pathy, axonal loss (neurogenic denervation) (9). Very long-standing and slowly progressive denervation is suggested when most of positive waves and fibrillation potentials are of very low amplitude, less than 50 µV. With low levels of muscle activation, the MUAP recruitment pattern can be assessed for discharge frequen-

cies, and higher rates support motor unit loss. Motor unit action potential waveforms can be inspected for increased amplitude and complexity in terms of polyphasia (greater than 4 phases) or polyturns (greater than 5 turns). In the context of a neuropathy, when denervation of muscles occurs, the remaining motor nerve fibers sprout collateral branches to reinnervate orphaned muscle fibers, and the anatomic motor unit increases in muscle fiber density but not in area. Reinnervated muscle fibers no longer discharge spontaneously, but within a muscle, abnormal spontaneous activity usually persists because the degree of collateral reinnervation is limited and subsequent denervation leads to permanently orphaned (denervated) muscle fibers. With reinnervation, the increased density of the anatomic motor unit is reflected in larger and more complex MUAP waveforms. In neuropathies that are progressing relatively rapidly, there will be ongoing denervation, marked by abnormal spontaneous activity, moderate to severe decreased recruitment, and complex MUAPs. In very slowly progressive neuropathies, there is sufficient time for

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Figure 9.3 Pattern of needle EMG changes from normal to ongoing to very chronic neuropathies. Columns on the left show electromyographic activity at rest, while columns at the right show motor unit action potential (MUAP) activity at low levels of muscle activation. Top: Normal muscle with absence of abnormal spontaneous activity and normal recruitment pattern and MUAP waveforms. Middle: Mild neurogenic changes with abnormal spontaneous activity and reduced MUAP recruitment and complex waveforms. Bottom: Very chronic neuropathy with low-amplitude abnormal spontaneous activity and very reduced MUAP numbers with high-amplitude and simple waveforms. maximal reinnervation; positive waves and fibrillation potentials from permanently orphaned muscle fibers will be of very low amplitude; and the motor units will be few in number and of high amplitude but will not be markedly complex as there has been sufficient time for the waveform to simplify. When MUAPs are observed whose amplitudes are 5 to 10 times the normal, consideration should be given for a hereditary neuropathy, the most slowly evolving form of neuropathy. The extent of denervation can be assessed by identifying the most proximal muscle with needle EMG abnormalities (10).

Limits of normal As with most biologic data, “normal limits” are defined from distributions of values from subjects who have no apparent disease that would affect the results. The pool of subjects should include a wide spectrum of ages and body sizes (height and weight). How limits of normal are set is controversial, but most laboratories use upper or lower limits (upper limit of normal [ULN] of distal latency and F wave latency, lower limit of normal [LLN] for amplitude and conduction velocity) set at 2 to 3 standard deviations. However, data for the different nerve conduction metrics may not be normally distributed, and other limits such as confidence intervals may be more appropriate (11). While it is preferable for each laboratory to gather its own normal data, this is rarely done. Most limits are handed down, and their origins are obscure. Since limits are statistical, some patient values may be close to the limits of normal and may be misinterpreted. Examples include the following: (1) questionably abnormal, mildly slow conduction velocities or mildly prolonged F wave latencies from the lower limb of a very tall individual because longer nerves are thinner and conduct more slowly; and (2) questionably normal, amplitude or conduction velocity values just

above the LLN but expected to be much higher if the nerve was truly normal. Thus, ULN and LLN should be viewed as reference and not absolute values and interpreted in the overall clinical context.

Nerve pathology and its electrodiagnostic manifestations Nerve conduction tests help in distinguishing 3 basic conditions of peripheral nerves (Figure 9.4) (12). The first state is normal conduction; this is seen when the vast majority of nerve fibers are myelinated and the axons intact. The second situation is axonal injury; this is seen when the primary injury to is to axons. Axonal damage disconnects fibers from their receptors (sensory nerves) or muscles (motor nerves). Subsets of fibers may be affected, and the remaining unaffected fibers conduct normally, or all fibers may be affected in severe neuropathies. Generally, axonal loss occurs at the distal ends of fibers, a process called “axonal dying-back.” The third case is caused by loss of myelin or alteration of impulse propagation; this results in slowing of conduction velocities or slowing to zero (conduction block). Demyelination generally occurs at multiple focal sites along a nerve. Slowed conduction velocity causes greater dispersion of arrival times of nerve action potentials at the recording electrode (abnormal temporal dispersion). Of note, there can be mixed patterns with primary demyelination and secondary axonal loss. Finally, there may be slowed conduction from reversible metabolic causes or from effects of immune mechanisms, with no obvious damage to myelin.

Normal Conduction The waveforms of SNAP and CMAP are influenced by normal temporal dispersion. The amplitude of SNAP falls markedly over greater distances, while CMAP

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amplitude falls minimally, and the negative peak duration increases minimally (Figure 9.4) (12). It is for this reason that most nerve conduction studies do not measure proximal sensory nerve amplitudes or conduction velocities. Normal conduction is defined as values within the laboratory limits of normal. Distal latency, F wave latency, and conduction velocity are influenced by limb length, limb temperature, and age.

Axonal Injury

Figure 9.4 Stylized comparisons between nerve conduction findings in primarily axon and primarily demyelinating neuropathies. Differences in CMAP between waveforms when stimulating at distal and proximal sites (proximal-to-distal amplitude ratio). Normal: Short distal latency and short latency from proximal stimulation site yields normal conduction velocity. There is normal temporal dispersion with very small reduction in CMAP amplitude to proximal stimulation (normal ratio). Primary axonal loss: Distal latency and latency from proximal stimulation site only slightly longer owing to loss of rapidly conducting fibers with normal ratio. Primary demyelination: Distal latency prolonged and conduction velocity slowed. Ratio of proximal to distal amplitude low due to phase cancellation.

Loss of axons results in fewer nerve fibers reaching the recording electrode and reduction in both SNAP and CMAP amplitudes. The SNAP amplitude is especially sensitive to axon loss owing to the lack of compensatory collateral reinnervation. Essentially, there is a linear relationship between the number of axons lost and the amplitude of the SNAP. The CMAP amplitude, in contrast, is less sensitive to early axonal owing to the supportive effects of collateral reinnervation. With mild denervation, collateral reinnervation keeps the number of innervated muscle fibers high, and the CMAP amplitude remains high, but with either further axonal loss or a very rapid rate of loss, greater numbers of muscle fibers remain denervated, and the CMAP amplitude falls. It is important to note that the effects of collateral sprouting can, in some cases, maintain CMAP amplitude above the LLN until more than 80% of axons are lost. In these cases, needle EMG can detect the effects of motor unit enlargement and verify that axonal loss has occurred. With axonal loss, each remaining nerve fiber conducts at its innate speed. Thus, measures of timing (distal latency, F wave latency, and conduction velocity) are reduced only to the extent of loss of large axons (Figure 9.4) (12). The degree of slowing in axonal neuropathy can be empirically assessed by reviewing data from patients with amyotrophic lateral sclerosis (ALS), a disorder characterized by reduced numbers of axons with no predilection to size: the distal latency and F wave latency are rarely longer than 125% of the ULN, and conduction velocity, rarely slower than 75% of the LLN (13). Temporal dispersion, as measured by negative CMAP peak duration, is largely unaffected in axonal neuropathies. Overall, with moderate to major axonal loss, the SNAP response will be absent and thus provide no information about conduction velocity.

Demyelination Multifocal demyelination affects nerve conduction at multiple regions along nerve fibers and nerve roots, resulting in some degree of slowed conduction in affected fibers. Thus, distal latency and F wave latency will be prolonged, and conduction velocity, slowed. The increased variability of nerve fiber conduction velocity results in abnormal temporal dispersion that is reflected in SNAP or CMAP with lower amplitude and longer duration than would be expected when evoked by stimulation

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at proximal sites (Figure 9.4) (12). The wider variation in nerve fiber conduction velocities leads to greater degrees of phase cancellation within the SNAP and CMAP waveform, causing low-amplitude responses. The sites of demyelination are generally not uniformly distributed along the length of a nerve, and thus, the effects of multifocal demyelination can best be demonstrated by measurements over longer nerve conduction distances. Abnormal temporal dispersion can markedly reduce SNAP amplitude, frequently to zero, and thus motor, responses are more robust and more commonly used to assess abnormal temporal dispersion. Conduction of individual nerve fibers may be infinitely slowed (conduction block), which can contribute to the reduction in the response amplitude. The degree of temporal dispersion can be measured in the CMAP waveform by the ratio of the amplitude or area of the proximal to the distal response (P:D ratio); however, the P:D ratio can also be affected by conduction block of axons between the 2 stimulation sites. A more direct measure is the CMAP negative peak duration value, comparing values from the proximal to the distal response; normally, the negative peak duration increases by less than 10% even over long distances (CMAP from Erb point stimulation compared to wrist stimulation [Figures 9.1, 9.2, 9.3]) (14). There is one important clinical exception with slowed conduction velocity without abnormal temporal dispersion. In certain hereditary neuropathies such as CharcotMarie-Tooth type 1, there is uniform slowing along the nerve (15). Thus, the CMAP amplitude does not markedly fall between distal and proximal stimulation sites (Figure 9.5), and the P:D ratio remains high. This is due to changes to myelin uniformly distributed all along nerve fibers. Conduction can also be mildly slowed by metabolic causes that do not affect myelin structurally, and diabetic neuropathies frequently show this pattern. There have been many efforts to design sets of nerve conduction criteria that can distinguish between pri-

mary axonal and primary demyelination in terms of the degree of slowing. The degree of demyelination is variable: when mild, there will be only small prolongations in distal and F wave latency and slowing of conduction velocity that may be within (or just beyond) normal limits. When more marked, there will be slowing greater than expected for the degree of axonal loss, and the amount of slowing can be referred back to timing values from patients with ALS (13). The published criteria are complex to apply, and a more simple set of guidelines, based on the degree of slowing in ALS, is in Table 9.1. These guidelines are not intended to be strict or exclusive but serve as a guide for when to consider a demyelinating component to a neuropathy.

Focal Conduction Block Conduction block refers to blockage of a large number of axons over a short segment of nerve. Focal conduction block occurs most frequently at sites of entrapment (median nerve at the wrist [carpal tunnel syndrome], ulnar nerve at the elbow [tardy ulnar palsy], peroneal nerve at the knee), resulting in mononeuropathies. In the context of peripheral neuropathies, focal conduction block is sought at sites away from entrapment sites. The pathology may represent focal demyelination (or alteration to myelin at the node of Ranvier) or block by other mechanisms such as alteration or block of membrane ion channels (16,17). Focal conduction block can be demonstrated by showing loss of CMAP amplitude across the site of block and normal amplitudes along nerve segments proximal and distal to the site. The blocking mechanism can be very specific, with block only of motor axons, with sensory axons unaffected, leading to the term multifocal motor neuropathy with conduction block (MMN) (18). There are other neuropathies with block of both motor and sensory fibers (Lewis-Sumner

Figure 9.5 Changes in CMAP waveforms with conduction over longer distances, with stimulation at the wrist, below the elbow, and above the elbow. Left: Normal waveforms. Middle: Waveforms from primary demyelinating neuropathy showing the effects of abnormal temporal dispersion. Right: Waveforms from Charcot-Marie-Tooth type 1 with uniform slowing and normal temporal dispersion.

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Table 9.1  Electrodiagnostic Guidelines Based on Findings From Patients With Amyotrophic Lateral Sclerosis* Distal latency: >125% of ULN Conduction velocity: 125% of ULN CMAP negative peak duration (measured as return of baseline of last negative peak): median nerve, >6.6 milliseconds ulnar nerve, >6.7 milliseconds peroneal nerve, >7.6 milliseconds tibial nerve, >8.8 milliseconds Prolonged proximal-to-distal negative CMAP peak duration: >30% *With the addition of other features that can be applied easily to help identify patients with greater slowing than expected for the degree of axonal loss. Abbreviations: CMAP, compound muscle action potential; LLN, lower limit of normal; ULN, upper limit of normal. Source: Cornblath et al (13) and Isose et al (19).

syndrome) (20). While the electrodiagnostic hallmark of conduction block is reduction of the CMAP across the site of block, the effects of abnormal temporal dispersion can also produce CMAP reductions due to increased phase cancellation that may be misinterpreted as conduction block. Pure focal conduction block has been defined as a more than 50% reduction of CMAP amplitude across the site of block without an increase in negative peak CMAP duration (60

1 2

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MRC sum score (at day 7 of admission) 51–60 41–50 31–40 0–30

0 3 6 9

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mEGOS

0–12

Abbreviations: mEGOS, modified Erasmus GBS Outcome Score; MRC, Medical Research Council. a Diarrhea in the 4 weeks preceding the onset of weakness. Source: Walgaard et al (132).

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10 11 12

Figure 12.3 Predicted fraction of patients unable to walk independently according to the mEGOS. Black line: predicted fraction of patients unable to walk independently at 4 weeks. Red line: predicted fraction of patients unable to walk independently at 3 months. Green line: predicted fraction of patients unable to walk independently at 6 months. Predictions based on mEGOS at hospital admission (A) and at day 7 of admission (B). The gray areas around the colored lines represent 90% CIs. Reprinted from Walgaard et al, Neurology, 2011 (132).

during IVIg treatment, particularly for patients at risk for renal tubular necrosis. Diluting the IVIg preparation, slowing the rate of infusion, and selecting products with low osmolality lessen the risk (136,137). The prevalence of selective IgA deficiency is 1:1000. When patients with IgA deficiency receive IVIg, the IgA in the IVIg may trigger an anaphylactic reaction. However, this is a rare complication occurring most frequently in patients with common variable immunodeficiency. Routine screening for IgA deficiency before treating a GBS patient with IVIg is not justified (137,138) when it would impose an undesirable delay in initiation of treatment. Thromboembolic events, including stroke and myocardial infarction, are rare during IVIg administration. The risk of a thromboembolic event was increased in one cohort of elderly individuals with 4 or more cardiovascular risk factors (eg, diabetes, hyperlipidemia, hypertension, smoking, coronary artery disease) (134). Corticosteroids Corticosteroid treatment is ineffective for treating GBS (114,131,139,140). In a Cochrane systematic review of 6 trials with 587 patients, the overall evidence showed no significant difference between the corticosteroid and noncorticosteroid treated patients in disability grade (140). In 4 trials of oral corticosteroids with 120 patients, there was significantly less clinical improvement after 4 weeks in patients treated with corticosteroids than without corticosteroids, suggesting that oral corticosteroids may slow recovery. Intravenous methylprednisolone alone does not produce significant benefit or harm. In combination with IVIg, intravenous methylprednisolone (eg, 500 mg/d for 5 days, administered within 48 hours of first dose of IVIg) may hasten recovery but does not appear to significantly affect the long-term outcome (140,141). Immunoadsorption Therapy Immunoadsorption therapy is an alternative technique to PE that does not require using a human blood prod-

uct as a replacement fluid, thereby reducing risk of infection or allergic reaction (142–144). Immunoadsorption removes immunoglobulins from the circulation without need for replacement with albumin or fresh frozen plasma because of the lower loss of albumin compared with PE. In one study, there were no differences in outcome between 13 patients with GBS treated with immunoadsorption and 11 patients treated with PE (144). There was also no difference observed in clinical outcome in a retrospective review of patients with GBS treated either with immunoadsorption, PE, and doublefiltration plasmapheresis. Fewer complications were reported with immunoadsorption (142). Combined Therapies PE followed by IVIg was shown to provide no statistically significant additional benefit compared with PE alone or IVIg alone (6). Immunoadsorption followed by IVIg also appears to be no more effective than IVIg alone (144). In 2003, the Quality Standards Subcommittee of the AAN did not recommend sequential treatment with PE followed by IVIg or immunoadsorption followed by IVIg (114).

Treatment of GBS Relapse Relapses of GBS, known as GBS treatment-related fluctuations (GBS-TRF), occur in ~10% of patients with GBS following PE or IVIg therapy. Rate of relapse is similar for PE and IVIg (5,6,12,145,146). The relapsing patient should probably be treated with the same treatment if that initial treatment was tolerated and thought to be efficacious the first time it was given. A longer interval between onset and treatment (145) and longer time to nadir (146) may be associated with a greater chance of relapse, but these associations likely reflect the characteristics of a patient’s immune activation more than the timing of immunotherapy. For instance, some patients initially diagnosed with GBS—with preceding infectious episode,

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abrupt onset of neuropathic symptoms and progression to clinical nadir within 4 weeks—are later rediagnosed as having acute CIDP (A-CIDP) because of persistence of active demyelination caused by an ongoing autoimmune process (147). The diagnosis of A-CIDP should be strongly considered if the patient deteriorates 8 weeks after onset or if there are 3 or more deteriorations (148). Additionally, patients with relapses who retain the ability to walk and have limited cranial nerve dysfunction are relatively more likely to have A-CIDP (148). It is also occasionally challenging to determine whether persistent deficits are caused by ongoing autoimmunity and demyelination or by secondary, residual axonal damage of previously active GBS. In such instances, repeat EDX testing might be helpful, and if testing suggests ongoing demyelination, CIDP, and treatment for CIDP (eg, corticosteroids) should be considered (147).

Treatment of MFS Untreated patients with MFS generally recover completely within months (66,71,77,147,149,150). Patients with MFS or a variant of MFS (eg, BBE) are frequently treated with immunotherapy (eg, PE, IVIg), but no randomized trials of immunotherapy for these conditions have been published (66,150), and it is unknown whether immunotherapy hastens recovery or improves outcome in these patients. Clinical recovery was recently analyzed retrospectively for 92 patients with MFS (147). IVIg appeared to slightly hasten the start of amelioration of ophthalmoplegia and ataxia compared with PE or conservative therapy, but the times to disappearance of symptoms were similar for all 3 groups. Furthermore, at 1 year, only 4 (4%) patients with MFS had residual symptoms (3 with diplopia, 1 with diplopia and ophthalmoplegia). Of the 4 patients who were not asymptomatic at 1 year, 1 had received IVIg, 2 had been treated with PE and 1 had received conservative treatment. Patients with mild or uncomplicated MFS may perhaps be treated conservatively (147). Patients with a more severe or complicated “anti-GQ1b antibody syndrome,” such as patients with BBE or with overlapping GBS, should probably be treated with immunotherapy (66,147).

SUPPORTIVE CARE Even with immunotherapy, mortality from GBS is approximately 5% and may be as high as 20% for ventilated patients (151). Diligent supportive care is essential to minimizing risk of mortality (21,23). Supportive care consensus guidelines have recently been published (23).

Monitoring and Management for Respiratory Failure Neuromuscular respiratory failure requiring mechanical ventilation occurs in 20% to 30% of GBS patients

(3,4,6,7,21,23–29). The neurologist must monitor for clinical signs of impending respiratory failure, including tachypnea, use of accessory muscles of respiration, asynchronous movements of the chest and abdomen, and tachycardia (23). Days between onset and admission, presence of facial and/or bulbar weakness, and Medical Research Council (MRC) sum scores are the main predictors of need for mechanical ventilation (152). The Erasmus GBS Respiratory Insufficiency Score (EGRIS) model was developed after analysis of a derivation cohort of 397 patients and validation cohort of 191 patients. In this model, points are assigned for days between onset and admission, presence or absence of facial and/or bulbar weakness at hospital admission, and MRC sum score of 6 muscles groups tested bilaterally at hospital admission. The 6 muscle groups used for the MRC sum score were shoulder abductors, elbow flexors, wrist extensors, hip flexors, knee extensors, and foot dorsiflexors. Table 12.4 outlines how to calculate the EGRIS (152). Prediction of need for mechanical ventilation within 1 week of admission can be determined from the EGRIS score as shown in Figure 12.4 (152). A vital capacity below 20 mL/kg, maximum inspiratory pressure (PImax) lower than 30 cm H2O or maximum expiratory pressure (PEmax) lower than 40 cm H2O predicts imminent respiratory arrest (23,153–155). Time from onset to admission of less than 1 week, facial weakness, inability to cough, inability to lift head off of pillow, and atelectasis on chest radiograph are other factors

Table 12.4  Erasmus GBS Respiratory Insufficiency Score for Predicting Respiratory Insufficiency and Need for Mechanical Ventilation Measure Days between onset of weakness and hospital admission

Facial and/or bulbar weakness at hospital admission MRC sum score at hospital admission

Categories

Score

>7 4–7

0 1

=3

2

Absence Presence

0 1

60–51 50–41 40–31 30–21

0 1 2 3 4

=20 EGRIS

0–7

Abbreviations: EGRIS, Erasmus GBS Respiratory Insufficiency Score; MRC, Medical Research Counsel. Source: Ref. 152.

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Percentage respiratory insufficiency

Score plot EGRIS 100% 90% 80% 70% 60% 50% 40% 30% 20% 10%

0% Derivation set 0/11 Validation set 1/23 0

1/49 1/48

4/92 3/45

21/112 B/44

21/56 5/16

19/34 6/8

13/19 2/3

4/4 1/1

1

2

3

4

5

6

7

EGRIS

Figure 12.4 Predicted probability of respiratory insufficiency and observed percentage of mechanical ventilation in derivation and validation cohorts, according to EGRIS. The black line reflects predicted probability based on the 2 cohorts. The size of the bullets in the graph reflects the size of the patient group with the corresponding EGRIS score in the cohorts. The red line represents the observed percentage of mechanical ventilation in the derivation cohort (n = 377) and the green line represents the percentage of mechanical ventilation in the validation cohort (n = 188). Reprinted from Walgaard et al, Ann Neurol, 2010 (152).

that in other studies have been associated with respiratory failure and need for mechanical ventilation (25,156– 158). Patients with demyelinating GBS also appear to be more likely to require mechanical ventilation (157,159). GBS patients who require mechanical ventilation are at high risk of developing a significant complication such as pneumonia, tracheobronchitis, pulmonary embolus, or bacteremia (160). In some GBS patients, mechanical ventilation is indicated because of severe bulbar dysfunction causing difficulty with clearing secretions, increasing the risk of aspiration and impairing gas exchange (23,25,28,29). The mean duration of mechanical ventilation for GBS is 2 to 6 weeks (3,4,6,117,156). Weaning from the ventilator should follow improvement in serial pulmonary function tests and strength (23). The necessity and timing of tracheostomy should be based on the status of the individual in the context of an understanding that early tracheostomy improves patient comfort and airway safety and may help weaning but that tracheostomy can result in permanent disfigurement and has been associated with life-threatening complications such as hemorrhage, infection, and inadvertent dislodgement of the tube (23). Percutaneous dilatational tracheostomy may be advantageous over traditional tracheostomy by allowing less risk of accidental extubation and a better cosmetic outcome (161). The decision to perform tracheostomy may wait 2 weeks following intubation, but if at 2 weeks the

patient does not show significant improvement in pulmonary function tests and strength then tracheostomy is probably indicated. If the pulmonary function tests are improving at 2 weeks, then it may be preferable to wait 1 more week to allow an attempt at weaning from the ventilator. The ratio of an integrated pulmonary function score (VC [mL/kg] + PImax [cm H2O] + PEmax [cm H2O] calculated before intubation and then at day 12 after ventilation can be used to predict the need for tracheostomy (156). A summated pulmonary function ratio (day 12 score divided by score day before intubation) greater than 1.0 (ie, improving parameters) is predictive of weaning from ventilator before 3 weeks, whereas a score less than 1.0 (ie, worsening parameters) predicts the need for ventilation beyond 3 weeks.

Monitoring and Management for Autonomic Nervous System Dysfunction Acute autonomic dysfunction develops in the majority of patients with GBS and is a significant cause of death in these patients. Cardiac and hemodynamic disturbances are the most serious and frequent complications, but GBS patients also frequently experience dysautonomia of bowel and bladder function. Sympathetic overactivity with parasympathetic underactivity is the most frequent pattern of autonomic outflow imbalance (30–33), but other patterns are seen, even throughout the disease course of an individual patient. Severe dysautonomia may be most likely to occur in severe cases of GBS when patients are at their clinical nadir, for instance, the ventilated ICU patient (34,36,162,163), although dysautonomia may occur early in the disease and resolve when paralysis is most severe (34). Cardiac and hemodynamic disturbance manifesting as hypertension, postural hypotension, and tachycardia occur in the majority of GBS patients (32–35,164,165). Blood pressure and heart rate monitoring is strongly recommended for at least severely affected cases and should be considered for milder cases (23,33). Cardiovascular monitoring should continue until the patient has begun to clinically improve or, if the patient required ventilation, until ventilatory support has been discontinued (23). Disturbances of heart rate and blood pressure should not always be assumed to be secondary to autonomic neuropathy, particularly if sustained or if the patient’s GBS is otherwise not severe or near clinical nadir. Pulmonary embolus, sepsis, dehydration, undertreated pain, and electrolyte disturbance may need to be considered in some clinical circumstances. Tachycardia Sinus tachycardia is the most commonly encountered manifestation of dysautonomia in GBS (34). Tachycardia is usually in the 100–120 beats per minute range and of little clinical significance (34,166). However, the presence of tachycardia signifies the presence of cardiac dysrhythmia in a GBS patient and may identify patients more at risk for severe bradycardia, heart block, and

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asystole. Severe bradycardia, heart block, and asystole necessitating resuscitation and placement of a cardiac pacemaker occur infrequently (32,34,162,163). Endotracheal suction and pharmacological agents may provoke bradycardia and asystole (34,162). Hyperoxygenation before endotracheal suction minimizes the effects of severe bradycardia. Hypertension Hypertension occurs in about one third of GBS patients (34,164). Hypertension is most frequently paroxysmal but may be sustained (34). Systolic blood pressure fluctuations may be extreme (32). Episodes of hypertension may be followed by hypotension or even sudden death (32). In most cases, the hypertension is mild and transient and does not warrant specific therapy, particularly in view of the fact that some GBS patients experience labile blood pressures with hypotension following hypertension (34). If the hypertension is severe and sustained, specific therapy may be necessary. In such cases, antihypertensives with a short half-life that can be titrated should be considered (34). Hypotension Postural and episodic hypotension occurs up to one third of GBS patients (32,34). Maintenance of intravascular volume and avoidance of diuretics and other drugs that lower blood pressure, whenever possible, are important measures to minimize hypotension. GBS patients at risk for hypotension should not be left unattended in a sitting or upright position (34). Urinary Retention Urinary retention may occur in up to one third of patients (32–34). Bladder dysfunction is particularly common in GBS patients who are nonambulatory and require mechanical ventilation (34). Urinary retention is likely secondary to sacral parasympathetic nerve and pudendal motor nerve dysfunction (33–34,167) and may be managed by a sterile, closed urinary drainage system (23,34,36). Gastrointestinal Motility Gastrointestinal motility disorders occur in approximately 15% of severely affected GBS patients (34,36). Upper gastrointestinal ileus may manifest as abdominal distention, pain, and cramping. Lower gastrointestinal ileus may manifest as constipation. Ileus may occur during the acute phase of worsening motor strength or later during the plateau or recovery phase. When ileus occurs during the acute GBS phase, it is usually accompanied by other features of dysautonomia (urinary retention, tachycardia, hypertension) and is presumed to occur on the basis of autoimmune damage of the parasympathetic vagal nerve (stomach, small intestines, and much of the colon) and sacral parasympathetic nerves (distal colon). In the later phases of GBS, ileus is not associated with other dysautonomia but rather with prolonged immobility and mechanical ventilation (36). Ileus is transient

but may persist for days to weeks. Routine abdominal examination, including auscultation, measurement of abdominal girth, and abdominal radiography, should be standard for GBS patients, particularly those with other dysautonomias, and should continue for GBS patients who require mechanical ventilation (36). Dysmotility can usually be effectively managed by suspension of enteral feeds, nasogastric suctioning, and administration of erythromycin or neostigmine (23,26). Parenteral nutrition may be necessary if ileus persists for more than a few days. Rectal tubes are sometimes employed. When possible, avoidance of narcotics is also helpful in lessening dysmotility. Prophylaxis for DVT Immobilization caused by GBS is a risk factor for development of DVT and pulmonary embolus. Subcutaneous fractionated or unfractionated heparin and support stockings are recommended for nonambulatory GBS patients until they are able to walk independently (23). These recommendations are based on the evidence that subcutaneous heparin (5000 U q 12 hours) or enoxaparin (40 mg q day) reduce the incidence of DVT in acutely ill medical patients and general, orthopedic, and urologic surgical patients (168,169) and the evidence that support stockings also reduce the risk of DVT (170). Inpatient Pain Management Pain is reported in the majority of GBS patients (2,15,18,19,23) and should be treated aggressively. In one prospective study of GBS patients, 47% reported pain that was “distressing,” “horrible,” or “excruciating” (18). The most common pain complaints are deep, aching back, lower extremity pain, and dysesthetic extremity pain. Pain intensity correlated poorly with degree of disability. In this study, 75% of GBS patients required oral or parenteral opioid analgesics and 30% were treated with intravenous morphine infusions (range, 1–7 mg/h). Narcotics may exacerbate gastrointestinal dysmotility and bladder distention, so clinicians should carefully monitor for these side effects (23,36). Gabapentin (eg, 15 mg/kg/d) (171) and carbamazepine (eg, 300 mg daily) (172) are reported to be effective for pain reduction in patients with GBS. Other adjuvant therapy (eg, mexilitine, tramadol, tricyclic antidepressant medications) may also be helpful in the short- and long-term management of neuropathic pain (23). Acetaminophen or nonsteroidal anti-inflammatory agents can also be tried as first line treatment but are often ineffective (18).

Issues following acute care hospitalization for patients with GBS Inpatient Rehabilitation Approximately 40% of patients hospitalized with GBS will need inpatient rehabilitation (173). Of patients who need inpatient rehabilitation, previous requirement for mechanical ventilation and other indicators of more

CHAPTER 12: Guillain-Barré Syndrome  179

severe GBS predict a longer rehabilitation stay. Rehabilitation management approaches for patients with GBS have been borrowed from the experiences of other neuromuscular diseases and also from the experiences of managing GBS patients during the acute care hospitalization. Many of the same issues that arise during the acute hospital stay remain during the inpatient rehabilitation stay. For instance, patients with GBS following inpatient hospitalization are likely to still be at increased risk for complications secondary to weakness and immobilization (eg, DVT, decubitus ulcer, postural hypotension), sensory loss (eg, compression neuropathy), dysautonomia (eg, bladder overdistention), restrictive pulmonary function (eg, sleep hypercapnea and hypoxia, pneumonia), weight loss (eg, decubitus ulcer, compression neuropathy), and psychosocial concerns (eg, depression). Muscle weakness may be associated with muscle shortening and joint contractures, complications that may be prevented by daily range-ofmotion exercises (173). Appropriate exercise regimens are utilized during rehabilitation to improve strength. Exercise regimens should avoid overworking muscle groups, which has been associated with paradoxical weakness and impedance of recovery (174,175). Orthotics should be prescribed to maximize motor function. For patients with significant proprioceptive loss and ataxia, therapy should include techniques for sensory reintegration and repetitive exercises to improve coordination (173).

Phases of Recovery Five phases of recovery in GBS have been described: experiencing dependency, encountering helplessness, wanting to know more about GBS, discovering inner strength and regaining independence (176).

Persistent Symptoms and Disability GBS has a serious long-term impact on the patient’s work and private life, even 3 to 6 years after the illness (177,178). Recovery is usually slow and can take years. Patients and families need to be informed about the pace and extent of recovery to limit overly optimistic or pessimistic expectations. Patients experience most of the recovery during the first year, especially the first 6 months but the majority of patients continue to experience recovery well into the second year and often beyond (177,179). In one study of adult patients who were queried 1 year after onset, more than half felt that they were not yet back to baseline and were still improving (179). At 1 year, two thirds still reported some disturbed sensation and/or loss of power; in many cases, these neuropathic symptoms were considered to be moderately or seriously annoying. Of those patients who reported feeling that they were cured 1 year post-GBS (which was less than half the cohort), the mean time to the perception of cure was 230 days. After 1 year and

even during the 3 to 6 years’ follow-up period, almost half the patients from this cohort reported inability to function at home as well as before GBS and/or an alteration of leisure activity (177,179). One fifth of patients still noticed improvement occurring 2.5 to 6.5 years after GBS (177). Persistent disability is seen in 20% to 30% of adult GBS patients (7,130,157,160,179,180–183) but is much less common in children (184,185). Long-term disability in adults is more common with axonal GBS and severe GBS, for example, mechanically ventilated patients (7,23). A majority of adult patients resume work, but about one third of patients either take a less demanding job or ultimately do not return to work (177,179,182,186). Fatigue Severe fatigue is a sequela of GBS in approximately two thirds of adult patients (182,187,188). It can persist for years and is considered by most patients to be one of the most disabling residual symptoms (188). Fatigue in patients who suffered GBS is significantly associated with reduced quality of life and is independent of muscle strength, sensory impairment, functional ability, and electrophysiological findings (188,189). Fatigue appears to not be associated with the level of functional disability at nadir, antecedent infections, and time to follow-up after GBS (187). In a randomized, controlled trial of amantadine for severe fatigue following GBS, amantadine was not superior to placebo (190). There are currently no other published studies for other pharmaceutical agents, such as modafinil, for treatment of post-GBS fatigue. Another study of patients with severe fatigue 6 months to 15 years following GBS found that a 12-week bicycle exercise training program had positive effects on patient-reported fatigue, anxiety, depression, functional outcome, and quality of life. These patients performed 3 supervised sessions of bicycling per week for 12 weeks. Each session consisted of a 5-minute warm-up and 30 minutes of cycling followed by 5 to 10 minutes of cooldown cycling (191). Eighty percent of patients in this cohort were motivated to continue with regular exercise. In general, clinicians should encourage patients with GBS to participate in an appropriate exercise program, for example, one that incorporates stationary bicycling, swimming, or walking. Persistent Pain Pain is a symptom present in the majority of GBS patients in the acute phase, but it is also present long after recovery (192). Pain was reported in 71% of GBS patients surveyed, on average, 10 years after diagnosis with the disease, and severe pain was reported in 8% of those surveyed (178). In another study of a prospective cohort of 156 patients, 38% reported pain after 1 year. In the majority of patients, the intensity of pain was moderate to severe (20). The management of chronic pain in GBS patients is not standardized, but similar treatment regimens targeting neuropathic pain (eg, gabapentin, amitriptyline, carbamazepine) are most likely to be beneficial.

180  Textbook of Peripheral Neuropathy

PROGNOSIS Numerous studies have looked at what factors might influence the course and outcome of GBS. Consideration of prognosis is important for inpatient management (eg, need for mechanical ventilation), patient and family counseling, and might someday influence dosing and choice of immunotherapy. It is believed that age, rapid disease progression, severe disease as indicated by GBS disability score or MRC sum score, preceding diarrhea, no preceding upper respiratory tract infection, positive C. jejuni serology, positive CMV serology, and EDX evidence of axonal GBS are all factors that are associated with poor prognosis (7,12,15,44,54,61,116,128–130,181). Presence of facial and bulbar involvement has been associated with an increased need for mechanical ventilation (152). Prognostic models are of particular interest for optimizing treatment. In one large study of ~600 patients, older age, preceding diarrhea, and low MRC sum score at hospital admission and at 1 week were independently associated with being unable to walk at 4 weeks, 3 months, and 6 months (132). Using these 3 prognostic factors, a mEGOS score can be calculated to determine the probability a patient will be unable to walk at these time points. Stratifying patients by prognosis should lead to more selective treatment trials that study more homogenous subgroups of GBS patients. For example, it would be of great value to learn if more aggressive immunotherapy improves prognosis for patients predicted to have worse outcomes despite conventional treatment. Currently, the mEGOS model predicts that a patient older than 60 years, with antecedent diarrhea, and an MRC subscore at admission of 25 (of 60) has an ~50% chance of not being able to walk at 6 months. In light of the heterogeneous outcomes with conventional therapy, including the 20% to 30% likelihood of permanent deficit, different or more aggressive treatment strategies merit study for patients predicted to do poorly; prognostic models, such as the mEGOS, are a critical step toward selecting these patients.

2010) showed an estimate age-adjusted rate ratio of 1.77, with a GBS incidence of 1.92 per 100  000 person-years among vaccinated persons and 1.21 per 100 000 personyears among unvaccinated persons (197). Vaccination remains the most effective method to prevent serious illness and death from the 2009 H1N1 influenza virus, as illness from H1N1 had a hospitalization rate of 222 per million and death rate of 9.7 per million. Recurrence of GBS following immunization also appears to be rare (23). However, there are only limited data available to guide clinicians and patients about whether future immunizations, such as annual influenza vaccination, are prudent for patients who have had GBS. One patient with a history of severe GBS went on to have 15 annual influenza vaccinations without incident (198). Of 311 patients in a British GBS patient organization who had received immunization after suffering GBS, eleven (3.5%) reported symptoms within 6 weeks of immunization (199). Symptoms, such as fatigue, weakness, paresthesias, or numbness, were almost always mild and always transient, although 1 patient reported loss of unassisted ambulation for 6 weeks. No patient needed hospitalization or treatment. Influenza, tetanus, and typhoid were the most common immunizations associated with relapse of GBS symptoms. In another study of 106 GBS patients who received flu vaccinations between 1 and 37 times (a total of 775 vaccinations), none had a recurrence of GBS (178). The current consensus guidelines state that immunizations are not recommended during the acute phase of GBS and probably “not during a period, possibly of 1 year,” after onset of GBS (23). Decisions about future immunizations should be made on a case-by-case basis, factoring in the benefits and risks of immunization and also the possibility that infection, such as influenza, may itself be associated with an increased risk of recurrence of GBS (198). If GBS occurred within 6 weeks of a particular immunization, more consideration should be given to avoid that particular immunization in the future (23).

IMMUNIZATIONS AND GBS There is either no or very minimal risk of GBS associated with routine immunization (193–196). The association of GBS and influenza vaccine, in particular, has received the most attention and study. Numerous studies from different populations over different years suggest that if there is an increased risk of GBS after seasonal influenza vaccination, the risk is likely not greater than 1 or 2 excess GBS cases per million vaccinations (177–179). The one exception was 1976, when vaccination against a novel swine-origin influenza A (H1N1) was associated with approximately 10 excess cases per 1 million vaccinations. An H1N1 swine-origin influenza virus emerged worldwide in 2009, prompting an H1N1 vaccination campaign and study of vaccine safety. Preliminary analysis from populations in the Emerging Infections Program in the United States (October 1, 2009, to May 10,

KEY POINTS AND CLINICAL PEARLS 1. GBS is an acute onset, immune-mediated disease of the peripheral nerves that reaches peak severity within 4 weeks of onset. 2. Respiratory or gastrointestinal system infections frequently precede the onset of GBS symptoms, especially C. jejuni, Mycoplasma pneumonia, CMV, and seasonal influenza virus. 3. Prompt recognition and treatment of GBS with IVIg or PE is essential to reduce morbidity. 4. Respiratory failure requiring mechanical ventilation occurs in ~20% of GBS patients with average ventilation duration of 2–6 weeks. Mechanical ventilation increases the risk of infection and pulmonary embolus.

CHAPTER 12: Guillain-Barré Syndrome  181

5. MFS, a GBS variant characterized by ophthalmoparesis, areflexia, and ataxia, is associated with anti-GQ1b antibodies in approximately 95% of patients. 6. Autonomic dysfunction occurs in the majority of hospitalized GBS patients and typically consists of tachycardia, urinary retention, and hypertension; more serious dysautonomias can occur.

References 1. Prineas JW. Pathology of the Guillain-Barré syndrome. Ann Neurol. 1981;9(suppl):6–19. 2. Haymaker W, Kernohan JW. The Landry-Guillain-Barré syndrome: clinicopathologic report of fifty fatal cases and a critique of the literature. Med J Aust. 1949;25:59–141. 3. Efficiency of plasma exchange in Guillain-Barré syndrome: role of replacement fluids. French Cooperative Group on plasma exchange in Guillain-Barré syndrome. Ann Neurol. 1987;22:753–761. 4. Plasmapheresis and acute Guillain-Barré syndrome. The Guillain-Barré syndrome study group. Neurology. 1985;35:1096–1104. 5. Van der Meche FG, Schmitz PI. A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barré syndrome. Dutch Guillain-Barré study group. N Engl J Med. 1992;326:1123–1129. 6. Randomised trial of plasma exchange, intravenous immunoglobulin, and combined treatments in Guillain-Barré syndrome. Plasma exchange/sandoglobulin GuillainBarré syndrome trial group. Lancet. 1997;349:225–230. 7. Chio A, Cocito D, Leone M, et al. Guillain-Barré syndrome: a prospective, population-based incidence and outcome survey. Neurology. 2003;60:1146–1150. 8. Hughes RA, Rees JH. Clinical and epidemiologic features of Guillain-Barré syndrome. J Infect Dis. 1997;176(suppl 2): S92–S98. 9. Alter M. The epidemiology of Guillain-Barré syndrome. Ann Neurol. 1990;27(suppl):S7–S12. 10. Willison HJ. The immunobiology of Guillain-Barré syndromes. J Peripher Nerv Syst. 2005;10:94–112. 11. Jacobs BC, Rothbarth PH, van der Meche FG, et al. The spectrum of antecedent infections in Guillain-Barré syndrome: a case-control study. Neurology. 1998;51:1110–1115. 12. Visser LH, van der Meche FG, Meulstee J, et al. Cytomegalovirus infection and Guillain-Barré syndrome: the clinical, electrophysiologic, and prognostic features. Dutch Guillain-Barré study group. Neurology. 1996;47:668–673. 13. Asbury AK, Cornblath DR. Assessment of current diagnostic criteria for Guillain-Barré syndrome. Ann Neurol. 1990;27(suppl):S21–S4. 14. Green DM, Ropper AH. Mild Guillain-Barré syndrome. Arch Neurol. 2001;58:1098–1101. 15. Winer JB, Hughes RA, Osmond C. A prospective study of acute idiopathic neuropathy. I. Clinical features and their prognostic value. J Neurol Neurosurg Psychiatry. 1988;51:605–612. 16. Levin KH. Variants and mimics of Guillain-Barré syndrome. Neurologist. 2004;10:61–74. 17. Hughes RA, Cornblath DR. Guillain-Barré syndrome. Lancet. 2005;366:1653–1666.

18. Moulin DE, Hagen N, Feasby TE, Amireh R, Hahn A. Pain in Guillain-Barré syndrome. Neurology. 1997;48:328–331. 19. Ravn H. The Landry-Guillain-Barré syndrome. A survey and a clinical report of 127 cases. Acta Neurol Scand. 1967;43(suppl 30):1–64. 20. Ruts L, Drenthen J, Jongen JLM, et al, on behalf of the Dutch GBS Study Group. Pain in Guillain-Barré syndrome. A long-term follow-up study. Neurology. 2010;75:1439–1447. 21. Ropper AH. The Guillain-Barré syndrome. N Engl J Med. 1992;326:1130–1136. 22. Asbury AK. Diagnostic considerations in Guillain-Barré syndrome. Ann Neurol. 1981;9(suppl):1–5. 23. Hughes RA, Wijdicks EF, Benson E, et al. Supportive care for patients with Guillain-Barré syndrome. Arch Neurol. 2005;62:1194–1198. 24. Gracey DR, McMichan JC, Divertie MB, Howard FM, Jr. Respiratory failure in Guillain-Barré syndrome: a 6-year experience. Mayo Clin Proc. 1982;57:742–746. 25. Lawn ND, Fletcher DD, Henderson RD, Wolter TD, Wijdicks EF. Anticipating mechanical ventilation in GuillainBarré syndrome. Arch Neurol. 2001;58:893–898. 26. Massam M, Jones RS. Ventilatory failure in the GuillainBarré syndrome. Thorax. 1980;35:557–558. 27. Newton-John H. Prevention of pulmonary complications in severe Guillain-Barré syndrome by early assisted ventilation. Med J Aust. 1985;142:444–445. 28. Chevrolet JC, Deleamont P. Repeated vital capacity measurements as predictive parameters for mechanical ventilation need and weaning success in the Guillain-Barré syndrome. Am Rev Respir Dis. 1991;144:814–818. 29. Ropper AH, Kehne SM. Guillain-Barré syndrome: management of respiratory failure. Neurology. 1985;35:1662–1665. 30. Flachenecker P, Hartung HP, Reiners K. Power spectrum analysis of heart rate variability in Guillain-Barré syndrome. A longitudinal study. Brain. 1997;120(10):1885–1894. 31. Flachenecker P, Wermuth P, Hartung HP, Reiners K. Quantitative assessment of cardiovascular autonomic function in Guillain-Barré syndrome. Ann Neurol. 1997;42:171–179. 32. Lichtenfeld P. Autonomic dysfunction in the GuillainBarré syndrome. Am J Med. 1971;50:772–780. 33. Zochodne DW. Autonomic involvement in Guillain-Barré syndrome: a review. Muscle Nerve. 1994;17:1145–1155. 34. Truax BT. Autonomic disturbances in the Guillain-Barré syndrome. Seminars in Neurology. 1984;4:462–468. 35. Tuck RR, McLeod JG. Autonomic dysfunction in GuillainBarré syndrome. J Neurol Neurosurg Psychiatry. 1981;44: 983–990. 36. Burns TM, Lawn ND, Low PA, Camilleri M, Wijdicks EF. Adynamic ileus in severe Guillain-Barré syndrome. Muscle Nerve. 2001;24:963–965. 37. Petzold A, Brettschneider J, Jin K, et al. CSF protein biomarkers for proximal axonal damage improve prognostic accuracy in the acute phase of Guillain-Barré syndrome. Muscle Nerve. 2009;40:42–49. 38. Albers JW, Kelly JJ, Jr. Acquired inflammatory demyelinating polyneuropathies: clinical and electrodiagnostic features. Muscle Nerve. 1989;12:435–451. 39. Uncini A, Manzoli C, Notturno F, et al. Pitfalls in electrodiagnosis of Guillain-Barré syndrome subtypes. J Neurol Neurosurg Psychiatry. 2010;81(10):1157–1163. 40. Ropper AH, Wijdicks EF, Shahani BT. Electrodiagnostic abnormalities in 113 consecutive patients with GuillainBarré syndrome. Arch Neurol. 1990;47:881–887.

182  Textbook of Peripheral Neuropathy 41. Gordon PH, Wilbourn AJ. Early electrodiagnostic findings in Guillain-Barré syndrome. Arch Neurol. 2001;58:913–917. 42. Albers JW, Donofrio PD, McGonagle TK. Sequential electrodiagnostic abnormalities in acute inflammatory demyelinating polyradiculoneuropathy. Muscle Nerve. 1985;8:528–539. 43. Cleland JC, Malik K, Thaisetthawatkul P, Herrmann DN, Logigian EL. Acute inflammatory demyelinating polyneuropathy: contribution of a dispersed distal compound muscle action potential to electrodiagnosis. Muscle Nerve. 2006;33:771–777. 44. Cornblath DR, Mellits ED, Griffin JW, et al. Motor conduction studies in Guillain-Barré syndrome: description and prognostic value. Ann Neurol. 1988;23:354–359. 45. McKhann GM, Griffin JW, Cornblath DR, et al. Plasmapheresis and Guillain-Barré syndrome: analysis of prognostic factors and the effect of plasmapheresis. Ann Neurol. 1988;23:347–353. 46. Crino PB, Zimmerman R, Laskowitz D, Raps EC, Rostami AM. Magnetic resonance imaging of the cauda equina in Guillain-Barré syndrome. Neurology. 1994;44:1334–1336. 47. Gorson KC, Ropper AH, Muriello MA, Blair R. Prospective evaluation of MRI lumbosacral nerve root enhancement in acute Guillain-Barré syndrome. Neurology. 1996;47: 813–817. 48. Weiss MD. Root enhancement in GBS. Neurology. 1997;48:1477. 49. Kaida K, Kusonoki S. Antibodies to gangliosides and ganglioside complexes in Guillain-Barré syndrome and Fisher syndrome: mini-review. J. Neuroimmunol. 2010;223:5–12. 50. Hughes R, Sanders E, Hall S, et al. Subacute idiopathic demyelinating polyradiculoneuropathy. Arch Neurol. 1992;49:612–616. 51. Oh SJ, Kurokawa K, de Almeida DF, Ryan HF Jr, Claussen GC. Subacute inflammatory demyelinating polyneuropathy. Neurology. 2003;61:1507–1512. 52. Asbury AK, Arnason BG, Adams RD. The inflammatory lesion in idiopathic polyneuritis. Its role in pathogenesis. Medicine (Baltimore). 1969;48:173–215. 53. Berciano J, Coria F, Monton F, et al. Axonal form of GuillainBarré syndrome: evidence for macrophage-associated demyelination. Muscle Nerve. 1993;16:744–751. 54. Feasby TE, Gilbert JJ, Brown WF, et al. An acute axonal form of Guillain-Barré polyneuropathy. Brain. 1986;109 (pt 6):1115–1126. 55. Feasby TE, Gilbert JJ, Brown WF, et al. Acute “axonal” Guillain-Barré polyneuropathy. Neurology. 1987;37:357. 56. Feasby TE, Hahn AF, Brown WF, et al. Severe axonal degeneration in acute Guillain-Barré syndrome: evidence of two different mechanisms? J Neurol Sci. 1993;116:185–192. 57. Ropper AH. Severe acute Guillain-Barré syndrome. Neurology. 1986;36:429–432. 58. Griffin JW, Li CY, Ho TW, et al. Pathology of the motorsensory axonal Guillain-Barré syndrome. Ann Neurol. 1996;39:17–28. 59. Griffin JW, Li CY, Macko C, et al. Early nodal changes in the acute motor axonal neuropathy pattern of the Guillain-Barré syndrome. J Neurocytol. 1996;25:33–51. 60. Sobue G, Li M, Terao S, et al. Axonal pathology in Japanese Guillain-Barré syndrome: a study of 15 autopsied cases. Neurology. 1997;48:1694–1700. 61. Hafer-Macko C, Hsieh ST, Li CY, et al. Acute motor axonal neuropathy: an antibody-mediated attack on axolemma. Ann Neurol. 1996;40:635–644.

62. McKhann GM, Cornblath DR, Griffin JW, et al. Acute motor axonal neuropathy: a frequent cause of acute flaccid paralysis in china. Ann Neurol. 1993;33:333–342. 63. Hiraga A, Mori M, Ogawara K, Hattori T, Kuwabara S. Differences in patterns of progression in demyelinating and axonal Guillain-Barré syndromes. Neurology. 2003;61:471–474. 64. Hiraga A, Mori M, Ogawara K, et al. Recovery patterns and long term prognosis for axonal Guillain-Barré syndrome. J Neurol Neurosurg Psychiatry. 2005;76:719–722. 65. Fisher M. An unusual variant of acute idiopathic polyneuritis (syndrome of ophthalmoplegia, ataxia and areflexia). N Engl J Med. 1956;255:57–65. 66. Overell JR, Willison HJ. Recent developments in Miller Fisher syndrome and related disorders. Curr Opin Neurol. 2005;18:562–566. 67. Yuki N, Taki T, Takahashi M, et al. Molecular mimicry between GQ1b ganglioside and lipopolysaccharides of Campylobacter jejuni isolated from patients with Fisher’s syndrome. Ann Neurol. 1994;36:791–793. 68. Ogawara K, Kuwabara S, Yuki N. Fisher syndrome or Bickerstaff brainstem encephalitis? Anti-GQ1b IgG antibody syndrome involving both the peripheral and central nervous systems. Muscle Nerve. 2002;26:845–849. 69. Chaudhry F, Gee KE, Vaphiades MS, Biller J, Jay W. GQ1b antibody testing in Guillain-Barré syndrome and variants. Semin Ophthalmol. 2006;21:223–227. 70. Radziwill AJ, Steck AJ, Borruat FX, Bogousslavsky J. Isolated internal ophthalmoplegia associated with IgG antiGQ1b antibody. Neurology. 1998;50:307. 71. Mori M, Kuwabara S, Fukutake T, Yuki N, Hattori T. Clinical features and prognosis of Miller Fisher syndrome. Neurology. 2001;56:1104–1106. 72. Odaka M, Yuki N, Yamada M, et al. Bickerstaff’s brainstem encephalitis: clinical features of 62 cases and a subgroup associated with Guillain-Barré syndrome. Brain. 2003;126:2279–2290. 73. Chiba A, Kusunoki S, Shimizu T, Kanazawa I. Serum IgG antibody to ganglioside GQ1b is a possible marker of Miller Fisher syndrome. Ann Neurol. 1992;31:677–679. 74. Chiba A, Kusunoki S, Obata H, Machinami R, Kanazawa I. Serum anti-GQ1b IgG antibody is associated with ophthalmoplegia in Miller Fisher syndrome and Guillain-Barré syndrome: clinical and immunohistochemical studies. Neurology. 1993;43:1911–1917. 75. Onodera M, Mori M, Koga M, et al. Acute isolated bulbar palsy with anti-GT1a IgG antibody subsequent to Campylobacter jejuni enteritis. J Neurol Sci. 2002;205:83–84. 76. Nagashima T, Koga M, Odaka M, Hirata K, Yuki N. Clinical correlates of serum anti-GT1a IgG antibodies. J Neurol Sci. 2004;219:139–145. 77. Fross RD, Daube JR. Neuropathy in the Miller Fisher syndrome: clinical and electrophysiologic findings. Neurology. 1987;37:1493–1498. 78. Nagaoka U, Kato T, Kurita K, et al. Cranial nerve enhancement on three-dimensional MRI in Miller Fisher syndrome. Neurology. 1996;47:1601–1602. 79. Susuki K, Koga M, Hirata K, Isogai E, Yuki N. A GuillainBarré syndrome variant with prominent facial diplegia. J Neurol. 2009;256:1899–1905. 80. Kashihara K, Shiro Y, Koga M, Yuki N. IgG anti-GT1a antibodies which do not cross react with GQ1b ganglioside in a pharyngeal-cervical-brachial variant of Guillain-Barré syndrome. J Neurol Neurosurg Psychiatry. 1998;65:799.

CHAPTER 12: Guillain-Barré Syndrome  183 81. Willison HJ. Ganglioside complexes as targets for antibodies in Miller Fisher syndrome. J Neurol Neurosurg Psychiatry. 2006;77:1002–1003. 82. Vargas F, Hilbert G, Gruson D, et al. Fulminant Guillain-Barré syndrome mimicking cerebral death: case report and literature review. Intensive Care Med. 2000;26: 623–627. 83. Rajdev SK, Sarma D, Singh R, Uttam R, Khilnani P. GuillainBarré syndrome mimicking cerebral death. Ind J Crit Care Med. 2003;7:50–52. 84. Levin KH. Variants and mimics of Guillain-Barré syndrome. Neurologist. 2004;10:61–74. 85. Schaublin GA, Michet CJ, Jr, Dyck PJ, Burns TM. An update on the classification and treatment of vasculitic neuropathy. Lancet Neurol. 2005;4:853–865. 86. Keesey JC. Clinical evaluation and management of myasthenia gravis. Muscle Nerve. 2004;29:484–505. 87. Cherington M. Clinical spectrum of botulism. Muscle Nerve. 1998;21:701–710. 88. Li J, Loeb JA, Shy ME, et al. Asymmetric flaccid paralysis: a neuromuscular presentation of West Nile virus infection. Ann Neurol. 2003;53:703–710. 89. Jeha LE, Sila CA, Lederman RJ, et al. West Nile virus infection: a new acute paralytic illness. Neurology. 2003;61:55–59. 90. Halperin JJ. Lyme disease and the peripheral nervous system. Muscle Nerve. 2003;28:133–143. 91. Steere AC. Lyme disease. N Engl J Med. 2001;345:115–125. 92. Donofrio PD, Wilbourn AJ, Albers JW, et al. Acute arsenic intoxication presenting as Guillain-Barré-like syndrome. Muscle Nerve. 1987;10:114–120. 93. Grattan-Smith PJ, Morris JG, Johnston HM, et al. Clinical and neurophysiological features of tick paralysis. Brain. 1997;120(pt 11):1975–1987. 94. Vedanarayanan VV, Evans OB, Subramony SH. Tick paralysis in children: electrophysiology and possibility of misdiagnosis. Neurology. 2002;59:1088–1090. 95. Albers JW, Fink JK. Porphyric neuropathy. Muscle Nerve. 2004;30:410–422. 96. Calderon-Gonzalez R, Rizzi-Hernandez H. Buckthorn polyneuropathy. N Engl J Med. 1967;277:69–71. 97. Piradov MA, Pirogov VN, Popova LM, Avdunina IA. Diphtheritic polyneuropathy: clinical analysis of severe forms. Arch Neurol. 2001;58:1438–1442. 98. Snider WD, Simpson DM, Nielsen S, et al. Neurological complications of acquired immune deficiency syndrome: analysis of 50 patients. Ann Neurol. 1983;14:403–418. 99. Roullet E, Assuerus V, Gozlan J, et al. Cytomegalovirus multifocal neuropathy in AIDS: analysis of 15 consecutive cases. Neurology. 1994;44:2174–2182. 100. Mori K, Hattori N, Sugiura M, et al. Chronic inflammatory demyelinating polyneuropathy presenting with features of GBS. Neurology. 2002;58:979–982. 101. Hafer-Macko CE, Sheikh KA, Li CY, et al. Immune attack on the Schwann cell surface in acute inflammatory demyelinating polyneuropathy. Ann Neurol. 1996;39:625–635. 102. Ilyas AA, Willison HJ, Quarles RH, et al. Serum antibodies to gangliosides in Guillain-Barré syndrome. Ann Neurol. 1988;23:440–447. 103. Oomes PG, Jacobs BC, Hazenberg MP, et al. Anti-GM1 IgG antibodies and campylobacter bacteria in Guillain-Barré syndrome: evidence of molecular mimicry. Ann Neurol. 1995;38:170–175.

104. Sheikh KA, Nachamkin I, Ho TW, et al. Campylobacter jejuni lipopolysaccharides in Guillain-Barré syndrome: molecular mimicry and host susceptibility. Neurology. 1998;51: 371–378. 105. Vriesendorp FJ, Mishu B, Blaser MJ, Koski CL. Serum antibodies to GM1, GD1b, peripheral nerve myelin, and Campylobacter jejuni in patients with Guillain-Barré syndrome and controls: correlation and prognosis. Ann Neurol. 1993;34:130–135. 106. Willison HJ. Ganglioside complexes: new autoantibody targets in Guillain-Barré syndromes. Nat Clin Pract Neurol. 2005;1:2–3. 107. Olsson Y. Topographical differences in the vascular permeability of the peripheral nervous system. Acta Neuropathol (Berl). 1968;10:26–33. 108. Ho TW, Mishu B, Li CY, et al. Guillain-Barré syndrome in northern china. Relationship to Campylobacter jejuni infection and anti-glycolipid antibodies. Brain. 1995;118(3): 597–605. 109. Yuki N, Taki T, Inagaki F, et al. A bacterium lipopolysaccharide that elicits Guillain-Barré syndrome has a GM1 ganglioside-like structure. J Exp Med. 1993;178:1771–1775. 110. Ho TW, Li CY, Cornblath DR, et al. Patterns of recovery in the Guillain-Barré syndromes. Neurology. 1997;48: 695–700. 111. Chiba A, Kusunoki S, Obata H, Machinami R, Kanazawa I. Ganglioside composition of the human cranial nerves, with special reference to pathophysiology of Miller Fisher syndrome. Brain Res. 1997;745:32–36. 112. Bril V, Ilse WK, Pearce R, et al. Pilot trial of immunoglobulin versus plasma exchange in patients with Guillain-Barré syndrome. Neurology. 1996;46:100–103. 113. Donofrio PD. Immunotherapy of idiopathic inflammatory neuropathies. Muscle Nerve. 2003;28:273–292. 114. Hughes RA, Wijdicks EF, Barohn R, et al. Practice parameter: immunotherapy for Guillain-Barré syndrome: report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2003;61:736–740. 115. Plasma exchange in Guillain-Barré syndrome: one-year follow-up. French Cooperative Group on plasma exchange in Guillain-Barré syndrome. Ann Neurol. 1992;32:94–97. 116. McKhann GM, Griffin JW, Cornblath DR, et al. Plasmapheresis and Guillain-Barré syndrome: analysis of prognostic factors and the effect of plasmapheresis. Ann Neurol. 1988;23:347–353. 117. McKhann GM, Griffin JW, Cornblath DR, Quaskey SA, Mellits ED. Role of therapeutic plasmapheresis in the acute Guillain-Barré syndrome. J Neuroimmunol. 1988;20:297–300. 118. Appropriate number of plasma exchanges in GuillainBarré syndrome. the French Cooperative Group on plasma exchange in Guillain-Barré syndrome. Ann Neurol. 1997;41:298–306. 119. Abd-Allah SA, Jansen PW, Ashwal S, Perkin RM. Intravenous immunoglobulin as therapy for pediatric GuillainBarré syndrome. J Child Neurol. 1997;12:376–380. 120. Jansen PW, Perkin RM, Ashwal S. Guillain-Barré syndrome in childhood: natural course and efficacy of plasmapheresis. Pediatr Neurol. 1993;9:16–20. 121. Jones HR. Childhood Guillain-Barré syndrome: clinical presentation, diagnosis, and therapy. J Child Neurol. 1996;11:4–12. 122. Vallee L, Dulac O, Nuyts JP, Leclerc F, Vamecq J. Intravenous immune globulin is also an efficient therapy of acute

184  Textbook of Peripheral Neuropathy Guillain-Barré syndrome in affected children. Neuropediatrics. 1993;24:235–236. 123. Epstein MA, Sladky JT. The role of plasmapheresis in childhood Guillain-Barré syndrome. Ann Neurol. 1990;28:65–69. 124. Raphael JC, Chevret S, Hughes RA, Annane D. Plasma exchange for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2001;(2):CD001798. 125. Esperou H, Jars-Guincestre MC, Bolgert F, Raphael JC, Durand-Zaleski I. Cost analysis of plasma-exchange therapy for the treatment of Guillain-Barré syndrome. French Cooperative Group on plasma exchange in Guillain-Barré syndrome. Intensive Care Med. 2000;26: 1094–1100. 126. Osterman PO, Fagius J, Lundemo G, et al. Beneficial effects of plasma exchange in acute inflammatory polyradiculoneuropathy. Lancet. 1984;2:1296–1299. 127. Yuki N, Tagawa Y, Hirata K. Minimal number of plasma exchanges needed to reduce immunoglobulin in GuillainBarré syndrome. Neurology. 1998;51:875–877. 128. Kuitwaard K, de Gelder J, Tio-Gillen AP, et al. Pharmacokinetics of intravenous immunoglobulin and outcome in Guillain-Barré syndrome. Annals of Neurology. 2009;66:592–603. 129. van Doorn PA, Kuitwaard K, Walgaard C, et al. IVIG treatment and prognosis in Guillain-Barré syndrome. J Clin Immunol. 2010;30(1): S74–S78. 130. van Koningsveld R, Steyerberg EW, Hughes RA, et al. A clinical prognostic scoring system for Guillain-Barré syndrome. Lancet Neurol. 2007;6:589–594. 131. Hughes RA, Newsom-Davis JM, Perkin GD, Pierce JM. Controlled trial prednisolone in acute polyneuropathy. Lancet. 1978;2:750–753. 132. Walgaard C, Lingsma HF, Ruts L, et al. Early recognition of poor prognosis in Guillain-Barré syndrome. Neurology. 2011;76(11):968–975. 133. Lehmann HC, Hartung HP, Hetzel GR, et al. Plasma exchange in neuroimmunological disorders: part 2. treatment of neuromuscular disorders. Arch Neurol. 2006;63:1066– 1071. 134. Caress JB, Hobson-Webb L, Passmore LV, Finkbiner AP, Cartwright MS. Case-control study of thromboembolic events associated with IV immunoglobulin. J Neurol. 2009;256:339–342. 135. Hughes RA, Donofrio P, Bril V, et al. Intravenous immune globulin (10% caprylate-chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebocontrolled trial. Lancet Neurol. 2008;7(2):136–144. 136. Dalakas MC. The use of intravenous immunoglobulin in the treatment of autoimmune neuromuscular diseases: evidence-based indications and safety profile. Pharmacol Ther. 2004;102:177–193. 137. Dalakas MC. Intravenous immunoglobulin in autoimmune neuromuscular diseases. JAMA. 2004;291:2367–2375. 138. Thornton CA, Ballow M. Safety of intravenous immunoglobulin. Arch Neurol. 1993;50:135–136. 139. Hughes RA, van Der Meche FG. Corticosteroids for treating Guillain-Barré syndrome. Cochrane Database Syst Rev. 2000;(3):CD001446. 140. Hughes RA, Swan AV, van Koningsveld R, van Doorn PA. Corticosteroids for Guillain-Barré syndrome. Cochrane Database Syst Rev. 2006;(2):CD001446.

141. van Koningsveld R, Schmitz PI, Meche FG, et al. Effect of methylprednisolone when added to standard treatment with intravenous immunoglobulin for Guillain-Barré syndrome: randomised trial. Lancet. 2004;363:192–196. 142. Okamiya S, Ogino M, Ogino Y, et al. Tryptophan-immobilized column-based immunoadsorption as the choice method for plasmapheresis in Guillain-Barré syndrome. Ther Apher Dial. 2004;8:248–253. 143. Haupt WF, Rosenow F, van der Ven C, Birkmann C. Immunoadsorption in Guillain-Barré syndrome and myasthenia gravis. Ther Apher Dial. 2000;4:195–197. 144. Haupt WF, Rosenow F, van der Ven C, Borberg H, Pawlik G. Sequential treatment of Guillain-Barré syndrome with extracorporeal elimination and intravenous immunoglobulin. J Neurol Sci. 1996;137:145–149. 145. Romano JG, Rotta FT, Potter P, et al. Relapses in the Guillain-Barré syndrome after treatment with intravenous immune globulin or plasma exchange. Muscle Nerve. 1998;21:1327–1330. 146. Visser LH, van der Meche FG, Meulstee J, van Doorn PA. Risk factors for treatment related clinical fluctuations in Guillain-Barré syndrome. Dutch Guillain-Barré study group. J Neurol Neurosurg Psychiatry. 1998;64:242–244. 147. Mori M, Kuwabara S, Fukutake T, Hattori T. Intravenous immunoglobulin therapy for Miller Fisher syndrome. Neurology. 2007;68:1144–1146. 148. Ruts L, Drenthen J, Jacobs B, van Doorn P. Distinguishing acute-onset CIDP from fluctuating Guillain-Barré syndrome. Neurology. 2010;74:1680–1686. 149. Mori M, Kuwabara S, Fukutake T, Hattori T. Plasmapheresis and Miller Fisher syndrome: analysis of 50 consecutive cases. J Neurol Neurosurg Psychiatry. 2002;72:680. 150. Overell J, Hsieh S, Odaka M, Yuki N, Willison H. Treatment for Fisher syndrome, Bickerstaff’s brainstem encephalitis and related disorders. Cochrane Database Syst Rev. 2007;1: CD004761. 151. Fletcher DD, Lawn ND, Wolter TD, Wijdicks EF. Longterm outcome in patients with Guillain-Barré syndrome requiring mechanical ventilation. Neurology. 2000;54: 2311–2315. 152. Walgaard C, Lingsma HF, Ruts L, Drenth J, van Koningsveld R, Garssen MJP, et al. Prediction of respiratory insufficiency in Guillain-Barré syndrome. Ann Neurol. 2010;67:781–787. 153. Gold R, Bayas A, Toyka KV. Autoimmune neuropathies— current aspects of immunopathologic diagnostics and therapy. Nervenarzt. 2005;76:1009–1023. 154. Sunderrajan EV, Davenport J. The Guillain-Barré syndrome: pulmonary-neurologic correlations. Medicine (Baltimore). 1985;64:333–341. 155. Pontoppidan H, Geffin B, Lowenstein E. Acute respiratory failure in the adult. N Engl J Med. 1972;287:743–752. 156. Lawn ND, Wijdicks EF. Post-intubation pulmonary function test in Guillain-Barré syndrome. Muscle Nerve. 2000;23:613–616. 157. Durand MC, Porcher R, Orlikowski D, et al. Clinical and electrophysiological predictors of respiratory failure in Guillain-Barré syndrome: a prospective study. Lancet Neurol. 2006;5:1021–1028. 158. Sharshar T, Chevret S, Bourdain F, Raphael JC, French Cooperative Group on Plasma Exchange in Guillain-Barré Syndrome. Early predictors of mechanical ventilation in Guillain-Barré syndrome. Crit Care Med. 2003;31:278–283.

CHAPTER 12: Guillain-Barré Syndrome  185 159. Durand MC, Lofaso F, Lefaucheur JP, et al. Electrophysiology to predict mechanical ventilation in Guillain-Barré syndrome. Eur J Neurol. 2003;10:39–44. 160. Henderson RD, Lawn ND, Fletcher DD, McClelland RL, Wijdicks EF. The morbidity of Guillain-Barré syndrome admitted to the intensive care unit. Neurology. 2003;60:17–21. 161. Holdgaard HO, Pedersen J, Jensen RH, et al. Percutaneous dilatational tracheostomy versus conventional surgical tracheostomy. A clinical randomised study. Acta Anaesthesiol Scand. 1998;42:545–550. 162. Emmons PR, Blume WT, DuShane JW. Cardiac monitoring and demand pacemaker in Guillain-Barré syndrome. Arch Neurol. 1975;32:59–61. 163. Favre H, Foex P, Guggisberg M. Use of demand pacemaker in a case of Guillain-Barré syndrome. Lancet. 1970;1:1062– 1063. 164. Singh NK, Jaiswal AK, Misra S, Srivastava PK. Assessment of autonomic dysfunction in Guillain-Barré syndrome and its prognostic implications. Acta Neurol Scand. 1987;75:101–105. 165. McLeod JG. Invited review: autonomic dysfunction in peripheral nerve disease. Muscle Nerve. 1992;15:3–13. 166. Clarke, E., Bayliss, R.I.S., Cooper, R. Landry-GuillainBarré syndrome: cardiovascular complications. Br Med J. 1954:1504–1507. 167. Kogan BA, Solomon MH, Diokno AC. Urinary retention secondary to Landry-Guillain-Barré syndrome. J Urol. 1981;126:643–644. 168. Samama MM, Cohen AT, Darmon JY, et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. prophylaxis in medical patients with enoxaparin study group. N Engl J Med. 1999;341:793–800. 169. Collins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. Overview of results of randomized trials in general, orthopedic, and urologic surgery. N Engl J Med. 1988;318: 1162–1173. 170. Clagett GP, Reisch JS. Prevention of venous thromboembolism in general surgical patients. Results of meta-analysis. Ann Surg. 1988;208:227–240. 171. Pandey CK, Bose N, Garg G, et al. Gabapentin for the treatment of pain in Guillain-Barré syndrome: a doubleblinded, placebo-controlled, crossover study. Anesth Analg. 2002;95:1719–1723. 172. Tripathi M, Kaushik S. Carbamezapine for pain management in Guillain-Barré syndrome patients in the intensive care unit. Crit Care Med. 2000;28:655–658. 173. Meythaler JM. Rehabilitation of Guillain-Barré syndrome. Arch Phys Med Rehabil. 1997;78:872–879. 174. Herbison GJ, Jaweed MM, Ditunno JF,Jr. Exercise therapies in peripheral neuropathies. Arch Phys Med Rehabil. 1983;64:201–205. 175. Pitetti KH, Barrett PJ, Abbas D. Endurance exercise training in Guillain-Barré syndrome. Arch Phys Med Rehabil. 1993;74:761–765. 176. Cooke JF, Orb A. The recovery phase in Guillain-Barré syndrome: moving from dependency to independence. Rehabil Nurs. 2003;28:105-108:130. 177. Bernsen RA, de Jager AE, Schmitz PI, van der Meche FG. Long-term impact on work and private life after GuillainBarré syndrome. J Neurol Sci. 2002;201:13–17.

178. Kuitwaard K, Bos-Eyssen M, Blomkwist-Markens P, van Doorn P. Recurrences, vaccinations and long-term symptoms in GBS and CIDP. J. Peripher Nerv Syst. 2009;14: 310–315. 179. Bernsen RA, de Jager AE, van der Meche FG, Suurmeijer TP. How Guillain-Barré patients experience their functioning after 1 year. Acta Neurol Scand. 2005;112: 51–56. 180. Rees JH, Thompson RD, Smeeton NC, Hughes RA. Epidemiological study of Guillain-Barré syndrome in South East England. J Neurol Neurosurg Psychiatry. 1998;64:74–77. 181. The prognosis and main prognostic indicators of GuillainBarré syndrome. A multicentre prospective study of 297 patients. The Italian Guillain-Barré Study Group. Brain. 1996;119(6):2053–2061. 182. Bernsen RA, de Jager AE, Schmitz PI, van der Meche FG. Residual physical outcome and daily living 3 to 6 years after Guillain-Barré syndrome. Neurology. 1999;53:409– 410. 183. Prevots DR, Sutter RW. Assessment of Guillain-Barré syndrome mortality and morbidity in the United States: implications for acute flaccid paralysis surveillance. J Infect Dis. 1997;175(1): S151–S155. 184. Bradshaw DY, Jones HR, Jr. Guillain-Barré syndrome in children: clinical course, electrodiagnosis, and prognosis. Muscle Nerve. 1992;15:500–506. 185. Vajsar J, Fehlings D, Stephens D. Long-term outcome in children with Guillain-Barré syndrome. J Pediatr. 2003;142:305–309. 186. de Jager AE, Minderhoud JM. Residual signs in severe Guillain-Barré syndrome: analysis of 57 patients. J Neurol Sci. 1991;104:151–156. 187. Garssen MP, Van Koningsveld R, Van Doorn PA. Residual fatigue is independent of antecedent events and disease severity in Guillain-Barré syndrome. J Neurol. 2006;253:1143–1146. 188. Merkies IS, Schmitz PI, Samijn JP, van der Meche FG, van Doorn PA. Fatigue in immune-mediated polyneuropathies. European Inflammatory Neuropathy Cause and Treatment (INCAT) Group. Neurology. 1999;53:1648– 1654. 189. Garssen MP, van Doorn PA, Visser GH. Nerve conduction studies in relation to residual fatigue in Guillain-Barré syndrome. J Neurol. 2006;253:851–856. 190. Garssen MP, Schmitz PI, Merkies IS, et al. Amantadine for treatment of fatigue in Guillain-Barré syndrome: a randomised, double blind, placebo controlled, crossover trial. J Neurol Neurosurg Psychiatry. 2006;77:61–65. 191. Garssen MP, Bussmann JB, Schmitz PI, et al. Physical training and fatigue, fitness, and quality of life in Guillain-Barré syndrome and CIDP. Neurology. 2004;63: 2393–2395. 192. Rudolph T, Larsen J, Farbu E. The long-term functional status in patients with Guillain-Barré syndrome. Eur J Neurol. 2008;15:1332–1337. 193. Hughes RA, Charlton J, Latinovic R, Gulliford MC. No association between immunization and Guillain-Barré syndrome in the United Kingdom, 1992 to 2000. Arch Intern Med. 2006;166:1301–1304. 194. Juurlink DN, Stukel TA, Kwong J, et al. Guillain-Barré syndrome after influenza vaccination in adults: a populationbased study. Arch Intern Med. 2006;166:2217–2221.

186  Textbook of Peripheral Neuropathy 195. Lasky T, Terracciano GJ, Magder L, et al. The GuillainBarré syndrome and the 1992-1993 and 1993-1994 influenza vaccines. N Engl J Med. 1998;339:1797–1802. 196. Haber P, Sejvar J, Mikaeloff Y, et al. Vaccines and GuillainBarré syndrome. Drug Safety. 2009;32(4):309–323. 197. CDC. Preliminary results: surveillance for Guillain-Barré syndrome after receipt of influenza A (H1N1) 2009 monovalent vaccine—United States: 2009-2010. MMWR. 2010;59:657–661.

198. Wijdicks EF, Fletcher DD, Lawn ND. Influenza vaccine and the risk of relapse of Guillain-Barré syndrome. Neurology. 2000;55:452–453. 199. Pritchard J, Mukherjee R, Hughes RA. Risk of relapse of Guillain-Barré syndrome or chronic inflammatory demyelinating polyradiculoneuropathy following immunisation. J Neurol Neurosurg Psychiatry. 2002;73: 348–349.

Christina M. Ulane and Thomas H. Brannagan

13

Chronic Inflammatory Demyelinating Polyradiculoneuropathy, Multifocal Motor Neuropathy, and Related Disorders Introduction

Clinical Manifestations

The chronic acquired demyelinating neuropathies encompass a group of immune-mediated demyelinating neuropathies that can be distinguished according to clinical and electrophysiological features. The most well-studied and common example in this category is chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Diagnostic criteria for CIDP vary, but its classic form is a clinical picture of symmetric proximal and distal weakness, with large fiber sensory loss, areflexia, cytoalbuminologic dissociation in cerebrospinal fluid (CSF), and nerve conduction studies consistent with segmental demyelination. The clinical course of the disease is progressive or relapsing-remitting and is responsive to immunosuppressive and immunemodulating therapies. Regional clinical variants of CIDP include distal weakness or sensory loss in distal acquired demyelinating syndrome (DADS) and asymmetric weakness and sensory loss with multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), which is also known as the Lewis-Sumner syndrome (LSS) (see Table 13.1). Although the precise mechanism of pathogenesis of CIDP is unknown, both cellular and humoral immunity appear to play a role. Related entities based on clinical and electrophysio­ logical findings include multifocal motor neuropathy (MMN), anti–myelin-associated glycoprotein (MAG) neuropathy and polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes (POEMS) syndrome. A distinct pathogenesis and response to treatment and specific antibodies can identify some of these patients. Peak incidence for CIDP is between 40 and 60 years; however, it can present at any age, including childhood. Prevalence ranges between 1 and 8.9 per 100  000 (1 in Southeastern England, 8.9 in Rochester, MN), with a slight male predominance (1,2). CIDP accounts for approximately 20% of patients with initially idiopathic neuropathy seen in neuropathy and neuromuscular centers (3,4).

The classic presentation of CIDP is a subacute onset of symmetric proximal and distal weakness of both the arms and the legs, with occasional involvement of the face and neck flexors. Sensory symptoms may be present, with numbness and tingling most common, but painful paresthesias are also possible. Predominantly large fiber sensory modalities are affected. Balance is often impaired due to loss of proprioception, and deep tendon reflexes are hypoactive or absent. Rare reports have noted central nervous system (CNS) involvement. Unlike Guillain-Barré syndrome (GBS), the autonomic nervous system is infrequently involved. Although cranial nerves may be affected, this tends to be in a minority of patients, but most often involves cranial nerve VII. By definition, symptoms are present for at least 2 months. Disease onset is usually insidious but can be acute and the course may be monophasic, relapsing-remitting, chronic progressive, or stepwise worsening. Antecedent nonspecific viral illnesses have been noted but less frequently than with GBS (5). Sixty percent of patients display the chronic progressive form and are usually older at age of onset, whereas 30% experience the relapsing course, which is associated with younger age of onset. Acute onset occurs in up to 16% of patients with CIDP, and children are most likely to develop the monophasic illness with remission. Although clinically and pathophysiologically similar to the acute inflammatory demyelinating polyradiculoneuropathies (AIDP/GBS), time course and relapse serve to differentiate these 2 diseases. Nadir of clinical symptoms for AIDP is within 4 weeks, whereas more than 8 weeks with CIDP. However, there are exceptions, and it can be challenging to distinguish acute onset CIDP from AIDP. There are also a group of patients who reach nadir of symptoms within 4 to 8 weeks, with clinical characteristics and treatment response similar to CIDP but with a monophasic course. It has been proposed that this group be defined as subacute inflammatory demyelinating polyradiculoneuropathy (SIDP) (6,7). 187

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Table 13.1  CIDP Regional Variants and Related Entities Disease CIDP (“classic”)

Clinical Features Symmetric proximal and distal weakness, with or without large fiber sensory loss

CIDP regional variants DADS

Symmetric distal weakness or sensory loss

MADSAM/LSS Asymmetric weakness and sensory loss MMN

Asymmetric weakness, initially in arms, without sensory loss

MAG neuropathy

Progressive distal weakness and sensory ataxia

POEMS

Similar to CIDP with lambda monoclonal protein and osteosclerotic myeloma

CIDP is reported in association with systemic diseases, but the exact nature of the relationship between these diseases and CIDP is unclear. Systemic diseases found in association with CIDP include human immunodeficiency virus (HIV) infection, lymphoma, POEMS, monoclonal gammopathy of undetermined significance (MGUS), hepatitis C virus (HCV) infection, inflammatory bowel disease, connective tissue disease, bone marrow and organ transplants, nephrotic syndrome, thyrotoxicosis, and hereditary neuropathies. In addition, patients with diabetes mellitus may develop CIDP. Some authors have proposed that the incidence of CIDP is increased in patients with diabetes (8,9); however, this has not been confirmed in a recent population-based study (2).

Differential Diagnosis The differential diagnosis for CIDP includes other acquired and inherited demyelinating neuropathies (see Table 13.2). In its acute presentation, CIDP can be difficult to distinguish from GBS. This distinction is important for treatment purposes. Time to symptom nadir and subsequent clinical course are often used to distinguish the two, however, this is not entirely specific, as up to 16% of patients with CIDP will reach nadir within 8 weeks and 8% to 16% of patients with GBS will worsen after initial treatment-related improvements. A prospective study identified and compared clinical and electrophysiological characteristics of patients with GBS vs acute CIDP. Characteristics more prevalent in GBS were

(1) nadir never past 8 weeks, (2) prominent sensory symptoms, (3) cranial nerve dysfunction, (4) respiratory failure, and (5) denervation potentials on electrophysiological studies. Inherited demyelinating neuropathies in the differential diagnosis for CIDP include CharcotMarie-Tooth (CMT) and hereditary neuropathy with liability to pressure palsy (HNPP). In contrast to CIDP, hereditary demyelinating neuropathies are characterized by earlier age of onset, positive family history, slowly progressive clinical course and uniform slowing of conduction velocities (10). In addition, neuropathy due to concurrent systemic disease, drugs, and toxins should be included in the differential diagnosis for CIDP (see Table 13.2 for detailed list).

Pathogenesis and Pathophysiology It is clear that CIDP is an autoimmune disease and the exact cause is unknown, but there is evidence for both T and B cells mediated dysfunction. Numerous investigations in both humans and animals provide insights into some of the mechanisms of pathogenesis. Histopathology, genetics, electrophysiological studies, various measures of immune function, response to treatment, and the search for biomarkers of disease have all contributed to the current knowledge regarding pathogenesis of CIDP.

Histopathology Nerve biopsy in CIDP demonstrates inflammatory changes. There is infiltration of macrophages and T cells, as well as segmental demyelination, remyelination, and onion bulb formation. These findings are nonspecific and similar to that seen in GBS and experimental autoimmune neuritis (animal model for inflammatory demyelinating disease). Demyelination, remyelination, and onion bulbs are also found in hereditary demyelinating neuropathies, although more often in a diffuse and uniform pattern. Clusters of macrophages surround endoneurial vessels more frequently in sural nerve biopsies of patients with CIDP compared with patients with hereditary neuropathies or normal controls (11). Breakdown of the blood-nerve barrier may be part of the pathology, suggested by evidence for decreased and mislocalized tight junction proteins by immunohistochemistry (12). In both CIDP and AIDP, T cells are found within the epineurium, perineurium, and endoneurium. T cells in both CIDP and AIDP demonstrate expression of CD73, which is a cell-surface enzyme that is required for lymphocyte entry into the brain and spinal cord (13). The CD28-related costimulatory molecule on T cells and its cognate ligand on macrophages, which are markers of T-cell activation, are seen in sural nerve biopsies of patients with both GBS and CIDP but not in patients with hereditary demyelinating neuropathies (14). In sum, the features of segmental demyelination, onion bulbs, and inflammation are not specific to CIDP,

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Table 13.2  Differential Diagnosis for CIDP and Variants Acquired demyelinating neuropathies

Immune/antibody associated AIDP/GBS MMN (anti-GM1 antibodies) POEMS syndrome Paraproteinemias Anti-MAG neuropathy Anti-sulfatide, anti-disialosyl ganglioside (sensory neuronopathy/ganglioneuritis) Anti-GM2 Anti-GD1b Infectious West Nile virus acute paralytic syndrome Tick paralysis Diptheria Toxic Hexane Thallium Arsenic Sodium cyanate

Hereditary demyelinating neuropathies

CMT type I Hereditary neuropathy with liability to pressure palsies Dejerine-Sottas (infants)

Other acquired neuropathies

Vasculitis Cyroglobulinemia

Rule out neuropathy from concurrent disease

HIV Diabetes Hypothyroidism Acromegaly Uremia Sarcoidosis Amyloidosis Myeloma Monoclonal gammopathies Lyme disease

Drugs

FK506 Perhexiline Amiodarone Bortezomib

and biopsy is often most useful as a means to exclude other causes of neuropathy and must be taken into consideration with the entire clinical and electrophysiological picture. Roughly a quarter of patients with CIDP have antibodies in the serum to peripheral nerve myelin proteins, such as the P0 and P2 proteins. This too is nonspecific, as a similar number of patients with GBS also have these antibodies (15,16). Antibodies to the PMP22 peripheral nerve myelin protein are found in patients with CIDP, GBS, and hereditary demyelinating neuropathies, rendering its significance unclear. These findings suggest antibodies against peripheral nerve myelin proteins may represent a response to, rather than cause of, damaged myelin (17).

Immunological Studies Both T- and B-cell responses play a role in the pathogenesis of CIDP. Fas receptor-mediated apoptosis of lymphocytes is an important endogenous mechanism for shutting down the immune response, and dysfunction of this system results in autoimmunity through impaired elimination of autoreactive T cells. Peripheral blood mononuclear cells from patients with CIDP show significantly reduced Fas-induced apoptosis (83%) compared with AIDP (59%) and healthy controls (43%) and may correlate with progressive or relapsing disease course (18,19). Interestingly, this decrease in Fas-mediated apoptosis in CIDP compared with AIDP and controls is present both at time of disease onset and after 18 months.

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Regulatory T cells are critical for maintaining immune tolerance and preventing autoimmunity primarily through secretion of cytokines that inhibit proliferation of immune cells. Patients with CIDP may have decreased number of circulating CD4+CD25+ regulatory T-cells (20) and defects in regulatory T-cell suppression of proliferation compared with healthy controls (21). Both B cells and myeloid precursor cells express the Fc-g receptor IIB (CD32B), an inhibitory receptor that binds the Fc portion of IgG, and is responsible for regulating IgG-mediated effector functions. CD32B knockout mice develop autoimmune disease, and polymorphisms in this gene are associated with systemic lupus erythematosus (SLE). This receptor is also required for the anti-inflammatory effects of intravenous immunoglobulin (IVIg). The peripheral monocytes, naïve B cells, and memory B cells in patients with CIDP before treatment with IVIg showed lower expression of Fc-g receptor IIB than controls. Furthermore, compared with matched controls patients with CIDP did not show an increase in expression of Fc-g receptor IIB with differentiation of naïve B cells to memory B cells. After treatment with IVIg, only CIDP patients with a clinical response showed increased expression of the Fc-g receptor IIB (22). MAG on myelin suppresses neurite growth by binding to a cell surface receptor, triggering a signal transduction cascade through the Rho-kinase pathway, which inhibits axon growth and is a key reason that axon regeneration is limited. MAG neuropathy is an acquired demyelinating neuropathy related to CIDP with progressive distal weakness and sensory ataxia. Studies have shown that anti-MAG antibodies inhibit growth of axons in vitro. The effects on axonal growth of murine dorsal root ganglion cells were tested with sera from patients with CIDP. When compared with sera from controls, sera from CIDP patients decreased axonal outgrowth length, and this process was reversed in the presence of a Rho-kinase inhibitor (23). This suggests that in CIDP there is perhaps a similar process inhibiting regeneration but by a distinct mechanism as anti-MAG antibodies are not found in CIDP.

Genetics Similar to other autoimmune diseases, CIDP is likely to have multiple genetic susceptibility loci, which are modulated by environmental effects. There is a slightly higher incidence of the Fc-g receptor IIB promoter polymorphism haplotype in patients with CIDP compared with controls. When homozygous, this polymorphism is strongly correlated with SLE and may be responsible for the lower expression of the receptor on B cells (22). This may in turn enhance dysregulation of IgG-mediated effector functions. In a study of Japanese patients with CIDP, a single nucleotide polymorphism in the TAG-1 gene correlated with response to IVIg. The TAG-1 gene encodes a protein expressed on axons and myelin sheaths, in

particular near the nodes of Ranvier, and is thought to participate in axonal-glial interactions (24). It has been implicated in animal models as a potential autoantibody target in demyelinating disease. The SH2D2A gene encodes a T-cell–specific adaptor protein involved in the early inhibition of T-cell activation. Polymorphisms of dinucleotide repeats in the promoter region occur more often in patients with CIDP than controls, with an odds ratio of 3 (25). This polymorphism causes reduced expression of the SH2D2A gene product, which in turn results in reduced secretion of interleukin-2 by T cells, an important cytokine in the regulation of autoimmunity. The same polymorphism was also found in patients with multiple sclerosis. The M3 allele of the a-1-antitrypsin protease inhibitor gene was found in higher proportion in patients with CIDP, GBS, and MS; this gene product may have an as yet undetermined role in the immune response (26).

Electrophysiological Studies Other studies attempted to assess whether there were changes in nerve conduction following treatment with IVIg. Patients with CIDP show improvement in the immediate period following IVIg treatment, which cannot be explained by remyelination or axonal regeneration, which occurs over the course of weeks. Detailed electrophysiological studies on patients before and immediately after treatment with IVIg demonstrated small but significant changes in excitability, as presumed from a decrease in chronaxie (strengthduration time constant) in patients with CIDP and MMN but not in controls (27).

Biomarkers Several investigations have revealed putative biomarkers for both CIDP and MMN, although no easily identified targets have been found. A pilot study using 2-dimensional difference in gel electrophoresis followed by mass spectroscopy identification of proteins compared CSF in patients with CIDP, GBS, and controls. Ten proteins were expressed at higher levels in CIDP compared with controls. One of these, transthyretin, was validated and compared with GBS because it was already known to be elevated in GBS. All the proteins identified are general markers of inflammation and degeneration and are unlikely to be specific (28). More promising results are revealed from skin and sural nerve biopsies. Skin biopsies taken from patients were subjected to gene microarray and quantitative realtime polymerase chain reaction (qPCR). A total of 5 genes were up-regulated and validated in CIDP compared with CMT controls and normal patients. All of these genes are involved in inflammation and immune function (29).

Diagnostic Evaluation

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Diagnosis of CIDP can be challenging and first requires a thorough history and neurological exam to establish a clear picture of the clinical features and time course (see above clinical features). Further evaluation should include lumbar puncture and CSF analysis, electrodiagnostic studies, and sometimes nerve biopsy (see Table 13.3). Response to treatment and magnetic resonance imaging (MRI) findings may also be helpful in establishing diagnosis.

CSF Analysis Lumbar puncture in patients with CIDP reveals normal opening pressure, fewer than 10 white blood cells (WBCs) per milliliter, and an elevated protein. This hallmark of cytoalbuminologic dissociation is found to be in 83% to 100% of patients with CIDP. Studies of the CSF should be sent to rule out other possibilities such as infection or malignancy.

Nerve Biopsy Nerve biopsy provides supporting evidence for the diagnosis of CIDP but is not required. Histopathology may be normal, but demyelination, remyelination, and signs of inflammation are often found. The limitations are that common biopsy sites (eg, sural nerve) are often less affected in CIDP, and there are risks of further neurological deficit and pain with biopsy of more commonly affected nerves.

Imaging MRI of the spinal cord and roots reveals hypertrophied nerve roots in ~50% of patients with CIDP, and there is often gadolinium enhancement of the nerve roots. This is especially true in childhood CIDP.

Electrophysiology Nerve conduction studies are an essential component in the diagnosis of CIDP and should be performed on any patient being evaluated for CIDP. Findings are consistent with multifocal or acquired demyelination, but these are not specific for CIDP. Although it is agreed upon that evidence of primary demyelination is required, numerous different criteria have been proposed. Each of these criteria, when taken in conjunction with other clinical and laboratory features, differs in sensitivity and specificity for identifying patients with CIDP. The hallmark findings include conduction block or temporal dispersion, reduced conduction velocity (beyond that caused by axonal loss), prolonged distal latency, and increased F-wave latency, or absent F waves. Historically, diagnosis relied mainly upon clinical signs and symptoms (30). As more cases were observed with increasing heterogeneity, broader criteria with clinical, laboratory, and electrophysiological components arose in order to increase sensitivity in diagnosis (31). The first set of stringent electrophysiological criteria was proposed by the American Academy of Neurology in 1991

for research purposes in order to achieve a high specificity (32). The diversity of clinical and electrophysiological findings and overlap of these parameters with other diseases have made it difficult to assemble a sufficiently sensitive and specific set of diagnostic criteria. Multiple research groups have set forth criteria that have minor but significant differences (see Table 13.4) (33,32,34–40). Although all criteria require demyelinating findings, the differences are in the number of findings required, how many nerves must be affected, and the specific definitions of each finding, which therefore affects both sensitivity and specificity as noted (41). As another adjunct to nerve conduction studies, there may be a role for somatosensory evoked potentials (SSEPs) in the diagnosis of CIDP in cases where sensory NCS are normal and the abnormal motor nerve studies suggest MMN or motor neuron disease (42).

Treatment OF CIDP First-line treatment for CIDP is with corticosteroids, intravenous immunoglobulin (IVIg), or plasmapheresis, based on either class I or II evidence. Studies of newer immunosuppressive and immunomodulatory agents have been small and shown mixed results, and some patients may benefit (43).

Corticosteroids Corticosteroids act as potent anti-inflammatory agents. They enter the cell and bind to their receptor, enter the nucleus, and induce transcription of a number of genes. Some of the effects are to decrease the number of circulating lymphocytes, decrease the release of inflammatory cytokines, decrease transmigration of leukocytes to sites of injury, and to increase the apoptosis of autoreactive T  cells in the peripheral nerve. Adverse effects include hyperglycemia, hypertension, gastritis, osteoporosis, aseptic necrosis of the hip, weight gain, myopathy, susceptibility to infection, mood disturbances, and suppression of the hypothalamic-pituitary-adrenal access (43). Treatment with corticosteroids is widely used based on several studies that revealed its effectiveness in CIDP and provide class II evidence for its use. A single randomized controlled trial in 1982 of 3 months of corticosteroid use vs no treatment demonstrated a small but significant improvement in disability, strength, and nerve conduction in patients with CIDP (44). Other studies since have shown efficacy for corticosteroids. The most common regimen is 60 mg prednisone daily for 6 weeks, followed by slow tapering according to individual disease course. Overall, corticosteroids are effective for 60% to 70% of patients with CIDP. A recent study compared the use of high-dose pulse dexamethasone to oral prednisone and found no difference in clinical response but some decrease in side effects in the pulse dose group (45).

Intravenous Immunoglobulin

Supportive

Mandatory: protein >45 mg/dL Supportive: cell count 2 mo

Saperstein

1. Motor and/or sensory >1 limb 2. Areflexia/hyporeflexia 3. Duration >2 mo

AAN

Clinical Criteria

Table 13.3  Comparison of Diagnostic Criteria for CIDP

Definite: clinical major, electrodiagnostic, and CSF (biopsy supportive) Probable: clinical major, electrodiagnostic or clinical major, CSF, and biopsy Possible: clinical major and 1 of 3 (electrodiagnostic, CSF, or biopsy) or clinical minor and 2 of 3 (electrodiagnostic, CSF, or biopsy)

Definite: clinical, electro­ diagnostic, CSF, and biopsy Probable: clinical, electrodiagnostic and CSF Possible: clinical and electrodiagnostic

Definite/Probable/Possible

Sensitivity: 43%–80%

Sensitivity: 81%–100%

Sensitivity: 47%–70%

Sensitivity: 11%–63% Specificity: 98%–100%

Sensitivity and Specificity

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Not mandatory

Absence of serum parap rotein, absence of genetic abnormality

Elevated protein, cell count Unequivocal demyelination and/or remyelination 5 fibers by EM or MRI with Gad enhancement in >6/50 teased fibers and/or hypertrophy of (supportive) cauda equina, lumbosacral, or cervical nerve roots, or brachial or lumbosacral plexuses (supportive)

Cytoalbuminologic dissociation supportive but not mandatory

Encouraged, not mandatory

Abbreviation: EFNS/PNS, European Federation of Neurological Societies and the Peripheral Nerve Society.

Chronic polyneuropathy, for >2 mo and either all of these 3   1. symmetric onset or symmetric exam   2. weakness in all 4 limbs   3. at least 1 limb with proximal weakness or electrodiagnostic criteria

Koski

Typical CIDP:   1. Chronic progressive, stepwise, or recurrent proximal and distal weakness and sensory dysfunction of all limbs   2. Areflexia/hyporeflexia   3. Duration >2 mo Atypical CIDP: one of   -distal weakness (DADS)   -pure motor or sensory   -asymmetric presentations (MADSAM, LSS)   -CNS involvement Exclude: diphtheria, drug/toxin, hereditary demyelinating neuropathies, sphincter dysfunction, MMN, anti-MAG antibodies

EFNS/PNS

1. Proximal and distal motor and/or sensory dysfunction in >1 limb 2. Areflexia/hyporeflexia 3. Duration >2 mo 4. Progressive, stepwise, or relapsing course

Van den Bergh, Pieret

1. Motor and sensory dysfunction >1 limb 2. Areflexia/hyporeflexia 3. Significant disability in arm or leg function 4. Duration >2 mo 5. Stable or worsening clinical condition

INCAT-modified

Definite: Typical or atypical clinical findings with definite electrodiagnostic findings OR probable CIDP + >1 supportive or possible CIDP + >2 supportive Probable: clinical criteria with possible electrodiagnostic findings or possible CIDP+ >1 supportive Possible: clinical criteria with possible electrodiagnostic findings

Sensitivity: 63%

Sensitivity: 34%–81% -Specificity: 96%

Sensitivity: 75%–79.5%

Sensitivity: 50%–95%

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Table 13.4  Comparison of Electrodiagnostic Criteria for CIDP Source and Year

Criteria

Definitions

AAN, 1991

3 of 4 abnormal:   1. CB/TD in ³1 nerve   2. CV in ³2 nerves   3. DL in ³2 nerves   4. FW in ³2 nerves

CB: >20% drop in CMAP amplitude from proximal to distal TD: >15% increase in duration after proximal stimulation CV: 80% LLN or 80% LLN, >150% ULN if CMAP amplitude 125% ULN if CMAP amplitude >80% LLN, >150% ULN if CMAP amplitude 50% drop in CMAP amplitude from proximal to distal, but variable depending on nerve TD: >30% increase in duration after proximal stimulation CV: 80% LLN or 80% LLN, >150% ULN if CMAP amplitude 125% ULN if CMAP amplitude >80% LLN, >150% ULN if CMAP amplitude 30% drop in CMAP amplitude from proximal to distal, excluding regions of compression TD: proximal CMAP duration ³30% of distal CMAP duration or distal CMAP duration ³9 ms (both measured as return to baseline after last negative peak above baseline) CV: 20% drop in negative peak area or peak-to-peak amplitude between proximal and distal sites; additional studies required (eg, stimulation across short segments or individual motor units) CV (significantly reduced): £80% LLN or 150% ULN if CMAP Amplitude 120% ULN or >150% ULN if CMAP amplitude 30% drop in amplitude from proximal to distal, except >50% drop at Erb’s point TD: >15% increase in duration after proximal stimulation CV: 80% LLN or 80% LLN or >150% ULN if CMAP amplitude 120% ULN if CMAP amplitude >80% LLN or >150% ULN if CMAP amplitude 50% in 2 nerves or in 1 nerve and other parameter in other nerve CB (probable): >30% in 2 nerves or in 1 nerve and other parameter in other nerve TD: >30% increase in duration in 2 nerves CV: 150% ULN in 2 nerves FW: latency 120% ULN or >150% ULN if CMAP amplitude 30% increase in duration after proximal stimulation in ³2 nerves CV: £70% LLN in 2 nerves DL: ³150% ULN in 2 nerves (excluding median neuropathy from carpal tunnel syndrome) FW: latency ³120% ULN in 2 nerves (³150% ULN if distal CMAP 50% of motor nerves tested DL: abnormal in >50% of motor nerves tested FW: latency abnormal in >50% of motor nerves tested (definitions of CV, DL, FW as per AAN criteria)

Abbreviations: CB, conduction block; CMAP, compound muscle action potential; CV, conduction velocity; DL, distal motor latency; FW, F-wave (latency and/or absence); TD, temporal dispersion.

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Intravenous immunoglobulins are thought to work by multiple mechanisms. Immunoglobulin is purified from human plasma (3000-10  000 donors), then stabilized with sugars or amino acids to prevent aggregation. The product is often treated with agents to inactivate hepatitis and HIV viruses. In the end IVIg contains >95% IgG and 8 weeks. • Diagnostic workup includes lumbar puncture, which shows cytoalbuminologic dissociation, and electrodiagnostic studies, which show evidence of multifocal demyelination. Imaging of the spine and biopsy may aid in diagnosis. • CIDP may be difficult to define without a universally present biomarker. Numerous criteria have been proposed, which include clinical features, electrodiagnostic criteria, cytoalbuminologic dissociation, and nerve biopsy (see Table 13.3). • Electrodiagnostic criteria for demyelination include conduction block, temporal dispersion, slow conduction velocity, and prolonged F-wave and distal motor latencies (see Table 13.4). • Pathogenesis of CIDP is unknown but there is clear evidence for immune dysregulation and evidence for both B- and T-cell dysfunction. • First-line therapy for CIDP includes corticosteroids, plasmapheresis, or IVIg; evidence supports each, and individual patient considerations will determine first choice. • First-line therapy for MMN is IVIg. Patients may worsen with corticosteroids or plasmapheresis.

References 1. Rajabally YA, Simpson BS, Beri S, Bankart J, Gosalakkal JA. Epidemiologic variability of chronic inflammatory demyelinating polyneuropathy with different diagnostic criteria: study of a UK population. Muscle Nerve. 2009;39(4):432–438. 2. Laughlin RS, Dyck PJ, Melton LJ, 3rd, Leibson C, Ransom J. Incidence and prevalence of CIDP and the association of diabetes mellitus. Neurology. 2009;73(1):39–45. 3. Dyck PJ, Oviatt KF, Lambert EH. Intensive evaluation of referred unclassified neuropathies yields improved diagnosis. Ann Neurol. 1981;10(3):222–226. 4. Barohn RJ. Approach to peripheral neuropathy and neuronopathy. Semin Neurol. 1998;18(1):7–18.

5. Brannagan TH, 3rd. Current diagnosis of CIDP: the need for biomarkers. J Peripher Nerv Syst. 2011;16(suppl): 1–11. 6. Hughes RA. The spectrum of acquired demyelinating polyradiculoneuropathy. Acta Neurol Belg. 1994;94(2): 128–132. 7. Oh SJ, Kurokawa K, de Almeida DF, Ryan HF, Jr., Claussen GC. Subacute inflammatory demyelinating polyneuropathy. Neurology. 2003;61(11):1507–1512. 8. Gorson KC, Ropper AH, Adelman LS, Weinberg DH. Influence of diabetes mellitus on chronic inflammatory demyelinating polyneuropathy. Muscle Nerve. 2000;23(1): 37–43. 9. Sharma KR, Cross J, Farronay O, Ayyar DR, Shebert RT, Bradley WG. Demyelinating neuropathy in diabetes mellitus. Arch Neurol. 2002;59(5):758–765. 10. Ruts L, Drenthen J, Jacobs BC, van Doorn PA. Distinguishing acute-onset CIDP from fluctuating GuillainBarre syndrome: a prospective study. Neurology. 2010;74 (21):1680–1686. 11. Sommer C, Koch S, Lammens M, Gabreels-Festen A, Stoll G, Toyka KV. Macrophage clustering as a diagnostic marker in sural nerve biopsies of patients with CIDP. Neurology. 2005;65(12):1924–1929. 12. Kanda T, Numata Y, Mizusawa H. Chronic inflammatory demyelinating polyneuropathy: decreased claudin-5 and relocated ZO-1. J Neurol Neurosurg Psychiatry. 2004; 75(5):765–769. 13. Meyer Zu Horste G, Reiners J, Lehmann HC, Airas L, Kieseier BC. CD73 is expressed on invading T lymphocytes in the inflamed peripheral nerve. Muscle Nerve. 2009;40(2):287–289. 14. Hu W, Janke A, Ortler S, Hartung HP, Leder C, Kieseier BC, Wiendl H. Expression of CD28-related costimulatory molecule and its ligand in inflammatory neuropathies. Neurology. 2007;68(4):277–282. 15. Khalili-Shirazi A, Atkinson P, Gregson N, Hughes RA. Antibody responses to P0 and P2 myelin proteins in GuillainBarre syndrome and chronic idiopathic demyelinating polyradiculoneuropathy. J Neuroimmunol. 1993;46(1–2): 245–251. 16. Allen D, Giannopoulos K, Gray I, Gregson N, Makowska A, Pritchard J, Hughes RA. Antibodies to peripheral nerve myelin proteins in chronic inflammatory demyelinating polyradiculoneuropathy. J Peripher Nerv Syst. 2005;10(2):174–180. 17. Ritz MF, Lechner-Scott J, Scott RJ, Fuhr P, Malik N, Erne B, Taylor V, Suter U, Schaeren-Wiemers N, Steck AJ. Characterisation of autoantibodies to peripheral myelin protein 22 in patients with hereditary and acquired neuropathies. J Neuroimmunol. 2000;104(2):155–163. 18. Comi C, Gaviani P, Leone M, Ferretti M, Castelli L, Mesturini R, Ubezio G, Chiocchetti A, Osio M, Muscia F, Bogliun G, Corso G, Gavazzi A, Mariani C, Cantello R, Monaco F, Dianzani U. Fas-mediated T-cell apoptosis is impaired in patients with chronic inflammatory demyelinating polyneuropathy. J Peripher Nerv Syst. 2006;11(1):53–60. 19. Comi C, Osio M, Ferretti M, Mesturini R, Cappellano G, Chiocchetti A, Carecchio M, Nascimbene C, Varrasi C, Cantello R, Mariani C, Monaco F, Dianzani U. Defective Fas-mediated T-cell apoptosis predicts acute onset CIDP. J Peripher Nerv Syst. 2009;14(2):101–106.

CHAPTER 13: CIDP, multifocal motor neuropathy, and related disorders  199 20. Sanvito L, Makowska A, Gregson N, Nemni R, Hughes RA. Circulating subsets and CD4(+)CD25(+) regulatory T cell function in chronic inflammatory demyelinating polyradiculoneuropathy. Autoimmunity. 2009;42(8):667–677. 21. Chi LJ, Wang HB, Wang WZ. Impairment of circulating CD4+CD25+ regulatory T cells in patients with chronic inflammatory demyelinating polyradiculoneuropathy. J Peripher Nerv Syst. 2008;13(1):54–63. 22. Tackenberg B, Jelcic I, Baerenwaldt A, Oertel WH, Sommer N, Nimmerjahn F, Lunemann JD. Impaired inhibitory Fcgamma receptor IIB expression on B cells in chronic inflammatory demyelinating polyneuropathy. Proc Natl Acad Sci USA. 2009;106(12):4788–4792. 23. Taniguchi J, Sawai S, Mori M, Kubo T, Kanai K, Misawa S, Isose S, Yamashita T, Kuwabara S. Chronic inflammatory demyelinating polyneuropathy sera inhibit axonal growth of mouse dorsal root ganglion neurons by activation of Rho-kinase. Ann Neurol. 2009;66(5):694–697. 24. Iijima M, Tomita M, Morozumi S, Kawagashira Y, Nakamura T, Koike H, Katsuno M, Hattori N, Tanaka F, Yamamoto M, Sobue G. Single nucleotide polymorphism of TAG-1 influences IVIg responsiveness of Japanese patients with CIDP. Neurology. 2009;73(17):1348–1352. 25. Notturno F, Pace M, De Angelis MV, Caporale CM, Giovannini A, Uncini A. Susceptibility to chronic inflammatory demyelinating polyradiculoneuropathy is associated to polymorphic GA repeat in the SH2D2A gene. J Neuroimmunol. 2008;197(2):124–127. 26. McCombe PA, Clark P, Frith JA, Hammond SR, Stewart GJ, Pollard JD, McLeod JG. Alpha-1 antitrypsin phenotypes in demyelinating disease: an association between demyelinating disease and the allele PiM3. Ann Neurol. 1985;18(4):514–516. 27. Boerio D, Creange A, Hogrel JY, Gueguen A, Bertrand D, Lefaucheur JP. Nerve excitability changes after intravenous immunoglobulin infusions in multifocal motor neuropathy and chronic inflammatory demyelinating neuropathy. J Neurol Sci. 2010;292(1–2):63–71. 28. Tumani H, Pfeifle M, Lehmensiek V, Rau D, Mogel H, Ludolph AC, Brettschneider J. Candidate biomarkers of chronic inflammatory demyelinating polyneuropathy (CIDP): proteome analysis of cerebrospinal fluid. J Neuroimmunol. 2009;214(1–2):109–112. 29. Lee G, Xiang Z, Brannagan TH, 3rd, Chin RL, Latov N. Differential gene expression in chronic inflammatory demyelinating polyneuropathy (CIDP) skin biopsies. J Neurol Sci. 2010;290(1–2):115–122. 30. Dyck PJ, Lais AC, Ohta M, Bastron JA, Okazaki H, Groover RV. Chronic inflammatory polyradiculoneuropathy. Mayo Clin Proc. 1975;50(11):621–637. 31. Barohn RJ, Kissel JT, Warmolts JR, Mendell JR. Chronic inflammatory demyelinating polyradiculoneuropathy. Clinical characteristics, course, and recommendations for diagnostic criteria. Arch Neurol. 1989;46(8):878–884. 32. Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Report from an Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. Neurology. 1991;41(5):617– 618. 33. Berger AR, Bradley WG, Brannagan TH, Busis NA, Cros DP, Dalakas MC, Danon MJ, Donofrio P, Engel WK, England JD, Feldman EL, Freeman RL, Kinsella LJ, Lacomis D, Latov N, Menkes DL, Sander HW, Thomas FP,

Triggs WJ, Windebank AJ, Wolfe GI. Guidelines for the diagnosis and treatment of chronic inflammatory demyelinating polyneuropathy. J Peripher Nerv Syst. 2003;8(4): 282–284. 34. Saperstein DS, Katz JS, Amato AA, Barohn RJ. Clinical spectrum of chronic acquired demyelinating polyneuropathies. Muscle Nerve. 2001;24(3):311–324. 35. Hughes R, Bensa S, Willison H, Van den Bergh P, Comi G, Illa I, Nobile-Orazio E, van Doorn P, Dalakas M, Bojar M, Swan A. Randomized controlled trial of intravenous immunoglobulin versus oral prednisolone in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol. 2001;50(2):195–201. 36. Koski CL, Baumgarten M, Magder LS, Barohn RJ, Goldstein J, Graves M, Gorson K, Hahn AF, Hughes RA, Katz J, Lewis RA, Parry GJ, van Doorn P, Cornblath DR. Derivation and validation of diagnostic criteria for chronic inflammatory demyelinating polyneuropathy. J Neurol Sci. 2009;277(1–2):1–8. 37. Van den Bergh PY, Hadden RD, Bouche P, Cornblath DR, Hahn A, Illa I, Koski CL, Leger JM, Nobile-Orazio E, Pollard J, Sommer C, van Doorn PA, van Schaik IN. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society—First Revision. Eur J Neurol. 2010;17(3):356–363. 38. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society—First Revision. J Peripher Nerv Syst. 2010;15(1): 1–9. 39. Van den Bergh PY, Pieret F. Electrodiagnostic criteria for acute and chronic inflammatory demyelinating polyradiculoneuropathy. Muscle Nerve. 2004;29(4):565–574. 40. Nicolas G, Maisonobe T, Le Forestier N, Leger JM, Bouche P. Proposed revised electrophysiological criteria for chronic inflammatory demyelinating polyradiculoneuropathy. Muscle Nerve. 2002;25(1):26–30. 41. De Sousa EA, Chin RL, Sander HW, Latov N, Brannagan TH, 3rd. Demyelinating findings in typical and atypical chronic inflammatory demyelinating polyneuropathy: sensitivity and specificity. J Clin Neuromuscul Dis. 2009;10(4):163–169. 42. Yiannikas C, Vucic S. Utility of somatosensory evoked potentials in chronic acquired demyelinating neuropathy. Muscle Nerve. 2008;38(5):1447–1454. 43. Brannagan TH, 3rd. Current treatments of chronic immunemediated demyelinating polyneuropathies. Muscle Nerve. 2009;39(5):563–578. 44. Dyck PJ, O’Brien PC, Oviatt KF, Dinapoli RP, Daube JR, Bartleson JD, Mokri B, Swift T, Low PA, Windebank AJ. Prednisone improves chronic inflammatory demyelinating polyradiculoneuropathy more than no treatment. Ann Neurol. 1982;11(2):136–141. 45. van Schaik IN, Eftimov F, van Doorn PA, Brusse E, van den Berg LH, van der Pol WL, Faber CG, van Oostrom JC, Vogels OJ, Hadden RD, Kleine BU, van Norden AG, Verschuuren JJ, Dijkgraaf MG, Vermeulen M. Pulsed high-dose dexamethasone versus standard prednisolone

200  Textbook of Peripheral Neuropathy treatment for chronic inflammatory demyelinating polyradiculoneuropathy (PREDICT study): a double-blind, randomised, controlled trial. Lancet Neurol. 2010;9(3): 245–253. 46. Hughes RA, Donofrio P, Bril V, Dalakas MC, Deng C, Hanna K, Hartung HP, Latov N, Merkies IS, van Doorn PA. Intravenous immune globulin (10% caprylatechromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy (ICE study): a randomised placebo-controlled trial. Lancet N­eurol. 2008;7(2):136–144. 47. Mendell JR, Barohn RJ, Freimer ML, Kissel JT, King W, Nagaraja HN, Rice R, Campbell WW, Donofrio PD, Jackson CE, Lewis RA, Shy M, Simpson DM, Parry GJ, Rivner MH, Thornton CA, Bromberg MB, Tandan R, Harati Y, Giuliani MJ. Randomized controlled trial of IVIg in untreated chronic inflammatory demyelinating polyradiculoneuropathy. Neurology. 2001;56(4):445–449. 48. Donofrio PD, Bril V, Dalakas MC, Deng C, Hanna K, Hartung HP, Hughes R, Latov N, Merkies I, van Doorn P. Safety and tolerability of immune globulin intravenous in chronic inflammatory demyelinating polyradiculoneuropathy. Arch Neurol. 2010;67(9):1082–1088. 49. Latov N, Deng C, Dalakas MC, Bril V, Donofrio P, Hanna K, Hartung HP, Hughes RA, Merkies IS, van Doorn PA. Timing and course of clinical response to intravenous immunoglobulin in chronic inflammatory demyelinating polyradiculoneuropathy. Arch Neurol. 2010;67(7):802–807. 50. Eftimov F, Winer JB, Vermeulen M, de Haan R, van Schaik IN. Intravenous immunoglobulin for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev. 2009(1):CD001797. 51. Dyck PJ, Litchy WJ, Kratz KM, Suarez GA, Low PA, Pineda AA, Windebank AJ, Karnes JL, O’Brien PC. A plasma exchange versus immune globulin infusion trial in chronic inflammatory demyelinating polyradiculoneuropathy. Ann Neurol. 1994;36(6):838–845. 52. Hahn AF, Bolton CF, Pillay N, Chalk C, Benstead T, Bril V, Shumak K, Vandervoort MK, Feasby TE. Plasmaexchange therapy in chronic inflammatory demyelinating polyneuropathy. A double-blind, sham-controlled, crossover study. Brain. 1996;119(pt 4):1055–1066. 53. Dyck PJ, Daube J, O’Brien P, Pineda A, Low PA, Windebank AJ, Swanson C. Plasma exchange in chronic inflammatory demyelinating polyradiculoneuropathy. N Engl J Med. 1986;314(8):461–465. 54. Mehndiratta MM, Hughes RA, Agarwal P. Plasma exchange for chronic inflammatory demyelinating  poly­ radiculoneuropathy. Cochrane Database Syst Rev. 2004(3): CD003906. 55. Berger AR, Herskovitz S, Scelsa S. The restoration of IVIg efficacy by plasma exchange in CIDP. Neurology. 1995;45(8):1628–1629. 56. Gorson KC, Allam G, Ropper AH. Chronic inflammatory demyelinating polyneuropathy: clinical features and response to treatment in 67 consecutive patients with and without a monoclonal gammopathy. Neurology. 1997;48(2):321–328. 57. Cocito D, Paolasso I, Antonini G, Benedetti L, Briani C, Comi C, Fazio R, Jann S, Mata S, Mazzeo A, Sabatelli M, Nobile-Orazio E. A nationwide retrospective analysis on the effect of immune therapies in patients with chronic in-

flammatory demyelinating polyradiculoneuropathy. Eur J Neurol. 2010;17(2):289–294. 58. Dalakas MC, Engel WK. Chronic relapsing (dysimmune) polyneuropathy: pathogenesis and treatment. Ann Neurol. 1981;9(suppl):134–145. 59. McCombe PA, Pollard JD, McLeod JG. Chronic inflammatory demyelinating polyradiculoneuropathy. A clinical and electrophysiological study of 92 cases. Brain. 1987;110(pt 6):1617–1630. 60. Dyck PJ, O’Brien P, Swanson C, Low P, Daube J. Combined azathioprine and prednisone in chronic inflammatorydemyelinating polyneuropathy. Neurology. 1985;35(8): 1173–1176. 61. Hughes RA, Swan AV, van Doorn PA. Cytotoxic drugs and interferons for chronic inflammatory demyelinating polyradiculoneuropathy. Cochrane Database Syst Rev. 2004(4):CD003280. 62. Randomised controlled trial of methotrexate for chronic inflammatory demyelinating polyradiculoneuropathy (RMC trial): a pilot, multicentre study. Lancet Neurol. 2009;8(2): 158–164. 63. Barnett MH, Pollard JD, Davies L, McLeod JG. Cyclosporin A in resistant chronic inflammatory demyeli­ nating polyradiculoneuropathy. Muscle Nerve. 1998;21(4): 454–460. 64. Mahattanakul W, Crawford TO, Griffin JW, Goldstein JM, Cornblath DR. Treatment of chronic inflammatory demyelinating polyneuropathy with cyclosporin-A. J Neurol Neurosurg Psychiatry. 1996;60(2):185–187. 65. Visudtibhan A, Chiemchanya S, Visudhiphan P. C­yclosporine in chronic inflammatory demyelinating polyradiculoneuropathy. Pediatr Neurol. 2005;33(5): 368–372. 66. Good JL, Chehrenama M, Mayer RF, Koski CL. Pulse cyclophosphamide therapy in chronic inflammatory demyelinating polyneuropathy. Neurology. 1998;51(6): 1735–1738. 67. Chaudhry V, Cornblath DR, Griffin JW, O’Brien R, Drachman DB. Mycophenolate mofetil: a safe and promising immunosuppressant in neuromuscular diseases. Neurology. 2001;56(1):94–96. 68. Mowzoon N, Sussman A, Bradley WG. Mycophenolate (CellCept) treatment of myasthenia gravis, chronic inflammatory polyneuropathy and inclusion body myositis. J Neurol Sci. 2001;185(2):119–122. 69. Umapathi T, Hughes R. Mycophenolate in treatmentresistant inflammatory neuropathies. Eur J Neurol. 2002;9(6): 683–685. 70. Gorson KC, Amato AA, Ropper AH. Efficacy of mycophenolate mofetil in patients with chronic immune demyelinating polyneuropathy. Neurology. 2004;63(4):715–717. 71. Toyka KV, Gold R. The pathogenesis of CIDP: rationale for treatment with immunomodulatory agents. Neurology. 2003;60(8 suppl 3):S2–S7. 72. Villa AM, Garcea O, Di Egidio M, Saizar R, Sica RE. Interferon beta-1a in chronic inflammatory demyelinating polyneuropathy: case report. Arq Neuropsiquiatr. 2004;62(3B): 892–894. 73. Vallat JM, Hahn AF, Leger JM, Cros DP, Magy L, Tabaraud F, Bouche P, Preux PM. Interferon beta-1a as an investigational treatment for CIDP. Neurology. 2003;60(8 suppl 3):S23–28.

CHAPTER 13: CIDP, multifocal motor neuropathy, and related disorders  201 74. Kuntzer T, Radziwill AJ, Lettry-Trouillat R, Naegeli C, Ochsner F, Erne B, Steck AJ, Bogousslavsky J. Interferonbeta1a in chronic inflammatory demyelinating polyneuropathy. Neurology. 1999;53(6):1364–1365. 75. Hadden RD, Sharrack B, Bensa S, Soudain SE, Hughes RA. Randomized trial of interferon beta-1a in chronic inflammatory demyelinating polyradiculoneuropathy. Neurology. 1999;53(1):57–61. 76. Gorson KC, Ropper AH, Clark BD, Dew RB, 3rd, Simovic D, Allam G. Treatment of chronic inflammatory demyelinating polyneuropathy with interferon-alpha 2a. Neurology. 1998;50(1):84–87. 77. Sabatelli M, Mignogna T, Lippi G, Milone M, Di Lazzaro V, Tonali P, Bertini E. Interferon-alpha may benefit steroid unresponsive chronic inflammatory demyelinating polyneuropathy. J Neurol Neurosurg Psychiatry. 1995;58(5): 638–639. 78. Choudhary PP, Thompson N, Hughes RA. Improvement following interferon beta in chronic inflammatory demyelinating polyradiculoneuropathy. J Neurol. 1995;242(4):252–253. 79. Hughes RA, Gorson KC, Cros D, Griffin J, Pollard J, Vallat JM, Maurer SL, Riester K, Davar G, Dawson K, Sandrock A. Intramuscular interferon beta-1a in chronic inflammatory demyelinating polyradiculoneuropathy. Neurology. 2010;74(8):651–657. 80. Gorson K, Hughes, R., Cros D. Efficacy of interferon beta-1a in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Neurology. 2008;70(A369). 81. Marsh EA, Hirst CL, Llewelyn JG, Cossburn MD, Reilly MM, Krishnan A, Doran M, Ryan AM, Coles AJ, Jones JL, Robertson NP. Alemtuzumab in the treatment of IVIGdependent chronic inflammatory demyelinating polyneuropathy. J Neurol. 2010;257(6):913–919. 82. Brannagan TH, 3rd, Patterson SK. Alemtuzumab: the future of chronic inflammatory demyelinating polyradiculoneuropathy treatment? Expert Rev Clin Immunol. 2010;6(3):319–321. 83. Nobile-Orazio E. Multifocal motor neuropathy. J Neuroimmunol. 2001;115(1-2):4–18. 84. Nobile-Orazio E, Cappellari A, Priori A. Multifocal motor neuropathy: current concepts and controversies. Muscle Nerve. 2005;31(6):663–680. 85. Kinsella LJ, Lange DJ, Trojaborg W, Sadiq SA, Younger DS, Latov N. Clinical and electrophysiologic correlates of elevated anti-GM1 antibody titers. Neurology. 1994;44(7):1278–1282. 86. Corbo M, Quattrini A, Lugaresi A, Santoro M, Latov N, Hays AP. Patterns of reactivity of human anti-GM1 antibodies with spinal cord and motor neurons. Ann Neurol. 1992;32(4):487–493.

87. Thomas FP. [Anti-Gm1 antibodies in motor system diseases and neuropathies]. Nervenarzt. 1990;61(12):704–710. 88. Ogawa-Goto K, Funamoto N, Ohta Y, Abe T, Nagashima K. Myelin gangliosides of human peripheral nervous system: an enrichment of GM1 in the motor nerve myelin isolated from cauda equina. J Neurochem. 1992;59(5):1844–1849. 89. Arasaki K, Kusunoki S, Kudo N, Kanazawa I. Acute conduction block in vitro following exposure to antiganglioside sera. Muscle Nerve. 1993;16(6):587–593. 90. Santoro M, Uncini A, Corbo M, Staugaitis SM, Thomas FP, Hays AP, Latov N. Experimental conduction block induced by serum from a patient with anti-GM1 antibodies. Ann Neurol. 1992;31(4):385–390. 91. Uncini A, Santoro M, Corbo M, Lugaresi A, Latov N. Conduction abnormalities induced by sera of patients with multifocal motor neuropathy and anti-GM1 antibodies. Muscle Nerve. 1993;16(6):610–615. 92. Van Es HW, Van den Berg LH, Franssen H, Witkamp TD, Ramos LM, Notermans NC, Feldberg MA, Wokke JH. Magnetic resonance imaging of the brachial plexus in patients with multifocal motor neuropathy. Neurology. 1997;48(5):1218–1224. 93. Azulay JP, Blin O, Pouget J, Boucraut J, Bille-Turc F, Carles G, Serratrice G. Intravenous immunoglobulin treatment in patients with motor neuron syndromes associated with anti-GM1 antibodies: a double-blind, placebo-controlled study. Neurology. 1994;44(3 pt 1):429–432. 94. Van den Berg LH, Kerkhoff H, Oey PL, Franssen H, Mollee I, Vermeulen M, Jennekens FG, Wokke JH. Treatment of multifocal motor neuropathy with high dose intravenous immunoglobulins: a double blind, placebo controlled study. J Neurol Neurosurg Psychiatry. 1995;59(3):248–252. 95. Federico P, Zochodne DW, Hahn AF, Brown WF, Feasby TE. Multifocal motor neuropathy improved by IVIg: randomized, double-blind, placebo-controlled study. Neurology. 2000;55(9):1256–1262. 96. Leger JM, Chassande B, Musset L, Meininger V, Bouche P, Baumann N. Intravenous immunoglobulin therapy in multifocal motor neuropathy: a double-blind, placebocontrolled study. Brain. 2001;124(pt 1):145–153. 97. Feldman EL, Bromberg MB, Albers JW, Pestronk A. Immunosuppressive treatment in multifocal motor neuropathy. Ann Neurol. 1991;30(3):397–401. 98. Donaghy M, Mills KR, Boniface SJ, Simmons J, Wright I, Gregson N, Jacobs J. Pure motor demyelinating neuropathy: deterioration after steroid treatment and improvement with intravenous immunoglobulin. J Neurol Neurosurg Psychiatry. 1994;57(7):778–783. 99. Carpo M, Cappellari A, Mora G, Pedotti R, Barbieri S, Scarlato G, Nobile-Orazio E. Deterioration of multifocal motor neuropathy after plasma exchange. Neurology. 1998;50(5):1480–1482. 100. Finsterer J, Derfler K. Immunoadsorption in multifocal motor neuropathy. J Immunother. 1999;22(5):441–442. 101. Stieglbauer K, Topakian R, Hinterberger G, Aichner FT. Beneficial effect of rituximab monotherapy in multifocal motor neuropathy. Neuromuscul Disord. 2009;19(7): 473–475.

14

Peter D. Donofrio

Medication-Related Neuropathy

because the medication can cause an axonopathy or a demyelinating neuropathy. Not all of the medications listed in Tables 14.1 to 14.3 will be discussed in the text.

INTRODUCTION Many etiologies exist for polyneuropathies including diabetes, vitamin deficiencies, uremia, connective tissue disorders, inheritance, and many others. Polyneuropathy as an adverse effect from medications is rare, but as the number of medications used to treat medical disorders increases, one must keep in mind the potential link between the patient’s neuropathy and his or her medications. Also to be considered is the superimposition of a medication-induced neuropathy in someone with a preexisting neuropathy such as the use of chemotherapeutic agents in patients with an underlying inherited or diabetic neuropathy. Jain et al has estimated the incidence of polyneuropathy from medications or toxins to be 2% to 4% (1). This manuscript will focus on commonly prescribed medications, immunosuppressant agents, and chemotherapeutic drugs that can lead to polyneuropathies as an undesired adverse effect. The presentation of patients with drug-related or induced polyneuropathy often does not differ from that of most chronic length-dependent neuropathies except for a few exceptions. The peripheral nervous system reacts to toxins in a limited manner. Thomas hypothesized that most toxins including medications produce damage in 1 of 4 regions of the peripheral nerve: (a) the distal sensory and motor axon (axonopathy), (b) the Schwann cell, leading to a demyelinating neuropathy, (c) the dorsal root ganglion (ganglionopathy or neuronopathy), and (d) the anterior horn cell or motor neuron (2). In keeping with this classification, most medication-induced neuropathies can be categorized into 1 of 4 groups depending upon the region of the peripheral nervous system where the primary pathologic process occurs (Tables 14.1–14.3). As is true of most classifications, not all drugs fit perfectly into a category, and some drugs can cause pathology in more than one region of the nerve as well as in the central nervous system. Tables 14.1 to 14.3 group medication-induced neuropathies by the major confirmed or presumed anatomic site of pathology. Several drugs are listed in more than one grouping

Amiodarone The most common neurological adverse effects of amiodarone are tremor, optic neuropathy, and peripheral neuropathy (3,4). The polyneuropathy typically begins between 5 and 12 months after amiodarone is first taken and is estimated to occur in 6% of patients who are treated for several months or longer (5). Unlike most toxic neuropathies, amiodarone gives rise to more than one type of pathological process in the peripheral nerve. The neuropathy may be primarily axon loss, demyelinating, or a combination as reflected in the nerve conduction studies (6,7). Nerve biopsy shows severe loss of large and small myelinated fibers as well as unmyelinated fibers (4). Not uncommonly, amiodarone can cause a polyneuropathy that appears strikingly similar to chronic inflammatory demyelinating polyneuropathy CIDP) in its clinical evolution and the electrodiagnostic findings of a multifocal demyelinating polyneuropathy (7). Sometimes patients may be treated for CIDP with several immunosuppressant medications before the diagnosis of amiodaroneinduced neuropathy is considered. Although a trial-off of amiodarone should be considered to distinguish between the 2 disorders, often, the diagnosis can be made by correlating the onset of the polyneuropathy to the introduction of amiodarone.

Amitriptyline Amitriptyline is a tricyclic antidepressant that has become a well-accepted treatment for neuropathic pain. Ironically, amitriptyline has been associated with the development of a peripheral neuropathy as described in several case reports (8,9). Zampollo et al reported a man who developed lower limb paresthesias, distal hypesthesia, and reduced ankle reflexes after taking 150 mg of amitriptyline uninterrupted for 2 years (9). Motor and 203

204  Textbook of Peripheral Neuropathy

Table 14.1  Anatomic Site of MedicationInduced Neuropathies: Axons

Table 14.3  Anatomic Site of MedicationInduce­d Neuropathies: Schwann Cell

Almitrine Amiodarone Amitriptyline Ara-C Bortezomib Carbimide Chloramphenicol Chloroquine Cimetidine Clioquinol Clofibrate Colchicine Cyanate Cyclosporin Danosine (ddl) Dichloroacetate Disopyramide Disulfiram Docetaxel Efosfamide Enalapril Ethambutol Ethioniamide Etretinate FIAU

Allopurinol Amiodarone Ara-C Gentamicin Griseofulvin Indomethacin Perhexiline Penicillamine Streptokinase Suramin Tacrolimus

Fluoroquinolones Hydralazine Gold Glutethimide Isoniazid

Lamivudine (3TC) Lansoprazole Leflunomide Linezolid Lithium Mefloquine Mercury Methaqualone Metronidazole Misonidazole Nitrofurantoin Nitrous Oxide Paclitaxel Phenelzine Phenytoin Podophyllin Propafenone Sulfapyridine Sulfasalazine Statins Stavudine (d4T) Suramin Tacrolimus Thalidomide TNF-a antagonists Vancomycin Vincristine Vinorelbine Zalcitabine (ddC)

sensory amplitudes were reduced, latencies were normal or prolonged, and conduction velocities were slowed, consistent with diffuse axon loss. When amitriptyline was discontinued, symptoms, signs, and  the electrophysiological abnormalities normalized within 3 years. Meadows et al reported a woman who developed an amitriptyline-induced neuropathy and whose sympTable 14.2  Anatomic Site of MedicationInduced Neuropathies: Dorsal Root Ganglion Cisplatin Carboplatin Efosfamide Etoposide (VP-16) Oxaliplatin Pyridoxine

TNF-a antagonists l-Tryptophan contaminant Zimeldine

toms remitted when treated with pyridoxine 500 mg/d (8). The authors hypothesized that amitriptyline produces a polyneuropathy in the same way as isoniazid, by depleting the availability of pyridoxal phosphate (8).

Clofibrate Clofibrate is a lipid-lowering agent that is used to treat patients who have elevated levels of cholesterol and triglycerides. It was prescribed more extensively before the development of the statin class of drugs used for the same purpose. Gabriel and Pearce reported a man with chronic renal failure on hemodialysis who developed a polyneuropathy approximately 1 year after taking clofibrate (10). Nerve conduction studies showed prolonged motor distal latencies and slowed conduction velocities consistent with a demyelinating neuropathy. The patient’s symptoms and signs resolved within 2 months of clofibrate discontinuation. The authors underscored the potential of clofibrate for causing peripheral nerve toxicity in patients with chronic renal failure

Colchicine Riggs et al first described a relationship between colchicine and a neuropathy and myopathy in 1986 (11). Their patient had taken large doses of colchicine for 5 years. The neurological examination was consistent with a severe sensory and motor neuropathy and a mild proximal myopathy. The muscle biopsy showed an increase in variability of myofiber size, rounded and atrophic myofibers, muscle fibers containing small vacuoles and subsarcolemmic deposits, and uneven staining of central muscle fibers. After discontinuing colchicine, the patient recovered except for persistent gait ataxia and distal hand weakness. In a larger study of 12 patients with colchicine myopathy and neuropathy, Kuncl et al

CHAPTER 14: Medication-Related Neuropathy  205

found similar abnormalities on clinical examination (12). Sural nerve biopsy in one patient identified mild loss of large myelinated axons, degenerating axons, and regenerating axon clusters. Biopsies of proximal muscles showed a distinctive vacuolar myopathy, in which the vacuoles were distributed either centrally or in the region of the subsarcolemma. After discontinuation of colchicine, the patient’s neurological function returned to normal within 4 weeks except for symptoms and signs of a mild neuropathy. The authors related the colchicine neuropathy and myopathy to renal dysfunction, as this adverse effect only occurred in patients with elevated serum creatinine and who were taking therapeutic doses of colchicine.

Dapsone Dapsone is commonly used to treat distinct dermatologic disorders such as dermatitis herpetiformis, pyoderma gangrenosum, acne conglobata, alopecia mucinosa, and leprosy. Several patients have been described who have developed a motor greater than sensory, distal greater than proximal polyneuropathy after taking dapsone (13,14). The neuropathy has been found in patients taking dosages ranging from 100 to 600 mg per day for several weeks to 16 years. An atypical feature of the neuropathy is greater involvement of the hands than the feet. Nerve conduction studies typically show normal to low normal conduction velocities, normal to prolonged distal latencies, and reduced CMAP amplitudes (15). The authors propose that dapsone has its primary effect on the motor soma and axons of the motor neuron (15). Marked improvement has occurred in all patients after discontinuation of dapsone. Similar to isoniazid, dapsone is metabolized by acetylation (16). Slow acetylation of the drug and accumulation of toxic blood and tissue levels have been implicated as the initiating steps in the development of the neuropathy (14,17).

Dichloroacetate Several of the drug-induced neuropathies only occur when the drug is administered in specific conditions. Dichloroacetate (DCA) is a lactic acid–lowering agent and has been used experimentally to treat mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) based on the premise that dichloroacetate lowers cerebral lactic acidosis and reduces neurological impairment. Kaufmann et al reported the onset of an unexpected peripheral neuropathy in 17 of 19 patients with MELAS treated with dichoroacetate (18,19). The neuropathy was primarily sensory and axon loss in terms of nerve fibers affected. The authors concluded that the DCA-associated neuropathy overshadowed any potential benefit of the medication for patients with MELAS. Other authors have opined that patients with MELAS and the A3243G mutation are particularly susceptible to DCA toxicity (19).

Disulfiram Disulfiram has been used since the 1940s as an agent to help the detoxification of chronic alcoholics. Mokri et al reported 4 patients with a disulfiram-induced motor and sensory symmetric polyneuropathy, varying from mild to severe (20). Initial symptoms of the neuropathy developed several weeks to 4 months after beginning the disulfiram. Nerve conduction studies showed absent sensory nerve action potentials, reduced amplitude of CMAPs, and slightly diminished nerve conduction velocities. In one patient, repeat nerve conduction studies 1 year later showed partial recovery of the SNAP in the median nerve and normalization of the conduction velocity in the motor fibers of the median and ulnar nerves. The investigators reported a decrease of both large and small myelinated fibers and axon degeneration in the sural nerve biopsy (20). Rare fulminant cases of disulfiraminduced neuropathy have been reported.

Ethambutol Ethambutol is a medication used with other antimycobacterial agents to treat tuberculosis. Optic neuritis is a well-known adverse effect of ethambutol therapy. Tugwell and James described 3 patients who developed a polyneuropathy 5 to 9 months after initiation of ethambutol therapy (21). The timing of the onset of the polyneuropathy was similar to the interval delay for optic neuritis. All patients had features consistent with a sensory greater than motor neuropathy. Nerve conduction studies showed reduced sensory nerve action potential amplitudes and slightly prolonged sensory distal latencies. Motor amplitudes were normal, and motor conduction velocities were either normal or slightly reduced. All 3 patients improved when the ethambutol was discontinued. An unpublished series of more than 1000 patients taking ethambutol reported 15 patients who complained of numbness in the extremities at some time while taking the medication.

Fluoroquinolones Fluoroquinolones have been described as causing a polyneuropathy, often beginning within 1 week of taking the medication (22,23). The major symptoms are paresthesia and numbness. The polyneuropathy is thought to occur more frequently in patients who have underlying predispositions for neuropathy including diabetes, renal insufficiency, and previous treatment with drugs known to cause a neuropathy. Patients typically recover within 2 weeks when the medication is stopped.

Gold In 1950, Doyle and Cannon reported the first extensive description of polyneuritis as an adverse reaction to gold therapy (24). They described a man who developed features of a severe motor and sensory polyneuropathy

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after receiving a cumulative dose of 900 mg of Myochrysine (450 mg of gold). At the peak of the neuropathy, the patient could not feed himself and complained of paresthesias from the feet to the rib cage. Physical examination revealed findings consistent with a severe motor and sensory polyneuropathy as well as marked incoordination, dysmetria, writhing movements of the hands (athetosis), and gait ataxia. The patient improved rapidly once the gold injections were discontinued. Walsh was the first to describe nerve conduction data in gold neuropathy (25). He reported results in a woman who developed a polyneuropathy after receiving a total of 85 mg of gold. The findings were in keeping with a sensory greater than motor axon loss neuropathy. A sural nerve biopsy showed loss of large and small diameter myelinated fibers. Teased fiber preparations demonstrated that most fibers were undergoing active axon degeneration, and only rare fibers showed segmental demyelination (25). Katrak et al reported electrophysiological and nerve biopsy results in 3 patients with gold-induced peripheral neuropathy (26). In 1 patient, nerve conduction studies were normal, whereas in the other 2 patients, abnormalities were recorded in almost all nerves tested. Many of the conduction rates (prolonged latencies and slowed conduction velocities) were sufficiently severe to suggest a demyelinating process. Nerve biopsy in 2 patients showed findings confirming axon degeneration. In all 3 patients, improvement occurred when the gold therapy was discontinued.

Griseofulvin Griseofulvin is a medication used to treat fungal infections particularly in the nails and nail beds. It is implicated in the cause of a sensory polyneuropathy in an elderly woman who was treated with griseofulvin twice, once for 4 months and later for 6 months (27). Nerve conduction studies showed findings consistent with a severe distal demyelinating sensory and motor polyneuropathy.

Hydralazine Hydralazine is a chelating agent and a carbonyl reagent that has been shown to form complexes with sulfhydryl groups. It inhibits enzymes involved in pyridoxine metabolism, and it is this capability to inhibit pyridoxine that accounts for the development of peripheral neuropathy in patients taking hydralazine. Although infrequently used for the treatment of hypertension, hydralazine was a mainstay of therapy several decades ago. Kirkendall and Page in 1962 reported 2 patients who developed symptoms and signs of a polyneuropathy after taking hydralazine for 3 to 8 months (28). In one patient, the neuropathy appeared to be primarily sensory. In the other, the neurological deficits were a foot drop and pronounced sensory symptoms and signs distally in

the legs. In both patients, stopping the hydralazine and adding pyridoxine lead to improvement in symptoms and strength within 2 to 4 weeks. Raskin and Fishman reported 2 additional patients who had  hydralazine­induced polyneuropathy, one who developed symptoms after 7 days and the other after 10 years (29).

Isoniazid Isoniazid is a hydrazide of isonicotinic acid. Its major route of metabolism is through acetylation to acetyl isoniazid (30). Isoniazid has been one of the mainstays of tuberculosis treatment for 5 decades. Isoniazid is another medication that causes peripheral neuropathy through its effect on pyridoxine metabolism (29). Studies have shown that a large bimodal variation in the metabolism of isoniazid exists among humans. Patients can be categorized into rapid or slow inactivators of isoniazid and this bimodality is genetically determined (31). Hughes and colleagues identified a polyneuropathy in 6 of 17 subjects taking isoniazid, 4 of whom were slow inactivators of isoniazid (32). Although the number of patients was small, they hypothesized that slow inactivators are more predisposed than rapid inactivators to develop polyneuropathy after treatment with isoniazid. Other investigators have shown that metabolism of isoniazid is inherited as an autosomal recessive trait (33). Slow acetylators are unable to metabolize isoniazid quickly leading to high blood levels and a greater propensity to develop a toxic neuropathy. In 1959, Money reported 84 patients with pulmonary tuberculosis who were receiving antituberculous therapy with isoniazid and para-aminosalicylic acid (33). Polyneuropathy was the most common of the neurological adverse effects. In almost all cases, the neuropathy did not develop until 6 months after the onset of isoniazid therapy. Sensory symptoms and signs were more common than weakness, and the lower extremities were more affected than the upper. Most patients improved when prescribed vitamin B supplementation despite the maintenance of isoniazid therapy. Ochoa described the neuropathological findings in 9 patients with isoniazid neuropathy (34). He observed a marked reduction in the number of myelinated fibers, the presence of denervated Schwann cell bands, and regenerated myelinated fibers. Mild slowing of nerve conduction velocities in the ulnar and peroneal nerves were reported in 6 of 9 patients.

Linezolid Linezolid is a synthetic antibiotic used to treat serious infections caused by gram-positive organisms. Numerous cases of optic neuropathy and severe painful motor and sensory peripheral neuropathy have been described to be associated with use of the drug (35). The drug is hypothesized to cause a neuropathy by causing mitochondrial damage. The optic neuropathy often resolves

CHAPTER 14: Medication-Related Neuropathy  207

when the drug is discontinued, but the polyneuropathy does not. The incidence of the neuropathy may relate to the duration of treatment.

Lithium It is well known that lithium in toxic doses may cause a tremor, but it can also lead to a severe polyneuropathy. Vanhooren et al reported 2 patients who developed an acute motor and sensory polyneuropathy as a result of lithium intoxication (36). Both patients initially presented with central nervous system manifestations including coma, hypertonia, conjugate eye deviation, Babinski signs, hemiparesis, and extrapyramidal signs. When consciousness was regained, one patient was found to have proximal weakness, and the other flaccid paralysis in the legs and areflexia. Motor nerve conduction studies showed reduced CMAP amplitudes and either normal or diminished conduction velocities. In one patient, the sural response was absent. Several months after clearing of the intoxication, improvement was documented in sensory and motor amplitudes. Sural nerve biopsy in one patient identified a moderate loss of myelinated fibers, mild endoneural fibrosis, and scattered vacuolated macrophages in which myelin debris was observed (36). Both patients improved from the lithium intoxication, but incompletely.

Mefloquine Mefloquine is an antimalarial agent used as prophylactic treatment to travelers to endemic areas and to treat multidrug-resistant plasmodia. Jha et al reported 2 patients who developed a rapidly progressive sensory and motor polyneuropathy and rash within 2 days of taking mefloquine (37). Electrophysiological studies were consistent with an axon-loss neuropathy. Both patients improved markedly within 3 to 6 months.

Metronidazole Metronidazole is a 5-nitromidazole antimicrobial used for the treatment of protozoan infections (trichomoniasis, giardiasis, and amoebiasis), as a bactericidal agent in anaerobic infections, and a treatment for Crohn disease. Several authors have reported a sensory neuropathy or neuronopathy in patients receiving metronidazole for the treatment of Crohn disease. Patients typically complain of paresthesias in the feet and hands. Sensory examination shows a distal gradient loss to small fiber more than large fiber perception in the setting of preserved strength. Nerve conduction studies show absent to reduced SNAP amplitudes and normal motor conduction studies (38,39). Sural nerve biopsy in the patient reported by Bradley et al identified a loss of many myelinated fibers and axonal degeneration in all of the remaining sensory fiber sizes (38). When metronidazole was discontinued in the 3 patients reported by Coxon, the sensory neuropathy improved completely in one,

partially in another, and remained static in the third (39).

Misonidazole Misonidazole is a 2-nitromidazole used as a red blood sensitizer before radiation therapy. It is chemically similar to metronidazole. Approximately one third of patients given misonidazole will develop a neuropathy. Melgaard et al reported 8 patients who developed a severe subacute sensory polyneuropathy after treatment with misonidazole for 3 to 5 weeks (40). The total dose of misonidazole varied between 17.0 and 22.0 g. All patients except one complained of severe pain and paresthesias in the feet and hands. Strength was rarely affected and deep tendon reflexes were preserved. On sensory testing, touch, pain sensation, vibration, and joint position sense were affected more in the feet than in the hands. Three to 5 months after discontinuation of the misonidazole, 4 patients were improved; 3 had died from the underlying carcinoma and 1 patient was unchanged. Nerve conduction studies were consistent with a severe primarily sensory neuropathy.

Nitrofurantoin Nitrofurantoin is a synthetic bacteriostatic antimicrobial. In years past, it was used to treat a wide range of grampositive and gram-negative organisms and is currently frequently prescribed for urinary tract infections. Several authors described a toxic neuropathy temporally related to the use of nitrofurantoin in 1956. The neuropathy can present as early as 1 to 2 weeks after initiation of nitrofurantoin therapy. The major manifestations are distal paresthesias, loss of sensory perception in the hands and feet, mild to moderate distal weakness, and areflexia (41). The neuropathy may resolve over time or it may become irreversible (41). Ellis reported 6 patients who developed an acute form of nitrofurantion-induced polyneuropathy (41). Three of the patients died from complications of the polyneuropathy; the relationship to nitrofurantion was not recognized and nitrofurantoin was continued until death. The other 3 patients made partial recoveries. All 6 patients had renal insufficiency, an observation also noted by Loughridge et al (42). This relationship lead to the recommendation that nitrofurantoin be used with caution in patients with renal insufficiency. Craven described 5 patients who developed a polyneuropathy after receiving treatment with nitrofurantoin (43). All of the 5 patients had normal BUN levels when the drug was first taken, yet all were determined to have mild renal insufficiency at the time the neuropathy developed clinically. Paul et al demonstrated in vitro that nitrofurantoin reversibly inhibits the formation of citrate at the stage of acetyl coenzyme A generation from pyruvate and coenzyme A (44). Inhibition should be greater when the blood level of nitrofurantoin is higher, a condition that exists in renal insufficiency.

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Toole and Parrish reviewed the world literature on nitrofurantoin neuropathy in 1973 (45). They noted that most patients experienced the onset of neuropathic symptoms within the first 6 weeks of treatment. The prescribed daily dosage ranged from 100 to 800 mg. Available follow-up information revealed that once nitrofurantoin was stopped, approximately one third experienced complete resolution of symptoms and signs, one half had residual disease, and one sixth remained unchanged. Nerve conduction findings in nitrofurantoin-induced polyneuropathy are scant. Nerve biopsy showed atrophy of the peripheral nerves (46).

nitrous oxide in patients with B12 deficiency neuropathy. It also creates concern for the use of nitrous oxide in patients with borderline B12 levels and patients with undiagnosed pernicious anemia or other causes of B12 deficiency. The risk of exposure of nitrous oxide to patients with neuropathy may be far greater than our present appreciation of the problem. Nitrous oxide should be considered in health-care professionals who present with a clinical presentation suggestive of subacute combined degeneration and who have access or exposure to anesthetics and in patients who admit to recreational sniffing of whipped cream dispensers (whippets).

Penicillamine Nitrous Oxide In 1978, Layzer et al reported 3 patients, 2 dentists, and 1 hospital technician who presented with symptoms of numbness and sensation of an electric shock passing from the toes to the neck after flexion of the neck (47). All 3 patients had a common history of excessive recreational use of nitrous oxide. In the same year, the same author described 15 additional patients with the same condition (48). He characterized the clinical presentation as a myeloneuropathy because of the combination of peripheral and central nervous system findings (48). All of his patients were dentists except for one, and all had abused nitrous oxide recreationally, except for 2 who were exposed to the inhalant professionally. In each case, the patient improved after cessation of the nitrous oxide. Five of the 15 patients continued to have moderate disability 6 weeks to 3 year after discontinuation of nitrous oxide. Because of its similarity to subacute combined degeneration, Layzer speculated that nitrous oxide might interfere with vitamin B12 metabolism. This hypothesis was furthered when Amess et al showed in patients undergoing cardiac bypass surgery that nitrous oxide inhalation produced an identical deoxyuridine suppression test result to that found in patients with vitamin B12 deficiency (49). As all of their patients had normal vitamin B12 concentrations, the data suggested that nitrous oxide interferes with vitamin B12 function. In this disorder, nerve conduction studies showed normal results in motor nerves and mild slowing of conduction velocities in sensory nerves. Sural nerve biopsy showed a normal number of nerve fibers, varying degrees of myelin ovoid formation, and rare fibers showing focal areas of axon swelling and denuded myelin. Unlike typical subacute combined degeneration, patients with nitrous oxide poisoning do not have a megaloblastic anemia. MRI scanning of the cervical and thoracic spine may show increase signal in the posterior column, a finding that may be misinterpreted as multiple sclerosis. The profound effect of nitrous oxide on B12 metabolism raises the awareness to carefully follow patients with pernicious anemia and neuropathy postoperatively when nitrous oxide is used in general anesthesia or, conversely, to encourage anesthesiologists to avoid

Penicillamine is a rare cause of polyneuropathy having been reported in a few patients when the treatment is used to manage rheumatoid arthritis (50,51). The neuropathy affects motor and sensory fibers and is demyelinating and axon loss in nature. Nerve pathology has shown extensive demyelination and axon loss and no evidence of inflammation or vasculitis that might be seen in a polyneuropathy from rheumatoid arthritis. Penicillamine-induced neuropathy is another example of a polyneuropathy caused by inhibition of pyridoxine metabolism. Penicillamine is a pyridoxine antagonist, and the neuropathy improves within several weeks when patients are given pyridoxine replacement.

Phenelzine Phenelzine is a nonselective monoamine oxidase inhibitor used to treat depression and anxiety. In rare cases, its use is associated with a sensory and motor neuropathy (52,53). The neuropathy is attributed to pyridoxine deficiency induced by the drug (52). This hypothesis was confirmed by Malcolm et al, who showed in 19 patients taking phenelzine a 54% reduction in the plasma level of pyridoxine (54). The neuropathy improves with repletion of pyridoxine.

Phenytoin Phenytoin has been commonly prescribed for epilepsy since its introduction in 1938. Lovelace and Horwitz identified 26 of 50 patients taking phenytoin who showed a peripheral neuropathy by clinical examination and electrophysiological study and in whom no other etiology could be found for the neuropathy (55). All patients had absent deep tendon reflexes in the lower extremities. Conduction velocities in the lower extremities ranged from 30 to 40 m/s in most affected patients, and the sensory and motor amplitudes were often low in amplitude, long in duration, and complex. The authors determined that the neuropathy was more likely to occur in patients who had taken phenytoin for more than 10 years. There was no correlation between the dosage of phenytoin and the development of a polyneuropathy.

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Shorvon and Reynolds followed 51 patients prospectively for 5 years with epilepsy who were prescribed either phenytoin or carbamazepine monotherapy (56). None of the patients receiving carbamazepine developed either clinical or electrophysiological features suggestive of a diffuse polyneuropathy. In the phenytoin group, none who were taking therapeutic doses developed clinical evidence of a neuropathy. In the group of patients taking phenytoin who developed polyneuropathy, review of the medical records uncovered recurrent toxic drug levels and low folic acid levels.

Podophyllin A prolonged severe polyneuropathy has been reported after both the topical use of podophyllin resin in the treatment of genital condylomata acuminata and the ingestion of podophyllin in an herbal laxative (57–59). The neuropathy may be accompanied by an enteritis, depression, and bone marrow depression (58). Nerve conduction studies and nerve biopsy have shown evidence consistent with axon loss.

Propafenone Propafenone hydrochloride is an antiarrhythmic medication used to treat supraventricular and ventricular arrhythmias. Galasso et al reported a patient who developed a painful sensory neuropathy after taking propafenone for 1 year (60). The neuropathy resolved when the drug was discontinued. Nerve conduction studies and thermoregulatory sweat testing were abnormal, and a sural nerve biopsy showed findings consistent with a distal small fiber neuropathy.

Pyridoxine Pyridoxine is an essential vitamin that has been consumed in large doses by individuals to aid in bodybuilding and has been prescribed as a treatment for premenstrual syndrome, carpal tunnel syndrome, schizophrenia, fibromyalgia, autism, and hyperkinesis. The minimum daily requirement of pyridoxine is 0.6 to 1.3 mg/d. Schaumburg et al reported a cohort of patients who developed a severe sensory neuropathy after taking from 2 to 6 g of pyridoxine daily for 2 to 40 months (61). All patients showed profound loss of most sensory modalities and were areflexic. All patients improved when pyridoxine was stopped, and 2 patients experienced almost complete recovery after 2 to 3 years of follow-up. The authors concluded that vitamin B6 in high doses was probably toxic to the dorsal root ganglia (61). In 1980, Krinke et al showed that large doses of pyridoxine produced a sensory neuronopathy in dogs; spinal cord pathology showed widespread neuronal degeneration in the dorsal root ganglia, the sensory nerve fibers in the peripheral nerves, dorsal columns of the spinal cord, and the descending spinal tract of the trigeminal nerves (62).

Although pyridoxine sensory neuronopathy is most commonly observed in individuals taking large doses of the vitamin, toxicity can be observed in patients ingesting much smaller doses. Of the 16 patients reported by Parry and Bredesen, 3 had been taking less than 1 g/d and 1 had taken only 100 to 200 mg for 3 years (63). Neuropathy has been reported as developing in patients taking doses as low as 24 mg/d (64).

Statins The statins are inhibitors of 3-hydroxy-3-methyl­glutaryl-coenzyme A (HMG-CoA) reductase, an enzyme that regulates the synthesis of cholesterol. In 1994, Jacobs reported the development of a sensory polyneuropathy in a patient who was treated with lovastatin for 2 years (65). The patient’s symptoms abated when lovastatin was discontinued but returned within 2 weeks when pravastatin was substituted for lovastatin. The following year, Ahmad reported 2 patients who had lovastatin-induced neuropathy (66). Nerve conduction study results were published in 4  patients with a polyneuropathy caused by simvastatin (67). Compound muscle action potential amplitudes were reduced in 3 of 4 patients, and all patients had absent or reduced sensory nerve action potential amplitudes. Motor and sensory conduction velocities were either normal or slightly slowed. The authors proposed that the simvastatin might produce toxicity through an adverse reaction on mitochondrial function. Inhibitors of HMG-CoA reductase, in addition to blocking cholesterol synthesis, also interfere with synthesis of dolichol and ubiquinone. A deficiency of ubiquinone, a key enzyme in the mitochondrial respiratory chain, might interfere with the energy utilization of the neuron and in turn produce a reversible polyneuropathy. Jeppesen et al reported similar electrophysiological results to those of Phan in 7 patients who developed a polyneuropathy after taking one of the following statin medications: lovastatin, fluvastatin, pravastatin, or simvastatin (68). Four of their patients had an irreversible neuropathy, a finding that the authors attributed to a longer exposure to the statins (4–7 years compared with 1–2 years). The polyneuropathy associated with statins is most often sensory or sensorimotor in type. There have been at least 2 case reports of patients who developed a mono­ neuritis multiplex after exposure to a statin medication and whose neuropathy improved after withdrawal of the drug and worsened with reintroduction (69,70). A patient developed a polyneuropathy resembling Guillain-Barré syndrome (GBS) after use of simvastatin (71). The neuropathy began 6 months after the medication was taken. Nerve conduction studies showed primarily axon loss features in sensory and motor fibers in the lower limbs. The spinal fluid protein level was 1.18 g/L (normal range, 0.20–0.45 g/L). The patient was treated with intravenous immunoglobulin (IVIg) over 5 days and recovered well over the

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course of the subsequent year. The authors hypothesized an acute hypersensitivity reaction to the statin lead to the development of a polyneuropathy resembling GBS (71). Substitution of one statin causing a polyneuropathy for another may not prevent the reoccurrence of a druginduced neuropathy. Ziajka and Wehmeier reported a patient who developed a neuropathy after taking lovastatin and whose symptoms returned when treated with simvastatin, pravastatin, and atorvastatin (72). The presence of renal failure and diabetes appears to increase the incidence of neuropathy in patients who take statins (73). Some physicians have challenged the relationship between statins and the development of polyneuropathy (74). Others recognize the relationship to be low risk and acknowledge that long-term exposure increases the chances for the neuropathy (4,14,16,75–77). One paper estimated the incidence of statin-induced neuropathy to be approximately 1 case per 10 000 patients taking statins; another manuscript estimated 60 cases per 100 000 (8,67,73,78). The Netherlands Pharmacovigilance Center in 2006 reported 17 patients who developed neuropathy associated with the use of statins and worsening of a preexisting polyneuropathy in 2 other patients. The polyneuropathies were associated with the prescription of simvastatin, atorvastatin, pravastatin, and rosumastatin. The time to onset of the polyneuropathy after taking the statin ranged from 1 day to 6 years. Eight of the patients did not note the onset of their neuropathy symptoms for 2 years or more. Approximately half of the patients experienced partial to complete recovery when the drug was stopped. The report concluded that long-term exposure to statins increases the risk for polyneuropathy, and this will take on greater importance as more patients worldwide are prescribed statins (79). Another study from Denmark reported a 4- to 14-fold increased risk for developing an idiopathic polyneuropathy in patients taking a statin medication compared with nonusers (80).

Thalidomide Thalidomide was initially manufactured as a sedative and hypnotic. In 1961, it was withdrawn from use because of teratogenesis and the propensity to cause phocomelia in neonates. Thalidomide is now undergoing resurgence as an effective treatment for several dermatologic conditions and has a role in the treatment of multiple myeloma, HIV infection, and rheumatologic disorders. Thalidomide was first described as causing a sensory and motor polyneuropathy in the early 1960s. The neuropathy is often associated with erythema of the hands and brittle fingernails. The incidence of neuropathy varies greatly from one report to another, with some authors reporting a neuropathy in up to 100% of patients exposed to thalidomide. The occurrence of neuropathy is probably related to the cumulative dose of thalidomide, and a total dose of 20 g is considered threatening (81).

Women and the elderly are most prone to developing the neuropathy, and it appears to be more common in patients who are slow drug acetylators. Most patients complain of paresthesias, hypesthesias, and leg cramps, greater distally than proximally, and more in the legs than in the upper extremities (82). Coasting is commonly observed for a month when thalidomide is discontinued. Small fiber modalities are often more affected than large fiber. Nerve conduction results are consistent with a sensory polyneuropathy (83). Complete recovery is the rule in approximately 25% of patients, whereas 30% improve partially and 45% do not recover (82).

Antiretroviral Medications Antiretroviral medications are categorized as nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs, protease inhibitors, fusion inhibitors, chemokine coreceptor antagonists, and integrase inhibitors. Peripheral neuropathy is associated with the use of the NRTIs: didanosine (ddl), zalcitabine (ddC), and stavudine (d4T), fialuridine (FIAU), and lamivudine (3TC) (84,85). All agents cause a polyneuropathy that is sensory greater than motor. The neuropathy typically presents 6 to 8 weeks after starting treatment and manifests as burning, paresthesia, and pain in the calves (84). Signs on neurological examination are commonly loss of small and large fiber sensory functions and absent ankle reflexes (77,85). The neuropathies are clinically indistinguishable from those of HIV-associated distal sensory neuropathy, yet the acute or subacute onset and rapid progression paralleling the use of the medications for HIV infection give a strong clue to the cause of the neuropathy as a toxic reaction to the agents. The toxic neuropathies are dose-dependent, and in the case of ddC, coasting may occur. In one study of ddC, all patients who received high dose (0.12–0.24 mg/kg/day) developed a distal sensory polyneuropathy (86). Because of the common toxicity of neuropathy after treatment with the NRTIs, lower doses are often used to initiate therapy. Even low doses of ddL, ddC, and d4T may cause a neuropathy in patients with preexisting subclinical neuropathy, inherited neuropathies, older patients, and those with poor nutrition. Usually, clinical improvement is observed 1 month after the discontinuation of the NRTI. The incidence of neuropathy may increase substantially if the NRTIs are used in a therapeutic regimen with hydroxyurea, a drug that itself is neurotoxic (87). The mechanism of neurotoxicity from the NRTIs is unknown but may relate to its inhibition of mitochondrial DNA g-polymerase.

Peripheral Neuropathies Associated With Chemotherapeutic Agents Many of the commonly prescribed chemotherapeutic agents can cause polyneuropathy, and they are listed in Table 14.4. They include the vinca alkaloids, the plati-

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num agents, the taxanes, suramin, cytosine arabinoside (Ara-C), etoposide, ifosfamide, and others. Vinca Alkaloids The term vinca alkaloid is derived from the extraction of the agent from the periwinkle plant. The vinca alkaloids consist of vincristine, vinblastine, vindesine, and vinorelbine. In a rank order of toxicity, vincristine is the most toxic, and the development of neuropathy is widely recognized by oncologists and neurologists (88). Some authors estimate that it occurs to some extent in most patients who receive the drug (84). Vincristine causes a dose-dependent sensory greater than motor and autonomic polyneuropathy. The neuropathy typically presents with paresthesia of the feet and hands and loss of ankle reflexes. Distal weakness may be present on examination but is clinically significant much less often. Unlike other chemotherapeutic agents, vincristine gives rise to an autonomic neuropathy that may manifest as abdominal pain, constipation, and sometimes an ileus (88). Fortunately, the neuropathy induced by vincristine is usually reversible once the chemotherapy is stopped, and complete recovery occurs in about 80% of patients, but the recovery may not be attained for 2 years (89). Coating may occur for several weeks to months after vincristine is discontinued. Nerve conduction studies confirm the findings expected in an axon loss sensory greater than motor neuropathy. Vincristine must be avoided in patients with preexisting inherited neuropathies, as the resulting cumulative neuropathy can be devastating and relatively permanent. Vinorelbine is less toxic than vincristine, causing a distal sensory neuropathy in 20% to 30% of patients treated (88). The neuropathy is severe in few patients. Platinum Agents The platinum chemotherapeutic agents consist of cisplatin, carboplatin, and oxaliplatin, and each share structural and toxicity properties. Cisplatin was the first agent developed and is used to treat ovarian, testicular, lung, bladder, head and neck, and germ cell tumors. It primarily causes a neuropathy by toxicity at the site of the dorsal root ganglion and thus causes a ganglioneuronopathy that affects the large more than small sensory fibers. This pathology predicts the deficits found on examination such as ataxia, loss of vibration, and joint position sense more than pain and cold perception, areflexia, as well as a Llermitte sign (90). Pain and weakness are not common. The neuronopathy commonly is manifested when the total dose exceeds 300 mg/m2 and occurs in almost all patients when the total dose is greater than 600 mg/ m2. Symptoms of the neuronopathy may not be noticed until 8 weeks after treatment is stopped (91). Coasting may be experienced for up to 6 months. Nerve conduction studies show markedly reduced or absent SNAPs and preserved motor nerve conduction function. Carboplatin has similar antitumor activity to cisplatin. It is more myelosuppressive than cisplatin and

much less neuropathic, as a neuronopathy is observed in only 6% of patients exposed to the chemotherapeutic agent and is usually mild (92). Oxaliplatin is structurally similar to cisplatin and is used to treat metastatic colorectal cancer. Taxanes The taxanes consist of paclitaxel and docetaxel, the latter a semisynthetic analogue of paclitaxel. They are used primarily to treat solid tumors, particularly breast and ovarian cancers. The major toxicity of paclitaxel is myelosuppression, but it becomes neurotoxic when used with granulocyte colony stimulating factor. The risk of neuropathy increases when high infusion rates are used and when incorporated with other neurotoxic agents such as cisplatin. The polyneuropathy of paclitaxel is primarily sensory in nature (88). Its severity depends on the cumulative dose and dose intensity per cycle (88). A large number of patients develop a polyneuropathy when doses of 135 to 200 mg/m2 every 3 weeks are taken (93). The neuropathy typically will develop after the third to seventh cycle but can arise within days of the first infusion. Neuropathy invariably develops when doses larger than 250 mg/m2 are used in single doses (93). As would be expected in a sensory polyneuropathy, the initial symptoms are numbness, paresthesia, and pain in the feet and ankles. In severe cases, the hands become numb, and ataxia may arise. Severe neuropathy often develops when the cumulative dose exceeds 1500 mg/ m2 and in patients with preexisting diabetes, alcoholic neuropathy, and inherited neuropathies (88). When paclitaxel is stopped, the neuropathy may progress for up to 4 weeks. The neuropathy resolves in mild cases, but up to 40% of patients are left with permanent sensory symptoms in the toes and feet, and some may have weakness below the knees and ataxia. Electrophysiological testing shows findings that are consistent with a sensory greater than motor axon loss polyneuropathy. The mechanism of toxicity is probably interference with axonal transport from the accumulation of disassembled microtubules in the dorsal root ganglion, axons, and Schwann cells (84). Some evidence exists that a-lipoic acid diminishes the symptoms of paclitaxel-induced neuropathy (94). Because of its semisynthetic relationship to paclitaxel, docetaxil-induced neuropathy shares many of the clinical characteristics of paclitaxel. Fortunately, when used in typical dosing, a clinically significant neuropathy is less common than after receiving paclitaxel (88). Slightly fewer than 50% of patient who receive docetaxil will develop a neuropathy. Severe neuropathy is not common, but it tends to occur when cumulative doses of >600 mg/m2 are taken (95). Similar to paclitaxel, it presents with numbness in the feet and hands after the third to fifth treatments. When docetaxil is stopped, coasting may take place for several months. Fortunately, most patients improve or are left with mild residual sensory symptoms. Approximately 5% of patients exposed to

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docetaxil will develop a proximal myopathy superimposed on the distal neuropathy.

the drug is taken, and the symptoms resolve within 2 weeks of stopping the drug (98).

Suramin Suramin is a hexasulfonated naphthylurea used to treat prostate cancer, adrenocortical, ovarian, and renal cell carcinoma, malignant thymomas, and non-Hodgkins lymphoma. Suramin toxicity causes 2 types of neuropathy: (a) a length-dependent, sensory greater than motor, axon loss neuropathy and (b) a subacute motor greater than sensory demyelinating neuropathy resembling CIDP or a prolonged case of GBS (96). Suramin has an unusually long half life of 40 to 50 days, which contributes to its neurotoxicity. The incidence of neuropathy ranges from 25% to 90%, and neurotoxicity appears to be more dependent on the peak suramin blood level rather than the cumulative dose (88). The length­dependent sensory greater than motor neuropathy is more commonly observed after treatment with suramin and is slowly reversible in most patients once chemotherapy is stopped. The motor demyelinating polyneuropathy is observed in about 10% of patients and may not occur until 1 to 5 months after suramin is first used as a treatment. As with CIDP and GBS, patient can become bedridden from the polyneuropathy and may require ventilatory support. The CSF protein is elevated, furthering the resemblance to CIDP and GBS. Most patients improve over 3 to 6 months. Plasma exchange can be useful to enhance recovery time.

Bortezomib Bortezomib is a chemotherapeutic agent used to treat multiple myeloma that is refractory to other agents. It is a member of the proteasome inhibitors. It causes a length-dependent painful primarily sensory polyneuropathy in 37% to 47% of patients who receive the drug (99,100).

Cytosine Arabinoside Acute cerebellar dysfunction is one of the most recognized toxicities of high-dose Ara-C. Ara-C has been described as causing several types of peripheral nervous system toxicities including a pure sensory polyneuropathy, an acute motor and sensory neuropathy similar to GBS, and bilateral brachial plexopathy (88). Fortunately, toxicity of the peripheral nervous system is rare. The neuropathy may begin within hours to 3 weeks after the Ara-C treatment is initiated. Etoposide (VP-16) Etoposide is a semisynthetic derivative of podophyllotoxin and is used to treat a wide variety of neoplasms, which include lymphoma, leukemia, testicular cancer, and small cell carcinoma of the lung. The polyneuropathy that develops after treatment with etoposide is primarily sensory and is most likely related to the effect of the drug on the dorsal root ganglion (97). The polyneuropathy from etoposide develops in up to 10% of patients receiving the drug; it tends to resolve completely once therapy is discontinued. Efosfamide Efosfamide is used to treat lymphomas, testicular and cervical carcinomas, sarcomas, and lung cancers. A neuropathy occurs in about 4% of patients who receive the chemotherapy and is typically sensory in manifestation (88). Symptoms begin within 10 days to 2 weeks after

Teniposide Teniposide is a chemotherapeutic agent whose mechanism is the production of breaks in DNA and DNA protein cross-links. It is used to treat small cell carcinoma of the lung and childhood acute lymphocytic leukemia. It has been shown to cause a polyneuropathy when used in combination with vincristine, methotrexate, and cyclophosphamide (101). Ixabepilone Ixabepilone is a microtubule-stabilizing agent commonly used to treat metastatic breast cancer (102). It can produce a sensory polyneuropathy and neutropenia as adverse events (102). The neuropathy is reversible and commonly resolves within 6 weeks and can be lessened by reducing the dose of the drug. Gemcitabine Dormann et al have reported the development of an autonomic neuropathy in a patient taking gemcitabine for non–small cell lung cancer (103). The symptoms of autonomic neuropathy (prolonged gastric emptying, long colonic transit time, low swallowing pressure, and lack of respiratory and circadian variation of heart rate) resolved within 4 weeks after stopping the drug. Hexamethylmelamine Hexamethylmelamine is an alkylating antineoplastic agent used to treat ovarian cancer refractory to other agents (104). In a study of 61 patients receiving hexamethylmelamine for platin-resistant ovarian carcinoma, 3 patients developed reversible neuropathy (105). Eribulin Eribulin is a nontaxane microtubule dynamic inhibitor used to locally treat advanced or metastatic breast cancer in patients who have been treated previously with at least 2 chemotherapeutic regimens. A recently published Adis drug profile described the incidence of peripheral neuropathy to be 5% to 8 % (106).

Neuropathies From Immunosuppressant Agents Tacrolimus Tacrolimus is an immunosuppressant that interferes with T-cell function and is primarily prescribed to prevent rejection of solid organ transplantation. Central nervous system toxicity in the form of headaches, encephalopathy, behavioral changes, seizures, and headache are more common than rare neuropathies. One type of neuropathy

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after tacrolimus therapy is a chronic demyelinating polyneuropathy that resembles CIDP or a more asymmetric form that begins about 2 to 10 weeks after initiation of therapy (107). Similarities to CIDP include areflexia, greater involvement of large than small fibers, and an elevated spinal fluid protein. The nerve conduction abnormalities also resemble CIDP, as patients have slowed conduction velocities, prolonged distal latencies, reduced CMAPs, and temporal dispersion of proximal CMAP amplitudes (107). Patients have improved after receiving IVIG and plasma exchange suggesting that the pathogenesis of this neuropathy is autoimmune and inflammatory. Another presentation of a tacrolimus-induced polyneuropathy is an acute, predominantly motor axon loss neuropathy that begins 1 to 2 weeks after the intake of drug, suggestive of GBS. The polyneuropathy can be devastating, producing facial weakness and quadriparesis. Most patients improve once tacrolimus is stopped. Leflunomide Leflunomide is a new immunosuppressant agent used to treat rheumatoid arthritis. Leflunomide is an isoxazole derivative and is structurally unrelated to other immunomodulatory drugs. It is a known inhibitor of the mitochondrial enzyme dihydroorotate dehydrogenase (DHODH), a key enzyme in the synthesis pathway of the pyrimidine ribonucleotide uridine monophosphate (rUMP) synthesis. It causes a painful sensory greater than motor axon loss polyneuropathy usually arising 3 to 6 months after therapy is begun. In a series of 113 patients treated with leflunomide in a rheumatology clinic in France, Martin et al reported the development of a neuropathy in 10% of patients (108). The patients who experienced the neuropathy were older than those who did not (69 vs 54 years), were more often diabetic, and were more commonly undergoing treatment with potentially neurotoxic drugs. Cyclosporine In 1999, Braun et al reported a patient who developed a motor and sensory axon loss polyneuropathy 18 months after the prescription of cyclosporine for the treatment of nodular prurigo (109). This occurred in the setting of normal cyclosporine levels. The neuropathy improved completely 3 months after the drug was stopped. Palmer and Toto also reported 3 cases of severe neuropathy in renal transplant patients who were treated with cyclosporine (110). Sayin et al recently reported a patient who developed a polyneuropathy 8 years after treatment with cyclosporine was initiated (111). The patient and nerve conduction studies improved when cyclosporine was stopped, and immunosuppression was accomplished by substituting rapamycin.

Tumor Necrosis Factor a Antagonists Tumor necrosis factor a (TNF-a) antagonists are used to treat patients with refractory autoimmune disorders including rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn disease, and ulcerative colitis. The

agents work at several levels of inflammation and immunogenesis to block or reduce damage at the vascular endothelium, blood nerve barrier, and to prevent access of immunoglobulins, cytokines, complement, macrophages, nitrogen oxide metabolites, and proteases to the sites of pathology (112). Three TNF-a antagonists are presently marketed: infliximab, etanercept, and adalimumab (112). Several presentations of peripheral neuropathy have been reported as adverse effects in patients receiving TNF-a antagonists (113). Those vary in manifestation from GBS to CIDP, Fisher syndrome, multifocal motor neuropathy, mononeuritis simplex or multiplex, and an axonal sensory or sensorimotor polyneuropathy (112). The timing and dosing of TNF-a antagonists has varied greatly in each patient for each condition. In some patients, the neuropathy developed within 8 hours of the first dose and in others after 2 years. Many patients improve once the TNF-a antagonist is stopped so treatment with corticosteroids, IVIG, or plasma exchange may not be necessary. The pathogenesis of TNF-a antagonistinduced neuropathy has been hypothesized as resulting from enhanced T-cell proliferation and cytokine production when the TNF-a antagonist modifies the antigenpresenting cell function, T-cell receptor signaling, and decreasing apoptosis of autoreactive T cells (112).

Medications for Gastrointestinal Disorders Proton pump inhibitors are commonly used to treat gastroesophageal reflux disease and peptic ulcers. In 2005, Rajabally and Jacob reported the onset of a sensory polyneuropathy in a woman who had been taking lansoprazole for 3 months (114). Nerve conduction studies showed sensory fiber involvement. She made a partial but incomplete improvement when the drug was stopped. Neuropathy has also been reported after taking omeprazole. Pouget et al reported a patient who developed a distal more than proximal 4 extremity neuropathy 4 days after cimetidine was taken (115). Electrophysiological studies and nerve biopsy showed evidence for an axon loss neuropathy. The patient began to improve 1 week after cimetidine was discontinued. Two other cases of cimetidine-induced neuropathy were described by Walls et al (116).

Summary Many medications have been implicated in causing polyneuropathy, and the list grows steadily. Medications can induce neuropathy by acting on the peripheral axon, the anterior horn cell, the dorsal root ganglion, or the Schwann cell. In addition to commonly prescribed medications, neuropathy can represent toxicity from chemotherapeutic agents, antiretroviral therapy of HIV, and most recently from prescription of the immunosuppressants and TNF-a antagonists. Recognition of this type of neuropathy requires a good knowledge of neurological literature, a high clinical suspicion, and review

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of the patient’s present and previous therapy when no other cause for neuropathy is evident.

References 1. Jain KK. Drug-induced peripheral neuropathies. In: Jain KK, ed. Drug-Induced Neurological Disorders. 2nd ed. Seattle: Hogrefe & Huber; 2001:263–294. 2. Thomas PK. The Peripheral Nervous System as a Target for Toxic Substances. Baltimore, MD: Williams & Wilkins; 1980. 3. Feiner LA, Younge BR, Kazmier FJ, Stricker BH, Fraunfelder FT. Optic neuropathy and amiodarone therapy. Mayo Clin Proc. 1987;62:702–717. 4. Meier C, Kauer B, Muller U, Ludin HP. Neuromyopathy during chronic amiodarone treatment. A case report. J Neurol. 1979;220:231–239. 5. Charness ME, Morady F, Scheinman MM. Frequent neurologic toxicity associated with amiodarone therapy. Neurology. 1984;34:669–671. 6. Jacobs JM, Costa-Jussa FR. The pathology of amiodarone neurotoxicity. II. Peripheral neuropathy in man. Brain. 1985;108(pt 3):753–769. 7. Zea BL, Leonard JA, Donofrio PD. Amiodarone Producing an Acquired Demyelinating and Axonal Polyneuropathy. Muscle Nerve. 1985;8:612. 8. Meadows GG, Huff MR, Fredericks S. Amitriptyline­related peripheral neuropathy relieved during pyridoxine hydrochloride administration. Drug Intell Clin Pharm. 1982; 16:876–877. 9. Zampollo A, Sozzi G, Basso F. Amitriptyline-related peripheral neuropathy. Case report. Ital J Neurol Sci. 1988;9:89–91. 10. Gabriel R, Pearce JM. Clofibrate-induced myopathy and neuropathy. Lancet. 1976;2:906. 11. Riggs JE, Schochet SS, Jr., Gutmann L, Crosby TW, DiBartolomeo AG. Chronic human colchicine neuropathy and myopathy. Arch Neurol. 1986;43:521–523. 12. Kuncl RW, Duncan G, Watson D, Alderson K, Rogawski MA, Peper M. Colchicine myopathy and neuropathy. N Engl J Med. 1987;316:1562–1568. 13. Rapoport AM, Guss SB. Dapsone-induced peripheral neuropathy. Arch Neurol. 1972;27:184–185. 14. Waldinger TP, Siegle RJ, Weber W, Voorhees JJ. Dapsoneinduced peripheral neuropathy. Case report and review. Arch Dermatol. 1984;120:356–359. 15. Gutmann L, Martin JD, Welton W. Dapsone motor neuropathy—an axonal disease. Neurology. 1976;26:514–516. 16. Gelber R, Peters JH, Gordon GR, Glazko AJ, Levy L. The polymorphic acetylation of dapsone in man. Clin Pharmacol Ther. 1971;12:225–238. 17. Koller WC, Gehlmann LK, Malkinson FD, Davis FA. Dapsone-induced peripheral neuropathy. Arch Neurol. 1977;34:644–646. 18. Kaufmann P, Engelstad K, Wei Y, et al. Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology. 2006;66:324–330. 19. Anselm IA, Darras BT. Dichloroacetate causes toxic neuropathy in MELAS: a randomized, controlled clinical trial. Neurology. 2006;67:1313; author reply 1313. 20. Mokri B, Ohnishi A, Dyck PJ. Disulfiram neuropathy. Neurology. 1981;31:730–735. 21. Tugwell P, James SL. Peripheral neuropathy with ethambutol. Postgrad Med J. 1972;48:667–670.

22. Cohen JS. Peripheral neuropathy associated with fluoroquinolones. Ann Pharmacother. 2001;35:1540–1547. 23. Hedenmalm K, Spigset O. Peripheral sensory disturbances related to treatment with fluoroquinolones. J Antimicrob Chemother. 1996;37:831–837. 24. Doyle JB, Cannon EF. Severe polyneuritis following gold therapy for rheumatoid arthritis. Ann Intern Med. 1950;33: 1468–1472. 25. Walsh JC. Gold neuropathy. Neurology. 1970;20:455–458. 26. Katrak SM, Pollock M, O’Brien CP, et al. Clinical and morphological features of gold neuropathy. Brain. 1980; 103:671–693. 27. Lecky BR. Griseofulvin-induced neuropathy. Lancet. 1990; 335:230–231. 28. Kirkendall WM, Page EB. Polyneuritis occurring during hydralazine therapy; report of two cases and discussion of adverse reactions to hydralazine. J Am Med Assoc. 1958;167:427–432. 29. Raskin NH, Fishman RA. Pyridoxine-deficiency neuropathy due to hydralazine. N Engl J Med. 1965;273:1182–1185. 30. Blakemore WF. Isoniazid. In: Spencer PS, Schaumberg HH, eds. Experimental and Clinical Neurotoxicology. Baltimore, MD: Williams & Wilkins; 1980:599. 31. Evans DAP. Pharmacogenetics. Am J Med. 1963;34:639–662. 32. Hughes HB, Biehl JP, Jones AP, Schmidt LH. Metabolism of isoniazid in man as related to the occurrence of peripheral neuritis. Am Rev Tuberc. 1954;70:266–273. 33. Money GL. Isoniazid neuropathies in malnourished tuberculous patients. J Trop Med. 1959;62:198–202. 34. Ochoa J. Isoniazid neuropathy in man: quantitative electron microscope study. Brain. 1970;93:831–850. 35. Bressler AM, Zimmer SM, Gilmore JL, Somani J. Peripheral neuropathy associated with prolonged use of linezolid. Lancet Infect Dis. 2004;4:528–531. 36. Vanhooren G, Dehaene I, Van Zandycke M, et al. Polyneuropathy in lithium intoxication. Muscle Nerve. 1990;13:204– 208. 37. Jha S, Kumar R. Mefloquine toxicity presenting with polyneuropathy—a report of two cases in India. Trans R Soc Trop Med Hyg. 2006;100:594–596. 38. Bradley WG, Karlsson IJ, Rassol CG. Metronidazole neuropathy. Br Med J. 1977;2:610–611. 39. Coxon A, Pallis CA. Metronidazole neuropathy. J Neurol Neurosurg Psychiatry. 1976;39:403–405. 40. Melgaard B, Hansen HS, Kamieniecka Z, et al. Misonidazole neuropathy: a clinical, electrophysiological, and histological study. Ann Neurol. 1982;12:10–17. 41. Ellis FG. Acute polyneuritis after nitrofurantoin therapy. Lancet. 1962;2:1136–1138. 42. Loughridge LW. Peripheral neuropathy due to nitrofurantoin. Lancet. 1962;2:1133–1135. 43. Craven RS. Furadantin neuropathy. Aust N Z J Med. 1971;1:246–249. 44. Paul MF, Paul HE, Kopko F, Bryson MJ, Harrington C. Inhibition by furacin of citrate formation in testis preparations. J Biol Chem. 1954;206:491–497. 45. Toole JF, Parrish ML. Nitrofurantoin polyneuropathy. Neurology. 1973;23:554–559. 46. Morris JS. Nitrofurantoin and peripheral neuropathy with megaloblastic anaemia. J Neurol Neurosurg Psychiatry. 1966;29:224–228. 47. Layzer RB, Fishman RA, Schafer JA. Neuropathy following abuse of nitrous oxide. Neurology. 1978;28:504–506.

CHAPTER 14: Medication-Related Neuropathy  215 48. Layzer RB. Myeloneuropathy after prolonged exposure to nitrous oxide. Lancet. 1978;2:1227–1230. 49. Amess JA, Burman JF, Rees GM, Nancekievill DG, Mollin DL. Megaloblastic haemopoiesis in patients receiving nitrous oxide. Lancet. 1978;2:339–342. 50. Pedersen PB, Hogenhaven H. Penicillamin-induced neuropathy in rheumatoid arthritis. Acta Neurol Scand. 1990;81:188–190. 51. Pool KD, Feit H, Kirkpatrick J. Penicillamine-induced neuropathy in rheumatoid arthritis. Ann Intern Med. 1981;95:457–458. 52. Heller CA, Friedman PA. Pyridoxine deficiency and peripheral neuropathy associated with long-term phenelzine therapy. Am J Med. 1983;75:887–888. 53. Goodheart RS, Dunne JW, Edis RH. Phenelzine associated peripheral neuropathy—clinical and electrophysiologic findings. Aust N Z J Med. 1991;21:339–340. 54. Malcolm DE, Yu PH, Bowen RC, O’Donovan C, Hawkes J, Hussein M. Phenelzine reduces plasma vitamin B6. J Psychiatry Neurosci. 1994;19:332–334. 55. Lovelace RE, Horwitz SJ. Peripheral neuropathy in long-term diphenylhydantoin therapy. Arch Neurol. 1968;18:69–77. 56. Shorvon SD, Reynolds EH. Anticonvulsant peripheral neuropathy: a clinical and electrophysiological study of patients on single drug treatment with phenytoin, carbamazepine or barbiturates. J Neurol Neurosurg Psychiatry. 1982;45:620–626. 57. Dobb GJ, Edis RH. Coma and neuropathy after ingestion of herbal laxative containing podophyllin. Med J Aust. 1984;140:495–496. 58. O’Mahony S, Keohane C, Jacobs J, O’Riordain D, Whelton M. Neuropathy due to podophyllin intoxication. J Neurol. 1990;237:110–112. 59. Filley CM, Graff-Richard NR, Lacy JR, Heitner MA, Earnest MP. Neurologic manifestations of podophyllin toxicity. Neurology. 1982;32:308–311. 60. Galasso PJ, Stanton MS, Vogel H. Propafenone-induced peripheral neuropathy. Mayo Clin Proc. 1995;70:469–472. 61. Schaumburg H, Kaplan J, Windebank A, et al. Sensory neuropathy from pyridoxine abuse. A new megavitamin syndrome. N Engl J Med. 1983;309:445–448. 62. Krinke G, Schaumburg HH, Spencer PS, Suter J, Thomann P, Hess R. Pyridoxine megavitaminosis produces degeneration of peripheral sensory neurons (sensory neuronopathy) in the dog. Neurotoxicology. 1981;2:13–24. 63. Parry GJ, Bredesen DE. Sensory neuropathy with lowdose pyridoxine. Neurology. 1985;35:1466–1468. 64. Katan MB. [How much vitamin B6 is toxic?]. Ned Tijdschr Geneeskd. 2005;149:2545–2546. 65. Jacobs MB. HMG-CoA reductase inhibitor therapy and peripheral neuropathy. Ann Intern Med. 1994;120:970. 66. Ahmad S. Lovastatin and peripheral neuropathy. Am Heart J. 1995;130:1321. 67. Phan T, McLeod JG, Pollard JD, Peiris O, Rohan A, Halpern JP. Peripheral neuropathy associated with simvastatin. J Neurol Neurosurg Psychiatry. 1995;58:625–628. 68. Jeppesen U, Gaist D, Smith T, Sindrup SH. Statins and peripheral neuropathy. Eur J Clin Pharmacol. 1999;54: 835–838. 69. Abellan-Miralles I, Sanchez-Perez RM, Perez-Carmona N, Diaz-Marin C, Mallada-Frechin J. [Multiple mononeuropathy associated to treatment with pravastatin]. Rev Neurol. 2006;43:659–661.

70. Scola RH, Trentin AP, Germiniani FM, Piovesan EJ, Werneck LC. Simvastatin-induced mononeuropathy multiplex: case report. Arq Neuropsiquiatr. 2004;62:540–542. 71. Rajabally YA, Varakantam V, Abbott RJ. Disorder resembling Guillain-Barre syndrome on initiation of statin therapy. Muscle Nerve. 2004;30:663–666. 72. Ziajka PE, Wehmeier T. Peripheral neuropathy and lipidlowering therapy. South Med J. 1998;91:667–668. 73. Peripheral neuropathy and statins. Prescrire Int. 2007;16: 247–248. 74. Formaglio M, Vial C. [Statin induced neuropathy: myth or reality?]. Rev Neurol (Paris). 2006;162:1286–1289. 75. Backes JM, Howard PA. Association of HMG-CoA reductase inhibitors with neuropathy. Ann Pharmacother. 2003;37:274–278. 76. Chong PH, Boskovich A, Stevkovic N, Bartt RE. Statin­associated peripheral neuropathy: review of the literature. Pharmacotherapy. 2004;24:1194–1203. 77. Corrao G, Zambon A, Bertu L, Botteri E, Leoni O, Contiero P. Lipid lowering drugs prescription and the risk of peripheral neuropathy: an exploratory case-control study using automated databases. J Epidemiol Community Health. 2004;58:1047–1051. 78. Brown WV. Safety of statins. Curr Opin Lipidol. 2008;19: 558–562. 79. de Langen JJ, van Puijenbroek EP. HMG-CoA-reductase inhibitors and neuropathy: reports to the Netherlands Pharmacovigilance Centre. Neth J Med. 2006;64:334–338. 80. Gaist D, Jeppesen U, Andersen M, Garcia Rodriguez LA, Hallas J, Sindrup SH. Statins and risk of polyneuropathy: a case-control study. Neurology. 2002;58:1333–1337. 81. Cavaletti G, Beronio A, Reni L, et al. Thalidomide sensory neurotoxicity: a clinical and neurophysiologic study. Neurology. 2004;62:2291–2293. 82. Ochonisky S, Verroust J, Bastuji-Garin S, Gherardi R, Revuz J. Thalidomide neuropathy incidence and clinicoelectrophysiologic findings in 42 patients. Arch Dermatol. 1994;130:66–69. 83. Lagueny A, Rommel A, Vignolly B, et al. Thalidomide neuropathy: an electrophysiologic study. Muscle Nerve. 1986; 9:837–844. 84. Pratt RW, Weimer LH. Medication and toxin-induced peripheral neuropathy. Semin Neurol. 2005;25:204–216. 85. Simpson DM. Selected peripheral neuropathies associated with human immunodeficiency virus infection and antiretroviral therapy. J Neurovirol. 2002;8(suppl 2): 33–41. 86. Berger AR, Arezzo JC, Schaumburg HH, et al. 2’,3’-Dideoxycytidine (ddC) toxic neuropathy: a study of 52 patients. Neurology. 1993;43:358–362. 87. Moore RD, Wong WM, Keruly JC, McArthur JC. Incidence of neuropathy in HIV-infected patients on monotherapy versus those on combination therapy with didanosine, stavudine and hydroxyurea. AIDS. 2000;14:273–278. 88. Collins MP, Amato AA. Peripheral nervous system disease associated with malignancy. In: Brown WF, Bolton CF, Aminoff MJ, eds. Neuromuscular Function and Disease: Basic, Clinical, and Electrodiagnostic Aspects. Philadelphia: WB Saunders; 2002:1185–1220. 89. Haim N, Epelbaum R, Ben-Shahar M, Yarnitsky D, Simri W, Robinson E. Full dose vincristine (without 2-mg dose limit) in the treatment of lymphomas. Cancer. 1994;73: 2515–2519.

216  Textbook of Peripheral Neuropathy 90. Cersosimo RJ. Cisplatin neurotoxicity. Cancer Treat Rev. 1989;16:195–211. 91. Mollman JE, Glover DJ, Hogan WM, Furman RE. Cisplatin neuropathy. Risk factors, prognosis, and protection by WR-2721. Cancer. 1988;61:2192–2195. 92. Canetta R, Rozencweig M, Carter SK. Carboplatin: the clinical spectrum to date. Cancer Treat Rev. 1985;12(suppl A): 125–136. 93. Wiernik PH, Schwartz EL, Strauman JJ, Dutcher JP, Lipton RB, Paietta E. Phase I clinical and pharmacokinetic study of taxol. Cancer Res. 1987;47:2486–2493. 94. Gedlicka C, Kornek GV, Schmid K, Scheithauer W. Amelioration of docetaxel/cisplatin induced polyneuropathy by alpha-lipoic acid. Ann Oncol. 2003;14:339–340. 95. Cortes JE, Pazdur R. Docetaxel. J Clin Oncol. 1995;13:2643– 2655. 96. Chaudhry V, Eisenberger MA, Sinibaldi VJ, Sheikh K, Griffin JW, Cornblath DR. A prospective study of suramininduced peripheral neuropathy. Brain. 1996;119(pt 6): 2039–2052. 97. Falkson G, van Dyk JJ, van Eden EB, van der Merwe AM, van den Bergh JA, Falkson HC. A clinical trial of the oral form of 4’-demethyl-epipodophyllotoxin-beta-d ethylidene glucoside (NSC 141540) VP 16-213. Cancer. 1975;35:1141–1144. 98. Patel SR, Forman AD, Benjamin RS. High-dose ifosfamideinduced exacerbation of peripheral neuropathy. J Natl Cancer Inst. 1994;86:305–306. 99. Davis NB, Taber DA, Ansari RH, et al. Phase II trial of PS-341 in patients with renal cell cancer: a University of Chicago phase II consortium study. J Clin Oncol. 2004;22: 115–119. 100. Kane RC, Bross PF, Farrell AT, Pazdur R. Velcade: U.S. FDA approval for the treatment of multiple myeloma progressing on prior therapy. Oncologist. 2003;8:508–513. 101. Giaccone G. Teniposide alone and in combination chemo­ therapy in small cell lung cancer. Semin Oncol. 1992;19: 75–80. 102. Denduluri N, Swain S. Ixabepilone: clinical role in metastatic breast cancer. Clin Breast Cancer. 2011;11:139–145.

103. Dormann AJ, Grunewald T, Wigginghaus B, Huchzermeyer H. Gemcitabine-associated autonomic neuropathy. Lancet. 1998;351:644. 104. Foster BJ, Harding BJ, Leyland-Jones B, Hoth D. Hexamethylmelamine: a critical review of an active drug. Cancer Treat Rev. 1986;13:197–217. 105. Vergote I, Himmelmann A, Frankendal B, Scheistroen M, Vlachos K, Trope C. Hexamethylmelamine as second-line therapy in platin-resistant ovarian cancer. Gynecol Oncol. 1992;47:282–286. 106. Perry CM. Eribulin. Drugs. 2011;71:1321–1331. 107. Wilson JR, Conwit RA, Eidelman BH, Starzl T, Abu­Elmagd K. Sensorimotor neuropathy resembling CIDP in patients receiving FK506. Muscle Nerve. 1994;17:528–532. 108. Martin K, Bentaberry F, Dumoulin C, et al. Peripheral neuropathy associated with leflunomide: is there a risk patient profile? Pharmacoepidemiol Drug Saf. 2007;16:74–78. 109. Braun R, Arechalde A, French LE. Reversible ascending motor neuropathy as a side effect of systemic treatment with ciclosporine for nodular prurigo. Dermatology. 1999;199:372–373. 110. Palmer BF, Toto RD. Severe neurologic toxicity induced by cyclosporine A in three renal transplant patients. Am J Kidney Dis. 1991;18:116–121. 111. Sayin R, Soyoral YU, Erkoc R. Polyneuropathy due to cyclosporine A in patients with renal transplantation: a case report. Ren Fail. 2011;33:528–530. 112. Stubgen JP. Tumor necrosis factor-alpha antagonists and neuropathy. Muscle Nerve. 2008;37:281–292. 113. Gabelle A, Antoine JC, Hillaire-Buys D, Coudeyre E, Camu W. [Leflunomide-related severe axonal neuropathy]. Rev Neurol (Paris). 2005;161:1106–1109. 114. Rajabally YA, Jacob S. Neuropathy associated with lansoprazole treatment. Muscle Nerve. 2005;31:124–125. 115. Pouge.t J, Pellissier JF, Jean P, Jouglard J, Toga M, Serratrice G. [Peripheral neuropathy during treatment with cimetidine]. Rev Neurol (Paris). 1986;142:34–41. 116. Walls TJ, Pearce SJ, Venables GS. Motor neuropathy associated with cimetidine. Br Med J. 1980;281:974–975.

Charlene Hoffman-Snyder and Benn E. Smith

15

Paraproteinemic Neuropathy: Distinguishing the Ominous From the Ordinary

INTRODUCTION

and skin changes (POEMS syndrome); (c) AL (immunoglobulin light-chain) amyloidosis; (d) cryoglobulinemia, and (e) heavy-chain diseases (3). When clinical features are present, they range from fatigue, weight loss, purpura, congestive heart failure, nephrotic syndrome, peripheral neuropathy, orthostatic hypotension, to mucocutaneous bleeding (6). Paraprotein-associated neuropathies have emerged as an important category of chronic adult-onset polyneuropathies, particularly because they warrant further evaluation for underlying malignancy or amyloid (7). In patients presenting with peripheral neuropathy of unknown cause, 10% will have a monoclonal protein, the majority of whom will be designated as a MGUS. The plasma cells disorders most often associated with neuropathy include MGUS, MM, smoldering myeloma, WM, SP, systemic AL amyloidosis, osteosclerotic myeloma (OSM, often with POEMS), and immunoglobulin deposition diseases. These are discussed further in this chapter (8). It is helpful to distinguish between monoclonal and polyclonal immune processes in plasma cell dyscrasias. Unlike monoclonal protein disorders, polyclonal increases in immunoglobulin are often associated with reactive or inflammatory diseases (9). Polyclonal immunoglobulins are produced by many clones of plasma cells. Blood levels of polyclonal g-globulin of 3 g/dL or more have been associated with liver disease, connective tissue disorders, chronic infections, and nonhematologic malignancies (10). On the other hand a monoclonal proliferation is more often associated with premalignant or malignant disease. There can be an overlap in antibodymediated pathogenic mechanisms among these different monoclonal and polyclonal antibodies (11). Monoclonal proteins (also called M proteins, myeloma proteins, or paraproteins) consist of 2 heavy polypeptide chains of the same class and subclass as well as 2 light polypeptide chains each of the same type. The different monoclonal proteins are known by letters corresponding to their heavy-chain classes, which are

Over the last 4 decades studies to clarify the pathogenesis of immune disorders involving the peripheral nervous system (PNS) have focused on mechanisms mediated by T cells. Not only are cellular infiltrates in the Guillain-­Barré syndrome often dominated by T cells, animal models of this disorder have been thought to be caused by T cells specific for PNS myelin. More recently, the role of B cells as influencing T-cell–mediated immune responses has given impetus to the idea that B cells are rational targets for immunotherapy in immune­mediated neuropathies (2). One such group of conditions is the neuropathies associated with paraproteinemia. The disorders encompassed in paraproteinemia or monoclonal gammopathy are subdivided by proliferation of particular individual clones of B cells, which secrete excess monoclonal protein into the bloodstream. This overproduction can be benign, low-grade potentially neoplastic, or frankly neoplastic. Monoclonal proteins are prevalent in 3% of the general population older than 50 years with rates increasing with age. Prevalence rates are higher for men than women and African Americans have a 3-fold higher age-adjusted prevalence rate than those of Caucasian decent (3,4). Other factors associated with an increase in the prevalence of monoclonal gammopathy of undetermined significance (MGUS) include family history, immunosuppression, and pesticide exposure (5). Paraproteinemias are usually asymptomatic and found on routine blood testing without associated symptoms or signs. Nevertheless, certain disease associations occur more often than by chance. These include (a) the premalignant MGUS, biclonal gammopathies, idiopathic Bence Jones proteinuria; (b) the malignant monoclonal gammopathies of multiple myeloma (MM), smoldering multiple myeloma (SMM), Waldenström macroglobulinemia (WM), uncommon malignant disorders of solitary plasmacytoma (SP), and polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, 217

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designated by Greek characters: γ in IgG, α in IgA, μ in IgM, δ in immunoglobulin D (IgD), and ε in immunoglobulin E (IgE). There are 4 subclasses for IgG, 2 subclasses for IgA, and no subclasses for IgM, IgD, or IgE. The lightchain types are kappa (κ) and lambda (λ). Each of these monoclonal proteins is produced by proliferation of single clonal population of plasma cells in the bone marrow. In most instances, the mechanism of monoclonal expansion of a single immunoglobulin-secreting plasma cell population remains unknown (7). A thorough review by Kyle and Rajkumar, however, suggests in at least 50% of MGUS there is evidence of genomic instability by molecular testing, including primary chromosomal translocations at the immunoglobulin heavy-chain locus 14q32 (50%), hyperdiploidy (40%), or unknown mechanisms (10%) (12–14). Interleukin 6 is a main growth factor for plasma cells, whereas CD126 is overexpressed in MGUS compared with normal plasma cells. A higher proportion of plasma cells in MGUS express CD45 than in myeloma. Changes in the microenvironment such as angiogenesis, suppression of cell-mediated immunity,

KEY POINTS •  Paraproteinemias are usually asymptomatic and found on routine blood testing without associated symptoms. •  Found in 3% of population older than 50 years •  Clinical features

° Fatigue °  Weight loss °  Purpura °  Congestive heart failure °  Nephrotic syndrome °  Neuropathy °  Orthostatic hypotension °  Mucocutaneous bleeding •  Diseases most often associated with paraproteinemias are

°  MGUS °  Malignant monoclonal gammopathies of MM or SMM

°  WM, uncommon malignant disorder of SP °  POEMS °  AL amyloidosis °  Cryoglobulinemia ° Heavy-chain diseases •  In patients presenting with idiopathic peripheral neuropathy 10% with have a monoclonal protein •  Identifying MGUS in patients with demyelinating nerve conduction problems is of value, as they have a higher response rate to treatable

adherence of myeloma cells to stroma, alteration of adhesion molecules, and stromal cytokine overexpression are all under study as possible contributors to the progression of MGUS to MM (10). Increased osteoclast activation and receptor activator of nuclear factor κ b ligand and decreased levels of osteoprotogerin result in lytic bone lesions and osteoporosis (10,15). The pathogenic link between monoclonal proteins and nerve damage is known in only a few instances. In IgM paraproteinemia, it is thought that the neuropathy is related to the reactivity of circulating antibodies directed against specific peripheral neural antigens such as myelin-associated glycoprotein (MAG), chondroitin sulfate, and sulfatide leading to complement-dependent nerve damage (11). Findings have demonstrated deposition of IgM protein within peripheral myelin of both large and small myelinated fibers, suggesting a role in the pathogenesis of neuropathy associated with antiMAG antibodies (8,16,17). In studying a feline model of experimental ataxic sensory polyganglionopathy with anti-MAG/SGPG antibodies, Ilyas et al suggested that these antibodies may be pathogenic in man (18). Investigating 20 patients with neuropathy and IgM monoclonal gammopathy, Eurelings et al found overrepresentation of V genes associated with bacterial immune responses, raising the possibility that this neuropathy may be a reaction to as yet unidentified bacterial antigens (19) (see Key Points in opposite column).

RECOGNITION OF MONOCLONAL PROTEINS Identification of M proteins is best achieved by serum protein electrophoresis. The immunofixation process distinguishes the immunoglobulin class and type of light chain. Densitometry is used to measure the monoclonal protein that is visible on serum electrophoresis and has replaced nephelometry as a more reliable method to quantify immunoglobulin levels. As a standard recommendation, 24-hour analysis of urine for protein excretion and urine protein electrophoresis with immunofixation are warranted to detect and quantify the monoclonal protein in urine (20). However, a recent study by Katzmann et al suggests this may not be necessary due to the highly sensitive serum free light-chain assay now available (21). Measurement of β2-microglobulin has not proved predictive of malignant transformation and is no longer recommended. If a monoclonal protein is found, additional hematologic studies (serum calcium, complete blood count, and serum creatinine) are needed. Although skeletal bone survey and aspirated bone marrow biopsy are generally performed to exclude myeloma, they are not considered necessary when the serum monoclonal spike is less than 1.5 g/dL, and other laboratory tests are normal (20). If abnormalities are detected on these investigations, appropriate tissue biopsies are recommended to exclude amyloidosis. When no monoclonal protein is uncovered, patients with motor polyradiculoneuropathy with demyelinating features on

CHAPTER 15: Paraproteinemic Neuropathy  219

nerve conduction studies should undergo cerebrospinal fluid examination, skeletal bone survey, and sural nerve biopsy. Sural nerve biopsy has shown mixed pathology (fiber loss, segmental demyelination, and axonal degeneration). In the IgM class, a more predominantly demyelinating process is observed. Patients with progressive axonal neuropathies with autonomic dysfunction require biopsy of appropriate tissues for the possibility of amyloidosis (22). Of note in the evaluation of patients for paraproteinemia, large amounts of monoclonal paraprotein in the serum can cause a range of spurious laboratory results including falsely elevated phosphate levels, artificially low highdensity lipoprotein titers, and falsely raised g-glutamyl transferase, bilirubin, and C-reactive protein (23).

ELECTROMYOGRAPHIC STUDIES Electromyographic changes in plasma cell disorders show abnormalities consistent with both demyelination and axonal degeneration. Nerve conduction is typically abnormal in motor and sensory fibers in both the upper and lower extremities. Conduction velocity of motor fibers is decreased below the normal range by 20% or more in a demyelinating neuropathy. Sensory nerve action potentials are consistently reduced in amplitude or unobtainable, more prominently in lower limb nerves. Frequently F-wave latencies are prolonged but not unduly when compared with the degree of nerve conduction slowing. In IgM neuropathies, the nerve conduction abnormalities tend to be more severe than in other classes of paraprotein. Needle examination demonstrates denervation changes (increased insertional activity with fibrillation) in more than 80% of patients. Findings of demyelination and denervation may both be present. The sural nerve is shows greater damage than the median nerve (7,24).

MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE MGUS is the most common plasma cell dyscrasia found in the general population, usually presenting asymptomatically after the fifth decade (25). It is considered a premalignant disorder characterized by limited monoclonal plasma cell proliferation in the bone marrow with no end-organ damage. About two thirds of the time after exclusion of amyloidosis, multiple or OSM, WM, lymphoma, or lymphoproliferative disease, no identifiable cause is found and the disorder is classified as being MGUS. Best characterized as premalignant, MGUS is not “benign” as it is linked to a lifelong risk of progression to MM or related disorders, making long-term follow-up necessary in all persons (26). An M protein is found in 3% to 4% of patients with a diffuse lymphoproliferative process, in the sera of patients with chronic lymphocytic leukemia with no recognizable effect on the clinical course, in the derma-

KEY POINTS: Electromyographic Studies •  Core workup for paraproteinemic neuropathy

°  Basic testing complete blood count, erythrocyte sedimentation rate, C-reactive protein, lactate dehydrogenase

°  Identification of M proteins is best achieved by serum protein electrophoresis

°  24-Hour analysis of urine for protein excretion and urine protein electrophoresis with immunofixation are warranted to detect and quantify the monoclonal protein in urine

°  EMG changes in plasma cell disorders

show abnormalities consistent with both demyelination and axonal degeneration •  Additional testing as indicated

°  If abnormalities are detected appropriate

tissue biopsies are recommended to exclude amyloidosis

°  In patients with polyradiculoneuropathies if

no paraproteins are detected additional studies of cerebrospinal fluid examination, skeletal bone survey, and sural nerve biopsy should be considered

°  Patients with progressive axonal neuropathies with autonomic dysfunction require biopsy of appropriate tissues for the possibility of amyloidosis

°  Bone marrow biopsy for high level of M protein °  Serum cryoglobulins if pain and abnormal liver function tests

°  CT of chest abdomen pelvis; PET/CT for

constitutional symptoms to rule out lymphoma

°  MRI neurography for focal nerve lesion °  MRI spine for radiculopathy, myelopathy, loss of control of bladder or bowel function

°  Serum VEGF for possible endocrine abnormalities, skin changes

tological diseases of lichen myxedematous, pyoderma gangrenosum, and necrobiotic xanthogranuloma, and more often in neurological disorders, both sensorimotor peripheral neuropathy and chronic inflammatory demyelinating polyneuropathy. MGUS occurs in approximately 5% to 10% of adult patients with chronic idiopathic axonal polyneuropathy (CIAP), which represents a 6-fold increase over rates in the general population (27). The typical clinical presentation of the MGUS protein classes associated with chronic polyneuropathy is insidiously progressive distal symmetric sensorimotor polyneuropathy usually beginning in the sixth decade. Sensory deficits are first noted in the toes and spread up the lower limbs to a greater extent than in the upper

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extremities. Muscle stretch reflexes are globally diminished or absent, usually with sparing of cranial nerves. Paresthesias, ataxia, and pain may be significant but seldom lead to complete debility. The neuropathy in MGUS is more often relentlessly progressive than the relapsing-remitting course of CIDP (28). Differentiating a patient with MGUS from one with another plasma cell disorder is difficult and based on clinical, laboratory, and additional diagnostic study findings. The initial studies are a complete blood count, serum creatinine, and serum calcium. If irregularities are identified in any of these studies, metastatic bone survey including long bones is done and bone marrow aspirate and biopsy is recommended if the M-protein value is ³15 g/dL, the paraprotein heavy-chain subclass is IgA or IgM, or an abnormal serum free light-chain (FLC) ratio is documented (29). Electrophysiological studies often show a mixed pattern with evidence of both demyelination and axonal degeneration. Motor nerve conduction velocities are often reduced below the lower limits of normal, and sensory nerve action potentials are consistently reduced or unobtainable. Needle electromyography shows changes consistent with ongoing denervation. Cerebrospinal fluid protein elevation can be seen, typically with no increase in cells. Sural nerve biopsies in patients with neuropathy associated with any monoclonal class associated with neuropathy show mixed axonal and demyelinating pathology (8). The monoclonal proteins associated with MGUS and polyneuropathy belong to the IgM, IgG and IgA heavy-chain classes. The classes are often considered separately in research and clinical practice because clinical and laboratory features of IgG and IgA MGUS neuropathies may distinguish these conditions and the response to treatment (7). IgM MGUS is distinct from IgG and IgA in several features: it is overrepresented in the neuropathy group when compared with the other classes, sensory ataxia occurs more frequently, nerve conduction study findings are significantly worse, and dispersion of compound muscle action potentials occurs more frequently. In the IgM MGUS group, there is interest in the role-associated pathogenic antibodies may play. In particular, anti-MAG antibodies occur in at least 50% of the patients with IgM MGUS neuropathy. Monoclonal IgM antibodies react to other peripheral nerve antigens, including chondroitin sulfate C, sulfatide, cytoskeletal proteins, trisulfated heparin disaccharide, and various gangliosides. These distinct characteristics raise the possibility of antibody­mediated neuropathy. In the heavy-chain class of IgG or IgA MGUS clinical neuropathy features can resemble those of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Because monoclonal proteins are not found in CIDP they are often considered as separate conditions. Nonetheless, patients with IgG and IgA MGUS neuropathy have responded to plasma exchange unlike those with IgM MGUS neuropathy

(28). The laboratory evaluation of MGUS neuropathy includes a variety of blood, electrophysiological, imaging, and pathology studies. A broad diagnostic approach helps to uncover common and uncommon associated disorders, some of which pose risks to life and long-term survival (30). Although MGUS is a common finding in clinical practice, determining whether the condition will remain stable or progress to MM is a significant challenge. MGUS is associated with progression to MM or related malignancy at a rate of 1% per year (9). A risk stratification construct can predict the likelihood of progression of MGUS based on 3 factors: (a) size of the M-protein value (the most influential predictor—the risk of progression of a serum M protein of 15 g/L being twice the risk of progression with a value of 5 g/L), (b) the type of immunoglobulin, and (c) the serum FLC ratio (9,29). Of 22 patients with IgM monoclonal gammopathy interphase fluorescence in situ hybridization (FISH) and other techniques, cytogenetic abnormalities occurred in approximately one third (31). Patients with MGUS need indefinite monitoring with repeat SPEP testing every 6 to 12 months. Although the natural history of evolution of MGUS to malignancy is being clarified, genetic changes, bone marrow angiogenesis, and various cytokines related to myeloma, bone disease, and possibly infectious agents may all play a role (19,31). Treatment recommendations for MGUS neuropathy are also in evolution. The decision to treat depends on the severity and temporal profile of the neuropathy. An indolent course with minor deficits (for instance, Neuropathy Impairment Score [NIS] £ 25) is best managed with watchful waiting and regular SPEP testing. If, however, the neuropathy is more severe (NIS > 25) and meets diagnostic criteria for CIDP, the patient may respond to immunomodulatory therapies. The first double-blind trial of plasmapheresis vs sham pheresis in MGUS neuropathy studied 39 patients with IgG, IgA, or IgM neuropathy; significant improvement in the NIS was documented in those with neuropathy associated with IgG or IgA but not IgM (1). Considering at least one class 1 or class 2 study, evidence-based guidelines from the American Academy of Neurology support the study of Dyck et al (1) and conclude that plasmapheresis is probably effective and should be considered for neuropathy associated with IgG or IgA paraproteinemia but not neuropathy associated with IgM (32). The response to plasmapheresis, intravenous immunoglobulin (IVIg), prednisone, or combinations has been promising, although some consider plasmapheresis to be an adjuvant treatment option. Intravenous cyclophosphamide has been suggested as a helpful approach to refractory neuropathy associated with monoclonal gammopathy (33). Intermittent cyclophosphamide with prednisone has been shown to be superior to placebo in this neuropathy (34). In patients with anti-MAG neuropathy, reduction of total IgM is associated with clinical benefit (35). Rituximab has been demonstrated to be efficacious in a

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KEY POINTS: MGUS •  MGUS most common plasma cell dyscrasia usually presenting in the fifth decade •  Considered a premalignant disorder, linked to a lifelong risk of progression to multiple myeloma or related disorder making long term follow-up necessary •  Patients with MGUS will indefinite monitoring with repeat SPEP testing every 6 to 12 months •  Typically presents as a chronic polyneuropathy, usually relentlessly progressive •  EMG shows mixed pattern of both demyelination and axonal degeneration •  Decisions to treat MGUS are in evolution with promising response to plasmapheresis, IVIg, prednisone, or combinations

randomized, double-blind, placebo-controlled study in anti-MAG neuropathy (36). Although IVIg or rituximab may be helpful for anti-MAG–associated IgM MGUS neuropathy, interferon a is not (37). Other therapeutic approaches that may be helpful in anti-MAG neuropathy include plasmapheresis and chemotherapeutic agents (38). When there is a rapid clinical deterioration of the neuropathy without or despite treatment, reevaluation for underlying malignant lymphoproliferative disorders or amyloidosis is prudent. There is a small increased risk of paraproteinemia in first-degree relatives of patients with MGUS but not enough to justify routine screening (39).

MULTIPLE MYELOMA AND SMOLDERING MULTIPLE MYELOMA MM is distinguished by the propagation of a single clone of plasma cells engaged in the production of a specific immunoglobulin. The natural history of MM is evolution from premalignant MGUS by unknown mechanisms. This neoplastic process occurs in bone marrow with invasion of adjacent bone resulting in skeletal destruction (40). Bone pain (particularly in the back or chest), weakness, pallor, and fatigue are the typical presenting clinical features of MM. Renal insufficiency, hypercalcemia, and anemia are other key clinical associations. Organ involvement includes kidney, liver although uncommon, increased propensity for infection and involvement of the nervous system (41). Classification of MM and other so-called immunosecretory disorders is based on integration of clinical, morphologic, laboratory, and molecular findings (42). Neurological involvement is usually related to spinal cord or root compression from lytic vertebral lesions with associated long tract and segmental symptoms and signs (43). Peripheral neuropathy

associated with MM is rare, occurring in about 5% of patients, most often presenting as a distal sensorimotor polyneuropathy. Nerve conduction studies and sural nerve biopsy are consistent with an axonal process with loss of myelinated fibers (43). The incidence of MM is approximately 4 per 100 000 per year, documentation of presence of bone marrow plasma cells >10%, presence of M protein, and evidence of lytic bone lesions or other underlying organ failure attributable to an underlying plasma disorder (44). Because AL amyloidosis complicates 30% to 40% of MM cases, patients with MM should have tissue or nerve biopsy performed to identify amyloidosis. Treatment for MM consists of external beam radiation, chemotherapy, autologous peripheral stem cell transplantation with conventional therapy, and novel targeted investigational approaches (45). In addition to the neuropathy associated with MM itself, treatment-related neuropathies often occur with agents such as thalidomide and bortezomib (46). SMM accounts for 15% of all cases of newly diagnosed MM. Similar to MGUS, SMM is classified as an asymptomatic premalignant condition. MGUS and SMM are distinguished from each other based on the size of the serum M-protein and bone marrow plasma cell percentage. Unlike MGUS, the risk to progression to MM is higher in SMM (1% MGUS vs 10%–20% in SMM). Most patients with SMM progress to MM in 3 to 4 years with some variability (47). Hematologic management of SMM such as MGUS is observation alone but with more frequent follow-up every 3 to 4 months (40).

VARIANT FORMS OF MULTIPLE MYELOMA Solitary Plasmacytoma SP may be confined to bone or arise in extramedullary sites. There are few reports of an association with solitary myelomas and peripheral neuropathy (28). The presence of biopsy-proven solitary lesion of bone or tissue with evidence of clonal plasma cells and the absence of end organ damage is suggestive of a plasmacytoma. MRI of the involved region, usually spine or pelvis, should be performed in addition to skeletal bone survey, as one third of the patients may have additional occult lesions. Surgical removal and irradiation of the involved site is the treatment of choice with close posttreatment surveillance because of the increased risk of progression to MM (9).

OSM and POEMS Syndrome A rare atypical plasma cell proliferative disorder can occur as single or multiple plasmacytomas that manifest as osteosclerotic lesions. Although these lesions can occur in isolation the full-blown syndrome is also important to recognize among the plasma cell disorders because it is treatable. The acronym POEMS is used to describe major clinical features. Although the key feature is 1 or more sclerotic bone lesions, Castleman disease (giant

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lymph node hyperplasia, angiofollicular lymph node hyperplasia), papilledema, peripheral edema, ascites, polycythemia, thrombocytyosis, fatigue, and clubbing are not included in the acronym despite the fact that they may also be present. Other designations for POEMS include OSM, Crow-Fukase syndrome, plasma cell dyscrasias, endocrinopathy, polyneuropathy (PEP) syndrome, and Takatsuki syndrome (48). Although POEMS occurs in about 2% of patients with MM, the associated neuropathy differs from that associated with MM in several regards. Onset is at an earlier age (median age is 51 years), gender ratio is skewed male, the electrophysiological pattern is demyelinating and predominantly motor neuropathy with slow motor nerve conduction velocities, and CSF protein levels are frequently elevated. An M protein is found in 90% of POEMS cases, almost exclusively composed of the λ light chains associated with IgG and IgA heavy chains. About 85% of patients present with peripheral neuropathy, which bears a striking resemblance to CIDP with symmetrical proximal and distal weakness and variable sensory loss. The clinical and electrophysiological similarities between CIDP and POEMS reinforce the need to screen for M protein in all patients presenting with acquired demyelinating neuropathy (48). Additional clinical features include 1 or more sclerotic bone lesions (primarily in skull or spine), respiratory problems, and the aforementioned associated clinical abnormalities. The pathogenesis of OSM is unclear but may at least in part be cytokine mediated with elevated vascular endothelial growth factor (VEGF) levels. The clinical course may vary from indolent to fulminating. Radiation therapy directed to the sclerotic lesions in the dose range of 40–50 cGy produces substantial improvement of clinical symptoms in more than 50% of patients with half showing improvement in neuropathy symptoms. Unlike in CIDP, neither plasmapheresis nor IVIg provides clinical benefit. For widespread involvement, autologous stem cell transplantation has been thought to be efficacious as has chemotherapy with mephalan and prednisone (49).

KEY POINTS: Multiple Myeloma •  Evolution of premalignant MGUS to a neoplastic process of unknown mechanism •  Common symptoms include bone pain, fatigue, pallor weakness •  Tissue biopsies to identify amyloidosis are suggested because 30% to 40% of MM cases have AL amyloidosis •  Variant forms of MM can occur: SP, OSM, POEMS syndrome

Waldenström Macroglobulinemia WM is the consequence of uncontrolled malignant proliferation of B cells and plasma cells, the latter secreting large amounts of IgM monoclonal protein. WM is only 10% to 20% as common as MM, affecting men slightly more often than women. The median age of onset is 65 years, with Caucasians being more affected then African Americans. Presenting clinical symptoms include weakness, fatigue, and manifestations of hyperviscosity syndrome (oronasal bleeding, blurred vision, dizziness, and dyspnea) (50). About a third of WM patients have symptoms of peripheral neuropathy (51). Chronic symmetric predominantly sensory polyneuropathy similar to MGUS neuropathy is the usual phenotype. Other presentations include pure sensory polyneuropathy, multiple mononeuropathies, and painful predominately sensory neuropathy with prominent dysautonomia often associated disordered gait. The central nervous system is rarely involved. When IgM binds to MAG or sulfatide, there is an associated increase in the frequency and severity of peripheral nerve involvement (51). In about half of WM patients, nerve conduction studies show slowed motor nerve conduction velocities and prolonged distal latencies consistent with demyelinating neuropathy. The serum protein electrophoresis in WM shows an IgM monoclonal spike of >3 g/dL, with 75% having κ light chains. Reduced IgG and IgA protein levels are often found, as is a small urine monoclonal light chain in the majority of patients. The diagnosis of WM requires evidence of bone-marrow infiltration by a low-grade lymphoplasmacytoid lymphoma with the detection of serum IgM monoclonal protein. Although bone marrow aspirates are hypocellular, marrow biopsy specimens are hypercellular with an increase in lymphocytes and plasma cells. Most patients have a moderate to severe normocytic, normochromic anemia. Sural nerve biopsy findings are similar to those seen in IgM MGUS (9,10,20). Reported median survival is approximately 5 years, adverse predictive factors being age older than 70 years, hemoglobin level less than 9 g/dL, weight loss, and cryoglobulinemia (9). Asymptomatic patients are considered to have smoldering WM and immediate therapy is not required (20). Indications for treatment initiation are anemia, thrombocytopenia and/or constitutional symptoms related to WM. Rituximab, nucleoside analogues, alkylating agents alone or in combination are the current treatment options for WM. Therapy is decided based on the age of the patient and the pace of the presentation. As no convincing randomized data exist to determine the best treatment option in WM, patients are preferably treated in well­designed, randomized controlled clinical trials (9,24,52).

Systemic AL Amyloidosis Amyloidosis is a multisystem disorder characterized by extracellular deposition of fibrillar proteins that accumulate in various tissues. Diagnosis is based on the

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recognition of amyloid deposits in the affected organs (9). Amyloid can be detected when biopsy material is stained with Congo red dye (which displays a characteristic apple-green birefringence under polarized light), methyl violet, or examined for characteristic ultrastructural changes by transmission electron microscopy. The use of the protein composition of the amyloid material has allowed for classification of several distinct types of localized or systemic amyloidosis as well as amyloidlike material in rare cases, which may be localized or systemic (9). Systemic AL amyloidosis is referred to as primary systemic amyloidosis or primary amyloidosis. AL (immunoglobulin light-chain) amyloidosis refers to the type of amyloidosis resulting from the amino­terminus variable segment of immunoglobulin light chain. It commonly presents in the absence of plasma cell dyscrasia but may occur in association with MM or WM. The source of AL amyloidosis is poorly understood but is thought to be a clone of either malignant or nonproliferative plasma cells that secrete amyloidogenic light-chain polypeptides (53). Common clinical features include polyneuropathy and a variety of medical syndromes. Peripheral neuropathy occurs in 15% to 30% of patients with AL amyloidosis and is the presenting feature in 10% of cases. The 5 predominant clinical patterns of peripheral neuropathy in a cohort of 65 patients with biopsy-proven amyloidosis who underwent autonomic testing were (a) generalized autonomic failure and painful polyneuropathy (62%), (b) generalized autonomic failure and painless polyneuropathy (17%), (c) isolated generalized autonomic failure (11%), (d) polyneuropathy without autonomic failure (6%), and (e) generalized autonomic failure and small-fiber neuropathy (5%) (54). The typically distal neuropathy often follows a slow, painful, and progressive course. Loss of small fiber modalities is seen initially with loss of light touch or vibratory sensation following, with most patients going on to develop autonomic dysfunction at some point in their course. Carpal tunnel syndrome from amyloid infiltration of the wrist flexor retinaculum will occur in about 25% of patients. Electrodiagnostic studies are typically consistent with axonal neuropathy, nerve conduction studies showing low-amplitude to absent sensory nerve action potential, low-amplitude compound muscle action potentials, and relatively preserved motor nerve conduction velocities and distal latencies. Needle examination frequently provides evidence of active denervation. Over half of amyloid patients have systemic organ involvement (nephrotic syndrome, cardiac failure, chronic diarrhea with wasting, hypoalbuminemia, cutaneous purpura, macroglossia, or hepatomegaly) (53). The clinical prognosis is poor with approximately 80% of patients succumbing within 36 months and nearly 50% with 12 months of initial diagnosis. With mortality primarily due to cardiac and less often renal failure, individuals without manifest cardiac and renal involvement have a better long-term prognosis (24,55).

KEY POINTS: Waldenström and Amyloidosis •  Waldenström macroglobulinemia: consequence of uncontrolled malignant proliferation of B cells and plasma cells, the latter secreting large amounts of IGM monoclonal protein

°  A third of WM patients have symptoms of PN °  Therapy is decided based on the age of patient

and the pace of the presentation and remains best treated in clinical trials •  Systematic AL amyloidosis: a multisystem disorder characterized by extracellular deposition of fibrillar proteins, which accumulates in various tissues

°  Amyloid is detected when biopsy material is stained with Congo red dye

°  Several distinct types exits localized or systemic °  Clinical features include polyneuropathy in 15% to 30% of patients and autonomic failure is also common, along with a variety of medical syndrome

Melphalan and prednisone has been the mainstays of therapy for amyloidosis with generally unsatisfactory results. Stem cell transplantation is offered to some eligible patients as well as novel trials with such agents as thalidomide (56). In a case-controlled study of 13 patients with autonomic neuropathy (AN) associated with AL amyloidosis matched with 95 amyloid patients without AN, autologous stem cell transplantation was found to be a relatively safely performed procedure, although patients with AN had a much worse prognosis (median survival 29 months) than those without AN (>60 months) (24,56).

MISCELLANEOUS DISORDERS Lower Motor Neuron Syndromes Multifocal motor neuropathy (MMN) is a syndrome affecting lower motor neurons associated with increased titers of serum IgM autoantibodies to GM1 ganglioside and less frequently to other glycolipids. It is distinguished by its characteristic clinical picture, specific electrodiagnostic abnormalities, and favorable response to IVIg. Patients usually present with slowly progressive, predominantly distal asymmetric limb weakness and wasting, primarily in the upper limbs. Deep tendon reflexes may be preserved early in the course of disease. Nerve conduction studies show evidence of multifocal motor conduction block in 1 or more nerves not limited to common sites of compression. The disorder is confined to motor axons with relative sparing of sensory axons (57,58). The prevalence of anti-GM1

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antibodies is the prototypic serological finding associated with MMN although the proportion of antibody-positive patients varies widely from 30% to 80% (57–59). A rare condition affecting 1 to 2 persons per 100  000, MMN occurs more frequently in men than women and has a mean age of onset close to 40 years (58). The effectiveness of IVIg therapy has been demonstrated in several studies and is widely considered the gold standard of treatment for MMN in the neuromuscular community (59). Even after salutary treatment responses, the antiglycolipid levels often remain unchanged, raising questions regarding their pathogenic role in MMN (59). A subset of patients with purely axonal motor neuropathy, raised anti-GM1 antibody titers, absence of conduction block, or other NCS features suggesting demyelination, and variable response to immunosuppressive therapy have been designated multifocal acquired motor axonopathy (MAMA) (45). Some patients fitting into the MAMA category have elevated anti-GD1 antibody titers (4). Because of immunohistochemical studies showing binding of antiganglioside antibodies to antigens on motor neuron cell bodies, axons at nodes of Ranvier, and motor endplates, an association between MAMA and motor neuron disease has been raised. Although cases of high titer IgM anti-GM1 ganglioside antibodies have been reported in this disorder, there is little evidence of a causal link (7).

Cryoglobulinemia Cryoglobulins are IgG or IgM proteins that precipitate when cooled, redissolve after warming, and circulate as immune complexes in the bloodstream. These immunoglobulins may be monoclonal, polyclonal, or both. Cryoglobulinemia is divided into 3 subtypes based on the composition of the cryoprecipitate: type 1, isolated monoclonal immunoglobulins; type II, a monoclonal mixture of an M protein with polyclonal immunoglobulins (IgG) in the setting of lymphoproliferative disease or hepatitis C; type III, polyclonal immunoglobulins in the setting of collagen vascular disease or other chronic inflammatory conditions (8). Cryoglobulinemia classically presents with purpura, arthralgias, asthenia, renal disease, and neuropathy. The disorder has most often been associated with hepatitis C virus (HCV) and less commonly lymphoproliferative disorders, connective tissue disease, and chronic infections with agents other than HCV. Peripheral neuropathy is reported in 17% to 56% of patients and may manifest as either acute or subacute distal symmetrical or asymmetrical sensorimotor polyneuropathy or as multiple mononeuropathies. Sensory symptoms usually precede motor manifestations. Most often axonal degeneration predominates electrophysiologically, although evidence suggesting demyelination may be present (57). The therapeutic approach to mild symptomatic cryoglobulinemia consists of conservative measures such as bed rest, avoidance of cold, use of analgesics, and consideration of low-dose steroid therapy. For more severe

forms complicated by glomerulonephritis, peripheral motor deficits and systemic vasculitis, plasmapheresis, high-dose corticosteroids, and cytotoxic therapy may be warranted. The potential benefits of agents such as melphalan, cyclophosphamide, or chlorambucil must be weighed against the long-term risks of myelodysplastic syndromes and acute leukemia. Interferon has been reported to be of benefit to those with HCV infection, although a majority relapses 6 months after discontinuation of therapy. Although purpuric lesions and liver function abnormalities often show a rapid response, the neuropathy and nephropathy are slower to improve. Rituximab has been suggested as an alternative to traditional chemotherapy (8,24).

SUMMARY The last few decades have seen increased clinical recognition of the peripheral neuropathies associated with paraproteinemia. At least 10% of de novo neuropathy patients have an M protein. Because of the higher risk of serious association with MM, WM, OSM, POEMS, lymphoma, and AL amyloidosis, these individuals require detailed investigation for specific underlying causes. The majority of paraproteinemic neuropathies are ultimately designated as having MGUS. The evaluation of paraproteinemia includes recognition, characterization, and quantitation of the M protein and performing additional testing including x-ray skeletal bone survey and aspirated

KEY POINTS: IgM MGUS Neuropathy vs Other MGUS Neuropathies •  IgM MGUS is overrepresented in peripheral neuropathy patients •  Detailed clinical investigation is warranted to determine possible association with serious pathology: multiple myeloma, Waldenström macroglobulinemia, osteoclerotic myeloma, POEMS lymphoma, and AL amyloidosis •  IgM MGUS usually has sensory ataxia than IgG or IgA •  IgM MGUS usually has demyelinating nerve conduction studies •  IgM MGUS is usually more severe clinically and electrophysiologically •  IgM MGUS is more frequently antibodyassociated (MAG, sulfatide, various gangliosides, etc) MGUS patients have a 25-year risk of progression to myeloma and warrant follow-up testing every 6 to 12 months for life •  IgM MGUS may respond less well to PLEX than IgG and IgA neuropathies •  IgM MGUS may respond better to other immune therapies

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bone marrow biopsy. Because the 25-year risk of progression to myeloma in MGUS is 30%, a recommendation for follow-up testing every 6 to 12 months with measurement of total protein concentration as well as SPEP and UPEP seems appropriate. Although no treatment is indicated for mild or subclinical MGUS or mild or incidental MGUS neuropathy, research in the arena of neoplastic plasma cell diseases has led to new therapies including novel immunotherapies, chemotherapies, and stem cell transplantation. Innovative research protocols are being pursued at a number of centers (www.clinicaltrials.gov). Recognition of syndromes associated with monoclonal gammopathies and peripheral neuropathy is essential for clinicians caring for patients with neuropathy, as is familiarity with treatment options, which may prove to be beneficial for selected individuals.

References 1. Dyck PJ, Low PA, Windebank AJ, et al. Plasma exchange in polyneuropathy associated with monoclonal gammopathy of undetermined significance. N Engl J Med. 1991;325:1482–1486. 2. Dalakas MC. B cells as therapeutic targets in autoimmune neurological disorders. Nat Clin Pract Neurol. 2008;4(10): 557–567. 3. Kyle RA, Therneau TM, Rajkumar SV, Larson DR, Plevak MF, Melton LJ, 3rd. Long-term follow-up of 241 patients with monoclonal gammopathy of undetermined significance: the original Mayo Clinic series 25 years later. Mayo Clin Proc. 2004;79(7):859–866. 4. Landgren O, Gridley G, Turesson I, et al. Risk of monoclonal gammopathy of undetermined significance (MGUS) and subsequent multiple myeloma among African American and white veterans in the United States. Blood. 2006;107(3):904–906. 5. Wadhera RK, Rajkumar SV. Prevalence of monoclonal gammopathy of undetermined significance: a systematic review. Mayo Clin Proc. 2010;85(10):933–942. 6. Silberman J, Lonial S. Review of peripheral neuropathy in plasma cell diorders. Hematol Oncol. 2008;26:55–65. 7. Kyle RA, Dyck PJ. Neuropathy associated with mono­ clonal gammopathies. In: Dyck PJ, Thomas PK, eds. Peripheral Neuropathy Vol 2. Philadelphia: Elsevier Saunders; 2005:2255–2276. 8. Dispenzieri A, Kyle RA. Neurological aspects of multiple myeloma and related disorders. Best Pract Res Clin Haematol. 2005;18(4):673–688. 9. Kyle RA, Rajkumar SV. Monoclonal gammopathies of undetermined significance. Rev Clin Exp Hematol. 2002;6(3): 225–252. 10. Kyle RA, Rajkumar SV. Monoclonal gammopathies of undetermined significance: a review. Immunol Rev. 2003;194: 112–139. 11. Quarles RH, Weiss MD. Autoantibodies associated with peripheral neuropathy. Muscle Nerve. 1999;22(7):800–822. 12. Kyle RA, Rajkumar SV. Multiple myeloma. N Engl J Med. 2004;351(18):1860–1873. 13. Latov N, Hays AP, Sherman WH. Peripheral neuro­ pathy and anti-MAG antibodies. Crit Rev Neurobiol. 1988; 3(4):301–332.

14. Chassande B, Leger JM, Younes-Chennoufi AB, et al. Peripheral neuropathy associated with IgM monoclonal gammopathy: correlations between M-protein antibody activity and clinical/electrophysiological features in 40 cases. Muscle Nerve. 1998;21(1):55–62. 15. Roodman GD. Role of the bone marrow microenvironment in multiple myeloma. J Bone Miner Res. 2002;17(11):1921–1925. 16. Gosselin S, Kyle RA, Dyck PJ. Neuropathy associated with monoclonal gammopathies of undetermined significance. Ann Neurol. 1991;30(1):54–61. 17. Yeung KB, Thomas PK, King RH, et al. The clinical spectrum of peripheral neuropathies associated with benign monoclonal IgM, IgG and IgA paraproteinaemia. Comparative clinical, immunological and nerve biopsy findings. J Neurol. 1991;238(7):383–391. 18. Ilyas AA, Gu Y, Dalakas MC, Quarles RH, Bhatt S. Induction of experimental ataxic sensory neuronopathy in cats by immunization with purified SGPG. J Neuroimmunol. 2008;193:87–93. 19. Eurelings M, Notermans NC, Lokhorst HM, et al. Immunoglobulin gene analysis in polyneuropaty associated with IgM monoclonal gammopathy. J Neuroimmunol. 2006:175:152–159. 20. Blade J. Clinical practice. Monoclonal gammopathy of undetermined significance. N Engl J Med. 2006;355(26):2765–2770. 21. Katzmann JA, Dispenzieri A, Kyle RA, et al. Elimination of the need for urine studies in the screening algorithm for monoclonal gammopathies by using serum immunofixation and free light chain assays. Mayo Clin Proc. 2006;81(12): 1575–1578. 22. Rajkumar SV, Dispenzieri A, Kyle RA. Monoclonal gammopathy of undetermined significance, Waldenstrom macroglobulinemia, AL amyloidosis, and related plasma cell disorders: diagnosis and treatment. Mayo Clin Proc. 2006;81(5):693–703. 23. King RI, Florkowski CM. How paraproteins can affect laboratory assays: spurious results and biological effects. Pathology. 2010;42(5):397–401. 24. Hoffman-Snyder C, Smith BE. Neuromuscular disorders associated with paraproteinemia Phys Med Rehabil Clin N Am. 2008:19(1), 61–79. 25. Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006;354(13),1362–1369. 26. Kyle RA, Rajkumar SV. Monoclonal gammopathy of undetermined significance. Br J Haematol. 2006;134(6),573–589. 27. Kissel JT, Mendell JR. Neuropathies associated with monoclonal gammopathies. Neuromuscul Disord. 1996;6(1):3–18. 28. Kyle RA, Dispenzieri A. Neuropathy associated with the monoclonal gammopathies. In: Noseworthy JH, ed. Neurological Therapeutics Principles and Practice. Vol 3. 2nd ed. Abingdon, Oxon: Informa Healthcare; 2006:2401–2414. 29. Rajkumar SV, Kyle RA, Therneau TM, et al. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood. 2005;106(3):812–817. 30. Živkoviˇc SA, Lacomis D, Lentzsch S. Paraproteinmic neuropathy. Leuk Lymphoma. 2009;50(9):1422–1433. 31. Eurelings M, Lokhorst HM, Notermans NC, et al. Cytogenetic aberrations in neuropathy associated with IgM monoclonal gammopathy. J Neurol Sci. 2007;260:124–131. 32. Cortese I, Chaudhry V, So YT, Cantor F, Cornblath DR, Rae-Grant A Evidence-based guideline update:

226  Textbook of Peripheral Neuropathy plasmapheresis in neurologic disorders Report of the Therapeutics and Technology Assessment Subcommitte of the American Academy of Neurology. Neurology. 2011;76: 294–300. 33. Hamidou M A, Belizna C, Wierlewsky S, et al. Intravenous cyclophosphamide in refractory polyneuropathy associated with IgM monoclonal gammopathy: an uncontrolled open trial Amer J Med. 2005;118(4):426–430. 34. Niermeijer JMF, Eurelings M, Lokhorst HM, et al. Intermittent cyclophosphamide with prednisone versus placebo for polyneuropathy with IgM monoclonal gammopathy Neurology. 2007;69:50–59. 35. Gorson KC, Ropper AH, Weinberg DH, Weinstein R. Treatment experience in patients with anti-myelin–associated glycoprotein neuropathy. Muscle Nerve. 2001;24:778–786. 36. Dalakas MC, Rakocevic G, Salajegheh M, et al. Placebo­controlled trial of rituximab in IgM anti-myelin–associated glycoprotein antibody demyelinating neuropathy. Ann Neruol. 2009;65:286–293. 37. Magy L, Vallat JM, Evidence-based treatment of chronic immune-mediated nekuropathies. Expert Opin Pharmacother. 2009;10(11):1741–1754. 38. Brannagan TH, 3rd. Current treatments of chronic immune-mediated demyelinating polyneuropathies. Muscle Nerve. 2009;39(5):563–578. 39. Kristinsson SY, Goldin LR, Björkholm M, et al. Genetic and immune-related factors in the pathogenesis of lymphoproliferative and plasma cell malignancies. Haematologica. 2009 94(11):1581–1589. 40. Blade J, Rosinol L. Smoldering multiple myeloma and monoclonal gammopathy of undetermined significance. Curr Treat Options Oncol. 2006;7(3):237–245. 41. Shaheen SP, Talwalkar SS, Medeiros LJ. Multiple myeloma and immunosecretory disorders. An update Adv Anat Pathol. 2008;15(4):196–208. 42. Lehmann HC, Hartung H-P, Meyer zu Hörste G, Kieseler BC Plasma exchange in immune-mediated neuropathies. Curr Opin Neurol. 2008;21:547–554. 43. Sirohi B, Powles R. Multiple myeloma. Lancet. 2004;363(9412):875–887. 44. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78(1):21–33. 45. Rajkumar SV, Kyle RA. Multiple myeloma: diagnosis and treatment. Mayo Clin Proc. 2005;80(10):1371–1382.

46. Mohty B, El-Cheidh J, Yakoub-Agha I, et al. Peripheral neuropathy and new treatment for multiple myeloma: background and practical recommendations Haematologica. 2010;95(2):311–319. 47. Rajkumar SV. MGUS and smoldering multiple myeloma: update on pathogenesis, natural history, and management. Hematol Am Soc Hematol Educ Program. 2005:340–345. 48. Dispenzieri A, Kyle RA. Multiple myeloma: clinical features and indications for therapy. Best Pract Res Clin Haematol. 2005;18(4):553–568. 49. Dispenzieri A, Moreno-Aspitia A, Suarez GA, et al. Peripheral blood stem cell transplantation in 16 patients with POEMS syndrome, and a review of the literature. Blood. 2004;104(10):3400–3407. 50. Dimopoulos MA, Anagnostopoulos A. Waldenstrom’s macroglobulinemia. Best Pract Res Clin Haematol. 2005;18(4):747–765. 51. Levine T, Pestronk A, Florence J, et al. Peripheral neuropathies in Waldenstrom’s macroglobulinaemia. J Neurol Neurosurg Psychiatry. 2006;77(2):224–228. 52. Treon SP, Gertz MA, Dimopoulos M, et al. Update on treatment recommendations from the Third International Workshop on Waldenstrom’s macroglobulinemia. Blood. 2006;107(9):3442–3446. 53. Kyle RA, Kelly JJ, Dyck PJ. Amyloidosis and neuropathy. In: Peripheral Neuropathy. Vol 2. Philadelphia: Elsevier Saunders; 2004:2427–2451. 54. Wang AK, Fealey RD, Gehrking TL, Low PA. Patterns of neuropathy and autonomic failure in patients with amyloidosis. Mayo Clin Proc. 2008;83(11):126–1230. 55. Gertz MA, Kyle RA. Amyloidosis with IgM monoclonal gammopathies. Semin Oncol. 2003;30(2):325–328. 56. Dingli D, Tan TS, Kumar SK, et al. Stem cell transplantation in patients with autonomic neuropathy due to primary (AL) amyloidosis. Neurology. 2010;74;913–918. 57. Leger JM, Behin A. Multifocal motor neuropathy. Curr Opin Neurol. 2005;18(5):567–573. 58. Meuth SG, Kleinshnitz C. Multifocal motor neuropathy: update on clinical characteristics,pathophysiologic al concepts and therapeutic options. Eur Neurol. 2010;63: 193–204. 59. Nobile-Orazio E, Gallia F, Tuccillo F, et al. Chronic inflammatory demyelinating polyradiculoneuropathy and multifocal motor neuropathy: a treatment update. Curr Opin Neurol. 2010;23(5):519–523.

16

John C. Kincaid

Neuropathies Due to Amyloidosis

INTRODUCTION

developed lymphoproliferative disorder such as multiple myeloma, Waldenström macroglobulinemia, and Bcell lymphoma. The median age at diagnosis is 65 years. Most patients are found to have a monoclonal protein by serum protein electrophoresis. Immunofixation is more sensitive than the standard serum electrophoresis. The entire immunoglobulin may be detected or just the light chain component. Urine immunoelectrophoresis shows monoclonal light chains in about two thirds of AL patients. Involvement of the kidney, heart, skin, and peripheral nerve produce the most common clinical features of this type of amyloidosis. Nephrotic syndrome consisting of proteinuria, hypoalbuminemia, and peripheral edema is the most common clinical presentation, being present in about 30% of patients. Cardiac involvement manifests as heart failure, present in about 25% of patients, and arrhythmia. Echocardiography demonstrates increased thickness of the ventricular walls. Skin involvement manifests with purpura, which commonly occurs in the upper eyelids. Other areas of the face and the neck may be involved. Peripheral nerve involvement manifests as carpal tunnel syndrome and generalized polyneuropathy. Carpal tunnel syndrome is present in about 25% of patients and polyneuropathy in about 20%. Both can be present in the same patient. Peripheral nerve symptoms may be present for months before the diagnosis of amyloidosis is established. Autonomic nervous system involvement produces impotence, orthostatic hypotension, impairment of sweating, and bowel dysmotility. Diarrhea is a common symptom of GI tract involvement. Amyloid may be incidentally found in skeletal muscle biopsies in patients who do not have myopathic symptoms. Less commonly extensive amyloid deposition in muscle produces stiffness or pseudohypertrophy.

Amyloidosis is a disorder in which extracellular aggregates of a specific protein accumulate (1). The aggregates impair normal tissue functions. Multiple organ systems can be involved depending on the particular protein and the pattern of deposition. The peripheral nervous system is often involved. The pattern of involvement can be focal such as carpal tunnel syndrome, a more generalized polyneuropathy, or both. In either of these scenarios, the nerve abnormalities appear insidiously and progress over years. The suspicion for amyloidosis should be raised when peripheral neuropathies and dysfunction of other systems such as the cardiac, gastrointestinal, and renal system occur concurrently without another apparent etiology. Amyloidosis should be also considered when focal and generalized peripheral neuropathies occur in an inherited pattern.

cLINICAL MANIFESTATIONS The amyloidoses were originally classified by the clinical settings in which they developed. The primary type referred to patients with no apparent predisposing disease. The secondary type referred to patients who developed amyloidosis in the setting of chronic systemic inflammatory or infectious diseases. The hereditary type referred to patients who had a family history of the same clinical illness. The original classification has evolved based on knowledge of the proteins that form the deposits. Under the revised classification, peripheral neuropathy occurs only in the primary and hereditary forms of amyloidosis.

Primary Amyloidosis The primary form of amyloidosis is now known to be due to deposition of the light chain component of immunoglobulins (2). This condition has also been termed AL amyloidosis, with AL referring to amyloid light chain. This is the most common form of systemic amyloidosis. It can occur in isolation or be part of a more well-

Hereditary Amyloidosis The hereditary types of amyloidosis that involve the peripheral nervous system produce 4 syndromes (1,3). One 227

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manifests as a sensorimotor autonomic polyneuropathy beginning in the lower extremities. Another begins with carpal tunnel syndrome followed years later by polyneuropathy. A third type causes impairment of renal function and, in some patients, a polyneuropathy. The fourth type causes visual disturbance due to involvement of the cornea and then dysfunction of other cranial nerves separately. A mild polyneuropathy may develop later in this type. A dominant pattern of inheritance is seen in each of these syndromes, and most patients are heterozygotes. The reports on patients in Portugal by Andrade provided the classic description of the lower extremity type neuropathy (4). This form of the disease begins insidiously between age 25 and 35 years with impairment of pain and thermal sensibility initially. Early reports characterize this as a “syringomyelic pattern.” Paresthesias, and impairment of large fiber sensory functions such as light touch and vibration develop later (5). Motor dysfunction is also a later feature and manifests first as toe and ankle weakness. Gastrointestinal function becomes disturbed due to the involvement of the autonomic nerves and may be an early manifestation of the condition. Symptoms of upper gastrointestinal tract involvement are early satiety and bloating, whereas lower track involvement causes constipation or diarrhea. Erectile dysfunction is often an early symptom in males. Pupillary constriction to light or to convergence can be impaired. The central border of the iris may develop a wavy, “scalloped” configuration. Cardiac dysfunction occurs due to amyloid accumulation in the muscle and as in the primary type can produce arrhythmia and congestive failure. The overall condition worsens over a 10- to 12-year time span and is often fatal secondary to progressive debilitation. This syndrome also occurs is families of non-Portuguese origin. Onset at later ages is seen in some of these families. This type of neuropathy has been designated familial amyloid polyneuropathy (FAP) type I. Reports on families of Swiss origin who resided in United States in northern Indiana provided the classic description of the amyloid neuropathy, which begins with carpal tunnel syndrome. In their 30s, patients would begin to experience typical carpal tunnel syndrome symptoms of pain and numbness in the hands. These symptoms improved with surgical decompression of the median nerve at the wrist. Eight to 10 years later, sensory loss might then develop in the lower extremities. Ocular dysfunction can occur and is due to amyloid accumulating in the vitreous humor. Cardiomyopathy develops and is the usual cause of death. Autonomic dysfunction is not as prominent in this type of hereditary amyloidoisis. A large kindred of German origin who originally resided in the state of Maryland and was not related to the Swiss kindred had a similar clinical picture. This pattern of initial carpal tunnel syndrome followed years later by polyneuropathy has been designated FAP II (1,3,6).

A third type of inherited amyloidosis that produces impairment of renal function without nephrotic syndrome and a variable degree of polyneuropathy was defined in patients from Iowa by Van Allen et al (8). The neuropathy is similar to that found in FAP I with lower extremity involvement occurring first at about age 30 to 40 years followed later by upper extremities abnormalities. This type of amyloidosis is designated FAP III (7). A fourth type of inherited amyloidosis that produces peripheral neuropathy has been reported in families from Finland (1,3,8). Clinical manifestations begin at age 30 to 40 years. Abnormalities of the cornea, cranial nerves, skin of the face and upper body, heart, and kidney due to amyloid deposition define this condition. Patients may report refractive error type symptoms or nonspecific ones such as photophobia. During ophthalmologic examination, they are found to have “lattice dystrophy,” which consists of lattice-like lines in the cornea observable during slit lamp examination. The corneal abnormality is now known to be due to amyloid deposition in the nerves that traverse it. Patients may complain of pruritus of the scalp and face, but weakness of the upper portion of the face is the first manifestation of cranial nerve dysfunction outside of the eye. This usually begins after the visual dysfunction. Other cranial nerves such as the trigeminal and hypoglossal can be involved later. A mild sensory polyneuropathy and carpal tunnel syndrome can also develop later. The skin of the face and upper body hangs loosely and becomes thickened. The skin changes are partly due to cranial neuropathy and also due to amyloid deposition in the skin. Cardiac and renal dysfunction can also occur but tend to be less prominent features. This type of amyloidosis has been designated FAP IV. It has also been found in families from Denmark, Czechoslovakia, Japan, the Netherlands, and the United States. An ancestral link to Finland was present in one of the families from the United States.

DIFFERENTIAL DIAGNOSIS The differential diagnosis of amyloid neuropathy includes any of the slowly evolving polyneuropathy syndromes. Diabetic neuropathy should be easily distinguishable by the abnormality in glucose handling. Alcoholism can produce a syndrome similar to the polyneuropathy of amyloidosis. Laboratory findings of hepatic dysfunction and macrocytosis heighten this possibility. Chronic inflammatory neuropathy can have a similar time course to amyloid polyneuropathy. The generalized loss of muscle stretch reflexes and the finding of a demyelinating pattern of abnormality in nerve conduction studies should distinguish this type of neuropathy from amyloidosis. The hereditary neuropathies of the Charcot-Marie-Tooth type can be considered but tend to present earlier in life and do not have the accompanying dysfunction of other organ systems characteristic of the amyloid related neuropathies.

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PATHOGENESIS AND PATHOPHYSIOLOGY Knowledge of normal protein structure is necessary for understanding the processes that lead to the accumulation of abnormal proteins in the amyloidoses. Proteins have several hierarchies of structure. The primary structure is dictated by the sequence of amino acids in the polypeptide chain. The secondary structure is the local turns and folds in the polypeptide chain resulting from hydrogen bond formation between carbonyl (CO) and amino (NH) components of the amino acids in the chain. This type of interaction may cause segments of the chain to assume a spiral configuration a helix or a planar configuration b sheet. The tertiary structure is determined by the tendency to fold into even more complex shapes and results from the optimization of thermodynamic forces on hydrophobic and hydrophilic side chains of the constituent amino acids. Disulfide bonds between cysteines along the chain also contribute to the tertiary structure. A quaternary level of structure occurs when several separate polypeptide chains come together to form the final protein (9). The tendency to take on a b-sheet configuration underlies the potential for amyloid formation. b-Sheet segments of the polypeptide chain may further organize into more extensive parallel, “stacked” folds. Accumulation of these type segments is the basis of amyloid formation. The propensity to form amyloid usually results from substitution of a single amino acid in the normal sequence of the polypeptide. The substitution modifies the protein’s natural folding pattern and enhances the potential to form b-sheet segments (10,11). Interestingly, amyloid deposits may contain both variant and normal protein. When histological specimens are viewed at the light microscopic level the amyloid deposits are globular, amorphous, and eosinophilic (12). When viewed at the electron microscopic level, the deposits are seen to consist of masses of nonbranching fibrils of about 10 nm in diameter and of variable length. At even higher levels of magnification, the fibrils are seen to be made up of several “protofilaments” that assume a spiral configuration around each other (10). Amyloid is characterized by the tendency to take up the histological stain Congo red. Congo red is thought to insert itself between adjacent protofilaments within an amyloid fibril (1,10). When the Congo red–stained tissue is viewed by polarized light microscopy, the red color is changed to green, producing “apple-green birefringence.” This is due to the Congo red–stained amyloid acting like a prism to separate light into different wave lengths. Green is the most prominent of these.

Specific Protein Abnormalities In primary amyloidosis, the l light chain of the immunoglobulin is the source of abnormal protein deposits (2). The variable region of the light chain has an inherent b-sheet structure and some subtypes of the light chain seem to be more likely to produce amyloid.

In the inherited forms of amyloidosis, FAP I and II are now known to be caused by mutations in the gene that codes for the protein transthyretin, which is also known as prealbumin (1,3,10,11). This protein is produced by the liver. Its biological function is to transport thyroxine and vitamin A in the serum. It also has metabolic functions in the CSF where it is produced by the choroid plexus and in the retina where it is produced by the retinal pigment epithelium. The monomeric protein is 127 amino acids in length. Four monomers come together to form the final protein. The mutations alter the amino acid sequence of the naturally occurring protein. The altered, often termed variant, protein has an enhanced tendency for b-sheet formation. Although more than 100 mutations have been found, only a few account for the majority of the cases in which clinical disease develops. Substitution of methionine for valine at position 30 of the 127 amino acid chain, designated Val30Met in standard genetic terminology, accounts for most of the FAP I cases. Substitution of serine for isoleucine at position 84 produces the Indiana-Swiss FAP II phenotype, whereas substitution of histidine for leucine at position 58 is found in the Maryland-German families with FAP II. Abnormal as well as normal protein is produced when mutations are present. The amyloid deposits is these syndromes usually consist of 60% to 70% variant protein and 30% to 40% normal. Mutations in the gene for apolipoprotein AI have been shown to be the cause of FAP III. This protein is a component of the high density fraction of serum lipids. It is 243 amino acids in length, and the final form is a monomer. A number of different mutations of this protein cause amyloidosis, but peripheral neuropathy occurs only in patients with the glycine to arginine substitution at position 26. A fragment of the full-length protein forms the amyloid. In contrast to FAP I and II, only the abnormal protein is found in the amyloid deposits (1,11). The amyloid in FAP IV is derived from the protein gelsolin (1,3,10,11). Gelsolin is a large protein involved with the assembly and regulation of actin. It is produced by skeletal muscle and monocytes. The protein exists in both cytoplasmic and secreted forms, the latter occurring in the plasma. Substitution of asparagine or tyrosine for aspartate at position 187 of the 755 amino acid chain occurs in patients who develop amyloidosis. A fragment of the full length of the protein is the source of the amyloid. The mechanism by which the amyloidosis produces peripheral neuropathy and dysfunction of other organs has not been established. Suggestions for the etiology of the neuropathies include direct compression of axons, compression of the neural capillaries, and direct toxic effects on either the axons or Schwann cells (1,3,10–12). Another curious feature of the inherited amyloidoses is that the abnormal protein, which will eventually form the amyloid deposits, is present in the patient since birth but only produces disease many decades later.

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DIAGNOSTIC EVALUATION

ing the assistance of an amyloid research center should be considered for aid in diagnosis and management. Institutions with special expertise in amyloidosis include Boston University, Indiana University, and Mayo Clinic–Rochester in the United States, University of Pavia in Italy, University College London in the United Kingdom, and the Universities of Kumamoto and Matsumoto in Japan (11).

The diagnosis of amyoidosis requires demonstration of amyloid deposits in a tissue sample from the patient. The results of other tests may provide supportive data but do not substitute for tissue verification. Protein electrophoresis and immunoelectrophoresis of the serum and urine should be performed looking for monoclonal immunoglobulin and excessive amounts of light chains (2). In AL amyloid patients, these tests should be positive in 80% of patients. Abdominal fat pad aspiration or rectal biopsy to obtain a sample of the submucosa may reveal amyloid deposits around blood vessels. These studies are positive in about 70% of patients with AL amyloid but are less often positive in the inherited forms of the disease. The transverse carpal ligament should be examined in patients with a family history of carpal tunnel syndrome who are undergoing decompressive surgery for carpal tunnel syndrome. Renal or hepatic biopsies tend to have a high yield in patients with the AL type of amyloid. Renal biopsy should show amyloid deposition in FAP III. Biopsy of a peripheral nerve such as the sural nerve is the best test for patients with polyneuropathy but may not always be positive at a single site due to patchy involvement along a nerve. When viewed at the light microscopic level with hematoxylin and eosin staining amyloid deposits are eosinophilic and amorphous (12). They are extracellular and appear to be crowding the surrounding structures. The deposits often appear first around intraneural blood vessels. The pattern of the light microscopic morphology of the amyloid and its pattern of Congo Red staining do not distinguish AL from hereditary forms. Representative histological sections of a peripheral nerve from a patient with amyloidosis are shown in Figure 16.1. When a hereditary form is being considered, gene testing may be helpful. Several tests for transthyretin mutations are available through commercial labs. Seek-

ELECTROPHYSIOLOGY Patients with amyloidosis who have a polyneuropathy demonstrate an axonal pattern of abnormality in the nerve conduction studies. The amplitudes of nerve action potentials in sensory conduction studies and the compound muscle action potentials in motor studies show proportionally greater degrees of abnormality than do the distal latencies or conduction velocities. Nerves of the lower limbs tend to become abnormal before those of the upper limbs. A typical pattern of abnormality early in the illness would be low amplitudes with normal latency or absent responses from the sural sensory nerves. At the same time motor studies from nerves such as the peroneal or posterior tibial would be expected to show low-amplitude compound muscle action potentials, normal distal latencies, and mildly slow conduction velocity values. Upper limb nerves tend to be normal early on unless carpal tunnel syndrome is present. As the disease progresses, conduction studies show further reduction of response amplitudes or loss of responses in the lower limbs and onset of abnormalities in upper limb studies. Slowing of conduction velocity into the range typical of a demyelinating neuropathy (lower limbs, 1.58 mg/dL, cardiomyopathy, severe gastrointestinal disease, and central nervous system disease); patients with none of these had a 5-year mortality of 12%, those with only 1 indicator had a 5-year mortality of 26%, whereas those with more than 1 indicator had a 5-year mortality of 46% (9,10).

SYSTEMIC VASCULITIC NEUROPATHY Primary Vasculitis For the nonspecialist, the classification and individual identity of the primary vasculitides is challenging because of their heterogenous and overlapping clinical and diagnostic features. The classification of the primary vasculitides is addressed by the American College of Rheumatology (ACR), which identifies criteria for PAN, Churg-Strauss syndrome, Wegener granulomatosis, hypersensitivity vasculitis, Henoch-Schönlein purpura, giant cell/temporal arteritis, and Takayasu arteritis; the Chapel Hill Consensus Conference uses pathological criteria to classify the vasculitides on the basis of vessel size, and includes additional entities such as microscopic polyangiitis, essential cryoglobulinemia vasculitis, cutaneous leucoclastic angiitis, and Kawasaki disease (11,12). Microscopic polyangiitis, Churg-Strauss syndrome, PAN, and Wegener granulomatosis, 4 varieties of vasculitis affecting medium to small vessels including the vasa nervorum, have the greatest propensity to involve nerves. Classification among these forms of vasculitis remains a challenge (13). The neuropathy can be present at onset of the systemic illness or develop months or years later. The reported incidence of vasculitic neuropathy in these primary vasculitides ranges from 20% to 80%. Mononeuropathy multiplex is more common than distal symmetrical neuropathy (14). Antineutrophil cytoplasmic antibodies (ANCAs) are present in more than 90% of cases of Wegener granulomatosis with renal involvement, in most cases of more limited Wegener, in half or more of patients with microscopic polyangiitis, and in a few patients with PAN or Churg-Strauss syndrome. The c-ANCA test is much more specific; the p-ANCA test with anti-myeloperoxidase (MPO) pattern is less sensitive and less specific; p-ANCA without MPO is the least specific finding. microscopic polyangiitis.

Microscopic polyangiitis a systemic disease that causes renal disease, especially rapidly progressive necrotizing glomerulonephritis, weight loss, skin involvement, arthralgias, myalgias, hypertension, pulmonary disease, especially alveolar hem-

CHAPTER 18: Vasculitic Neuropathies  247

orrhage, and cardiac complications (15). Most patients have ANCA (75% per Guillevin). Biopsy, especially renal biopsy, shows vasculitis of smaller vessels—arterioles, venules, or capillaries; medium size arteries may also be affected. This involvement of the smaller vessels in microscopic polyangiitis distinguishes it pathologically from classic PAN, which spares the smaller vessels. In one series nearly three fifths of patients with microscopic polyangiitis had mononeuritis multiplex (15); the prevalence of neuropathy has been not quite as high in other series (16) (Table 18.2). churg-strauss syndrome.

Churg-Strauss syndrome is a rare variant of systemic vasculitis, in which asthma, sinusitis, pulmonary infiltrates, and eosinophilia often precede other manifestations of systemic vasculitis. By the ACR criteria, the diagnosis is probable if a patient has 4 of the following: asthma, blood eosinophilia of 10% or higher, neuropathy, fleeting pulmonary infiltrates, a­bnormal paranasal sinuses, or biopsy showing extravascular eosinophilic infiltrates (17). The eosinophilia can be striking, over 50% in many patients; ESR (erythrocyte sedimentation rate) and CRP (C-reactive protein) can be normal or abnormal; ANCA is usually negative. The diagnosis of Churg-Strauss syndrome should be strongly suspected when a patient with asthma or sinusitis, particularly if eosinophilia is present, develops mononeuritis multiplex, which is often the first manifestation of the vasculitic phase of the illness. In some series, nearly four fifths of patients have peripheral nerve disease, usually mononeuritis multiplex (18). Strokes and cranial neuropathies are less common neurological consequences of Churg-Strauss syndrome.

polyarteritis nodosa. PAN is a vasculitis of medium sized vessels. Contemporary understanding of PAN has been refined by distinguishing it from microscopic polyangiitis and by realizing that many cases are associated with chronic hepatitis B infection. PAN commonly affects the peripheral nervous system, kidneys, skin, and gastrointestinal tract. Hypertension is common. Less common is affliction of the central nervous system,

Table 18.2  Distribution of Nerve Involvement Among 49 Patients With Mononeuritis Multiplex Caused by Microscopic Polyangiitis Superficial peroneal neuropathy Deep peroneal neuropathy Ulnar neuropathy Radial neuropathy Bilateral neuropathies Unilateral neuropathies Cranial neuropathies Source: Adapted from Guillevin et al (15).

43 23 18 10 47 2 6

heart, eye, and lung. Patients often have generalized symptoms such as fever, weight loss, arthralgias, and myalgias. Most patients have some laboratory confirmation of inflammation such as elevated ESR or CRP, but specific autoantibodies such as ANCA are not common. The diagnosis is usually confirmed by biopsy, often of nerve, muscle, or skin, or by abdominal angiography, which can show renal or gastrointestinal microaneurysms or stenoses. Muscle or nerve biopsy can be positive for vasculitis in patients without clinical evidence of peripheral nerve dysfunction, especially when the biopsied sensory nerve was abnormal by nerve conduction studies (19). Chronic hepatitis C infection can also be associated with medium-sized vessel vasculitis (20). This manifestation of hepatitis C infection is clinically and histologically consistent with PAN. Most, but not all patients, have abnormal liver function tests. Other presentations of neuropathy with hepatitis C infection are discussed below. As many as three fourths of patients with PAN have clinical peripheral neuropathy, almost always as mononeuritis multiplex; peripheral nerve involvement is even more common in PAN patients who are infected with hepatitis B (21). Cutaneous PAN is a related vasculitis that affects skin, causing tender subcutaneous nodules, livedo reticularis, cutaneous ulcers, and necrosis, but sparing most other organ systems (22). However, an occasional patient with cutaneous PAN does develop vasculitic neuropathy; conversely, a few patients with nonsystemic vasculitic neuropathy develop skin lesions later in their illnesses. The prognosis of cutaneous PAN is much better than that of systemic PAN. granulomatosis. Wegener granulomatosis is a form of vasculitis with predilection for the upper and lower respiratory tracts and kidneys. The pathology shows granulomas in addition to small-vessel vasculitis. The patients usually have c-ANCAs, especially if they have renal disease. In the Mayo Clinic series of 324 consecutive patients, nearly one sixth had peripheral neuropathy; mononeuritis multiplex was 7 times more common than distal symmetrical polyneuropathy; nearly 7% had cranial neuropathies (23). In a prospective study observing patients for a median of 19 months, more than 40% had peripheral neuropathy, with distal symmetric neuropathy a bit more common than mono­ neuritis multiplex (24). Thus, peripheral neuropathy is a bit less common in Wegener than in PAN, Churg-Strauss syndrome, or microscopic polyangiitis. When neuropathy occurs in patients with Wegener, it can be milder and appear later in the course of the disease (14).

wegener

cryoglobulinemia. Cryoglobulinemia is associated with small-vessel vasculitis. Cryoglobulins are immunoglobulins that precipitate in the cold. Type I cryoglobulins are usually IgM monoclonal antibodies that can occur in Waldenström macroglobulinemia or multiple myeloma.

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Type II are also called mixed cryoglobulins because they have both monoclonal and polyclonal components; type III are polyclonal. Types II or III can be associated with a variety of conditions including rheumatic diseases, malignancies including lymphoproliferative diseases, and many different infections, especially hepatitis C. Essential mixed cryoglobulinemia refers to cases without a known underlying condition. Type II or type III cryoglobulinemias can be associated with varied clinical manifestations, which can take a relapsing remitting course (25). Over half the patients have purpura; other aspects each occur in less than a quarter of patients: edema, neuropathy, renal disease, arthralgia, livedo reticularis, Raynaud phenomenon, ­cutaneous ulcers, or digital infarcts. In patients with type II or type III cryoglobulinemia, the neuropathy is much more likely to be a distal symmetrical axonal neuropathy, rather than mononeuritis multiplex (26). Small or large fibers can be involved. Typical symptoms are those of sensory neuropathy such as pain, tingling, thermal dysesthesia, sensory ataxia, or restless leg syndrome. The nerve biopsy in patients with type II or type III cryoglobulinemia and neuropathy often shows epineurial vasculitis (27–29). In some patients with neuropathy and cryoglobulinemia, especially type I, the neuropathy is demyelinating rather than vasculitic (30). small-vessel vasculitis. Cryoglobulinemia is only one of the many causes of small-vessel vasculitis, which affects capillaries, postcapillary venules, and arterioles less than 30 mm in diameter. Other causes are serum sickness, hypersensitivity reactions to drugs or chemicals, infections, autoimmune connective tissue diseases, Henoch-Schönlein purpura, malignancies, hypocomplementemic urticarial vasculitis, and other vasculitides. The associations with infections, malignancies, and rheumatic diseases are discussed in subsequent sections. The most common clue to small-vessel vasculitis is skin lesions, especially palpable purpura but also splinter hemorrhages or digital infarcts. Skin biopsy shows leukocytoclastic vasculitis much more often than lymphocytic vasculitis. Most cases of small-vessel vasculitis are instances of hypersensitivity vasculitis, affecting only skin. When small-vessel vasculitis does cause neuropathy, distal symmetrical neuropathies are much more common than mononeuritis multiplex or mononeuropathies. Occasionally, the skin biopsy confirms the diagnosis of vasculitis, whereas there is little or no inflammation evident on nerve or muscle biopsy (31,32). giant cell arteritis.

Giant cell arteritis, also called temporal arteritis, is a disease that inflames large elastic arteries, larger than epineural vessels. It develops after the age of 50 years, classically causes headache, temporal artery tenderness, and elevated ESR, and can also cause ischemic and inflammatory disease of other large vessels. Patients often have the systemic syndrome of polymyalgia rheumatica. Ischemic optic

neuropathy or stroke are its most feared neurologically complications. Brachial plexopathies, mono­ neuropathies, mononeuritis multiplex, or symmetrical distal neuropathies affect a small fraction of patients (33,34). Patients with polymyalgia rheumatica have increased incidence of carpal tunnel syndrome due to wrist synovitis (35). Vasculitis Secondary to Connective Tissue Disease Each of the autoimmune connective tissue diseases, such as rheumatoid arthritis, lupus erythematosus, Sjögren syndrome, mixed connective tissue disease, and systemic sclerosis, can cause varied peripheral nerve syndromes. Some aspects of these connective tissue diseases can include vasculitis; however, vasculitic neuropathy accounts for only a fraction of the peripheral nerve disease associated with these conditions. When a patient with a connective tissue disease develops peripheral nerve dysfunction, careful clinical, electrodiagnostic, and sometimes pathological evaluation is needed to understand the pathogenesis of the peripheral nerve disease and to plan therapy. rheumatoid arthritis. Rheumatoid arthritis is a chronic, inflammatory, symmetrical polyarthritis, especially of the metacarpophalangeal, proximal interphalangeal, and metatarsophalangeal joints. Rheumatoid vasculitis is an infrequent, severe complication of rheumatoid arthritis that causes systemic manifestations of medium- and small-vessel vasculitis, often including mononeuritis multiplex. However, in most patients with rheumatoid arthritis, more common peripheral nerve manifestations are distal symmetrical sensory or sensorimotor neuropathies or carpal tunnel syndrome (36). Many patients have evidence of subclinical neuropathy by laboratory evaluations such as electrodiagnosis or autonomic testing. In a few patients with neuropathy and rheumatoid arthritis, sural nerve biopsy will show perivascular mononuclear cell infiltrates or even necrotizing vasculitis (36). sjögren syndrome. Sjögren syndrome is an autoimmune inflammatory disease with diverse manifestations. Its hallmark is involvement of exocrine glands, especially salivary glands leading to xerostomia and lacrimal glands leading to xerophthalmia. However, only a minority of patients with sicca (dry eyes and dry mouth) have Sjögren syndrome, and diagnosis of Sjögren syndrome requires objective evidence of sicca and of autoimmunity such as lymphocytic destruction of salivary glands on lip biopsy and the presence of autoantibodies such as anti-Ro (SSA) or anti-La (SSB). Among the varied systemic effects of Sjögren syndrome are forms of vasculitis such as small-vessel leukocytoclastic vasculitis, smallvessel lymphocytic vasculitis, or, less commonly, medium-vesse­l vasculitis like that of polyartertis nodosa. In some series, more than half of patients with Sjögren syndrome have some peripheral neurological disease

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Table 18.3  Clinicopathological Classification

Table 18.5  ACR Classification Criteria for

of 92 Patients With Primary Sjögren Syndrome– Associated Neuropathy

Systemic Lupus Erythematosus

Form of Neuropathy Sensory ataxic neuropathy Painful sensory neuropathy without sensory ataxia Trigeminal neuropathy Multiple mononeuropathy Multiple cranial neuropathy Radiculoneuropathy Autonomic neuropathy

Number of Patients 36 18 15 11 5 4 3

Source: Mori et al (38).

(37). The peripheral nerve complications of Sjögren syndrome are varied (Tables 18.3 and 18.4) and usually not associated with vasculitis. However, sural nerve biopsy of patients who present with mononeuritis multiplex often shows vasculitis (38). Patients who present with the sensory ataxic neuropathy occasionally have vasculitis on sural nerve biopsy, but the more typical pathology in these patients is lymphocytic infiltration of dorsal root and sympathetic ganglia, hence the alternative terms for this presentation—sensory neuronopathy or ganglioneuronitis. Other neuropathic presentations of Sjögren syndrome will occasionally show some mononuclear perivascular infiltrates on sural nerve biopsy but do not typically have epineurial vasculitis. systemic lupus erythematosus. Systemic lupus erythematosus is a multisystem, autoimmune, inflammatory illness. The ACR classification criteria for systemic lupus erythematosus (Table 18.5) are neither fully sensitive nor specific for the diagnosis but do emphasize the importance of autoantibodies in the diagnosis and the protean possible manifestations. Adding another layer of complexity to systemic lupus erythematosus, the ACR lists 19 types of neurological complications; most neurologists would subdivide these even more precisely (Table 18.6). Carpal tunnel syndrome is the most common peripheral nerve complication of systemic lupus erythematosus (39). The other forms of peripheral nerve disease listed in Table 18.6 affect about a fifth of patients

Table 18.4  Other Neuropathic Presentations Associated With Sjögren Syndrome Guillian-Barré syndrome Carpal tunnel syndrome Motor neuropathy or neuronopathy Autonomic neuropathy Source: Refs 94–96.

  1. Malar rash   2. Discoid rash   3. Photosensitive rash   4. Oral ulcers   5. Nonerosive arthritis in 2 or more joints   6. Pleuritis or pericarditis   7. Glomerulonephritis or proteinuria   8. Seizures or psychosis   9. Hemolytic anemia, leukopenia, lymphopenia, or thrombocytopenia 10. Immunologic laboratory abnormality, such as antibodies to double-stranded DNA or the SM antigen or a false-positive serological test for syphilis 11. Positive antinuclear antibody test that is not caused by a medication Patients are considered to have lupus if they meet 4 criteria and have no alternative diagnostic explanation for the abnormalities. Source: Tan et al (97).

with lupus (37,40). Vasculitic mononeuritis multiplex is an infrequent complication of systemic lupus erythematosus. However, some lupus patients with mild symmetrical distal sensory neuropathy would show epineurial vasculitis if their nerves were biopsied; this pathological finding does not require aggressive immunosuppressive therapy unless other aspects of the presentation dictate immunosuppression. In other connective tissue diseases such as Behçet syndrome (41–43), mixed connective tissue disease (44), or systemic sclerosis (45,46) peripheral nerve complications are less common, and vasculitic neuropathies are rare. Sarcoidosis Sarcoidosis is an idiopathic granulomatous inflammatory disease with the potential to affect many organs, causing abnormalities such as interstitial lung disease, lymphadenopathy, hepatosplenomegaly, uveitis, arthral­ gias, skin lesions including erythema nodosum, and central nervous system disease. Among patients with neurosarcoidosis, perhaps 1 in 12 has some form of clinical peripheral neuropathy (47). The neuropathies can take many forms including cranial neuropathies, especially of the facial nerve, distal symmetrical sensory neuropathy, Guillian-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, and mononeuritis multiplex. Many more have subclinical neuropathy that is demonstrable by nerve conduction studies (48). Regardless of the clinical presentation, the pathology often shows epineurial granulomas, inflammatory cells

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Table 18.6  Neurological Syndromes O­bserved in Systemic Lupus Erythematosus Aseptic meningitis Cerebrovascular disease Demyelinating disease Headache Movement disorder (chorea) Myelopathy Seizure disorder Acute confusional state Anxiety disorder Cognitive dysfunction Mood disorder Psychosis acute inflammatory demyelinating polyneuropathy Autonomic disorder Mononeuropathy, single or multiplex Myasthenia gravis Cranial neuropathy Plexopathy Polyneuropathy Source: ACR Ad Hoc Committee on Neuropsychiatric Lupus (98).

in the perineurium, and sometimes necrotizing vasculitis (49,50). Concomitant muscle biopsies also commonly show granulomas and may show necrotizing vasculitis. Muscle biopsies also often show granulomas in patient with sarcoidosis who have no clinical nerve or muscle dysfunction (51). Vasculitis Secondary to Infection Clinically evident peripheral neuropathy affects about 10% of patients with hepatitis C infection and takes varied forms (52). Another fraction of patients (5% in the prospective series for Santoro et al) has abnormal nerve conduction findings without clinical manifestations of neuropathy. Some present with a PAN type of systemic vasculitis; in these patients the neuropathy is most often mononeuritis multiplex and the nerve pathology is necrotizing vasculitis (20). Others present with a distal symmetrical sensory neuropathy, which may be the first clinical manifestation of a small-vessel vasculitis; they often have palpable purpura but are less likely to have more severe systemic illness; nerve pathology is likely to show mononuclear cells around venules, capillaries, or small arterioles without necrosis or interruption of the vessel wall (20). Cryoglobulinemia is common in patients with hepatitis C infection; however, peripheral neuropathy is also frequent in patients with hepatic C infection who do not have cryoglobulinemia (52). Necrotizing vasculitis is just one of many mechanisms that can cause neuropathy in patients infected with HIV

(53–55). Some cases of neuropathy in patients with HIV infection are associated with cryoglobulinemia and perhaps benefitted from treatment of the cryoglobulinemia (56). Nerve vasculitis can occur in many other infections including cat scratch fever, cytomegalovirus (CMV), HTLV I/II, and Lyme disease (6,57–59). Paraneoplastic Vasculitis All patients with vasculitic neuropathy should be considered for occult malignancy. Vasculitis, especially leukocytoclastic vasculitis and PAN, can be associated with malignancy (60). The malignancies seen in patients with vasculitis include hematological ones, such as myelodysplastic and lymphoproliferative diseases, and solid tumors, with a wide range of locations (61,62). Vasculitic neuropathy is more likely with solid tumors than with hematological ones (60). Anti-Hu autoantibodies may be associated particularly with small-cell lung cancer.

Nonsystemic Vasculitic Neuropathy In contrast to the systemic, multiorgan conditions where vasculitis affects multiple tissue types, vasculitis may also be restricted to a single organ such as the skin, lungs, gastrointestinal tract, or central or peripheral nervous system. Vasculitis limited to peripheral nerve has been known since at least 1985 (63). Dyck et al described 20 such patients and proposed the term nonsystemic vasculitic neuropathy (64). There are now several more reported cohorts with vasculitis restricted exclusively or mostly to the peripheral nervous system, even after extensive periods of follow-up (65–70). Nonsystemic vasculitic neuropathy causes at least a quarter of all cases of vasculitic neuropathy. Clinical features and response to treatment of nonsystemic vasculitic neuropathy are similar to those of systemic vasculitic neuropathy. Some patients have systemic features such as fever or weight loss. Over long-term follow-up, a few patients develop vasculitis restricted to the skin without involving other organs. The prognosis of nonsystemic vasculitic neuropathy is generally better than that of systemic vasculitis neuropathy (71). Patients with nonsystemic vasculitic neuropathy have less frequent episodes of neurological progression. Nonetheless, many patients relapse after initial responses to treatment. Reported Kaplan-Meier 5-year mortality rates of 13% to 15% are lower than the mortality rates of systemic vasculitis, especially if there has been renal, cardiac, gastrointestinal, or central nervous system involvement with the latter (67,68,72). Among those surviving over 2 years, most are walking without assistance; however, many have chronic pain (Table 18.7) (68). Possible Variants Like nonsystemic vasculitic neuropathy, diabetic lumbosacral radiculoplexus neuropathy has an acute painful presentation caused by nerve ischemia and pathological inflammation of vasa nervorum (73). The inflammatory infiltrates are vascular and perivascular mononuclear

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Table 18.7  Status after 2 Years Among 40 Survivors of Nonsystemic Vasculitic Neuropathy

Final Disability Asymptomatic Mild to moderate Moderately severe, requiring assistance to walk Severe, nonambulatory Chronic pain

Percentage of Patients 12.5 67.5 17.5 2.5 60

Source: Data from Collins et al (68).

cells in small arterioles, venules, and capillaries. As in other forms of vasculitic neuropathy, direct immunofluorescence usually shows vascular deposits of IgG, IgM, and C3 (74). However, diabetic lumbosacral plexus neuropathy is distinguished by its restricted distribution, monophasic course, and good prognosis. Nondiabetics occasionally have a clinical syndrome of lumbosacral radiculoplexus neuropathy with similar symptoms, timing, neurological deficits, and pathology to those patients with diabetes (75). Neuralgic amyotrophy (also called Parsonage-Turner syndrome or acute brachial plexitis) has many characteristics of vasculitic mononeuritis multiplex: sudden onset, prominent pain, patchy involvement of varied nerves or portions of the brachial plexus. Because of its characteristic clinical presentation, usually limited to 1 limb, and monophasic course of pain resolution followed by slow recovery of nerve function, patients rarely undergo nerve biopsy. However, some patients do have mononuclear inflammatory infiltrates of epineurial vessels without necrotizing changes in the vessel wall when the plexus is biopsied (76). Wartenberg migrant sensory neuritis is a rare condition characterized by multifocal or recurrent focal cutaneous neuropathies. The onset is typically acute and painful with sensory loss in the distribution of cutaneous nerves. Many patients report stretching the affected limb before onset, but moving the affected limb often increases the pain, so the movement may lead to discovery of symptoms rather than be the cause of the neuropathy. Biopsy of an affected nerve can show vascular inflammatory infiltrates in the epineurium and fascicular axonal damage (77). However, the course is usually benign, occasionally with sensory episodes involving other cutaneous nerves but rarely with more severe neuropathy, so aggressive immunosuppressive treatment is not warranted (78).

DIFFERENTIAL DIAGNOSIS The differential diagnosis of distal symmetrical neuropathies is extensive and discussed throughout this book. Only a small minority of all distal symmetrical

neuropathies are caused by vasculitis. The clues to vasculitis as a cause of these neuropathies include associated systemic diseases, laboratory evidence of inflammation, asymmetric or stepwise onset, and persistent asymmet­ ries by examination or on electrodiagnostic testing. Vasculitic neuropathy is very prominent in the differential diagnosis of mononeuritis multiplex and in mononeuropathies that are not localized to usual compression sites. Sudden painful onset is another important clue. Depending on the clinical setting many other causes of multiple mononeuropathies might merit consideration: 1. Multiple compression neuropathies, particularly in diabetics and other with an underlying diffuse neuropathy or in those with hereditary liability to pressure palsies 2. Immune-mediated neuropathies that can present asymmetrically such as multifocal acquired demyelinating sensory and motor neuropathy, asymmetric chronic inflammatory demylinating polyneuropathy, and multifocal motor neuropathy with conduction block 3. Infectious neuropathies, which are not always mediated by vasculitis, including leprosy, herpes zoster, Lyme borreliosis, HIV, CMV, and trichinosis 4. Vasculopathic neuropathies due to intravenous drug abuse 5. Ischemic neuropathies due to causes such as cholesterol emboli, sickle cell disease, or hyperviscosity 6. Neuropathies due hemorrhagic diatheses 7. Neuropathies in eosinophilic myalgia or hypereosinophilic syndromes 8. Neuropathies due to lymphatoid granulomatosis 9. Neoplastic nerve invasion 10. Multiple nerve tumors, as in neurofibromatosis 11. Neuropathies due to amyloidosis 12. Porphyric neuropathy 13. A minority of toxic neuropathies; examples include neuropathies in toxic oil syndrome, after jellyfish stings, or in lead intoxication 14. Neuropathies caused by multifocal trauma

DIAGNOSTIC EVALUATION Most patients with multiple mononeuropathies deserve consideration of vasculitic neuropathy. In patients with distal symmetric polyneuropathy, impetus to search for vasculitic neuropathy includes stepwise progression, asymmetries by clinical examination or electrodiagnosis, or laboratory evidence of inflammation or systemic disease. Patients with distal sensory neuropathy deserve routine laboratory evaluation for nonvasculitic causes of neuropathy such as diabetes or prediabetes, vitamin B12 deficiency, or monoclonal gammopathy (79). Every patient with suspected vasculitic neuropathy needs a careful assessment for disease of other organ

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Table 18.8  Sensitivity of Combined Superficial Peroneal Nerve and Peroneus Brevis Muscle in Patients With Suspected Vasculitis

(99) (88)

Sensitivity of Nerve Biopsy (%) 55 54

systems, extending from history and physical examination to complete blood count, complete metabolic panel, urinalysis, and chest imaging. Vasculitis is frequently associated with nonspecific laboratory findings such as elevated ESR and CRP, anemia, and peripheral leukocytosis. In patients with nonsystemic vasculitic neuropathy, ESR is often mildly elevated, although almost never over 75 mm/hr; perhaps half of patients have mild anemia. Routinely, patients with suspected vasculitic neuropathy need additional laboratory work that can give clues to specific causes of systemic vasculitis: antinuclear antibodies (ANA), rheumatoid factor, ANCA, complement (C3, C4, total), cryoglobulins, hepatitis B surface antigen, and hepatitis C antibodies (80). A wide variety of studies merit consideration in selected cases: SSA/SSB antibodies, evaluation for sicca, or salivary gland biopsy if Sjögren syndrome is suspected; cyclic citrullinated peptide antibodies when there is clinical question of rheumatoid arthritis, testing for infections such as HIV, CMV, or Lyme disease; paraneoplastic antibodies or imaging studies for neoplasia; visceral angiography when PAN is being considered. The CSF of patients with vasculitic neuropathy shows normal cell counts but may show mild protein elevation, up to 110 mg/dL. However, if systemic vasculitis involves the central nervous system, some patients can have pleocytosis or higher protein levels. If the vasculitis involves not only vasa nervorum but also larger arteries as well, vascular changes can sometimes to demonstrated by MRA (magnetic resonance angiography) of limb arteries (81). A study of patients with vasculitis of the tibial nerve showed that ultrasound could demonstrate enlargement of the affected nerve (82).

Sensitivity of Muscle Biopsy (%) 46 30

Combined Sensitivity (%) 70 60

practice is to obtain a muscle biopsy along with a nerve biopsy. A convenient approach is to biopsy the superficial peroneal nerve and the peroneus brevis muscle through the same incision. If the sural nerve is biopsied, a separate incision is needed to biopsy a muscle such as the vastus lateralis. The nerve biopsy should be of the whole nerve, rather than fascicular, because the pathology is often asymmetric, sparing some fascicles. The necrotizing vasculitis can be patchy, so serial sections of the specimen should be evaluated. Definite pathological evidence of vasculitic neuropathy is nerve or muscle tissue that shows active or chronic vasculitis without an alternative cause of the pathology such as lymphoma, lymphatoid granulomatosis, or amyloidosis (80). Active vasculitis is securely diagnosed when infiltrating inflammatory cells are seen in the vessel wall together with evidence of endoneurial or epineurial vessel damage, which is suggested by hemorrhage into or around the vessel wall, thrombosis of the lumen, fibrinoid necrosis of the muscularis layer, injury to the endothelium or internal elastic lamina, abnormal smooth muscle cells in the media, or leukocytoclasia (Figures 18.1 and 18.2). Chronic vasculitis is diagnosed when mononuclear inflammatory cells in the vessel wall are accompanied by signs of chronic vascular damage and repair: chronic thrombosis and recanalization of the lumen, hyperplasia of the intima, or fibrosis of the media, adventia, or periadventitia.

Nerve Biopsy A secure diagnosis of vasculitic neuropathy requires tissue biopsy before initiating treatment. A suspicion of vasculitic neuropathy remains one of the main indications to perform peripheral nerve biopsy. Typically, a symptomatic (and preferably electrodiagnostically abnormal, with sensory nerve action potential reduced in amplitude or absent) distal sensory nerve is biopsied, usually the sural, superficial peroneal, or superficial radial. Muscle biopsy often shows signs of vasculitis even in cases where nerve biopsy is negative, so diagnostic yield is increased by obtaining nerve and muscle biopsies simultaneously (66) (Table 18.8). Now, common

Figure 18.1 Nerve biopsy showing inflammatory changes in an epineurial artery. H&E x100 (courtesy of Dr. Hume Gultekin).

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The nerve damage is predominantly axonal. When axonal damage predominates and combines with vascular or perivascular inflammation, but criteria for definite vasculitis are not present, other findings can suggest probable vasculitis neuropathy. Immunohistochemical staining techniques may identify markers of immunologically mediated vascular injury such as IgM and IgG immunoglobulins, complement, and inflammatory cell markers (74). Other evidence of probable vasculitic neuropathy can be hemosiderin deposits, asymmetric or multifocal pattern of the axonal degeneration, prominent active axonal degeneration, or muscle biopsy showing myofiber necrosis, regeneration, or infarcts that are not due to underlying myopathy (80). Vasculitic neuropathy is still a possible diagnosis when the nerve biopsy shows axonal degeneration and either vessel wall inflammation without specific vessel damage or the signs of vessel damage described above without vessel inflammation. These findings of possible vasculitic neuropathy are nonspecific for vasculitis. When these abnormalities are the only findings on nerve pathology, a diagnosis of vasculitic neuropathy requires other clinical support or more definitive evidence of vasculitis in other organs. Nerve biopsy is relatively well-tolerated with low risk of complications; the sural nerve tends to produce a slightly smaller area of residual numbness than the superficial peroneal. Skin biopsy may show reduced epidermal nerve fiber density in some cases of vasculitic neuropathy, but this is a nonspecific finding. Skin biopsy can also be useful if leukocytoclastic vasculitis is under consideration, especially if the patient has palpable purpura.

ELECTROPHYSIOLOGY Electrodiagnostic studies (nerve conduction studies and electromyography) confirm the presence of an axonal

neuropathy and lend support to the diagnosis of vasculitic neuropathy when an asymmetrical or multifocal pattern of nerve injury is identified. Sensory nerve action potential and compound muscle action potential amplitudes may be depressed or absent depending on the pattern of nerve involvement, whereas distal latencies and conduction velocities are relatively preserved, consistent with an axonal process. Side-to-side comparisons are especially important to identify slight amplitude asymmetries that raise the index of suspicion for a vasculitic etiology. On motor nerve conduction tests, lower amplitude responses to proximal stimulation than to distal stimulation (“conduction block”) is often deemed evidence of demyelination. This phenomenon has been described in 4 settings with vasculitic neuropathy. The first is “pseudoconduction block”: an acutely ischemic nerve will not conduct when stimulated proximal to the site of ischemia but will conduct for a few days distal to the ischemic site. Patients with acute vasculitic neuropathies may show “conduction block” initially, but serial studies show loss of amplitude to distal stimulation so that “conduction block” disappears (83,84). However, an occasional patient may have early conduction block but does not develop later loss of amplitude to distal stimulation (85). Third, chronic axonal neuropathy can lead to temporal dispersion and phase cancellation of the compound muscle action potential on proximal stimulation, which can be mistaken for conduction block (86). Finally, a rare patient might have both vasculitic neuropathy and immunologically mediated conduction block (87). Electromyography demonstrates features of denervation and extends the physical examination to characterize the distribution as mononeuropathy, mononeuritis multiplex, or distal polyneuropathy, symmetrical or asymmetrical. About three quarters of patients with vasculitic neuropathy have fibrillations or positive sharp waves in many affected muscles, but, at least early in the course, less than a quarter have long duration voluntary motor unit potentials (88).

TREATMENT

Figure 18.2 Nerve biopsy showing high-power view of peripheral nerve vasculitis: Vessel wall infiltrated by mononuclear cells, leukocytic debris, and fibrinoid necrosis. H&E x400 (courtesy of Dr. Hume Gultekin).

Vasculitic neuropathy is often dramatically responsive to immunosuppressive treatment. However, there are no randomized controlled trials of treatment of vasculitic neuropathy because of its rarity and diverse and heterogenous clinical manifestations. A recent Cochrane review concluded that there were no studies of sufficient merit to permit a systematic review of treatment for vasculitic neuropathy (89). The Peripheral Nerve Society Guideline on immunosuppressive therapy for nonsystemic vasculitic neuropathy based its Best Practice recommendations for treatment on class U evidence (80) (Table 18.9). Therefore, choice of treatment tends to be based on clinical experience and extrapolation from treatment of systemic vasculitides. As vasculitic

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Table 18.9  Options for Treatment of Nonsystemic Vasculitic N­europathy: Best Practices Guidelines of the P­eripheral Nerve Society Based on Class U Evidence Treatment

Indication

No immunosuppression

Patients clinically stable for 3 mo or improving, who have no active vasculitis by nerve biopsy

Corticosteroids

Most common first-line therapy

Cyclophosphamide

Rapidly progressive neuropathy or neuropathy progressing on corticosteroids

Azathioprine or methotrexate

Added to or replacing steroids to minimize dose and duration of steroids; used after or in place of cyclophosphamide

Source: Collins et al (80).

n­europathy is a potentially debilitating but rarely lifethreatening illness, side effects of treatment need to be balanced with therapeutic benefit. When nonsystemic vasculitic neuropathy is improving without treatment or has been clinically stable for 3 months or more and when a recent nerve biopsy has not shown evidence of active vasculitis, one option is deferring immunosuppressive treatment and following the patient closely (80). Corticosteroids are the mainstay of therapy. Mild nonsystemic vasculitic neuropathy or indolent systemic disease is frequently treated with steroids alone. We might start oral prednisone at a dose of 1.0 to 1.5 mg/ kg/d, continue until a clinical response is seen, and then transition to alternate day dosing followed by a slow taper, such as decreasing the alternate day dose by 5 or 10 mg/d each month. Similarly, the Peripheral Nerve Society Guideline on therapy of nonsystemic vasculitic neuropathy extrapolates from experience in treatment of Wegener and recommends the following: 1. Start treatment with prednisone at 1.0 mg/kg/d. 2. Taper daily prednisone to 25 mg at 3 months, 15 to 20 mg at 4 months, and 10 mg at 6 months. 3. Continue low-dose prednisone (5–7.5 mg/d) from 6 to 18 months (80). For patients with severe or rapidly progressive neurological deficits, high-dose intravenous methylpredni-

solone (eg, 1 g daily for 3–5 days) can be given before starting the oral prednisone. Combination therapy with an immunosuppressive or steroid-sparing agent is generally favored when patients have more aggressive disease with multiorgan involvement or progression despite steroids. Combination therapy is more effective than prednisone monotherapy in inducing long-term remission and in improving disability. We consider immunosuppressive medications early because they do not become effective until weeks or months after they are started. Randomized controlled clinical trial data validate this approach of using steroids and cyclophosphamide for patients with Wegener granulomatosis and microscopic angiitis; clinicians sometimes extrapolate from this experience to use these agents when other vasculitic neuropathies progress despite corticosteroid treatment. There is debate whether daily oral or weekly intravenous cyclophosphamide therapy is preferred for treatment of systemic vasculitis (90). The Peripheral Nerve Society Guidelines for treatment of nonsystemic vasculitic neuropathy advocate weekly intravenous use to decrease potential toxicity and include detailed suggestions for monitoring bladder toxicity (80). Toxic effects include nausea and vomiting, hemorrhagic cystitis, transitional cell cancer of the bladder, infertility, other malignancies that may occur years later, and dose-related bone marrow suppression with susceptibility to infection. Close clinical monitoring with regular blood counts and urinalysis are essential to promptly identify serious toxic effects, which may require discontinuation of the drug. In general, some clinicians use prolonged induction courses of 6 to 12 months, hoping to reduce recurrence rates, after which, another immunosuppressant (eg, methotrexate, azathioprine) is continued as maintenance, often for a year or more before weaning. Others make the switch to less toxic immunosuppressants as early as after 3 months of cyclophosphamide. Azathioprine or methotrexate are alternatives when cyclophosphamide is not tolerated or for maintenance therapy after remission is induced with corticosteroids with or without cyclophosphamide (91,92). Other agents used in the same manner include cyclosporine, mycophenolate mofetil, or leflunomide. Rituximab was not inferior to cyclophosphamide in a treatment trial of Wegener or microscopic polyangitis (93), and based on experience, some clinicians use rituximab, intravenous immunoglobulin, or plasmapheresis for treatment of vasculitic neuropathy. All of the immunosuppressive therapies have potentially serious side effects. Many neurologists will want to consult with a rheumatologist or other expert in these therapies to choose therapy and plan monitoring for toxicity. Judging whether vasculitic neuropathy is progressive despite therapy can be difficult and requires assessment of objective clinical and laboratory parameters,

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rather than simply relying on patients’ accounts of their symptoms. Pain needs symptomatic treatment but is not a good measure of success of immunosuppression. Careful neurological examination of strength and sensation and electromyography studies are more reliable measures of disease activity; however, because infarcted nerve recovers slowly, persistent neurological deficits are usually not indicative of treatment failure; in contrast, when a patient develops new neurological deficits during treatment, more aggressive therapy is usually needed. Serological evidence of inflammation, such as elevated ESR or CRP, when present, is another parameter to follow during treatment. When patients have vasculitic neuropathy secondary to other conditions such as connective tissue disease, infection, or malignancy, treatment of the underlying condition usually determines the role of therapeutic immunosuppression. For example, immunosuppressants may increase viremia when vasculitis is associated with viral infection, such as hepatitis B and C.

KEY POINTS AND CLINICAL PEARLS • Vasculitic neuropathy may be found in isolation or as part of a systemic condition. • A high index of suspicion is required to identify this relatively rare condition, which is often highly responsive to immunosuppressant therapy. • Vasculitic neuropathy is typically painful; although the most suggestive pattern of involvement is mononeuritis multiplex, whether multifocal, asymmetric, or symmetrical patterns of nerve involvement may occur. Sensory-only neuropathy may occur, but m­otoronly presentation is distinctly rare. • Steroids are first-line therapy, but combination immunosuppressive therapy, most commonly with cyclophosphamide, is often necessary to induce remission, particularly in aggressive or systemic disease.

REFERENCES 1. Griffin JW. Vasculitic neuropathies. Rheum Dis Clin North Am. 2001;27:751–760, vi. 2. Ohkoshi N, Mizusawa H, Oguni E, et al. Sural nerve biopsy in vasculitic neuropathies: morphometric analysis of the caliber of involved vessels. J Med. 1996;27:153–170. 3. Dyck PJ, Conn DL, Okazaki H. Necrotizing angiopathic neuropathy: three-dimensional morphology of fiber degeneration related to sites of occluded vessels. Mayo Clin Proc. 1972;47:461–475. 4. Enevoldson TP, Wiles CM. Severe vasculitic neuropathy in systemic lupus erythematosus and cyclophosphamide. J Neurol Neurosurg Psychiatry. 1991;54:468–469.

5. Feit H, Tindall RSA, Glasberg M. Sources of error in the diagnosis of Guillain-Barre syndrome. Muscle Nerve. 1982;5:111–117. 6. Said G, Lacroix C. Primary and secondary vasculitic neuropathy. J Neurol. 2005;252:633–641. 7. Ramchandren S, Chaudhry V, Hoke A, et al. Peripheral nerve vasculitis presenting as complex regional pain syndrome. J Clin Neuromuscul Dis. 2008;10:61–64. 8. Seo JH, Ryan HF, Claussen GC, et al. Sensory neuropathy in vasculitis: a clinical, pathologic, and electrophysiologic study. Neurology. 2004;63:874–878. 9. Gayraud M, Guillevin L, le Toumelin P, et al. Long-term followup of polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome. Arthritis Rheum. 2001;44:666–675. 10. Guillevin L, Pagnoux C. Therapeutic strategies for systemic necrotizing vasculitides. Allergol Int. 2007;56: 105–111. 11. Fries JF, Hunder GG, Bloch DA, et al. The American College of Rheumatology 1990 criteria for the classification of vasculitis. Summary. Arthritis Rheum. 1990;33: 1135–1136. 12. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum. 1994;37:187–192. 13. Watts R, Lane S, Hanslik T, et al. Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies. Ann Rheum Dis. 2007;66:222–227. 14. Cattaneo L, Chierici E, Pavone L, et al. Peripheral neuropathy in Wegener’s granulomatosis, Churg-Strauss syndrome and microscopic polyangiitis. J Neurol Neurosurg Psychiatry. 2007;78:1119–1123. 15. Guillevin L, Durand-Gasselin B, Cevallos R, et al. Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients. Arthritis Rheum. 1999;42:421–430. 16. Lane SE, Watts RA, Shepstone L, et al. Primary systemic vasculitis: clinical features and mortality. Quarterly J Med. 2005;98:97–111. 17. Masi AT, Hunder GG, Lie JT, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum. 1990;33:1094–1100. 18. Wolf J, Bergner R, Mutallib S, et al. Neurologic complications of Churg-Strauss syndrome—a prospective monocentric study. Eur J Neurol. 2010;17:582–588. 19. Wees SJ, Sunwoo IN, Oh SJ. Sural nerve biopsy in systemic necrotizing vasculitis. American J Med. 1981;71:525–532. 20. Cacoub P, Maisonobe T, Thibault V, et al. Systemic vasculitis in patients with hepatitis C. J Rheumatol. 2001;28: 109–118. 21. 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;62:616–626. 22. Morgan AJ, Schwartz RA. Cutaneous polyarteritis nodosa: a comprehensive review. Int J Dermatol. 2010;49:750–756. 23. Nishino H, Rubino FA, DeRemee RA, et al. Neurological involvement in Wegener’s granulomatosis: an analysis of 324 consecutive patients at the Mayo Clinic. Ann Neurol. 1993;33:4–9.

256  Textbook of Peripheral Neuropathy 24. de Groot K, Schmidt DK, Arlt AC, et al. Standardized neurologic evaluations of 128 patients with Wegener granulomatosis. Archives of Neurology. 2001;58:1215–1221. 25. Bryce AH, Kyle RA, Dispenzieri A, et al. Natural history and therapy of 66 patients with mixed cryoglobulinemia. Am J Hematol. 2006;81:511–518. 26. Gemignani F, Brindani F, Alfieri S, et al. Clinical spectrum of cryoglobulinaemic neuropathy. J Neurol Neurosurg Psychiatry. 2005;76:1410–1414. 27. Nemni R, Corbo M, Fazio R, et al. Cryoglobulinaemic neuropathy. A clinical, morphological and immunocytochemical study of 8 cases. Brain. 1988;111:541–552. 28. Vital C, DeminiŠre C, Lagueny A, et al. Peripheral neuropathy with essential mixed cryoglobulinemia: biopsies from 5 cases. Acta Neuropathol (Berlin). 1988;75:605– 610. 29. Chad D, Pariser K, Bradley WG, et al. The pathogenesis of cryoglobulinemic neuropathy. Neurology. 1982;32: 725–729. 30. Lippa CF, Chad DA, Smith TW, et al. Neuropathy associated with cryoglobulinemia. Muscle Nerve. 1986;9: 626–631. 31. Filosto M, Cavallaro T, Pasolini G, et al. Idiopathic hypocomplementemic urticarial vasculitis-linked neuropathy. J Neurol Sci. 2009;284:179–181. 32. Yamanaka Y, Hiraga A, Arai K, et al. Leucocytoclastic vasculitic neuropathy diagnosed by biopsy of normal appearing skin. J Neurol Neurosurg Psychiatry. 2006;77: 706–707. 33. Caselli RJ, Daube JR, Hunder GG, et al. Peripheral neuropathic syndromes in giant cell (temporal) arteritis. Neurology. 1988;38:685–689. 34. Pfadenhauer K, Roesler A, Golling A. The involvement of the peripheral nervous system in biopsy proven active giant cell arteritis. J Neurol. 2007;254:751–755. 35. O’Duffy JD, Hunder GG, Wahner HW. A follow-up study of polymyalgia rheumatica: evidence of chronic axial synovitis. J Rheumatol. 1980;7:685–693. 36. Agarwal V, Singh R, Wiclaf, et al. A clinical, electrophysio­ logical, and pathological study of neuropathy in rheumatoid arthritis. Clin Rheumatol. 2008;27:841–844. 37. Harboe E, Tjensvoll AB, Maroni S, et al. Neuropsychiatric syndromes in patients with systemic lupus erythematosus and primary Sjogren syndrome: a comparative population-based study. Ann Rheum Dis. 2009;68: 1541–1546. 38. Mori K, Iijima M, Koike H, et al. The wide spectrum of clinical manifestations in Sjögren’s syndrome–associated neuropathy. Brain. 2005;128:2518–2534. 39. Omdal R, Mellgren SI, Husby G. Clinical neuropsychiatric and neuromuscular manifestations in systemic lupus erythematosus. Scand J Rheumatol. 1988;17:113–117. 40. Omdal R, Loseth S, Torbergsen T, et al. Peripheral neuropathy in systemic lupus erythematosus—a longitudinal study. Acta Neurol Scand. 2001;103:386–391. 41. Kidd D, Steuer A, Denman AM, et al. Neurological complications of Behçet’s syndrome. Brain. 1999;122:2183–2914. 42. Atasoy HT, Tunc TO, Unal AE, et al. Peripheral nervous system involvement in patients with Behçet disease. Neurologist 2007;13:225–230. 43. Siva A, Saip S. The spectrum of nervous system involvement in Behçet’s syndrome and its differential diagnosis. J Neurol. 2009;256:513–529.

44. Kimber TE, Scott G, Thompson PD, et al. Vasculitic neuropathy and myopathy occurring as a complication of mixed connective tissue disease. Aust N Z J Med. 1999;29: 82–83. 45. Lee P, Bruni J, Sukenik S. Neurological manifestations in systemic sclerosis (scleroderma). J Rheumatol. 1984;11: 480–483. 46. Poncelet AN, Connolly MK. Peripheral neuropathy in scleroderma. Muscle Nerve. 2003;28:330–335. 47. Zuniga G, Ropper AH, Frank J. Sarcoid peripheral neuropathy. Neurology. 1991;41:1558–1561. 48. Challenor YB, Felton CP, Brust JCM. Peripheral nerve involvement in sarcoidosis: an electrodiagnostic study. J Neurol Neurosurg Psychiatry. 1984;47:1219–1222. 49. Said G, Lacroix C, Planté-Bordneuve V, et al. Nerve granulomas and vasculitis in sarcoid peripheral neuropathy. A clinicopathological study of 11 patients. Brain. 2002;125:264–275. 50. Vital A, Lagueny A, Ferrer X, et al. Sarcoid neuropathy: clinico-pathological study of 4 new cases and review of the literature. Clin Neuropathol. 2008;27:96–105. 51. Stjenberg N, Cajander S, Truedsson H, et al. Muscle involvement in sarcoidosis. Acta Med Scand. 1981;209: 213–216. 52. Santoro L, Manganelli F, Briani C, et al. Prevalence and characteristics of peripheral neuropathy in hepatitis C viru­s population. J Neurol Neurosurg Psychiatry. 2006;77: 626–629. 53. Ferrari S, Vento S, Monaco S, et al. Human immunodeficiency virus–associated peripheral neuropathies. Mayo Clin Proc. 2006;81:213–219. 54. Bradley WG, Verma A. Painful vasculitic neuropathy in HIV-a infection: relief of pain with prednisone therapy. Neurology. 1996;47:1446–1451. 55. Calabrese LH, Estes M, Yen-Lieberman B, et al. Systemic vasculitis in association with human immunodeficiency virus infection. Arthritis Rheum. 1989;32:569–576. 56. Stricker RB, Sanders KA, Owen WF, et al. Mononeuritis multiplex associated with cryoglobulinemia in HIV infection. Neurology. 1992;42:2103–2105. 57. Meyer MF, Hellmich B, Kotterba S, et al. Cytomegalovirus infection in systemic necrotizing vasculitis: causative agent or opportunistic infection? Rheumatol Int. 2000;20: 35–38. 58. Stockmeyer B, Schoerner C, Frangou P, et al. Chronic vasculitis and polyneuropathy due to infection with Bartonella henselae. Infection. 2007;35:107–109. 59. Tezzon F, Corradini C, Huber R, et al. Vasculitic mononeuritis multiplex in patient with Lyme disease. Ital J Neurol Sci. 1991;12:229–232. 60. Fain O, Hamidou M, Cacoub P, et al. Vasculitides associated with malignancies: analysis of sixty patients. Arthritis Rheum. 2007;57:1473–1480. 61. Oh SJ. Paraneoplastic vasculitis of the peripheral nervous system. Neurol Clin. 1997;15:849–863. 62. Zivkovic SA, Ascherman D, Lacomis D. Vasculitic neuropathy—electrodiagnostic findings and association with malignancies. Acta Neurol Scand. 2007;115:432–436. 63. Kissel JT, Slivka AP, Warmolts JR, et al. The clinical spectrum of necrotizing angiopathy of the peripheral nervous system. Ann Neurol. 1985;18:251–257. 64. Dyck PJ, Benstead TJ, Conn DL, et al. Nonsystemic vasculitic neuropathy. Brain. 1987;110:843–854.

CHAPTER 18: Vasculitic Neuropathies  257 65. Davies L, Spies JM, Pollard JD, et al. Vasculitis confined to peripheral nerves. Brain. 1996;119:1441–1448. 66. Said G, Lacrois-Ciaudo C, Fujimura H, et al. The peripheral neuropathy of necrotizing arteritis: a clinicopathological study. Ann Neurol. 1988;23:461–465. 67. Puechal X, Said G. Necrotizing vasculitis of the peripheral nervous system: nonsystemic or clinically undetectable? Arthritis Rheum. 1999;42:824–825. 68. Collins MP, Periquet MI, Mendell JR, et al. Nonsystemic vasculitic neuropathy. Insights from a clinical cohort. Neurology. 2003;61:623–630. 69. Kararizou E, Davaki P, Karandreas N, et al. Nonsystemic vasculitic neuropathy: a clinicopathological study of 22 cases. J Rheumatol. 2005;32:853–858. 70. Sugiura M, Koike H, Iijima M, et al. Clinicopathologic features of nonsystemic vasculitic neuropathy and microscopic polyangiitis-associated neuropathy: a comparative study. J Neurol Sci. 2006;241:31–37. 71. Collins MP, Periquet MI. Isolated vasculitis of the peripheral nervous system. Clin Exp Rheumatol. 2008;26: S118–130. 72. Collins MP, Periquet MI, Mendell JR, et al. Nonsystemic vasculitic neuropathy: insights from a clinical cohort. Neurology. 2003;61:623–630. 73. Dyck PJB, Norell JE, Dyck PJ. Microvasculitis and ischemia in diabetic lumbrosacral radiculoplexus neuropathy. Neurology. 1999;53:2113–2121. 74. Collins MP, Periquet-Collins I, Sahenk Z, et al. Direct immunofluoresence in vasculitic neuropathy: specificity of vascular immune deposits. Muscle Nerve. 2010;42: 62–69. 75. Dyck PJ, Norell JE. Non-diabetic lumbosacral radiculoplexus neuropathy: natural history, outcome and comparison with the diabetic variety. Brain. 2001;124:1197–1207. 76. Suarez GA, Giannini C, Bosch EP, et al. Immune brachial plexus neuropathy: suggestive evidence for an inflammatory-immune pathogenesis. Neurology. 1996;46:559–561. 77. Nicolle MW, Barron JR, Watson BV, et al. Wartenberg’s migrant sensory neuritis. Muscle Nerve. 2001;24:438–443. 78. Stork AC, van der Meulen MF, van der Pol WL, et al. Wartenberg’s migrant sensory neuritis: a prospective follow-up study. J Neurol. 2010;257:1344–1348. 79. England JD, Gronseth GS, Franklin G, et al. Practice P­arameter: evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidencebased review). Report of the American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Academy of Physical Medicine and Rehabilitation. Neurology. 2009;72: 185–192. 80. Collins MP, Dyck PJ, Gronseth GS, et al. Peripheral Nerve Society Guideline on the classification, diagnosis, investigation, and immunosuppressive therapy of non-systemic vasculitic neuropathy: executive summary. J Peripher Nerv Syst. 2010;15:176–184. 81. Sanada M, Terada M, Suzuki E, et al. MR angiography for the evaluation of non-systemic vasculitic neuropathy. Acta Radiol. 2003;44:316–318.

82. Ito T, Kijima M, Watanabe T, et al. Ultrasonography of the tibial nerve in vasculitic neuropathy. Muscle Nerve. 2007;35:379–382. 83. Ropert A, Metral S. Conduction block in neuropathies with necrotizing vasculitis. Muscle Nerve. 1990;13:102–105. 84. McCluskey L, Feinberg D, Cantor C, et al. “Pseudoconduction block” in vasculitic neuropathy. Muscle Nerve. 1999;22:1361–1366. 85. Jamieson PW, Giuliani MJ, Martinez AJ. Necrotizing angiopathy presenting with multifocal conduction block. Neurology. 1991;41:442. 86. Ahdab R, Michel M, Neves DO, et al. Persistent multifocal pseudo-conduction blocks in vasculitic neuropathy without antiganglioside antibodies. Muscle Nerve. 2009;40: 290–293. 87. Notturno F, Caporale CM, Di Muzio A, et al. Persistent multifocal conduction block in vasculitic neuropathy with IgM anti-gangliosides. Muscle Nerve. 2007;36:547–552. 88. Collins MP, Mendell JR, Periquet MI, et al. Superficial pero­ neal nerve/peroneus brevis muscle biopsy in vasculitic neuropathy. Neurology. 2000;55:636–643. 89. Vrancken AF, Hughes RA, Said G, et al. Immunosuppressive treatment for non-systemic vasculitic neuropathy. Cochrane Database Syst Rev. 2007:CD006050. 90. Walters GD, Willis NS, Craig JC. Interventions for renal vasculitis in adults. A systematic review. BMC Nephrol. 2010;11:12. 91. Pagnoux C, Mahr A, Hamidou MA, et al. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N Engl J Med. 2008;359:2790–2803. 92. Jayne D, Rasmussen N, Andrassy K, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med. 2003;349:36–44. 93. Stone JH, Merkel PA, Spiera R, et al. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363:221–232. 94. Katz JS, Houroupian D, Ross MA. Multisystem neuronal involvement and sicca complex: broadening the spectrum of complications. Muscle Nerve. 1999;22:404–407. 95. Kaplan JG, Rosenberg R, Reinitz E, et al. Invited review: peripheral neuropathy in Sjögren’s syndrome. Muscle Nerve. 1990;13:570–579. 96. Andonopoulos AP, Lagos G, Drosos AA, et al. The spectrum of neurological involvement in Sjögren’s syndrome. Br J Rheumatol. 1990;29:21–23. 97. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25:1271–1277. 98. A. C. R. Ad Hoc Committee on Neuropsychiatric Lupus Syndromes. The American College of Rheumatology nomenclature and case definitions of neuropsychiatric lupus syndromes. Arthritis Rheum. 1999;42:599–608. 99. Chia L, Fernandez A, Lacroix C, et al. Contribution of nerve biopsy findings to the diagnosis of disabling neuropathy in the elderly. A retrospective review of 100 consecutive patients. Brain. 1996;119:1091–1098.

Marcos R.G. de Freitas and Fernando de Mendonça Cardoso

19

Infectious Neuropathies INTRODUCTION

LEPROSY

Infectious neuropathies comprise an important treatable cause of preventable peripheral neuropathy worldwide (1). Several infectious agents may cause either directly or indirectly damage to peripheral nerves (Table 19.1). Leprosy leads to various patterns of nerve lesions and is common in some geographic areas, especially in Africa, South America, and Asia (2). Retroviral infection, which includes infection with the HIV, has now spread worldwide. This virus is responsible for a number of disabling peripheral neuropathies (3). Human T-lymphotrophic viruses (HTLV) are responsible for the HTLV-I–associated myelopathy or tropical spastic paraparesis and may also cause peripheral nerve involvement and inflammatory myopathy (4). Hepatitis C virus (HCV) infection is considered a health problem in the world. Peripheral neuropathy is a common extrahepatic manifestation in patients with HCV (5). Diphtheritic neuropathy continues to occur in small epidemics areas of underdevelopment countries (6). Chagas disease (CD), which is due to infection with Trypanosoma cruzi, affects more than 15 million people in Latin America. It is accompanied by mostly subclinical peripheral nerve involvement and cardiac manifestations, from lesions of the autonomic nervous system and cardiac muscle (7). Lyme disease (LD) is a frequent zoonosis found in the northern hemisphere and is considered an infectious disease caused by spirochetes belonging to the Borrelia burgdorferi complex transmitted by ticks of the Ixodes ricinus group (8). Postherpetic neuralgia (PHN) is a painful and difficult to treat complication of acute herpes zoster. Current treatment options provide only partial relief and are often limited by poor tolerability (9). Moreover, drugs used in the treatment of systemic infections may also damage the peripheral nerve system (PNS).

Introduction Leprosy is one of the most common causes of peripheral nerve disease in the world. Although overall prevalence of the disease is declining, leprosy continues to be a relevant cause of infectious neuropathy in subtropical and tropical countries. When left untreated, it is of progressive course with permanent damage. Failure of early detection of leprosy often leads to severe disability despite eradication of mycobacterium at a later date (9). In most populations, over 95% of individuals are naturally immune (10). It still remains a stigmatizing disease. Multidrug therapy (MDT), which cures the infection, has led to the understanding that leprosy can be effectively treated before disability (11) (Figure 19.1).

Prevalence Leprosy still represents one of the major public health problems in about 80 countries within Asia, Africa, and Latin America, mainly in India and Brazil (World Health Organization [WHO] 2010) (12). According to the report, the number of newly detected cases was 249 007 in 2008, or a 3.5% decrease compared with 2007 (13). Mycobacterium leprae Mycobacterium leprae is an obligatory intracellular parasite with tropism for macrophages and Schwann cells (14). This preference is determined by the attachment of the bacterium onto the a-2 chain “G” unit found in the basal lamina of Schwann cells. This lamina (layer) is only found in peripheral nerves. Following this attachment, the mycobacterium/lamina complex then binds with intracellular as well as plasma membrane elements such as a-dystroglycan, and subsequently introduces itself into the cell. Once inside, the bacterium multiplies very slowly. At a given moment, T cells will recognize the bacterium inside as hence trigger subacute and later chronic inflammatory response. This results in progressive damage to both myelinated and nonmyelinated nerve fibers followed by replacement of functional tissue by conjunctive tissue (15). The phenolic glycolipid 1 (PGL-1) is a cell-wall antigen on the surface of M. leprae (16). It binds to complement. This combination complement–

Table 19.1  Infectious Agents Virus: HIV-1 and HIV-2, HTLV-1 and HTLV-2, HBV, HCV, VZV Bacteria: M. leprae, B. burgdorferi, C. diphtheriae Parasitic: T. cruzi 259

260  Textbook of Peripheral Neuropathy

tion period is extremely variable. It may be long as 10 to 20 years. Exposure to the bacillus is not sufficient for the disease to develop. Factors such as nutrition, hygiene, and crowded housing play an important role. The onset of the disease may occur at any age. It is of interest that there is a male preponderance in the lepromatous form and a female excess in tuberculoid type (25). Leprosy affects the skin, eyes, nerves, reticulum­endothelial system as well as causing systemic manifestations.

Classification

Figure 19.1 Leprosy: deformity in the right foot. Note absorption of the first and second toes. M. leprae binds to macrophages and monocytes. The bacillus attaches to Schwann cells via PGL-1 binding (17). It preferentially invades the nonmyelinating Schwann cells, where the bacilli multiply in large numbers. Myelinproducing Schwann cells are not susceptible to invasion by the bacilli (18). PGL-1 may be detected in health persons in endemic areas. The measurement of PGL-1 levels may be ordered to influence the treatment, as it becomes lower in individuals well treated (19). One study showed the destructive effects of leprosy upon the expression of neural markers and the integrity of the nerve fibers. Immunoperoxidase staining against neural l markers of axons, neurofilament, nerve growth factor receptor, protein gene product 9.5, and Schwann cells (myelin basic protein, S-100 protein, and NGFR) were performed in 11 nerve biopsies of patients with pure neuritic leprosy (PNL) (20). There was reduced immune histochemical expression of neural markers and loss of myelinated fibers. Fibrosis is responsible for irreversible nerve damage in leprous neuropathy. The mast cells contribute to epineural collagenization through their tryptase secretion. The relationship was remarkable between fibrosis of the epineurium but not of the endoneurium (21). The finding of M. leprae in the endothelial cells besides the Schwann cells was confirmed in ultrastructural studies in nerve biopsies from 4 borderline tuberculoid and 4 lepromatous patients. The bacillary loaded endothelial cell was found to release M. leprae into the lumen through the ruptured membrane (22).

Transmission Both nasal secretions and skin from untreated multibacillary (MB) cases of leprosy are capable of shedding M. leprae to the environment, which may be deposited on either or both the nasal and skin epithelia of the contacts with the potential for initiating infection (23). Haematogenous dissemination is widely accepted is the most likely route of infection in lepromatous form (24). The incuba-

The accepted classification of leprosy made by Ridley and Jopling (26) is based on clinical, histological, and immunological criteria and subdivided leprosy into groups: tuberculoid (TT), borderline tuberculoid (BT), borderline (BB), borderline lepromatous (BL), and lepromatous (LL). A minor form was added later: indeterminate (I). At one pole of the spectrum, patients with TT leprosy have relatively good cell-mediated immunity against M. leprae. Patients with LL leprosy are anergic to the bacillus. Antibodies against M. leprae antigens are produced strongly in patients with TT disease and production is low in patients with LL disease. In 1982, WHO (27) recommended an additional classification, of paucibacillary (PB) and MB. It is a simpler classification and has changed. Initially, it incorporated slit skin smears, but now, all patients with 6 or more skin lesions are classified as MB patients. The PB category is heterogeneous and comprises patients with patients with indeterminate, TT, BT, BB, and even BL type. The MB category is equally heterogeneous and comprises BL  and LL patients. The WHO classification remains useful for allocating patients to treatment groups. To better understand the immunology, pathology, prognosis, and risk factors of the disease, it is better to use the Rydley-Jopling classification. The two classifications should be seen as complementary rather than exclusive (28). The form of the leprosy does not depend of the bacillus but on the response of the host to the presence of bacilli. In LL, the macrophages are incapable of killing the bacilli, and in BB, there is a vigorous cell-mediated immunity response that results in death of the organism. There is a type of leprosy called the pure neuritic form (PNL) without any skin lesions. The patients with PNL are frequently misdiagnosed. Some studies suggest that that about 4% to 10% of patients with leprosy have a pure neural involvement (11,29–32). Silent neuropathy is characterized by impairment of sensory and motor functions without skin signs, nerve tenderness, and pain, paresthesia, or numbness, which are symptoms of neuritis (33).

Clinical Forms Clinical and pathological manifestations are determined by the natural resistance of the host to invasion of M. leprae. Neural involvement includes damage to the nerve

CHAPTER 19: Infectious Neuropathies  261

trunks as well as to the cutaneous nerve endings, resulting in autonomic, sensory, and motor symptoms. Sensory forms of leprosy are the earliest as well as the most common clinical forms of disease, but predominantly motor forms also are known to occur. The most commonly involved nerves are the ulnar, median, posterior auricular, superficial radial, common fibular, superficial fibular, and posterior tibial, in that order (34,35). The involvement of these nerves causes an increase in bulk size; thus, the nerve is painful upon palpation, accompanied by both sensory and motor abnormalities. When the small cutaneous nerve endings and autonomic nerves are damaged hypo/hyperestesia as well as anydrosis occurs. In PNL, mononeuritis and mononeuritis multiplex are the most common clinical presentations but distal symmetric neuropathy with hypo/anesthesia and no motor abnormalities may also occur (35). Cranial nerve involvement in leprosy does not appear to be rare. There is clinical evidence of cranial nerve involvement in 18% of patients with leprosy, the facial and trigeminal nerve being the most affected (36). In 19 cases of PNL, mononeuropathy represented 79%, multiple mono­ neuropathy 10.5%, and polyneuropathy 10.5% of the neuropathies detected (32). The ulnar nerve is the most affected (Figure 19.2). Nerve conduction studies and the electromyography (EMG) pattern show a mainly axonal neuropathy (94.7%) (32). In a few cases, there is a distal symmetric neuropathy with temperature and pain anesthesia without muscle weakness. In these cases, the tendon reflex may be retained and the electrophysiological studies may be normal. In this form of PNL (predominantly small-fiber polyneuropathy), only the nerve biopsy can establish a diagnosis of leprosy (34). There is no significant correlation between the severity of the clinical signs and the histopathological findings.

Nerve Enlargement In a multicenter study in north India, 303 MB patients were followed for 2 years. There was nerve enlargement in 94% of patients, and the main risk factor for neurop-

Figure 19.3 Leprosy: enlarged great auricular nerve (arrow).

athy was the presence of skin lesions overlying nerve trunks (37). Thickening of nerves was found in 8 cases of 14 patients with small fiber polyneuropathy due to leprosy (34) (Figure 19.3). In some patients in endemic regions, we have observed asymptomatic nerve hypertrophy. Performing biopsies in these nerves may show evidence of LL (38).

Reactions Some leprous patients may develop inflammatory events due to hypersensitivity host responses, thus interrupting the stable and chronic course of the disease. These are the so-called leprosy reactions. Type 1 Reaction: Type 1 reaction or reversal reaction (RR) is a late cellular hypersensitivity reaction type IV. Neuritis is an important feature. Preexistent lesions become steadily more swollen, redden, and even ulcerate. New lesions may arise. Local hypersensitivity of lesions is common with resulting pain upon minor trauma. Fever, malaise, and anorexia may be present. Facial swelling as well as swelling of the legs and upper limbs is characteristic (2,10,14,25). Type 2 Reaction: Type 2 reaction or erythema nodosum leprosum (ENL) is a systemic disorder affecting multiple organs. Nodules and painful, raised red papules are characteristic. Accompanying these nodules are uveitis, iridocyc­ litis, episcleritis, neuritis, arthritis, dactylitis, lymphadenitis, and orchitis. Fever, prostration, anorexia as well as other constitutional symptoms are frequent, with the finding of chronic or subacute inflammatory infiltrates and areas of conjunctive tissue with or without bacilli (2,10,39).

Diagnosis Figure 19.2 Leprosy: ulnar palsy due to the involvement of the nerve at the level of the elbow.

Although the diagnosis of leprosy is clinical, in some cases, mainly of PNL, it is necessary to perform some

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examinations to confirm the diagnosis. In endemic countries where PNL could present with different types of neuropathy the diagnosis may be difficult (34). Electrophysiological features Although nerve conduction studies and EMG do not contribute to the diagnosis of PNL, it may help classify the type of peripheral neuropathy in leprosy. Leprosy causes a predominantly axonal neuropathy, more severe on the lower limbs, and the sympathetic skin response is almost always reduced (32–40). The near-nerve technique is a sensitive method in detecting early nerve lesions; it evaluates the function of small fibers in leprous neuropathy. Abnormality of the sensory action potential component recorded is the main finding in lepromatous or borderline-leprous neuropathy (41), whereas slowing of conduction indicating demyelination was recorded maximum in the ulnar nerve across the elbow, suggestive of site specific abnormality (40).

leprosy consist of mononeuropathy or multiple mono­ neuropathy, the nerve histopathology pattern is tilted toward the tuberculoid leprosy pole. In these cases, the nerve biopsy showed granulomas with giant cells and caseous necrosis (43) (Figure 19.4A). In the polyneuritic form, the histological findings are consistent with the lepromatous features containing an intense inflammatory infiltrate that consists of macrophages, plasma cells, and lymphocytes mainly in the endoneural space (34–44) (Figure 19.4B). We can see also the presence of vacuolated “foamy cells,” mild fibrosis of endoneurium, perineurium, and epineurium, and asymmetrical partial or total loss of fibers (34,35). Presence of M. leprae or its remnants in the nerves or skin is the main confirmatory feature (Figure 19.4C). The routine staining procedures of the bacillus such as Fite or Wade stains are the most commonly used colorations (43). In healed and residual nerves, there was total fibrosis of the endoneurium and perineurium (44) (Figure 19.4D).

Pathology Nerve biopsy with histopathological study is the gold standard for definitive diagnosis of the disease. Histological classification of a nerve biopsy specimen in leprosy is based chiefly on the character of the cellular infiltrate and the bacillary load (42). As most cases of pure neural

Other Examinations Polymerase chain reactions for M. leprae reaction in nerve biopsies may be positive in 47% of leprosy (10,20,25), mainly in LL (46), being useful in differentiating between leprosy and other inflammatory neuropathies. Detection

Figure 19.4 Leprosy: sural nerve biopsy. A, Epithelioid granuloma. Note Langerhans giant cell (arrow) and inflammatory infiltration (arrowhead) (hematoxylin and eosin, original magnification ´200). B, Intense mononuclear inflammatory infiltrate in the endoneurium, perineurium, and epineurium (arrow) (hematoxylin and eosin, original magnification ´100). C, Abundant acid-fast bacilli are seen, many arranged in so-called globi (arrows) (Wade, original magnification ´1000). D, Fibrosis and thickness of the endoneurium (arrow), perineurium, and epineurium (arrow head) (Gomori trichrome, original magnification ´200).

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of antibodies against polar glycopeptidolipids-1 (PGPL-1) may be useful as an additional laboratory to help PNL diagnosis (16–19). Recently, high-resolution sonography has been used to demonstrate nerve enlargement and inflammation in leprosy (47).

Treatment In 1982, a WHO Study Group recommended MDT. MDT consists of 3 drugs: dapsone, rifampicin, and clofazimine, and this drug combination is most beneficial in eradicating the pathogen and improving the patient’s condition. Dapsone is safe in the dosage used in MDT and side effects are rare. Rifampicin is given once a month. No toxic effects have been reported after monthly administration. Clofazimine is most active when administered daily. The drug is well tolerated and virtually nontoxic in the dosage used for MDT (27). In MB leprosy, the standard regimen is rifampicin 600 mg once a month, dapsone 100 mg daily, and clofazimine 300 mg once a month and 50 mg daily for 12 months. In PB leprosy, the standard regimen is rifampicin 600 mg once a month and dapsone 100 mg daily for 6 months (12). Since 1995, the WHO provides free MDT for all patients in the world (12). Second-line drugs are minocycline as well as fluorquinolones such as pefloxacine and ofloxacine. Whenever nerve decompression in leprosy is discussed as a preventive surgery, it may help to remove the external compression on the nerve, improving circulation and allowing a better response to the drugs, mainly steroids (48). It seems that low-dose steroids can partially reverse nerve function impairment and reactions in the short term, but the effect is not sustained in the long term (49).

Treatment of the Reactions Treatment of the reactions in nerves usually requires immunosuppressive or immunomodulating drugs. The therapy with higher doses of steroids is useful in type 1 reaction (RR) (50). Oral prednisone or prednisolone are the most often used drugs. Dosages vary from 30–40 to 60–80 mg/d in severe cases. There is some evidence for the benefit of prednisolone, thalidomide, and clofazimine in reaction type 2 (ENL) (39).

Conclusion Treatment of leprosy needs to be fully integrated into general health services. This is a key to successful elimination of the disease. The stigma of leprosy has to be changed at the global, national, and local levels (12).

an HIV infection has remained stable since the year 2000, and the rate of new cases per year has declined (3). It has been estimated that between 39% and 70% of patients with either the AIDS syndrome or infected with HIV present with neurological manifestations. Clinical neuropathy is seen in 30% of such patients and in virtually 100% of patients at autopsy (51). The introduction of antiretroviral drugs, especially the highly active retroviral treatment (HAART) regimen was able to modify the natural history of the disease. The annual incidence of neuropathy before the advent of these drugs was about 7% in patients with CD4 counts lower than 200 (52). Maschke et al have demonstrated a reduction in both incidence and prevalence rates after the introduction of the HAART drugs (53). Lichtenstein et al also showed reduction after its use. (54). However, there are authors who still consider both rates to be very high or even rising (55).

Pathogenesis The involvement of the PNS may be the result of either direct viral infection/lesion or immunosuppression, eventually leading to opportunistic infections. Neuropathy occurs at any stage of clinical infection but is most commonly seen during the advanced ones. Risk factors for the development of clinical neuropathy in HIV patients include age, use of estavudine or didanosidine (56), diabetes, CD4 counts between 50 and 199 cells/mm3 (54), a viral load of more than 10  000/ mm3, nutritional deficiency, and exposure to alcoholic beverages. Hulgan et al demonstrated that polyneuropathy is more commonly seen in patients carrying the T-­ mitochondrial haplotype (57). Its pathogenesis is multifactorial. Exposure to toxins (especially pharmaceutical drugs) and infections play an important role. Modifications in mitochondrial DNA are found in patients with neuropathies due to anti­ retroviral drugs.

Clinical Features The PNS may be affected in various ways: 1. Symmetric, distal polyneuropathy 2. Toxic neuropathy due to the antiretroviral drugs 3. Demyelinating inflammatory polyneuropathy 4. Mononeuropathy multiplex 5. Diffuse infiltrative lymphocytic syndrome 6. Progressive polyradiculopathy 7. Dysautonomic neuropathy.

HIV INFECTION Introduction

Distal Symmetric Polyneuropathy

HIV infection is pandemic. There is currently no region in the world where HIV has not been identified. However, the percentage rate of persons currently living with

Distal symmetric polyneuropathy (DSP) is the most common clinical presentation of polyneuropathy in HIV-infected patients. The clinical picture consists of

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pain on the lower limbs, beginning from the feet and worsening upon walking or at nighttime. Hyperalgesia and alodynia are common. Decrease in strength is not common, and whenever present, it is restricted to the intrinsic muscles of the foot. Neurological examinations shows reduction or even abolition of the deep tendon reflexes as well as thermal and painful stimuli abnormalities in the feet. Nerve conduction studies are those of an axonal neuropathy (58). Nerve biopsy shows axonal lesions and, in some cases, diffuses inflammatory, lymphocytic infiltrates (1).

Toxic Neuropathy Due to Antiretroviral Drugs The clinical picture of polyneuropathy induced by antiretroviral drugs is exactly identical to that of DSP. It is more frequently seen with protease inhibitors such as indinavir, stavudine, and didanosidine. Simpson and Tagliati described 69 patients with acute or subacute sensory-motor neuropathy who had taken reverse transcriptase inhibitor drugs (59).

Demyelinating Inflammatory Polyneuropathy Acute or chronic inflammatory demyelinating polyneuropathy may also occur. It usually occurs at the beginning of the disease when the patient is not immunosuppressed by the disease. They may also occur during the initial stages of antiretroviral therapy, with the apparent improvement of immunological counts. They are clinically identical to the neuropathies of HIV-negative patients. Slightly increased cell counts (pleocytosis) upon cerebrospinal fluid (CSF) analysis also occur (60). Treatment usually consists of plasmapheresis, intravenous immunoglobulin therapy, and respiratory support.

Mononeuropathy Multiplex It may occur in the initial or advanced stages of the disease. When in the initial stages of HIV disease, it is often due to vasculitis, whereas advanced stage mononeuropathy multiplex is most typically due to CMV infection, herpes zoster, or hepatitis C (61) (Figure 19.5).

Diffuse Infiltrative Lymphocytic Syndrome In this syndrome, there is a markedly increased CD8 counts in the blood as well as diffuse inflammatory infiltrates in various tissues, including the peripheral nerves. Clinically, an acute or sub acute painful multi­ focal polyneuropathy is seen.

Diffuse Polyradiculopathy It consists of acute lumbosacral pain progressing distally to the legs, followed by an equally acute decrease in muscle strength, sensory abnormalities, and sphincter disturbance It occurs in patients during the advanced stage of immunodepression; lymphoma, syphilis, mycobacteria, CMV, and herpes zoster are the most common clinical causes.

Dysautonomic Neuropathy Manifestations such as orthostatic hypotension, diarrhea, excessive sudoresis, and pupillary abnormalities are frequent in seropositive patients. They may occur either alone or associated with DSP (1).

Treatment In cases of DSP, treatment basically consists of pain control. Several drugs may be used (tricyclic antidepressants, antiepileptic drugs, serotonin reuptake inhibitors, and opioids). Coenzyme Q10 improved the general condition of patients with DSP due to use of drugs as the protease inhibitors, increasing the production of aden­ osine triphosphate but was responsible for worsening of pain (62). Lidocaine 5% gel is a safe but ineffective agent in the treatment of pain in HIV-associated DSP. (63). Regenerative treatments consisting of neural repair drugs are still under study (64), as is also erythropoietin in preventing axonal damage (65).

HTLV-1 AND HTLV-2 INFECTION Introduction

Figure 19.5 HIV mononeuropathy multiplex: superficial peroneal nerve biopsy showing necrotizing vasculitis of an occluded epineural artery (arrow) and early recanalization (arrowhead) (hematoxylin and eosin, original magnification ´400).

HTLV-1 and HTLV-2 viruses were the first retrovirus to be described to cause lesions in the nervous system. It has been estimated that approximately 18 million people are currently infected worldwide. However, only around 4% of them actually develop neurological signs and symptoms. Infection by HTLV-1 is endemic to certain countries such as Japan, Jamaica, and several other nations of Latin and Central America. Epidemiological

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data on HTLV infection in general are still not well characterized, although infection is rising among Native Americans and intravenous drug users (66).

Clinical Features HTLV-1 is clinically associated with adult T-cell leukemia and with HTLV-1–associated tropical spastic paraparesis/myelopathy (PET/MAH). Simultaneous occurrence of both clinical syndromes is decidedly rare but has been described in the medical literature (67). The HTLV-2 virus causes a syndrome clinically similar to PET/MAH and to tropical ataxic neuropathy. The HTLV-1 and HTLV-2 viruses are also associated with neurological manifestations other than PET/MAH. Biswas et al performed neurological examination in 153 HTLV-1, 388 HTLV-2, and 810 HTLV-seronegative individuals. Participants diagnosed with spastic paraparesis were excluded. HTLV-1 and HTLV-2 participants were more likely than seronegative participants to have leg weakness, impaired heel walking, impaired toe walking, impaired tandem gait, Babinski sign, impaired vibration sense, and sphincter symptomatology (68).

Peripheral Nerve Involvement The involvement of the PNS by the HTLVs has been supported by several authors (69). Leite et al. have shown case-control studies of blood donors had an involvement rate of 8.6% compared with only 2.6% in seronegative patients (70). However, Biswas et al were unable to demonstrate any relevant association between HTLV-1/HTLV-2 infection and polyneuropathy (68). Peripheral nerve involvement may occur alone (69) or in combination with spinal cord disease (71). The most common symptoms of PNS involvement are paresthesias (numbness, burning pain among others) coupled with symmetrically bilateral leg pain. Strength on neurological examination is found to be normal with reduced or abolished deep tendon reflexes as well as sensory abnormalities in a stocking-like distribution. Eventually, sphincter symptoms may occur due to spinal cord involvement (72). The upper limbs may be involved asymmetrically (73).

Pathogenesis Physiopathogenesis remains obscure. There is no evidence of direct neural involvement by the virus. The clinical association with systemic autoimmune diseases (such as Sjögren syndrome) along with axonal lesions found in nerve roots of inflammatory origin suggests that an autoimmune-mediated inflammatory mechanism may be involved (74).

Nerve Conduction/Nerve Biopsy Nerve conduction and EMG studies show a mixed pattern (axonal and demyelinating processes) and sural

Figure 19.6 HTLV-1 polyneuropathy: sural nerve biopsy. A small epineural vessel surrounded by mononuclear inflammatory cells (arrow) (hematoxylin and eosin, original magnification ´400). nerve biopsy may show a demyelinative/remyelinative process along with axonal degeneration with or without perivascular inflammation (Figure 19.6) (75).

HEPATITIS C VIRUS Introduction HCV is an RNA virus transmitted through sexual contact or through blood transfusion. Its prevalence is estimated to be around 3% worldwide especially in northern Brazil, Asia, Africa, and Eastern Europe (5).

Clinical Features It is the cause of both hepatic (acute hepatitis, chronic active hepatitis, cirrhosis, and hepatocarcinoma) as well as extrahepatic (glomerulonephritis, sicca syndrome, acute porphyria, thyroiditis, and peripheral neuropathy) syndromes. Polyneuropathy is frequently associated with the presence of cryoglobulins. The so-called cryoglobulinemia is a clinical entity associated with the presence of proteins that precipitate upon exposure to cold. It can be primary or secondary. It is estimated that around 50% of HCV-infected patients have cryoglobulinemia. However, polyneuropathy may also occur without cryoglobulinemia (5). Involvement of the PNS may be in the form of polyneuropathy, mononeuropathy, mononeuropathy multiplex, or cranial neuropathy (76,77). Advancing age is the main risk factor for polyneuropathy linked to HCV. Santoro et al evaluated 234 patients infected with the HCV virus; 15.3% had involvement of the PNS, whereas 10.6% were asymptomatic. These patients either have clinical polyneuropathy or had mononeuropathy multi­ plex (78). Nemmi et al examined 51 HCV-infected patients with polyneuropathy. In those with cryoglobulinemia, sensory-motor polyneuropathy predominated,

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whereas in patient without cryoglobulinemia, cranial polyneuropathy was the principal clinical form (79). Although HCV-associated polyneuropathy is mainly axonal, mononeuropathy multiplex and demyelinating polyneuropathy responsive to immunomodulation therapy have been described. Serological assays for HCV must be carried out, especially in patients diagnosed with hypergammaglobulinemia and IgM monoclonal gammopathy (80–81). Histopathological analysis will reveal epineural vasculitis, axonal degeneration, and demyelination (Figure 19.7A, B). Severity of the neuropathy depends upon the intensity of the inflammatory reaction as well as on the type of vessel involved. In those neuropathies associated with vasculitis, mononeuropathy multiplex is the most common, whereas in those without vasculitis, polyneuropathy predominates (82).

Pathogenesis Physiopathogenesis is still unknown. De Martino et al discovered HCV RNA fragments on neurons, suggesting direct viral damage (83). Another hypothesis is an immune-mediated response prompted by the virus, thus resulting in perivascular inflammation and vasculitis (84).

Treatment Treatment of HCV-associated polyneuropathy with or without cryoglobulinemia should be on an individualized basis. Eradication of the virus, suppression of B-cell clonal expression and cryoglobulins production as well as symptomatic/supportive therapy are all included as options (5). Drugs such as corticosteroids, rituximab, colchicine, cyclosporine, interferon a, peginterferon, and ribavirin may also be used, as is also plasmapheresis.

DIPHTHERITIC NEUROPATHY Introduction Diphtheria is an acute, infectious contagious disease of the upper bronchial airways caused by the Corynebacterium diphteriae microorganism. It used to be the principal cause of death among children before the advent of immunization. After implementation of the vaccine, the incidence rate of diphtheria dropped considerably (85). By the end of the 1980s and early 1990s, there was resurgence in its incidence rate in Eastern Europe and Russia (86).

Clinical Features The initial clinical picture consists of an inflammatory reaction of the upper airways that result in odinophagia, cough, fever, nasal secretion, and general malaise. As a result of the local release of Corynebacterium-produced exotoxin, patients may present with palatal paralysis (resulting in hoarseness of voice and dysphagia) along with paralysis of gaze accommodation. It is estimated that PNS involvement in diphtheria is approximately 20% of cases. Logina et al encountered a 15% incidence (87). The risk of developing neuropathic diphtheria was in direct proportion to the severity of the initial diphtheritic infection (88). Patients progressed to a subacute, sensory-motor demyelinating polyneuropathy with involvement of cranial nerves and dysautonomic symptoms (89). Neurological manifestations generally began 8 to 12 weeks after initial diphtheritic infection, although earlier onset has also been observed (87). Logina et al evaluated 50 patients with diagnosis of polyneuropathic diphtheria (87). A clinical course of biphasic mode was observed. Bulbar symptoms would improve partially at an initial stage, stabilize, and then

Figure 19.7 HCV polyneuropathy: superficial peroneal nerve biopsy. A, Necrotizing vasculitis with vessel structure marked altered with almost occlusion of the lumen, fibrinoid degeneration (arrow) surrounded by a mononuclear inflammatory cell infiltrate (arrow head) (hematoxylin and eosin, original magnification ´400). B, A great fiber loss with some fibers undergoing active axonal degeneration (arrows) (toluidine blue, original magnification ´400).

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Table 19.2  Differences Between Diphtheritic Neuropathy and Guillain-Barré S­yndrome Diphtheritic Neuropathy Cranial nerve involvement Low point Clinical course Need for respiratory support Risk of disability or death Multisystem involvement

Always >4 wk Biphasic ++ ++ Yes

Guillain-Barré Syndrome Frequently III, IV, and V ), with a mixed impression of tingling, burning, and dysesthesia, and with an inability to know where her right hand was in the dark. On examination, the deficits were strictly localized in the right upper extremity, with areflexia, loss of all sensations, and with a predominant loss of proprioception of the fingers. Pseudoathetosis, shown in this series of photographs, is characterized by the presence of undulating and writhing movements of the right fingers when the eyes are closed. With permission from Elsevier Masson France (4).

painful symptoms that involve, sometimes asymmetrically, both proximal and distal sites of the body, including the trunk and the face. The upper limbs may be preferably involved, and the patient is unable to appreciate the slight movements at the interphalangeal joints by passively moving 1 digit. As the pathological process becomes more extensive, loss of such recognition for the hand or entire extremity develops, with abnormal finger-to-nose test. Some patients develop pseudoathetoid (waver) movements in the hands or fingers when asked to hold hands outstretched while eyes are closed (Figure 20.1). In the foot, the perceptions of motion, position, and vibration may be equally affected, with an abnormal heel-to-knee-to-toe test and an early Romberg sign when the patient is able to stand with his feet together while his eyes are open but sways or falls when they are closed. The gait may be unsteady, particularly when asked to walk tandem by placing one heel directly in front of the opposite toes. These manifestations have led to the designation of “ataxic neuropathies,” a misleading term because it could also include demyelinating neuropathies. In some patients, neuropathic pain and predominantly small-fiber sensory loss involve proximal regions of the limbs, face, and trunk, either sparing the acral extremities or with simultaneous involvement of distal and proximal areas in a non-length–dependent pattern. This pattern suggests that the pathology may be localized to small-fiber neurons in the DRG and is similar to what had been described clinically and pathologically in patients with Fabry disease (27).

Common Pattern of SNN A recent study has proposed diagnostic criteria for SNN (26). Logistic regression was used to test sets of clinical, EDX, cerebrospinal fluid (CSF) parameters, and paraneoplastic antibody results to retrospectively discriminate patients with SNN and distal sensory neuropathies. The optimum set of criteria for SNN was tested prospectively in 37 patients with sensory neuropathies and accurately identified 81.6% of them as SNN. This study proposes to use a validated score to recognize SNN independently of the underlying cause (Table 20.1).

GENERAL INVESTIGATIONS Electrophysiological Testings The most common abnormality of nerve conduction in SNN is absent or low-amplitude sensory action potentials (SAPs) with normal or relatively preserved conduction velocities in the clinically involved extremity. Most published series report a widespread decrease in SAPs amplitudes, which involved both upper and lower limb nerves, even in patients with asymmetrical or patchy clinical presentation (28–30), arguing for a need of systematic and bilateral recording of the median, ulnar, radial, superficial peroneal, and sural sensory nerves. In the recently published SNN score (26) (Table 20.1), at least 1 SAP should be absent or 3 SAPs should have an amplitude 6.5 Yes Points a.  Ataxia in the lower or upper limbs at onset or full development +3.1 ¨ b.  Asymmetrical distribution of sensory loss at onset or full development +1.7 ¨ c.  Sensory loss not restricted to the lower limbs at full development +2.0 ¨ d. At least 1 SAP absent or 3 SAP 6.5 and if 1. The initial workup does not show biological perturbations or EDX findings excluding SNN; and 2. The patient has 1 of the following disorders: onconeural antibodies or a cancer within 5 years (34), cisplatin treatment, SS (74); or 3. MRI shows high signal in the posterior column of the spinal cord. C. A diagnosis of SNN is definite if DRG degeneration is pathologically demonstrated although DRG biopsy is not recommended.

Blood and Biological Parameters Erythrocyte sedimentation and other systemic markers are usually normal. Serological markers (rheumatoid factor, antinuclear antibodies) may suggest specific connective tissue disorders.

CSF examination is usually normal or demonstrates a slightly elevated protein value (18,19,29,33). In one study in which CSF was examined in 48 patients (3 cisplatin, 24 paraneoplastic, and 21 likely SNN), it was significantly abnormal in patients with paraneoplastic SNN with a

Table 20.2  Differential Diagnosis of Sensory Neuronopathy Neuropathy

Examples

Remarks

Infectious ataxic neuropathies

Syphilis, diphtheria, human T-cell lymphotropic virus, HIV

Appropriate laboratory testing needed

Tropical ataxic neuropathy

Strachan syndrome, Cuba epidemic neuropathy, Konzo epidemic paralytic disease

Appropriate laboratory testing needed

Neuropathy associated with gammopathy

Neuropathy associated with osteosclerotic myeloma, with monoclonal gammopathies of undetermined significance and with Waldenström macroglobulinemia, POEMS syndrome

Workup for underlying cancer and appropriate laboratory testing needed, see EFNS/PNS guidelines (118)

Chronic inflammatory demyelinating polyneuropathy

–

Progressive polyradiculoneuropathy with clinical course for >2 mo, see EFNS/PNS guidelines (119)

Inherited neuropathy

Friedreich ataxia, ataxia with vitamin E deficiency, abetalipoproteinemia, SANDO with mutation of the POLG gene, combined SNN, and motor neuron disorders

Family history often negative, DNA analysis needed

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more frequent raised protein level and oligoclonal pattern (26). Pleocytosis suggests infiltrative or infectious conditions, particularly HIV infection, but is reported in 80% of limbic encephalitis, potentially associated with paraneoplastic SNN (34). A number of molecules that are principally localized to the neuronal compartment of the peripheral nerve have been identified as relevant to the pathogenesis of autoimmune neuropathy (7). These antigens include the paraneoplastic antigens HU, CV2, and amphiphysin, which are associated with the development of paraneoplastic SNN and the antidisialosyl gangliosides antibodies. In the paraneoplastic SNN, the origin of the immune response is presumed to be against the tumor cells in which the neural antigens are inappropriately expressed. When the antigens are expressed on the plasma membrane, the immunopathology is primarily dependent on antibody-mediated processes. However, in those paraneoplastic syndromes involving an intracellular antigen, the mechanism of pathogenesis is not clear, but there is evidence for the involvement of cytotoxic T cells. In the mid-1980s, investigators described antibodies in the serum and CSF of patients with small-cell lung carcinoma (SCLC) and SNN that were subsequently shown to recognize specific antigens expressed on neural cells and the underlying tumor (35). A number of such nervous system–specific autoantibodies have now been described in a variety of paraneoplastic neurological diseases (36). Among the antibodies directed against neural antigens in serum and CSF, the most characteristic being antibodies directed against neuronal nuclear antigens, anti-HU or ANNA-1 (both nomenclature remain in current use). Among 979 patients with paraneoplastic neurological syndrome recruited from 20 European centers (36), the onconeural antibody profile confirmed Hu as the most frequent antibody (38.8%), followed by Yo or anti-Purkinje cell antibodies (13.4%). All other antibodies had frequencies below 10.0%. The antibody types were within the spectrum for onconeural antibodies and in association with paraneoplastic neurological syndrome have significant diagnostic value for an underlying cancer, with an association between anti-Hu antibodies, the subacute SNN and SCLC; and between anti-amphiphysin and anti-CV2 and paraneoplastic SNN and other sensorimotor neuropathy and SCLC, breast, colon, prostate, thymoma; and other cancers for the peripheral neuropathies (7,36). In 1985, circulating IgM antibodies reacting with NeuAc (a2-8) NeuAc (a2-3) Gal-configured disialosyl gangliosides (including GD1b, GD3, GT1b, and GQ1b) were first described in a patient with chronic sensory neuropathy (37). Since then, neuropathies associated with IgM antibodies against disialosyl residues have been defined as either sensory ataxic neuropathy associated with anti-GD1b IgM antibody (38), or chronic sensory ataxic neuropathy associated with antidisialosyl IgM antibodies, a so called chronic ataxic neuropathy in-

volving ophthalmoplegia, IgM paraprotein, cold agglutinins, and disialosyl antibodies (CANOMAD) (39). The most prominent feature of these neuropathies is sensory ataxia with relatively well-preserved muscle strength and small-fiber sensation. An immunohistochemical study showed localization of GD1b in the neurons of human DRG (40,41). Moreover, experimental sensory neuropathy is induced by sensitization with monospecific GD1b (41). GD1b, therefore, is recognized as a putative target molecule for serum antibodies.

Biopsies Morphological studies have focused on the sural nerve, with only a few reports of DRGs (8–10,13–21). In sural nerve biopsy and autopsy material, the characteristic features are a marked fiber loss, active axonal degeneration, and cellular infiltrates around epineurial blood vessels. There may be fascicle-to-fascicle variation in the degree of fiber loss or axonal degeneration, and necrotizing vasculitis may also be seen. We observed similar findings (Figure 20.2). The characteristic findings in the DRGs are inflammation and neuron loss with formation of residual nodules of Nageotte (clusters of supporting cells). The majority of inflammatory cells are T lymphocytes with scattered macrophages (Figure 20.3). Because of the risks involved, spinal ganglion biopsy is rarely performed and should be restricted to only a select group of patients (13).

DISORDERS ASSOCIATED WITH SNN Paraneoplastic Subacute SNN Introduction and Epidemiological Data Paraneoplastic neuropathies may occur in isolation such as the disorder described in 1948 by Denny-Brown (5), but more commonly, there is a complex syndrome with a concomitant involvement of both the central and the peripheral nervous systems, called paraneoplastic encephalomyelitis (PEM) with subacute SNN or PEM/SNN (1,2,7). There is abundant evidence that the paraneoplastic SNNs represent disordered autoimmunity, the exact pathogenic mechanisms are yet to be elucidated (7). In a clinicopathological review of 69 patients with paraneoplastic neurological disease, Henson and Urich (42) recognized that SNN and encephalomyelitis frequently developed together, particularly in association with SCLC. With the recognition and detection of anti-Hu antibodies (see the General Investigations section) in the serum of patients with PEM or SNN it was observed that these were different manifestations of the same underlying disease process. These anti-Hu antibodies react with a family of protein antigens of 35 to 40 kDa present in neurons and some tumors, especially SCLC. The binding of an antibody to a particular neural antigen on the exposed cellular structure of a fixed brain

A

C

B

n 16

Control (n=124) Patient (n=229) F= 30000 µm2

14 12 10 8 6 4 2

Control

2

4

8

6

10

12 µm

Figure 20.2 A, Sural nerve biopsy from a 61-year-old woman with SS and sensory neuronopathy with gait ataxia, demonstrating loss of nerve fibers. B, Age-matched control patient (Thionin blue, original magnification ×600). The histogram shows the loss of large and small nerve fibers. C, Same case as in A, with lymphocytic epineural blood vessel wall infiltration without necrosis, showing the presence of vasculitis (hematoxylin and eosin, original magnification ×400). With permission from John Wiley & Sons (1). A

B

C

N N CD8 E

D

CD4 F

N N Perforin

CD45 RO

MHC I

Figure 20.3 Pathological examination of a lumbar DRG from a patient with sensory neuronopathy and anti-Hu antibodies who died 14 months after the onset of SSN. A, There is evidence of massive mononuclear cell infiltration with signs of degenerating neurons (indicated by asterisks) (hematoxylin and eosin, original magnification X20). (B) Presence of cytotoxic CD8 T cells (indicated by arrows) surrounding a neuron (N) (immunostaining, original magnification X40). C, Interstitial distribution of CD4 helper T cells and macrophages (indicated by arrows) (immunostaining, original magnification X40). D, Direct neuronal (N) involvement is shown by the release of perforin granules by a cytotoxic T cell (indicated by arrows) in close contact with a sensory neuron (immunostaining, original magnification X100). E, Expression of CD45RO by the inflammatory cells indicates that they are of the memory subset (immunostaining, original magnification X40). F, Enhanced expression of MHC class I molecules by the satellite cells of a sensory neuron (N), favoring T-cell antigen recognition (immunostaining, original magnification X40). Reproduced with permission from John Wiley & Sons (1). 277

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section does not indicate the mode of pathogenicity of the neurological syndrome; this varies. For example, anti-Hu is directed against nuclear antigens (a family of RNA binding proteins normally expressed in the nervous system); presumably, these ectopically expressed nuclear antigens become externalized during the antitumor immune response. Although high-titer IgG antibodies against Hu and related antigens occur in the circulation and CSF, it has not been possible to demonstrate any cytopathic effect of this antibody on neurons, although the antibody can be detected in the nuclei of the exposed cells (43); for example, passive transfer of anti-Hu–containing IgG into animals does not induce disease (44). In anti-Hu syndromes the neuropathology is thought to be cell mediated (45) and the antibody is merely an immunological accompaniment. SNN is a rare paraneoplastic complication. In a prospective study of 150 consecutive patients with SCLC, only 1 patient was found with SNN and 2 patients had the Lambert-Eaton myasthenic syndrome (LEMS) (46). In another study of 203 patients, 5 had peripheral neuropathy with no cause and 5 others manifested antibody-mediated paraneoplastic neurological syndromes (LEMS, limbic encephalitis, cerebellar degeneration) (47). There is less information regarding the incidence of neuropathy in breast and gynecological malignancies (48). The prevalence of malignancy associated neuropathy in patients with peripheral neuropathy is not accurately known. From 422 consecutive patients with peripheral neuropathy, 26 were analyzed who concomitantly had carcinoma but no tumorous infiltration, drug toxicity, or cachexia (49). Twenty-one (5%) of these patients had either antineuronal antibodies or a short interval between onset of neuropathy and diagnosis of malignancy or a clinical course consistent with a paraneoplastic etiology. The remaining 5 patients had a long interval between onset of neuropathy and malignancy and a chronic progressive course suggesting a coincidental association. Clinical Manifestations They are well characterized (5,7,50–52). Symptoms include combination of paresthesias, sensory loss, and dysesthesia; pain is often severe. At onset, the distribution is frequently multifocal or asymmetrical and can be confused with mononeuritis multiplex. The upper limbs are usually affected first. Sensory loss, with a predominantly loss of proprioception, extends over all 4 limbs and may affect the face, chest, or abdomen. This results in lower-limb ataxia and an unsteady gait, and in the upper limbs, some patients develop pseudoathetoid movements in the hands (see the previous General Clinical Presentation section). Loss of taste and hearing may be seen (53). Tendon reflexes are reduced or absent. Strength is usually preserved unless there is some degree of motor axon loss (54). The most frequent manifestation of PEM/SNN is SNN, occurring in 74% of cases. However, it is predomi-

nant in only 50% to 60% of patients and clinically pure in only 24% (34,54). About 50% to 75% of the patients develop more widespread neurological involvement, including limbic encephalitis, encephalomyelitis, medullary syndrome, with or without pontine or bulbar manifestations, dysautonomia, cerebellar degeneration, and LEMS (51,54–56). In one large series of 200 patients with anti-Hu antibodies, neurological dysfunction was confined to 1 area of the nervous system in 30% patients (SNN, 48; cerebellar ataxia, 4; limbic encephalitis, 4; brainstem encephalitis, 2; intestinal pseudo-obstruction, 1; parietal encephalitis, 1) (54). The other patients had evidence of multifocal involvement. A predominant neurological syndrome was identified in 118 of them, whereas in 22 more than 1 syndrome predominated during the clinical evolution. The onset is usually subacute (a few days to several weeks) and rapidly progressive, although occasional patients have an indolent course with slow progression over months. Usually, paraneoplastic SNN is a severe disease. Many patients become bedridden and die from complications of bed rest or inactivity rather than from cancer progression. However, a subset undergoes an indolent course, with a very limited extension of the sensory loss and absence of progression after several months or years (57). The onset of neuropathy precedes diagnosis of cancer in the majority of cases (77%–88%), with a median interval from onset of symptom to tumor diagnosis 3.5 to 6 months (range, 1–47 months) depending on the series (51,54,55,57). Like other paraneoplastic syndromes, SNN usually presents in middle or older age. Age above 60 years, severe neurologic disability score at diagnosis, more than 1 area of the nervous system affected, and absence of treatment predict survival and neurologic outcome (54). Diagnosis The classical paraneoplastic SNN should be considered if all the following criteria are present (34): subacute onset with a Rankin score of at least 3 before 12 weeks of evolution, onset of numbness, and often pain, marked asymmetry of symptoms at onset, involvement of the arms, proprioceptive loss in the areas affected, and EDX studies that show marked, but not restricted, involvement of the sensory fibers with absent SAPs in at least 1 of the nerves studied. A recent study has advanced diagnostic criteria for possible, probable, or definite SNN using a composite score (Table 20.1) (26). Several large series have found that 85% of patients with PEM/SNN and high titers of anti-Hu antibodies have detectable underlying neoplasm, most commonly SCLC. However, a wide variety of cancers, including breast, prostate, ovarian, endometrial, and undefined adenocarcinomas, neuroblastomas, and germ cell t­umors, have been reported (54,55,57,58). Tumor diagnosis may be challenging, when the tumor is restricted to the mediastinal lymph nodes (59). When conventional radiological methods are negative, whole-body

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[18F]fluorodeoxyglucose positron emission tomography (18FDG-PET) is recommended (59,60). This has a high sensitivity but is not specific, as inflammatory tissues can take up the tracer. In 15 patients with a paraneoplastic neurological syndrome and anti-Hu antibodies, radiological methods led to the diagnosis of cancer in 12 patients but not in the other 3, whereas 18FDG-PET showed abnormal uptake in the mediastinum in all 15 patients, in accordance with the expected location of the malignancy (59). Laboratory investigations and electrodiagnostic findings have already been described (see the Blood and Biological Parameters and Electrophysiological Testings section). Detection of anti-Hu antibodies is of great value in the diagnosis of cancer. The estimated specificity is 99%, but the sensitivity is only 82%, so the absence of anti-Hu antibodies in patients suspected of having SNN does not exclude an underlying cancer (61). This finding highlights the importance of the Graus criterion (34) that paraneoplastic syndrome may be diagnosed in the absence of a malignant neoplasm or onconeural antibodies when the patient profile fulfills the other criteria for classic paraneoplastic syndrome. There is a lack of correlation between the Hu-Ab titers and the tumor evolution probably reflecting that HuAbs are a surrogate marker of the evolving immune response (62). Antibodies against the synaptic vesicle protein amphiphysin (described in paraneoplastic stiff-man syndrome and breast cancer) and against CV2 (associated with cerebellar degeneration, uveitis, and peripheral neuropathy with a variety of cancers) have subsequently been demonstrated to be rarely associated with SNN, with and without anti-Hu antibodies (36). The pathological lesions in SNN have long been known in DRGs and in sural nerve (see the previous Biopsies section) (8–10). In DRGs, they consist of mononuclear cell infiltrates surrounding sensory neurons undergoing degeneration. Ultimately, the lost neurons are replaced by a proliferation of satellite cells, and presence of intraneuronal IgG deposits, anti-Hu antibodies cannot be demonstrated anymore from the lesions. Currently, T cells are thought to be mainly responsible for the disease. Although CD4 helper T cells are found around vessels and between sensory neurons, CD8 cytotoxic T cells are situated mainly around neurons and sometimes penetrate the capsule of satellite cells to come in close contact with sensory neurons. Some of these lymphocytes express the cytotoxicity-associated proteins, perforin, and TIA-1 (Figure 20.3). Although an autoimmune pathogenesis for PEM/SNN is indicated by the presence of specific anti-Hu antibodies in serum and CSF, lymphocytic pleocytosis and oligoclonal bands in CSF, and inflammatory infiltrates in affected areas of the nervous system, the exact pathogenic mechanisms remain uncertain. The central theory of pathogenesis is however based on the presence of specific anti-Hu antibodies that react with an underlying tumor and on the concept of

molecular mimicry whereby expression of neuronal antigens by the tumor leads to a breakdown of immune tolerance and subsequent immune-mediated neuronal damage (7). Treatment This is largely disappointing, and antitumor therapy seems to be more effective than immunomodulatory therapy. Large series failed to demonstrate a clear benefit of intravenous immunoglobulin (IVIg), steroids, plasma exchange, or cyclophosphamide, either alone or in combination (55,57,58,63). There are uncontrolled studies that report stabilization of treated patients with IVIg (64,65), combined immunosuppressive treatment (66,67), rituximab treatment (68), but its significance is difficult to assess given the tendency of the SNN to plateau in untreated cases and the occurrence of occasional spontaneous remission (57). A large series of PEM/SNN concluded that a trial with immunotherapy should be considered in PEM patients when antineoplastic treatment is not possible because a tumor is not found or when PEM/SNN appears during or after tumor treatment (54). Based on this and on clinical observations that T-cell autoimmune diseases regress during pregnancy, 15 patients with anti-Hu antibodies were treated in a prospective, uncontrolled, and unblinded trial with 10 000 IU daily of human chorionic gonadotropin administered by intramuscular injection during 12 weeks. Seven (47%) patients improved or stabilized (69). The authors conclude that human chorionic gonadotropin may have immunomodulatory activity and may modify the course of Hu-paraneoplastic syndromes. The results of antitumor therapy are more promising. In a large series, treatment of the tumor was a predictor of improvement or stabilization of the neurological disorder (51,54,57,63), suggesting that early diagnosis of the cancer gives the best chance of helping the neurological disorder before it becomes too devastating.

Dysimmune SNN Introduction The dysimmune SNNs are uncommon but represent the most frequently encountered cause of SNN. They include disorders of the DRG thought to be immune mediated, excluding cases associated with malignancy and toxins affecting primary sensory neurons. In 1968, 2 patients were reported with acute pure sensory neuropathy not associated with malignancy with multifocal radicular sensory loss with selective loss of large-diameter sural nerve fibers suggested DRG as locus of disease (70). Additional case reports confirmed this distinct clinical entity (33,71,72). In the 1990s, other findings such as the acute or subacute, often focal, onset in the absence of inflammation in distal peripheral nerve suggested an immune mediated or vascular process at the level of DRG (18,29,30). Since then, several authors have

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reported detailed clinical, electrodiagnostic, biological, and pathological data for cases with acute, subacute, or chronic SNN most often associated with SS [see reviews in (1–3)]. Clinical Manifestations In dysimmune SNNs, there is a large variation in clinical presentation, with a mixture of ataxia and pain syndrome (see the General Clinical Presentation section), with sensory disturbances often unilateral, strikingly asymmetric, at times predominantly in the upper limbs but may also initially involve the trunk, face, or lower limbs. These signs may be associated with autonomic signs, such as Adie pupil, anhidrosis, postural hypotension, areflexia with normal strength. The course ranges from an abrupt to an indolent progression over several years. Although symptoms and signs are asymmetric at onset, they become symmetric as the disease becomes generalized (29,30). The clinical manifestations of neuropathy preceded the development of an isolated sicca complex (keratoconjunctivits sicca and xerostomia) or laboratory findings consistent with SS in most p­atients. Thus, in most patients, neuropathy developed first and then the diagnosis of SS may be made years later (18,19,73). This chronological sequence is true for all forms of neuropathy but is more characteristic in the SNN forms. Extraneural symptoms, such as pancreatitis and interstitial pneumonia, also can precede the clinical manifestations of SS. Peripheral neuropathy is the presenting problem in most patients, and SSassociated neuropathy has been shown to manifest as a variety of forms: in a study with 92 patients (19), 36 had SNN, 18 painful sensory neuropathy without sensory ataxia, 11 multiple mononeuropathy, 5 multiple cranial neuropathy, 15 trigeminal neuropathy, 3 autonomic neuropathy, and 4 radiculoneuropathy based on the predominant neuropathic symptoms. Acute or subacute onset was seen more frequently in multiple mononeuropathy and multiple cranial neuropathy, whereas chronic progression was predominant in other forms of neuropathy. Abnormal pupils and orthostatic hypotension were particularly frequent in sensory ataxic, painful, trigeminal, and autonomic neuropathy. SNN frequently had painful features, autonomic symptoms and trigeminal nerve involvement. Painful sensory neuropathy also had autonomic and trigeminal nerve involvement, as well as sensory ataxic features. Diagnosis With Special Interest on SS These observations strongly suggest that neural tissues, particularly DRG cells and probably autonomic ganglion cells, are the primary targets in SS in addition to the salivary and lacrimal glands, and visceral organs including the pancreas, lung, and thyroid. A revised version of the European criteria has been proposed by an American-European Consensus Group (74) based on sicca symptoms, ocular signs, objective evidence of

salivary gland involvement, and presence in the serum of autoantibodies to Ro (SSA) or La (SSB) antigens. The broad heterogeneity in the clinical and analytical features of patients with primary SS observed in some recent study (75) shows that our understanding of this systemic autoimmune disease is still evolving and that the different criteria used for the diagnosis of primary SS lead to different visions of the disease. The 2002 criteria, in which anti-Ro/La antibodies and/or positive salivary gland biopsy are mandatory, principally classify patients with the most pronounced extraglandular and immunological expression. This subset of patients is easily diagnosed using these criteria, whereas patients with a predominantly sicca-limited disease, especially males, the elderly, and immunonegative patients, and patients with other manifestations not included in this classification criteria such as arthralgia, cytopenia, parotid enlargement, and Raynaud phenomenon are excluded. The 2002 criteria do not cover the broad clinical and immunological heterogeneity of primary SS, and primary SS should be considered as a systemic autoimmune disease that can express in many guises beyond sicca involvement. Pathological data suggest an immune disorder directed against neural elements, with involvement of large and small DRG cells with retrograde axonopathy, as described in many cases with electrodiagnostic studies (undetectable SAPs) or on nerve biopsies (Figure 20.2). The events that lead to the autoimmune response and the underlying cause of SS remain enigmatic; however, lymphocytic disturbances, including ectopic germinal center formation, and aberrations of cellular signaling, play a significant role in this disorder, together with an underlying genetic predisposition that may vary between populations and additional factors priming or triggering the syndrome, such as hormonal influences, environmental factors, and infectious agents (76). Laboratory and clinical evidence suggest that proinflammatory cytokines, particularly tumor necrosis factor (TNF) a, may also play a role. Treatment SS without extraglandular manifestations is a relatively benign entity, and treatment is supportive and primarily directed against sicca complaints (77). The traditional antirheumatic agents show limited efficacy in the systemic process and use of systemic TNF-a inhibitors has been very disappointing. B-cell–depleting treatments and other newer biologic therapies appear more promising. Specific treatment of the neuropathy depends on the pathogenesis of nerve involvement. In SNN, response to treatment has been disappointing in most patients. Some patients improve after plasma exchange. Chen et al. (78) reported dramatic and sustained improvement in 2 of 4 patients with SNN secondary to SS after 5 to 9 sessions of plasma exchange, with no detectable benefit in the other 2 patients, and suggested early treatment with plasma exchange. Also IVIg has been reported to

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be beneficial in longstanding SNN (79–81). In one study, IVIg was given to 5 patients with severe disabilities for an average of 12 years. Four patients showed remarkable improvement, 2 of whom responded after the first course (79), but controlled trials are lacking. Intramuscular interferon a recently demonstrated benefit in cases of sensory ataxic and sensorimotor neuropathy, with additional improvement in sicca symptoms, antibody titers, and salivary gland histology (82). Infliximab, although ineffective for uncomplicated SS, was of benefit in a case of severe sensory neuropathy (83), indicating that anti–TNF-a therapy may have a role in subgroups of patients with severe disease. In a case of SS-associated IVIg-dependent ataxic neuropathy, rituximab administration demonstrated a marked IVIg-sparing effect not observed in patients with other assumed antibody­mediated neuropathies (84). Based on the limited number of patients treated, there may be marked differences in the rates of favorable therapeutic response among the neuropathic forms, reflecting major differences in the causes of neuropathy. Prednisone is likely a good candidate for multiple mononeuropathy and multiple cranial neuropathy, and favorable improvement may be seen in the painful dysesthesias of the painful sensory neuropathy and radiculoneuropathy forms with IVIg therapy. Although these symptomatic therapeutic responses were seen in certain patients, overall progression of the neuropathic symptoms as well as of SS syndrome itself occurred (19).

Autoimmune Ataxic Syndromes Acute Sensory Ataxic Neuropathy There is a clinical spectrum of autoimmune acute ataxic syndromes, ranging from sensory ataxic Guillain-Barré syndrome (GBS) to ataxic syndromes in which limb weakness is absent, such as Fisher syndrome (FS) and Bickerstaff brainstem encephalitis (BBE) (85). Based on Fisher and Bickerstaff’s findings, “progressive, relatively symmetric external ophthalmoplegia, and ataxia by 4 weeks” are the clinical features necessary for the diagnoses of both BBE and FS (86). Although “hyporeflexia or areflexia” and clear consciousness are required for the diagnosis of FS, “impaired consciousness” is required for that of BBE. Hyporeflexia or areflexia is not an exclusion criterion for the diagnosis of BBE because half of the original patients had hyporeflexia or areflexia. Studies published in the 1990s showed that serum anti-GQ1b IgG antibody levels are frequently elevated in patients with FS or BBE. In a large published series of 581 patients (86), anti-GQ1b IgG antibodies were positive in 68% of BBE patients and in 83% of FS. The presence of common antecedent infectious agents such as Campylobacter jejuni and Haemophilus influenzae in both conditions supports the hypothesis that BBE and FS have similar etiologies, as is the case for GBS and FS. Muscle spindles, proprioceptive transducers within the muscles, are an integral part of the g-reflex loop. They

contain specialized muscle fibers that have motor innervation and are enriched by a sensory ending. The neural components and intrafusal muscle fibers of these spindles may be important targets in FS patients because they are labeled by a monoclonal antibody against bseries gangliosides, including GQ1b, in mice and rats (87) and a monoclonal anti-GQ1b/GT1a antibody in humans (88). The latter staining pattern suggests that the group 1a afferents in muscle spindles contain GQ1b. Human immunohistochemical studies using a monoclonal antiGQ1b/GT1a antibody have shown the existence of some large neurons in DRG, which could be group 1a neurons (89). GQ1b at the NMJs of oculomotor muscles and on muscle spindles may be targets and produce the characteristic combination of FS clinical symptoms. The probable sequence of events in the pathogenesis of BBE and FS therefore is as follows: Infection by a microorganism bearing the GQ1b epitope induces production of antiGQ1b IgG antibodies in certain patients. The anti-GQ1b antibodies bind to GQ1b expressed on the oculomotor nerves and muscle spindles, inducing FS. In some cases, anti-GQ1b antibodies also enter the brainstem in areas where the BBB is deficient (eg, the area postrema) and binds to GQ1b, which may be expressed on the brainstem reticular formation, inducing BBE. The finding that both conditions have autoantibodies in common suggested that the autoimmune mechanisms are the same in both and are not distinct conditions. Common autoantibodies, antecedent infections, and neuroimaging and neurophysiological results from a large study offer conclusive evidence that these conditions form a continuous spectrum with variable central and peripheral nervous system involvement. A new eponymic terminology “Fisher-Bickerstaff syndrome” may be helpful for nosology (85). Because randomized controlled trials have established the efficacy of plasma exchange and IVIg for GBS, either treatment should be given to patients with FS/GBS or BBE/GBS overlap. Their efficacy for treating Fisher-Bickerstaff syndrome, however, has yet to be shown as there have been no randomized controlled trials (90). Chronic Sensory Ataxic Neuropathy Associated With Antidisialosyl Ganglioside Antibodies In contrast to the acute FS associated with IgG autoantibodies against disialosyl epitopes, including GD1b and GQ1b, monoclonal IgM antidisialosyl ganglioside antibodies are typically associated with chronic ataxic neuropathy with ophthalmoplegia, IgM paraprotein, cold agglutinins, and anti-GD1b disialosyl antibodies (CANOMAD) (39). In this syndrome, the IgMs react with the disialosyl epitope shared by gangliosides GD1b, GQ1b, GT1c, and GD3 (also see the General Investigations section). This form of sensory ataxic neuropathy, occasionally with ophthalmoplegia or bulbar signs, affects large sensory fibers and is characterized by distal paresthesias, numbness, prominent ataxia,

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areflexia, and mild or no limb weakness. Experimental sensitization with GD1b cause ataxic sensory neuropathy in rabbits and humans due to antibody-mediated damage to the primary sensory neurons (see the General Investigations section). The neuropathy is usually chronic and slowly progressive but can also have a relapsing course. Electrodiagnostic studies and nerve biopsy show both demyelinating and axonal features. A partial response to IVIg and rituximab sometimes occurs (91).

Toxic or Chemotherapy-Induced SNN Chemotherapy-induced peripheral neurotoxicity is a common and potentially disabling side effect of some widely used anticancer agents and can be a pure sensory and painful neuropathy (with thalidomide, cisplatin, oxaliplatin, or carboplatin) or a mixed sensorimotor neuropathy with or without involvement of the autonomic nervous system (with vincristine, paclitaxel, bortezomib, or suramin) (20,21,92,93). With vinca alkaloids and platinum analogues, a so-called coasting phenomenon due to a delayed release of the toxic drugs accumulated in tissues, is responsible for the development or worsening of the neuropathy up to several weeks after treatment interruption (93). In all cases, the neurotoxicity significantly interferes with function and compromises the quality of life. In general, the peripheral nervous system has a great capacity for regeneration in response to injury, but for regeneration to occur, the cell body must be spared, and this is not the case in SNN associated with thalidomide, cisplatin, oxaliplatin, or carboplatin. Depending on the dosage and agent used, symptoms sometimes resolve completely, but in most instances, chemotherapy-induced peripheral neurotoxicity is only partly reversible even when the tumor has been successfully treated by the drugs. In individual cases, neuropathy can evolve even after a single application of the drug. A general predisposition for developing chemotherapyinduced neuropathy has been observed in nerves previously damaged by diabetes mellitus, alcohol, or inherited neuropathy (94). The incidence varies depending on the conditions. Severe neuropathy can occur in 3% to 7% of patients treated with single but in up to 38% of those receiving polychemotherapy regimens. The neurotoxicity of cisplatin and carboplatin is well documented. The first signs of the predominantly SNN appear about 1 month after initiation of therapy. The extent of the neuropathy correlates with the cumulative dose of the platinum compound but also depends on the dose received at each administration. Neuropathy can follow exposure to amounts as low as 200 mg/m2, but doses above 400 mg/m2 always lead to neuronal damage (21). The clinical picture of the neuropathy is a predominantly SNN with diminished vibration perception, loss of tendon reflexes, and discomforting paresthesias, starting in the lower extremities. The intensity of

paresthesias ranges from light tingling to extensive pain. In advanced stages, the patient is ataxic, with a pronounced gait disturbance due to impaired proprioception; other symptoms include muscle cramps and Lhermitte phenomenon or a similar perception consisting of an electrical sensation in the shoulder girdle. This is due to demyelination of the dorsal roots and columns. Electrodiagnostic studies detect low SAP amplitude and secondary demyelinating neuropathy (reduced nerve conduction velocity) relatively late after the clinical manifestation of symptoms. The sural nerve is the most sensitive indicator for the neuropathy. Motor nerves are normally spared. Oxaliplatin is a platinum analog similar to the approved drugs, cisplatin and carboplatin. The most common toxicity resulting from oxaliplatin therapy is neurotoxicity, with early neuromyotonic discharges and then cold-sensitive paresthesias, which are unique among the manifestations of platinum complexes studied to date. They occur at low total cumulative doses, are always reversible, and do not require discontinuation of therapy. However, a peripheral sensory neuropathy also occurs, with symptoms similar to those of cisplatin. The risk of developing a severe neurological disturbance is related to the cumulative dose, generally becoming a clinical problem when the cumulative dose approximates 800 mg/m2. It is reversible but may last for several months and may even require discontinuation of treatment. The mechanism of neurotoxicity induced by platinum drugs may involve the accumulation of platinum within DRG cells. However, in contrast to cisplatin, oxaliplatin leads to retention of platinum due to slower clearance rather than greater accumulation. Currently, there is no treatment that can significantly improve the clinical signs and symptoms of chemotherapyinduced peripheral neurotoxicity or SNN. Symptomatic treatment of paresthesias and pain with ion-channel blockers, such as carbamazepine or gabapentin, has proved effective. Carbamazepine (600–1200 mg daily) is particularly effective in the treatment of early hyperpathic symptoms under oxaliplatintherapy. Tricyclic antidepressants are also used as first-line therapy. Different strategies to prevent neuropathy have been developed in experimental models, and some have reached clinical application; these include adrenocorticotropic hormone analogues, amifostine (an organic thiophosphate), reduced glutathione, insulin-like growth factor 1, nerve growth factor, and neurotrophin 3. This is a heterogeneous group of compounds, most of which have failed to show any benefit in preclinical trials. Prophylactic measures for chemotherapy-induced neuropathies are a real challenge. In animal models with neuropathies induced by cisplatin, vincristine, or taxol growth factors, neuroprotective compounds or gene therapy resulted in neuroprotection (95). A recently published doubleblind vs placebo clinical trial showed that vitamin E (a-tocopherol 400 mg/d) may have a neuroprotective effect (96).

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SNN and Pyridoxine Toxicity Although pyridoxine (vitamin B6) deficiency causes distal, predominantly sensory neuropathy pyridoxine has also been identified as a neurotoxicant. During the 1980s, the medical community was alerted to a neurological disease occurring in individuals consuming large quantities of vitamin B6 for prolonged periods of time (97,98). Since then, many more cases of pyridoxine neuropathy, some patients taking as little as 200 mg/d, have been described (22,99). It can occur with chronic use of pyridoxine supplementation over several years and also with acute overdosage with parenteral pyridoxine (100). A normal adult will require 1 to 2 mg of pyridoxine per day. This is adequately supplied by a normal diet. Requirements are increased in pregnancy, in malnourished patients, and in patients who are taking drugs that cause a depletion of pyridoxine, for example, isoniazid, theophyllines, and penicillamine. Patients with pyridoxine neuropathy present a pure sensory neuropathy with signs of large-fiber sensory involvement, resulting in a pronounced sensory ataxia. Except for minimal weakness, there is no evidence of motor involvement. No sign of central nervous system dysfunction, except a transient Lhermitte phenomenon, has been described. Neurological disability gradually improves with discontinuation of pyridoxine. Although there are no recent data on the prevalence of pyridoxineinduced SNN, this condition should be considered in a patient presenting with a sensory neuropathy. In animal models, pyridoxine intoxication causes a predominant, but not exclusive, degeneration of large-diameter neurons in the DRG and the large sensory fibers derived from those neurons (99,101). This pattern is supported by electrodiagnostic data showing a decrement in the H-wave amplitude but no change in the direct motor response.

Non–Length-Dependent Small-Fiber Ganglionopathy The syndrome of small-fiber ganglionopathy with early involvement of the face, trunk, or proximal limbs is not well recognized and contrasts with the burning feet syndrome of small-fiber neuropathy and classical large fiber features of sensory ganglionopathy. Twelve men and 11 women, with an average age of 50 years, were reported from 4 centers (27). Neuropathic pain developed over days or over months. The pain was characterized as burning, prickling, shooting, or allodynic. There was loss of pinprick sensation in affected regions in 19, with minimal or no loss of large fiber sensibility. Laboratory findings included abnormal glucose metabolism in 6 patients, Sjögren syndrome in 3, and monoclonal gammopathy, sprue, and hepatitis C infection in 1 each, with the remainder idiopathic. SAPs were normal in 12 and were reduced in the hands but normal in the legs in 6. Skin biopsy in 14 of 17 showed reduced nerve fiber

density in the thigh equal to or more prominent than in the calf. Two of 7 patients improved with immune therapies, 13 symptomatically with analgesic medications. Ten considered the pain disabling at the last follow-up.

Inherited Disorders With Degeneration of DRG Cells Friedreich Ataxia Friedreich ataxia, an autosomal recessive neurodegenerative disease, is the most common of the inherited ataxias (102) and the most frequently encountered inherited ataxia with electrodiagnostic features of SNN (103). The cardinal clinical features are progressive gait and limb ataxia, absent lower limb reflexes, extensor plantar responses, dysarthria, and reduction in or loss of vibration sense and proprioception. Cardiomyopathy, scoliosis, and foot deformity are common but nonessential features. The phenotype spectrum is broader than previously considered, suggesting the usefulness of genetic testing of the FRDA gene in all patients with idiopathic ataxia (104). Ataxia With Vitamin E Deficiency Ataxia with vitamin E deficiency is a rare autosomal recessive neurodegenerative disease, due to mutations in TTPA gene (105), which encodes for a-TTP, a cytosolic liver protein that is presumed to function in the intracellular transport of a-tocopherol. This disease is characterized clinically by symptoms with often striking resemblance to those of Friedreich ataxia. The neurological symptoms include ataxia, dysarthria, hyporeflexia, and decreased vibration sense, sometimes associated with cardiomyopathy and retinitis pigmentosa (106). Vitamin E supplementation improves symptoms and prevents disease progress (107). Abetalipoproteinemia A SNN can be observed in familial hypocholesterolemia, namely abetalipoproteinemia, hypobetalipoproteinemia, and chylomicron retention disease, a rare genetic disease that causes malnutrition and growth failure. The diagnosis is based on a history of chronic diarrhea with fat malabsorption and abnormal lipid profile. Upper endoscopy and histology reveal fat-laden enterocytes, whereas vitamin E deficiency is invariably present. Creatine kinase (CK) is usually elevated and hepatic steatosis is common. Genotyping identifies the Sar1b gene mutation. Treatment and follow-up remain poorly defined (108). Mitochondrial Disorders Several phenotypes previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO) harbor proprioceptive ataxia, with ophthalmoplegia, and have been reported in relation with nuclear mutation of the mitochondrial DNA with

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mutation of the polymerase g (POLG) gene (109). The enlarging spectrum of sensory ataxic neuropathies associated with mitochondrial DNA (mtDNA) instability and POLG mutations should be recognized and considered in the differential diagnosis of this unusual presentation. Despite a growing appreciation of mitochondrial SNN phenotypes, there are a number of potential pitfalls in relation to confirming a diagnosis. First, the POLGassociated diseases are widely heterogeneous, and within the sensory ataxic phenotypes, there may be much overlap between syndromes as well as absence or delayed emergence of certain features such as ophthalmoparesis (108). Second, muscle biopsy may be normal, and multiple mtDNA deletions may be difficult to demonstrate (110). Combined SNN and Motor Neuron Disorders The combination of severe sensory and motor neuronopathy is rarely encountered in clinical practice. It has been reported in patients with paraneoplastic Hu antibodies (see above), in facial onset sensory and motor neuronopathy (111), and in rare genetic diseases such as Tangier disease and the A382P TDP-43 mutation in the TARDBP gene (112).

DIFFERENTIAL DIAGNOSIS The differential diagnosis involves distinguishing SNN from other sensory polyneuropathies, diseases primarily affecting posterior column fibers being beyond the scope of this discussion (Table 20.2).

Infectious Ataxic Neuropathies In the preantibiotic era, syphilis was the most frequent cause of myelopathy (113). Patients presented with sensory levels, lower extremity weakness, pyramidal signs, and variable degrees of bladder and bowel dysfunction but also with polyradiculopathy. Pathologies have been related to meningomyelitis, meningovascular disease, and cord atrophy (tabes dorsalis) and also to cord compression from gummae or syphilitic osteitis. Tabes dorsalis is caused by the degeneration of the postganglionic sensory nerve roots and dorsal columns of the spinal cord due to syphilitic pachymeningitis, especially at the lower thoracic and lumbar levels. This results in abolished or reduced tendon reflexes, ataxia, loss of pain sensation, foot ulcers, arthropathy, and lancinating pain. In contrast to peripheral neuropathy or ganglionopathy, SAPs are normal. Guidelines recommend treatment of neurosyphilis with 18 to 24 million units of intravenous aqueous penicillin per day for 10 to 14 days. Diphtheric Polyneuropathy Diphtheric polyneuropathy occurs in 15% of patients after severe pharyngeal infection. The most frequent manifestations include bulbar paralysis or a demyelinating disorder resembling GBS (114). Impairment of

deep sensation is frequent and, in some cases, can result in an ataxic pseudotabetic neuropathy. Human T-Cell Lymphotropic Virus Human T-cell lymphotropic virus I or II has been associated with some cases of tropical ataxic neuropathy (see below) (115,116). HIV Peripheral neuropathy is a common complication of HIV infection and has a broad spectrum of manifestations. The most frequent is a predominantly sensory and painful distal neuropathy, which is almost universal in the late stages of HIV infection. However, a few patients have been reported with a subacute ataxic sensory ganglionopathy (11,12).

Tropical Ataxic Neuropathies Tropical ataxic neuropathies encompass a heterogeneous group of disorders characterized by an ataxic syndrome associated with other manifestations, including paraparesis, optic nerve involvement, and mental disorders (117). Most of these are caused by nutritional factors and attributed to toxiconutritional causes. The disorder has been reported in prisoners of war (Strachan syndrome) and as epidemic neuropathy in Cuba, epidemic paralytic disease (Konzo) in Congo, and in Nigeria.

Demyelinating Neuropathies The EFNS/PNS guidelines on the definition, investigation, and treatment of chronic inflammatory demyelinating polyradiculoneuropathy and of patients with paraproteinemic demyelinating neuropathy have been recently revised (118,119). These 2 neuropathies are the most common differential diagnosis of SNN.

CONCLUSIONS SNN is a clinically, histologically, and pathogenetically distinct category of sensory neuropathy. Although it may not be easy to separate ganglionopathies from other sensory ataxic neuropathies, electrodiagnostic studies are useful in demonstrating an asymmetrical or multifocal reduction in amplitude of the proximal and distal SAPs. One important factor in the pathogenesis is the access of the autoantibodies to the target antigen in the central and peripheral nervous system in dysimmune and paraneoplastic neuronopathies. Dysimmune sensory ganglionitis may be responsive to immunosuppressive therapy, whereas the paraneoplastic, toxic neuronopathies, and associated SNN with genetic diseases are generally refractory. There is a great need to expand the number of confirmed therapies and explore treatments that could potentially stop or reverse damage to the DRG.

CHAPTER 20: Sensory Neuronopathies or Ganglionopathies  285

KEY POINTS AND CLINICAL PEARLS • Those disorders are characterized by primary

•

•

•

•

degeneration of sensory neurons in DRG. They encompass neoplastic or dysimmune causes and toxic agents and are more rarely encountered with genetic disorders. Non-length–dependent distribution of sensory loss and almost pure EDX sensory involvement are the distinctive signs, but in neoplastic SNN, combined neurological manifestations, such as autonomic neuropathy, motor neuron disorder, limbic dysfunction, or cerebellar signs usually occur. Investigations include EDX studies (all cases), imaging techniques (neoplastic cases), blood and biological parameters, CSF examination (all cases except toxic), sural nerve biopsy (dysimmune cases), as well as genetic testing (selective cases). Diagnosis of SNN is possible based on examination and on results of the EDX studies, probable as related to the biological workup and imaging data, and definite if DRG degeneration is pathologically proven (DRG biopsy not recommended). A validated score to recognize SNN independently of the underlying cause is available. Treatments are tailored to the underlying cause.

References 1. Kuntzer T, Antoine JC, Steck AJ. Clinical features and pathophysiological basis of sensory neuronopathies (ganglionopathies). Muscle Nerve. 2004;30:255–268. 2. Sghirlanzoni A, Pareyson D, Lauria G. Sensory neuron diseases. Lancet Neurol. 2005;4:349–361. 3. Smith BE, Windebank AJ, Dyck PJ. Nonmalignant inflammatory sensory polyganglionopathy. In: Dyck PJ, Thomas PK, eds. Peripheral Neuropathy. 4th ed. Philadelphia: Elsevier Saunders; 2005:2309–2320. 4. Kuntzer T. [Ganglionopathies: evolving concept and ideas on management]. Rev Neurol (Paris). 2006;162:1268–1272. 5. Denny-Brown D. Primary sensory neuropathy with muscular changes associated with carcinoma. J Neurol Neurosurg Psychiatry. 1948,73–87. 6. Denny-Brown D. Hereditary sensory radicular neuropathy. J Neurol Neurosurg Psychiatry. 1951;14:237–252. 7. Spies JM, McLeod JG. Paraneoplastic neuropathy. In: Dyck PJ, Thomas PK, eds. Peripheral Neuropathy. 4th ed. Philadelphia: Elsevier Saunders; 2005:2471–2487. 8. Dalmau J, Furneaux HM, Rosenblum MK, Graus F, Posner JB. Detection of the anti-Hu antibody in specific regions of the nervous system and tumor from patients with paraneoplastic encephalomyelitis/sensory neuronopathy. Neurology. 1991;41:1757–1764.

9. Graus F, Campo E, Cruz-Sanchez F, Ribalta T, Palacin A. Expression of lymphocyte, macrophage and class I and II major histocompatibility complex antigens in normal human dorsal root ganglia. J Neurol Sci. 1990;98:203–211. 10. Wanschitz J, Hainfellner JA, Kristoferitsch W, Drlicek M, Budka H. Ganglionitis in paraneoplastic subacute sensory neuronopathy: a morphologic study. Neurology. 1997;49:1156–1159. 11. Esiri MM, Morris CS, Millard PR. Sensory and sympathetic ganglia in HIV-1 infection: immunocytochemical demonstration of HIV-1 viral antigens, increased MHC class II antigen expression and mild reactive inflammation. J Neurol Sci. 1993;114:178–187. 12. Scaravilli F, Sinclair E, Arango JC, Manji H, Lucas S, Harrison MJ. The pathology of the posterior root ganglia in AIDS and its relationship to the pallor of the gracile tract. Acta Neuropathol. 1992;84:163–170. 13. Colli BO, Carlotti CG Jr, Assirati JA Jr, Lopes LS, Marques W, Jr, Chimelli L, Neder L, Barreira AA. Dorsal root ganglionectomy for the diagnosis of sensory neuropathies. Surgical technique and results. Surg Neurol. 2008;69: 266–273. 14. Griffin JW, Cornblath DR, Alexander E, Campbell J, Low PA, Bird S, Feldman EL. Ataxic sensory neuropathy and dorsal root ganglionitis associated with Sjögren’s syndrome. Ann Neurol. 1990;27:304–315. 15. Hainfellner JA, Kristoferitsch W, Lassmann H, Bernheimer H, Neisser A, Drlicek M, Beer F, Budka H. T-cell–mediated ganglionitis associated with acute sensory neuronopathy. Ann Neurol. 1996;39:543–547. 16. Kurokawa K, Noda K, Mimori Y, Watanabe C, Katayama S, Nakamura S, Sannomiya K, Yamamoto S, Tahara E. A case of pandysautonomia with associated sensory ganglionopathy. J Neurol Neurosurg Psychiatry. 1998;65:278–279. 17. Okajima T, Yamamura S, Hamada K, Kawasaki S, Ideta T, Ueno H, Tokuomi H. Chronic sensory and autonomic neuropathy. Neurology. 1983;33:1061–1064. 18. Sobue G, Yanagi T, Hashizume Y. Chronic progressive sensory ataxic neuropathy with polyclonal gammopathy and disseminated focal perivascular cellular infiltrations. Neurology. 1988;38:463–467. 19. Mori K, Iijima M, Koike H, Hattori N, Tanaka F, Watanabe H, Katsuno M, Fujita A, Aiba I, Ogata A, Saito T, Asakura K, Yoshida M, Hirayama M, Sobue G. The wide spectrum of clinical manifestations in Sjögren’s syndrome–associated neuropathy. Brain. 2005;128:11–34. 20. Gill JS, Windebank AJ. Cisplatin-induced apoptosis in rat dorsal root ganglion neurons is associated with attempted entry into the cell cycle. J Clin Invest. 1998;101: 2842–2850. 21. Krarup-Hansen A, Helweg-Larsen S, Schmalbruch H, Rorth M, Krarup C. Neuronal involvement in cisplatin neuropathy: prospective clinical and neurophysiological studies. Brain. 2007;130:4–88. 22. Windebank AJ, Low PA, Blexrud MD, Schmelzer JD, Schaumburg HH. Pyridoxine neuropathy in rats: specific degeneration of sensory axons. Neurology. 1985;35:1617– 1622. 23. Xu Y, Sladky JT, Brown MJ. Dose-dependent expression of neuronopathy after experimental pyridoxine intoxication. Neurology. 1989;39:1077–1083. 24. Kusunoki S, Shimizu J, Chiba A, Ugawa Y, Hitoshi S, K­anazawa I. Experimental sensory neuropathy induced

286  Textbook of Peripheral Neuropathy by sensitization with ganglioside GD1b. Ann Neurol. 1996; 39:424–431. 25. Asbury AK. Sensory neuronopathy. Semin Neurol. 1987;7:58–66. 26. Camdessanche JP, Jousserand G, Ferraud K, Vial C, Petiot P, Honnorat J, Antoine JC. The pattern and diagnostic criteria of sensory neuronopathy: a case-control study. Brain. 2009;132:7–33. 27. Gorson KC, Herrmann DN, Thiagarajan R, Brannagan TH, Chin RL, Kinsella LJ, Ropper AH. Non-length dependent small fibre neuropathy/ganglionopathy. J Neurol Neurosurg Psychiatry. 2008;79:163–169. 28. Lauria G, Pareyson D, Sghirlanzoni A. Neurophysiological diagnosis of acquired sensory ganglionopathies. Eur Neurol. 2003;50:146–152. 29. Windebank AJ, Blexrud MD, Dyck PJ, Daube JR, Karnes JL. The syndrome of acute sensory neuropathy: clinical features and electrophysiologic and pathologic changes. Neurology. 1990;40:584–591. 30. Griffin JW, Cornblath DR, Alexander E, Campbell J, Low PA, Bird S, Feldman EL. Ataxic sensory neuropathy and dorsal root ganglionitis associated with Sjögren’s syndrome. Ann Neurol. 1990;27:304–315. 31. Auger RG, Windebank AJ, Lucchinetti CF, Chalk CH. Role of the blink reflex in the evaluation of sensory neuronopathy. Neurology. 1999;53:407. 32. Mori K, Koike H, Misu K, Hattori N, Ichimura M, Sobue G. Spinal cord magnetic resonance imaging demonstrates sensory neuronal involvement and clinical severity in neuronopathy associated with Sjögren’s syndrome. J Neurol Neurosurg Psychiatry. 2001;71:488–492. 33. Dalakas MC. Chronic idiopathic ataxic neuropathy. Ann Neurol. 1986;19:545–554. 34. Graus F, Delattre JY, Antoine JC, Dalmau J, Giometto B, Grisold W, Honnorat J, Smitt PS, Vedeler C, Verschuuren JJ, Vincent A, Voltz R. Recommended diagnostic criteria for paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry. 2004;75:1135–1140. 35. Graus F, Cordon-Cardo C, Posner JB. Neuronal antinuclear antibody in sensory neuronopathy from lung cancer. Neurology. 1985;35:538–543. 36. Giometto B, Grisold W, Vitaliani R, Graus F, Honnorat J, Bertolini G. Paraneoplastic neurologic syndrome in the PNS Euronetwork database: a European study from 20 centers. Arch Neurol. 2010;67:330–335. 37. Ilyas AA, Quarles RH, Dalakas MC, Fishman PH, Brady RO. Monoclonal IgM in a patient with paraproteinemic polyneuropathy binds to gangliosides containing disialosyl groups. Ann Neurol. 1985;18:655–659. 38. Susuki K, Yuki N, Hirata K. Features of sensory ataxic neuropathy associated with anti-GD1b IgM antibody. J Neuroimmunol. 2001;112:181–187. 39. Willison HJ, O’Leary CP, Veitch J, Blumhardt LD, Busby M, Donaghy M, Fuhr P, Ford H, Hahn A, Renaud S, Katifi HA, Ponsford S, Reuber M, Steck A, Sutton I, Schady W, Thomas PK, Thompson AJ, Vallat JM, Winer J. The clinical and laboratory features of chronic sensory ataxic neuropathy with anti-disialosyl IgM antibodies. Brain. 2001;124:1968–1977. 40. Kusunoki S, Mashiko H, Mochizuki N, Chiba A, Arita M, Hitoshi S, Kanazawa I. Binding of antibodies against GM1 and GD1b in human peripheral nerve. Muscle Nerve. 1997;20:840–845.

41. Kusunoki S, Hitoshi S, Kaida K, Arita M, Kanazawa I. Monospecific anti-GD1b IgG is required to induce rabbit ataxic neuropathy. Ann Neurol. 1999;45:400–403. 42. Henson RA, Urich H. Encephalomyelitis with carcinoma. In: Henson RA, Urich H, eds. Cancer and the Nervous System. Oxford: Blackwell Scientific; 1982:314–345. 43. Smeenk RJ. Antinuclear antibodies: cause of disease or caused by disease? Rheumatology (Oxf). 2000;39:581–584. 44. Tanaka K, Tanaka M, Inuzuka T, Nakano R, Tsuji S. Cytotoxic T lymphocyte–mediated cell death in paraneoplastic sensory neuronopathy with anti-Hu antibody. J Neurol Sci. 1999;163:159–162. 45. Benyahia B, Liblau R, Merle-Beral H, Tourani JM, Dalmau J, Delattre JY. Cell-mediated autoimmunity in paraneoplastic neurological syndromes with anti-Hu antibodies. Ann Neurol. 1999;45:162–167. 46. Elrington GM, Murray NM, Spiro SG, Newsom-Davis J. Neurological paraneoplastic syndromes in patients with small cell lung cancer. A prospective survey of 150 patients. J Neurol Neurosurg Psychiatry. 1991;54:764–767. 47. van Oosterhout AG, van de Pol M, ten Velde GP, Twijnstra A. Neurologic disorders in 203 consecutive patients with small cell lung cancer. Results of a longitudinal study. Cancer. 1996;77:1434–1441. 48. Croft P, Wilkinson M. Carcinomatous neuromyopathy. Its incidence in patients with carcinoma of the lung and carcinoma of the breast. Lancet. 1963;1:184–188. 49. Antoine JC, Mosnier JF, Absi L, Convers P, Honnorat J, Michel D. Carcinoma associated paraneoplastic peripheral neuropathies in patients with and without antionconeural antibodies. J Neurol Neurosurg Psychiatry. 1999;67:7–14. 50. Camdessanche JP, Antoine JC, Honnorat J, Vial C, Petiot P, Convers P, Michel D. Paraneoplastic peripheral neuropathy associated with anti-Hu antibodies. A clinical and electrophysiological study of 20 patients. Brain. 2002;125:166–175. 51. Chalk CH, Windebank AJ, Kimmel DW, McManis PG. The distinctive clinical features of paraneoplastic sensory neuronopathy. Can J Neurol Sci. 1992;19:346–351. 52. Horwich MS, Cho L, Porro RS, Posner JB. Subacute sensory neuropathy: a remote effect of carcinoma. Ann Neurol. 1977;2:7–19. 53. Graus F, Rene R. Paraneoplastic neuropathies. Eur Neurol.1993;33:279–286. 54. Graus F, Keime-Guibert F, Rene R, Benyahia B, Ribalta T, Ascaso C, Escaramis G, Delattre JY. Anti-Hu–associated paraneoplastic encephalomyelitis: analysis of 200 patients. Brain. 2001;124:1138–1148. 55. Dalmau J, Graus F, Rosenblum MK, Posner JB. Anti-Hu– associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients. Medicine (Baltimore) 1992;71:59–72. 56. Saiz A, Bruna J, Stourac P, Vigliani MC, Giometto B, Grisold W, Honnorat J, Psimaras D, Voltz R, Graus F. AntiHu–associated brainstem encephalitis. J Neurol Neurosurg Psychiatry. 2009;80:404–407. 57. Sillevis SP, Grefkens J, de LB, van den Bent M, van PW, Hooijkaas H, Vecht C. Survival and outcome in 73 anti-Hu positive patients with paraneoplastic encephalomyelitis/ sensory neuronopathy. J Neurol. 2002;249:745–753. 58. Lucchinetti CF, Kimmel DW, Lennon VA. Paraneoplastic and oncologic profiles of patients seropositive for

CHAPTER 20: Sensory Neuronopathies or Ganglionopathies  287 type 1 antineuronal nuclear autoantibodies. Neurology. 1998;50:652–657. 59. Antoine JC, Cinotti L, Tilikete C, Bouhour F, Camdessanche JP, Confavreux C, Vighetto A, Renault-Mannel V, Michel D, Honnorat J. [18F]fluorodeoxyglucose positron emission tomography in the diagnosis of cancer in patients with paraneoplastic neurological syndrome and anti-Hu antibodies. Ann Neurol. 2000;48:105–108. 60. Rees JH, Hain SF, Johnson MR, Hughes RA, Costa DC, Ell PJ, Keir G, Rudge P. The role of [18F]fluoro-2-deoxyglucosePET scanning in the diagnosis of paraneoplastic neurological disorders. Brain. 2001;124:2223–2231. 61. Molinuevo JL, Graus F, Serrano C, Rene R, Guerrero A, Illa I. Utility of anti-Hu antibodies in the diagnosis of paraneoplastic sensory neuropathy. Ann Neurol. 1998;44:976–980. 62. Llado A, Mannucci P, Carpentier AF, Paris S, Blanco Y, Saiz A, Delattre JY, Graus F. Value of Hu antibody determinations in the follow-up of paraneoplastic neurologic syndromes. Neurology. 2004;63:1947–1949. 63. Keime-Guibert F, Graus F, Fleury A, Rene R, Honnorat J, Broet P, Delattre JY. Treatment of paraneoplastic neurological syndromes with antineuronal antibodies (anti-Hu, anti-Yo) with a combination of immunoglobulins, cyclophosphamide, and methylprednisolone. J Neurol Neurosurg Psychiatry. 2000;68:479–482. 64. Blaes F, Strittmatter M, Merkelbach S, Jost V, Klotz M, Schimrigk K, Hamann GF. Intravenous immunoglobulins in the therapy of paraneoplastic neurological disorders. J Neurol. 1999;246:299–303. 65. Uchuya M, Graus F, Vega F, Rene R, Delattre JY. Intravenous immunoglobulin treatment in paraneoplastic neurological syndromes with antineuronal autoantibodies. J Neurol Neurosurg Psychiatry. 1996;60:388–392. 66. Mowzoon N, Bradley WG. Successful immunosuppressant therapy of severe progressive cerebellar degeneration and sensory neuropathy: a case report. J Neurol Sci. 2000;178:63–65. 67. Oh SJ, Dropcho EJ, Claussen GC. Anti-Hu–associated paraneoplastic sensory neuropathy responding to early aggressive immunotherapy: report of two cases and review of literature. Muscle Nerve. 1997;20:1576–1582. 68. Coret F, Bosca I, Fratalia L, Perez-Griera J, Pascual A, Casanova B. Long-lasting remission after rituximab treatment in a case of anti-Hu–associated sensory neuronopathy and gastric pseudoobstruction. J Neurooncol. 2009;93:421–423. 69. van BF, de Graaf MT, Bromberg JE, Hooijkaas H, van den Bent MJ, de Beukelaar JW, Khan NA, Gratama JW, van der Geest JN, Frens M, Benner R, Sillevis Smitt PA. Human chorionic gonadotropin treatment of anti-Hu–associated paraneoplastic neurological syndromes. J Neurol Neurosurg Psychiatry. 2010;81:1341–1344. 70. Dyck PJ, Gutrecht JA, Bastron JA, Karnes WE, Dale AJ. Histologic and teased-fiber measurements of sural nerve in disorders of lower motor and primary sensory neurons. Mayo Clin Proc. 1968;43:81–123. 71. Sterman AB, Schaumburg HH, Asbury AK. The acute sensory neuronopathy syndrome: a distinct clinical entity. Ann Neurol. 1980;7:354–358. 72. Malinow K, Yannakakis GD, Glusman SM, Edlow DW, Griffin J, Pestronk A, Powell DL, Ramsey-Goldman R, Eidelman BH, Medsger TA Jr. Subacute sensory neuro­ nopathy secondary to dorsal root ganglionitis in primary Sjögren’s syndrome. Ann Neurol. 1986;20:535–537.

73. Grant IA, Hunder GG, Homburger HA, Dyck PJ. Peripheral neuropathy associated with sicca complex. Neurology. 1997;48:855–862. 74. Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, ­Alexander EL, Carsons SE, Daniels TE, Fox PC, Fox RI, Kassan SS, Pillemer SR, Talal N, Weisman MH. Classification criteria for Sjögren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis. 2002;61:554–558. 75. Ramos-Casals M, Solans R, Rosas J, Camps MT, Gil A, Del Pino-Montes J, Calvo-Alen J, Jimenez-Alonso J, Mico ML, Beltran J, Belenguer R, Pallares L. Primary Sjögren syndrome in Spain: clinical and immunologic expression in 1010 patients. Medicine (Baltimore). 2008;87:210–219. 76. Hansen A, Lipsky PE, Dorner T. Immunopathogenesis of primary Sjögren’s syndrome: implications for disease management and therapy. Curr Opin Rheumatol. 2005;17:558–565. 77. Thanou-Stavraki A, James JA. Primary Sjögren’s syndrome: current and prospective therapies. Semin Arthritis Rheum. 2008;37:273–292. 78. Chen WH, Yeh JH, Chiu HC. Plasmapheresis in the treatment of ataxic sensory neuropathy associated with Sjögren’s syndrome. Eur Neurol. 2001;45:270–274. 79. Takahashi Y, Takata T, Hoshino M, Sakurai M, Kanazawa I. Benefit of IVIG for long-standing ataxic sensory neuronopathy with Sjögren’s syndrome. Neurology. 2003;60:503–505. 80. Molina JA, Benito-Leon J, Bermejo F, Jimenez-Jimenez FJ, Olivan J. Intravenous immunoglobulin therapy in sensory neuropathy associated with Sjögren’s syndrome. J Neurol Neurosurg Psychiatry. 1996;60:699. 81. Pascual J, Cid C, Berciano J. High-dose i.v. immunoglobulin for peripheral neuropathy associated with Sjögren’s syndrome. Neurology. 1998;51:650b–6651. 82. Yamada S, Mori K, Matsuo K, Inukai A, Kawagashira Y, Sobue G. Interferon alfa treatment for Sjögren’s syndrome associated neuropathy. J Neurol Neurosurg Psychiatry. 2005;76:576–578. 83. Caroyer JM, Manto MU, Steinfeld SD. Severe sensory neuronopathy responsive to infliximab in primary Sjögren’s syndrome. Neurology. 2002;59:1113–1114. 84. Gorson KC, Natarajan N, Ropper AH, Weinstein R. Rituximab treatment in patients with IVIg-dependent immune polyneuropathy: a prospective pilot trial. Muscle Nerve. 2007;35:66–69. 85. Yuki N. Fisher syndrome and Bickerstaff brainstem encephalitis (Fisher-Bickerstaff syndrome). J Neuroimmunol. 2009;215:1–9. 86. Ito M, Kuwabara S, Odaka M, Misawa S, Koga M, Hirata K, Yuki N. Bickerstaff’s brainstem encephalitis and Fisher syndrome form a continuous spectrum: clinical analysis of 581 cases. J Neurol. 2008;255:674–682. 87. Willison HJ, O’Hanlon GM, Paterson G, Veitch J, Wilson G, Roberts M, Tang T, Vincent A. A somatically mutated human antiganglioside IgM antibody that induces experimental neuropathy in mice is encoded by the variable region heavy chain gene, V1-J Clin Invest. 1996;97:1155– 1164. 88. Liu JX, Willison HJ, Pedrosa-Domellof F. Immunolocalization of GQ1b and related gangliosides in human extraocular neuromuscular junctions and muscle spindles. Invest Ophthalmol Vis Sci. 2009;50:3226–3232.

288  Textbook of Peripheral Neuropathy 89. Kusunoki S, Chiba A, Kanazawa I. Anti-GQ1b IgG antibody is associated with ataxia as well as ophthalmoplegia. Muscle Nerve. 1999;22:1071–1074. 90. Overell JR, Hsieh ST, Odaka M, Yuki N, Willison HJ. Treatment for Fisher syndrome, Bickerstaff’s brainstem encephalitis and related disorders. Cochrane Database Syst Rev. 2007,CD004761. 91. Delmont E, Jeandel PY, Hubert AM, Marcq L, Boucraut J, Desnuelle C. Successful treatment with rituximab of one patient with CANOMAD neuropathy. J Neurol. 2010;257:655–657. 92. Antoine JC, Camdessanche JP. Peripheral nervous system involvement in patients with cancer. Lancet Neurol. 2007;6:75–86. 93. Quasthoff S, Hartung HP. Chemotherapy-induced peripheral neuropathy. J Neurol. 2002;249:9–17. 94. Hildebrandt G, Holler E, Woenkhaus M, Quarch G, Reichle A, Schalke B, Andreesen R. Acute deterioration of Charcot-Marie-Tooth disease IA (CMT IA) following 2 mg of vincristine chemotherapy. Ann Oncol. 2000;11:743–747. 95. Umapathi T, Chaudhry V. Toxic neuropathy. Curr Opin Neurol. 2005;18:574–580. 96. Pace A, Giannarelli D, Galie E, Savarese A, Carpano S, Della GM, Pozzi A, Silvani A, Gaviani P, Scaioli V, Jandolo B, Bove L, Cognetti F. Vitamin E neuroprotection for cisplatin neuropathy: a randomized, placebo-controlled trial. Neurology. 2010;74:762–766. 97. Dalton K, Dalton MJ. Characteristics of pyridoxine overdose neuropathy syndrome. Acta Neurol Scand. 1987;76:8–11. 98. Schaumburg H, Kaplan J, Windebank A, Vick N, Rasmus S, Pleasure D, Brown MJ. Sensory neuropathy from pyridoxine abuse. A new megavitamin syndrome. N Engl J Med. 1983;309:445–448. 99. Xu Y, Sladky JT, Brown MJ. Dose-dependent expression of neuronopathy after experimental pyridoxine intoxication. Neurology. 1989;39:1077–1083. 100. Albin RL, Albers JW, Greenberg HS, Townsend JB, Lynn RB, Burke JM Jr, Alessi AG. Acute sensory neuropathyneuronopathy from pyridoxine overdose. Neurology. 1987;37:1729–1732. 101. Chung JY, Choi JH, Hwang CY, Youn HY. Pyridoxine induced neuropathy by subcutaneous administration in dogs. J Vet Sci. 2008;9:127–131. 102. Delatycki MB, Williamson R, Forrest SM. Friedreich ataxia: an overview. J Med Genet. 2000;37:1–8. 103. Arnold P, Boulat O, Maire R, Kuntzer T. Expanding view of phenotype and oxidative stress in Friedreich’s ataxia patients with and without idebenone. Swiss Arch Neurol Neurosurg Psychiatry. 2006;157:169–176. 104. Schols L, Amoiridis G, Przuntek H, Frank G, Epplen JT, Epplen C. Friedreich’s ataxia. Revision of the phenotype according to molecular genetics. Brain. 1997;120:2131– 2140. 105. Hentati A, Deng HX, Hung WY, Nayer M, Ahmed MS, He X, Tim R, Stumpf DA, Siddique T, Ahmed. Human alphatocopherol transfer protein: gene structure and mutations in familial vitamin E deficiency. Ann Neurol. 1996;39:295– 300. 106. Mariotti C, Gellera C, Rimoldi M, Mineri R, Uziel G, Zorzi G, Pareyson D, Piccolo G, Gambi D, Piacentini S, Squitieri F, Capra R, Castellotti B, Di DS. Ataxia with isolated vitamin E deficiency: neurological phenotype, clinical

follow-up and novel mutations in TTPA gene in Italian families. Neurol Sci. 2004;25:130–137. 107. Doria-Lamba L, De GE, Cristiani E, Fiocchi I, Montaldi L, Grosso P, Gellera C. Efficacious vitamin E treatment in a child with ataxia with isolated vitamin E deficiency. Eur J Pediatr. 2006;165:494–495. 108. Peretti N, Sassolas A, Roy CC, Deslandres C, Charcosset M, Castagnetti J, Pugnet-Chardon L, Moulin P, Labarge S, Bouthillier L, Lachaux A, Levy E. Guidelines for the diagnosis and management of chylomicron retention disease based on a review of the literature and the experience of two centers. Orphanet J Rare Dis. 2010;5:24. 109. McHugh JC, Lonergan R, Howley R, O’Rourke K, Taylor RW, Farrell M, Hutchinson M, Connolly S. Sensory ataxic neuropathy dysarthria and ophthalmoparesis (SANDO) in a sibling pair with a homozygous p.A467T POLG mutation. Muscle Nerve. 2010;41:265–269. 110. Van GG, Luoma P, Rantamaki M, Al MA, Kaakkola S, Hackman P, Krahe R, Lofgren A, Martin JJ, De JP, Suomalainen A, Udd B, Van BC. POLG mutations in neurodegenerative disorders with ataxia but no muscle involvement. Neurology. 2004;63:1251–1257. 111. Vucic S, Tian D, Chong PS, Cudkowicz ME, Hedley-Whyte ET, Cros D. Facial onset sensory and motor neuronopathy (FOSMN syndrome): a novel syndrome in neurology. Brain. 2006;129:12–90. 112. Camdessanché JP, Belzil VV, Jousserand G, Rouleau GA, Créac’h C, Convers P, Antoine JC. Sensory and motor neuronopathy in a patient with the A382P TDP-43 mutation. Orphanet J Rare Dis. 2011;6:4. 113. O’donnell JA, Emery CL. Neurosyphilis: a current review. Curr Infect Dis Rep. 2005;7:277–284. 114. Logina I, Donaghy M. Diphtheritic polyneuropathy: a clinical study and comparison with Guillain-Barre syndrome. J Neurol Neurosurg Psychiatry. 1999;67:433–438. 115. Harrington WJ Jr, Sheremata W, Hjelle B, Dube DK, Bradshaw P, Foung SK, Snodgrass S, Toedter G, Cabral L, Poiesz B. Spastic ataxia associated with human T-cell lymphotropic virus type II infection. Ann Neurol. 1993;33: 411–414. 116. Sheremata WA, Harrington WJ Jr, Bradshaw PA, Foung SK, Raffanti SP, Berger JR, Snodgrass S, Resnick L, Poiesz BJ. Association of ‘(tropical) ataxic neuropathy’ with HTLV-II. Virus Res. 1993;29:71–77. 117. Oluwole OS, Onabolu AO, Link H, Rosling H. Persistence of tropical ataxic neuropathy in a Nigerian community. J Neurol Neurosurg Psychiatry. 2000;69:96–101. 118. Joint Task Force of the EFNS and the PNS. European Federation of Neurological Societies/Peripheral Nerve Society Guideline on management of paraproteinemic demyelinating neuropathies. Report of a Joint Task Force of the European Federation of Neurological Societies and the Peripheral Nerve Society—first revision. J Peripher Nerv Syst. 2010;15:185–195. 119. Van den Bergh PY, Hadden RD, Bouche P, Cornblath DR, Hahn A, Illa I, Koski CL, Leger JM, Nobile-Orazio E, Pollard J, Sommer C, van Doorn PA, van Schaik IN. European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society—first revision. Eur J Neurol. 2010;17:356–363.

Elias Abou-Zeid and Peter D. Donofrio

21

Porphyric Neuropathies Introduction

40- to 50-fold; this increases the incorporation of intra­ cellular heme into hepatic cytochromes, leading to depletion in the reserve of heme. As the heme concentration decreases, the first step in porphyrin metabolism, which is also the rate-limiting step, is disinhibited, and the porphyrin metabolic pathway is activated. Patients with porphyria who have a partial deficiency in one of the enzymes of the heme biosynthesis pathway accumulate certain heme precursors upstream to the enzymatic defect. The specific enzyme deficiency predicts which heme precursors accumulate excessively in tissues and body fluids or become excreted in the urine and feces where they undergo oxidation into dark red–pigmented porphyrins. Some of these heme precursors may be neurotoxic when present in excess amounts, producing several clinical symptoms including neuropathy, which is the focus of this chapter.

Porphyria derives from the Greek word porphyrus or porphura, which means red or purple. It is believed that this term is borrowed from the Phoenicians, who extracted the purple pigment from purpura mollusks to dye the garments of their royal family (1). The name is likely to describe the purple discoloration of feces and urine in patients during an attack (1). This urine discoloration occurs after the colorless freshly voided urine is exposed to the air and ambient light. The oxygen present in the air oxidizes the porphyrin precursors to pigmented porphyrins turning the urine red or purple, characterizing certain types of porphyria (2). This reaction helped clinicians to diagnose porphyria in an era when metabolic and genetic testing was not available. Porphyria is the result of impaired porphyrinogen formation or impaired heme biosynthesis and occurs only rarely from excess porphyrin production (3). It is a group of 8 diseases caused by defects in heme biosynthesis. The heme biosynthesis pathway contains 8 steps, and dysfunction in each of those steps is associated with a specific porphyria. Seven porphyrias are the result of a partial enzyme deficiency. Recently, a new form of porphyria due to a gain of function mechanism has been characterized (3). Heme is synthesized in every eukaryotic and prokaryotic cell and carries out many important functions. The liver produces approximately 15% of the body’s heme; the bone marrow produces the remainder. In the red blood cells and the muscles, heme is incorporated in the hemoglobin and myoglobin, respectively, where it binds and transports oxygen to different tissues, which is essential for aerobic metabolism. In the liver, heme is involved mainly in the mitochondrial respiratory chain, where it transports electrons to cytochromes (4). Besides its role in oxygen transportation and cytochrome formation, heme plays a role in some enzyme activity like tryptophan pyrrolase, which catalyses the oxidation of tryptophan. The heme-containing microsomal cytochrome P450 is of utmost importance in the metabolism of many drugs as well as several endogenous and exogenous substances that can precipitate an acute attack of porphyria. Cytochrome inducers like barbiturates increase the synthesis activity of hepatic cytochrome as much as

Historical Overview Stokvis (5) reported the first case of porphyria in 1889, and Campbell (6) described its pathology in 1898. Shortly thereafter, Dobrschansky (7) recognized that barbiturates could produce attacks of porphyria in susceptible individuals. In 1937, Waldenström (8) described more than 100 patients with acute porphyria, most of them from a small village in Northern Sweden. Waldenström was able for the first time to diagnose some of the patient’s family members with predisposition for porphyria. He treated the urine of patients known to have porphyria and their relatives with Ehrlich reagent (p-dimethylaminobenzaldehyde), causing it to turn red in the presence of excess porphyrin precursors. Later, he proposed that porphyrias could result from enzyme defects in the heme pathway and was also the first to use the term acute intermittent porphyria (AIP), calling this disease a little imitator in distinction to the more common manifestations of neurosyphilis. A screening test for porphobilinogen (PBG) was introduced in 1941 by Watson, who also was Fischer’s coworker (9). He also introduced hematin for treatment of acute porphyrias in 1978 (10). Porphyria also has been related to vampire and werewolf myths (11); it was suggested as the cause of the episodic insanity of King George III evident in the regency 289

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crisis of 1788. The first suggestion of this theory came in 1966, in a paper titled “The Insanity of King George III: A Classic Case of Porphyria” by MacAlpine and Hunter (12) with a follow-up in 1968, “Porphyria in the Royal Houses of Stuart, Hanover and Prussia” (13). However, this theory has been challenged; in 2010, an exhaustive analysis of historical records revealed that the porphyria claim was based on selective interpretation of contemporary medical and historical sources (14). While the accumulation of porphyrins is usually caused by a genetic mutation, toxins (such as alcohol excess) and environmental contaminants can also cause the disease. The most notorious environmental episode happened in Turkey in the 1950s, when 4000 people developed a form of porphyria after eating wheat seeds that had been sprayed with a fungicide, hexachlorobenzene (15). Hundreds died; subsequently, the use of the fungicide was banned around the world.

A to glycine to form 5-aminolevulinic acid (ALA). Biosynthesis of 1 heme molecule requires 8 molecules of glycine and succinyl coenzyme A. Pyridoxine (pyridoxal 5’-phosphate) is an important cofactor for this reaction, and a deficiency can inhibit ALAS. This reaction is the rate-limiting step in heme formation. There are 2 isoforms of the ALAS enzyme. Aminolevulinic acid synthase 1 is coded by a gene on chromosome 3, is ubiquitous, and is found mainly in the liver. Amino­ levulinic acid synthase 2 is coded by a gene on chromosome X and is specific to the erythropoietic cells; its synthesis rate is limited by iron availability and is not inhibited by heme (16). Genetic defects of the ALAS2 gene resulting in enzymatic loss of function cause X-linked sideroblastic anemia without porphyria. Recently, genetic mutations of the ALAS2 gene causing enzymatic increase in function have been shown to result in a clinical presentation very similar to that of erythropoietic protoporphyria, without ferrochelatase deficiency. This new porphyria is called X-linked dominant erythropoietic protoporphyria (17). 5-Aminolevulinic acid is transported next to the cytosol (Figure 21.1), where 2 molecules of ALA are condensed to form the basic monopyrrole ring, PBG, a reaction that is catalyzed by aminolevulinic acid dehydratase (ALAD). Next, 4 pyrrole rings are assembled by PBG deaminase (PBG-D) in a stepwise fashion, resulting in a highly unstable hydroxymethylbilane. Uroporphyrinogen III synthase rapidly closes the linear tetrapyrrole chain of the highly unstable hydroxymethylbilane

Porphyrin Metabolism Heme is synthesized in every human cell, but it is primarily produced in the erythropoietic cells for hemoglobin synthesis and the liver parenchymal cells for synthesis of cytochromes and hemoproteins. The biosynthesis pathway is illustrated in Figure 21.1. The first enzyme and the last 3 in the pathway are localized in the mitochondria; the 4 intermediate enzymes are cytosolic. In the mitochondria, aminolevulinic acid synthase (ALAS) catalyzes the combination of succinyl coenzyme

X-linked dominant protoporphyria

Mitochondria

Cytosol ALA dehydrates porphyria

Succinyl CoA

ALAS2

+

ALA

PBG

ALAD

ALAS1

Glycine

PBGD

Erythropoietic protoporphyria

FECH

Protoporphyrin IX PPOX

Acute intermittent porphyria

Hyroxymethylbilane

Congenital erythropoietic porphyria

Spontaneous cyclisation

Fe2+

UROIIIS

Variegata porphyria

Uroporphyrinogen III

Uroporphyrinogen I UROD

Protoporphyrinogen IX

Porphyria cutanea tarda

CPO Coproporphyrinogen III

Hereditary coproporphyria

Coproporphyrinogen I

Figure 21.1 Haeme biosynthetic pathway and porphyrias Green boxes=hepatic porphyrias. Red boxes=erythropoietic porphyrias. ALA=5-aminolaevulinic acid. PBG=porphobilinogen. I, III, or IX=type isomers. ALAS=ALA-synthase. ALAD=ALAdehydratase. PBGD=porphobilinogen deaminase. UROIIIS=uroporphyrinogen III synthase. UROD=uroporphyrinogen decarboxylase. CPO=coproporphyrinogen oxidase. PPOX=protoporphyrinogen oxidase. FECH=ferrochelatase. Fe2+=ferrous iron.

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to form the initial tetrapyrrole ring. In the absence of uroporphyrinogen III synthase, hydroxymethylbilane may also be nonenzymatically closed to form uroporphyrinogen I, which is normally excreted in only minute amounts. The carboxylic groups of the uroporphyrinogen are removed by uroporphyrinogen decarboxylase, in the cytosol leading to the formation of coproporphyrinogen. Coproporphyrinogen III results from the decarboxylation of uroporphyrinogen III, and coproporphyrinogen I results from the decarboxylation of uroporphyrinogen I. Coproporphyrinogen is then transported to the mitochondria where, in the presence of, oxygen coproporphyrinogen oxidase (CPOX) catalyzes the removal of the carboxyl group and the 2 hydrogens from the coproporphyrinogen and forms vinyl groups at these positions, resulting in protoporphyrinogen IX. In the seventh step of heme biosynthesis, 6 hydrogen atoms are removed from protoporphyrinogen IX to form protoporphyrin IX, a reaction catalyzed by

ALAS2

ALAD

Gain of function X EPP Deficiency

ADP

Deficiency PBGD

AIP Deficiency

UROIIIS

CEP Deficiency PCT

UROD Deficiency

HC

CPOX Deficiency PPOX Ferrochelatase

VP Deficiency

EPP

Figure 21.2 Enzyme dysfunction in porphyria; ALAS2: aminolevulinic acid synthase 2, ALAD: aminolevulinic acid dehydratase, PBGD: porphobilinogen deaminase, UROIIIS: Uroporphyrinogen III synthase, UROD: uroporphyrinogen decarboxylase, CPOX: coproporphyrinogen oxidase, PPOX: protoporphyrinogen oxidase, X EPP: X-linked dominant erythropoietic protoporphyria, ADP: aminolevulinatedehydratase deficiency porphyria, CEP: congenital erythropoietic porphyria, AIP: acute intermittent porphyria, PCT: porphyria cutanea tarda, HC: hereditary coproporphyria, VP: variegate porphyria, EPP: erythropoietic protoporphyria.

protoporphyrinogen oxidase (PPOX). The oxidation of protoporphyrinogen may also occur nonenzymatically. Finally, iron (Fe2+) is incorporated into protoporphyrin IX by a mitochondrial ferrochelatase, also known as heme synthase, to form a heme molecule (Figure 21.1). The different types of enzyme abnormality corresponding to the differrnt types of porphyria are summarized in Figure 21.2.

Classification and Clinical Features Commonly, the different forms of porphyria are divided into erythropoietic and hepatic (4). This classification takes in consideration the tissue that is preferentially affected or where the metabolic defect occurs. The erythropoietic porphyrias affect mainly red blood cell production; they include erythropoietic protoporphyria, congenital erythropoietic porphyria, and X-linked erythropoietic protoporphyria. This group of porphyrias will not be discussed in this chapter because their clinical symptoms are primarily restricted to skin sensitivity without neurologic disorders. Hepatic porphyrias are a group of 5 porphyrias that includes ALAD deficiency porphyria (ADP) or Doss porphyria, AIP, hereditary coproporphyria (HC), variegate porphyria (VP), and porphyria cutanea tarda (PCT). In this group, the enzyme deficiency occurs in the liver. All of the hepatic porphyrias may cause neuropathy and neuropsychiatric manifestations except PCT. So the focus of this chapter will be on 4 types of porphyria: ADP, AIP, VP, and HC. 1. Aminolaevulinate Dehydratase Deficiency Porphyria Aminolevulinic acid dehydratase deficiency porphyria was first reported in Germany in 1979 (18). This is the only form of porphyria that is not transmitted following an autosomal dominant trait. Only 6 cases of this rare disorder confirmed by immunologic and molecular analyses have been reported (18–21). The symptoms in this disease are similar to those seen in AIP. The clinical spectrum is variable, ranging from acute neurovisceral attacks in young adulthood to the onset of a mild, predominantly motor polyneuropathy at the age of 63 years. The only child with ADP reported was a 3-yearold boy who had profound neonatal hypotonia followed by intermittent episodes of anorexia, recurrent attacks of pain, vomiting, hyponatremia, and symptoms of polyneuropathy affecting motor functions including respiration, leading to death (21). Aminolevulinic acid dehydratase deficiency porphyria can be differentiated from AIP by its autosomal recessive inheritance, by the lack of PBG overproduction, and by the markedly decreased ALAD activity. Biochemical abnormalities in the 6 cases were similar; erythrocytic ALAD activity was decreased by 88% to 98%. There is little information about effective treatment. Acute episodes should be managed like other acute porphyrias. Carbohydrate loading and hematin therapies

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have been helpful in some but not all cases; liver transplantation has little effect on the symptoms or biochemical profile, suggesting irreversible neural damage. 2. Acute Intermittent Porphyria Acute intermittent porphyria is caused by a partial deficiency of PBG-D, which is the third enzyme in the heme metabolism pathway. Acute intermittent porphyria is the most common type of acute porphyria in most countries except South Africa, where the prevalence of VP is higher. The prevalence of AIP is estimated to be of the order of 1 in 10 000 to 1 in 100 000 in the white population. In European countries, it affects approximately 75 000 people. In the United States, its prevalence is estimated to be around 5 to 10 in 100 000 (22). The highest prevalence of AIP has been described in northern Sweden, where it is around 100 in 100 000 (23). In a study in Finland and France, the prevalence of low PBG-D activity was approximately 1 in 500. Clinical expression of AIP is highly variable; 50% to 90% of heterozygote patients who are genetically predisposed to a porphyric attack remain asymptomatic throughout life. Most of the patients exhibit only mild clinical symptoms (24). Porphyric attacks are extremely rare before puberty. In most cases, the first attack manifests between 15 and 40 years of age (25). Some patients may have continuous symptoms, but most symptomatic patients have welldefined attacks with relatively asymptomatic intervening remissions. Many environmental, endogenous, and exogenous factors have been implicated in precipitating an acute attack of porphyria. Stress, alcohol, starvation, infection, drugs such as barbiturates, and changes in hormonal state are the main culprits (24). During an attack, most symptoms like abdominal pain, constipation, diarrhea, elevated temperature, tachycardia, seizure, mental status changes, and weakness are related to the associated neurologic dysfunction. Abdominal pain mimicking acute surgical abdomen and dark or red urine are seen in approximately 90% of patients. Vomiting is also common and is found in around 60% of patients. Constipation is 6 times more common than diarrhea (23). Other symptoms like fever and diarrhea are highly variable. Hepatocellular carcinoma is reported to be 61 to 114 times higher in patients with AIP (24,26), and it is the cause of death in about 25% of these patients (27). Chronic hypertension has been shown to be more prevalent in patients who manifest AIP than in those with latent AIP or in healthy controls. Hypertension prevalence is estimated to be around 56% in one large Swedish AIP family study. Despite higher blood pressure, however, cardiovascular mortality was not higher among patients with AIP (24,26). The prevalence of chronic renal failure is considered higher among patients with AIP (24,26). 3. Variegate Porphyria Variegate porphyria is characterized by deficiency in protoporphyrinogen oxidase (PPOX). Variegate porphyria has been more recognized since Dean and Barnes (28) reported a study on patients and families in South

Africa suffering with this type of porphyria. In this study, the term variegate porphyria was proposed to emphasize the variety of symptoms that patients with this type of disorder may have. Variegate porphyria is common among the white population in South Africa. It is estimated that at least 10 000 residents of South Africa are affected with VP, with an incidence of approximately 1 in 300. Affected individuals in South Africa are thought to be descendants of Jan Gerrit van Deventer, a burgher of the Cape, and Ariaantje Adriaansse, a Dutch orphan, whose marriage took place at the Cape in 1688. Clinically, VP causes acute attacks that are indistinguishable from AIP, but unlike AIP, VP can also cause cutaneous symptoms, which explains why VP is referred to as a neurocutaneous porphyria. As in AIP, the clinical course of the acute attacks may be chronic or acute and deadly in 10% of the cases (29). It can also be self limiting or progressive. As in AIP, endogenous or exogenous factors like alcohol ingestion, starvation or dieting, infection, drugs, and hormones can precipitate an attack. The cutaneous symptoms seen in patients with VP are very similar to those seen in PCT and are also due to due porphyrins deposition in the skin. One study from South Africa was conducted on 24 patients (14 with AIP and 10 with VP) with 112 consecutive acute porphyric attacks (30). Patients with VP were significantly older and demonstrated equal sex ratio, while the male-female ratio in patients with AIP was 2:12. In addition, patients with AIP were at higher risk for an acute attack, with a relative risk of 14.3. However, no significant difference in the frequency of serious complications or in outcome could be shown. Interestingly, drug exposure was a frequent precipitant of the acute attack in VP, whereas hormonal factors were more important in AIP. Mean urine precursor levels, blood pressure, pulse rate, and heme arginate therapy requirement were all significantly higher in patients with AIP. 4. Hereditary Coproporphyria The term hereditary coproporphyria was used first by Berger and Goldberg (31) in 1955 when they reported 4 patients who excreted large quantities of coproporphyrin in feces and urine. Similar cases had been reported previously in 1928, 1936, and 1949. It was 40 years from the recognition of HC as a distinct disorder to the discovery of the CPOX genetic and enzymatic defect responsible for this disease. Like AIP, women are more commonly affected. This autosomal dominant porphyria is less frequent than AIP and VP. Less than 30% of genetically predisposed patients experience an acute attack (32). Like VP, HC can cause cutaneous symptoms in addition to acute porphyric attack that are identical in semiology to AIP. The cutaneous photosensitivity usually occurs in the setting of jaundice during an acute attack, so it has been postulated, but not established, that these phenomena occur in conjunction with the inhibitory effect of bilirubin on CPOX (33). During an acute attack, the most common symptom is abdominal pain (80%),

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and jaundice at birth that is associated with accumulation of harderoporphyrin in feces (39). Skin lesions can sometimes be seen, but neurologic symptoms have not been described. During childhood and adulthood, a mild chronic residual anemia is observed (38,39).

General Clinical Features and Presentation

Figure 21.3 Photograph taken during an acute episode of quadriparesis, respiratory failure, and photodistribution skin lesions. The skin lesions were characterized by mechanical fragility, multiple blisters and bullae, and rupture of bullae into open sores. The patient had biochemical evidence of coproporphyria, although a diagnosis of VP could not be completely excluded. Reprinted from Albers Oxford University Press (2).

followed by vomiting (40%) and muscle weakness, neuro­ psychiatric disorders, and constipation (around 30% each). Skin lesions are less common, with a frequency of around 25%. Seizures, hypertension, jaundice, tachycardia, and diarrhea occur in less than 20% (34,35). Even though the acute attack of HC is indistinguishable from that of AIP, HC is a milder disease than AIP. However, HC attacks can be severe and life threatening owing to respiratory muscle paralysis (34–36). 5. Rare Recessive Acute Hepatic Porphyrias All dominant forms of hepatic porphyria have recessive variants. Those are rare and manifest in infancy or early childhood. Orange discoloration of the urine suggests the diagnosis. This group includes ADP, AIP, VP, and HC. Homozygote AIP has been diagnosed in only 5 patients (37). Even though the clinical picture varies, patients are usually severely affected. They do not exhibit the typical attacks seen in dominant AIP. Homozygote VP was first described by Kordac in 1984 in 2 siblings. Approximately 15 cases have been reported so far. Clinically, patients have cutaneous lesions and skeletal abnormalities of the hand, clinodactyly and flexion deformities of the fingers. Patients with homozygote VP have a CPOX activity of less than 20% of normal, yet none of these patients had an acute attack. Homozygote HC (HCP) is caused by biallelic mutations of the CPO gene. It results in 2 different phenotypes depending on the location of the mutations (38,39). In one type, patients have developmental as well as psychomotor retardation, skeletal abnormalities, and skin photosensitivity. In the other type, called harderoporphyria, patients present with hemolytic anemia

Although the porphyrias can be a source of confusion for clinicians, this condition is readily recognized when presenting during an acute attack with the classic triad of abdominal pain, psychosis, and neuropathy. However, in practice, porphyric attacks are rarely typical, and only rarely is the correct diagnosis made early in the course of the illness. The acute hepatic porphyrias, with the exception of PCT, exhibit similar systemic and neurologic involvement as prominent features. The primary difference between the 3 disorders is the presence of skin lesions among patients with HC and VP but not those with AIP. The skin lesions are related to deposition of photosensitive porphyrins in the skin, producing bullae (Figure 21.3), increased fragility, and hypertrichosis (Figure 21.4) (2,40). Skin lesions may be the only clinical manifestation in some patients with VP (60% of patients) and occur rarely (5%) in patients with HC (41). Most attacks of porphyria follow a predictive course. Attacks typically begin with abdominal pain or a prodromal phase of mild behavioral changes that include anxiety, restlessness, and insomnia (42,43). Most the patients have gastrointestinal symptoms such as abdominal pain, nausea, vomiting, constipation and, occasionally, diarrhea. The abdominal pain is usually severe and poorly localized, and the presentation is dramatic, sometimes leading to unnecessary exploratory

Figure 21.4 Hypertrichosis, is one of the signs of cutaneous hepatic and hepatoerythropoietic porphyrias Cutaneous symptoms in VP, hereditary coproporphyria, and porphyria cutanea tarda. Reprinted with permission from Puy H et al. (41).

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surgery. Abdominal imaging shows only mild ileus in most cases. In face of unexplained abdominal pain, it is not uncommon for patients with a porphyric attack to be diagnosed with conversion or somatization disorder, especially when psychiatric features are part of the clinical picture. Mental status and psychiatric manifestations develop in approximately 20% to 30% of patients. They are nonspecific and include varying degrees of neurotic or hysterical behaviors like depression, disorientation, delirium, hallucination, and occasionally coma (43). Generalized tonic-clonic or partial complex seizures are common during an acute attack; they can be due to hyponatremia or hypomagnesemia or simply might be a manifestation of porphyria. Pyramidal signs are very rare. Transient and permanent nonspecific brain MRI abnormalities have rarely been described. The most common focal deficit is cortical blindness secondary to occipital lobe infarction (44). Cerebellar syndrome and posterior reversible leukoencephalopathy have also been described in acute porphyria (45,46). In the same series, pain, cramps, and myalgia were prominent in 17 patients, in 5 of whom muscular pain was the first symptom of motor involvement. Depending on the pattern of nerve involvement, focal or generalized rapidly progressive muscle wasting without fasciculation was seen in two thirds of patients. In one series, the deep tendon reflexes were absent or diminished in more than 90% of cases, of which 40% had total areflexia. In about 40% of these patients, the ankle jerks were normal despite loss or diminution of all of the other reflexes (43). Complete or partial cranial neuropathy is a common finding in acute attacks of porphyria. Ridley (43) reported that 19 of 29 attacks in 24 patients with porphyria had accompanying cranial neuropathies. The 2 most commonly affected nerves were the 10th and the 7th. The 5th, 11th, and 12th cranial neuropathies were seen less often. Acute attacks are rare before puberty and after menopause, with a peak occurrence within the third decade. They are more common in women than in men probably because hormone levels affect heme metabolism, and progesterone, estrogen, and testosterone all activate ALAS (47). Attacks may be precipitated by many factors, the most important being medications and starvation because glucose inhibits ALAS. Most patients have one or a few attacks and then recover. Less than 10% develop recurrent acute attacks.

Neuropathy In 1937, Waldenström (8) reported multiple neurologic symptoms in 60 of 143 cases of AIP. Based on information derived from patients diagnosed with porphyria (presumably because of porphyric attacks), approximately 10% to 40% develop neuropathy (48). Many forms of neuropathy have been reported in porphyric patients. They include pure motor, pure sen-

sory, sensorimotor, small fiber, and autonomic neuropathy, which can be isolated or in combination with the other forms of neuropathy (49). Albers (48) described the different forms of neuropathy seen in porphyric patients in an article published in 1978. Of the 524 cases with a tentative diagnosis of porphyria reviewed, 115 patients had AIP, and 193 had PCT. The remaining 216 patients had unclassified porphyria or suspected porphyria without laboratory confirmation. Four patients with PCT (2%) had mild sensory neuropathy. Twenty patients with AIP (17%) had polyneuropathy: 3 sensory, 12 motor, and 5 sensorimotor. a. Sensory symptoms are not uncommon during an acute porphyric attack. They can be present with or without evidence of sensory loss. Early reports on porphyric neuropathy by Garcin and Lapresle stated that sensory loss is rare, discrete, and always transitory (43). Later Goldberg reported sensory involvement in 19 of his 50 cases. Ridley in 1969 reported sensory loss or impairment in approximately 70% of patients with acute porphyria. Half of those patients had a distal “stocking and glove” type, and the rest had more proximal sensory impairment, affecting the proximal parts of the limbs and trunk, sometimes in a “bathing trunks” distribution. Sensory recovery is usually faster than the weakness. The sensory defect lasts in most cases for several days. In some cases, sensory function recovery can be delayed for several weeks, and only occasionally, it persists for years. b. Porphyric neuropathy usually presents with  a  combined autonomic neuropathy and peripheral neuropa­ thy. Many features of an acute attack are suggestive of, or can be explained by, autonomic neuropathy. These include sinus tachycardia, atrial fibrillation, atrial flutter, excessive sweating, episodic diaphoresis, fever, labile hypertension, postural hypotension, severe vomiting, sphincteric disturbance, constipation, and occasional diarrhea (50). Ridley (43) noted that tachycardia invariably preceded the development of peripheral neuropathy and respiratory paralysis. Moreover, Ridley explained the transient and labile hypertension by damage to the vagal nerves. Goldberg has proposed that the pain, constipation, vomiting, and occasionally, diarrhea during the acute attacks of porphyria have a neurogenic basis. Experts agree that the decreased gastric motility, intestinal atonia and dilatation, pseudoobstruction, and constipation are due to a metabolic autonomic dysfunction affecting the myenteric plexus (51). However, the cause of abdominal symptoms is still controversial (52–54).  Sphincteric dysfunction likely represents an autonomic dysfunction. Ridley found vesical and/ or rectal sphincteric disturbances in more than 50% of the attacks. Using the Valsalva maneuver, heart rate response to standing, heart rate variation during deep breathing, postural drop in blood pressure, and sustained hand grip tests, Laiwah et al (55) demon-

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strated parasympathetic and sympathetic cardiac autonomic impairment in porphyric patients during an acute attack. c. Peripheral neuropathy in porphyria is primary motor and characterized by weakness as well as hyporeflexia or areflexia. It can be severe and life threatening owing to respiratory failure, which is caused by paralysis of the respiratory muscles. The neuropathy can be acute and can present as early as 2 to 3 days after the onset of symptoms. However, in most cases, the onset of the neuropathy is usually delayed. Several series reported the lag of peripheral neuropathy symptoms. They usually begin after the onset of the abdominal pain, the psychiatric disorders, and other central nervous system (CNS) manifestations. In one series, neuropathy was delayed up to 2 1/2 months after the abdominal pain began (43). In this series, only 2 of the 25 patients had developed a neuropathy after the beginning of the attack. In another series, 80% of the porphyric neuropathies were evident within a month of the onset of abdominal pain (40). In rare cases, neuropathy can be chronic and progressing slowly over a period of 2 to 3 months. In many patients, the neuropathy does not achieve maximum severity for 1 to 4 weeks. Most of the patients reached maximum deficit at 2 weeks in one series and 1 month in another (43). Patients should be observed carefully during the course of their neuropathy because of the increased risk of respiratory failure. The weakness in acute porphyric attack is most commonly proximal and progressive, but it can manifest in other distributions. i. The predominant distal symmetric involvement commonly seen in peripheral polyneuropathies is uncommon in porphyric neuropathy. Usually, proximal involvement of the upper extremities is more frequent and more severe than distal and lower extremity involvement as described by Ridley (43). About half of the patients have weakness that starts in the upper extremities; most of these patients have a more severe proximal weakness (43). One third of the patients have lower extremity weakness onset, and 15% develop weakness simultaneously in the arms and legs. Asymmetric weakness is also common, and antigravity muscles, which have high metabolic demand, are more prone to paralysis. This unusual distribution of weakness is possibly due to a disturbance of neuronal function, causing acute and severe “dying back” axonal degeneration that is greater in the neuron with higher metabolic requirement. Acute quadriparesis has been frequently reported in acute porphyric attacks. Albers reported this type of weakness in 11 of the 12 patients with motor neuropathy; Sorenson (56) reported similar findings in 41 of 95 patients, and Flügel and Druschky (57) described tetraplegia in 6 of their 16 patients with AIP.

ii. The weakness in porphyric neuropathy is not always proximal. An ascending paralysis due to porphyria has been described by many experts (43). However, this is the exception rather than the rule as mentioned by Waldenström (8). When a patient with a history of gastrointestinal illness presents with an acute-onset ascending motor neuropathy, areflexia, and respiratory insufficiency, he can easily be misdiagnosed with Guillain-Barré syndrome (GBS) especially when cerebrospinal fluid (CSF) laboratory analysis  showed albuminocytologic dissociation. Because of these striking similarities between porphyric neuropathy and GBS, some clinicians believe that many patients diagnosed with GBS actually have porphyric neuropathy. The diagnosis of porphyric neuropathy may not be considered until the second attack, because recurrent GBS is uncommon. Urine porphyrins are examined routinely in clinical studies of inflammatory neuropathy to rule out porphyria (56). None of the 450 patients screened for the North American study of plasmapheresis and acute GBS was excluded because of porphyria (58), thus demonstrating the rarity of porphyria. None of the 11 patients with recurrent GBS in a study published in 2004 was found to be positive for porphyria (59). iii. Isolated palsies of the finger or wrist extensors in porphyria have been reported by Waldenström (8) and Garcin and Lapresle. Garcin and Lapresle were the first to draw attention to the close similarity between such cases and lead poisoning. Both disorders cause abdominal pain, constipation, tachycardia, hypertension, limb paralysis, and encephalopathy (60). In addition the neuropathy in both disorders is acute, involves motor nerve fibers more than sensory fibers, shows a multifocal distribution, affects the arms preferentially, and is bilateral but not necessarily symmetric. Lead neuropathy shows a predilection for the extensor muscles and distal parts of the limbs; plumbism, however, causes more proximal weakness (43). In both disorders there is a disturbance of porphyrin metabolism with greatly increased excretion of 5-aminolaevulic acid in the urine. Acute lead intoxication may interrupt later stages of porphyrin metabolism, particularly the formation of PBG (61). The increased urinary excretion of ALA and coproporphyrin in lead poisoning is thought to be due to ALAD inhibition (4). This disruption of heme synthesis is believed to contribute to the different symptoms, including neuropathy seen with lead toxicity (62). It is possible that lead intoxication only precipitates porphyric neuropathy in susceptible individuals; it is also possible that the biochemistry of lead neuropathy is very similar to porphyric neuropathy. d. In addition to the large fiber polyneuropathy commonly described in porphyric patients, the small

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fibers may be affected. In 2007, Hsieh (63) reported a 60-year-old man with quadriplegia and respiratory failure secondary to a severe acute attack of AIP whose skin biopsy from the lower extremity showed small fiber neuropathy. Moreover, 3 consecutive skin biopsies of the distal lower limb were taken, and they demonstrated some correlation between the progression of the patient’s clinical condition and the severity of the small fiber neuropathy. e. Other than the motor, autonomic, small fiber, and sensory fibers affected by porphyria, the spinocere­ bellar and gamma efferent fibers to muscle spindles may also be affected. This type of neuropathy may explain the tremor and ataxia in some cases in the early stages of the neuropathy (43). The prognosis after an attack of acute hepatic porphyric is generally good. In Ridley’s (43) series, recovery was complete in 85% of cases and incomplete in 15% in one series. The resolution of the gastrointestinal symptoms, the autonomic dysfunction, and the CNS manifestations is rapid once the attack abates. The resolution of the motor and sensory neuropathy is usually slower. The recovery depends on the severity of axonal degeneration. Recovery usually occurs over many months and sometimes years, distal muscles being slower to recover. In one series, the shortest time for complete paralysis of proximal muscles to recover was 6 months compared to 1 year for a distal  muscle. After recurrent attacks, the defi­cits  from the neuropathy accumulate, leading to slower and incomplete nerve regeneration. Long-term prognosis depends on a rapid diagnosis and treatment of an acute attack as well as preventing recurrent attacks.

Electrophysiologic Findings Electrophysiologic evidence shows that porphyria is primary an axonal motor neuropathy. On nerve conduction studies (NCSs), there is reduced compound muscle action potential (CMAP) and borderline-reduced conduction velocity. The needle electromyography (EMG) shows abnormal spontaneous activity and reduced recruitment. In later phases, prolonged polyphasic and high-amplitude motor units may also be seen. Only a few papers studying the electrophysiologic findings in patients with porphyria have been reported. Even though most of the studies are reported on patients with AIP, there is no evidence that other types of hepatic porphyrias differ in the types of neuropathy they produce; the variable electrodiagnostic findings in patients with AIP have been attributed to the timing of the studies at different stages of the acute porphyric attack (57,64). The electrodiagnostic findings of porphyric neuropathy are not unique to its condition. Yet the results of NCS and EMG are important in differentiating patients with porphyria from other disorders causing an acute or subacute motor neuropathy, most commonly GBS. In most instances, the diagnosis of porphyria may not

be considered until the electrodiagnostic results appear atypical for GBS and suggest another diagnosis. Ridley in 1969 and Maytham and Eales (64) in 1971 reported acute denervation and a reduced recruitment pattern in weak muscles of patients with acute porphyric attacks. Later, Flügel and Druschky in 1977 (57) reported low-amplitude or absent motor nerve responses on NCSs in patients studied during the acute attack; they also recorded abnormal spontaneous activity on the EMG, suggesting an axonal loss rather than demyelinating etiology. Shortly thereafter, Albers (48) in 1978 reported a retrospective study on 115 patients with AIP. Only 12 had motor neuropathy, of which 11 had acute quadriparesis. Electrodiagnostic evaluation was performed on only 8 of those 11 patients. Amplitude of CMAP of at least 1 nerve was reduced in 7 of the 8 patients; nerve conduction velocity was reduced less often (48). Needle EMG early after the onset of weakness showed reduced motor unit recruitment with little or no abnormality in amplitude or duration. Fibrillation potentials were recorded as early as 1 to 2 weeks after the onset of the quadriparesis in the paraspinal muscles. At 3 weeks postparesis, fibrillation potentials were recorded from proximal muscles with normal motor unit action potentials. At 4 to 5 weeks, abnormal spontaneous activity was recorded from distal muscles but was more abundant in the more proximal muscles. In general, the abnormalities were most prominent in proximal muscles and sometimes more prominent in the arms than the legs, a finding consistent with the clinical observation. Nerve conduction studies performed more than 5 months after the weakness onset showed an increase in the CMAP amplitude compared to earlier results; and the EMG was characterized by high-amplitude, long-duration, and polyphasic motor units with only mild distal fibrillation potentials, consistent with ongoing reinnervation of proximal muscles by axonal sprouting of intact axons (48). Sensory NCSs were performed on 6 of the 8 patients, and results were normal in 4. Only one patient had low-amplitude median sensory nerve action potential; the other patient started with reduced sensory nerve action potential amplitude of the median and sural nerves, which progressed to total absence 2 weeks later. Most importantly, the findings were not those of an acquired demyelinating neuropathy and therefore atypical of those usually obtained in GBS; no patient had conduction block or temporal dispersion. A small percentage of patients with GBS have an axonal form of neuropathy, and the findings are indistinguishable from those of porphyric neuropathy. Despite a lot of evidence supporting the axonal predominantly motor type of neuropathy seen in most porphyric patients, there are a few reports in the literature suggesting that porphyric symptoms might be related to a demyelinating disorder, a neuromuscular junction transmission defect, or a myopathy. a. In an abstract presented at the American Association of Electromyography and Electrodiagnosis in San

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Diego, California, on October 7 to 8, 1988  (p 957– 984), a 58-year-old female patient with an acute attack of VP had an NCS that showed abnormal temporal dispersion, partial motor conduction block, reduced conduction velocities below 80% of the lower limit of normal, prolonged distal latencies exceeding 120% of the upper limit of normal, and absent or prolonged F response latencies. The sural nerve biopsy showed findings of mixed axonal degeneration and acquired demyelinating. These findings are indistinguishable from those seen with GBS. It is possible, yet unlikely, that this patient had VP and GBS. It is also possible that the neuropathy associated with porphyria is heterogeneous, with some patients demonstrating axonal loss and other demonstrating findings consistent with an acquired demyelinating polyneuropathy. Alternatively, it is possible that the electrodiagnostic findings suggestive of acquired demyelination simply reflect secondary demyelination associated with axonal death. Supportive of this theory are identical findings associated with acute arsenic intoxication. Early after arsenic intoxication, some patients’ NCS results are indistinguishable from GBS. Those patients progress to develop severe axonal neuropathy with absent motor and sensory responses on NCSs and prominent abnormal spontaneous activity and absent voluntary motor unit action potentials. b. Feldman’s work on animal models suggested that PBG and porphobilin might cause neuromuscular junction transmission abnormalities, resulting in porphyric weakness. However, repetitive nerve stimulation at 2 Hz on 2 patients with porphyria in Albers’ series did not show any abnormalities. c. The EMG of a patient with acute porphyric attack seen at Massachusetts General Hospital showed smallamplitude polyphasic motor units with early recruitment in proximal muscles, raising the possibility of proximal myopathy in porphyria (27). Although these findings are suggestive of a proximal porphyric myopathy, the myopathic motor units may represent selective involvement of the terminal axons of motor units, possibly due to failure of conduction or a functional impairment of neuromuscular transmission (2). Electrophysiologic studies performed on asymptomatic patients with AIP after recovery from an acute attack of neuropathy indicate that most patients recover completely, but a small percentage show evidence of a chronic neuropathy (57).

Biochemical Findings Normally, small amounts of heme metabolites are excreted in the urine. During an acute porphyric attack, these metabolites are excreted in excess. The specific enzyme deficiency in the heme metabolism pathway predicts which heme precursors will accumulate up-

stream of the enzymatic defect and subsequently will be excreted. Each type of hepatic porphyria has a unique pattern of urinary and fecal heme precursor excretion. Measurement of these heme precursors allows in many cases an accurate diagnosis and classification of the specific type of hepatic porphyria. Until now, biochemical studies are still the most widely used testing for a specific diagnosis of porphyria. 1. Aminolevulinic Acid Dehydratase Deficiency Porphyria Aminolevulinic acid dehydratase deficiency porphyria is a result of ALAD deficiency, which catalyzes the formation of PBG from 2 molecules of ALA. During an acute attack, urinary ALA levels are elevated. The activity of the ALAD in affected patient can be as low as 1%. The most potent inhibitor of the enzyme is succinylacetone, a structural analogue of ALA, which is found in patients with hereditary tyrosinemia; this explains why 40% of children with tyrosinemia develop ALAD porphyria (65). Lead also inhibits ALAD activity by displacing Zn2+ from the enzyme and can cause similar clinical and metabolic features to ALAD porphyria. Therefore, Desnick recommends confirming the diagnosis of ALA dehydratase-deficient porphyria with adenosine diphosphate mutation analysis. 2. Acute Intermittent Porphyria During an acute attack, patients with AIP always excrete increased amounts of the porphyrin precursors, ALA and PBG, in urine (66). Total fecal porphyrin concentration remains normal. Porphobilinogen can be detected using qualitative tests like the Watson-Schwartz and Hoesch tests. These 2 tests are based on the reaction of PBG with p-dimethylaminobenzaldehyde (Ehrlich reagent) in acid solution to form a red compound (67). Although the former (Watson-Schwartz) is superior, both lack sensitivity and specificity (68). A quantitative assay using anion-exchange chromatography with spectrophotometry of the p-dimethylaminobenzaldehyde–PBG complex described by Mauzerall and Granick (69) in 1956 is more sensitive and specific. It is important to remember that these tests are not specific for AIP, because they measure urinary PBG, which is excreted in lesser quantities also in VP and HCP. Acute intermittent porphyria can also be diagnosed directly by measuring a decreased erythrocytic PBG-D activity, which, with some exceptions, mirrors the hepatic PBG-D activity. To determine this enzyme activity, PBG is used as a substrate, and the uroporphyrin I formed is measured by spectrofluorometry (70). In general, patients with AIP have 50% of the enzyme activity that is found in healthy people. However, this test has many limitations that restrict its usefulness in diagnosing AIP. There are wide individual variations of PBG-D activity among healthy controls (71). In addition, the normal and pathologic values overlap; moreover, the erythrocyte PBG-D activity is normal in the variant form of AIP where the uroporphyrinogen I synthase defect

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is manifested in the liver but not in red cells (72,73). This variant of AIP is due to alternative splicing of the erythroid and wild type isoform (74). It is still the most widely used method to diagnose AIP, but it is unreliable in infants younger than 8 months and in individuals with hematologic abnormalities. It is estimated that about 80% of patients with AIP have abnormal enzyme activity (75). It is also important to note that during the asymptomatic phase, more than one half of patients with AIP do not excrete PBG in urine, and neither do children before puberty. So detection in this group of patients requires measurement of the defective enzyme activity or DNA analysis. 3. Variegate Porphyria Variegate porphyria is characterized by a deficiency of PPOX, the penultimate enzyme in heme biosynthesis (76). It is located on the cytosolic surface of the inner mitochondrial membrane and catalyzes the conversion of protoporphyrinogen IX to protoporphyrin IX. Protoporphyrinogen oxidase deficiency in VP results in a reduced levels of heme, which leads to an increased activity of ALAS in the liver. Subsequently, porphyrins and/or porphyrin precursors like ALA and PBG are overproduced, accumulate, and are excreted in a specific and characteristic pattern (76,77). During severe acute episodes of VP, urinary ALA, PBG, and coproporphyrinogen as well as fecal protoporphyrin and coproporphyrin are usually increased. However normal values for ALA and PBG are sometimes seen in the latent phase and during mild attacks (76,77). Therefore, normal values for urinary ALA and PBG do not exclude VP. Fecal porphyrin and protoporphyrin are more important diagnostically than urinary ALA and PBG in VP. In addition, fecal protoporphyrin level is usually higher than coproporphyrin level (76). This increase of stool porphyrins can be observed during acute phases and also in remission (76). Quantitative analysis of PPOX activity in lymphocytes and fibroblasts is used, but test results are not always conclusive (77). Patients with VP have a unique defined plasma fluorescence emission maximum at an excitation wavelength of 626 nm that separates them from all other types of porphyria (78,79). However, this test is not sensitive for detecting asymptomatic carriers, especially children (78). 4. Hereditary Coproporphyria Hereditary coproporphyria is caused by a CPOX enzyme deficiency. The enzyme is soluble in the intermembrane space of mitochondria. It catalyzes the oxidative decarboxylation of coprogen to protogen. In most cases of HC, the enzyme activity is reduced to nearly 50% in heterozygote patients; in very rare cases of HCP, presumed to be homozygous for the coproporphyrinogen III oxidase defect, it is about 2%. Typically, during an acute attack of HC, there is increased urinary excretion of PBG and ALA as well as urinary and fecal coproporphyrinogen; a small amount of protoporphyrinogen can also be detected in the feces. The biochemical picture, though, is dominated by a

dramatic increase in fecal excretion of coproporphyrinogen (10–200 times compared with controls), specifically coproporphyrin isomer III. A ratio of fecal coproporphyrinogen III to coproporphyrinogen I isomers greater than 2 correlates with decreased CPOX activity (34). In the lymphocytes, the activity of CPOX in patients with HC is usually about 50% of that found in control samples. Yet, early diagnosis of HCP is difficult because patients with HCP in the subclinical or latent phase only show a slight-to-moderate increase of metabolite excretion. Many efforts have been made to diagnose subclinical patients, so future attacks can be prevented. Measuring heme precursor levels of enzyme activity tests is invasive and technically difficult. In 1992, Sieg (3) first described the diagnostic value of the fecal coproporphyrin isomers I and III. He reported that asymptomatic carriers in families with HCP can be detected by a fecal coproporphyrin III to I ratio increased to greater than 2. Therefore, HCP can be detected by fecal coproporphyrin III to coproporphyrin I ratio greater than 2 regardless of the stage of the disease.

Diagnostic Strategies Metabolite studies are usually the first step in establishing the diagnosis of porphyria because they are less expensive and invasive than the enzymatic assays and the genetic testing. Urinary PBG level is the essential first step to diagnose a suspected acute porphyric attack (80,81). 5-Aminolevulinic acid is not essential to establish the diagnosis. However, it is helpful in the rare ADP. Also, ALA level can be elevated in some metabolic causes of abdominal pain, like lead poisoning. Urinary PBG and ALA are increased in all 3 acute hepatic porphyrias (AIP, HCP, and VP), although the concentrations are higher and longer lasting in AIP than in the other 2 types. When urinary PBG levels are very high (>10 times the upper limit), treatment can be started immediately; however, further laboratory testing is still needed to diagnose the specific type of porphyria (41). Measurement of urinary porphyrins is unhelpful and might be misleading because of frequent and nonspecific coproporphyrinuria in many common disorders. The distinction between HCP and VP used to be difficult because it relies on the relative amounts of coproporphyrin and protoporphyrin present, not an absolute threshold amount. Presently, the first-line test for the diagnosis of VP is plasma fluorescence emission spectroscopy because of a unique emission peak at 624 to 628 nm (Table 21.1), but it does not distinguish AIP from HCP, because both have a similar emission peak at 620 nm (78). In AIP, urinary excretion levels of ALA and PBG are markedly elevated. Although urinary ALA and PBG are also increased, in contrast, HCP produces marked elevations of coproporphyrinogen in urine and feces during an attack. Thus, urinary porphyrin analysis alone is not sufficient for discrimination. Total fecal porphyrin concentration is high in HCP with coproporphyrin as the main

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component and a ratio of isomer III to isomer I greater than 2.0, whereas it is usually normal in AIP. Total fecal porphyrin concentration is also increased in VP, with protoporphyrin concentrations (protoporphyrin IX) greater than those for coproporphyrin. Occasionally, during an acute attack, metabolite studies alone are not sufficient for a precise diagnosis of a specific type of porphyria. In these cases, genetic testing or enzymatic essays can be used. Metabolite studies are not as useful between attacks or in patients with latent porphyria, because these patients often excrete normal amounts of heme precursor. In addition, when elevated levels are found, they may be present in confusing patterns (82). Yet metabolite studies are still used before genetic testing and enzymatic essays. VP and HCP that are in remission or presymptomatic are diagnosed respectively with fluo­rescence emission spectroscopy of plasma and a ratio of fecal coproporphyrin isomer III to isomer I of more than 2 (Table 21.1). The sensitivity of the fluorescence emission spectroscopy is 60% and specificity 100% if the patient is older than 15 years. The fecal coproporphyrin isomer III to isomer I ratio is sensitive in adults, but the sensitivity is not established in children (83). Genetic testing analysis to identify the mutation is the gold standard for family screening to identify those with latent disease. Enzyme measurements are reserved for families in whom a mutation cannot be identified. It is important to keep in mind that not all patients with increased levels of heme precursors have porphyria. Most patients referred with a presumptive diagnosis of porphyria have mild, nonspecific increases in porphyrin excretion. These patients have what is called secondary porphyrias. Secondary porphyrias may be caused by many conditions that are associated with overproduction and increased excretion of porphyrin precursors; these include, for example, diabetes mellitus, liver disease, and iron deficiency anemia. In addition, porphyrin precursors may be overproduced and overexcreted secondary to some particular substance. This is another form of secondary porphyria termed intoxication porphyria. Excessive ingestion of ethanol results in an accumulation of iron, which inhibits uroporphyrinogen decarboxylase and thereby interferes with porphyrin metabolism (62). Similarly, numerous medications induce the hepatic cytochrome P450 system and produce modest elevations of urinary coproporphyrinogen among healthy individuals. There are no clinical manifestations associated with the secondary or toxic porphyrias. Correction of the underlying problem or removal from exposure to the offending substance decreases levels to normal values. However, additional laboratory evaluations, including measurement of excretion of heme precursors in feces, may be required to distinguish these patients from those with HC.

Laboratory Abnormalities Ridley (43) reported the CSF results of 13 of the 25 patients with intermittent porphyria. In 12 patients, the

protein content did not exceed 70 mg/dL, and in 1, it was 100 mg/dL. The highest cell count was 7/mm3. Hyponatremia is the most striking electrolyte abnormality seen in porphyric patients. It can be attributed to inappropriate antidiuretic hormone secretion syndrome and occurs in approximately 40% of cases (41).

Genetic Analysis The overwhelming majority of patients, or asymptomatic carriers with hepatic porphyria, are heterozygous for a certain gene mutations. Therefore, the disease is transmitted from a generation to the next, as an autosomal dominant trait. In porphyria, a 50% residual enzyme activity, provided by the normal gene, is not enough to prevent disease phenotypic manifestation. Only a few patients with AIP, HCP, PCT, and ALAD deficiency, however, are found to have both alleles of the genes mutated (by homozygous or compound heterozygous mutations); these patients have less than 50% enzymatic activity. There have been tremendous advances in the understanding of the genetic and molecular basis for porphyria. The genes responsible for the different types of porphyria have been mapped and cloned, and diseasespecific mutations, identified. For the hepatic porphyrias with neuropathy, a total of 529 mutations have been identified. More updated results can be found in the Human Gene Mutation Database at http://www.hgmd. cf.ac.uk. Aminolevulinic acid dehydratase deficiency porphyria, the rarest of all hepatic porphyrias, is unique because it is the only form of hepatic porphyria that is not transmitted as an autosomal dominant trait. Although only 6 cases have been reported, is it estimated that 2% of the Swedish population are carriers. The ALAD gene has been mapped to Chromosome 9q33.1. A total of 12 mutations have been discovered, 9 missense or nonsense point mutations, 1 small deletion, and 2 intronic point mutations at the splicing site resulting in frameshift mutations. Prenatal diagnosis by analysis of ALAD enzyme activity or gene mutation in a chorionic villus sample or amniocytes is possible. The PBG-D or hydroxymethylbilane synthase gene on Ch11q23.3 is responsible for AIP. Approximately 317 mutations have been discovered in the HMBS gene. Most are present only in the few families in which they were discovered. It is important to remember that the PBG-D protein exists under 2 isoforms, deriving from 2 different mRNA by alternative splicing. The erythroid mRNA is unique in that it contains an extra exon 1, which is spliced out in the other cells of the body. Therefore, a mutation in this region does not cause AIP, leading to a false-positive erythrocyte assay. However, commonly, molecular defects occur in other portions of the gene, producing abnormal hepatic and erythroid isoforms of PBG-D. This allows the biomolecular diagnosis of AIP by testing the enzyme activity in the erythrocytes. Hereditary coproporphyria is due to a mutation

Acute attacks

PBG, ALA, porphyrins

Urine

+/– Zn-proto IX Uro I, copro I

+/– Zn-proto IX

Normal Copro I

Isocopro, hepta

–

Proto IX > copro III

6l8–620

615–618

624–627

618–620

618–620

Plasma

UROD gene sequencing, low UROD activity in RBC

ALAD gene sequencing, low ALAD activity in RBC UROS and GATA1c gene sequencing, low UROS activity in RBC

Plasma peak only in adults, PPOX gene sequencing, low PPOX activity in lymphocytes

CPOX gene sequencing, low CPOX activity in lymphocytes

PBGD gene sequencing, low PBGD activity in RBC (classic form) or in lymphoblastoid cells (variant form)

Methods to Detect Presymptomatic Carriers DNA analysisa and enzyme activity peakb (nm)

Abbreviations: ALA, 5-aminolaevulinic acid; AIP, acute intermittent porphyria; copro, coproporphyrin; HC, hereditary coproporphyria; hepta, heptacarboxy I–porphyrin; isocopro, isocoproporphyrin; PBG, porphobilinogen; proto, protoporphyrin; RBC, red blood cell; VP, variegate porphyria; uro, uroporphyrin; UROD, uroporphyrinogen decarboxylase; UROS, uroporphyrinogen III synthase; Zn, zinc. a DNA analysis should be used whenever possible to confirm diagnosis in proband. Identification of mutation in unequivocally affected family member is a prerequisite for family investigation. b Fluorescence emission peak. c X-linked erythroid-specific transcription factor GATA-binding protein 1 mutation has been reported in one case of congenital erythropoietic porphyria. Source: Puy et al (41).

Investigations should be done in association with specialist porphyria centers.

Rare recessive porphyrias ALA dehydratase Acute and chronic ALA, copro III porphyria (125 270) neuropathy Severe photosensitivity Uro I, copro I Congenital with or without erythropoietic hemolysis porphyria (606 938)a Hepatoerythropoietic Severe photosensitivity Uro III, hepta porphyria (176 100)

–

–

RBC

Copro III, ratio isomer III/l > 2.0

Useful only to distinguish AIP from HC and VP

Stool

Biochemical Findings in Symptomatic Patientsa

Acute or cutaneous porphyrias Hereditary Acute attacks or skin PBG, ALA, Coproporphyria fragility and blisters porphyrins (121 300) Variegate porphyria Acute attacks or skin PBG, ALA, (176 200) fragility and blisters copro III

Acute porphyria Acute intermittent porphyria (176 000)

Main Clinical Presentation

Table 21.1  Summary of the Clinical Symptoms, Biochemical Findings, and Methods of Diagnosis in Different Types of Porphyria

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CHAPTER 21: Porphyric Neuropathies  301

in the CPOX gene. Coproporphyrinogen oxidase gene organization was reported by Delfau-Larue 1994. It is encoded by a 14-kilobase  (kb) CPO gene containing 7 exons and 6 introns localized on 3q12.40. Fifty-one mutations have been identified. Hereditary coproporphyria is usually transmitted as an autosomal dominant disorder; however, few homozygous affected subjects have been reported. These patients have a CPOX activity of less than 10% of normal. Homozygous CP with a CPOX gene mutation can result in a different type of porphyria called harderoporphyria. All 5 patients with harderoporphyria reported to date are homoallelic or heteroallelic for the same missense mutation in the CPO gene (K404E encoded by exon 6). Apparently, harderoporphyrin accumulates instead of coproporphyrin when the mutations disrupt the active site of the enzyme. VP is due to a mutation in the PPOX gene; Taketani demonstrated that the PPOX gene has 13 exons and spans about 8 kb. In 1995, the human PPOX cDNA was cloned and the PPOX gene mapped to 1q22-23. Approximately 149 mutations in the PPOX gene have been identified. Of those, the R59W point mutation is of particular interest. In one study, the R59W mutation was present in 43 of 45 patients with VP from 26 of 27 South African families investigated but not in 34 unaffected relatives or 9 unrelated British patients with PPOX deficiency. Also, at least one of the South African families can be shown to be descended from the founder of South African VP. This defect may represent the founder gene effect associated causally with VP in South Africa. This founder effect by a Dutch immigrant in 1688 might explains why the R59W mutation is the most common mutation in VP in South Africa (0.3% of white South African) (84). Despite the major genetic advances in porphyrias, the diagnosis of the vast majority of subjects is still based on biochemical analysis of the pattern of excess porphyrin and porphyrin precursors in plasma and urinary concentrations. Nonetheless, DNA testing is the most accurate and reliable method for determining a specific type of porphyria and is considered the gold standard for the diagnosis of porphyria. In a study by Whatley et al (85) in 2009, the diagnostic sensitivity of mutation detection was determined by searching for mutations in 467 unrelated patients. The genetic test diagnostic sensitivity was as followed: AIP, 98.1%; HCP, 96.9%; and VP, 100%. Negative predictive values were as follows: AIP, 0.98; HCP, 0.97; and VP, 1.00.

Pathology and Pathophysiology The myriad of clinical symptoms seen during an acute attack of porphyria can be explained by central and peripheral nervous system dysfunction. In the peripheral nervous system, the weakness is explained by a predominantly motor neuropathy of the axonal type as suggested clinically and electrophysiologically. The electrodiagnostic findings correlate with the pathologic evidence of axonal loss and wallerian degeneration seen

in autopsies and nerve biopsies. The first autopsy on a patient with acute porphyria precipitated by sulphonal was done in 1903 (86); axonal degeneration and patchy demyelination of the femoral nerve were described. Although isolated areas of demyelination have occasionally been described, demyelination is more often associated with axonal disruption. Therefore, the demyelination is likely to be secondary to axonal degeneration. Most studies favor the axonal lesion as the primary event on the basis of both autopsy and biopsy. In contrast to the typical-length dependent pattern seen with metabolic axonopathies, porphyria may affect short motor axons early (eg, innervating proximal muscles and cranial nerves). This implies pathology in the spinal root or at the level of the cell body. In fact, neuronal loss and chromatolysis of cells of the anterior horn of the spinal cord are typically seen on autopsy. This damage is presumed to result from retrograde degeneration following axonal damage. It is possible that neurotoxic substances that accumulate in porphyria may access the peripheral nervous system through the neuromuscular junction where the blood-nerve barrier is lacking then are transported to the cell body, causing its death (27). Pure sensory nerves are frequently spared. These pathologic changes are nonspecific, and a diagnosis of porphyric neuropathy cannot be established by nerve biopsy. This hypothesis explains the CNS dysfunction, but the mechanism by which a defect in heme metabolism produces neuropathy is still largely unknown. 1. A major hypothesis relates the neuropathy in porphyria to heme deficiency alone. Heme deficiency leads to decreased levels of key heme proteins such as cytochromes and nitric oxide synthases in various tissues, resulting in direct or indirect effects on the nervous system. Heme is an essential component of the mitochondrial electron transport chain and is critical to aerobic metabolism and adenosine triphosphate production. Therefore, highly energy-dependent functions like fast axonal transport are disrupted and result in axonal death. However, an inconsistency in this hypothesis is that the intraneuronal heme pool should not diminish during an acute attack of hepatic porphyria, because there is little cytochrome P450 activity in the nervous system, and ALA synthase should not be induced (87). Neuronal aerobic metabolism, therefore, would not be compromised. Also, other conditions that impair heme synthesis, such as iron deficiency, are not known to produce similar syndromes (88). 2. All porphyric attacks occur in the setting of elevated heme precursors levels (66). It has been hypothesized that the accumulation of these precursors and metabo­ lites that are overproduced by the liver play a role in central as well as peripheral neurotoxicity. It is well known that many substances, including some essential vitamins, are neurotoxic when present in a sufficient dose. The one precursor common to all the

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porphyrias is ALA. There is much evidence suggesting that ALA is the key factor leading to neuronal toxicity, both peripheral and central, supported by the following observations. a. Increase in ALSA1 activity leads to an increase in ALA synthesis, which can induce an attack in porphyric patients. In fact, events like hormonal fluctuations during the menstrual cycle, fasting, smoking, infections, inflammation, and exposure to porphyrinogenic drugs that induce ALAS1 or increase the demand for heme synthesis in the liver and subsequently deinhibit ALAS1 precipitate an acute attack in porphyric patients (89,90). Most drugs that exacerbate porphyria are closely associated with induction of cytochrome P450 enzymes, which increase hepatic heme turnover. b. 5-Aminolevulinic acid is a structural analog of g-aminobutyric acid (GABA) and interacts with GABA receptors. It is also a pro-oxidant because of the presence of a potentially reactive keto group on the molecule, and this property has been implicated in d-ALA–induced damage to GABA receptors and to mitochondria. Consistent with this mechanism are the findings that CNS and liver toxicity associated with ALA exposure are reduced by coadministration of the antioxidants melatonin and bilirubin. 5-Aminolevulinic acid may be responsible, in part, for the peripheral neuropathy observed in subjects receiving dichloroacetate. Myelinating cocultures of Schwann cells and sensory neurons exposed to ALA are associated with a pronounced reduction in the levels of myelin-associated lipids and proteins, including myelin protein zero and peripheral myelin protein 22. In addition, ALA has been shown to block peripheral myelin formation. Moreover, ALA can undergo enolization and autooxidation in the presence of heavy metals such as iron; this may lead to the generation of free oxygen radicals, which causes damage to cell structures in general. There is experimental evidence that ALA induces necrotic cell death of mouse astrocytes (91). In one study, injections of 40 mg ALA per kg every other day for 2 weeks in rats led to increased parameters of oxidative stress in nervous tissue, such as increased superoxide dismutase activity, and signs of protein and lipid damage. Also, even though ALA does not ordinarily cross the blood-brain or blood-nerve barrier, during an attack, ALA appears in measurable quantities in the CSF. c. Tyrosinemia type I and acute lead poisoning are associated with increased urinary ALA excretion, and in both conditions, symptoms resembling those of acute porphyria such as abdominal pain and peripheral neuropathy occur. Arguments against the ALA hypothesis are the high excretion of ALA in many symptomless patients with

AIP and no effects (except temporary light sensitivity) after ALA administration to healthy volunteers or patients with AIP. The question about whether ALA can produce some or even all of the symptoms of acute porphyria, therefore, has remained a controversial issue.

Treatment There is no specific treatment for porphyric neuropathy. Treating the neuropathy commonly associated with porphyria depends on treating the underlying disease using abortive therapies during the acute attack and preventative therapies during the latent phase or between attacks. During an acute attack, treatment can be divided into symptomatic, directed only to treat the symptoms, and disease modifying, directed at aborting the attack. The symptomatic and supportive treatments of an acute porphyric attack can be complicated owing to the variety and sometimes severity of symptoms. These include pain, nausea, vomiting, diarrhea, constipation, hypertension, hyponatremia, restlessness, agitation, and respiratory failure (Table 21.2). Potentially, many medications can be used to treat all these symptoms (Table 21.3). It is important to choose the medications that are safe in porphyria and avoid those known to precipitate or accentuate an acute attack, particularly those that induce cytochrome P450 enzymes and therefore hepatic heme precursors. Table 21.3 lists medications that are generally considered safe for use during attacks of acute porphyria. Medications commonly used are opiates and acetaminophen for pain control. Gabapentin has also been used successfully as described in case reports (92). Nausea and vomiting are usually treated with promazine, chlorpromazine, cyclizine, and ondansetron. For constipation, bulk laxatives, senna, and lactulose can be used. Lorazepam has been used safely for insomnia and anxiety, as well as chlorpromazine for hallucination. Managing autonomic dysfunction, especially hypertension and tachycardia, is critical. Patients should be observed in the intensive care unit because of the risk of arrhythmia and dramatic or accentuated response to hypertensive medications. Hypertension and tachycardia often respond to propranolol or related medications. Treatment of hypertension should begin at low doses using medications with a short half-life (93). Hyponatremia might be severe and reflect a syndrome of inappropriate anti­ diuretic hormone secretion. Careful and balanced hydration and electrolyte replacement are very important to prevent neurologic complications of hyponatremia, such as seizures. It is important to recognize potential photosensitivity among patients with HC or VP; ideally, the patient should be provided a dark room. Respiratory failure is the most dreaded complication of acute porphyric attack. Observation and careful attention for early signs of respiratory muscle weakness that require intensive care monitoring is important. The primary treatment of porphyric neuropathy is directed at the underlying cause, recognizing that there

CHAPTER 21: Porphyric Neuropathies  303

Table 21.2  Management of Acute Porphyria: Human Hemein Stabilized With Arginine (Normosang) Is Not Available in the United States, but Lyophilized Hemein Is

Preventive Supportive Specific   Repress heme synthesis   Hyponatremia and fasting

Treatment Measures Prescribe drugs from safe drug list; avoid alcohol, smoking, soft drugs (cannabis), dieting, and fasting; carry medical alert cards or jewelry Stop porphyrinogenic drugs

Hemin (4 mg·kg–1·d–1 for 3–4 consecutive days) Maintain fluid and calorie intake Mild cases: 2 L normal saline containing 5%–10% dextrose or glucose (>200 g/d) Severe hyponatremia: infusion of 3% saline (500 mmol/L), correction 16 years) (18,46,47). Patients have progressive central and peripheral demyelination and present with progressive weakness, hypotonia, clumsiness, and dysarthria. Late signs include dementia, spasticity, seizures, and loss of vision and hearing. There are

CHAPTER 24: Peripheral Neuropathies in Childhood  343

conflicting reports as to the long-term efficacy of bone marrow transplant in MLD (48–50), although it remains the standard of care in patients with MLD diagnosed early in the course of their disease (51). Other progressive lipid storage disorders have some histological evidence of lipid deposition within peripheral nerves (ie, GM1 and GM2 gangliosidoses, Gaucher disease, Niemann-Pick disease, and Farber disease); however, only rare cases of GM2 gangliosidosis are associated with autonomic dysfunction and sensorimotor polyneuropathy (52). Infantile refsum disease belongs to a group of peroxisome (PEX) biogenesis disorders that include infantile refsum disease (least severe), neonatal adrenoleukodystrophy (intermediate severity), and Zellweger syndrome (most severe) (53). The clinical phenotypes were described before biochemical and molecular studies confirmed that these 3 syndromes are each caused by dysfunctional peroxisomes and thus are part of the same disease spectrum (54). Evaluation of these patients demonstrates the presence of elevated serum levels of phytanic acid, pipecolic acid, and very-long-chain fatty acids. Mutations in 12 different PEX genes are now defined; however, clinical testing is not available for each of the respective genes. Children with infantile refsum disease present with global developmental delay, retinitis pigmentosa, demyelinating PN, hepatic dysfunction, coagulopathy, and sensorineural hearing loss (53). The clinical course is variable. Some of these children may eventually learn to walk. Classic refsum disease typically presents in late childhood with progressive retinitis pigmentosa and night blindness, anosmia, cerebellar ataxia, sensorineural hearing loss, progressive demyelinating sensorimotor polyneuropathy, cardiac arrhythmia, and ichthyosis (55).

Inborn Errors of Metabolism Tyrosinemia type I is a rare autosomal recessive inborn error of metabolism. Patients have acute and chronic liver disease, hepatocellular carcinoma, and renal Fanconi syndrome. Some of these patients present with acute neurological crises; 42% have painful polyneuropathy crises (56). Gastrointestinal dysmotility and muscle weakness can also occur. EMG and nerve biopsy demonstrate axonal degeneration with secondary demyelination (56). Treatment consists of dietary restriction of tyrosine and phenylalanine. More recently, NTBC (2-[2nitro-4-trifluoromethylbenzoyl]-1, 3-cyclohexane-dione) has proven to be effective at reducing the hepatic, renal, and neuropathic crises (57). Vitamin B12 (cobalamin) deficiency is an uncommon cause of polyneuropathy in children; this typically presents during infancy. This is related to inadequate cobalamin intake; this occurs in strictly breastfed infants of vegetarian mothers or vegan mothers or mothers with pernicious anemia (58,59). Rare cases also exist of infant vitamin B12 deficiency because of congenital intrinsic

factor deficiency (60), impaired intestinal absorption (61), impaired vitamin B12 transport within the blood (ie, transcobalamin II deficiency) (62), or cobalamindependent enzyme defects (63). Patients with vitamin B12 deficiency are highly susceptible to certain inhaled anesthetic agents (eg, nitrous oxide) as exposure further depletes cobalamin stores (64). Intramuscular vitamin B12 replacement results in clinical improvement of infants with nutritional deficiency or malabsorption, although long-term neurological sequelae are common (65). Older children with vitamin B12 deficiency (typically due to malabsorption, celiac, or Crohn disease) may present with ataxia and distal lower extremity paresthesia. Symptoms are predominantly because of the involvement of spinal posterior columns, corticospinal tract, and spinothalamic tract, although peripheral nerve involvement (sensory > motor) is also seen (66).

Hereditary Sensory Autonomic Neuropathies The HSAN are clinically heterogeneous and genetically distinct disorders that result from atrophy and degeneration of peripheral sensory and autonomic neurons. Dyck and Ohta (67) classified HSAN according to clinical and nerve biopsy findings. His classification system is still in use today with genetic testing now clinically available for all HSAN groups. Hereditary sensory autonomic neuropathies types 2 to 5 demonstrate autosomal recessive inheritance and congenital or early-childhood onset (68). All HSAN patients have small-fiber sensory dysfunction and varying degrees of autonomic dysfunction (particularly HSAN types 3 and 4). Autonomic nerve dysfunction is demonstrated by the absent (HSAN types 2 to 5) or attenuated (HSAN type 1) skin flare reaction to intradermal histamine injection (69,70). Because nerve conductions studies evaluate large-fiber myelinated nerves, these are typically normal in many patients with early or infantile forms of HSAN. Hereditary sensory autonomic neuropathies type 2 is the exception, with patients demonstrating a severe, early loss of large- > small-fiber sensory nerves (71). HSAN type 1 is the most common form of hereditary sensory neuropathy demonstrating symptom onset in adolescence or early adulthood as well as autosomal dominant inheritance. It also is characterized by small>> large-fiber sensory nerve involvement (72,73) without significant clinical autonomic dysfunction. It is caused by mutation of the serine polmitoyltransferase long-chain base subunit 1 (SPTLC1) gene. Clinical symptoms are slowly progressive and do not usually become apparent until late in adolescence, usually between age 10 and 30 years. (73). Progressive paresthesias develop. Lack of normal sensation can eventually also lead to secondary foot ulceration or toe amputations, although this occurs much later in life compared with other forms of HSAN (types 2–5). Motor and autonomic symptoms are usually minor (73). Nerve conduction studies typically

344  Textbook of Peripheral Neuropathy

have preserved SNAPs because the smallest unmyelinated C fibers are predominantly affected. HSAN type 2 presents in infancy or early childhood. Mutations of the HSN2 genes lead to the loss of all sensory modalities having a classic stocking and glove distribution. Severe injury and self-mutilation are common (similar to HSAN type 4). The child exhibits painless finger and foot ulceration, osteomyelitis, and spontaneous amputation. Patients with HSAN type 2 rarely show clinically significant evidence for autonomic dysfunction in contrast to HSAN types 3 and 4 (74). Rare patients with HSAN type 2 may have central apneas (69). Patients exhibit an absent skin flare after intradermal histamine injection. Muscle stretch reflexes are absent. Muscle strength is normal or slightly decreased. Electrodiagnostic testing demonstrates absent SNAPs; this is because of severe large fiber myelinated A alpha and A delta sensory nerve involvement. This provides another key feature differentiating HSAN type 2 from other hereditary sensory polyneuropathies, wherein the primary abnormality affects the very small unmyelinated C fibers. HSAN type 3, initially called Riley-Day syndrome or familial dysautonomia, is the best known among the various hereditary sensory neuropathies. This disorder arises from mutations of the IKBKAP genes that encode kinase complex-­associated proteins. Clinical features are evident from birth; these include a marked smallfiber sensory dysfunction (pain, temperature), as well as severe autonomic dysfunction manifested by cardiovascular instability and gastrointestinal dysmotility. Five cardinal clinical criteria exist for an HSAN type 3 diagnosis; these include (1) absent overflow emotional tears, (2) absent fungi form papillae on the dorsum of the tongue, (3) absent patellar muscle stretch reflexes, (4) absent skin flare after intradermal histamine injection, and (5) Ashkenazi Jewish heritage (75–77). The intradermal histamine injection must be interpreted cautiously in children less than 6 weeks old because of the tendency for equivocal results and a possibility of false-positives in some normal neonates (78,79). Approximately 40% of patients with HSAN type 3 survive beyond age 20 years (80). These older survivors have frequent long-term complications involving autonomic, cardiovascular (ie, postural hypotension, hypertensive crisis, and excessive sweating), and gastrointestinal dysfunctions (ie, dysmotility and vomiting crises). Self-injury and self-mutilation are not as severe as that seen in HSAN type 4. Nevertheless, patients with HSAN type 3 are still at risk for painless foot and corneal ulceration (80). Data pertaining to long-term cognitive outcome are conflicting with more recent reports noting normal adult intellect (80) in contrast to earlier investigations from the same investigator noting a high rate of below-average intelligence (81). HSAN type 4 is also known as congenital insensitivity to pain with anhidrosis, which results from mutation of the NTRK1 genes (82). Children show symptoms

shortly after birth with hypotonia, profound insensitivity to pain, and autonomic dysfunction (severe hypohydrosis or anhidrosis with resulting hyperpyrexia). These patients with HSAN type 4 possess intact overflow emotional tearing and do not exhibit cardiovascular or gastrointestinal dysregulation seen in HSAN type 3. Infants experience severe self-mutilation of their tongue, lips, hands, and feet. Painless fractures, foot ulceration, and Charcot joints are common. Decreased corneal sensitivity and muscle stretch reflexes are observed. Cognitive impairment is typically seen. Intradermal injection of histamine fails to elicit the normal flare response (83). Because this disorder primarily involves small-fiber dysfunction, EMG reveals normal sensory responses in HSAN type 4 (83) because of preserved large fiber function. HSAN type 5 is an extremely rare disorder with only a few well described cases. Infants with this disorder have similar congenital insensitivity to pain and temperature (like HSAN type 4); however; they do not demonstrate anhydrosis or hypohydrosis (84). Mutation of the nerve growth factor beta gene is linked to this disorder (84).

POLYNEUROPATHIES OF CHILDHOOD Early-Onset Inherited Polyneuropathies (CMT1, CMT2, CMTX) Charcot-Marie-Tooth neuropathy, also called HMSN, is the most common group of hereditary PNs. The disease prevalence (all CMT types) is approximately 1 in 2,500 people (85). Charcot-Marie-Tooth disorders are classified according to inheritance pattern (autosomal dominant, recessive, and X-linked) and electrodiagnostic test findings (demyelinating, axonal) (86). CMT Type 1 This is the primary demyelinating form of CMT disease that has an autosomal dominant inheritance. Patients generally present in early adolescence with symptoms of distal muscle weakness (foot drop) and atrophy, increasing clumsiness and falls and/or structural foot abnormalities including pes cavus, callus, or even ulcer formation (87). Many patients will have an upper extremity tremor, which was initially thought to represent a different disorder (Roussy-Levy syndrome) but has been since proven to be part of the group of hereditary neuropathies (88). Weakness and sensory loss slowly progress over decades in patients with CMT1. Nerve conduction studies are the primary means for differentiating the demyelinating CMT1 from its axonal counterpart (CMT2). Peripheral nerves in CMT1 exhibit prolonged distal latencies and moderate to severe slowing of conduction velocities less than 75% of normal values (ie, upper limbs: M

A

Occurs with doses >200 mg/m2; often begins suddenly

CHAPTER 29: Laboratory Evaluation of Peripheral Neuropathies  447

Table 29.2  Drugs and Toxins Associated With Axonal Polyneuropathy (continued) Associated Drug/ Toxin

Sensory, Motor, or Sensorimotor

Axonal or Demyelinating

S>M

A

S>M

A

Arsenic (insecticide, herbicide; also from smelting and wood preservative industries); might be given with suicidal or homicidal intent

SM

A; acutely may Onset with painful sensory symptoms have D followed by weakness; prominent systemic effects (gastrointestinal symptoms, anemia) and skin/nail changes (Mees lines); acute intoxication may cause GBS-like polyneuropathy with proximal nerve demyelination; however, most acute and chronic intoxications cause distal symmetric axonal polyneuropathy

Carbon disulphide (solvent used in manufacture of rayon cellophane film)

S>M

A

Sensory symptoms followed by motor deficits; primary central distal axonopathy; neurofilamentous swelling of axons causes retraction of paranodal myelin and slowing of nerve conduction

Ethylene oxide (gas sterilization)

SM

A

Usually inhalational exposure; inprovement follows termination of exposure

Hexacarbons: n-hexane and methyl, n-butyl ketone (solvents)

SM

A and D

Exposure via inhalation such as inhalational abuse of gasoline or glue

Lead, inorganic (industrial uses in batteries, smelting)

Pure M or M > S

A

Primarily motor neuropathy; arms (wrist drop) affected more than legs; occurs with systemic effects (gastrointestinal symptoms, anemia)

Mercury (metallic and vapor)

M>S

A

Predominantly motor neuropathy; can mimic GBS; might occur with CNS effects (lethargy, emotional lability, tremor)

Drugs Thalidomide (sedativehypnotic; antiinflammatory, immunomodulatory)

Vincristine (antineoplastic)

Comment

Initial symptoms always sensory often with profound insensitivity to pain and touch; sensory nerve conduction studies useful for detecting subclinical neuropathy Onset with sensory symptoms in hands more so than in feet; if weakness occurs, medication should be stopped; autonomic neuropathy (gastroparesis, constipation, urinary retention) frequent

Toxins

(continued on next page)

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Table 29.2  Drugs and Toxins Associated With Axonal Polyneuropathy (continued) Associated Drug/ Toxin

Sensory, Motor, or Sensorimotor

Axonal or Demyelinating

Comment

Toxins Organophosphates (insecticides, petroleum additives)

M>S

A

Thallium (rodenticides)

S>M

A

Neuropathy is delayed by 10–20 days after exposure; also myelopathy with lower limb spasticity and loss of proprioception Painful sensory symptoms prominent; occurs with systemic effects (gastrointestinal symptoms, anemia); alopecia is hallmark but does not occur until 2–3 weeks after exposure

Abbreviation: CNS, central nervous system. Source: England and Asbury (3). a Continued worsening for several weeks after cessation of toxic exposure.

Other Tests Related to Systemic Diseases or Infections Some of these tests have been discussed already since many of these conditions cause both an axonal and demyelinating neuropathy. The ones that are solely or predominantly associated with demyelinating polyneuropathy will be reviewed below.

serum protein electrophoresis with immunofixation.

Approximately 10% of patients with acquired demyelinating polyneuropathy have an associated monoclonal gammopathy, usually an IgM (1,38,104). This is significantly higher than the percentage reported in studies on other populations (1,38). Approximately half of these Negative Family History

Positive Family History EMG/NCS Demyelinating

First tier

MPZ mut 5% PMP22 mut 2.5%

Third tier

PMP22 dup 70%

Second tier

AD

Axonal

X

AD

GJB1 12%

MFN2 mut 33%

AR

PRX mut EGR2 mut LITAF mut GDAP1 mut

EMG/NCS

AR

Index of suspicion for CMT high 30% of mutations are de novo, molecular testing

X

GJB1 12%

MPZ mut 5%

RAB7 mut GDAP1 mut GARS mut NEFL mut HSPB1 mut

Demyelinating PMP22 dup GJB1 mut

Axonal MFN2 mut GJB1 mut

MPZ mut 5% PMP22 mut 2.5%

MPZ mut 5%

EGR2 mut LITAF mut PRX mut GDAP1 mut

RAB7 mut GARS mut NEFL mut HSPB1 mut GDAP1 mut

Figure 29.1  Evaluation of suspected hereditary neuropathies. Decision algorithm for use in the diagnosis of suspected hereditary polyneuropathies using family history and nerve conduction studies. Reprinted with permission from England et al. Neurology, 2009 (1). Abbreviations: AD, autosomal dominant; AR, autosomal recessive; GDAP1, ganglioside-induced differentiation-associated protein 1; EGR2, early growth response 2; EMG, electromyography; GARS, glycyl-transfer RNA synthetase; GJB1, gap junction beta 1 protein (connexin 32); HSPB1, heat shock protein beta-1; LITAF, lipopolysaccharide-induced tumor necrosis factor a; MFN2, mitofusin 2; MPZ, myelin protein zero; NCS, nerve conduction study; NEFL, neurofilament light chain; PMP22, peripheral myelin protein 22; PRX, periaxin; RAB7, small guanosine triphosphatase late endosomal protein; X, X-linked.

CHAPTER 29: Laboratory Evaluation of Peripheral Neuropathies  449

patients have antibodies directed against myelin-associated glycoprotein, which will be discussed later (105). As previously mentioned, MGUS is the most commonly identified by SPEP. They were originally called benign monoclonal gammopathies, but the new terminology is more appropriate since approximately 25% of these patients develop a hematologic malignancy after long-term follow-up (39). Immunoglobulin M heavy chains are overrepresented in patients with MGUS and neuropathy compared to patients with only MGUS, accounting for 55% of these patients (39). Nonetheless, IgG and IgA are also represented in 35% and 10% of these patients, respectively (39). Patients with MGUS with or without anti-MAG antibodies present with a slowly progressive, sensory greater than motor polyneuropathy. The results of EDX studies are variable in anti-MAG–negative patients with either demyelinating or axonal features (39). The EDX features of anti-MAG neuropathy will be discuss below. Waldenstrom macroglobulinemia represents only 2% of all patients with a monoclonal gammopathy (39). It produces an IgM monoclonal protein that has a k light chain in 80% of cases (39). The neuropathy is similar to that seen in IgM-MGUS, and it may even test positive for anti-MAG antibodies (39). Osteosclerotic myeloma is a rare condition. The M protein is usually composed of l chains associated with IgG or, less commonly, IgA (39). The neuropathy is often the presenting manifestation of this malignant plasma cell dyscrasia (39). It resembles CIDP, with proximal and distal weakness, diffuse trace or absence of myostatic reflexes, and variable sensory loss (39). As in CIDP, the pathology is demyelinating (39). Osteosclerotic m­yeloma may be associated with POEMS syndrome, characterized by the type of polyneuropathy, organomegaly, e­ndocrinopathy, M protein, and skin changes (106). antineural antibodies.

Few studies report the sensitivity and specificity of the antineural antibodies, and their range is broad and variable. This may be due to differences in the antibody assays, the value of the titer considered as a threshold for positivity, or the spectrum of the patients tested (107). Perhaps, this is also the reason for the overlap of many of these antibodies in different syndromes. Thus, results should be interpreted in the context of the typically associated clinical picture.

anti-mag antibody. The first antibody recognized in acquired polyneuropathies was anti-MAG (108). A large study comparing antibodies against this glycoprotein and the glycolipids GM1, GM2, GD1a, and DG1b showed that anti-MAG has the highest sensitivity (45.1 %) (105,108). Patients with anti-MAG antibodies usually present in middle age with a slowly progressive distal symmetric, predominantly large fiber sensory polyneuropathy. Unlike in neuropathy of MGUS without anti-MAG, gait ataxia and upper extremity tremor are more prominent (39). The EDX pattern is very unique, with slowing in dis-

tal nerve segments and disproportionate prolongation of distal latencies, different also from the monoclonal IgM antisulfatide neuropathy described earlier (109). Therefore, it is reasonable to check levels of anti-MAG antibodies in patients with these clinical and EDX features. antigangliosides with disialosyl moieties. The features of CANOMAD or chronic ataxic neuropathy with ophthalmoplegia, M protein, cold agglutination, and disialosyl antibodies are described in the name (21,40). These antibodies bind to GD3, GD1b, GT1b, or GQ1b ganglioside (40). GQ1b, as mentioned earlier, is the same target identified in patients with a similar syndrome, MillerFisher syndrome, but with an acute presentation. According to a review of 18 individuals with these antibodies, most of these patients had a demyelinating process (40). anti-gm1 antibody. Among the antiglycolipid antibodies, anti-GM1 IgM, has received the most attention because of its association with multifocal motor neuropa­thy. Multifocal motor neuropathy, as its name implies, is not a DSP but rather an asymmetric, purely motor syndrome with EDX findings of conduction block (110). Although antibodies such as anti-GD1b and anti-GM2, among o­thers, have been also described in this condition, recent evidence suggests that GM1 IgM has the highest prevalence (43%) (111). Furthermore, higher titers were associated with more severe weakness and disability (111). antisulfatide antibodies.

Most of these antibodies have been discussed under axonal polyneuropathies. A sulfatide in a lipid membrane environment is the target in GALOP syndrome (110). GALOP stands for gait disorder, autoantibody, late onset, and polyneuropathy, which characterizes the clinical picture (110,112). Although EDX studies are heterogeneous, 80% of patients meet demyelinating criteria (110,113). Antibodies for this syndrome can be ordered as anti-GALOP antibodies. Other Antibodies

and transglutaminase antibodies. Even though ataxia due to cerebellar and/or axonal sensory neuropathies is the most common manifestation of gluten sensitivity, mononeuropathy multiplex and demyelinating neuropathies have also been reported (56,114–116). (See section on CD above.) antigliadin

Infections

cytomegalovirus. The progressive polyradiculopathy in patients with HIV is usually attributed to cytomegalovirus (CMV) infection (117). It is postulated that both AIDP and CIDP in patients with HIV can be differentiated from progressive polyradiculopathy secondary to CMV infection (117). The main differences are the stage of HIV infection in which they are encountered and the cell profile in the CSF. Although CIDP can present any time during the course of the infection, AIDP develops usually in very early stages of HIV. On the contrary, CMV polyradiculopathy presents late in the course of the disease, in

450  Textbook of Peripheral Neuropathy

Table 29.3  Diseases, Drugs, and Toxins Associated With Demyelinating Polyneuropathy Associated Disease, Drug, or Toxin

Sensory, Motor, or Sensorimotor

Axonal or Demyelinating

Diabetes mellitus (very common)

S, SM, or rarely M

A and D

Chronic liver disease

S or SM

A and D

Polyneuropathy usually mild

Lymphoma (Hodgkin and non-Hodgkin)

SM

A and D

Usually axonal but sometimes demyelinating polyneuropathy

MM

S, M, or SM

A

Uncommon and usually axonal

Myeloma (osteosclerotic)

SM

D

Usually demyelinating; might be associated with POEMS syndrome

S or SM

D

IgM most common; may bind to MAG; usually demyelinating predominantly sensory polyneuropathy

Amiodarone (antiarrhythmic)

SM

D and A

Prominent demyelination; also tremor, optic neuropathy; dose related

Chloroquine (antimalarial)

SM

A and D

Mild demyelination; principal toxicity is myopathy

Suramin (antiparasitic, antineoplastic)

M>S

D and A

Prominent demyelination; resembles GBS; related to maximal plasma levels >350 g/mL

Arsenic (insecticide, herbicide; also from smelting and wood preservative industries); might be given with suicidal or homicidal intent

SM

A; acutely may have D

Onset with painful sensory symptoms followed by weakness; prominent systemic effects (gastrointestinal symptoms, anemia) and skin/ nail changes (Mees lines); acute intoxication may cause a Guillain-Barré–like syndrome

Diphtheria toxin (protein exotoxin from Corynebacterium diphtheriae)

SM

D

Rare; begins 8–12 weeks after infection; may be confused with GBS

Hexacarbons: n-hexane and methyl; n-butyl ketone (solvents)

SM

A and D

Exposure via inhalation such as inhalational abuse of gasoline or glue

Comment

Diseases Most common cause of chronic polyneuropathy

MGUS IgM

Drugs

Toxins

Abbreviation: MAG, myelin-associated glycoprotein. Source: England and Asbury (3).

CHAPTER 29: Laboratory Evaluation of Peripheral Neuropathies  451

patients with low CD4 counts. The CSF in patients with HIV with inflammatory demyelinating neuropathies is characterized by a mild lymphocytic pleocytosis (117). In contrast, the CSF in CMV polyradiculopathy has polymorphonuclear pleocytosis and hypoglycorrhachia (117). The diagnosis of CMV polyradiculopathy is made in the appropriate clinical setting, when the above CSF findings and a positive test result for CMV DNA in the CSF are present. A superimposed CMV myelitis can be present. toxins and drugs. Most toxic neuropathies, as listed in Table 29.2, are axonal (1,93). Diphtheria toxin, n-hexane, arsenic, tacrolimus, gold, procainamide, amiodarone, suramin, and cytosine arabinoside are the exceptions (93). Additional etiologies for demyelinating neuropathies are listed in Table 29.3.

LABORATORY EVALUATION FOR ACUTE POLYNEUROPATHY Immune-Mediated Acute Polyneuropathies Acute inflammatory demyelinating polyneuropathy or GBS is the most common of the polyneuropathies presenting acutely, with an incidence of 1.3 to 1.6 in 100 000 (118,119). The main ancillary test in the diagnosis of GBS, besides EDX studies, is the evaluation of CSF. The classic finding of albuminocytologic dissociation, that is, increased protein level with normal cell count, is present in 80% to 90% of patients with GBS (118). There are a few potential caveats: CSF protein level may be normal in the first 2 to 3 weeks, and very occasionally, patients may have a lymphocytic pleocytosis greater than 10 cells per mm3 (118). However, the presence of a lymphocytic pleocytosis should prompt one to consider other etiologies, such as infectious agents, especially early HIV infection (70). (Please see HIV section.) Several antiglycolipid antibodies have been described in association with GBS (26). For example, serum IgG antiGM1 antibody has been associated with acute motor axonal neuropathies, especially in China, Japan, and Third-World countries. This antibody is associated with an axonal form of GBS termed acute motor axonal neuropathy, which is usually preceded by Campylobacter jejuni infection (108). However, the diagnostic value of the antineural antibodies in classic GBS is inconclusive given the broad range of specificities among all of them. Nonetheless, in some of the GBS variants, such as Miller-Fisher syndrome, a more clear and constant association has been reported with anti-GQ1b/GT1a antibodies (108). In cases where the classic clinical triad of ophthalmoplegia, ataxia, and areflexia is missing, the anti-GQ1b antibody might help to establish the diagnosis.

mon infectious agents causing acute neuropathies will be reviewed below. West Niles Virus Although encephalitis is the most common neurologic manifestation of West Niles virus infection, a motor neuronopathy and a demyelinating neuropathy have been identified (120). Besides encephalitis, the most common neurologic complication of West Nile virus is poliomyelitis with asymmetric flaccid weakness secondary to lower motor neuron damage. Antibody detection tests are commercially available. Rabies In addition to the well-recognized encephalitis or the so-called “furious form,” rabies causes a less common “paralytic form” (121). The clinical presentation has been compared to GBS, with acute ascending weakness and autonomic dysfunction (121,122). Sometimes, the weakness starts in the extremity closest to the site of inoculation, but the final outcome is always a severe quadriplegia. The EDX studies most commonly suggest an axonal process (121,122). Unlike GBS, the CSF shows a lymphocytic pleocytosis. Rabies antibodies in serum and CSF should be ordered.

Systemic Diseases Acute intermittent porphyria, although uncommon, is described to produce an acute axonal polyneuropathy. Urine porphyrin analysis is the recommended laboratory test upon that diagnostic suspicion. Clinical pictures similar to GBS have also been reported secondary to sarcoid and connective tissue diseases, such as systemic lupus erythematosus (61,123,124). In patients with sepsis and multiorgan failure, a critical illness polyneuropathy may occur (125). The role of laboratory tests in these cases is to exclude other treatable and reversible conditions.

Toxins Toxic neuropathies can present acutely but are frequently associated with systemic manifestations, including CNS involvement (Tables 29.2 and 29.3). Vitamin B6 excess can cause an acute sensory neuronopathy, as mentioned previously.

Metabolic Derangements Cases resembling GBS have been associated with hypophosphatemia, mostly secondary to hyperalimentation (126,127). An acute syndrome characterized by rapidly progressive weakness has been described in acute renal failure (75).

Infections

CONCLUSIONS

Infections, such as HIV, CMV, hepatitis B and C, and that in Lyme disease, have been previously discussed as an etiology for an acute polyneuropathy. Other uncom-

Multiple etiologies may be responsible for a DSP. Some etiologies are easily treatable, such as some vitamin deficiencies, while others indicate a less favorable course and

452  Textbook of Peripheral Neuropathy

prognosis, such as some lymphoproliferative diseases. The diagnosis of a genetic neuropathy carries implications not only for patients but also for their offspring. Regardless of all efforts, 20% to 25% of peripheral neuropathies remain cryptogenic (3). The cryptogenic peripheral neuropathies have a mild, slowly progressive course (4–7). In summary, the search for the cause of the neuropathies is important in counseling patients regarding management and prognosis, even when no cause is found.

Key Points • The laboratory evaluation of chronic DSP should include the following as screening tests: blood glucose levels, serum B12 levels with or without metabolites (MMA and Hcy), and serum IFE, as per the Polyneuropathy Task Force’s guidelines (1). • In addition to the above laboratory studies, CBC, comprehensive metabolic panel, erythrosedimentation rate, and thyroid function tests are also recommended based upon expert opinions (1,4–7). • Other tests specific for inherited neuropathies, rheumatologic conditions, infectious agents, and toxins, among others, are indicated based upon clinical suspicion and the results of the aforementioned tests. • The classification of polyneuropathies according to the anatomic localization, fiber type involved, onset and course, and pathogenesis (ie, demyelination versus axonal damage) is essential in narrowing the differential diagnosis accordingly. • A stepwise laboratory evaluation guided by this differential diagnosis is an appropriate and cost-effective method to achieve this end.

References 1. England JD, Gronseth GS, Franklin G, et al. Practice Parameter: Evaluation of distal symmetric polyneuropathy: Role of laboratory and genetic testing (an evidence-based review). Neurology. 2009;72:185–192. 2. England JD, Gronseth GS, Franklin G, et al. Distal symmetric polyneuropathy: A definition for clinical research. Neurology. 2005;64(2):199–207. 3. England JD, Asbury AK. Peripheral neuropathy. Lancet. 2004;363:2151–2161. 4. Jann S, Beretta S, Bramerio M, et al. Prospective follow-up study of chronic polyneuropathy of undetermined cause. Muscle Nerve. 2001;24:1197–1201. 5. McLeod JG, Tuck RR, Pollard JD, et al. Chronic polyneuropathy of undetermined cause. J Neurol Neurosurg Psychiatry. 1984;47:530–535. 6. Notermans NC, Wokke JH, Franssen H, et al. Chronic idiopathic polyneuropathy presenting in middle or old age:

a clinical and electrophysiological study of 75 p­atients. J Neurol Neurosurg Psychiatry. 1993;10:1066–1071. 7. Notermans NC, Wokke JH, van der Graaf Y, et al. Chronic idiopathic axonal polyneuropathy: a five year follow up. J Neurol Neurosurg Psychiatry. 1994;57: 1525–1527. 8. Anonymous. Report of the American Diabetes Association on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 2010;33(suppl 1):S62. 9. Duyff RF, Van den Bosch J, Laman DM, et al. Neuromuscular findings in thyroid dysfunction: a prospective clinical and electrodiagnostic study. J Neurol Neurosurg Psychiatry. 2000;68:750–755. 10. Asmahan F. Al-Shubaili, Sameer A, et al. Axonal and demyelinating neuropathy with reversible proximal conduction block, an unusual feature of vitamin B12 deficiency. Muscle Nerve. 1998;21:1341–1343. 11. Kumar N, Nutritional neuropathies. Neurol Clin. 2007; 25(1):209–255. 12. Marcuard SP, Albernaz L, Khazanie PG. Omeprazole therapy causes malabsorption of cyanocobalamin (vitamin B12). Ann Intern Med. 1994;120:211–215. 13. Jameson M, Roberts S, Anderson NE, et al. Nitrous oxide-induced vitamin B(12) deficiency. J ClinNeurosci. 1999;6(2):164–166. 14. Lubec D, Muellbacher W, Finsterer J, et al. Diagnostic work-up in peripheral neuropathy: an analysis of 171 cases. Postgrad Med J. 1999;75:723–727. 15. Saperstein DS, Wolfe GI, Gronseth GS, et al. Challenges in the identification of cobalamin-deficient polyneuropathy. Arch Neurol. 2003;60:1296–1301. 16. Lindenbaum J, Rosenberg IH, Wilson PWF, et al. Prevalence of cobalamin deficiency in the Framingham elderly population. Am J ClinNutr. 1994;60:2–11. 17. Savage DG, Lindenbaum J, Stabler SP, Allen RH. Sensitivity of serum methylmalonic acid and total homocysteine determinations for diagnosing cobalamin and folate deficiencies. Am J Med. 1994;96:239–246. 18. Carmel R. Folic acid. In: Shils ME, Shike M, Ross AC, et al, eds. Modern Nutrition in Health and Disease. 10th ed. Baltimore: Lippincott Williams and Wilkins; 2006: 470–481. 19. Parry TE. Folate responsive neuropathy. Presse Med. 1994; 23:131–137. 20. Goodman BP, Bosch EP, Ross MA, Hoffman-Snyder C, Dodick DD, Smith BE. Clinical and electrodiagnostic findings in copper deficiency myeloneuropathy. J Neurol Neurosurg Psychiatry. 2009;80(5):524–527. 21. Riggins S, England JD. Ataxias related to sensory neuropathies. In: Subramony SH, Durr A, eds. Handbook of Clinical Neurology. In Press: Elsevier; 2011. 22. Halfdanarson TR, Kumar N, Li CY, et al. Hematologica­l manifestations of copper deficiency: a retrospective r­eview. Eur J Haematol. 2008;80(6):523–531. 23. Greenberg SA, Briemberg HR. A neurological and hematological syndrome associated with zinc excess and copper deficiency. J Neurol. 2004;251(1):111–114. 24. Albin RL, Albers JW, Greenberg HS, et al. Acute sensory neuropathy-neuronopathy from pyridoxine overdose. Neurology. 1987;37(11):1729–1732. 25. Schaumburg H, Kaplan J, Windebank A, et al. Sensory neuropathy from pyridoxine abuse. A new megavitamin syndrome. N Engl J Med. 1983;309:445–448.

CHAPTER 29: Laboratory Evaluation of Peripheral Neuropathies  453 26. Dalton K, Dalton MJ. Characteristics of pyridoxine overdose neuropathy syndrome. Acta Neurol Scand. 1987;76(1): 8–11. 27. Mackey AD, Davis SR, Gregory JFI. Vitamin B6. In: Shils ME, Shike M, Ross AC, et al, eds. Modern Nutrition in Health and Disease. 10th ed. Baltimore: Lippincott W­illiams and Wilkins; 2006:452–461. 28. Koike H, Iijima M, Mori K, et al. Postgastrectomy p­olyneuropathy with thiamine deficiency is identical to beriberi neuropathy. Nutrition. 2004;20(11–12):961–966. 29. Kuriyama M, Yokomine R, Arima H, et al. Blood vitamin B1, transketolase and thiamine pyrophosphate (TPP) e­ffect in beriberi patients, with studies employing discriminant analysis. Clin Chim Acta. 1980;108(2):159–168. 30. Nordentoft M, Timm S, Hasselbalch E, et al. Thiamine pyrophosphate effect and erythrocyte transketolase activity during severe alcohol withdrawal syndrome. Acta Psychiatr Scand. 1993;88(2):80–84. 31. Traber MG, Jialal I. Measurement of lipid-soluble vitamins—further adjustment needed? Lancet. 2000;355:2013– 2014. 32. Ropper AH. Accelerated neuropathy of renal failure. Arch Neurol. 1993;50(5):536–539. 33. Chaudhry V, Corse AM, O’Brian R, et al. Autonomic and peripheral (sensorimotor) neuropathy in chronic liver disease: a clinical and electrophysiologic study. Hepatology. 1999;29(6):1698–1703. 34. Vina ER, Fang AJ, Wallace DJ, et al. Chronic inflammatory demyelinating polyneuropathy in patients with systemic lupus erythematosus: prognosis and outcome. Semin Arthritis Rheum. 2005;35(3):175–184. 35. Lacomis D, Zivkovic´ SA. Approach to vasculitic neuropathies. J Clin Neuromuscul Dis. 2007;9(1):265–276. 36. Guillevin L, Lhote F, Gherardi R. Polyarteritisnodosa, microscopic polyangiitis, and Churg-Strauss syndrome: clinical aspects, neurologic manifestations, and treatment. Neurol Clin. 1997;15(4):865–886. 37. Pestronk A. Autoantibodies and immune polyneuropathies. In: Katirji B, Kaminski H, Preston D, et al, eds. Neuromuscular Disorders in Clinical Practice. Woburn: Butterworth-Heinemann; 2002:48–57. 38. Kelly J, Kyle R, O’Brien PC, et al. Prevalence of monoclonal protein in peripheral neuropathy. Neurology. 1981;31:1480. 39. Kissel JT, Mendell JR. Neuropathies associated with monoclonal gammopathies. Neuromuscul Disord. 1996;6(1): 3–18. 40. Willison HJ, O’Leary CP, Veitch J, et al. The clinical and laboratory features of chronic sensory ataxic neuropathy with anti-disialosyl IgM antibodies. Brain. 2001;124(pt 10): 1968–1977. 41. Quarles RH, Weiss MD. Autoantibodies associated with peripheral neuropathy. Muscle Nerve. 1999;22(7):800–822. 42. Ponsford S, Willison H, Veitch J, et al. Long-term clinical and neurophysiological follow-up of patients with peripheral, neuropathy associated with benign monoclonal gammopathy. Muscle Nerve. 2000;23(2):164–174. 43. Susuki K, Yuki N, Hirata K. Features of sensory ataxic neuropathy associated with anti-GD1b IgM antibody. J Neuroimmunol. 2001;112(1–2):181–187. 44. Carpo M, Meucci N, Allaria S, et al. Anti-sulfatide IgM antibodies in peripheral neuropathy. J Neurol Sci. 2000;176(2):144–150.

45. Petratos S, Turnbull VJ, Papadopoulos R, et al. High-titre IgM anti-sulfatide antibodies in individuals with IgM paraproteinaemia and associated peripheral neuropathy. Immunol Cell Biol. 2000;78(2):124–132. 46. Erb S, Ferracin F, Fuhr P, et al. Polyneuropathy attributes: a comparison between patients with anti-MAG and antisulfatide antibodies. J Neurol. 2000;247(10):767–772. 47. Tschernatsch M, Stolz E, Strittmatter M, et al. Antinuclear antibodies define a subgroup of paraneoplastic neuropathies: clinical and immunological data. J Neurol Neurosurg Psychiatry. 2005;76(12):1702–1706. 48. Antoine JC, Mosnier JF, Absi L, et al. Carcinoma associated paraneoplastic peripheral neuropathies in patients with and without anti-onconeural antibodies. J Neurol Neurosurg Psychiatry. 1999;67(1):7–14. 49. Amato AA, Collins MP. Neuropathies associated with malignancy. Semin Neurol. 1998;18(1):125–144. 50. Dalmau J, Graus F, Rosenblum MK, et al. Anti-Hu– associated paraneoplastic encephalomyelitis/sensory neuronopathy. A clinical study of 71 patients. Medicine (Baltimore). 1992;71(2):59–72. 51. Senties-Madrid H, Vega-Boada F. Paraneoplastic syndromes associated with anti-Hu antibodies. Isr Med Assoc J. 2001;3(2):94–103. 52. Molinuevo JL, Graus F, Serrano C, et al. Utility of anti-Hu antibodies in the diagnosis of paraneoplastic sensory neuropathy. Ann Neurol. 1998;44(6):976–980. 53. Graus F, Ribalta T, Campo E, et al. Immunohistochemical analysis of the immune reaction in the nervous system in paraneoplastic encephalomyelitis. Neurology. 1990;40(2):219–222. 54. Dalmau J, Furneaux HM, Gralla RJ, et al. Detection of the anti-Hu antibody in the serum of patients with small cell lung cancer—a quantitative Western blot analysis. Ann Neurol. 1990;27(5):544–552. 55. Antoine JC, Honnorat J, Camdessanché JP, et al. Paraneoplastic anti-CV2 antibodies react with peripheral nerve and are associated with a mixed axonal and demyelinating peripheral neuropathy. Ann Neurol. 2001;49(2): 214–221. 56. Hadjivassiliou M, Grünewald RA, Davies-Jones GA. Gluten sensitivity as a neurological illness. J Neurol Neurosurg Psychiatry. 2002;72(5):560–563. 57. Ainslie GM, Benatar SR. Serum angiotensin converting enzyme in sarcoidosis: sensitivity and specificity in diagnosis: correlations with disease activity, duration, extrathoracic involvement, radiographic type and therapy. Q J Med. 1985;55(218):253–270. [ABSTRACT] 58. Khan AH, Ghani F, Khan A, et al. Role of serum angiotensin converting enzyme in sarcoidosis. J Pak Med Assoc. 1998;48(5):131–133. [ABSTRACT] 59. Sainani GS, Mahbubani V, Trikannad V. Serum angiotensin converting enzyme activity in sarcoidosis and pulmonary tuberculosis. J Assoc Physicians India. 1996;44(1):29–30. [ABSTRACT]. 60. Podwysocki B, Skowron-Szlósarczyk S, Zwolin´ski J, et  al. The usefulness of serum angiotensin-converting e­nzyme test in the diagnosis of sarcoidosis. Mater Med Pol. 1991;23(2):121–124. [ABSTRACT] 61. Said G, Lacroix C, Planté-Bordeneuve V, et al. Nerve granulomas and vasculitis in sarcoid peripheral neuropathy: a clinicopathological study of 11 patients. Brain. 2002;125:264–275.

454  Textbook of Peripheral Neuropathy 62. Burns TM, Dyck PJ, Aksamit AJ, et al. The natural history and long-term outcome of 57 limb sarcoidosis neuropathy cases. J Neurol Sci. 2006;244(1–2):77–87. 63. Hoitsma E, Marziniak M, Faber CG, et al. Small fibre neuropathy in sarcoidosis. Lancet. 2002;359(9323): 2085–2086. 64. Scott TS, Brillman J, Gross JA. Sarcoidosis of the peripheral nervous system. Neurol Res. 1993;15(6):389–390. 65. Oksanen V, Fyhrquist F, Somer H, et al. Angiotensin converting enzyme in cerebrospinal fluid: a new assay. Neurology. 1985;35:1220–1223. 66. Chapelon C, Ziza JM, Piette JC, et al. Neurosarcoidosis: signs, course and treatment in 35 confirmed cases. Medicine. 1990;69:261–276. 67. Scott TF. Neurosarcoidosis: progress and clinical aspects. Neurology. 1993;43:8–12. 68. Skacel M, Antunes SL, Rodrigues MM, et al. The diagnosis of leprosy among patients with symptoms of peripheral neuropathy without cutaneous lesions: a follow-up study. Arq Neuropsiquiatr. 2000;58(3B):800–807. 69. van Brakel WH, Nicholls PG, Wilder-Smith EP, et al. Early diagnosis of neuropathy in leprosy—comparing diagnostic tests in a large prospective study (the INFIR cohort study). PLoS Negl Trop Dis. 2008;2(4):212. 70. Ferrari S, Vento S, Monaco S, et al. Human immunodeficiency virus–associated peripheral neuropathies. Mayo Clin Proc. 2006;81(2):213–219. 71. Centers for Disease Control (CDC). Update: serologic testing for HIV-1 antibody—United States, 1988 and 1989. MMWR Morb Mortal Wkly Rep. 1990;39(22):380–383. 72. Santoro L, Manganelli F, Briani C, et al. Prevalence and characteristics of peripheral neuropathy in hepatitis C virus population. J Neurol Neurosurg Psychiatry. 2006;77(5):626–629. 73. Cacoub P, Renou C, Rosenthal E, et al .Extrahepatic manifestations associated with hepatitis C virus infection. A prospective multicenter study of 321 patients. Medicine (Baltimore). 2000;79(1):47–56. 74. Apartis E, Léger JM, Musset L, et al. Peripheral neuropathy associated with essential mixed cryoglobulinaemia: a role for hepatitis C virus infection? J Neurol Neurosurg Psychiatry. 1996;60(6):661–666. 75. Ropper AH. The Guillain-Barré syndrome. N Engl J Med. 1992;326(17):1130–1136. 76. Caporale CM, Capasso M, Ragno M, et al. Lewis-Sumner syndrome in hepatitis C virus infection: a possible pathogenetic association with therapeutic problems. Muscle Nerve. 2006;34(1):116–121. 77. Berger JR, Ayyar R, Sheremata WA. Guillain-Barré syndrome complicating acute hepatitis B.A case with detailed electrophysiological and immunological studies. Arch Neurol. 1981;38:366–368. 78. Zaltron S, Puoti M, Liberini P, et al. High prevalence of peripheral neuropathy in hepatitis C virus infected patients with symptomatic and asymptomatic cryoglobulinaemia. Ital J Gastroenterol Hepatol. 1998;30(4):391–395. 79. Sexton DJ. Diagnosis of Lyme Disease. Up to date. Oct 11, 2010. Web. 20 May, 2011. http://www.uptodate. com/contents/diagnosis-of-lymedisease?source=search_ result&selectedTitle=2%7E150. 80. Halperin J, Luft BJ, Volkman DJ, et al. Lyme neuroborreliosis. Peripheral nervous system manifestations. Brain. 1990;113:1207.

81. England JD, Bohm RP Jr, Roberts ED, et al. Mononeuropathy multiplex in rhesus monkeys with chronic Lyme disease. Ann Neurol. 1997;41(3):375. 82. Centers for Disease Control and Prevention (CDC). Recommendations for test performance and interpretation from the Second National Conference on Serologic Diagnosis of Lyme Disease. MMWR Morb Mortal Wkly Rep. 1995;44(31):590. 83. Leite AC, Silva MT, Alamy AH, et al. Peripheral neuropathy in HTLV-I infected individuals without tropical spastic paraparesis/HTLV-I–associated myelopathy. J Neurol. 2004;251(7):877–881. 84. Saeidi M, Sasannejad P, Foroughipour M, et al. Prevalence of peripheral neuropathy in patients with HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/ TSP). Acta Neurol Belg. 2011;11(1):41–44. 85. Kiwaki T, Umehara F, Arimura Y, et al. The clinical and pathological features of peripheral neuropathy accompanied with HTLV-I associated myelopathy. J Neurol Sci. 2003;206(1):17–21. 86. Puccioni-Sohler M, Rios M, Carvalho SM, et al. Diagnosis of HAM/TSP based on CSF proviral HTLV-I DNA and HTLV-I antibody index. Neurology. 2001;57(4): 725–727. 87. Rubin DI, Daube JR. Subacute sensory neuropathy associated with Epstein-Barr virus. Muscle Nerve. 1999; 22(11):1607–1610. 88. Grose C, Henle W, Henle G, et al. Primary Epstein-Barrvirus infections in acute neurologic diseases. N Engl J Med. 1975;20;292(8):392–395. [ABSTRACT] 89. Liveson JA, Goodgold J. Mononeuritis multiplex associated with infectious mononucleosis. Can J Neurol Sci. 1974;1(3):203–205. [ABSTRACT] 90. Cresswell F, Eadie J, Longley N, et al. Severe GuillainBarré syndrome following primary infection with varicella zoster virus in an adult. Int J Infect Dis. 2010;14(2): e161–e163. 91. Lehmann HC, Hartung HP. Varicella-zoster virus: another trigger of Guillain-Barré syndrome? Clin Infect Dis. 2010;51(5):531–533. 92. Mellion M, Gilchrist JM, de la Monte S. Alcohol-related peripheral neuropathy: nutritional, toxic, or both? Muscle Nerve. 2011;43(3):309–316. 93. Misra UK, Kalita J. Toxic neuropathies. Neurol India. 2009;57:697–705. 94. Toyooka K, Fujimura H. Iatrogenic neuropathies. Curr Opin Neurol. 2009;22:475–479. 95. Szigeti K, Lupski JR. Charcot-Marie-Tooth disease. Eur J Hum Genet. 2009;17:703–710. 96. Verhoeven K, Claeys KG, Zuchner S, et al. MFN2 mutation distribution and genotype/phenotype correlation in Charcot-Marie-Tooth type 2. Brain. 2006;129: 2093–2102. 97. Janssen EA, Kemp S, Hensels GW, et al. Connexin32 gene mutations in X-linked dominant Charcot-Marie-Tooth disease (CMTX1). Hum Genet. 1997;99:501–505. 98. Reilly MM. Inherited metabolic neuropathies. In: Katirji B, Kaminski H, Preston D, et al, eds. Neuromuscular Disorders in Clinical Practice. Woburn: ButterworthHeinemann; 2002:526–530. 99. Braathen GJ, Sand JC, Lobato A, et al. Genetic epide­ miology of Charcot-Marie-Tooth in the general population. [Abstract]. Eur J Neurol. 2010;18(1):39–48.

CHAPTER 29: Laboratory Evaluation of Peripheral Neuropathies  455 100. Nelis E, Van Broeckhoven C, De Jonghe P, et al. Estimation of the mutation frequencies in Charcot-Marie-Tooth disease type 1 and hereditary neuropathy with liability to pressure palsies: a European collaborative study. Eur J Hum Genet. 1996;4:25–33. 101. Boerkoel CF, Takashima H, Garcia CA, et al. CharcotMarie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation. Ann Neurol. 2002;51:190–201. 102. Saperstein DS, Katz JS, Amato AA, et al. Clinical spectrum of chronic acquired demyelinating polyneuropathies. Muscle Nerve. 2001;24(3):311–324. 103. Ad Hoc Subcommittee of the American Academy of Neurology AIDS Task Force. Research criteria for diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Neurology. 1991;41(5):617–618. 104. Latov N. Pathogenesis and therapy of neuropathies associated with monoclonal gammopathies. Ann Neurol. 1995;37(suppl l):S32–S42. 105. Kahn SN, Bina M. Sensitivity of immunofixation electrophoresis for detecting IgM paraproteins in serum. Clin Chem. 1988;34:1633–1635. 106. Kulkarni GB, Mahadevan A, Taly AB, et al. Clinicopathological profile of polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes (POEMS) syndrome. J Clin Neurosci. 2011;18(3):356–360. 107. Isoardo G, Ferrero B, Barbero P, et al. Anti-GM1 and antisulfatide antibodies in polyneuropathies. Threshold titers and accuracy. Acta Neurol Scand. 2001;103(3):180–187. 108. Willison HJ, Yuki N. Peripheral neuropathies and antiglycolipid antibodies. Brain. 2002;125:2591–2625. 109. Kaku D, England JD, Sumner AJ. Distal accentuation of conduction slowing in polyneuropathy associated with antibodies to myelin associated glycoprotein and sulfated glucuronylparagloboside. Brain. 1994;117:941–947. 110. Pestronk A. Autoantibodies and immune polyneuropathies. In: Katirji B, Kaminski H, Preston D, et al, eds. Neuromuscular Disorders in Clinical Practice. Woburn: Butterworth-Heinemann; 2002:48–57. 111. Cats EA, Jacobs BC, Yuki N, et al. Multifocal motor neuropathy: association of anti-GM1 IgM antibodies with clinical features. Neurology. 2010;75(22):1950–1951. 112. Minagar A. GALOP syndrome: a treatable immunemediated late-age onset polyneuropathy with gait ataxia. South Med J. 2004;97(4):333–334.

113. Pestronk A, Choksi R, Bieser K, et al. Treatable gait disorder and polyneuropathy associated with high titer serum IgM binding to antigens that copurify with myelin-associated glycoprotein. Muscle Nerve. 1994;17(11):1293–1300. 114. Chin RL, Sander HW, Brannagan TH, et al. Celiac neuropathy. Neurology. 2003;60:1581–1585. 115. Bushara, KO. Neurologic presentation of celiac disease. Gastroenterology. 2005;128:S92–S97. 116. Hernandez L, Green PH. Extraintestinal manifestations of celiac disease. Curr Gastroenterol Rep. 2006;8(5):383–389. 117. Ferrari S, Vento S, Monaco S, et al. Human immunodeficiency virus–associated peripheral neuropathies. Mayo Clin Proc. 2006;81(2):213–219. 118. Chiò A, Cocito D, Leone M, et al. Guillain-Barré syndrome: A prospective, population-based incidence and outcome survey. Neurology. 2003;60;1146. 119. Hughes RAC, Rees JH. Clinical and Epidemiologic Features of Guillain-Barré Syndrome. J Infect Dis. 1997; 176(suppl 2):S92–S98. 120. Burton JM, Kern RZ, Halliday W, et al. Neurological manifestations of West Nile virus infection. Can J Neurol Sci. 2004;31(2):185–193. 121. Gadre G, Satishchandra P, Mahadevan A, et al. Rabies viral encephalitis: clinical determinants in diagnosis with special reference to paralytic form. J Neurol Neurosurg Psychiatry. 2010;81:812–820. 122. Sheikh KA, Ramos-Alvarez M, Jackson AC, et al. Overlap of pathology in paralytic rabies and axonal Guillain-Barré syndrome. Ann Neurol. 2005;57(5):768–772. 123. Chaudhuri KR, Taylor IK, Niven RM, et al. A case of systemic lupus erythematosus presenting as Guillain-Barré syndrome. Br J Rheumatol. 1989;28(5):440–442. 124. AïtBenhaddou E, Birouk N, El Alaoui-Faris M, et al. Acute Guillain-Barré–like polyradiculoneuritis revealing acute systemic lupus erythematosus: two case studies and review of the literature. Rev Neurol (Paris). 2003;159(3):300–306. 125. Bolton CF. Neuromuscular manifestations of critical illness. Muscle Nerve. 2005;32:140–163. 126. Sebastian S, Clarence D, Newson C. Severe hypophosphataemia mimicking Guillain-Barré syndrome. Anaesthesia. 2008;63(8):873–875. 127. Iguchi Y, Mori K, Koike H, et al. Hypophosphataemic neuropathy in a patient who received intravenous hyperalimentation. J Neurol Neurosurg Psychiatry. 2007;78(10): 1159–1160.

Index

AANEM (American Association of Neuromuscular and Electrodiagnostic Medicine) guidelines, 154 Abductor pollicis brevis (APB), 10, 10t Abetalipoproteinemia, 76–77, 283, 352 Abuse, drugs of, 356 Accommodation paralysis, 429 Acetaminophen, 178 Acetylators, 206 Acoustic neuromas, 400 Acquired demyelinating polyneuropathies, 444 Acromegaly, 312 Acrylamide neuropathy, 87–89. See also Toxic neuropathies clinical manifestations, 87–88 diagnostic evaluation, 89 differential diagnosis, 88–89, 88t, 89t electrophysiology, 88 treatment, 89 Activities of daily living (ADL), 157 Acute autonomic dysfunction, 177–178 gastrointestinal motility, 178 hypertension, 178 hypotension, 178 inpatient pain management, 178 prophylaxis for DVT, 178 tachycardia, 177–178 urinary retention, 178 Acute care hospitalization for GBS patients. See Guillain-Barré syndrome (GBS) Acute inflammatory demyelinating polyneuropathy (AIDP), 171, 172, 172f, 238, 331–332 Acute intermittent porphyria (AIP), 171t, 289, 292, 297–298, 353 Acute motor and sensory axonal neuropathy (AMSAN), 169 Acute motor axonal neuropathy (AMAN), 168, 347, 348 Acute neuropathies. See Peripheral neuropathies, laboratory evaluation of Acute-onset paralysis in children, 348t Acute porphyria, management of, 303t Acute sensory ataxic neuropathy, 281 Adjuvant analgesics, 328 Adjuvant therapy, 178 AIN. See Anterior interosseous nerve ALADIN III trial, 64 Albers-Schonberg disease, 413 Alcohol, 444 Alcoholic neuropathy (ALN), 80. See also Nutritional neuropathies defined, 80 diagnostic evaluation, 80

etiology, 80 pathogenesis, 80 TD and, 80 therapy, 80 Aldose reductase inhibitors for diabetic neuropathy, 64–65 Alemtuzumab, 197 Allgrove syndrome, 426 Allodynia, 326 ALN. See Alcoholic neuropathy American Academy of Neurology (AAN), 173 American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM), 154 American College of Rheumatology (ACR) classification, 249t Aminolaevulinate dehydratase deficiency porphyria, 291–292 Aminolevulinic acid, 290 Aminolevulinic acid dehydratase deficiency, 297 Aminolevulinic acid synthase (ALAS), 290 Amiodarone, 203 Amitriptyline, 203, 204, 327 Amivudine, 210 Amyloid neuropathy. See Autonomic peripheral neuropathy Amyloidosis, 222, 424 clinical manifestations, 227–228 diagnostic evaluation, 230, 230f differential diagnosis of, 228 electrophysiology, 230–231 hereditary, 227–228 pathogenesis and pathophysiology, 229 primary, 227 secondary, 442 specific protein abnormalities, 229 treatment of, 231–232 Amyotrophic lateral sclerosis (ALS), 122, 124t, 197 Anatomy median nerve, 9–10, 9f radial nerve, 19, 19f ulnar nerve, 15, 15f ANCAs. See Antineutrophil cytoplasmic antibodies Angiitis, 313 Angiokeratomas, 353 Angiotensinconverting enzyme (ACE), 392 Ankle bracing, 114 weakness, 109 Ankle-foot orthosis, 347 Anosmia, 399

458  index Anterioposterior x-rays, 157 Anterior interosseous nerve (AIN), 9, 10t Anterior interosseous neuropathy, 14–15, 14t. See also Median neuropathy diagnosis, 14 treatment, 14–15 Anterior primary rami (APR), 131, 132f Anterior tibialis muscle, 125 Anticonvulsants, 327 Antidepressants, 327 Antiganglioside antibodies, 168 Antigangliosides with disialosyl moieties, 449 Antigliadin antibodies, 442, 449 Anti-GM1 antibody, 449 Anti-GQ1b antibodies, 169, 170 Anti-Hu antibody, 427, 442 Anti-MAG antibody, 449 Antineural antibodies, 442, 449 Antineuronal nuclear antibody (type 1), 427 Antineutrophil cytoplasmic antibodies (ANCA), 45, 246, 441 Antioxidant agents for diabetic neuropathy, 64 Antiretroviral medications, 210, 264 Antisulfatide antibodies, 449 Antiviral medication, 161 APB. See Abductor pollicis brevis Apolipoprotein-B, 352 Ara-C, 211 Arachnoiditis, 161 Arborization, 117 Arsenic, 356, 447t Arsenic neuropathy, 89–91. See also Toxic neuropathies clinical manifestations, 89–90, 90f diagnostic evaluation, 90–91 differential diagnosis, 89t, 90 electrophysiology, 90, 90f treatment, 91 Ataxia and vitamin E deficiency, 77, 283, 352 Ataxic neuropathy, chronic, 276 Atypical DPN, 57 Autoimmune ataxic syndromes, 281–282 acute sensory ataxic neuropathy, 281 chronic sensory ataxic neuropathy, 281–282 Autoimmune autonomic ganglionopathy, 427 Autoimmune infection and MM, 41, 42t Autonomic nervous system dysfunction, 177–178 Autonomic neuropathy, 2–3 acute, 427 clinical manifestations, 238–239 diagnostic evaluation, 239 pathogenesis and pathophysiology, 239 treatment, 239 Autonomic peripheral neuropathy amyloid neuropathy background, 423–424 familial amyloid polyneuropathy, 424–425 primary amyloidosis, 424 diabetic autonomic neuropathy generalized, 421, 422 and impaired glucose tolerance, 423 transient autonomic dysfunction, 423 treatment-induced diabetic neuropathy, 423 due to infectious diseases

botulism, 428 Chagas disease, 429 diphtheria, 429 HIV infection, 428–429 leprosy, 429 hereditary autonomic neuropathies allgrove syndrome, 426 Fabry disease, 426 type I HSAN, 425 type II HSAN, 425 type III HSAN, 425–426 type IV HSAN, 426 type V HSAN, 426 immune-mediated autonomic neuropathies acute/subacute autonomic neuropathies, 427 autoimmune autonomic ganglionopathy, 427 inflammatory demyelinating polyneuropathy, 428 known immune-mediated disorders, 427–428 parainfectious autonomic neuropathy, 428 paraneoplastic autonomic neuropathies, 427, 427t outline of, 421, 422t toxic neuropathies, 429 Autonomic reflex testing, 239 Autosomal dominant inheritance, 107, 109–111, 110f. See also Demyelinating CMT Autosomal recessive disorder, 342 Autosomal recessive inheritance, 112–113 Autosomal recessive sensory ataxia of Charlevoix Saguenay (ARSACS), 351–352 Autosomal recessive trait, 206 Axilla radial neuropathy at, 19 Axillary neuropathy, 22–23, 23t Axonal Charcot-Marie-Tooth disease, 112 Axonal degeneration versus segmental demyelination, 42, 43t Axonal injury, 122, 169 Axonal loss, 111 Axonal neurofilament (NfH), 168 Axonal neuropathy, acute, 172–173 Axonal polyneuropathies acquired antigliadin antibodies, 442 anti-Hu antibody, 442 cerebrospinal fluid, 443 cryoglobulins, 443 endocrine tests, 439–440 laboratory tests, 443–444 serum angiotensin-converting enzyme, 442–443 tests related to systemic diseases/infections, 441–442 toxins, 444 vitamin levels, 440–441 inherited, 444 Axonal transport, 153 Axons, 204t Azathioprine, 196, 254 Babinski signs, 6 Bariatric surgery (BS), 311 bypass procedures, 80 neuropathy related to, 80–82 clinical features, 81 etiology, 81

index  459 pathogenesis, 81 therapy, 81–82 restrictive procedures, 80 Bassen-Kornzweig disease, 352 Bence Jones proteins, 441 “Benedictine” hand, 16 Benign monoclonal gammopathies, 449 Benign paroxysmal positional vertigo (BPPV), 399 Bickerstaff’s brainstem encephalitis (BBE), 169–170, 281 Biopsies, 276, 277f Bladder dysfunction, 178, 231, 421 Blink reflex, 383, 392–393 Blood, 63 and biological parameters, 275, 276 pressure monitoring, 177 Bolton’s neuropathy (BN) clinical features, 363–364 differential diagnosis of, 368–370, 369t, 370t critical illness myopathy, 368, 370 neuromuscular junction (NMJ) abnormalities, 370 electrophysiological studies, 364–365 mechanisms, 366, 367, 368 nerve and muscle pathology, 365–366, 365f, 366f–367f overview of, 363 prevalence, 363 therapy and prognosis, 371 Bone disorders, 413 Borrelia burgdorferi, 41, 355 Borreliosis. See Lyme disease (LD) Bortezomib, 212 Botulinum toxin, 91–92, 92t. See also Toxic neuropathies clinical manifestations, 91 diagnosis, 91–92 electrophysiology, 91 treatment, 92 Botulism, 171t, 428 Brachial and lumbosacral plexopathy disorders of brachial plexus, 138–145 Burner or stinger syndrome, 139–140 hereditary neuralgic amyotrophy, 141 medial brachial fascial compartment syndrome, 142, 142f median sternotomy brachial plexopathy, 141f, 142 neoplastic plexopathy, 142–143 neuralgic amyotrophy, 140–141 neurogenic thoracic outlet syndrome, 141–142, 141f radiation-induced brachial plexopathy, 143 rucksack palsy, 140 trauma, 139 disorders of lumbosacral plexus hematoma, 145 lumbosacral radiculoplexus neuropathy (LRPN), 143–144 neoplastic lumbosacral plexopathy, 144 obstetric lumbosacral plexopathy, 144–145 radiation-induced lumbosacral plexopathy, 144 trauma, 145 evaluation of clinical features, 137–138, 137t electrodiagnostic evaluation, 138, 138t outline of, 131, 131t pathology and pathophysiology, 136–137 plexus anatomy

brachial plexus, 131–133, 132f, 133f lumbosacral plexus, 133–136, 133f, 134f, 134t, 135t Brachial plexitis, acute, 251 Brachial plexopathy, 113 Brachial plexus, 131–133 cords, 133 divisions and anatomy, 132, 133f roots, 131, 132f terminal nerves, 133 trunks, 132 Brainstem syndromes, 407–409, 408t–409t BS. See Bariatric surgery Buckthorn toxicity, 171t Bulbar-predominant dysfunction, 349 Burner or stinger syndrome, 139–140 Burning feet syndrome, 79 Bypass procedures of bariatric surgery, 80 Bystander injury, 169 Camp foot, 79 Cancer, neuropathies with tumor infiltration cranial neuropathies, 314–315 neuropathies, 315 plexopathies, 315 radicuplopathies, 315 Cannabis, 328 Capillary stasis, 153 Capsaicin, 329, 329f Carbamates toxicity, 97. See also Toxic neuropathies Carbamazepine, 282 Carbon disulfide neuropathy, 89t, 92–93. See also Toxic neuropathies clinical manifestations, 92–93 diagnosis, 89t, 93 electrophysiology, 93 treatment, 93 Carbon disulphide, 447t Carboplatin, 211 Carcinomatous meningitis, 161, 315 Cardiac autonomic neuropathy (CAN), 422 Cardiovascular monitoring, 177 Carpal tunnel syndrome (CTS), 227, 231, 249, 316. See also Median neuropathy diagnosis of, 11, 11t diagnostic tests, 13 electrophysiology in, 11–13, 12t treatment, 13 Cauda equina, 151, 152f Cavernous sinus syndrome, 414 Cavernous sinus thrombosis, 414 CB. See Conduction block Celiac disease, 310, 428 Central nervous system (CNS), 341 fungal infections, 411 Central pontine myelinolysis, 370 Central sensitization, 326 Cerebellar ataxia, 234t Cerebellar dysfunction, acute, 211 Cerebellar syndrome, 294 Cerebellopontine angle, 414–415 tumor, 391, 401

460  index Cerebrospinal fluid (CSF), 443 analysis, 140, 191 findings in GBS, 168 testing, 416 Cerebrotendinous xanthomatosis (CTX), 352 Cerebrovascular disease, 353 Cervical nerve roots, 150 Cervical radiculopathy, 150t Cervical radiculoplexus neuropathy diabetes mellitus and, 60–61 Chagas disease, 267, 429 Charcot-Marie-Tooth (CMT) neuropathy, 188, 344–347, 345t Charcot-Marie-Tooth disease classification, 107–113, 108t with autosomal recessive inheritance, 112–113 axonal CMT, 112 demyelinating/dysmyelinating CMT, 107, 109–111, 110f inherited neuropathies with nerve susceptibility, 111–112 X-linked CMT, 111 diagnosis, 113–114 hereditary brachial plexopathy, 113 management, 114 peripheral neuropathy and, 4, 6 Cheilitis granulomatosa, 381 Chemotherapeutic agents bortezomib, 212 cytosine arabinoside, 212 efosfamide, 212 eribulin, 212 etoposide, 212 gemcitabine, 212 hexamethylmelamine, 212 ixabepilone, 212 platinum agents, 211 suramin, 212 taxanes, 211 teniposide, 212 vinca alkaloid, 211 Chemotherapy-induced peripheral neurotoxicity, 282 Chemotherapy-induced SNN, 282–283 Childhood immunization, 267 Childhood polyneuropathies, 340f Chironex fleckeri, 429 Chronic hepatic disease, 309 Chronic idiopathic axonal polyneuropathy (CIAP), 219 Chronic inflammatory demyelinating polyneuropathy (CIDP), 332 in diabetes mellitus, 59–60 peripheral neuropathy and, 4 Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), 350–351 biomarkers, 190 clinical manifestations of, 187–188 diagnosis of, 190–191, 192t–193t CSF analysis, 191 imaging, 191 nerve biopsy, 191 differential diagnosis for, 188, 189t electrophysiology, 190, 191, 194t–195t genetics, 190 histopathology, 188, 189

immunological studies, 189–190 overview of, 187, 188t treatment of corticosteroids, 191 immunosuppressive/immunomodulatory agents, 196–197 intravenous immunoglobulins, 191, 196 plasmapheresis, 196 Chronic inflammatory neuropathy, 228 Chronic meningitis. See Multiple cranial neuropathies (MCN) Chronic obstructive pulmonary disease (COPD), 312–313 Chronic sensory ataxic neuropathy, 281–282 Churg-Strauss syndrome (CSS), 45, 247 CIDP. See Chronic inflammatory demyelinating polyneuropathy Ciguatera poisoning, 429 Ciguatoxins, 429 Cisplatin, 211, 446t “Claw” hand, 16 Clofazimine, 263 Clofibrate, 204 Clostridium botulinum, 428 CMAP. See Compound muscle action potential CMT. See Charcot-Marie-Tooth disease Coasting, 210 Cobalamin, 343 deficiency, 440 (see also Vitamin B12 deficiency, neuropathy and) Cockayne syndrome, 352 Colchicine, 204–205, 446t Collapsing-response mediator proteins (CRMP), 237 Collet-Sicard syndrome, 415 Common peroneal nerve, 32–33, 32t, 33t Complete blood count (CBC), 441 Compound muscle action potential (CMAP), 44, 118, 119f, 122f, 123f, 138, 141, 155, 168, 197, 309, 364, 382 Computed tomography (CT), 157 Conduction block (CB), 253 autoimmunity and, 41 electrodiagnosis, 44, 44f, 45f Conductive hearing loss, 400 Congenital sensory neuropathy, 425 Congo red-stained tissue, 229, 230f Connective tissue diseases rheumatoid arthritis (RA), 316 scleroderma, 317 Sjögren syndrome, 316–317 systemic lupus erythematosus (SLE), 315–316 Connective tissue disorders vasculitis secondary to, 46–47 Copper, 440 Copper deficiency, neuropathy and, 77–78, 78t clinical features, 77–78 diagnostic evaluation, 78 etiology, 77 pathogenesis, 77 therapy, 78 Coproporphyrinogen, 291, 298, 299 Coproporphyrinogen oxidase, 301 Cords, 133 Corneal reflex testing, 379 Corticosteroids, 175, 191, 254, 310 Corynebacterium diphtheriae, 266, 354

index  461 Cranial nerve, 399 Cranial neuropathies, 246, 314–315, 316 diabetes mellitus and, 60 Craniofacial trauma, 390 Creatine kinase (CK), 283 Critical illness myopathy (CIM), 368, 370 Critical illness polyneuropathy (CIP). See Bolton’s neuropathy (BN) Crocodile tears, 380 Crohn disease treatment, 207 Crow-fukase syndrome, 238 Cryoglobulinemia, 224, 247–248, 310 Cryoglobulins, 443 CSS. See Churg-Strauss syndrome CTS. See Carpal tunnel syndrome Cutaneous nerve biopsy, 317 Cyclooxygenase 2 (Cox-2), 153 Cyclophosphamide, 196, 220 Cyclosporine, 196, 213 Cytochrome, 289 Cytomegalovirus (CMV), 171t, 449, 450–451 polyradiculopathy, 332–333 radiculitis, 161 Cytosine arabinoside, 212 DAN. See Diabetic autonomic neuropathy Dapsone, 205, 263, 446t D-drugs (neurotoxic dideoxynucleoside), 333 Deep peroneal nerve, 32t, 33–34, 33f, 33t Dejerine-Sottas disease (DSD), 107, 340, 342, 346 peripheral neuropathy and, 4 Demyelinating CMT, 107, 109–111, 110f genetics, 109 nerve conduction testing, 109–110 pathology, 110–111, 110f Demyelinating inflammatory polyneuropathy, 264 Demyelinating neuropathies, 284 clinical manifestations, 238 diagnostic evaluation, 238 electrophysiology, 238 hereditary neuropathy with liability to pressure palsies, 51–52, 52f MMN, 52 pathogenesis and pathophysiology, 238 treatment, 238 Demyelinating polyneuropathies acquired, 444 antigangliosides with disialosyl moieties, 449 antigliadin and transglutaminase antibodies, 449 anti-GM1 antibody, 449 anti-mag antibody, 449 antineural antibodies, 449 antisulfatide antibodies, 449 cytomegalovirus (CMV), 449, 450–451 inherited, 444 serum protein electrophoresis with immunofixation, 448–449 toxins and drugs, 451 Demyelination, 122–123, 123f, 124t, 169, 172 muscle weakness and, 43 segmental versus axonal degeneration, 42, 43t Denervation, 113, 365, 365f

Densitometry, 218 Dental abscesses, 390 Deoxyuridine suppression test, 208 Dermatome, 150 Diabetes, 161, 311, 421 Diabetes Control and Complications Trial (DCCT), 422 Diabetes Control and Complications Trial (DCCT) Research Group, 64 Diabetes mellitus cervical radiculoplexus neuropathy, 60–61 CIDP in, 59–60 cranial neuropathies and, 60 erectile dysfunction and, 59 mononeuropathies in, 60 thoracic radiculopathies, 60 urinary incontinence and, 59 Diabetic amyotrophy, 143, 161 Diabetic autonomic neuropathy. See Autonomic peripheral neuropathy Diabetic autonomic neuropathy (DAN), 59 DPN and, 59 Diabetic lumbosacral radiculoplexus neuropathy (DLRPN), 57–58 Diabetic mononeuritis multiplex, 47 clinical manifestations, 47 diagnostic evaluation, 47 electrophysiology, 47 pathophysiology, 47 treatment, 47 Diabetic neuropathy, 354 CIDP, 59–60 (see also Chronic inflammatory demyelinating polyneuropathy) clinical manifestations, 57–61 diabetic autonomic neuropathy, 59 diagnostic evaluation, 63 differential diagnosis, 61 DLRPN, 58–59 DPN, 57–58 (see also Diabetic sensorimotor polyneuropathy electrophysiology, 63–64 with impaired glucose tolerance, 58 MM and, 51 overview, 57 pathophysiology/pathogenesis, 61–63, 62f, 63f treatment, 64–65 treatment-induced, 423 Diabetic radiculoplexus neuropathies, 59 Diabetic sensorimotor polyneuropathy (DPN), 57–58 atypical, 57 autonomic neuropathy and, 59 typical, 57 Diarrhea, 227, 231 diabetic, 421 Dichloroacetate, 205, 355 Diffuse infiltrative lymphocytic syndrome, 264 Diffuse polyradiculopathy, 264 Dihydroorotate dehydrogenase (DhoDh), 213 Diphtheria, 354, 429 Diphtheric polyneuropathy, 284 Diphtheritic neuropathy clinical features, 266–267 diagnosis, 267, 267t treatment, 267

462  index Diptheria, 171t Direct muscle stimulation (DMS), 365 Disc degeneration, 153 Distal acquired demyelinating syndrome (DADS), 187, 188t Distal axonopathy, 233 Distal latency, 122, 122f Distal sensory neuropathy, 325–330, 328t anticonvulsants, 327 antidepressants, 327 cannabis, 328 opioids for, 329–330 topical agents capsaicin, 329, 329f lidocaine, 329 Distal sensory polyneuropathy, 325 Distal symmetric polyneuropathy (DSP), 263–264 chronic (see Peripheral neuropathies, laboratory evaluation of) Distal weakness, 211 Disulfide bonds, 229 Disulfiram, 205, 446t Diuretics, 231 DLRPN. See Diabetic lumbosacral radiculoplexus neuropathy Docetaxil-induced neuropathy, 211 Dorsal root ganglia (DRG), 149, 152, 203, 204t, 331 biopsy, 317 degeneration of cells, 283–284 Dorsal scapular neuropathy, 396t DPN. See Diabetic sensorimotor polyneuropathy “Dry” beriberi, 70 Dying back neuropathy, 87, 233 Dysautonomia, 177, 427, 428 Dysautonomic neuropathy, 264 Dysesthesias, 313 Dysimmune SNN, 279–281 clinical manifestations, 280 diagnosis of, 280 overview of, 279–280 treatment, 280–281 Dysmotility, 178 Early-onset inherited polyneuropathies, 344–347, 345t Echocardiography, 227 EDC. See Extensor digitorum communis Eden-Lange procedure, 398 EDX findings in GBS, 167 Efosfamide, 212 EIP. See Extensor indicis proprius Elbow, ulnar neuropathy at, 15–17, 16t Electrodiagnosis, 6 MM, 44, 44f, 45f (see also Mononeuropathy multiplex (MM)) Electrodiagnosis for peripheral neuropathies anatomy, 117–118 clinical/electrodiagnostic features focal conduction block neuropathies, 127f, 128 primary axonal neuropathies, 125–126, 126f, 128 primary demyelinating neuropathies, 126, 127f, 128 electrodiagnostic study interpretation, 125 patient history, 124 study design, 124 study strategies, 124–125 limits of normal, 121

needle EMG, mechanics of, 118–121, 121f nerve conduction, mechanics of, 118, 119f, 120f nerve pathology, 121–124, 122f axonal injury, 122 demyelination, 122–123, 123f, 124t focal conduction block, 123–124, 124t normal conduction, 121–122 outline of, 117 Electrodiagnostic (EDX) study, 253, 311 Electrodiagnostic (EDX) testing. See Spinal nerve roots Electroencephalography (EEG), 170 Electromyography (EMG), 219, 219t, 235, 253, 261, 393. See also Needle electromyography MM, 44 (see also Mononeuropathy multiplex ulnar neuropathy at elbow, 16t at wrist, 18t Electrophysiology, 190, 191, 194t–195t, 197, 230–231, 235, 237, 238, 239, 253, 262, 296–297, 397–398. See also Facial nerve; Trigeminal nerve acrylamide neuropathy, 88 arsenic neuropathy, 90, 90f botulinum toxin, 91 carbon disulfide neuropathy, 93 in CTS, 11–13, 12t diabetic mononeuritis multiplex, 47 diabetic neuropathy, 63–64 hepatitis, 49 HIV infection, 49 HNPP, 52 lead neuropathy, 95 leprosy, 50 LSS, 52 Lyme disease, 49 malignancy, MM and, 48 mercury toxicity, 95–96 MMN, 52 n-Hexane neuropathy, 93, 94f organophosphorus (OP) compounds toxicity, 96–97 radial neuropathy, 21t sarcoidosis, 51 sensory perineuritis, 51 sickle cell disease, 47 systemic vasculitis, 46 TCE neuropathy, 100 thallium neuropathy, 98 ulnar neuropathy at elbow, 16–17, 16t at wrist, 17–19, 18t EMG. See Electromyography Endocrine disorders, 348 neuropathies with acromegaly, 312 hyperthyroidism, 312 hypothyroidism, 311–312 Endocrine tests glucose and related tests, 439–440 thyroid-stimulating hormone, 440 Endoneurium, 152 Entrapment MM and, 42, 42t neuropathies of upper extremity, 9–25 (see also Upper extremity, entrapment neuropathies of)

index  463 Environmental toxic neuropathies. See Toxic neuropathies Enzyme dysfunction in porphyria, 291f Enzyme replacement therapy, 353, 426 Epidural injection, 161 Epidural steroids, 158 Epineurial vessel wall necrosis, 310 Epineurium, 152 Epithelioid granuloma, 262f Epstein-Barr virus, 443–444 Erasmus GBS Respiratory Insufficiency Score (EGRIS), 176, 176t, 177f Erb’s point stimulation, 197 Erectile dysfunction, 228, 231, 422 diabetes mellitus and, 59 Eribulin, 212 Erythema nodosum leprosum (ENL), 261 Erythrocyte sedimentation rate (ESR), 275, 441 Erythromelalgia, 353 Esophageal dysmotility, 428 Essential cryoglobulinemia, 443 Ethambutol, 205, 446t Ethylene oxide, 447t Etoposide, 212 Exercise regimens, 179 Experimental allergic neuritis (EAN), 167 Extensor digitorum communis (EDC), 10t Extensor indicis proprius (EIP), 10t Extramedullary vascular disorders, 413 Extraneural symptoms, 280 Eye disease, 333 lubrication, 384 Fabry disease, 353, 426 Facial diplegia and paresthesias (FDP), 170 Facial myokymia, 380 Facial nerve anatomy, 375–377, 376f, 377f, 378f clinical manifestations, 377–379 diagnostic evaluation, 381 differential diagnosis, 379–381, 379t electrophysiology, 381–383 blink reflex, 383 facial nerve motor nerve conduction study, 382–383 needle electromyography, 383 injury, 381 mononeuropathy, 313 palsy, 375 treatment, 383–385 Facial numbness causes of, 389t evaluation of patients, 392t Facial paralysis, 379t Facial weakness and dysathria, 169 Familial amyloid polyneuropathy (FAP), 228, 424–425, 425, 444 Fascicular sparing (FS), 44 Fasciculations, 364 FCR. See Flexor carpi radialis FCU. See Flexor carpi ulnaris FDI. See First dorsal interosseous FDP. See Flexor digitorum profundus FDP II/III. See Flexor digitorum profundus to digits 2 and 3

FDS. See Flexor digitorum superficialis Femoral nerve, 28–29, 28f, 29t. See also Lower extremities, mononeuropathies of Fialuridine, 210 Fibrillation, 383 Fibrosis, 260 Fibrous dysplasia, 413 First dorsal interosseous (FDI), 10t Flexor carpi radialis (FCR), 9, 10t Flexor carpi ulnaris (FCU), 15 Flexor digitorum profundus (FDP), 10t Flexor digitorum profundus to digits 2 and 3 (FDP II/III), 9 Flexor digitorum superficialis (FDS), 9, 10t Flexor pollicis longus (FPL), 9, 10t Fluorescence in situ hybridization (FISH), 220 Fluoroquinolones, 205 Focal brainstem lesions, 407 Focal conduction block, 123–124, 124t neuropathies, 127f, 128 Focal cranial neuropathies, 375–402. See also Facial nerve; Spinal accessory nerve; Trigeminal nerve Folate deficiency, neuropathy and, 78–79 clinical features, 79 diagnostic evaluation, 79 etiology, 78–79 pathogenesis, 78–79 therapy, 79 Folic acid, 440 Foot deformities, 109 muscle atrophy, 125 Footdrop in peripheral neuropathy, 3–4 FPL. See Flexor pollicis longus Friedreich ataxia (FA), 283, 351–352 abetalipoproteinemia (Bassen-Kornzweig disease), 352 ataxia with vitamin E deficiency, 352 autosomal recessive sensory ataxia of Charlevoix Saguenay, 351–352 differential diagnosis, 351 FS. See Fascicular sparing F waves, 155 Gabapentin, 302, 327, 328t, 329t Gadolinium enhancement, 157 Galactocerebrosidase (GAlC), 342 GALOP syndrome, 449 g-aminobutyric acid (GABA), 302 Ganglionopathies, 427. See also Simpler sensory neuronopathies (SNN) Gastric surgery, neurologic complications, 81 Gastrointestinal disorders medications for, 213 neuropathies with bariatric surgery, 311 chronic hepatic disease, 309 gluten sensitivity, 310–311 infectious hepatitis, 310 symptoms, 353 Gastrointestinal dysmotility, 343 Gastrointestinal function, 228 Gastrointestinal motility, 178 Gastroparesis, diabetic, 421

464  index Gaze palsies, 415 GBS. See Guillain-Barré syndrome (GBS) Gel electrophoresis, 190 Gemcitabine, 212 Genetic testing, 345 Genital condylomata acuminata treatment, 209 Genitofemoral nerve, 27–28. See also Lower extremities, mononeuropathies of Giant axonal neuropathy, 352–353 Giant cell arteritis, 248 Gigaxonin (GAN), 113, 352 Gliosis, 331 Globoid cell leukodystrophy (GCL), 340 Glomus tumors, 415 Glucose and related tests, 439–440 tolerance, 423 Gluteal nerve inferior, 35 superior, 35 Gluten-sensitive enteropathy, 428 Gluten sensitivity, 310–311 Gold, 205–206 Gradenigo syndrome, 389, 415 Granuloma formation, 313 Granulomatous inflammation MM and, 42, 42t Griseofulvin, 206 Guillain-Barré syndrome (GBS), 161, 167–181, 238, 347–350, 428 acute axonal neuropathy, 172–173 acute inflammatory demyelinating polyradiculoneuro­ pathy (AIDP), 171, 172, 172f ancillary testing, 349 clinical features of, 167 clinical presentation, 347–348 CSF findings in, 168 diagnostic criteria, 349 differential diagnosis, 348–349 disability score, 174t EDX findings in, 167 history of, 167 immunization and, 180 immunotherapy, 173–175, 174t, 175f incidence of, 167 inpatient rehabilitation, 178–179 MFS, treatment of, 176 Miller Fisher syndrome (MFS), 173 mimics and differential diagnosis, 170, 171t peripheral neuropathy and, 4 persistent symptoms and disability, 179 phases of recovery, 179 prognosis, 180, 350 radiographic findings in, 168 serum autoantibodies in, 168 supportive care for autonomic nervous system dysfunction, 177–178 for respiratory failure, 176–177, 176t, 177f treatment, 349–350 of GBS relapse, 175–176 variants of, 168–170 acute motor and sensory axonal neuropathy (AMSAN), 169

acute motor axonal neuropathy (AMAN), 168 Bickerstaff’s brainstem encephalitis (BBE), 169–170 facial diplegia and paresthesias (FDP), 170 Miller Fisher syndrome (MFS), 169–170 pharyngealcervical-brachial (PCB), 170 Guillain-Barré syndrome treatment-related fluctuations (GBS-TRF), 175 Gyromitra esculenta, 74 HAART theory, 333–334 Haematogenous dissemination, 260 Haeme biosynthetic pathway, 290f Harderoporphyria, 293 Head injury, 399 Heavy metals, 171t Hematin, 303 Hematologic disorders, 47–48 ITP, 47–48 sickle cell disease, 47 Hematoma, 145 Heme, 289, 290, 298 Hemifacial spasm, 380 Hepatic disease, chronic, 309 Hepatic porphyria, 291, 304t Hepatitis, 49 clinical manifestations, 49 diagnostic evaluation, 49 electrophysiology, 49 infectious, 310 pathophysiology, 49 treatment, 49 Hepatitis C virus (HCV), 224, 247 clinical features, 265–266 pathogenesis, 266 treatment, 266 Hepatitis viruses, 443 Hepatocellular carcinoma, 292 Hepatosplenomegaly, 352 Hereditary amyloidosis, 227–228 Hereditary autonomic neuropathies. See Autonomic peripheral neuropathy Hereditary brachial plexopathy, 113 Hereditary coproporphyria, 292–293, 298 Hereditary motor and sensory neuropathies (HMSN), 342 Hereditary neuralgic amyotrophy (HNA), 113, 141 Hereditary neuropathy, 346 Hereditary neuropathy with liability to pressure palsy (HNPP), 42, 51–52, 52f, 107, 111, 188 clinical manifestations, 51 diagnostic evaluation, 52 electrophysiology, 52 pathophysiology, 51–52, 52f treatment, 52 Hereditary sensory autonomic neuropathies (HSAN), 343–344, 425–426 Herpes varicella-zoster, 444 Herpes zoster clinical features, 268 infection, 161 postherpetic neuralgia (PHN), 268 treatment, 268–269, 269t Hexacarbons, 447t Hexamethylmelamine, 212

index  465 N-hexane neuropathy, 93–94. See also Toxic neuropathies clinical manifestations, 93 diagnosis, 89t, 93–94, 94f electrophysiology, 93, 94f treatment, 94 HIV antibody detection, 443 HIV infection, 49, 171t, 284, 354–355, 411, 428–429 clinical features, 263 clinical manifestations, 49 demyelinating inflammatory polyneuropathy, 264 description of, 263 diagnostic evaluation, 49 diffuse infiltrative lymphocytic syndrome, 264 diffuse polyradiculopathy, 264 distal symmetric polyneuropathy (DSP), 263–264 dysautonomic neuropathy, 264 electrophysiology, 49 mononeuropathy multiplex, 264, 264f pathogenesis, 263 pathophysiology, 49 toxic neuropathy, 264 treatment, 49, 264 HIV infection and antiretroviral therapy associated neuropathies, 325–332, 325t acute inflammatory demyelinating polyneuropathy, 331–332 chronic inflammatory demyelinating polyneuropathy (CIDP), 332 distal sensory neuropathy, 325–330 mononeuritis multiplex (MM), 332 pathogenesis of HIV-DSP, 330–331, 330f burden of HIV in world, 324–325, 324f cytomegalovirus polyradiculopathy, 332–333 HAART theory, 333–334 historical overview of, 323 HIV neuropathic pain treatment, 328t HNPP. See Hereditary neuropathy with liability to pressure palsy Homocysteine (Hcy), 440 Horner syndrome, 143, 415 House-brackmann facial grading scale, 379 H-reflex, 155, 168 Human T-cell leukemia virus (HTLV), 443 Human T-lymphotrophic viruses (HTLV), 264–265, 284 clinical features, 265 nerve conduction/nerve biopsy, 265, 265f pathogenesis, 265 peripheral nerve involvement, 265 Hydralazine, 206, 446t Hydroxymethylbilane, 291 Hydroxymethylbilane synthesase (HMBS), 353 Hyperoxygenation, 178 Hyperpathia, 326 Hypertension, 178, 247, 292 Hyperthyroidism, 312 Hypertrichosis, 293f Hypocupremia. See Copper deficiency, neuropathy and Hypoglossal nerve, 400 Hypoglycemia, 423 Hyponatremia, 302 Hypotension, 178 Hypothyroidism, 311–312 Hypoxia, 313

Idebenone, 351 Idiopathic bell palsy, 379 Idiopathic granulomatous inflammatory disease, 249 Idiopathic thrombocytopenic purpura (ITP), 41 Idiopathic trigeminal sensory neuropathy, 390 Ileus, 178 Iliohypogastric nerve, 27. See also Lower extremities, mononeuropathies of Ilioinguinal nerve, 27. See also Lower extremities, mononeuropathies of Imaging studies radial neuropathy, 20 Immune-mediated acute polyneuropathies, 451 Immune-mediated autonomic neuropathies. See Autonomic peripheral neuropathy Immune-mediated neuropathies, 251 Immunization, 349 and GBS, 180 Immunoadsorption therapy, 175 Immunofixation electrophoresis, 424, 441 Immunoglobulin, 191, 196 Immunoglobulin M antisulfatide antibodies, 442 Immunological studies, 189–190 Immunologic electromicroscopic analysis, 111 Immunoperoxidase staining, 260 Immunosecretory disorders, 221 Immunosuppressant agents, 212–213 cyclosporin, 213 leflunomide, 213 tacrolimus, 212–213 Immunosuppressive/immunomodulatory agents, 196–197 Immunotherapy, 173–175, 174t, 175f combined therapies, 175 corticosteroids, 175 immunoadsorption therapy, 175 intravenous immunoglobulin, 173–174 plasma exchange, 173 and potential adverse events, 174–175, 174t, 175f Impaired glucose tolerance, 423 neuropathy with, 58 Inborn errors of metabolism, 343 Infantile beriberi, 70 Infections, MM and, 41–42, 42t, 48–50 hepatitis, 49 HIV, 49 leprosy, 49–50, 50f Lyme disease, 48–49 Infectious ataxic neuropathies, 284 diphtheric polyneuropathy, 284 HIV, 284 human T-cell lymphotropic virus, 284 Infectious hepatitis, 310 Infectious meningitis, 411 Infectious neuropathies, 251. See also HIV infection chagas disease, 267 classification of, 260 clinical forms, 260–261, 261f diagnosis, 261–262 diphtheria, 354 diphtheritic neuropathy, 266–267, 267t hepatitis C virus (HCV), 265–266 herpes zoster, 268–269 HTLV-1/HTLV-2 infections, 264–265, 265f

466  index Infectious neuropathies (cont.) human immunodeficiency virus (HIV), 354–355 leprosy, 259, 260f, 354 lyme disease, 268, 355 nerve enlargement, 261, 261f overview of, 259, 259t pathology, 262, 262f prevalence mycobacterium leprae, 259–260 reactions, 261 transmission, 260 treatment, 263 Inferior gluteal nerve, 35. See also Lower extremities, mononeuropathies of Inflammatory demyelinating polyneuropathy, 428 Inflammatory demyelinating polyradiculoneuropathy, 126 Inflammatory disorders, MM and, 50–51 sarcoidosis, 50–51, 51f sensory perineuritis, 51, 51f Inflammatory mediators, 153 Inflammatory polyneuropathies chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), 350–351 Guillain-Barré syndrome (GBS), 347–350 Multifocal acquired demyelinating sensory and motor (MADAM), 351 Inflammatory radiculitis, 149 Infliximab, 281 Infraclavicular plexus, 132 Infraorbital nerve, 387 Inherited amyloidosis, 228 Inherited axonal polyneuropathies, 444 Inherited demyelinating polyneuropathies, 444 Inherited disorders, DRG cells and abetalipoproteinemia, 283 ataxia with vitamin E deficiency, 283 combined SNN and motor neuron disorders, 284 Friedreich ataxia, 283 mitochondrial disorders, 283–284 Inherited peripheral neuropathies. See Charcot-Marie-Tooth (CMT) disease Inherited polyneuropathies, 342 Inpatient pain management, 178 Inpatient rehabilitation, 178–179 Insulin neuritis, 61, 423 Insulin therapy, 371 Insulin treatment for diabetic neuropathy, 64 Interferons, 196 Interleukin 6, 218 Internal neurolysis, 139 Intoxication porphyria, 299 Intravenous cyclophosphamide, 220 Intravenous immunoglobulin, 173–174, 191, 196, 351 Intravenous methylprednisolone, 175 Inverted champagne bottle legs in peripheral neuropathy, 4 Ischemia, 153 nerve and MM, 42–43 Ischemic neuropathies, 251 Isoniazid, 206, 446t Isonicotinic acid, 206 ITP. See Idiopathic thrombocytopenic purpura

IV immunoglobulin for diabetic neuropathy, 65 Ixabepilone, 212 Jamaican neuritis, 79 Jugular foramen syndrome, 415 Keane’s series, 409, 411 Krabbe disease, 340, 342 Lambert-Eaton myasthenic syndrome (LEMS), 278 Lamotrigine, 327, 328t Lateral femoral cutaneous nerve, 28, 28t. See also Lower extremities, mononeuropathies of Lateral inferior pontine, 408t Lead, 356, 447t intoxication, 295 Lead neuropathy, 94–95. See also Toxic neuropathies clinical manifestations, 94–95 diagnosis, 92t, 95 electrophysiology, 95 treatment, 95 Leflunomide, 213 Lepromatous leprosy, 354 Leprosy, 49–50, 50f, 259, 260f, 429, 443 clinical manifestations, 49–50 diagnostic evaluation, 50 electrophysiology, 50 lepromatous, 354 pathophysiology, 50 treatment, 50 Leptomeningeal seeding of tumor, 315 Lewis-Sumner syndrome (LSS), 187, 188t autoimmunity and, 41, 42t clinical manifestations, 52 diagnostic evaluation, 52 electrophysiology, 52 pathophysiology, 52 treatment, 52 Lhermitte phenomenon, 282 Lidocaine, 264, 329 Ligament of Struthers, entrapment of, 14 Ligamentum flavum, 151 Limits of normal, 121 Linezolid, 206–207 a-lipoprotein deficiency, 352 Lithium, 207 Liver function tests, 441 Long thoracic nerve (LTN), 23–24, 23t Long thoracic neuropathy, 23–24, 23t, 396t Lorazepam, 302 Lower cranial nerve (CN) syndromes, 415 Lower extremities, mononeuropathies of, 27–35 common peroneal nerve, 32–33, 32t, 33t deep peroneal nerve, 32t, 33–34, 33f, 33t femoral nerve, 28–29, 28f, 29t genitofemoral nerve, 27–28 iliohypogastric nerve, 27 ilioinguinal nerve, 27 inferior gluteal nerve, 35 lateral femoral cutaneous nerve, 28, 28t obturator nerve, 29t, 30–31, 30f, 30t overview of, 27

index  467 posterior tibial nerve, 34–35 saphenous nerve, 29–30 sciatic nerve, 31–32, 31f, 31t, 32t superficial peroneal nerve, 32t, 34, 34f, 34t superior gluteal nerve, 35 sural nerve, 32 tibial nerve, 34 Lower motor neuron (LMN), 377, 379t Lower motor neuron (LMN) syndromes, 223–224 LSS. See Lewis-Sumner syndrome LTN. See Long thoracic nerve Lumbar plexus, 133–135 branches of, 134t Lumbar puncture, 191, 381 Lumbar radiculopathy, 150t biomechanical model of, 153 Lumbosacral plexopathy. See Brachial and lumbosacral plexopathy Lumbosacral plexus, 133–136, 133f, 134f, 134t, 135t lumbar plexus, 133–135, 134t sacral plexus, 135–136, 135t Lumbosacral radiculopathy, 156–157 Lumbosacral radiculoplexus neuropathy (LRPN), 143–144 Lyme disease (LD), 48–49, 161, 268, 355, 380, 411, 443 clinical manifestations, 48 diagnostic evaluation, 48–49 electrophysiology, 49 pathophysiology, 48 treatment, 49 Lyme neuroborreliosis, 171 Lymphoma, 315 Lysosomal storage disorders, 342–343 Macrophage invasion, 348 Madrid syndrome, 79 Magnetic resonance angiography (MRA), 392, 417 Magnetic resonance imaging (MRI), 140, 157, 168, 235, 274, 315 CTS and, 13 Malignancy, MM and, 42, 42t, 48 clinical manifestations, 48 diagnostic evaluation, 48 electrophysiology, 48 pathophysiology, 48 treatment, 48 Marble bone disease, 413 Marine toxins, 429 Mastoid segment, 376 Mechanical allodynia, 153 Mechanical stresses, 111–112 Mechanical ventilation, 177, 177f Meckel cave, 386, 388 Medial brachial fascial compartment syndrome, 142, 142f Medial inferior pontine, 408t Medial medullary syndrome, 409t Medial midpontine, 408t Medial superior pontine, 408t Median nerve anatomy, 9–10, 9f Median neuropathy, 9–15, 9f, 10t–14t. See also Upper extremity, entrapment neuropathies of anterior interosseous neuropathy, 14–15, 14t CTS, 10–13, 10t–12t (see also Carpal tunnel syndrome)

median nerve, anatomy, 9–10, 9f proximal, 13–14, 13t at wrist, 10–13 Median sternotomy brachial plexopathy, 141f, 142 Medical Research Council (MRC) sum scores, 176 Medication-induced neuropathies amiodarone, 203 amitriptyline, 203, 204 anatomic site of, 204t antiretroviral medications, 210 chemotherapeutic agents, 210–212 clofibrate, 204 colchicine, 204–205 dapsone, 205 dichloroacetate, 205 disulfiram, 205 ethambutol, 205 fluoroquinolones, 205 gold, 205–206 griseofulvin, 206 hydralazine, 206 from immunosuppressant agents, 212–213 isoniazid, 206 linezolid, 206–207 lithium, 207 medications for gastrointestinal disorders, 213 mefloquine, 207 metronidazole, 207 misonidazole, 207 nitrofurantoin, 207–208 nitrous oxide, 208 outline of, 203 penicillamine, 208 phenelzine, 6 phenytoin, 208–209 podophyllin, 209 propafenone hydrochloride, 209 pyridoxine, 209 statins, 209–210 thalidomide, 210 tumor necrosis factor a antagonists, 213 Mefloquine, 207 Melkersson-rosenthal syndrome, 381 Melphalan, 223 Membrane attack complex (MAC), 172 Meningeal parasitic infections, 411 Meningitis chronic, 411–413 infectious, 411 neoplastic, 412 noninfectious inflammatory, 411–412 Mercury, 447t Mercury toxicity, 95–96. See also Toxic neuropathies clinical manifestations, 95 diagnosis, 96 electrophysiology, 95–96 treatment, 96 Metabolic derangements, 451 Methotrexate, 254 Metronidazole, 207, 446t Mexiletine, 328t MFS. See Miller Fisher syndrome Microscopic polyangiitis, 246–247, 247t

468  index Microsomal triglyceride transfer protein (MTP), 352 Microtubule-stabilizing agent, 212 Microvasculitis, 149 Midbrain syndromes, 408t Miller-Fisher syndrome (MFS), 169–170, 173, 347 treatment of, 176 Mimics of GBS, 170, 171t MiniPM, 156 Misonidazole, 207, 446t Mitochondrial disorders, 283–284, 348 and neuropathy, 354 Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MelAS), 205 Mitochondrial recessive ataxia syndrome (MIRAS), 283 MM. See Mononeuropathy multiplex MMN. See Multifocal motor neuropathy Modified Erasmus GBS Outcome Score (mEGOS), 174, 174t, 175f Molecular mimicry, 170, 173 Monoclonal gammopathy, 238 Monoclonal gammopathy of undetermined significance (MGUS), 219–221, 221t, 224t, 441 Monoclonal proteins (M proteins), 217, 218, 219 recognition of, 218–219 Monomers, 229 Mononeuritis multiplex (MM), 332 Mononeuropathies, 1, 312, 313. See also Peripheral neuropathy defined, 27 in diabetes mellitus, 60 (see also Diabetes mellitus) of lower extremities, 27–35 (see also Lower extremities, mononeuropathies of) of upper extremity, 9–22 (see also Upper extremity, entrapment neuropathies of) Mononeuropathy multiplex (MM), 264, 264f axonal versus demyelinating, 42, 43t defined, 1, 41 demyelinating neuropathies, 51–52 diabetic neuropathy, 51 (see also Diabetic neuropathy) diagnosis, clinical approach, 42–43, 43t electrodiagnosis, 44, 44f, 45f hematologic disorders, 47–48 (see also Hematologic disorders) infections, 41–42, 42t, 48–50 (see also Infections, MM and) inflammatory disorders, 50–51 (see also Inflammatory disorders, MM and) malignancy, 42, 42t, 48 (see also Malignancy, MM and) overview of, 41 pathogenesis, 41–42, 42t pathophysiology, 41–42, 42t treatment, 44 vasculitides, 45–47 (see also Vasculitis) Monosynaptic spinal reflex, 155 Morvan disease, 425 Motor and sensory nerve conduction studies, 154–155 Motor nerves, 117 conduction velocity, 220 Motor nerve stimulation (MNS), 365 Motor neuron disorders, 284 Motor neuropathy/neuronopathy clinical manifestations, 235 diagnostic evaluation, 237 electrophysiology, 237 pathogenesis and pathophysiology, 235, 236 treatment, 237

Motor unit action potential (MUAP), 119, 121f, 155 Motor unit potentials (MUP), 365 Multidrug therapy (MDT), 259 Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), 187, 188t, 351 Multifocal acquired motor axonopathy (MAMA), 224 Multifocal demyelination, 122 Multifocal motor neuropathy (MMN), 52, 223 autoimmunity and, 41, 42t clinical manifestations, 52, 197 diagnostic evaluation, 52, 197 differential diagnosis of, 197 electrophysiology, 52, 197 pathogenesis/pathophysiology, 197 pathophysiology, 52 treatment, 52 treatment of, 197–198 Multifocal motor neuropathy with conduction block, 123 Multiple compression neuropathies, 251 Multiple cranial neuropathies (MCN) bone disorders, 413 brainstem syndromes, 407–409, 408t–409t chronic meningitis infectious meningitis, 411 neoplasms affecting clivus/skull base, 412–413 neoplastic meningitis, 412 noninfectious inflammatory meningitis, 411–412 diagnostic evaluation, 416–417, 416t disorders of CN groups cavernous sinus syndrome, 414 cerebellopontine angle, 414–415 lower cranial nerve syndromes, 415 peripheral nervous system considerations, 415, 415t extramedullary etiologies of, 410t extramedullary vascular disorders, 413 overview of, 409–411, 410t trauma, 413–414 treatment, 417–418 Multiple myeloma (MM), 445t. See Paraproteinemic neuropathy Multiple nerve tumors, 251 Multiple sclerosis–induced trigeminal neuralgia, 391 Muscle wasting, 113 Muscle weakness, 109, 179 demyelination and, 43 Musculocutaneous neuropathy, 24, 24t Myasthenia gravis, 171t, 381 Mycobacterium leprae, 259–260, 354, 429 Mycophenolate mofetil, 196 Myelopathy, acute, 171t Myotome, 150 Myotonic dystrophy, 370 Narcotics, 178 Nasociliary nerve, 387 Nasopharyngeal carcinomaoccurs, 412 Necrotizing vasculitis, 250, 252, 316 Needle electromyography, 155–157, 220, 296, 364, 383 lumbosacral radiculopathy, 156–157 paraspinal mapping, 156 thoracic radiculopathy, 156 Needle EMG, 138, 138t mechanics of, 118–121, 121f

index  469 Needle examination peripheral neuropathy and, 6 Neoplastic lumbosacral plexopathy, 144 Neoplastic meningitis, 412 Neoplastic plexopathy, 142–143 Nephrotic syndrome, 227 Nerve biopsy, 188, 191, 203, 239, 252–253, 252f, 262, 264, 265, 265f, 312, 366 enlargement, 261, 261f fiber conduction velocity, 118 ischemia, 317 and muscle pathology, 365–366, 365f, 366f–367f pathology (see Electrodiagnosis for peripheral neuropathies) Nerve conduction, 265, 265f block, 153 mechanics of, 118, 119f, 120f waveform metrics, 120f Nerve conduction studies (NCS), 109–110, 112, 138t, 154, 155, 170 Nerve of Furcul, 136 Neural foramen, 153 Neuralgic amyotrophy, 140–141, 251 Neurogenic scapular winging, 396t Neurogenic thoracic outlet syndrome, 141–142, 141f Neuroimaging, 391, 392 Neurologic examination for diabetic neuropathy, 63 in peripheral neuropathy, 3–4 Neuromas, 139 Neuromuscular junction (NMJ) disorders, 370, 381 Neuromuscular respiratory failure, 176 Neuronopathy, 5 Neuropathic pain, 283 first-line treatments for, 159t–160t Neuropathy, 294–296 alcoholic, 80 for amyloidosis (see Amyloidosis) diabetic, 57–66 (see also Diabetic neuropathy) from immunosuppressant agents (see Immunosuppressant agents) of lower extremities (see Lower extremities, mononeuropathies of) nutritional, 69–80, 70t, 71t–73t, 78t (see also Nutritional neuropathies) related to bariatric surgery (BS), 80–82 toxic, 87–101 (see also Toxic neuropathies) of upper extremity (see Upper extremity, entrapment neuropathies of) Neuropathy impairment score (NIS), 64, 220 Neurosarcoidosis, 411 Neurotoxic dideoxynucleoside antiretrovirals, 333 Neurotoxicity, 210 Niacin. See Vitamin B3 deficiency, neuropathy and Nicotinic acid. See Vitamin B3 deficiency, neuropathy and Nicotinic ganglionic acetylcholine receptor autoantibody, 239 NIS. See Neuropathy impairment score Nitric oxide, 368 Nitrofurantoin, 207–208, 446t 2-nitromidazole, 207 Nitrous oxide, 208, 446t N-methylnicotinamide niacin deficiency and, 74

Noninfectious inflammatory meningitis, 411–412 Non-length-dependent small-fiber ganglionopathy, 283 Nonnerve tissues, 354 Nonsteroidal anti-inflammatory drugs (NSAID), 158, 178 Nonsystemic vasculitic neuropathy (NSVN), 41, 250–251, 251t Normal conduction, 121–122 Normal limits, 121 NSVN. See Nonsystemic vasculitic neuropathy Nucleoside reverse transcriptase inhibitors (NrTIs), 210 Nucleus pulposus, 153 Numb chin syndrome, 390 Nutritional neuropathies, 69–80, 70t, 71t–73t, 78t copper deficiency, 77–78, 78t folate deficiency, 78–79 general considerations, 69, 70t overview, 69 Strachan syndrome, 79–80 vitamin B3 deficiency, 70, 74 vitamin B6 deficiency, 74–75 vitamin B12 deficiency, 75–76 vitamin B1 deficiency and, 69–70 vitamin E deficiency, 76–77 Nystagmus, 415 Obesity, 311 Obstetric lumbosacral plexopathy, 144–145 Obturator nerve, 29t, 30–31, 30f, 30t. See also Lower extremities, mononeuropathies of Occipital condyle syndrome, 400 Ocular dysfunction, 228 OGTT. See Oral glucose tolerance test Olfactory nerve dysfunction, 399 Onion bulbs, 110 OP. See Opponens pollicis (OP); Organophosphorus (OP) compounds toxicity Open penetrating injuries, 139 Opiates, 158 OPIDN. See OP-induced delayed neuropathy OP-induced delayed neuropathy (OPIDN), 96–97 Opioids, 329–330 Opponens pollicis (OP), 10t Optic neuritis, 205 Oral glucose tolerance test (OGTT), 58 Orbital pathology, 390 Organophosphates, 448t Organophosphorus (OP) compounds toxicity, 96–97. See also Toxic neuropathies clinical manifestations, 96 diagnosis, 92t, 97 electrophysiology, 96–97 treatment, 97 Orthostatic hypotension, 231, 280, 427 Orthotics, 114, 179 Osteopetrosis, 413 Osteosclerotic myeloma (OSM), 221, 449 Oxaliplatin, 211 Paclitaxel, 211 Pain, 114, 140 radiation, 150t Paint (toluene) inhalation, chronic, 356 Palmaris longus (PL), 10t PAN. See Polyarteritis nodosa

470  index Pancoast tumor, 143 para-aminosalicylic acid, 206 Paraesthetic-causalgic syndrome, 79 Paragangliomas, 415 Parainfectious autonomic neuropathy, 428 Paraneoplastic autonomic neuropathy, 427, 427t Paraneoplastic encephalomyelitis (PEM), 276 Paraneoplastic neuropathy autonomic neuropathy, 238–239 demyelinating neuropathies (acute and chronic), 238 description of, 233 motor neuropathy/neuronopathy, 235–237 sensory-motor axonal neuropathy, 237–238 sensory neuronopathy, 233–235, 234t, 236t vasculitic disorders, 239 Paraneoplastic subacute SNN clinical manifestations, 278 diagnosis, 278–279 epidemiological data, 276, 278 treatment, 279 Paraneoplastic vasculitis, 250 Paranodal myelin, 172 Paraproteinemic neuropathy cryoglobulinemia, 224 electromyographic studies, 219, 219t lower motor neuron syndromes, 223–224 monoclonal gammopathy of undetermined significance (MGUS), 219–221, 221t, 224t monoclonal proteins, recognition of, 218–219 multiple myeloma (MM) osteosclerotic myeloma (OSM), 221 polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS), 221–222, 222t and smoldering multiple myeloma (SMM), 221 solitary plasmacytoma (SP), 221 systemic AL amyloidosis, 222–223 Waldenström macroglobulinemia (WM), 222, 223t overview of, 217–218, 218t Paraspinal mapping, 156 Paraspinal muscles, 155 Parenteral nutrition, 178 Paresthesias, 311 Parsonage-Turner syndrome, 140, 251, 397 Pathophysiology diabetic mononeuritis multiplex, 47 diabetic neuropathy, 61–63, 62f, 63f hepatitis, 49 HIV infection, 49 HNPP, 51–52, 52f leprosy, 50 LSS, 52 Lyme disease, 48 malignancy, MM and, 48 MM, 41–42, 42t (see also Mononeuropathy multiplex (MM)) MMN, 52 sarcoidosis, 50 sensory perineuritis, 51 sickle cell disease, 47 systemic vasculitis, 45–46 Patient education, 158 Penicillamine, 208

Percutaneous dilatational tracheostomy, 177 Periaxin (PRX) gene, 113 Peripheral myelin protein 22 (PMP22), 51 Peripheral nerve, 203, 227 electron micrograph of, 330f involvement, 265 maturation, 339 types and function, 2t Peripheral nerve society guidelines, 254 Peripheral nervous system (PNS), 41, 263, 415, 415t vasculitis restricted to, 46 Peripheral neuropathies, 1–6, 2t, 221. See also Chemotherapeutic agents clues to diagnosis, 4–5 common, 1–3 electrodiagnosis, 6 etiologies, 1–5 mononeuritis multiplex, 1 mononeuropathy, 1 needle examination, 6 neurologic examination, 3–4 polyneuropathy (see Polyneuropathy) types, 1 Peripheral neuropathies, laboratory evaluation of for acute neuropathies immune-mediated acute polyneuropathies, 451 infections, 451 metabolic derangements, 451 systemic diseases, 451 toxins, 451 for distal symmetric polyneuropathy (DSP), chronic axonal polyneuropathies, 439–444, 445t, 446t–448t, 448f demyelinating polyneuropathies, 444, 448, 449–451, 450t Peripheral neuropathies in childhood peripheral nerve maturation, 339 polyneuropathies clinical approach, 339–341, 340f, 341f electrodiagnostic testing, 341–342 polyneuropathies of childhood cerebrotendinous xanthomatosis (CTX), 352 cockayne syndrome, 352 diabetic neuropathy, 354 early-onset inherited polyneuropathies, 344–347, 345t erythromelalgia, 353 Fabry disease, 353 Friedreich ataxia (FA), 351–352 giant axonal neuropathy, 352–353 infectious neuropathies, 354–355 inflammatory polyneuropathies, 347–351 mitochondrial disorders and neuropathy, 354 porphyrias, 353 tangier disease, 352 toxic neuropathies, 355–356 vasculitic neuropathies, 351 xeroderma pigmentosum, 352 polyneuropathy of infancy early-onset inherited polyneuropathies, 342 hereditary sensory autonomic neuropathies (HSAN), 343–344 inborn errors of metabolism, 343 lysosomal storage disorders, 342–343

index  471 Pernicious anemia, 440 Peroneal nerve. See also Lower extremities, mononeuropathies of common, 32–33, 32t, 33t deep, 32t, 33–34, 33f, 33t superficial, 32t, 34, 34f, 34t Persistent disability, 179 Pharyngealcervical-brachial (PCB), 170 Phenelzine, 6 Phenolic glycolipid (PGL), 259 Phenytoin, 208–209, 446t Phospholipas, 153 Phosphoribosyl pyrophosphate synthetase (PRPS), 346 Phrenic nerve, 364 PIN. See Posterior interosseous neuropathy PL. See Palmaris longus Plasma exchange (PE), 173 Plasmapheresis, 196 Platinum chemotherapeutic agents, 211 Plexopathies, 315 Plexus anatomy. See Brachial and lumbosacral plexopathy PMP22. See Peripheral myelin protein 22 PNS. See Peripheral nervous system Podophyllin, 209 Poliomyelitis, 171t Polyangiitis, microscopic, 246–247, 247t Polyarteritis nodosa (PAN), 45, 247 Polyclonal immunoglobulins, 217 Polymerase chain reactions, 262 Polymorphism, 190 Polyneuritis cranialis, 415 Polyneuropathy, 1, 203, 266f, 267. See also Peripheral neuropathy conditions mimicking, 6 etiologists for, 5, 5t evaluation of, 5–6 prevalence of, 1 Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS), 221–222, 222t Polyradiculoneuropathy, 168 Polyradiculopathy, 171t Porphobilinogen (PBG), 289, 297 Porphyria, 353, 445t Porphyric neuropathies, 251 biochemical findings acute intermittent porphyria (AIP), 297–298 aminolevulinic acid dehydratase deficiency, 297 hereditary coproporphyria, 298 variegate porphyria, 298 classification acute intermittent porphyria, 292 aminolaevulinate dehydratase deficiency porphyria, 291–292 hereditary coproporphyria, 292–293 rare recessive acute hepatic porphyrias, 293 variegate porphyria, 292 clinical features, 293–294, 293f description of, 289 diagnostic strategies, 298–299, 300t electrophysiologic findings, 296–297 genetic analysis, 299, 301 historical overview of, 289–290 laboratory abnormalities, 299 neuropathy, 294–296

pathology and pathophysiology, 301–302 porphyrin metabolism, 290–291, 290f, 291f treatment, 302–304, 303t, 304t Porphyrin metabolism, 290–291, 290f, 291f Positron emission tomography, 143 Posterior interosseous neuropathy (PIN), 20 symptoms, 20 Posterior tibial nerve, 34–35 Postherpetic neuralgia (PHN), 259, 268, 391 PQ. See Pronator quadratus Prealbumin, 424 Prednisone, 223, 281 Pregabalin, 327, 328t, 329t Primary amyloidosis, 227, 424 Primary axonal neuropathies, 125–126, 126f, 128 Primary biliary cirrhosis (PBC), 309 Primary demyelinating neuropathies, 126, 127f, 128 Primary leptomeningeal lymphoma, 412 Primary vasculitic neuropathies, 351 Primary vasculitis Churg-Strauss syndrome, 247 cryoglobulinemia, 247–248 giant cell arteritis, 248 microscopic polyangiitis, 246–247, 247t polyarteritis nodosa (PAN), 247 small-vessel vasculitis, 248 tests for, 441 Wegener granulomatosis, 247 Pronator quadratus (PQ), 9, 10t Pronator syndrome, 14 Pronator teres (PT), 9, 10t Propafenone hydrochloride, 209 Prophylaxis for DVT, 178 Prostaglandin E2 (PGE-2), 153 Prostaglandin synthesis, 153 Protofilaments, 229 Proton pump inhibitors, 213 Protoporphyrinogen oxidase (PPO), 291, 292 Proximal median neuropathy, 13–14, 13t. See also Median neuropathy ligament of Struthers, entrapment of, 14 Pronator syndrome, 14 treatment, 14 Pseudoathetosis, 274 Pseudoconduction block, 253 PT. See Pronator teres Pudendal nerve, 136 Pulmonary disorders, neuropathies with chronic obstructive pulmonary disease (COPD), 312–313 sarcoidosis, 313–314 Pyridone excretion, low niacin deficiency and, 74 Pyridoxine, 209, 290, 446t deficiency, 440 (see Vitamin B6 deficiency, neuropathy and) toxicity, 74, 283 Quadriparesis, 171t Quality Standards Subcommittee, 173 Quantitative sudomotor axon reflex test (QSART), 423 Rabies, 451 Radial nerve anatomy of, 19, 19f

472  index Radial neuropathy, 19–22, 19f, 20t–21t. See also Upper extremity, entrapment neuropathies of at axilla, 19 diagnosis, 20, 20t electrophysiology, 21t imaging studies, 20 PIN, 20 (see also Posterior interosseous neuropathy (PIN)) radial nerve, anatomy of, 19, 19f at spiral groove, 19–20 superficial radial sensory neuropathy, 20 treatment, 20, 22 Radiation-induced brachial plexopathy, 143 Radiation-induced lumbosacral plexopathy, 145 Radiculopathy, 152–154, 315. See also Spinal nerve roots Radiographs ulnar neuropathy, 17 Radiography, 168 Ramsay Hunt syndrome, 380, 384 Rankin score, 278 Rare recessive acute hepatic porphyrias, 293 RDA. See Recommended daily allowance Recommended daily allowance (RDA) of pyridoxine, 75 Rectal tubes, 178 Red blood sensitizer, 207 Reinnervation, 120 Relapses of GBS, 175–176 Renal dysfunction, 353 Renal failure, neuropathies with, 314 Respiratory failure, 176–177, 176t, 177f Restrictive procedures of bariatric surgery, 80 Retroclavicular plexus, 132 Retropharyngeal space syndrome, 415 Reversal reaction (RR), 261 Rheumatoid arthritis (RA), 248, 316 Rheumatologic tests, 441 Ribonucleotide uridine monophosphate (rUMP), 213 Rifampicin, 263 Rituximab, 220 Romberg sign, 3, 6 Roots, 131, 132f Roussey-Levy syndrome, 109 Roux-en-Y gastric bypass (RYGB), 80 Rucksack palsy, 140 RYGB. See Roux-en-Y gastric bypass Sacral plexus, 135–136 anatomy, 134f branches of, 135t Saphenous nerve, 29–30. See also Lower extremities, mononeuropathies of Sarcoid neuropathy, 314 Sarcoidosis, 50–51, 51f, 249–250, 313–314 clinical manifestations, 50 diagnostic evaluation, 50–51 electrophysiology, 51 pathophysiology, 50 treatment, 51 Sarcoid radiculopathy, 313 Scapular winging, 396t, 397t Schwann cells, 110, 113, 203, 204t

Sciatic nerve, 31–32, 31f, 31t, 32t. See also Lower extremities, mononeuropathies of Scleroderma, 317 Secondary porphyrias, 299 Secondary vasculitic neuropathies, 351 Secondary vasculitis rheumatoid arthritis, 248 Sjögren syndrome, 248–249, 249t systemic lupus erythematosus, 249 Selective serotonin norepinepherine reuptake inhibitors, 158 Selective serotonin reuptake inhibitors, 158 Sensorimotor polyneuropathies, 339 Sensorineural hearing loss, 400 Sensory action potentials (SAP), 274 Sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO), 284 Sensory gait ataxia, 3 Sensory-motor axonal neuropathies clinical manifestations, 237 diagnostic evaluation, 237–238 electrophysiology, 238 treatment, 238 Sensory nerve action potential (SNAP), 44, 118, 138, 141, 152, 154, 219, 309, 339, 364 Sensory neuronopathy clinical manifestations, 233–234, 234t diagnostic evaluation, 235 electrophysiology, 235 pathogenesis and pathophysiology, 235 treatment, 235 Sensory perineuritis, 51, 51f clinical manifestations, 51 diagnostic evaluation, 51 electrophysiology, 51 pathophysiology, 51 treatment, 51 Sensory testing for diabetic neuropathy, 63 Serological markers, 275 Serologic testing for copper deficiency, 78, 78t Serum angiotensin-converting enzyme (SACE), 442–443 Serum autoantibody, 168 Serum protein electrophoresis (SPEP), 222, 439, 441–442 with immunofixation, 448–449 Severe dysautonomia, 177 Sickle cell disease, 47 clinical manifestations, 47 diagnostic evaluation, 47 electrophysiology, 47 pathophysiology, 47 treatment, 47 Silent neuropathy, 260 Simpler sensory neuronopathies (SNN) biopsies, 276, 277f blood and biological parameters, 275, 276 clinical manifestations, 273, 274, 274f common pattern of, 274, 275t diagnosis of, 275t differential diagnosis of, 275t demyelinating neuropathies, 284 infectious ataxic neuropathies, 284 tropical ataxic neuropathies, 284

index  473 disorders associated with autoimmune ataxic syndromes, 281–282 degeneration of DRG cells, 283–284 dysimmune SNN, 279–281 non–length-dependent small-fiber ganglionopathy, 283 paraneoplastic subacute SNN, 276–279 SNN and pyridoxine toxicity, 283 toxic or chemotherapy-induced SNN, 282–283 electrophysiological testings, 274 imaging techniques, 274 onset and rate of evolution, 273 overview of, 273 Sinus tachycardia, 177–178 Sjögren syndrome, 248–249, 249t, 316–317 Skin biopsy, 248 morphology, 426 Small-cell lung carcinoma (SCLC), 276, 278 Small-vessel vasculitis, 248 Smoldering multiple myeloma (SMM), 221 SNAP. See Sensory nerve action potential SNN. See Simpler sensory neuronopathies (SNN) Solitary plasmacytoma (SP), 221 Somatosensory evoked potentials (SSEP), 191, 274 Spectrofluorometry, 297 Sphincteric dysfunction, 294 Spinal accessory nerve anatomy of, 394–395, 394f clinical manifestations, 395–396, 396t diagnostic evaluation, 397 differential diagnosis, 396–397, 397t electrophysiology, 397–398 treatment, 398–399 Spinal accessory neuropathy, 24–25, 24t, 396t Spinal nerve roots, 149–161, 152f anatomy of, 149–152, 151f, 152f electrodiagnostic (EDX) testing AANEM guidelines for radiculopathy, 154 late responses, 155 motor and sensory nerve conduction studies, 154–155 needle electromyography, 155–157 imaging of, 157 outline of, 149, 150t radiculopathy nondiscogenic/nonspondylitic causes of, 150t pathophysiology of, 152–154 symptoms of, 154 treatment for disorders, 157–161, 159t–160t Spinal nerve root segment, anatomy of, 151f Spinal stenosis, 149 Spiral groove radial neuropathy at, 19–20 Staphylococcus, 414 Statins, 209–210 Stavudine, 210 Stem cell transplantation, 424 Sternocleidomastoid (SCM), 395 Stinger syndrome, 139–140 Stocking-and-glove loss peripheral neuropathy and, 3 Stocking-glove distribution, 326 Strachan syndrome, 79–80

diagnostic evaluation, 79 therapy, 79–80 Subacute autonomic neuropathies, 427 Subacute inflammatory demyelinating polyradiculoneuropathy (SIDP), 169, 187 Superficial peroneal nerve, 32t, 34, 34f, 34t biopsy, 264f Superficial radial sensory neuropathy, 20 Superior gluteal nerve, 35. See also Lower extremities, mononeuropathies of Supraclavicular plexus, 132 Suprascapular neuropathy, 22 differential diagnosis of, 22, 22t treatment, 22 Sural nerve, 32. See also Lower extremities, mononeuropathies of biopsy, 114, 205, 207, 208, 262 Sural sparing pattern, 168 Suramin, 212 Surgical management, 158 SYDNEY trial, 64 Synovial cytokines, 153 Syphilis, 161 Systemic AL amyloidosis, 222–223 Systemic diseases, 188, 451 Systemic immunomodulatory treatment, 153 Systemic inflammatory response syndrome (SIRS), 363, 367 Systemic lupus erythematosus (SLE), 190, 249, 249t, 315–316 Systemic vasculitic neuropathy. See Vasculitic neuropathy Systemic vasculitidies, 412 Systemic vasculitis, 45–46, 45f clinical manifestations, 45 diagnostic evaluation, 46 electrophysiology, 46 pathophysiology, 45–46 treatment, 46 Systolic blood pressure, 178 Tabes dorsalis, 6 Tachycardia, 177–178 Tacrolimus, 212–213 Tangier disease, 352 Taxanes, 211–212 Taxol, 446t TCE. See Trichloroethylene TD. See Thiamine deficiency Temporal arteritis, 248 Tendon reflexes, 124 Teniposide, 212 Terminal nerves, 133 Thalidomide, 210, 355, 447t Thallium, 448t Thallium neuropathy, 97–99. See also Toxic neuropathies clinical manifestations, 98 diagnosis, 98–99, 98t electrophysiology, 98 treatment, 99 Thiamine deficiency (TD), 69–70, 440–441. See also Vitamin B1 deficiency, neuropathy and alcoholic neuropathy and, 80 Thoracic radiculopathies, 156 diabetes mellitus and, 60

474  index Thromboembolic events, 175 Thyroid-stimulating hormone (TSH), 439, 440 Tibial nerve, 34. See also Lower extremities, mononeuropathies of posterior, 34–35 Tic douloureux, 390 Tick paralysis, 171t, 348 Tinel sign CTS and, 10 (see also Carpal tunnel syndrome) at elbow, 16 Tolosa-Hunt syndrome, 414, 415 Tomacula, 111 Topical agents. See Distal sensory neuropathy Toxic neuropathies, 87–101, 264, 355–356, 429 acrylamide, 87–89 (see also Acrylamide neuropathy) arsenic, 89–91 (see also Arsenic neuropathy) botulinum, 91–92, 92t carbamates, 97 carbon disulfide, 89t, 92–93 (see also Carbon disulfide neuropathy) element mercury, 95–96 lead, 94–95 n-hexane, 93–94 (see also N-hexane neuropathy) organophosphorus compounds, 97–98 overview, 87 thallium, 97–99 trichloroethylene, 99–101 Toxic or chemotherapy-induced SNN, 282–283 Toxin-mediated sensorimotor neuropathy, 429 Toxins, 444, 451 and drugs, 451 peripheral neuropathy and, 4–5 Traction injuries, 139 Tramadol, 158 Transglutaminase antibodies, 449 Transient autonomic dysfunction, 423 Transmission electron microscopy, 223 Transthyretin, 424 Trapezius, 395 Trauma, 139, 145, 413–414 Trichloroethylene (TCE) neuropathy, 99–101 (see also Toxic neuropathies) clinical presentation, 99–100 diagnosis, 100 electrophysiology, 100 treatment, 101 Tricyclic antidepressant, 203, 393 Trigeminal nerve anatomy of, 385–387, 385f, 386f clinical manifestations, 387–388, 387f diagnostic evaluation, 391–392, 392t differential diagnosis, 388–391, 389t electrophysiology blink reflex, 392–393 electromyography, 393 treatment, 393–394 Tropical ataxic neuropathies, 79, 284 Truncal/intercostal neuropathies, 313 Trunks, 132 Trypanosoma cruzi, 259, 429 Tryptophan, 289 Tuberculoid lesions, 354 Tuberculosis treatment, 206

Tumor, 391, 414 diagnosis, 279 infiltration (see Cancer, neuropathies with) necrosis factor a antagonists, 213 Tumor necrosis factor (TNF), 153 Typical DPN, 57 Tyrosinemia, 302, 343 Ulnar mononeuropathy, 316 Ulnar nerve anatomy of, 15, 15f dysfunction, clinical features of, 15–19 Ulnar neuropathy, 15–19, 15f, 15t–18t. See also Upper extremity, entrapment neuropathies of at elbow, 15–17, 16t diagnostic tests, 17 electrophysiology, 16–17, 16t treatment, 17 ulnar nerve, anatomy of, 15, 15f at wrist, 17–19, 17t–18t clinical syndromes, 17, 17t electrophysiology, 17–19, 18t Ultrasonography (US) CTS and, 13 ulnar neuropathy, 17 Unilateral facial nerve, 355 Upper extremity, entrapment neuropathies of, 9–25 mononeuropathies, 9–22 focal, 22–25 median neuropathy, 9–15, 9f, 10t–14t (see also Median neuropathy) radial neuropathy, 19–22, 19f, 20t–21t (see also Radial neuropathy) ulnar neuropathy, 15–19, 15f, 15t–18t (see also Ulnar neuropathy) overview of, 9 Upper motor neuron (UMN), 377, 379t Uremic polyneuropathy, 314 Urinary incontinence diabetes mellitus and, 59 Urinary retention, 178 Urine porphyrins, 295 Uroporphyrinogen, 290 US. See Ultrasonography Vaccination, 393 Valsalva maneuver, 294 Varicella zoster virus (VZV), 268 Variegate porphyria, 292, 298 Vasculitic neuropathy, 171t, 351 clinical aspects of, 245–246 clinical manifestations, 239 description of, 245, 246t diagnostic evaluation, 239, 251–253, 252t nerve biopsy, 252–253, 252f differential diagnosis, 251 electrophysiology, 239, 253 nonsystemic, 250–251, 251t pathogenesis and pathophysiology, 239, 245 systemic paraneoplastic vasculitis, 250 primary vasculitis, 246–248, 247t sarcoidosis, 249–250

index  475 secondary to connective tissue disease, 248–249, 249t secondary to infection, 250 treatment, 239, 253–255, 254t Vasculitis diabetic mononeuritis multiplex, 47 (see also Diabetic mononeuritis multiplex) MM and, 41, 42t restricted to PNS, 46 secondary to connective tissue disorders, 46–47 systemic, 45–46, 45f (see also Systemic vasculitis) Vasculopathic neuropathies, 251 Vectorial transmission, 429 Vernet syndrome, 415 Vertical segment, 376 Vestibular schwannomas, 414 Villaret syndrome, 415 Vinca alkaloids, 211, 429 Vincristine, 211, 355, 447t Vinorelbine, 211 Vitamin B1 deficiency, neuropathy and, 69–70 Vitamin B3 deficiency, neuropathy and, 70, 74 Vitamin B6 deficiency, neuropathy and, 74–75 Vitamin B12 deficiency, 343, 440, 445t neuropathy and, 75–76 Vitamin E deficiency, 283 Vitamin E deficiency, neuropathy and, 76–77 clinical features, 76–77 diagnostic evaluation, 77 etiology, 76 pathogenesis, 76 therapy, 77 Vitamin levels

B12 deficiency, 440, 445t copper, 440 folic acid, 440 homocysteine (Hcy), 440 vitamin B1, 440–441 vitamin B6, 440 vitamin E, 441 von Frey hypersensitivity, 331 Waldenström macroglobulinemia (WM), 222, 223t, 449 Wallerian degeneration, 136, 382 Wartenberg migrant sensory neuritis (WMSN), 42, 51, 251 Wegener granulomatosis (WG), 42, 247 Weight loss, 161 Wernicke-Korsakoff encephalitis, 70 Wernicke-Korsakoff syndrome, 440 Western blot, 443 West Nile encephalomyelitis, 171 West Nile virus infection, 451 “Wet” beriberi, 70 WG. See Wegener granulomatosis Winger’s brace, 398 WMSN. See Wartenberg migrant sensory neuritis Wrist median neuropathy at, 10 ulnar neuropathy at, 17–19, 17t–18t Xeroderma pigmentosum, 352 X-linked Charcot-Marie-Tooth (CMTX) disease, 111 Zoster vaccine, 393 Zygapophyseal joint cartilage, 153