Textbook of the Neurogenic Bladder, 2016 Third Edition

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Textbook of the

NEUROGENIC BLADDER Third Edition

Textbook of the

NEUROGENIC BLADDER Third Edition Edited by

Jacques Corcos Sir Mortimer B. Davis Jewish General Hospital McGill University Montreal, Quebec, Canada

David Ginsberg Keck School of Medicine of USC Los Angeles, California, USA

Gilles Karsenty Aix-Marseille University La Conception Hospital Marseille, France

Boca Raton London New York

CRC Press is an imprint of the Taylor & Francis Group, an informa business

CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2016 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Version Date: 20150414 International Standard Book Number-13: 978-1-4822-1555-7 (eBook - PDF) This book contains information obtained from authentic and highly regarded sources. While all reasonable efforts have been made to publish reliable data and information, neither the author[s] nor the publisher can accept any legal responsibility or liability for any errors or omissions that may be made. The publishers wish to make clear that any views or opinions expressed in this book by individual editors, authors or contributors are personal to them and do not necessarily reflect the views/opinions of the publishers. The information or guidance contained in this book is intended for use by medical, scientific or health-care professionals and is provided strictly as a supplement to the medical or other professional’s own judgement, their knowledge of the patient’s medical history, relevant manufacturer’s instructions and the appropriate best practice guidelines. Because of the rapid advances in medical science, any information or advice on dosages, procedures or diagnoses should be independently verified. The reader is strongly urged to consult the relevant national drug formulary and the drug companies’ and device or material manufacturers’ printed instructions, and their websites, before administering or utilizing any of the drugs, devices or materials mentioned in this book. This book does not indicate whether a particular treatment is appropriate or suitable for a particular individual. Ultimately it is the sole responsibility of the medical professional to make his or her own professional judgements, so as to advise and treat patients appropriately. The authors and publishers have also attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained. If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint. Except as permitted under U.S. Copyright Law, no part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC), 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com

Contents

Introduction List of contributors

Part I The normal genitourinary tract 1. Simplified anatomy of the vesicourethral functional unit Saad Aldousari and Jacques Corcos 2. Pharmacology of the lower urinary tract Karl-Erik Andersson 3. Integrated physiology of the lower urinary tract Naoki Yoshimura, Jeong Yun Jeong, Dae Kyung Kim, and Michael B. Chancellor

ix xi

11. Pathophysiology of autonomic dysreflexia Teresa Danforth and David Ginsberg

139 145

1

12. Pathophysiology of spinal shock Magdy Hassouna, Tarek Hassouna, Nader Elmayergi, and Mazen Abdelhady

9

Part III Neurologic pathologies responsible for the development of the neurogenic bladder

33

13. Systemic illnesses (diabetes mellitus, sarcoidosis, alcoholism, and porphyrias) Stephanie Kielb, Laurie Bachrach, and Nancy Rios

3

4. Physiology of normal sexual function 49 Pierre Clément, Hélène Gelez, and​François Giuliano

Part II Functional pathology of the lower urinary tract 73 5. Epidemiology of the neurogenic bladder Patrick B. Leu and Ananias C. Diokno

75

6. Ultrastructure of neurogenic bladders Axel Haferkamp

89

7. Pathophysiology of neurogenic detrusor overactivity Alexandra McPencow and Toby C. Chai 8. Pathophysiology of detrusor underactivity/ acontractile detrusor Dae Kyung Kim and Michael B. Chancellor

97

109

9. Pathophysiology of the low-compliant bladder 125 Véronique Phé, Emmanuel Chartier-Kastler, Jean-Marc Soler, and Pierre Denys 10. Dyssynergic sphincter Gérard Amarenco, Samer Sheikh Ismael, and Jean-Marc Soler

133

14. Other peripheral neuropathies (lumbosacral herpes zoster, genitourinary herpes, tabes dorsalis, Guillain–Barré syndrome) Vincent W.M. Tse and Anthony R. Stone 15. Peripheral neuropathies of the lower urinary tract following pelvic surgery and radiation therapy Richard T. Kershen and Timothy B. Boone

151 153

163

169

16. Dementia and lower urinary tract dysfunction 179 Ryuji Sakakibara 17. Pathologies of the basal ganglia, such as Parkinson’s and Huntington’s diseases Teruyuki Ogawa, Satoshi Seki, Naoki Yoshimura, and Osamu Nishizawa 18. Urinary dysfunction in multiple system atrophy Ryuji Sakakibara, Tatsuya Yamamoto, Tomoyuki Uchiyama, and Fuyuki Tateno 19. Multiple sclerosis Jaspreet Singh Parihar, Hari S.G.R. Tunuguntla, Line Leboeuf, and Angelo E. Gousse 20. Other diseases (transverse myelitis, tropical spastic paraparesis, progressive multifocal leukoencephalopathy, Lyme’s disease) Tomáš Hanuš

199

209

223

243

vi

Contents

21. Cerebrovascular accidents, intracranial tumors, and urologic consequences David J. Osborn, W. Stuart Reynolds, and Roger R. Dmochowski

259

35. Advanced urodynamics: Toward clinical useful neuroimaging in urology Bertil F.M. Blok

383

36. Normal urodynamic parameters in children Diego Barrieras and Orchidée Djahangirian

389

37. Urodynamics in infants and children Kate Abrahamsson, Gundela Holmdahl, and Ulla Sillén

395

38. Normal urodynamic parameters in adults Romain Caremel and Jacques Corcos

411

22. Intervertebral disk prolapse Patrick J. Shenot and M. Louis Moy

269

23. Cauda equina injury Patrick J. Shenot and M. Louis Moy

275

24. Tumors of the spinal cord Homero Bruschini, J. Pindaro P. Plese, and Miguel Srougi

281

25. Tethered cord syndrome Shokei Yamada, Brian S. Yamada, and Daniel J. Won

287

39. Electrophysiological evaluation: Basic principles and clinical applications John P. Lavelle

26. Spinal cord injury and cerebral trauma Jerzy B. Gajewski

299

40. Practical guide to diagnosis and follow-up of patients with neurogenic bladder dysfunction 443 Jacques Corcos

27. Cerebral palsy, cerebellar ataxia, AIDS, phacomatosis, neuromuscular disorders, and epilepsy Christopher Kobylecki, Ling K. Lee, and Mark W. Kellett 28. Syringomyelia and lower urinary tract dysfunction Marc Le Fort, Jean-Jacques Labat, and Brigitte Perrouin-Verbe

311

329

337

30. The voiding diary Matthew Young and Eric S. Rovner

347

31. The pad-weighing test Matthew Young and Eric S. Rovner

351

32. Endoscopic evaluation of neurogenic bladder Romain Caremel, Saad Aldousari, and Jacques Corcos

355

33. Imaging techniques in the evaluation of neurogenic bladder dysfunction John T. Stoffel 34. Evaluation of neurogenic lower urinary tract dysfunction: Basic urodynamics Benjamin M. Brucker, Christopher E. Kelly, and Victor W. Nitti

Part V Classification 447 41. Classification of lower urinary tract dysfunction Anne M. Suskind and J. Quentin Clemens

449

Part VI Treatment 453

Part IV Evaluation of neurogenic bladder dysfunction 335 29. Clinical evaluation: History and physical examination Chasta Bacsu and Gary E. Lemack

425

42. Conservative treatment Jean-Jacques Wyndaele 43. Management of neurogenic bladder with suprapubic cystostomy Romain Caremel, Andrew Feifer, and Jacques Corcos

455

467

44. Systemic and intrathecal pharmacologic treatment Shachar Aharony and Jacques Corcos

473

45. Intravesical pharmacologic treatment for neurogenic detrusor overactivity Christopher P. Smith

489

46. Management of autonomic dysreflexia 503 Romain Caremel, Guy Breault, and Jacques Corcos 363

47. Electrical stimulation for bladder management 511 Dennis Bourbeau, Bastian Amend, and Karl-Dietrich Sievert

373

48. Surgery to improve reservoir function Manfred Stöhrer and Jürgen Pannek

523

49. Surgery to improve bladder outlet function Jack C. Hou and Philippe E. Zimmern

531

Contents 50. Urinary diversion Sender Herschorn and Greg G. Bailly 51. The trans-appendicular continent cystostomy technique (Mitrofanoff principle) Bernard Boillot, Jacques Corcos, and Paul Mitrofanoff 52. Tissue engineering and cell therapies for neurogenic bladder augmentation and urinary continence restoration René Yiou

545

563

571

53. Restoration of complete bladder function by neurostimulation Michael Craggs and Sarah Knight

583

54. Neuroprotection and repair after spinal cord injury Daniel Yavin and Steven Casha

599

Part VII Special considerations on meningomyelocele 617 55. Neural tube defects: Etiology, prevention, and prenatal diagnosis 619 Atsuo Kondo, Shinji Katsuragi, and Osamu Kamihira 56. Initial management of meningomyelocele children Stuart B. Bauer

633

57. Intravesical electrical stimulation in newborns, infants, and children 645 Sang Won Han, Young Jae Im, and Eun Kyoung Choi 58. Fecal incontinence in the neurogenic bladder patient Jennifer H. Yang, Nima Harandi, Paula J. Wagner, and Anthony R. Stone 59. Adult myelomeningocele Paul W. Veenboer and J.L.H. Ruud Bosch

Part VIII Synthesis of treatment 60. Treatment alternatives for different types of neurogenic bladder dysfunction in children Roman Jednak and Joao Luiz Pippi Salle 61. An overview of treatment alternatives for different types of neurogenic bladder dysfunction in adults Jacques Corcos and David Ginsberg

651

659

669 671

685

vii

Part IX Complications 697 62. Complications related to neurogenic bladder dysfunction I: Infection, lithiasis, and neoplasia Gamal Ghoniem 63. Complications related to neurogenic bladder dysfunction II: Vesicoureteral reflux and renal insufficiency Claire C. Yang and Brandon M. Haynes 64. Benign prostatic hyperplasia and lower urinary tract symptoms in men with neurogenic bladder Jeffrey Thavaseelan and Akhlil Hamid

699

709

719

Part X Sexual dysfunction in neurologic disorders 731 65. Pathophysiology of male sexual dysfunction after spinal cord injury Pierre Denys and Clément Chéhensse

733

66. Sexual consequences of multiple sclerosis and other central nervous system disorders Maarten Albersen and Dirk De Ridder

741

67. Treatment modalities for erectile dysfunction in neurological patients Reinier-Jacques Opsomer

747

68. Fertility issues in men with spinal cord injury 755 Jeanne Perrin, Blandine Courbiere, Vincent Achard, and Catherine Metzler-Guillemain 69. Pregnancy in spinal cord injury Carlotte Kiekens

Part XI Prognosis and follow-up

765

771

70. Evolution and follow-up of lower urinary tract dysfunction in spinal cord–injured patients 773 Marc Le Fort, Marie-Aimée Perrouin-Verbe, and Jean-Jacques Labat 71. Neurogenic bladder surveillance in children Steve S. Kim

Part XII Reports and guidelines 72. Reports and guidelines in relation to neurogenic bladder dysfunction: A selection Ornella Lam Van Ba and Jacques Corcos Index 799

781

789 791

Introduction

I am pleased to present this new edition of the Textbook of the Neurogenic Bladder. Physicians and other health professionals, spanning a wide range of expertise, have praised the previous editions. These readers have gained immense knowledge, beneficial for advising patients, students, and colleagues. For the two previous editions and the other works that have resulted from these editions, I welcomed the opportunity to work with Dr. Erick Schick. I will never forget our collaborations and earnest discussions about this topic, which occupied a substantial part of our professional lives. Erick decided not to participate in this new edition. Recently, he retired from his clinical and teaching duties, after several decades of remarkable contributions to patients’ well-being and students’ education. My enthusiasm for electronic communication devices caused me to question the pertinence of yet another hard-copy textbook. Despite my initial reservations, there are many reasons for continuing along the “traditional” path. Most importantly, the majority of the chapters have been updated from previous editions, some of them requiring very few updates on account of the generally slow rate of scientific progress. An electronic version would have required that each contributor rewrites his/ her chapter(s) without using any previous material, as publication rights belong to the publisher. The available time frame would not allow for such a massive undertaking. Moreover, the value of a hard-copy book is in its role as a reference book. It is undeniably interesting to have a global view of all the chapters, which is still difficult to achieve on a computer. Finally, as with the previous editions, it is a welcome addition to the reference collections of health professionals. To oversee the present edition, I have selected two coeditors to share the immense workload that is required in such a venture. Both David Ginsberg and Gilles Karsenty represent what North America and Europe have to offer in terms of competency, dedication, and resolve, in the field of voiding dysfunction. In the selection of these two outstanding young clinicians and teachers, I have secured the

future of this important textbook for the next quarter of a century. Jacques Corcos This textbook is essential to contemporary medicine because it covers a topic that is seldom taught in medical school or residency. Furthermore, we believe that this book can be a valuable reference for nurses and technicians involved in the care of the frequently seen patients. Neurogenic bladder/sphincter dysfunctions are common ailments at all ages. They occur following congenital, acquired, or degenerative conditions, and almost all neurogenic conditions are associated with some type of lower urinary tract dysfunction. In this new edition, we have maintained the same structure as the previous editions. After a brief section covering lower urinary tract anatomy and physiology and an update on epidemiology, a large component of the book (21 chapters) focuses on the pathophysiology of the v­ arious types of dysfunctions. Our guiding theme was better understanding to allow for better learning. The clinical section follows, focusing on evaluation and treatment. Different types of treatments from behavioral to surgical are reviewed, including the most recent and sophisticated pharmacotherapy and tissue engineering. A special section is devoted to myelomeningocele, which has lifelong repercussions on voiding and requires good team collaboration of a variety of healthcare providers at every stage of life. Complications, sexual function, fertility, maternity aspects, and prognostic factors bring the textbook to its completion with each topic covered in detail by several authors for a better overall understanding and a variety of guidelines on management. We have been extremely impressed by the acceptance rates of our contributors and even more by their extensive amount of work to update, rewrite, or compose these remarkable chapters. We have selected those who we believe to be the most competent individuals for each topic. The selection criteria included our combined k­ nowledge of individual interests and publication records. We are convinced

x

Introduction

that many outstanding specialists have not been invited to contribute and we hope that they will forgive us and understand that, when editing a textbook, there is a limited availability of space. We sincerely hope that this textbook will contribute to better understanding and treatment of patients with neurogenic voiding dysfunction and that, as with previous

editions, it will be consulted by a variety of health professionals who will use it as their reference resource. Jacques Corcos David Ginsberg Gilles Karsenty

List of contributors

Mazen Abdelhady, MD, MSc Toronto Western Hospital University of Toronto Toronto, Canada

Karl-Erik Andersson, MD, PhD Wake Forest Institute for Regenerative Medicine Wake Forest University School of Medicine Winston Salem, North Carolina

Kate Abrahamsson, MD Pediatric Urology Section Queen Silvia Children’s Hospital Sahlgrens Academy, University of Gothenburg Gothenburg, Sweden

Laurie Bachrach, MD Department of Urology Northwestern University Chicago, Illinois

Vincent Achard, MD, PhD AP-HM La Conception Hospital CECOS-Lab. Biology of Reproduction, Gynepole Marseille, France Shachar Aharony, MD Department of Urology McGill University Montréal, Canada Maarten Albersen, MD, PhD University Hospitals Leuven and National MS Center Melsbroek, Belgium

Chasta Bacsu, MD Department of Urology UT Southwestern Medical Center Dallas, Texas Greg G. Bailly, MD, FRCSC Department of Urology Dalhousie University and Attending Urologist QEII Health Sciences Centre Halifax, Canada Diego Barrieras, MD Université de Montréal CHU Sainte-Justine Montréal, Canada

Saad Aldousari, MD Department of Urology McGill University Montréal, Canada

Stuart B. Bauer, MD Department of Urology Boston Children’s Hospital and Harvard Medical School Boston, Massachusetts

Gérard Amarenco, MD Service de Neuro-Urologie et d’ Explorations Périnéales Hôpital Tenon, Paris, France

Bertil F.M. Blok, MD, PhD Erasmus MC Department of Urology Rotterdam, the Netherlands

Bastian Amend, MD Department of Urology Eberhard-Karls University Tuebingen, Germany

Bernard Boillot, MD Adolescent and Reconstructive Urology University Hospital Grenoble, France

xii

List of contributors

Timothy B. Boone, MD, PhD Weill Cornell Medical College New York City, New York and Department of Urology Institute for Academic Medicine Texas A&M College of Medicine, Houston Campus and Houston Methodist Hospital Houston, Texas J.L.H. Ruud Bosch, MD, PhD, FEBU Department of Urology University Medical Center Utrecht Utrecht, the Netherlands Dennis Bourbeau, PhD Cleveland FES Center and Louis Stokes Cleveland Department of Veteran Affairs and Case Western Reserve University Cleveland, Ohio Guy Breault, MD Department of Urology McGill University Montréal, Canada Benjamin M. Brucker, MD Department of Urology New York University School of Medicine New York City, New York Homero Bruschini, MD, PhD Division of Urology University of São Paulo School of Medicine São Paulo, Brazil Romain Caremel, MD Department of Urology McGill University Montréal, Canada Steven Casha, MD, PhD, FRCSC University of Calgary Spine Program and the Department of Clinical Neurosciences and Foothills Medical Centre Alberta, Canada Toby C. Chai, MD Department of Urology Yale School of Medicine New Haven, Connecticut

Michael B. Chancellor, MD William Beaumont School of Medicine Oakland University Rochester, Michigan Emmanuel Chartier-Kastler, MD, PhD Voiding Disorders and Neurourology Program Faculté de médecine Pitié-Salpêtrière Université Paris 6 (Pierre et Marie Curie) and Urology Department Groupe Hospitalier Pitié-Salpétrière Paris, France Clément Chéhensse, MD Neuro-Urology and Andrology Unit Raymond Poincaré Hospital AP-HP and Université de Versailles Saint Quentin Versailles, France Eun Kyoung Choi, RN, CPNP, PhD Bladder-Urethra Rehabilitation Clinic Department of Pediatric Urology Severance Children’s Hospital Seoul, South Korea J. Quentin Clemens, MD, MS Department of Urology Alfred Taubman Health Center University of Michigan Ann Arbor, Michigan Pierre Clément, PharmD, PhD Pelvipharm Laboratories and Faculty of Health Sciences University of Versailles-Saint Quentin en Yvelines Montigny le Bretonneux, France Jacques Corcos, MD, FRCS(S) Department of Urology McGill University Montréal, Canada Blandine Courbiere, MD, PhD Institut Méditerranéen de Biodiversité et d’Ecologie marine et continentale (IMBE) Aix-Marseille Université (AMU) Biogenotoxicology Human Health & Environment and AP-HM La Conception Hospital Department of Gynecology, Obstetrics, and Reproduction, Gynepole Marseille, France

List of contributors Michael Craggs, PhD, BSc (Hons), MSB, CBiol, CSci, MIPEM, Fellow, Royal Society of Medicine (London) Division of Surgery & Interventional Science University College London London, United Kingdom and London Spinal Cord Injury Centre Royal National Orthopaedic Hospital NHS Trust Stanmore, United Kingdom Teresa Danforth, MD Department of Urology Keck School of Medicine of USC University of Southern California Los Angeles, California Pierre Denys, MD Neuro-Urology and Andrology Unit Raymond Poincaré Hospital AP-HP Université de Versailles Saint Quentin Versailles, France Ananias C. Diokno, MD Department of Urology William Beaumont School of Medicine Oakland University Rochester, Michigan Orchidée Djahangirian, MD Université de Montréal CHU Sainte-Justine Montréal, Canada Roger R. Dmochowski, MD Department of Urology Vanderbilt University Medical Center Nashville, Tennessee Nader Elmayergi, MD Toronto Western Hospital University of Toronto Toronto, Canada Andrew Feifer, MD Department of Urology McGill University Montréal, Canada Jerzy B. Gajewski, MD, FRCSC Department of Urology Dalhousie University Halifax, Canada

Hélène Gelez, PhD Pelvipharm Laboratories and Faculty of Health Sciences University of Versailles-Saint Quentin en Yvelines Montigny le Bretonneux, France Gamal Ghoniem, MD, FACS Division of Female Urology Pelvic Reconstruction Surgery & Voiding Dysfunction University of California—Irvine Medical Center Orange, California David Ginsberg, MD, DSc Department of Urology Keck School of Medicine of USC University of Southern California Los Angeles, California François Giuliano, MD, PhD Pelvipharm Laboratories and Faculty of Health Sciences University of Versailles-Saint Quentin en Yvelines Montigny le Bretonneux, France and AP-HP, Neuro-Uro-Andrology Department of Physical Medicine and Rehabilitation Raymond Poincaré Hospital Garches, France Angelo E. Gousse, MD Herbert Wertheim College of Medicine Florida International University Miramar, Florida Axel Haferkamp, MD Clinic of Urology and Pediatric Urology University Hospital Frankfurt Goethe University Frankfurt, Germany Akhlil Hamid, MD Fiona Stanley Hospital University of Western Australia Perth, Western Australia Sang Won Han, MD, PhD Department of Pediatric Urology Severance Children’s Hospital Yonsei University College of Medicine Seoul, South Korea

xiii

xiv

List of contributors

Tomáš Hanuš, MD, DSc Department of Urology First Faculty of Medicine Charles University and General Teaching Hospital Prague, Czech Republic Nima Harandi, MSRF School of Medicine University of California, Davis Sacramento, California Magdy Hassouna, MD, PhD, FRCSC Toronto Western Hospital University of Toronto Toronto, Canada Tarek Hassouna, MD Toronto Western Hospital University of Toronto Toronto, Canada Brandon M. Haynes, MD Department of Urology University of Washington Seattle, Washington Sender Herschorn, BSc, MDCM, FRCSC Division of Urology University of Toronto Toronto, Canada Gundela Holmdahl, MD Pediatric Urology Section Queen Silvia Children’s Hospital and Sahlgrens Academy, University of Gothenburg Gothenburg, Sweden Jack C. Hou, MD Department of Urology UT Southwestern Medical Center Dallas, Texas

Roman Jednak, MD, FRCSC Department of Pediatric Surgery (Urology) Division of Pediatric Urology Montréal Children’s Hospital/ McGill University Health Centre Montréal, Canada Jeong Yun Jeong Department of Urology Center for Health Promotion Samsung Medical Center Sungkyunkwan University School of Medicine Seoul, South Korea Osamu Kamihira, MD Department of Urology Komaki Shimin Hospital Aichi, Japan Shinji Katsuragi, MD, PhD Department of Obstetrics and Gynecology Sakakibara Heart Institute Tokyo, Japan Mark W. Kellett, MBBS, BMedSci (Hons), MD, FRCP Greater Manchester Neurosciences Centre Salford Royal NHS Foundation Trust Salford, United Kingdom Christopher E. Kelly, MD Department of Urology New York University School of Medicine New York City, New York Richard T. Kershen, MD Female Urology, Neurourology and Voiding Dysfunction Tallwood Urology and Kidney Institute Hartford Healthcare Medical Group Hartford, Connecticut

Young Jae Im, MD Department of Pediatric Urology Severance Children’s Hospital Yonsei University College of Medicine Seoul, South Korea

Carlotte Kiekens, MD Physical and Rehabilitation Medicine University Hospitals Leuven Leuven, Belgium

Samer Sheikh Ismael, MD Service de Neuro-Urologie Hôpital Tenon, APHP Paris, France

Stephanie Kielb, MD Department of Urology Northwestern University Chicago, Illinois

List of contributors Dae Kyung Kim, MD, PhD Department of Urology Eulji University School of Medicine Daejeon, South Korea

Line Leboeuf, MD, FRCSC Department of Urology University of Montréal Montréal, Canada

Steve S. Kim, MD, MSCE Department of Urology University of Southern California and Division of Pediatric Urology Children’s Hospital Los Angeles Los Angeles, California

Ling K. Lee, MD Urology Department Royal Bolton Hospital NHS Foundation Trust Bolton, United Kingdom

Sarah Knight, MA, PhD, MIPEM Division of Surgery and Interventional Science University College London London, United Kingdom and London Spinal Cord Injury Centre Royal National Orthopaedic Hospital NHS Trust, Brockley Hill Stanmore, United Kingdom Christopher Kobylecki, MRCP, MB ChB, PhD Department of Neurology Greater Manchester Neurosciences Centre Salford Royal NHS Foundation Trust Salford, United Kingdom and Centre for Clinical and Cognitive Neurosciences Institute of Brain Behaviour and Mental Health University of Manchester Manchester, United Kingdom

Marc Le Fort, MD Service de Médecine Physique et de Réadaptation Neurologique Saint-Jacques University Hospital Nantes, France Gary E. Lemack, MD Department of Urology UT Southwestern Medical Center Dallas, Texas Patrick B. Leu, MD Department of Urology University of Nebraska Medical Center and The Urology Center, P.C. Omaha, Nebraska Alexandra McPencow, MD Division of Urogynecology Department of Obstetrics and Gynecology Yale School of Medicine New Haven, Connecticut

Atsuo Kondo, MD, PhD Department of Urology Atsuta Rehabilitation Hospital Nagoya, Japan

Catherine Metzler-Guillemain, MD, PhD AP-HM La Conception Hospital CECOS Lab Biology of Reproduction, Gynepole Marseille, France

Jean-Jacques Labat, MD Clinique Urologique Federal Center of Pelvic Perineology Hôtel-Dieu University Hospital Nantes, France

Paul Mitrofanoff, MD Paediatric Surgery University Hospital Rouen, France

Ornella Lam Van Ba, MD Department of Urology McGill University Montréal, Canada

M. Louis Moy, MD Department of Urology University of Florida College of Medicine Gainesville, Florida

John P. Lavelle, MB, FRCSI Stanford University & Veteran’s Affairs Palo Alto Health Care System Palo Alto, California

Osamu Nishizawa, MD, PhD Department of Urology Shinshu University School of Medicine Matsumoto, Japan

xv

xvi

List of contributors

Victor W. Nitti, MD Department of Urology New York University School of Medicine New York City, New York Teruyuki Ogawa, MD, PhD Department of Urology Shinshu University School of Medicine Matsumoto, Japan Reinier-Jacques Opsomer, MD Cliniques Universitaires Saint-Luc Entre de Pathologie Sexuelle Masculine Division of Urology Université Catholique de Louvain Brussels, Belgium David J. Osborn, MD Department of Urology Walter Reed National Military Medical Center Bethesda, Maryland

Véronique Phé, MD Faculté de médecine Pitié-Salpêtrière Université Paris 6 (Pierre et Marie Curie) and Urology Department Groupe Hospitalier Pitié-Salpétrière Paris, France J. Pindaro P. Plese, MD, PhD Department of Neurology University of São Paulo School of Medicine São Paulo, Brazil W. Stuart Reynolds, MD Department of Urology Vanderbilt University Medical Center Nashville, Tennessee Dirk De Ridder, MD, PhD, FEBU University Hospitals Leuven Leuven, Belgium

Jürgen Pannek, MD Department of Neurourology Swiss Paraplegic Centre Nottwil, Switzerland

and

Jaspreet Singh Parihar, MD Robert Wood Johnson Medical School and Robert Wood Johnson University Hospital New Brunswick, New Jersey

Nancy Rios, MD University of Illinois College of Medicine Chicago, Illinois

Jeanne Perrin, MD, PhD Institut Méditerranéen de Biodiversité et d’Ecologie marine et continentale (IMBE) Aix-Marseille Université (AMU) and Biogenotoxicology Human Health & Environment Campus Timone - Faculté de Pharmacie IRD Avignon Université and AP-HM La Conception Hospital CECOS Lab Biology of Reproduction, Gynepole Marseille, France Brigitte Perrouin-Verbe, MD Service de Médecine Physique et de Réadaptation Neurologique Saint-Jacques University Hospital Nantes, France Marie-Aimée Perrouin-Verbe, MD Service d’Urologie Cavale Blanche University Hospital Brest, France

National MS Center Melsbroek, Belgium

Eric S. Rovner, MD Department of Urology Medical University of South Carolina Charleston, South Carolina Ryuji Sakakibara, MD, PhD Neurology, Internal Medicine Sakura Medical Center Toho University Sakura, Japan Joao Luiz Pippi Salle, MD, PhD, FAAP, FRCSC Department of Surgery Division of Urology Sidra Medical and Research Center Doha, Qatar Satoshi Seki, MD, PhD Department of Urology Shinshu University School of Medicine Matsumoto, Japan Patrick J. Shenot, MD, FACS Department of Urology Jefferson Medical College Philadelphia, Pennsylvania

List of contributors Karl-Dietrich Sievert, MD, PhD, FACS, FRCS Department of Urology Eberhard-Karls University Tuebingen, Germany Ulla Sillén, MD Pediatric Urology Section Queen Silvia Children’s Hospital Sahlgrens Academy, University of Gothenburg Gothenburg, Sweden Christopher P. Smith, MD, MBA, MSS Department of Urology Baylor College of Medicine Houston, Texas Jean-Marc Soler, MD Neurologic Rehabilitation Unit Centre Bouffard-Vercelli Cerbère, France Miguel Srougi, MD, PhD Division of Urology University of São Paulo School of Medicine São Paulo, Brazil John T. Stoffel, MD Division of Neurourology, Pelvic Reconstructive Surgery University of Michigan Urology Center Ann Arbor, Michigan Manfred Stöhrer, MD, PhD Department of Urology University of Essen Essen, Germany Anthony R. Stone, MD Department of Urology University of California, Davis, School of Medicine Sacramento, California Anne M. Suskind, MD, MS Department of Urology University of Michigan Alfred Taubman Health Center Ann Arbor, Michigan Fuyuki Tateno, MD, PhD Neurology, Internal Medicine Sakura Medical Center and Toho University Sakura, Japan

xvii

Jeffrey Thavaseelan, MD, MBBS FRACS Fiona Stanley Hospital St. John of God Hospital and University of Notre Dame Perth, Western Australia Vincent W.M. Tse, MB, BS (Hons), MS, FRACS (Urol) Department of Urology Concord Hospital and University of Sydney Sydney, Australia Hari S.G.R. Tunuguntla, MD, MS, MCh Division of Urology Department of Surgery Robert Wood Johnson Medical School New Brunswick, New Jersey Tomoyuki Uchiyama, MD, PhD Neurology, Internal Medicine Sakura Medical Center and Toho University Sakura, Japan Paul W. Veenboer, MD Department of Urology University Medical Center Utrecht Utrecht, the Netherlands Paula J. Wagner, NP Department of Urology University of California, Davis Medical Center Sacramento, California Daniel J. Won, MD, FAAP Department of Neurosurgery Kaiser Permanente Medical Center Fontana, California Jean-Jacques Wyndaele, MD, DSci, PhD Department of Urology and Urologic Rehabilitation University of Antwerp Brasschaat, Belgium Brian S. Yamada, MD Department of Urology and Urologic Rehabilitation Saratoga Hospital Saratoga Springs, New York

xviii

List of contributors

Shokei Yamada, MD, PhD, FACS, FAANS Department of Neurosurgery Loma Linda University School of Medicine Loma Linda, California and Department of Neurosurgery Arrowhead Regional Medical Center Colton, California and Department of Neurosurgery Kaiser Permanente Medical Center Fontana, California Tatsuya Yamamoto, MD, PhD Neurology, Internal Medicine Sakura Medical Center Toho University Sakura, Japan Claire C. Yang, MD University of Washington Harborview Medical Center Seattle, Washington Jennifer H. Yang, MD Pediatric Urology University of California, Davis, Children’s Hospital and University of California, Davis, School of Medicine Sacramento, California

Daniel Yavin, MD University of Calgary Spine Program and the Department of Clinical Neurosciences Foothills Medical Centre Alberta, Canada René Yiou, MD, PhD Service d’Urologie CHU Henri Mondor Créteil, France Naoki Yoshimura, MD, PhD Department of Urology University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania Matthew Young, MD Department of Urology Medical University of South Carolina Charleston, South Carolina Philippe E. Zimmern, MD Department of Urology UT Southwestern Medical Center Dallas, Texas

Part I The normal genitourinary tract

1 Simplified anatomy of the vesicourethral functional unit Saad Aldousari and Jacques Corcos

Introduction The bladder and urethra should necessarily be described together. Functionally, these two organs cannot be dissociated and, anatomically, their connections are too imbricated to distinguish them as two different organs. The pelvic floor, with its muscles, fascia, and ligaments, is a separate anatomic entity, but, functionally, it is also an important component of urethra–vesical physiology.1

The bladder The bladder (Figure 1.1), located in the pelvis behind the pubic bone, can be divided into two portions. The dome, the upper part of the bladder, is spherical, extensible, and

mobile. The median umbilical ligament (urachus) ascends from its apex behind the anterior abdominal wall to the umbilicus, and the peritoneum behind it creates the median umbilical fold. In males, the superior surface of the dome is completely covered by the peritoneum e­ xtending slightly to the base. It is in close contact with the sigmoid colon and the terminal coils of the ileum. In females, the difference arises from the posterior reflection of the peritoneum on the anterior face of the uterus, forming the vesico–uterine pouch. In both sexes, the inferolateral part of the bladder is not covered by the peritoneum. In adults, the bladder is completely retropubic and can be palpated only if it is in overdistension. In contrast, at birth, it is relatively high and is  an abdominal organ. It descends progressively, reaching its adult position at puberty.

Dome Bladder

Bladder

Ureterovesical junction Base

Prostate

Urethrovesical junction Prostatic urethra

Pubis

Membranous urethra External sphincter and pelvic floor Urethra

Corpora spongiosum

Spongiosum urethra

(a)

Figure 1.1 Anatomy of the vesicosphincteric unit in man. (a) Sagittal view and (b) frontal view.

(b)

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Textbook of the Neurogenic Bladder as it forms a ring-like structure at the level of the bladder neck. The outer longitudinal layers are thickest posteriorly at the bladder base, providing a strong trigonal support. Laterally, fibers from this sheet pass anteriorly and fuse to form a loop around the bladder neck, participating in the continence mechanism. The female bladder neck, on the other hand, differs from that of the male in that its sphincteric function is limited. Some authors have denied its existence altogether.2

Ureteral orifices

Arcus muscle fibers of the trigone

Arcus muscle fibers of the detrusor Urethral orifice

Figure 1.2 Trigone endovesical view.

The base of the bladder, i.e., the lower part, is fixed. The trigone, at the post part of the bladder base, is a triangular area between three orifices: two ureteral orifices and a urethral orifice or bladder neck. At the level of the vesicourethral junction, the ureters cross the bladder wall obliquely in a length of 1–2 cm. This type of path through the bladder wall creates a valve mechanism, preventing urine reflux toward the ureters when bladder pressure increases. This is achieved by the fact that the ureter pierces the bladder wall obliquely. As the ureter passes through a hiatus in the detrusor (intramural ureter), it is compressed and closed completely by detrusor contraction. This intravesical portion of the ureter lies immediately beneath the bladder urothelium, and, therefore, it is backed by a strong plate of detrusor muscle. It is believed that with bladder filling, this results in passive occlusion of the ureter, like a flap valve. At the level of the vesicourethral junction or bladder neck, the original disposition of the muscle fibers allows closure during the bladder-filling phase (Figure 1.2).

Detrusor muscle The detrusor muscle can be described as a sphere of smooth muscle bundles. It is a complex imbrication of smooth muscle fibers without a well-defined orientation, but is usually viewed as an external and internal longitudinal layer with a circular intermediate layer. These layers are inseparable in the upper aspect of the bladder. On the other hand, near the bladder neck, they are clearly separable into the three layers mentioned earlier. In men and women, the muscle fibers of the inner longitudinal layer extend down into the urethra in a funnel-shaped structure, allowing continence and emptying of the bladder. In men, the middle circular layer forms a circular preprostatic sphincter, which is responsible for continence,

Bladder mucosa The bladder mucosa, folded when the bladder is empty, is loosely adhered to the submucosal tissue and the detrusor. Over the trigone and all around the bladder neck it becomes much more adhered. The bladder mucosa is richly vascularized and very sensitive to pain, distention, temperature, and so on. Deep to this, the lamina propria forms a relatively thick layer of fibroelastic connective tissue that allows considerable distension. This layer is traversed by numerous blood vessels and contains smooth muscle fibers collected into a poorly defined muscularis mucosa. Beneath this layer lies the smooth muscle of the bladder wall.

The urethra Female urethra The female urethra is 4 cm long and approximately 6 mm in diameter. It begins at the internal vesical orifice, extends downward and forward behind the symphysis pubis, and terminates at the external urethral meatus about 2  cm behind the glans clitoris. The urethral mucosa is surrounded by a rich, spongy, estrogen-dependent submucosal vascular plexus encased in fibroelastic and muscular tissue. The outer layer of the female urethra, covered two-thirds of its proximal length by a striated muscle, represents the external urinary sphincter. This sphincter has its largest diameter in the middle part of the urethra. The striated urogenital sphincter has two distinct portions: the upper portion, which is arranged circularly around the urethra, corresponds to the rhabdosphincter, whereas the lower portion comprises arch-like muscular bands (Figure 1.3). Many small mucous glands open into the urethra, forming what are called the paraurethral ducts, which are usually located on the lateral margin of the external urethral orifice.2

Male urethra The male urethra (see Figure 1.1a,b) is 18–20 cm long and is usually divided into three portions: the proximal or prostatic urethra, the membranous urethra (both included in

Simplified anatomy of the vesicourethral functional unit

5

Trigonal ring Urinary trigone Vagina Detrusor loop

Pubic symphysis Urethral rhabdosphincter Urethrovaginal sphincter Compressor urethra

}

Distal urethral sphincter

Figure 1.3 Architectural organization of the striated urethral sphincter. Location of its three components: the urethral rhabdosphincter, the compressor urethra, and the urethrovaginal sphincter.

the posterior urethra), and the anterior urethra (composed of bulbar, pendulous urethra, and fossa navicularis).3,4

••

••

••

The first segment (3–4 cm) is mainly a thin tube of smooth muscle lined by mucosa and extending through the prostate from the bladder neck to the apex of the prostate. At the origin of the prostatic urethra, the smooth muscle surrounding the bladder neck is arranged in a distinct circular collar, which becomes continuous distally with the capsule of the prostate. The internal sphincter extends from the internal vesical meatus through the prostatic urethra to the level of the verumontanum, providing passive continence via the sympathetic supply. The prostatic urethra ends distal to the verumontanum. The second segment, erroneously called the membranous urethra (there is nothing membranous at that level), is also known as sphincteric urethra. The external sphincter has an omega shape and surrounds the urethra with a fibrotic segment in its posterior midline. It is 2 cm long and 3–5 mm in thickness. It has an outer layer of striated muscle and an inner layer of smooth muscle, intrinsic to the urethral wall, making it both a voluntary and an involuntary unit. Surrounding the external sphincter is a layer of periurethral striated muscle fibers, providing assistance in voluntary control (i.e., interruption of voiding). The last segment, the spongiosum urethra, is contained in the corpus spongiosum of the penis and extends from the previous segment to the urethral meatus. Its diameter is 6 mm when passing urine. It is dilated at its commencement to form the intrabulbar fossa and again within the glans penis, where it becomes the navicular fossa. All along the urethra, numerous small mucous glands (urethral glands) open into its lumen.

Vascular and lymphatic supply of the bladder and urethra The superior and inferior vesical arteries are branches of the internal iliac arteries. The obturator and gluteal arteries also participate in the bladder arterial supply. In females, an additional branch is derived from the uterine and vaginal arteries. Venous drainage forms a complex, extensive network around the bladder and into a plexus on its inferolateral face, ending in the internal iliac veins. Lymphatic drainage originates from all layers of the bladder and ends in the external iliac nodes. Most urethral lymphatic drainage terminates in the external iliac nodes, except for the spongiosum urethra and the glans penis where it goes to the deep inguinal nodes and from there to the external iliac nodes.3

Urethrovesical unit innervation Three nerves provide an anatomic and somatic innervation to the bladder (Figure 1.4).5–7

Hypogastric nerve The hypogastric nerve has motor and sensory fibers. It originates from preganglionic spinal neurons of the thoracolumbar intermediolateralis cord at the level of T10 to L1.8 Preganglionic axons reach the paravertebral sympathetic ganglionic chain, where they synapse with ganglionic neurons. Postganglionic axons cross the superior hypogastric plexus to reach the vesical or interior hypogastric plexus.

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Textbook of the Neurogenic Bladder but some noradrenergic fibers participate in the composition of the pelvic plexus. The bladder, including the trigone, is profusely supplied by nerves from a dense plexus among the detrusor muscle fibers. The majority of these nerves are cholinergic and follow the vascular supply, only rarely extending among the nonstriated muscle components of the bladder and urethra.

Spinal cord

Pudendal nerves

T10 T11

Sympathetic chain

T12 L1 Lumbar spinal cord

Inferior mesenteric ganglion Hypogastric nerve

Sacral S1 spinal cord S2 S3 S4

(–) (–) Pelvic plexus

Pelvic nerve

Pudendal nerve

(+)

Bladder

External sphincter

Figure 1.4 Spinal cord centers and nerves responsible for micturition.

The adrenergic innervations delivered by these nerves are β type at the level of the dome, and α1 type at the level of the bladder base and neck (superficial trigone). The global effects of adrenergic bladder innervation are relaxation of the dome and contraction of the bladder neck. The hypogastric nerves are mainly adrenergic, but also have cholinergic as well as peptidergic contingents whose function is not well understood. In contrast to the rich sympathetic innervation of the bladder neck in males, the bladder neck in females receives mainly cholinergic fibers and much less adrenergic innervation. This difference in nerve supply may relate to the main genital function attributed to the bladder neck in males and its lesser importance in females.

Pelvic nerves The pelvic nerves represent the parasympathetic component of bladder innervation. Their fibers arise from the second to the fourth sacral segments of the spinal cord and merge at the level of the vesical plexus, from where branches reach the bladder. These fibers are cholinergic,

The pudendal nerve, arising from the spinal motor neurons of Onuf’s nucleus located at the base of the anterior horn of S2–S4, conveys both motor and sensory fibers. Their axons cross the pudendal plexus composed of the second, third, and fourth sacral nerves and merge to constitute the pudendal nerves that are responsible for the innervation of all the striated muscles of the pelvic floor, including the urethral and anal sphincters. A study conducted at the University Hospital Zurich by Reitz et al.9 has shown that somatosensory fibers of the pudendal nerve are projected onto sympathetic thoracolumbar neurons controlling the bladder neck, a process called neuromodulation. It works on a spinal level and confers bladder neck competence and continence. The authors have also shown that involuntary detrusor contractions because of bladder overactivity can be suppressed by electrical stimulation of pudendal nerve. This was explained by the fact that the stimulated pudendal afferents are directed in the spinal cord to influence both the inhibitory effects of the hypogastric or pelvic nerves on the bladder dome and the excitatory effects of the hypogastric nerve on the bladder neck through α-adrenergic receptors.

Nonadrenergic/noncholinergic innervation Numerous neurotransmitters have been detected and studied in the intramural ganglia of the bladder, such as somatostatin, substance P, neurokinin, and bombesin. The anatomic and physiologic relationships between nonadrenergic/noncholinergic innervations and cholinergic/ adrenergic innervations are still being debated.

Afferent fibers The origins of these sensory nerves incorporate different types of subepithelial receptors (simple or complex vesicles), capsulated or not, but with controversial distributions and functions (Figure 1.5). Present in sympathetic and adrenergic innervation, these sensory fibers transmit pain and awareness of distension to the central structures. Bladder afferents mainly follow the pelvic nerves. Urethral afferents follow the pelvic nerves for the proximal

Simplified anatomy of the vesicourethral functional unit

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Posterior column

Anterolateral column Spinothalamic column

Figure 1.5 Transverse cut of the spinal cord showing the ascendant and descendant pathways of the vesicosphincteric innervation. Paracentral lobule + – – +

Superior frontal gyrus Anterior cingulate gyrus

+

Amygdala –

–

– +

+ –

Pre optic Septal nucleus region

Superior cingulate gyrus

Reticular matter

Figure 1.6 Micturition integration brain centers.

urethra, the hypogastric nerve for the midportion, and the pudendal nerves for the rest of the urethra and sphincter. However, their distribution is not clear, and major overlapping exists. The spinal sensory pathway (need to urinate, pain, temperature, urgency, and sexual arousal) is found in the anterolateral white columns. Fibers transmitting conscious sensitivity (bladder distention, ongoing micturition, and tactile pressure) follow the posterior columns, synapsing in the gravelis nucleus and cuneatus of the brainstem before reaching the lateral ventral posterior nucleus of the thalamus and the cortex. All these afferent pathways have important connections at the spinal cord and brainstem with micturition motor fibers and the limbic system that explain the affective component of micturition.

Micturition integration centers Micturition is not only an autonomic function but also a voluntary and emotional function under upper central nervous system control (Figures 1.5 through 1.7).

Micturition centers at the level of the brain Micturition is regulated voluntarily by cortical centers at the level of the frontal lobe and diffusively in the premotrice area (paracentral lobule). The emotional control of micturition is complex and involves the limbic system with participation of the hypothalamus, the hippocampus, the callosal gyrus, the supraorbitary cortex, the amygdala, and several nonspecific thalamic nuclei.

Locus caeruleus and subcaeruleus nucleus At the level of the brainstem, particularly the pons and the medulla, stimulation of the locus caeruleus complex (LCC) and subcaeruleus nucleus complex provokes contraction or relaxation of the vesicosphincteric units located in the anterior and dorsal parts of the pons and being a component of the Barrington center. Neurons of the LCC are mainly

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Textbook of the Neurogenic Bladder Striated sphincter frontal center Detrusor frontal center Hypothalamic center

Limbic center

Pons center

Hypogastric nerve

Bladder

Thoracolumbar center Pelvic nerve Sacral center

Pudendal nerve

Figure 1.7 Micturition integration centers and nerves.

nonadrenergic, but all kinds of neurotransmitters are involved (cholinergic, serotoninergic, enkephalinergic, etc.). The LCC influences micturition through ascending and descending fibers. The ascending fibers regulate emotional and voluntary decision processes. Descending connections arise from the ventral part of the LCC and innervate most of the cord. Two catecholaminergic pathways follow the intermediolateral column and reach the  sympathetic thoracolumbar and the parasympathetic sacral neurons.

References 1. Galeano C, Corcos J, Schick E. Anatomie simplifiée de l’unité fonctionnelle vesico-urethrale. In: Corcos J, Schick E, eds. Les Vessies Neurogènes de l’Adulte. Paris, France: Masson, 1996.

2. Haab F, Sebe P, Mondet F, Ciofu C. Functional anatomy of the bladder and urethra in females. In: Corcos J, Schick E, eds. The Urinary Sphincter. New York: Marcel Dekker, 2001. 3. Meyers RP. The male striated urethral sphincter. In: Corcos J, Schick E, eds. The Urinary Sphincter. New York: Marcel Dekker, 2001. 4. Dyson M. The urinary system. In: Williams PL, ed. Gray’s Anatomy. Edinburgh, United Kingdom: Churchill Livingstone, 1995. 5. Thomson AS, Dabhoiwala NF, Verbeek FJ, Lamers WH. The functional anatomy of the ureterovesical junction. Br J Urol 1994; 73: 284–91. 6. Brooks JD, Chao W-M, Kerr J. Male pelvic anatomy reconstructed from the visible human data set. J Urol 1998; 159: 868–72. 7. Williams PL, Warwick R, Dyson M, Bannister LH. Gray’s Anatomy, 37th ed. New York: Churchill Livingstone, 1989. 8. Rosenstein DI, Alsikafi NF. Diagnosis and classification of urethral injuries. Urol Clin N Am 2006; 33: 73–85. 9. Reitz A, Schmid DM, Curt A, Knapp PA, Schurch B. Afferent fibers of the pudendal modulate sympathetic neurons controlling the bladderneck. Neurourol Urodyn 2003; 22: 597–601.

2 Pharmacology of the lower urinary tract Karl-Erik Andersson

Introduction

Pontine micturition center

Spinal control mechanisms

Ganglia

Somatic

+

Symp.

The central nervous mechanisms for the regulation of micturition are still not completely known. The normal micturition reflex is mediated by a spinobulbospinal pathway, passing through relay centers in the brain. In principle, the central pathways are organized as on–off switching circuits (Figures 2.1 and 2.2).1 During bladder filling, once threshold tension is achieved, afferent impulses, conveyed mainly by the pelvic nerve, reach centers in the central nervous system (CNS). It has been proposed that the afferent neurons send information to the periaqueductal gray (PAG), which in turn communicates with the pontine tegmentum, where two different regions involved in micturition control have been described in cats.2 One is a dorsomedially located M region, corresponding to Barrington's nucleus or the pontine micturition center (PMC). A more laterally located L-region may serve as a pontine urine storage center (PSC), which has been suggested to suppress bladder contraction and regulate the external sphincter muscle activity during urine storage. The M- and L-regions may represent separate functional systems, acting independently.3

PAG

Paras.

Nervous control

Cortical and diencephalic mechanisms

Af ferents

The normal bladder functions, storage and elimination of urine, are based on a coordinated interplay of reciprocal contraction and relaxation of the bladder and the outflow region. This interaction is regulated by neural circuits in the brain and spinal cord, which coordinate the activity of the detrusor and that of the smooth and striated muscles of the outflow region. The nervous mechanisms for this control involve a complex pattern of efferent and afferent signaling in parasympathetic, sympathetic, and somatic nerves. This chapter briefly reviews the principles of nervous control of micturition, and then focuses on the peripheral mechanisms involved in the contraction and relaxation of the bladder and urethra.

MICTURITION

-

Figure 2.1 Voiding reflexes involve supraspinal pathways, and are under voluntary control. During bladder emptying, the spinal para­ sympathetic (paras.) outflow is activated, leading to bladder contraction. Simultaneously, the sympathetic (symp.) outflow to urethral smooth muscle, and the somatic outflow to urethral and pelvic floor striated muscles are turned off, and the outflow region relaxes. PAG, periaqueductal gray.

The peripheral nervous mechanisms for bladder emptying and urine storage involve efferent and afferent signaling in parasympathetic, sympathetic, and somatic nerves. These nerves either maintain the bladder in a relaxed state,

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Textbook of the Neurogenic Bladder STORAGE

Parasympathetic innervation

Cortical and diencephalic mechanisms

T T L

PAG

L

Pontine micturition center

S2 Spinal control mechanisms

S3 S4

Pelvic nerve

Paras.

Af ferents

Ganglia ACh (+) Somatic

Symp.

-

ACh (+) NO (-)

+ +

Figure 2.2 During storage, there is continuous and increasing afferent activ­ ity from the bladder. There is no spinal parasympathetic (paras.) outflow that can contract the bladder. The sympathetic (symp.) outflow to urethral smooth muscle and the somatic outflow to urethral and pelvic floor striated muscles keep the outflow region closed. Whether or not the sympathetic innervation to the blad­ der (not indicated) contributes to bladder relaxation during filling in humans has not been established. PAG, periaqueductal gray.

while the outflow region is contracted, enabling urine storage at low intravesical pressure, or initiate micturition by relaxing the outflow region and contracting the bladder smooth muscle. Parasympathetic activation excites the bladder and relaxes the outflow region (Figure 2.3), and sympathetic activation inhibits the bladder body and excites bladder outlet and urethra (Figure 2.4). Somatic nerves activate the striated urethral sphincter (rhabdosphincter) (Figure 2.5). The sensory (afferent) innervation, which anatomically can be found in the parasympathetic, sympathetic, and somatic nerves, transmits information about bladder filling and contractile bladder activity to the CNS. Parasympathetic neurons, mediating contraction of the detrusor smooth muscle and relaxation of the outflow region, are located in the sacral parasympathetic nucleus

ACh Pelvic plexus

Figure 2.3 The parasympathetic (pelvic nerve) innervation mediates con­ traction of the bladder (acetylcholine, ACh, muscarinic r­ eceptors) and relaxation of the urethra (NO, nitric oxide). T, thoracic; L, lumbar; S, sacral segments.

in the spinal cord at the level of S2–S4.4 The axons pass through the pelvic nerve and synapse with the postganglionic nerves in either the pelvic plexus, in ganglia on the surface of the bladder (vesical ganglia), or within the walls of the bladder and urethra (intramural ganglia).5 The preganglionic neurotransmission is mediated by acetylcholine (ACh) acting on nicotinic receptors. This transmission can be modulated by adrenergic, muscarinic, purinergic, and peptidergic presynaptic receptors.4 The postganglionic neurons in the pelvic nerve mediate the excitatory input to the human detrusor smooth muscle by releasing ACh acting on muscarinic receptors. However, an atropine-resistant component has been demonstrated, particularly functionally and morphologically, to alter human bladder tissue (see the Section “Nonadrenergic– noncholinergic mechanisms”). The pelvic nerve also conveys parasympathetic fibers to the outflow region and the urethra. These fibers exert an inhibitory effect and thereby relax the outflow region. This is mediated partly by nitric oxide (NO), although other transmitters might be involved.6,7

Pharmacology of the lower urinary tract Sympathetic innervation

11

Somatic innervation

T T L L

Onuf’s nucleus

S2 S3 S4

NA +(a)

Pudendal nerve

NA +(a)

Hypogastric nerve

NA -(b)

Pelvic nerve

Inf. mes. ganglia

(-) Pelvic plexus

Figure 2.4 Sympathetic innervation (hypogastric nerve)–mediated con­ traction of the bladder outlet and urethral smooth muscle (NA, noradrenaline, α-adrenoceptors) and relaxes the bladder (NA, noradrenaline, β-adrenoceptors). T, thoracic; L, lumbar; S, sacral segments.

Most of the sympathetic innervation of the bladder and urethra originates from the intermediolateral nuclei in the thoracolumbar region (T10–L2) of the spinal cord. The axons travel either through the inferior mesenteric ganglia and the hypogastric nerve, or through the paravertebral chain and enter the pelvic nerve. Thus, sympathetic signals are conveyed in both the hypogastric and the pelvic nerves. The predominant effects of the sympathetic innervation of the lower urinary tract (LUT) in man are inhibition of the parasympathetic pathways at spinal and ganglion levels, and mediation of contraction of the bladder base and the urethra. However, in several animals, the adrenergic innervation of the detrusor is believed to relax the detrusor directly. Noradrenaline is released in response to electrical stimulation of detrusor tissues in vitro, and the normal response of detrusor tissues to released noradrenaline is relaxation. Somatic motor neurons, activating the external urethral sphincter (EUS), are located in the Onuf's nucleus, a circumscribed region of the sacral ventral horn at the level of S2–S4. EUS motor neurons send axons to the ventral roots and into the pudendal nerves. The sensory (afferent) nerves monitor the urine volume and pressure during urine storage, transmitting the information to the CNS.8,9 Most of the sensory innervation

Figure 2.5 During storage, activity in somatic nerves (pudendal nerve) keeps the striated urethral sphincter (rhabdosphincter) closed. During micturition, this activity is suppressed.

of the bladder and urethra reach the spinal cord via the pelvic nerve and dorsal root ganglia. In addition, some ­afferents reach the spinal cord through the hypogastric nerve. The  afferent nerves of the EUS travel through the pudendal nerve to the sacral region of the spinal cord.5 There are several populations of afferents in the ­bladder. The most important for the micturition process are myelinated Aδ fibers and unmyelinated C fibers. The Aδ fibers respond to passive distension and active ­contraction ­(low-­t hreshold ­afferents), thus conveying ­information about bladder ­fi lling.10 The activation threshold for Aδ fibers is 5–15 mm H2O, which is the intravesical pressure at which humans report the first sensation of bladder filling.4 C fibers have a high ­mechanical threshold and respond primarily to ­chemical irritation of the bladder mucosa or cold.11,12 Following chemical irritation, the C-fiber afferents exhibit spontaneous firing when the bladder is empty, and increased fi ­ ring during bladder distension.11 These fibers are normally inactive and are therefore termed “silent fibers.”

Bladder Local control of the bladder The cholinergic and adrenergic mechanisms involved in bladder storage and emptying functions have been extensively investigated.1,13–15 Nonadrenergic–noncholinergic

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Textbook of the Neurogenic Bladder

(NANC) bladder mechanisms, on the other hand, have been studied mainly in research animals, and their relevance in humans has not been established.15

Cholinergic mechanisms Cholinergic nerves Although histochemical methods that stain ACh esterase (AChE) are not specific for ACh-containing nerves, AChE staining has been used as an indirect marker of cholinergic nerves.5 The vesicular ACh transporter (VACht) is a marker specific for cholinergic nerve terminals.16 In rat bladder, detrusor smooth muscle bundles are supplied with a very rich number of VAChT-positive terminals, which also contain neuropeptide Y (NPY), nitric oxide synthase (NOS), and vasoactive intestinal polypeptide (VIP).17 Similar findings have been made in human bladders of neonates and children.18 The muscle coat of the bladder showed a rich cholinergic innervation, and small VAChT-immunoreactive neurons were found scattered throughout the detrusor muscle. VAChT-immunoreactive nerves were also observed in a suburothelial location in the bladder. The function of these nerves is unclear, but a sensory function or a neurotrophic role with respect to the urothelium cannot be excluded.18

Muscarinic receptors ACh, acting on muscarinic receptors on the detrusor myocytes, is a main contractile transmitter in the mammalian bladder. Muscarinic receptors comprise five subtypes, encoded by five distinct genes.19 In the human bladder, the mRNAs for all muscarinic receptor subtypes have been demonstrated.20–22 M2 predominates over M3 receptor subtype (3:1 ratio).20–24 These receptors have been located not only on the detrusor myocytes but also on other structures, including urothelium, interstitial cells (ICs), and suburothelial nerves.22,25 Detrusor smooth muscle contains muscarinic receptors, mainly of the M2 and M3 subtypes.22,26–29 The receptors are functionally coupled to G proteins, but the signal transduction systems are different.26–28 The M3 receptors in the human detrusor are believed to be the most important for detrusor contraction.22,30 In bladder strips from M3 knockout mice, 95% of the contraction induced by carbachol was mediated by the M3 receptors.31 However, these mice had an almost normal cystometric pattern owing to the remaining purinergic activation mechanism.32 Stimulation of M3 receptors has previously been considered to cause contraction through phosphoinositide hydrolysis.33,34 However, several studies have suggested that other signaling pathways may also be involved.22,35–37 There may be species differences in the signaling pathways

used by the different muscarinic receptor subtypes.38 However, taken together, available evidence suggests that the main pathways for M3 receptor activation of the human detrusor are calcium influx via L-type calcium channels and inhibition of myosin light chain phosphatase through activation of Rho-kinase and protein kinase C, leading to increased calcium sensitivity of the contractile machinery.22,37,39,40 The functional role of M2 receptors has not been clarified, but it has been suggested that M2 receptors may oppose sympathetically mediated smooth muscle relaxation through β-adrenoceptors (ARs).41 M2 receptor stimulation may also activate nonspecific cation channels,42 inhibit K adenosine triphosphate (KATP) channels through activation of protein kinase C,43,44 and use other signaling pathways.38 An investigation using M2, M3, and M2/M3 double knockout mice revealed that the M2 receptor may have a role in indirectly mediating bladder contractions by enhancing the contractile response to M3 receptor activation, and that minor M2 receptor-mediated contractions may also occur.45 On the other hand, in certain disease states, the contribution of M2 receptors to detrusor contraction may increase. Thus, in the denervated rat bladder, M2 receptors, or a combination of M2 and M3, mediated contractile responses.38,46–49 In obstructed, hypertrophied rat bladders, there was an increase in total and M2 recep­tor density, whereas there was a reduction in M3 r­ eceptor density.49 The  functional significance of this change for voiding  function has not been established, and other experiments on the human detrusor22 could not confirm these observations. Pontari et al.50 analyzed bladder muscle specimens from patients with neurogenic bladder dysfunction to determine whether the muscarinic receptor subtype mediating contraction shifts from M3 to M2 receptor subtype, as found in the denervated, hypertrophied rat bladder. They concluded that although normal detrusor contractions are mediated by the M3 receptor subtype, in patients with neurogenic bladder dysfunction, contractions can be mediated by the M2 receptors. Muscarinic receptors may also be located on the presynaptic nerve terminals and participate in the regulation of transmitter release. The inhibitory prejunctional muscarinic receptors have been classified as M2 in the rabbit51,52 and rat,53 and M4 in the guinea pig,54 rat,55 and human56 bladder. Prejunctional facilitatory muscarinic receptors appear to be of the M1 subtype in the rat and rabbit urinary bladder.49,50,53 Prejunctional muscarinic facilitation has also been detected in human bladders.57 The muscarinic facilitatory mechanism seems to be upregulated in overactive bladders (OABs) from chronic spinal cord transected rats. The facilitation in these preparations is primarily mediated by M3 muscarinic receptors.57 Muscarinic receptors have also been located on the urothelium/suburothelium,25,28,58 but their functional importance has not been clarified. It has also been suggested that

Pharmacology of the lower urinary tract muscarinic receptors on structures other than the myocyte (urothelium/suburothelium) may be involved in the release of an unknown inhibitory factor.28,59,60 Several studies have suggested that muscarinic receptors mediate the activation of bladder afferent nerves.60 De Laet et  al.61 demonstrated an inhibitory effect of systemically given oxybutynin on the afferent part of the ­micturition reflex in rats by recording afferent activity in  the pelvic nerve. These findings are in line with the clinical ­observations that antimuscarinics at clinically recommended doses have little effect on voiding contractions and may act mainly during the bladder storage phase, increasing bladder capacity.62,63 The muscarinic receptor ­functions may be changed in different urological d ­ isorders, such as outflow obstruction, neurogenic bladders, idiopathic detrusor overactivity (DO), and diabetes.22,64

Adrenergic mechanisms Adrenergic nerves Fluorescence histochemical studies have shown that the body of the detrusor receives a relatively sparse innervation by noradrenergic nerves. The density of noradrenergic nerves increases markedly toward the bladder neck, where the smooth muscle receives a dense noradrenergic nerve supply, particularly in the male. The importance of the noradrenergic innervation of the bladder body has been questioned since patients with a deficiency in dopamine β-hydroxylase, the enzyme that converts dopamine to noradrenaline, void normally.65 Noradrenergic nerves also occur in the lamina propria of the bladder, only some of which are related to the vascular supply. Their functional significance remains to be shown.

α-Adrenoceptors In the human detrusor, β-ARs dominate over α-ARs, and the normal response to noradrenaline is relaxation.13 The number of α-ARs in the human detrusor was found to be low, and in some studies, it was too low for a reliable quantification.66 Malloy et  al. reported that even if the total α1-AR expression was low, it was reproducible. Among the high-affinity receptors for prazosin, only α1A and α1D mRNAs were expressed in the human bladder. The relation between the different subtypes was α1D: 66% and α1A: 34%, with no expression of α1B.67 Even if α-ARs have no significant role in normal bladder contraction, there is evidence that this may change after, e.g., bladder outlet obstruction.68 However, Nomiya et al. concluded that neither an upregulation of α1-ARs nor a downregulation of β-ARs occurs in human obstructed bladder, and that it was not likely that detrusor α1-ARs are responsible for the overactivity observed in patients with bladder outflow obstruction (BOO).69

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It has been shown that α1-ARs are located prejunctionally on cholinergic nerve terminals in the rat urinary bladder.70 Activation of these receptors facilitates ACh release and enhances neurogenic contractions. Terazosin inhibited phenylephrine-induced facilitation of the neurally evoked contractions and facilitation of ACh release.71 Szell et al.72 found that the α1A-AR subtype on the cholinergic nerve terminals mediated the prejunctional facilitation. Trevisani et al.73 examined the influence of α1-ARs on neuropeptide release from primary sensory neurons of the LUT in rats. The α1-agonist, phenylephrine, caused an intracellular Ca2+ mobilization in cultured lumbar and sacral dorsal root ganglion neurons as well as a release of substance P (SP) from terminals of capsaicin-sensitive sensory neurons from the lumbar enlargement of the dorsal spinal cord and urinary bladder and increased plasma protein extravasation in the urinary bladder. These effects were abolished by alfuzosin. The authors concluded that α1-ARs are functionally expressed by capsaicin-sensitive, nociceptive, primary sensory neurons of the rat LUT, and their activation may contribute to signal irritative and nociceptive responses arising from this region. Parts of the beneficial effects of α1-AR antagonists in the amelioration of storage symptoms in the LUT could be derived from their inhibitory effect on neurogenic inflammatory responses. All α1-AR subtypes can be located in the urothelium, and it has been suggested, based on rat studies,74 that α1AARs can modulate bladder afferent activity under pathophysiological conditions. A study in humans suggested a relationship between the expression of α1dD-AR mRNA in the bladder mucosa and storage-phase urodynamics in LUT symptom/benign prostatic obstruction (LUTS/ BPO) patients, suggesting a role of α1D-ARs in bladder sensation.75

β-Adrenoceptors In the human detrusor, β-ARs were shown to be atypical, having functional characteristics of neither β1- nor β2-ARs.76,77 Normal as well as neurogenic human detrusors are able to express β1-, β2-, and β3-AR mRNA, and selective β3-AR agonists effectively relaxed both types of detrusor muscle.78–83 An investigation comparing the subpopulations of β-ARs in research animals revealed significant differences among species.84 Studies in human detrusor tissue revealed 97% expression of β3-AR mRNA over β1- (1.5%) and β2-AR mRNA (1.4%), concluding that if the amount of mRNA reflects the population of receptor protein, β3-AR mediate bladder relaxation.85 This is in accordance with several in vitro studies, and it seems that atypical β-AR-mediated responses reported in early studies of β-AR antagonists are mediated by β3-ARs.78–83,86–88 It can also partly explain why the clinical effects of selective β2-AR agonists in bladder overactivity have

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been controversial and largely inconclusive.89 It has been s­peculated that in DO associated with outflow obstruction, there is a lack of inhibitory β-AR-mediated ­noradrenaline response, but this has never been verified in humans.69,90,91 The generally accepted mechanism by which β-ARs induce detrusor relaxation in most of the species is activation of adenylyl cyclase with the subsequent formation of cAMP. However, there is evidence suggesting that in the bladder, K+ channels, particularly BKCa channels, may be more important in β3-AR-mediated relaxation than cAMP.92–94 The normal stimulus for the activation of the micturition reflex is considered to be distension of the bladder, initiating activity in in-series-coupled, low-threshold mechanoreceptive (Aδ) afferents.95 If this response to distension is decreased by the detrusor muscle being relaxed and more compliant, the afferent activity needed to initiate micturition will be delayed and bladder capacity increased. Such an effect may be obtained by stimulating the β3-ARs on the detrusor muscle. There are reasons to believe that the spontaneous contractile, phasic activity of the detrusor smooth muscle during filling can not only create tone in the detrusor muscle but also generate afferent input (afferent noise), contributing to OAB/DO. In fact, Aizawa et al.96 found that mirabegron could inhibit filling-induced activity not only in mechanosensitive Aδ-fibers but also in C-fiber primary bladder afferents. β3-AR agonists have a pronounced effect on autonomous contractile activity in detrusor muscle in vitro97 and nonvoiding contractions in vivo,98 which may be an important basis for their clinical effects. Since β-ARs are present in the urothelium,99 their possible role in bladder relaxation has been investigated.99,100 However, to what extent a urothelial signaling pathway contributes in vitro and in vivo to the relaxant effects of β-AR agonists in general, and β3-AR agonists specifically, remains to be elucidated. Randomized controlled trials have shown that the selective β3-AR agonist, mirabegron, for which most of the information is available and which is approved in Japan, United States, and the European Union, reduces the number of micturitions and incontinence episodes in a 24-hour period compared with placebo.82 The most common adverse effects recorded are dry mouth (placebo level) and gastrointestinal disturbances rated as mild to moderate. Small rises in mean heart rate (1 beat/minute) and blood pressure (1 mmHg) have been found in OAB patients. There are proof-of-concept studies for other β3-AR selective agonists such as solabegron and ritobegron.83 Other agents, e.g., TRK-380101 are in preclinical development for the treatment of OAB. Available information suggests that β3-AR agonists are effective and safe, and may be a promising alternative to antimuscarinics in the treatment of OAB.

Afferent signaling from the urothelium/suburothelium Recent evidence suggests that the urothelium/suburothelium may serve not only as a passive barrier but also as a specialized sensory and signaling unit, which, by producing NO, ATP, and other mediators, can control the activity in afferent nerves and thereby the initiation of the micturition reflex.102–106 Both afferent and autonomic efferent nerves are located in close proximity to the urothelium.107–108 The urothelium has been shown to express nicotinic, muscarinic, tachykinin, adrenergic, bradykinin, and transient receptor potential (TRP) receptors.102–106 Lips et al.109 directly analyzed the ACh content in the urothelium and characterized the molecular component of its synthesis and release machinery. They found ACh to be present in the urothelium in a nanomolar range per gram of wet weight. RT-PCR data supported the presence of carnitine acetyltransferase (CarAT) but not choline acetyltransferase (CHAT). Vesicular ACh transporter (VAChT), used by neurons to shuffle ACh into synaptic vesicles, was detected in subepithelial cholinergic nerve fibers, but not by RT-PCR or immunohistochemistry in the urothelium. Polyspecific organic cation transporters (OCTs) 1 and 3 are expressed by the urothelium. The quaternary ammonium–based trospium chloride inhibits cation transport by OCTs. The authors concluded that this urothelial nonneuronal cholinergic system differs widely from that of neurons with respect to molecular components of the ACh synthesis and release machinery. Consequently, these two systems might be differentially targeted by pharmacologic approaches.

Transient receptor potential channels Low pH, high K, increased osmolality, and low temperatures can influence afferent nerves, possibly via effects on the vanilloid receptor (capsaicin-gated ion channel, TRPV1), which is expressed in both afferent nerve terminals and urothelial cells.106,110,111 TRPV1 is expressed throughout the afferent limb of the micturition reflex pathway, including urinary bladder unmyelinated (C-fiber) nerves that detect bladder distension or the presence of irritant chemicals.112,113 TRPV1 is expressed by urothelial cells as well as by afferent nerves in proximity to urothelial cells in the urinary bladder.106 Birder et al.110 showed that TRPV1-null mice are anatomically normal. However, bladder function seems to be altered, including a reduction of in vitro, stretch-evoked ATP release and membrane capacitance. Urothelial cells from TRPV1-null mice were also shown to exhibit a decrease in hypotonic-evoked ATP release.110 Other TRP channels may be involved in the control of micturition.111 TRPV1 is co-expressed with TRPA1, and TRPA1 is known to be present on capsaicin-sensitive

Pharmacology of the lower urinary tract primary sensory neurons. Activation of this channel can induce DO in animal models. TRPV4 is a Ca2+-permeable stretch-activated cation channel, involved in stretchinduced ATP release, and TRPV4-deficient mice exhibit abnormal frequencies of voiding and nonvoiding contractions in cystometric experiments. TRPM8 is a cool receptor expressed in the urothelium and suburothelial sensory fibers. It has been implicated in the bladder-cooling reflex and in idiopathic DO. The occurrence of other members of the TRP superfamily in the LUT has been reported, but information on their effects on LUT functions is scarce. Thus, there seem to be several links between activation of different members of the TRP superfamily and LUT dysfunction.

Adenosine triphosphate ATP, generated by the urothelium, has been suggested as an important mediator of urothelial signaling.106,114 P2X and P2Y purinergic receptor subtypes are expressed in cells (urothelium, nerves, and myofibroblasts) that are situated near the luminal surface of the bladder. ATP was shown to potentiate the response of vanilloids in sensory neurons by lowering the threshold for protons, capsaicin, and heat.115 Thus, ATP possibly triggers pain when released from injured or damaged cells.104,106 Supporting such a view, intravesical ATP induces DO in conscious rats.116 Furthermore, mice lacking the P2X3 receptor were shown to have hypoactive bladders.117,118 There seem to be other, thus far unidentified, factors in the urothelium that could influence bladder function.15 Even if these mechanisms are shown to be involved in the pathophysiology of OAB, their functional importance remains to be established.

Interstitial cells A network of ICs, extensively linked by Cx43-containing gap junctions, was found to be located beneath the urothelium in the human bladder.119–123 This interstitial cellular network was suggested to operate as a functional syncytium, integrating signals and responses in the bladder wall. ICs have been identified with antibodies against KIT, vimentin, and more recently, PDGFRα, using confocal microscopy. ICs also form a network within the detrusor muscle.123–125 The ultrastructural profile of the bladder ICs is comparable with that of the gastrointestinal ICs. However, in normal tissues, the bladder ICs have only a partial overlap with myofibroblasts; specifically, myosin and desmin filaments and fibronexus are absent, leading some to suggest that the myofibroblast phenotype is not present in the normal bladder.126,127 Myofibroblasts are considered to be smooth muscle–like fibroblasts found in many tissues of

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the body, where they have functions in growth, repair, and wound healing. It is not yet known whether ICs in the lamina propria change to a myofibroblast phenotype under pathophysiologic stresses, such as inflammation or ischemia, but it has recently been reported that suburothelial ICs change to a fibroblastic phenotype in bladder pain syndrome and in neurogenic bladder.128 Available data do not support a pacemaking role for detrusor-layer ICs, and it is possible that detrusor IC may act as a brake, preventing coordinated smooth muscle contraction during filling. Although detrusor smooth muscle itself exhibits spontaneous contractile, electrical, and calcium signaling activity, there is reason to believe that this activity is modulated by cells within the lamina propria. The hypothesis that lamina propria ICs are involved in the modulation of detrusor smooth muscle activity appears to be strengthened by data on the diseased bladder. An association between bladder overactivity and increased number of laminia propria ICs has been reported for obstructed guinea pig bladder129 and human neurogenic and idiopathic OAB.130 Several observations indicate that laminia propria ICs could be involved in the coordination of local bladder signaling processes. Mukerji et al.131 reported muscarinic (M2 and M3) receptors immunoreactivity on cells in the LP resembling IC, a finding confirmed by Grol et  al.132 Mukerji et al.131 suggested that these cells could respond to cholinergic signaling. However, Sui et al.133 reported that suburothelial IC did not respond to carbachol but application of ATP elicited Ca2+ transients. P2Y6 receptors may mediate these excitatory responses.134 Further studies on spinal cord injured (SCI) rats, where laminia propria ICs are upregulated, suggested that this effect of ATP and other P2Y agonists could increase spontaneous contractile activity in the bladder.134 Xue et  al.135 demonstrated that vimentin+ (and some KIT+) laminia propria ICs in the human bladder expressed hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, particularly HCN4. This channel is specialized for the If current, which is a characteristic of pacemaker cells, and it was suggested that HCN4 could be involved in the generation of spontaneous bladder activity during filling. However, further functional studies are needed to put these data into proper perspective. The function(s) of bladder IC are incompletely understood, and it seems that laminia propria IC and detrusor IC may serve different functions. Because of their localization, laminia propria ICs have been suggested to form structural and physiological links between urothelial cells, sensory nerves, and/or detrusor smooth muscle cells. Moreover, laminia propria IC might be involved in the pathophysiology of bladder disorders, e.g., the neurogenic bladder, and in the interstitial cystitis, where local signaling processes are considered to be important.123

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Nonadrenergic–noncholinergic mechanisms In most animal species, the bladder contraction induced by stimulation of nerves consists of at least two components: one atropine resistant and one mediated by NANC mechanisms.13 NANC contractions have been reported to occur in normal human detrusor, even if not representing more than a few percent of the total contraction in response to nerve stimulation.136–138 However, a significant degree of NANC-mediated contraction may exist in ­morphologically and/or functionally changed human bladders, and has been reported to occur in hypertrophic bladders, idiopathic detrusor instability, interstitial cystitis bladder, neurogenic bladders, and aging bladder.137–145 The NANC component of the nerve-induced response may be responsible for up to 40%–50% of the total bladder contraction.

Nonadrenergic–noncholinergic neurotransmission: Adenosine triphosphate There is good evidence that the transmitter responsible for the NANC component is ATP, acting on P2X receptors found in the detrusor smooth muscle membranes of rats and humans.15,146,147 The receptor subtype predominating in both species seemed to be the P2X1 subtype. Moore et  al.148 reported that detrusor from patients with idiopathic detrusor instability had a selective absence of P2X3 and P2X5 receptors, and suggested that this specific lack might impair control of detrusor contractility and contribute to the pathophysiology of urge incontinence. On the other hand, O'Reilly et al.142 found that in patients with idiopathic detrusor instability, P2X2 receptors were significantly elevated, whereas other P2X receptor subtypes were significantly decreased. They were unable to detect a purinergic component of nerve-mediated contractions in control (normal) bladder specimens, but there was a significant purinergic component of approximately 50% in unstable bladder specimens. They concluded that this abnormal purinergic transmission in the bladder might explain symptoms in these patients. The same group confirmed that the P2X1 receptor was the predominant purinoceptor subtype also in the human male bladder.142 They found that the amount of P2X1 receptor per smooth muscle cell was larger in obstructed than in control bladders. This suggests an increase in purinergic function in the OAB arising from bladder outlet obstruction. Evidence suggesting that ATP may be involved in afferent signaling in the urinary bladder was first presented by Ferguson et al.,149 who showed that ATP was released from the rabbit urothelium in response to stretch. They postulated that the released ATP could activate suburothelial sensory nerves, thus generating a signal that could activate

the micturition reflex. It has also been confirmed by other investigators that ATP can be produced by and released from the urothelium.118 The postulated target for ATP, the P2X3 receptor, has been shown to be expressed on smalldiameter primary sensory neurons.150,151 In the bladder, P2X2/3 receptors have been demonstrated not only on suburothelial nerves, but also on the urothelium.106,152,153 Functionally, Namasivayam et  al.,154 using an in vitro pelvic nerve–afferent rat model, showed that afferent activity induced by bladder distension was reduced by up to 75% after desensitization with α,β-methylene ATP; the results were consistent with the view that ATP is released from the bladder urothelium by distension, and activates pelvic nerve afferents. Further supporting the role of ATP, cystometry in P2X3-deficient mice revealed decreased voiding frequency, increased bladder capacity and voiding volume, but normal bladder pressures.117 On the basis of these findings, the authors suggested that P2X3 receptors are involved in the normal physiological regulation of afferent pathways controlling volume reflexes in the urinary bladder, and thus P2X3 receptor-containing neurons may serve as volume receptors. Further supporting a role for ATP in urothelial signaling, Pandita and Andersson116 found that intravesical instillation of ATP could induce bladder overactivity in unanesthetized, freely moving rats. The ATP-induced effects were effectively counteracted by the P2X3 receptor antagonist, TNP–ATP, which by itself caused an increase in bladder capacity. Interestingly, the effects of ATP could be prevented by pretreatment with L-arginine, and by the NK-2 receptor antagonist, SR 48968, suggesting that both NO and tachykinins could interfere with the actions of ATP.116

Nonadrenergic–noncholinergic neurotransmission: Neuropeptides Various bioactive peptides have been demonstrated to be synthesized, stored, and released in the human LUT, including atrial natriuretic peptide (ANP), bradykinin, calcitonin gene-related peptide (CGRP), endothelin (ET), enkephalins, gala-nin, NPY, somatostatin, SP and VIP.13 However, their functional roles have not been established.15 In human bladder, Uckert et al.155 found contractant effects of SP and ET-1, a relaxant effect of VIP, and very little effects of ANP and CGRP. As stated by Maggi,156 neuropeptide-containing, capsaicin-sensitive primary afferents in the bladder and urethra may not only have a sensory function (sensory neuropeptides), but also act as a local effector on efferent function. In addition, they may play a role as neurotransmitters and/or neuromodulators in the bladder ganglia and at the neuromuscular junctions. As a result, the peptides may be involved in the mediation of various effects, including micturition reflex activation, smooth muscle contraction,

Pharmacology of the lower urinary tract potentiation of efferent neurotransmission, and  changes in vascular tone and permeability. Evidence for this is based mainly on experiments in animals. Studies on isolated human bladder muscle strips have failed to reveal any specific local motor response attributable to a ­capsaicin-sensitive innervation.157 However, cystometric evidence that capsaicin-sensitive nerves may modulate the afferent branch of the micturition reflex in humans has been presented.157 In a few patients suffering from bladder hypersensitivity disorders, intravesical capsaicin produced a long-lasting, symptomatic improvement. It has been discussed whether peptides are involved in the pathogenesis of DO. Results from immunohistochemical studies have provided evidence that outflow obstruction, which is commonly associated with DO, causes a reduction in the density of peptide-containing nerves.158,159 Tachykinins  Endogenous tachykinins, SP, neurokinin A (NKA), and neurokinin B (NKB), are widely distributed in the central and peripheral nervous system. They are found in afferent pathways of the bladder and urethra, and there is considerable evidence that they act as transmitters in sensory nerves.4,159 In addition, these peptides have been shown to produce diverse biological effects, such as smooth muscle contraction, facilitation of transmitter release from nerves, vasodilatation, and increased plasma permeability. Their actions are mediated by the activation of three distinct receptor types: NK-1, NK-2, and NK-3. Rat and guinea pig detrusors contain both NK-1 and NK-2 receptors, whereas the NK-2 receptor seems to be the only mediator of contractile responses to tachykinins in human bladder smooth muscle, where the potency of neurokinins was shown to be NKA > NKB >> SP.160 Nociceptive transmission is mainly mediated through NK-1 receptors. The potential role of tachykinins, particularly SP, in the atropine-resistant component of the contractile response induced by electrical stimulation, has been studied by several investigators.13,161 With few exceptions, these studies did not favor the view that SP, released from postganglionic nerve-terminals, has an excitatory transmitter role. However, evidence has been presented that SP may play a role in the afferent branch of the micturition reflex.1,13 Green et  al.161 tested the hypothesis that aprepitant, an NK-1 receptor antagonist, may be efficacious in the treatment of urge urinary incontinence. In a double-blind, randomized, placebo-controlled, parallel-group pilot study on postmenopausal women with a history of urge urinary incontinence or mixed incontinence, they found that aprepitant significantly decreased the average daily number of micturitions and urgency episodes compared with placebo and concluded that NK-1 receptor antagonism may represent a novel therapeutic approach to treating OAB. However, the effects of aprepitant, and also of another NK-1 receptor antagonist, serlopitant, were not considered to offer advantages in efficacy compared to antimuscarinics.162

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Endothelins  Endothelins (ET-1, ET-2, ET-3) and ET (ETA, ETB) receptors have been demonstrated in the bladder. Via their receptors, ETs can initiate both shortterm (contraction) and long-term (mitogenesis) events in targets cells in the bladder and urethra. Saenz de Tejada et  al.163 demonstrated ET-like immunoreactivity in the transitional epithelium, serosal mesothelium, vascular endothelium, smooth muscles of the detrusor (nonvascular) and vessels, and in fibroblasts of the human bladder. This cellular distribution was confirmed in in situ hybridization experiments. The authors suggested that ETs may act as an autocrine hormone in the regulation of the bladder wall structure and smooth muscle tone, and that it may regulate cholinergic neurotransmission by a paracrine mechanism. In patients with benign prostatic hypertrophy (BPH), the density of ET receptors in the bladder was significantly lower than in men without this disorder.164 ET-1 is known to induce contraction in animal as well as human detrusor muscle.13,165 The contractile effect of ETs seems to be mediated mainly by the ETA receptor, and the ETB receptor could not be linked to contraction.165 However, in human bladder smooth muscle, ETs may not only have a contractile action, but could also be linked to proliferative effects. Supporting this view, Khan et al.166 found that ETA and ETB receptor antagonists inhibited rabbit detrusor and bladder neck smooth muscle cell proliferation, and they suggested that ET-1 antagonists may prevent smooth muscle cell hyperplasia associated with partial BOO. Many authors have suggested that ET may play a pathophysiological role in bladder outlet obstruction associated with BPH.30 In the bladder, ETs may be implicated in d ­ etrusor hypertrophy and its functional consequences. Thus, Schröder et  al.167 studied the effect of an orally administered endothelin-converting enzyme (ECE) inhibitor by cystometry in conscious rats with and without BOO. They concluded that ECE inhibition did not prevent an increase in bladder weight after BOO, but it appeared to have a beneficial effect on detrusor function and decrease DO in conscious rats. Vasoactive intestinal polypeptide  VIP was shown to inhibit spontaneous contractile activity in isolated detrusor muscle from several animal species and from humans, but do have little effect on contractions induced by muscarinic receptor stimulation or by electrical stimulation of nerves.13 Uckert et al.155 found a moderate relaxant effect of VIP on isolated, carbacholcontracted human detrusor, and a less than twofold increase in intracellular cyclic adenosine monophosphate (cAMP) concentration. In isolated rat bladder, VIP had no effect, and in isolated guinea pig bladder, VIP produced contraction. Stimulation of the pelvic nerves in cats increased the VIP output from the bladder, and increased bladder blood flow, although moderate.168 VIP injected intravenously induced bladder relaxation

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in dogs.169 On the other hand, VIP given intravenously to patients in a dose high enough to cause increases in heart rate, had no effect on cystometric parameters.170 Plasma concentrations of VIP were obtained, which, in other clinical investigations, had been sufficient to cause relaxation of smooth muscle.170 Even if a decrease in VIP concentrations has been found in bladders from patients with idiopathic DO, the role of this peptide in bladder function has not been established.171 Calcitonin gene-related peptide CGRP is widely distributed in nerve endings in the bladder and considered a sensory neuromodulator.156 However, if CGRP has a role in the control of bladder motility it is controversial. In pig detrusor, CGRP did not alter the response to potassium, carbachol, SP, or electrical field stimulation (EFS).172 In hamsters, CGRP caused dose-dependent inhibition of the response to EFS, but about 20% of the preparations did not respond.173 In human detrusor strips, the relaxing effect of CGRP on carbachol-induced contraction was negligible, despite a slight increase in cyclic guanosine monophosphate (cGMP) levels.155 Most probably, the main role of CGRP is that of a sensory neuromodulator. Neuropeptide Y  NPY and noradrenaline are stored in separate vesicles at sympathetic nerve terminals, and NPY is preferentially released at high frequencies of stimulation.174 In rat bladders, abundant NPY-containing nerves were found, and exogenously added NPY contracted detrusor strips and potentiated the noncholinergic motor transmission. A possible motor transmitter function of the peptide in the rat bladder was suggested.13,175 However, other investigators researching in rat and guinea pig bladders found no contractile response to exogenous NPY, but found inhibitory effects on cholinergic and NANCinduced contractions.176,177 The human bladder is richly endowed with NPY-containing nerves.178–181 In neonates and children, small ganglia scattered throughout the detrusor muscle of urinary bladder were found, of which approximately 95% contained NPY.18 It seems as if NPY can be found in adrenergic as well as cholinergic nerves. However, in the human bladder only very few if any functional NPY receptors were found.182 Thus a role for NPY in bladder function remains to be established.

Nonadrenergic–noncholinergic neurotransmission: Prostanoids Prostanoids are synthesized from the common precursor, arachidonic acid, in a process catalyzed by the enzyme cyclooxygenase (COX). This process occurs locally in both bladder muscle and mucosa, and is initiated not only by various physiological stimuli such as stretch of the detrusor muscle, but also by injuries of the vesical mucosa, nerve stimulation, and agents such as ATP and mediators

of inflammation.183–185 There seem to be species variations in the spectrum of prostanoids and the relative amounts synthesized and released by the urinary bladder. Biopsies from the human bladder were shown to release prostanoids in the following quantitative order: PGI2 > PGE2 > PGF2α > TXA2.185 PGF2α, PGE1, and PGE2 contract isolated detrusor muscle, whereas PGE1 and PGF2α relax or have no effect on urethral smooth muscle.13 Even if prostaglandins have contractile effects on the human bladder, it is still unclear whether they contribute to the pathogenesis of DO. Prostanoids may affect the bladder in two ways: directly by effects on the smooth muscle and/or indirectly via effects on the neurotransmission.186 Probably, prostanoids do not act as true effector messengers along the efferent arm of the micturition reflex, but rather as a neuromodulator of the efferent and afferent neurotransmission.186,187 An important physiological role might be sensitization of sensory nerves. Evidence for a sensitizing effect of PGE2 has also been demonstrated in vivo. It was shown in the rat urinary bladder that intravesical instillation of PGE2 lowered the threshold for reflex micturition, an effect, which was blocked by systemic capsaicin desensitization. Indomethacin pretreatment and systemic capsaicin increased the micturition threshold without affecting the amplitude of the micturition contraction.186 Since intravesical PGE2 did not reduce the residual volume in capsaicin-pretreated animals, it was suggested that endogenous prostanoids enhance the voiding efficiency through an effect, direct or indirect, on sensory nerves. Prostanoids may also be involved in the pathophysiology of different bladder disorders. As pointed out by Maggi,186 in cystitis there may be an exaggerated prostanoid production leading to intense activation of sensory nerves, increasing the afferent input. Schröder et al.188 investigated whether the PGE2 receptor EP1 was involved in the regulation of normal micturition, the response to intravesical PGE2 administration, and the development of bladder hypertrophy and overactivity because of BOO. Moderate BOO was created in EP1receptor knockout (EP1KO) mice and their wild type (WT) counterparts. After 1 week, cystometry was performed in conscious animals before and after PGE2 instillation. Findings were compared to those in unobstructed control animals. There was no difference between unobstructed EP1KO and WT mice in urodynamic parameters, but EP1KO mice did not respond to intravesical PGE2 instillation, whereas WT mice showed DO. The lack of EP1 receptor did not prevent bladder hypertrophy because of BOO. After BOO, WT mice had pronounced DO, while this was negligible in EP1KO mice. It was concluded that the EP1 receptor appears not to be essential for normal micturition or the mediation of bladder hypertrophy because of BOO, but has a role in the development of DO caused by PGE2 and outlet obstruction.

Pharmacology of the lower urinary tract COX is the pivotal enzyme in the prostaglandin synthesis. It has been established that this enzyme exists in two isoforms, one constitutive (COX-1) and one inducible (COX-2).189 The constitutive form is responsible for the normal physiological biosynthesis, whereas the inducible COX-2 is activated during inflammation.190–192 Park et al.192 demonstrated that the expression of COX-2 was increased as a consequence of BOO. If prostaglandins generated by COX-2 contribute to bladder overactivity, selective inhibitors of COX-2 would, theoretically, be one possible target for pharmacological therapy. Whether or not available selective COX-2 inhibitors would be useful as treatment for bladder overactivity remains to be established. Lee et al.193 investigated if a new PE1-receptor antagonist, PF-2907617-02, would influence the regulation of normal micturition in rats, and if it affected bladder function in animals and rats with partial BOO. They found PF-2907617-02 results in a significantly increased bladder capacity, micturition volume, and micturition interval, but no effect on other urodynamic parameters. Intravesical PGE2 induced DO. The antagonist significantly reduced the stimulatory effects of PGE2. In obstructed animals, PF-2907617-02 significantly increased micturition interval, but not bladder capacity and residual volume. The drug also decreased the frequency and amplitude of nonvoiding contractions. The authors concluded that the EP1 receptor was involved in the initiation of the micturition reflex, both in normal rats and in animals with BOO. It may also contribute to the generation of DO after BOO; thus, EP1 antagonists may have potential as a treatment of DO in humans. However, in patients with the OAB syndrome, a selective EP1-receptor antagonist was ineffective.194

Nonadrenergic–noncholinergic neurotransmission: Nitric oxide Evidence has accumulated that L-arginine-derived NO is responsible for the main part of the inhibitory NANC responses in the LUT.13 However, NO may have different roles in the bladder and the urethra. Nitrergic nerves  In biopsies taken from the lateral wall and trigone regions of the human bladder, a plexus of NADPH-diaphorase-containing nerve fibers was found.195 Samples from the lateral bladder wall contained many NADPH-reactive nerve terminals, particularly in the subepithelial region immediately beneath the urothelium; occasionally, they penetrated into the epithelial layer. Immunohistochemical investigations of pig bladder revealed that the density of NO synthase (NOS) immunoreactivity was higher in trigonal and urethral tissue than in the detrusor.196 Functional effects of nitric oxide  Relaxations to electrical stimulation were found in small biopsy preparations of

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the human detrusor.197 The relaxations were sensitive to the NOS-inhibitor NG-nitro-L-arginine (L-NOARG), but insensitive to tetrodotoxin; and it was suggested that NO, generated from the detrusor, was important for bladder relaxation during the filling phase. However, Elliott and Castleden198 were unable to demonstrate a nerve-mediated relaxation in human detrusor. In the pig detrusor, the NO-donor SIN-1 and exogenous NO–relaxed muscle preparations were precontracted by carbachol and ET-1 by approximately 60%. However, isoprenaline was about 1000 times more potent than SIN-1 and NO and caused complete relaxation. Nitroprusside, SIN-1, and NO were only moderately effective in relaxing isolated rat, pig, and rabbit detrusor muscles, compared to their effects on the urethral muscles.96,199,200 It appears to be unlikely that NO has a major role as a neurotransmitter causing direct relaxation of the detrusor smooth muscle, since the detrusor sensitivity to NO and agents acting via the cGMP system is low.201 This is also reflected by the finding in rabbits that cGMP is mainly related to urethral relaxation, and cAMP to urinary bladder relaxation.202 However, this does not exclude that NO may modulate the effects of other transmitters, or that it has a role in afferent neurotransmission.

Phosphodiesterases LUT smooth muscle can be relaxed by drugs increasing the intracellular concentrations of cAMP or cGMP.15,201,203 Multiple types of adenylyl cyclases exist, which catalyze the formation of cAMP.204,205 In LUT smooth muscles, increases in cAMP seem to have a main role in bladder relaxation, whereas cGMP is important for urethral relaxation.15,202,203,206. Several agents, acting through different receptors linked to adenylyl cyclase, or directly stimulating the enzyme, have been shown to relax the bladder and simultaneously to increase the intracellular concentrations of cAMP. Many endogenous agents as well as drugs have cGMP as their common mediator in eliciting different physiological responses. There are multiple types of soluble and particulate guanylyl cyclases that catalyze cGMP synthesis.207 Soluble guanylyl cyclase is the target of NO, which binds to its heme moiety and activates the enzyme with resulting increase in cGMP. cGMP, in turn, regulates protein phosphorylation, ion channel conductivity, and phosphodiesterase (PDE) activity. Both cAMP and cGMP are degraded by PDEs, a heterogenous group of hydrolytic enzymes.208–212 Since cAMP seems to be more important than cGMP for detrusor function, the cAMP pathway in this tissue has been the most extensively investigated pathway. Truss et  al.213–217 demonstrated the presence of five PDE isoenzymes (PDE1–5) in human and porcine detrusor and suggested that the cAMP pathway and the calcium/calmodulinstimulated PDE (PDE1) could be of functional importance in the regulation of detrusor tone. The same enzymes were

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demonstrated in the rat218 and rabbit bladder.219 Further studies revealed mRNA for PDEs 1A, 1B, 2A, 4A, 4B, 5A, 7A, 8A, and 9A in human bladder tissue.155 PDE1 was shown to be localized in the epithelium of the human urinary tract, including ureteral and bladder urothelium.220 Significant relaxation of human detrusor muscle in vitro, paralleled by increases in cyclic nucleotide levels, was induced by papaverine, vinpocetine (nonselective inhibitor of PDE1), and forskolin, suggesting that the cAMP pathway and PDE1 may be important in regulation of smooth muscle tone.214 In vitro, human detrusor muscle was relatively inert to sodium nitroprusside and to agents acting via the cGMP system.214 However, animal studies indicated that the NOS pathway involves not only the detrusor but also the urothelium/suburothelium; and the urothelium expresses neuronal NOS (nNOS) and produces cGMP221. This would mean that inhibitors of cGMP degradation could also influence bladder function via these structures. However, it has not been established which PDE enzymes are located to these tissues – a subject for future research. PDE4 has been implicated in the control of bladder smooth muscle tone. PDE4 inhibitors (PDE4-Is) reduced the in vitro control response of bladder strips,223,224 and also suppressed rhythmic bladder contractions of the isolated guinea pig bladder.225 PDE5-Is are currently used in the treatment of male LUTS.226 The precise mechanism(s) of action of PDE5-I on LUTS remains to be elucidated. PDE5-I may act on several pathways, including upregulating NO/cGMP activity, downregulating Rho-kinase activity, modulating autonomic nervous system overactivity of bladder and prostate afferent nerves, increasing pelvic blood perfusion, and reducing inflammation.227,228 Several clinical trials on the effect of PDE5-I on male LUTS have been published. In these studies, different PDE5-Is (sildenafil, vardenafil, tadalafil, and UK-369003) and combinations of an α-blocker (alfuzosin or tamsulosin) and PDE5-I were compared to placebo or to α-blocker alone. According to a recent meta-analysis, the use of PDE5-I alone was associated with a significant improvement of International Prostate Symptom Score (IPSS) at the end of the studies compared to placebo.98 The association of α-blocker and PDE5-I significantly improved IPSS and maximum flow rate at the end of the studies compared to α-blockers alone.226,229 Tadalafil is now approved by the U.S. Food and Drug Administration (FDA) for male LUTS management.

Conclusion There is abundant evidence that cholinergic neurotransmission is predominant in the activation of the human detrusor. This may not be the case in animals, which should be considered when animal models are used for the study of bladder function. Release of ACh, which stimulates M3

and M2 receptors on the detrusor smooth muscle cells, leads to bladder contraction. Other neurotransmitters/ modulators (e.g., ATP) have been demonstrated in the bladder of both animals and humans, but their roles in the human bladder remain to be established.

Urethra Sufficient contraction of the urethral smooth muscle is an important function to provide continence during the storage phase of the micturition cycle. Equally important is a coordinated and complete relaxation during the voiding phase. The normal pattern of voiding in humans is characterized by an initial drop in urethral pressure followed by an increase in intravesical pressure.13,230 The mechanism of this relaxant effect has not been definitely established, but several factors may contribute. One possibility is that the drop in intraurethral pressure is caused by the stimulation of muscarinic receptors on noradrenergic nerves, diminishing NA release and thereby tone in the proximal urethra. Another is that contraction of longitudinal urethral smooth muscle in the proximal urethral, produced by released ACh, causes shortening and widening of the urethra, with a concomitant drecrease in intraurethral pressure. A third possibility is that a NANC mechanism mediates this response.13

Cholinergic mechanisms Cholinergic nerves The urethral smooth muscle receives a rich cholinergic innervation, the functional role of which is largely unknown. Most probably, the cholinergic nerves cause relaxation of the outflow region at the start of micturition by releasing NO and other relaxant transmitters, based on the principle of co-transmission, as multiple transmitters were found to be co-localized in cholinergic nerves. In pig, urethra co-localization studies revealed that AChEpositive and some NOS-containing nerves had profiles that were similar. These nerves also contained NPY and VIP. NO-containing nerves were present in a density lower than that of the AChE-positive nerves, but higher than the density of any peptidergic nerves.231 Coexistence of ACh and NOS in the rat major pelvic ganglion was demonstrated by double immunohistochemistry.232 In the rat urethra, co-localization studies confirmed that NOS and VIP are contained within a population of cholinergic nerves.16

Muscarinic receptors In rabbits, there are fewer muscarinic receptor–binding sites in the urethra than in the bladder.233 Muscarinic receptor agonists contract isolated urethral smooth

Pharmacology of the lower urinary tract muscle from several species, including humans, but these responses seem to be mediated mainly by the longitudinal muscle layer.13 Investigating the whole length of the human female urethra, it was found that ACh contracted only the proximal part and the bladder neck.234 If this contractile activation is exerted in the longitudinal direction, it should be expected that the urethra is shortened and that the urethral pressure decreases. Experimentally, in vitro resistance to flow in the urethra was only increased by high concentrations of ACh.234–236 However, in humans, tolerable doses of bethanechol and emeprone had little effect on intraurethral pressure.237,238 Prejunctional muscarinic receptors may influence the release of both NA and ACh in the bladder neck/urethra. In urethral tissue from both rabbit and humans, carbachol decreased and scopolamine increased concentrationdependent release of [3H]NA from adrenergic and [3H] choline from cholinergic nerve terminals.239 This would mean that released ACh could inhibit NA release, thereby decreasing urethral tone and intraurethral pressure. Studies in the pig urethra show that M2 receptors are predominant over M3. In addition, contraction of the circular muscle appears to be mediated by M2 and M3, while the longitudinal response is mainly mediated by M3 receptors.202,240 This may have clinical interest since subtype selective antimuscarinic drugs (M3) are being introduced as a treatment of bladder overactivity.

Adrenergic mechanisms Adrenergic nerves The well-known anatomical differences between the male and female urethra are also reflected in the innervation. In the human male, the smooth muscle surrounding the preprostatic part of the urethra is richly innervated by both cholinergic and adrenergic nerves, and considered a sexual sphincter, contracting during ejaculation and thus preventing retrograde transport of sperm.241 The role of this structure in maintaining continence is unclear, but probably not essential. In the human female, the muscle bundles run obliquely or longitudinally along the length of the urethra, and in the whole human female urethra, as well as in the human male urethra below the preprostatic part, there is only a scarce supply of adrenergic nerves.5,242 Fine varicose nerve terminals can be seen along the bundles of smooth muscle cells, running both longitudinally and transversely. Adrenergic terminals can also be found around blood vessels. Co-localization studies in animals have revealed that adrenergic nerves, identified by immunohistochemistry using tyrosine hydroxylase (TH), also contain NPY.243 Chemical sympathectomy in rats resulted in a complete disappearance of the adrenergic nerves, while NOS-containing nerve fibers were not affected by

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the treatment.244 This suggests that NOS is not contained within adrenergic nerves. Both α- and β-ARs have been found in isolated urethral smooth muscle from animals as well as humans. 235,245–247 α-Adrenoceptors  In humans, up to about 50% of the intraurethral pressure is maintained by stimulation of α-ARs, as judged from results obtained with α-AR antagonists and epidural anesthesia in urodynamic studies.248–249 In human urethral smooth muscle, both functional and receptor-binding studies have suggested that α1-AR subtype is the predominating postjunctional α-AR.13,250 However, most in vitro investigations of human urethral α-ARs were done in males, and the results support the existence of a sphincter structure in the male proximal urethra, which cannot be found in the female. Other marked differences between sexes in the distribution of α1- and α2-ARs (as found in rabbits), or in the distribution of α1-AR subtypes, do not seem to occur.251 Separating the entire length of the isolated human female urethra into seven parts, from the external meatus to the bladder neck, it was found that NA (α1 and α2), but not clonidine (α2), produced concentration-dependent contractions in all parts, with a peak in middle to proximal urethra.234 Also, a similarity in patterns between NA-induced contraction and the urethral pressure profile in the human urethra was demonstrated. Among the three high affinity α1-AR subtypes (α1A, α1B, α1D) identified in molecular cloning and functional studies, α1A seems to predominate in the human LUT. However, a receptor with low affinity for prazosin (the α1L-AR) was found to be prominent in the human male urethra and may represent a functional phenotype of the α1A-AR.252,253 In the human female urethra, the expression and distribution of α1-AR subtypes were determined, and mRNA for the α1A subtype was predominant. Autoradiography confirmed the predominance of the α1A-AR.251 The abovementioned studies suggest that the sympathetic innervation helps to maintain urethral smooth muscle tone through α1-AR receptor stimulation. If urethral α1-ARs are contributing to the LUTS, which can also occur in women, an effect of α1-AR antagonists should be expected in women with these symptoms.254,255 This was found to be the case in some studies, but was not confirmed in a randomized, placebo-controlled pilot study, which showed that terazosin was not effective for the treatment of prostatism-like symptoms in aging women.256 Urethral α2-ARs are able to control the release of NA from adrenergic nerves, as shown in in vitro studies. In the rabbit urethra, incubated with [3H]NA, electrical stimulation of nerves caused a release of [3H], which was decreased by NA and clonidine and increased by the α2-AR antagonist, rauwolscine.239 Clonidine was shown to reduce intraurethral pressure in humans, an effect that may be attributed partly to a peripheral effect on adrenergic nerve

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terminals.257 More probable, however, this effect is exerted on the CNS with a resulting decrease in peripheral sympathetic nervous activity. The subtype of prejunctional α2-AR involved in [3H]NA secretion in the isolated guinea pig urethra was suggested to be of the α2A subtype.54 Prejunctional α2-AR regulation of transmitter release is not confined to adrenergic nerves.13 Electrical field stimulation (EFS) (frequencies above 12 Hz) of spontaneously contracted smooth muscle strips from the female pig urethra, evoked long-lasting, frequency-dependent relaxations in the presence of prazosin, scopolamine, and the NOS inhibitor L-NOARG, suggesting the release of an unknown relaxation-producing mediator. Treatment with a selective α2-AR agonist markedly reduced the relaxations evoked by EFS at all frequencies tested (16–30 Hz). This inhibitory effect was completely antagonized by the α2-AR antagonist rauwolscine, and the results suggested that the release of the unknown mediator in the female pig urethra can be modulated via α2-ARs.258 β-Adrenoceptors  In humans, the β-ARs in the bladder neck were suggested to be of the β2 subtype, as shown by receptor-binding studies using subtype selective antagonists.259 However, β3-ARs can be found in the striated urethral sphincter.260 Although the functional importance of urethral β-ARs has not been established, they have been the targets for therapeutic intervention. Selective β2-AR agonists have been shown to reduce intraurethral pressure, while β-AR antagonists did not influence intraurethral pressure in acute studies.261–264 The theoretical basis for the use of β-AR antagonists in the treatment of stress incontinence is that the blockade of urethral β-ARs may enhance the effects of NA on urethral α-ARs. Even if propranolol has been reported to have beneficial effects in the treatment of stress incontinence, this does not seem to be an effective treatment.13 After selective β2-AR antagonists have been used as a treatment of stress incontinence, it seems paradoxical that the selective β2-AR agonist, clenbuterol, was found to cause significant clinical improvement in women with stress incontinence.265 The positive effects were suggested to be a result of an action on urethral striated muscle and/ or the pelvic floor muscles.260,266

Nonadrenergic–noncholinergic mechanisms The mechanical responses for autonomic nerve stimulation and for intraarterial ACh injection on resistance to flow in the proximal urethra were tested in male cats. It was found that sacral ventral root stimulation produced an atropine-sensitive constriction when basal urethral resistance was low, but produced dilatation when resistance was high.267 The latter response was reduced, but not

abolished, by atropine. When urethral constriction had been produced by phenylephrine, injection of ACh produced a consistent decrease in urethral resistance, which was then not reduced by atropine. It was suggested that parasympathetic dilatation of the urethra may be mediated by an unknown NANC transmitter released from postganglionic neurons. The predominant transmitter is believed to be NO.

Nonadrenergic–noncholinergic neurotransmission: Nitric oxide NO has shown to be an important inhibitory neurotransmitter in the LUT.13,268 NO-mediated responses in smooth muscle preparations are found to be linked to an increase in cGMP formation, which has been demonstrated in several urethra preparations.200,202,206,269 Subsequent activation of a cGMP-dependent protein kinase (cGK) has been suggested to hyperpolarize the cell membrane, probably by causing a leftward shift of the activation curve for the K+ channels, thereby increasing their open probability.270,271 There have also been reports suggesting that NO in some smooth muscles might act directly on the K+ channels.272,273 Other mechanisms for NO-induced relaxations, mediated by cGMP, might involve reduced intracellular Ca2+ levels by intracellular sequestration or reduced sensitivity of the contractile machinery to Ca2+, both mechanisms acting without changing the membrane potential.274 Electrophysiological registrations from urethral smooth muscle are scarce, however, following NANC-stimulation in some preparations of urethral smooth muscle from male rabbits, a hyperpolarization was found.275 Persson et  al. 276 investigated the cGMP pathway in mice lacking cGK type I (cGKI). In the WT controls, EFS elicited frequency-dependent relaxations in urethral preparations. The relaxations were abolished by L-NOARG and instead a contractile response occurred. In cGKI -/- urethral strips, the response to EFS was practically absent, but a small relaxation generally appeared at high stimulation frequencies (16–32 Hz). This relax­a nt response was not inhibited by L-NOARG, suggesting the  occurrence of additional relaxant transmitter(s). 276 The abundant occurrence of NOSimmunoreactive nerve fibers in the rabbit urethra also supports the present view of NO as the main inhibitory NANC-mediator. 200 Using cGMP antibodies, target cells for NO were localized in rabbit urethra. Spindle-shaped cGMP-IR cells, distinct from the smooth muscle cells, formed a network around and between the urethral smooth muscle bundles. 277 Similar cGMP-IR ICs were found in guinea pig and human bladder/urethra, but in contrast to the findings in rabbits, smooth muscle cells with cGMP immunoreactivity were found in the urethra tissues, following stimulation with sodium nitroprusside. 278 The occurrence of cGMP immunoreactivity in smooth muscle cells seems logical since NO is believed

Pharmacology of the lower urinary tract

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to stimulate guanylyl cyclase with subsequent cGMP formation in the cells. The function of the ICs has not been established, but since they have morphological similarities to the ICs of Cajal (ICC) in the gut, which are considered pacemaker cells, it has been speculated that they also may have a similar function in the LUT. Studies performed in rabbit urethra tissue showed regular spontaneous depolarization of these interstitial cells, suggesting that they indeed may have pacemaker function.279 This may differ from the function of the interstitial cells in the bladder.280,123

Thus, the mechanism and site(s) of action for these positive effects of the PDE5-Is have not been established.227,228 The  lack of effect on flow rate suggests that the site action may be different from that of α1-AR antagonists. Considering preclinical experimental evidence, a relaxant effect on urethral smooth muscle could be expected, and may not be completely excluded.

Role of phosphodiesterases

The role of carbon monoxide (CO) in urethral function is still controversial. It has been assumed that CO causes relaxation through the cGMP pathway. A weak relaxant effect of exogenous CO, compared to NO, was found in the rabbit urethra, suggesting that CO is not an important mediator of relaxation in this tissue.277 However, there are known interspecies differences of urethral relaxant responses to CO. In guinea pig urethra, the maximal relaxant response to CO did not exceed 15% ± 3%, compared to 40% ± 7% in pigs.269,281 The distribution of the CO-producing enzymes heme oxygenases, HO-1 and HO-2 was investigated in urethral smooth muscle of several species. In guinea pigs, HO-2 immunoreactivity was found in all nerve cell bodies of intramural ganglia, localized between smooth muscle bundles in the detrusor, bladder base, and proximal urethra.281 In the pig urethra, HO-2 immunoreactivity was found in coarse nerve trunks and HO-1 immunoreactivity in nerve cells, coarse nerve trunks, and varicose nerve fibers within urethral smooth muscle. In strip preparations, exogenously applied CO evoked a small relaxation associated with a small increase in cGMP, but not cAMP, content.283 However, HO-2 and the NO-producing enzyme, nNOS, were found coexisting in nerve trunks of human male and female urethras, suggesting the possibility of interaction between both systems.284 Nassem et al.285 found that in the presence of hydrogen peroxide, the relaxation responses to both CO and NO in the rabbit urethra were significantly increased, and it was suggested that hydrogen peroxide may amplify NOand CO-mediated responses. In pigs, an even more pronounced increase in relaxant response to CO in female pig urethra, using YC-1, a stimulator of sGC, suggested a possible role for CO as possible messenger function for urethral relaxation.269

NO has been demonstrated to be an important inhibitory neurotransmitter in the smooth muscle of the urethra and its relaxant effect is associated with increased levels of cGMP.15 However, few investigations have addressed the cAMP- and cGMP-mediated signal transduction pathways and its key enzymes in the mammalian urethra. Morita et al. 202 examined the effects of isoproterenol, prostaglandin E1 and E2, and SNP on the contractile force and tissue content of cAMP and cGMP in the rabbit urethra. They concluded that both cyclic nucleotides can produce relaxation of the urethra. Werkstrom et al.281 demonstrated the significance of NO and cGMP in the control of urethral relaxation. Using female pig urethral smooth muscle, they studied NANC relaxations induced by electrical field stimulation, and observed that the NOS inhibitor L-NOARG inhibited relaxations registered at low frequencies of stimulation. Measurement of cyclic nucleotides in preparations subjected to continuous nerve stimulation revealed an increase in cGMP. In the presence of L-NOARG, there was a significant decrease in cGMP content in comparison to the control tissue. Werkstrom et  al.282 also characterized the distribution of PDE5, cGMP, and PKG1 in female pig and human urethra, and evaluated the effect of pharmacological inhibition of PDE5 in isolated smooth muscle preparations. After stimulation with the NO donor, DETA NONO-ate, the cGMP immunoreactivity (IR) in urethral and vascular smooth muscles increased. There was a wide distribution of cGMP- and vimentin-positive ICs between pig urethral smooth muscle bundles. PDE5 IR could be demonstrated within the urethral and vascular smooth muscle cells, but also in vascular endothelial cells that expressed cGMP IR. Nerve-induced relaxations of urethral preparations were enhanced at low concentrations of sildenafil, vardenafil, and tadalafil, whereas there were direct smooth muscle relaxant actions of the PDE5-Is at high concentrations. The occurrence of other cGMPdegrading PDEs in the male urethral structures does not seem to be studied. Randomized-controlled studies (RCT) on sildenafil282 and tadalafil283 analyzed the impact of PDE5-Is on LUTS. Both studies found significant improvements in IPSS, but there was interestingly no change in maximum flow rate.

Nonadrenergic–noncholinergic neurotransmission: Carbon monoxide

Nonadrenergic–noncholinergic neurotransmission: Vasoactive intestinal polypeptide In various species, VIP-containing urethral ganglion cells have been demonstrated, and numerous VIP-IR nerve fibers have been observed around ganglion cells, in the

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bladder neck, in the urethral smooth muscle layers, in lamina propria, and in association with blood vessels.5 However, if the findings have relevance in man is yet to be proven. In the pig urethra, VIP and NOS seem to be partly co-localized within nerve fibres.231 In the rabbit urethra, VIP-IR nerve fibers occurred throughout the smooth muscle layer, although the number of nerves was lower than that of NOS-immunoreactive structures, and a marked relaxation of the isolated rabbit urethral muscle to VIP was reported.277 Both pelvic and hypogastric nerve stimulation in dogs increased the bladder venous effluent VIP concentration, supporting the view that VIP can also be released from urethral nerves.168 VIP had a marked inhibitory effect on the isolated female rabbit urethra contracted by NA or EFS, without affecting NA release, but in human urethral smooth muscle, relaxant responses were less consistent. However, a modulatory role in neurotransmission could not be excluded.286 Infusion of VIP in humans in amounts that caused circulatory side effects, had no effects on urethral resistance, although plasma concentrations of VIP were obtained, which, in other clinical investigations, had been sufficient to cause relaxation of the lower esophageal sphincter and to depress uterine contraction.170 Therefore, the physiological importance of VIP for the LUT function in humans was questioned, and it is still unclear whether or not VIP contributes to NANCmediated relaxation of the human urethra.170

Nonadrenergic–noncholinergic neurotransmission: Adenosine triphosphate ATP has been found to cause smooth muscle relaxation via G-protein-coupled P2Y receptors.287 ATP may also induce relaxation via breakdown to adenosine. In strips of precontracted guinea pig urethra, it was found that ATP caused relaxation and inhibited spontaneous electrical activity.288 In precontracted preparations, ATP had almost no effect on EFS-induced relaxation in isolated male rabbit circular urethral smooth muscle; however, suramin, a nonselective P2Y-purinoceptor antagonist, and L-NOARG, both concentration-dependently attenuated the relaxation. ATP and related purine compounds (AMP and ADP) each reduced induced tonic contractions in a concentration-dependent manner. The outflow of ATP, measured using the luciferase technique, was markedly increased by EFS.289 The findings suggested that P2Ypurinoceptors exist in the male rabbit urethra, and ATP and related purine compounds may play a role in NANC neurotransmission. This conclusion was further supported in studies on circular strips of hamster proximal urethra precontracted with arginine vasopressin. EFS caused frequency-dependent relaxations, which were attenuated by suramin and reactive blue. Exogenous ATP produced

concentration-related relaxations, which also were attenuated by suramin and reactive blue.290 The relevance of this system in human remains to be established.

Nonadrenergic–noncholinergic neurotransmission: Hydrogen sulfide Endogenous H2S synthesized from L-cysteine by the action of the pyridoxal-5-phosphate–dependent enzyme, cystathionine γ-lyase and cystathionine β-synthase, exerts a wide range of peripheral biological actions, including smooth muscle contraction and relaxation in the LUT. In the rat detrusor, the H2S donor, NaHS, produces contraction by stimulating capsaicin-sensitive primary afferents, which releases tachykinins such as SP or NKA, possibly by activating the nonselective cation channel TRPV1 or a related ion channel in the sensory nerves.291,292 TRPA1 channel was expressed on C-fiber bladder afferents and urothelial cells, and the fact that intravesical TRPA1 channel activators initiate DO suggest a possible role for these channels in bladder sensory transduction.293 TRPA1 IR was also noted in nerve fibers distributed in suburothelial and muscular layers in the human urethra, where NaHS produces smooth muscle relaxation.294 Fernandes et  al.295 found that endogenous H2S synthesized by cystathionine γ-lyase and released from intramural nerves acts as a powerful signaling molecule in NO-independent inhibitory transmission to the pig bladder neck. Whether or not these results are valid also for the human bladder neck/urethra remains to be established.

Summary Available information supports the idea that sympathetic activity, via release of NA and stimulation of urethral smooth muscle α1-ARs, is a main factor in the maintenance of intraurethral pressure and thus of continence. NO, produced by NOS within cholinergic nerves, seems to be the predominant inhibitory neurotransmitter in the urethra, even if there is good evidence for the existence of other, as yet unidentified, inhibitory transmitters.

References 10. Morrison JFS, Steers WD, Brading AF et al. Neurophysiology and neuropharmacology. In: Abrams P, Cardozo L, Khoury S, Wein A, eds. Incontinence, 1st ed. Plymbridge, United Kingdom: Plymbridge Distributors, 2002: 83–163. 11. Griffiths DHG, Dalm E, de Wall H. Control and coordination of bladder and urethral function in the brainstem of the cat. Neurourol Urodyn 1990; 9: 63–82. 12. Blok BF, Holstege G. Two pontine micturition centers in the cat are not interconnected directly: Implications for the central organization of micturition. J Comp Neurol 1999; 403: 209–18.

Pharmacology of the lower urinary tract 13. de Groat WC, Boot AM, Yoshimura N. Neurophysiology of micturition and its modification in animal models of human diseases. In: Maggi CA, ed. Nervous Control of the Urogenital System, Vol 3. London: Harwood Publishers, 1993: 227–90. 14. Lincoln JBG. Autonomic innervation of the urinary bladder and urethra. In: Maggi CA, ed. Nervous control of the Urogenital System, Vol 3. London: Harwood Academic Publishers, 1993: 33–68. 15. Werkstrom V et al. Factors involved in the relaxation of female pig urethra evoked by electrical field stimulation. Br J Pharmacol 1995; 116: 1599–604. 16. Hashimoto S et al. Nitric oxide-dependent and -independent neurogenic relaxation of isolated dog urethra. Eur J Pharmacol 1993; 231: 209–14. 17. Yoshimura N, de Groat WC. Neural control of the lower urinary tract. Int J Urol 1997; 4: 111–25. 18. Kanai A, Andersson KE. Bladder afferent signaling: Recent findings. J Urol 2010; 183(4): 1288–95. 19. Janig W, Morrison JF. Functional properties of spinal visceral afferents supplying abdominal and pelvic organs, with special emphasis on visceral nociception. Prog Brain Res 1986; 67: 87–114. 20. Habler HJ et  al. Activation of unmyelinated afferent fibers by mechanical stimuli and inflammation of the urinary bladder in the cat. J Physiol 1990; 425: 545–62. 21. Fall M et al. A bladder-to-bladder cooling reflex in the cat. J Physiol 1990; 427: 281–300. 22. Andersson K. Pharmacology of lower urinary tract smooth muscles and penile erectile tissues. Pharmacol Rev 1993; 45: 253–308. 23. de Groat WC, Yoshimura N. Pharmacology of the lower urinary tract. Annu Rev Pharmacol Toxicol 2001; 41: 691–721. 24. Andersson KE, Arner A. Urinary bladder contraction and relaxation: Physiology and pathophysiology. Physiol Rev 2004; 84: 935–86. 25. Arvidsson U et  al. Vesicular acetylcholine transporter (VAChT) protein: A novel and unique marker for cholinergic neurons in the central and peripheral nervous systems. J Comp Neurol 1997; 378: 454–67. 26. Persson KAK, Alm P. Choline acetyltransferase and vesicular acetylcholine transporter protein in neurons innervating the rat lower urinary tract. Proc Soc Neurosci 1997; 596. 27. Dixon JS et al. The distribution of vesicular acetylcholine transporter in the human male genitourinary organs and its co-localization with neuropeptide Y and nitric oxide synthase. Neurourol Urodyn 2000; 19: 185–94. 28. Caulfield MP, Birdsall NJ. International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev 1998; 50: 279–90. 29. Sigala S et al. Differential gene expression of cholinergic muscarinic receptor subtypes in male and female normal human urinary bladder. Urology 2002; 60: 719–25. 30. Hinata N et al. Quantitative analysis of the levels of expression of muscarinic receptor subtype RNA in the detrusor muscle of patients with overactive bladder. Mol Diagn 2004; 8: 17–22. 31. Andersson KE. Muscarinic acetylcholine receptors in the urinary tract. Handb Exp Pharmacol 2011; 202: 319–44. 32. Wang P et al. Muscarinic acetylcholine receptor subtypes mediating urinary bladder contractility and coupling to GTP binding proteins. J Pharmacol Exp Ther 1995; 273: 959–66. 33. Yamaguchi O et  al. Evaluation of mRNAs encoding muscarinic receptor subtypes in human detrusor muscle. J Urol 1996; 156: 1208–13. 34. Mukerji G et al. Localization of M2 and M3 muscarinic receptors in human bladder disorders and their clinical correlations. J Urol 2006; 176: 367–73. 35. Eglen RM et al. Muscarinic receptor subtypes and smooth muscle function. Pharmacol Rev 1996; 48: 531–65. 36. Hegde SS, Eglen RM. Muscarinic receptor subtypes modulating smooth muscle contractility in the urinary bladder. Life Sci 1999; 64: 419–28.

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37. Chess-Williams R. Muscarinic receptors of the urinary bladder: Detrusor, urothelial and prejunctional. Auton Autacoid Pharmacol 2002; 22: 133–45. 38. Eglen RM. Muscarinic receptor subtypes in neuronal and nonneuronal cholinergic function. Auton Autacoid Pharmacol 2006; 26: 219–33. 39. Andersson KE, Wein AJ. Pharmacology of the lower urinary tract: Basis for current and future treatments of urinary incontinence. Pharmacol Rev 2004; 56: 581–631. 40. Matsui M et al. Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M3 subtype. Proc Natl Acad Sci USA 2000; 97: 9579–84. 41. Igawa Y et al. Cystometric findings in mice lacking muscarinic M2 or M3 receptors. J Urol 2004; 172: 2460–4. 42. Andersson KE et  al. Muscarinic receptor stimulation of phosphoinositide hydrolysis in the human isolated urinary bladder. J Urol 1991; 146: 1156–9. 43. Harriss DR et  al. Expression of muscarinic M3-receptors coupled to inositol phospholipid hydrolysis in human detrusor cultured smooth muscle cells. J Urol 1995; 154: 1241–5. 44. Jezior JR et al. Dependency of detrusor contractions on calcium sensitization and calcium entry through LOE-908-sensitive channels. Br J Pharmacol 2001; 134: 78–87. 45. Wibberley A et  al. Expression and functional role of Rho-kinase in rat urinary bladder smooth muscle. Br J Pharmacol 2003; 138: 757–66. 46. Schneider T et  al. Signal transduction underlying carbacholinduced contraction of rat urinary bladder. I. Phospholipases and Ca2+ sources. J Pharmacol Exp Ther 2004; 308: 47–53. 47. Braverman AS, Ruggieri MR Sr. Muscarinic receptor transcript and protein density in hypertrophied and atrophied rat urinary bladder. Neurourol Urodyn 2006; 25: 55–61. 48. Takahashi R et al. Ca2+ sensitization in contraction of human bladder smooth muscle. J Urol 2004; 172: 748–52. 49. Peters SL et al. Rho kinase: A target for treating urinary bladder dysfunction. Trends Pharmacol Sci 2006; 27: 492–7. 50. Hegde SS et al. Functional role of M2 and M3 muscarinic receptors in the urinary bladder of rats in vitro and in vivo. Br J Pharmacol 1997; 120: 1409–18. 51. Kotlikoff MI et  al. M2 signaling in smooth muscle cells. Life Sci 1999; 64: 437–42. 52. Bonev AD, Nelson MT. Muscarinic inhibition of ATP-sensitive K+ channels by protein kinase C in urinary bladder smooth muscle. Am J Physiol 1993; 265: C1723–8. 53. Nakamura K et  al. Protein kinase G activates inwardly rectifying K(+) channel in cultured human proximal tubule cells. Am J Physiol Renal Physiol 2002; 283: F784–91. 54. Ehlert FJ et  al. The M2 muscarinic receptor mediates contraction through indirect mechanisms in mouse urinary bladder. J Pharmacol Exp Ther 2005; 313: 368–78. 55. Braverman A et al. M2 receptors in genito-urinary smooth muscle pathology. Life Sci 1999; 64: 429–36. 56. Braverman AS et al. M2 muscarinic receptor contributes to contraction of the denervated rat urinary bladder. Am J Physiol 1998; 275: R1654–60. 57. Braverman AS et al. Interaction between muscarinic receptor subtype signal transduction pathways mediating bladder contraction. Am J Physiol Regul Integr Comp Physiol 2002; 283: R663–8. 58. Braverman AS, Ruggieri MR Sr. Hypertrophy changes the muscarinic receptor subtype mediating bladder contraction from M3 toward M2. Am J Physiol Regul Integr Comp Physiol 2003; 285: R701–8. 59. Pontari MA et al. The M2 muscarinic receptor mediates in vitro bladder contractions from patients with neurogenic bladder dysfunction. Am J Physiol Regul Integr Comp Physiol 2004; 286: R874–80. 60. Tobin G, Sjogren C. In vivo and in vitro effects of muscarinic receptor antagonists on contractions and release of [3H]acetylcholine in the rabbit urinary bladder. Eur J Pharmacol 1995; 281: 1–8.

26

Textbook of the Neurogenic Bladder

61. Inadome A et  al. Prejunctional muscarinic receptors modulating acetylcholine release in rabbit detrusor smooth muscles. Urol Int 1998; 61: 135–41. 62. Somogyi GT, de Groat WC. Evidence for inhibitory nicotinic and facilitatory muscarinic receptors in cholinergic nerve terminals of the rat urinary bladder. J Auton Nerv Syst 1992; 37: 89–97. 63. Alberts P. Classification of the presynaptic muscarinic receptor subtype that regulates 3H-acetylcholine secretion in the guinea pig urinary bladder in vitro. J Pharmacol Exp Ther 1995; 274: 458–68. 64. D’Agostino G et  al. M4 muscarinic autoreceptor-mediated inhibition of 3H-acetylcholine release in the rat isolated urinary bladder. J Pharmacol Exp Ther 1997; 283: 750–6. 65. D’Agostino G et al. Prejunctional muscarinic inhibitory control of acetylcholine release in the human isolated detrusor: Involvement of the M4 receptor subtype. Br J Pharmacol 2000; 129: 493–500. 66. Somogyi GT, de Groat WC. Function, signal transduction mechanisms and plasticity of presynaptic muscarinic receptors in the urinary bladder. Life Sci 1999; 64: 411–8. 67. Mansfield KJ et al. Muscarinic receptor subtypes in human bladder detrusor and mucosa, studied by radioligand binding and quantitative competitive RT-PCR: Changes in ageing. Br J Pharmacol 2005; 144: 1089–99. 68. Fovaeus M et  al. A non-nitrergic smooth muscle relaxant factor released from rat urinary bladder by muscarinic receptor stimulation. J Urol 1999; 161: 649–53. 69. Yokoyama O et  al. Effects of tolterodine on an overactive bladder depend on suppression of C-fiber bladder afferent activity in rats. J Urol 2005; 174: 2032–6. 70. De Laet K et al. Systemic oxybutynin decreases afferent activity of the pelvic nerve of the rat: New insights into the working mechanism of antimuscarinics. Neurourol Urodyn 2006; 25: 156–61. 71. Finney SM et al. Antimuscarinic drugs in detrusor overactivity and the overactive bladder syndrome: Motor or sensory actions? BJU Int 2006; 98: 503–7. 72. Blake-James BT et  al. The role of anticholinergics in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia: A systematic review and meta-analysis. BJU Int 2007; 99: 85–96. 73. Andersson KE. New roles for muscarinic receptors in the pathophysiology of lower urinary tract symptoms. BJU Int 2000; 86(Suppl 2): 36–42. 74. Gary TRD. Lessons learned from dopamine beta-hydroxylase deficiency in humans. News Physiol Sci 1994; 9: 35–9. 75. Michel MC, Vrydag W. Alpha1-, alpha2- and beta-adrenoceptors in the urinary bladder, urethra and prostate. Br J Pharmacol 2006; 147(Suppl 2): S88–119. 76. Malloy BJ et  al. Alpha1-adrenergic receptor subtypes in human detrusor. J Urol 1998; 160: 937–43. 77. Hampel C et al. Modulation of bladder alpha1-adrenergic receptor subtype expression by bladder outlet obstruction. J Urol 2002; 167: 1513–21. 78. Nomiya M, Yamaguchi O. A quantitative analysis of mRNA expression of alpha 1 and beta-adrenoceptor subtypes and their functional roles in human normal and obstructed bladders. J Urol 2003; 170: 649–53. 79. Persson K et  al. Spinal and peripheral mechanisms contributing to hyperactive voiding in spontaneously hypertensive rats. Am J Physiol 1998; 275: R1366–73. 80. Somogyi GT et al. Prejunctional facilitatory alpha 1-adrenoceptors in the rat urinary bladder. Br J Pharmacol 1995; 114: 1710–6. 81. Szell EA et al. Smooth muscle and parasympathetic nerve terminals in the rat urinary bladder have different subtypes of alpha (1) adrenoceptors. Br J Pharmacol 2000; 130: 1685–91. 82. Trevisani M et  al. The influence of alpha(1)-adrenoreceptors on neuropeptide release from primary sensory neurons of the lower urinary tract. Eur Urol 2007; 52(3): 901–8.

83. Yanase H, Wang X, Momota Y et al. The involvement of urothelial alpha 1A adrenergic receptor in controlling the micturition reflex. Biomed Res 2008; 29(5): 239–44. 84. Kurizaki Y, Ishizuka O, Imamura T et al. Relation between expression of α(1)-adrenoceptor mRNAs in bladder mucosa and urodynamic findings in men with lower urinary tract symptoms. Scand J Urol Nephrol 2011; 45(1): 15–9. 85. Nergardh A et al. Characterization of the adrenergic beta-receptor in the urinary bladder of man and cat. Acta Pharmacol Toxicol (Copenh) 1977; 40: 14–21. 86. Larsen JJ. Alpha and beta-adrenoceptors in the detrusor muscle and bladder base of the pig and beta-adrenoceptors in the detrusor muscle of man. Br J Pharmacol 1979; 65: 215–22. 87. Igawa Y et  al. Functional and molecular biological evidence for a possible beta3-adrenoceptor in the human detrusor muscle. Br J Pharmacol 1999; 126: 819–25. 88. Takeda M et al. Evidence for beta3-adrenoceptor subtypes in relaxation of the human urinary bladder detrusor: Analysis by molecular biological and pharmacological methods. J Pharmacol Exp Ther 1999; 288: 1367–73. 89. Igawa Y, Aizawa N, Homma Y. Beta3-adrenoceptor agonists: Possible role in the treatment of overactive bladder. Korean J Urol 2010; 51(12): 811–8. 90. Michel MC, Ochodnicky P, Homma Y, Igawa Y. β-adrenoceptor agonist effects in experimental models of bladder dysfunction. Pharmacol Ther 2011; 131(1): 40–9. 91. Andersson KE, Martin N, Nitti V. Selective β3-adrenoceptor agonists in the treatment of the overactive bladder. J Urol 2013; 190:1173–80. 92. Igawa Y, Michel MC. Pharmacological profile of β(3)-adrenoceptor agonists in clinical development for the treatment of overactive bladder syndrome. Naunyn Schmiedebergs Arch Pharmacol 2013; 386(3): 177–83. 93. Yamazaki Y et  al. Species differences in the distribution of betaadrenoceptor subtypes in bladder smooth muscle. Br J Pharmacol 1998; 124: 593–9. 94. Yamaguchi O. Beta3-adrenoceptors in human detrusor muscle. Urology 2002; 59: 25–9. 95. Igawa Y et al. Relaxant effects of isoproterenol and selective beta3adrenoceptor agonists on normal, low compliant and hyperreflexic human bladders. J Urol 2001; 165: 240–4. 96. Tanaka N et  al. Beta(3)-adrenoceptor agonists for the treatment of frequent urination and urinary incontinence: 2-[4-(2-[[(1S,2R)2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl]amino]ethyl) phenoxy]-2-methylpropionic acid. Bioorg Med Chem 2001; 9: 3265–71. 97. Woods M et  al. Efficacy of the beta3-adrenergic receptor agonist CL-316243 on experimental bladder hyperreflexia and detrusor instability in the rat. J Urol 2001; 166: 1142–7. 98. Andersson KE et al. The basis for drug treatment of the overactive bladder. World J Urol 2001; 19: 294–8. 99. Rohner TJ et al. Altered in vitro adrenergic responses of dog detrusor msucle after chronic bladder outlet obstruction. Urology 1978; 11: 357–61. 100. Tsujii T et al. A possible role of decreased relaxation mediated by beta-adrenoceptors in bladder outlet obstruction by benign prostatic hyperplasia. Br J Pharmacol 1992; 107: 803–7. 101. Frazier EP, Mathy MJ, Peters SL, Michel MC. Does cyclic AMP mediate rat urinary bladder relaxation by isoproterenol? J Pharmacol Exp Ther 2005; 313(1): 260–7. 102. Frazier EP, Peters SL, Braverman AS, Ruggieri MR Sr, Michel MC. Signal transduction underlying the control of urinary bladder smooth muscle tone by muscarinic receptors and beta-adrenoceptors. Naunyn Schmiedebergs Arch Pharmacol 2008; 377(4–6): 449–62. 103. Uchida H, Shishido K, Nomiya M, Yamaguchi O. Involvement of cyclic AMP-dependent and -independent mechanisms in the relaxation of rat detrusor muscle via beta-adrenoceptors. Eur J Pharmacol 2005; 518(2–3): 195–202.

Pharmacology of the lower urinary tract 104. Iggo A. Tension receptors in the stomach and the urinary bladder. J Physiol 1955; 128(3): 593–607. 105. Aizawa N, Homma Y, Igawa Y. Effects of mirabegron, a novel β3-adrenoceptor agonist, on primary bladder afferent activity and bladder microcontractions in rats compared with the effects of oxybutynin. Eur Urol 2012; 62(6): 1165–73. 106. Biers SM, Reynard JM, Brading AF. The effects of a new selective beta3-adrenoceptor agonist (GW427353) on spontaneous activity and detrusor relaxation in human bladder. BJU Int 2006; 98(6): 1310–4. 107. Gillespie JI, Palea S, Guilloteau V et al. Modulation of non-voiding activity by the muscarinergic antagonist tolterodine and the β(3)adrenoceptor agonist mirabegron in conscious rats with partial outflow obstruction. BJU Int 2012; 110(2 Pt 2): E132–42. 108. Otsuka A, Shinbo H, Matsumoto R, Kurita Y, Ozono S. Expression and functional role of beta-adrenoceptors in the human urinary bladder urothelium. Naunyn Schmiedebergs Arch Pharmacol 2008; 377(4–6): 473–81. 109. Murakami S, Chapple CR, Akino H, Sellers DJ, Chess-Williams R. The role of the urothelium inmediating bladder responses to isoprenaline. BJU Int 2007; 99(3): 669–73. 110. Kanie S, Otsuka A, Yoshikawa S et  al. Pharmacological effect of TRK-380, a novel selective human β3-adrenoceptor agonist, on mammalian detrusor strips. Urology 2012; 79(3): 744. 111. Andersson KE. Bladder activation: Afferent mechanisms. Urology 2002; 59: 43–50. 112. de Groat WC. The urothelium in overactive bladder: Passive by stander or active participant? Urology 2004; 64: 7–11. 113. Birder LA, de Groat WC. Mechanisms of disease: Involvement of the urothelium in bladder dysfunction. Nat Clin Pract Urol 2007; 4: 46–54. 114. Birder LA. Involvement of the urinary bladder urothelium in signaling in the lower urinary tract. Proc West Pharmacol Soc 2001; 44: 85–6. 115. Birder L, Andersson KE. Urothelial signaling. Physiol Rev 2013; 93(2): 653–80. 116. Dickson A et  al. Peptidergic sensory and parasympathetic fiber sprouting in the mucosa of the rat urinary bladder in a chronic model of cyclophosphamide-induced cystitis. Neuroscience 2006; 139: 671–85. 117. Jen PY et  al. Immunohistochemical localization of neuromarkers and neuropeptides in human fetal and neonatal urinary bladder. Br J Urol 1995; 75: 230–5. 118. Lips KS et al. Acetylcholine and molecular components of its synthesis and release machinery in the urothelium. Eur Urol 2007; 51: 1042–53. 119. Birder LA et al. Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1. Nat Neurosci 2002; 5: 856–60. 120. Andersson KE, Gratzke C,Hedlund P. The role of the transient receptor potential (TRP) superfamily of cation-selective channels in the management of the overactive bladder. BJU Int 2010; 106(8): 1114–27. 121. Maggi CA. Prostanoids as local modulators of reflex micturition. Pharmacol Res 1992; 25: 13–20. 122. Chancellor MB, de Groat WC. Intravesical capsaicin and resiniferatoxin therapy: Spicing up the ways to treat the overactive bladder. J Urol 1999; 162: 3–11. 123. Burnstock G. Purine-mediated signaling in pain and visceral perception. Trends Pharmacol Sci 2001; 22: 182–8. 124. Tominaga M et  al. Potentiation of capsaicin receptor activity by metabotropic ATP receptors as a possible mechanism for ATPevoked pain and hyperalgesia. Proc Natl Acad Sci USA 2001; 98: 6951–6. 125. Pandita RK, Andersson KE. Intravesical adenosine triphosphate stimulates the micturition reflex in awake, freely moving rats. J Urol 2002; 168: 1230–4.

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126. Cockayne DA et al. Urinary bladder hyporeflexia and reduced painrelated behaviour in P2X3-deficient mice. Nature 2000; 407: 1011–5. 127. Vlaskovska M et  al. P2X3 knock-out mice reveal a major sensory role for urothelially released ATP. J Neurosci 2001; 21: 5670–7. 128. Sui GP et al. Gap junctions and connexin expression in human suburothelial interstitial cells. BJU Int 2002; 90: 118–29. 129. Sui GP et al. Electrical characteristics of suburothelial cells isolated from the human bladder. J Urol 2004; 171: 938–43. 130. Brading AF, McCloskey KD. Mechanisms of disease: Specialized interstitial cells of the urinary tract—An assessment of current knowledge. Nat Clin Pract Urol 2005; 2: 546–54. 131. McCloskey KD. Interstitial cells of Cajal in the urinary tract. Handb Exp Pharmacol 2011; (202): 233–54. 132. McCloskey KD. Bladder interstitial cells: An updated review of current knowledge. Acta Physiol (Oxf) 2013; 207(1): 7–15. 133. Koh BH, Roy R, Hollywood MA et al. Platelet-derived growth factor receptor-α cells in mouse urinary bladder: A new class of interstitial cells. J Cell Mol Med 2012; 16: 691–700. 134. Monaghan KP, Johnston L, McCloskey KD. Identification of PDGFR α positive populations of interstitial cells in human and guinea pig bladders. J Urol 2012; 188: 639–47. 135. Wiseman OJ, Fowler CJ, Landon DN. The role of the human bladder lamina propria myofibroblast. BJU Int 2003; 91: 89–93. 136. Eyden B. Are there myofibroblasts in normal bladder? Eur Urol 2009; 56: 427–9. 137. Gevaert T, De Vos R, Everaerts W et al. Characterization of upper lamina propria interstitial cells in bladders from patients with neurogenic detrusor overactivity and bladder pain syndrome. J Cell Mol Med 2011; 15(12): 2586–93. 138. Kubota Y, Hashitani H, Shirasawa N et  al. Altered distribution of interstitial cells in the guinea pig bladder following bladder outlet obstruction. Neurourol Urodyn 2008; 27(4): 330–40. 139. Roosen A, Datta SN, Chowdhury RA et al. Suburothelial myofibroblasts in the human overactive bladder and the effect of botulinum neurotoxin type A treatment. Eur Urol 2009: 55(6): 1440–8. 140. Mukerji G, Yiangou Y, Grogono J et al. Localization of M2 and M3 muscarinic receptors in human bladder disorders and their clinical correlations. J Urol 2006; 176: 367–73. 141. Grol S, Essers PB, van Koeveringe GA et al. M(3) muscarinic receptor expression on suburothelial interstitial cells. BJU Int 2009; 104: 398–405. 142. Sui GP, Wu C, Fry CH. Characterization of the purinergic receptor subtype on guinea-pig suburothelial myofibroblasts. BJU Int 2006; 97: 1327–31. 143. Fry CH, Young JS, Jabr RI et al. Modulation of spontaneous activity in the overactive bladder: The role of P2Y agonists. Am J Physiol Renal Physiol 2012; 302: F1447–54. 144. Xue L, Li Y, Han X et al. Investigation of hyperpolarization-­activated cyclicnucleotide-gated channels in interstitial cells of Cajal of human bladder. Urology 2012; 80: 224.e13–18. 145. Luheshi GN, Zar MA. Presence of non-cholinergic motor transmission in human isolated bladder. J Pharm Pharmacol 1990; 42: 223–4. 146. Sjogren C et al. Atropine resistance of transmurally stimulated isolated human bladder muscle. J Urol 1982; 128: 1368–71. 147. Sibley GN. A comparison of spontaneous and nerve-mediated activity in bladder muscle from man, pig and rabbit. J Physiol 1984; 354: 431–43. 148. Smith CC. In vitro response of human bladder smooth muscle in unstable obstructed male bladders: A study of pathophysiological causes. Neurourol Urodyn 1994; 134: 14–5. 149. Bayliss M et al. A quantitative study of atropine-resistant contractile responses in human detrusor smooth muscle, from stable, unstable and obstructed bladders. J Urol 1999; 162: 1833–9. 150. Saito M et al. [Response of the human neurogenic bladder induced by intramural nerve stimulation]. Nippon Hinyokika Gakkai Zasshi 1993; 84: 507–13.

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Textbook of the Neurogenic Bladder

151. O’Reilly BA et al. P2X receptors and their role in female idiopathic detrusor instability. J Urol 2002; 167: 157–64. 152. Palea S et al. Evidence for purinergic neurotransmission in human urinary bladder affected by interstitial cystitis. J Urol 1993; 150: 2007–12. 153. Wammack RWE, Dienes HP, Hohenfellner R. Die Neurogene blase in vitro. Akt Urol 1995; 26: 16–8. 154. Yoshida M et al. Age-related changes in cholinergic and purinergic neurotransmission in human isolated bladder smooth muscles. Exp Gerontol 2001; 36: 99–109. 155. Lee HY et al. Distribution of P2X receptors in the urinary bladder and the ureter of the rat. J Urol 2000; 163: 2002–7. 156. O’Reilly BA et al. A quantitative analysis of purinoceptor expression in the bladders of patients with symptomatic outlet obstruction. BJU Int 2001; 87: 617–22. 157. Moore KH et  al. Loss of purinergic P2X(3) and P2X(5) receptor innervation in human detrusor from adults with urge incontinence. J Neurosci 2001; 21: RC166. 158. Ferguson DR et al. ATP is released from rabbit urinary bladder epithelial cells by hydrostatic pressure changes—A possible sensory mechanism? J Physiol 1997; 505(Pt 2): 503–11. 159. Chen CC et al. A P2X purinoceptor expressed by a subset of sensory neurons. Nature 1995; 377: 428–31. 160. Dunn PM et al. P2X receptors in peripheral neurons. Prog Neurobiol 2001; 65: 107–34. 161. Elneil S et al. Distribution of P2X(1) and P2X(3) receptors in the rat and human urinary bladder. Pharmacology 2001; 63: 120–8. 162. Yiangou Y et al. Capsaicin receptor VR1 and ATP-gated ion channel P2X3 in human urinary bladder. BJU Int 2001; 87: 774–9. 163. Namasivayam S et  al. Purinergic sensory neurotransmission in the urinary bladder: An in vitro study in the rat. BJU Int 1999; 84: 854–60. 164. Uckert S et al. Possible role of bioactive peptides in the regulation of human detrusor smooth muscle—Functional effects in vitro and immunohistochemical presence. World J Urol 2002; 20: 244–9. 165. Maggi C. The dual, sensory and “efferent” function of the capsaicinsensitive primary sensory neurons in the urinary bladder and urethra. In: Maggi CA, ed. Nervous Control of the Urogenital System, Vol 1. London: Harwood Publishers, 1993: 348–422. 166. Maggi CA et al. Cystometric evidence that capsaicin-sensitive nerves modulate the afferent branch of micturition reflex in humans. J Urol 1989; 142: 150–4. 167. Chapple CR et al. Loss of sensory neuropeptides in the obstructed human bladder. Br J Urol 1992; 70: 373–81. 168. Maggi CA. The mammalian tachykinin receptors. Gen Pharmacol 1995; 26: 911–44. 169. Green SA, Alon A, Ianus J et  al. Efficacy and safety of a neurokinin-1 receptor antagonist in postmenopausal women with overactive bladder with urge urinary incontinence. J Urol 2006; 176(6 Pt 1): 2535–40. 170. Giuliani S et  al. Characterization of the tachykinin neurokinin-2 receptor in the human urinary bladder by means of selective receptor antagonists and peptidase inhibitors. J Pharmacol Exp Ther 1993; 267: 590–5. 171. Frenkl TL, Zhu H, Reiss T et al. A multicenter, double-blind, randomized, placebo controlled trial of a neurokinin-1 receptor antagonist for overactive bladder. J Urol 2010; 184(2): 616–22. 172. Saenz de Tejada I et al. Endothelin in the urinary bladder. I. Synthesis of endothelin-1 by epithelia, muscle and fibroblasts suggests autocrine and paracrine cellular regulation. J Urol 1992; 148: 1290–8. 173. Kondo S et al. Benign prostatic hypertrophy affects the endothelin receptor density in the human urinary bladder and prostate. Urol Int 1995; 54: 198–203. 174. Okamoto-Koizumi T et  al. Pharmacological and molecular biological evidence for ETA endothelin receptor subtype mediating mechanical responses in the detrusor smooth muscle of the human urinary bladder. Clin Sci (Lond) 1999; 96: 397–402.

175. Khan MA et al. Possible role of endothelin-1 in the rabbit urinary bladder hyperplasia secondary to partial bladder outlet obstruction. Scand J Urol Nephrol 2000; 34: 15–20. 176. Schröder A, Tajimi M, Matsumoto H et  al. Protective effect of an oral endothelin converting enzyme inhibitor on rat detrusor function after outlet obstruction. J Urol 2004; 172(3): 1171–4. 177. Andersson PO et al. Bladder vasodilatation and release of vasoactive intestinal polypeptide from the urinary bladder of the cat in response to pelvic nerve stimulation. J Urol 1987; 138: 671–3. 178. Andersson PO et al. Urinary bladder and urethral responses to pelvic and hypogastric nerve stimulation and their relation to vasoactive intestinal polypeptide in the anaesthetized dog. Acta Physiol Scand 1990; 138: 409–16. 179. Klarskov P et  al. Vasoactive intestinal polypeptide concentration in human bladder neck smooth muscle and its influence on urodynamic parameters. Br J Urol 1987; 60: 113–8. 180. Gu J et  al. Vasoactive intestinal polypeptide in the normal and unstable bladder. Br J Urol 1983; 55: 645–7. 181. Persson K et al. Difference in the actions of calcitonin gene-related peptide on pig detrusor and vesical arterial smooth muscle. Acta Physiol Scand 1991; 143: 45–53. 182. Giuliani S et al. The role of sensory neuropeptides in motor innervation of the hamster isolated urinary bladder. Naunyn Schmiedebergs Arch Pharmacol 2001; 364: 242–8. 183. Lacroix JS et  al. Sympathetic vascular control of the pig nasal mucosa (III): Co-release of noradrenaline and neuropeptide Y. Acta Physiol Scand 1989; 135: 17–28. 184. Iravani MM, Zar MA. Neuropeptide Y in rat detrusor and its effect on nerve-mediated and acetylcholine-evoked contractions. Br J Pharmacol 1994; 113: 95–102. 185. Zoubek J et al. A comparison of inhibitory effects of neuropeptide Y on rat urinary bladder, urethra, and vas deferens. Am J Physiol 1993; 265: R537–43. 186. Lundberg JM et al. Effects of neuropeptide Y (NPY) on mechanical activity and neurotransmission in the heart, vas deferens and urinary bladder of the guinea-pig. Acta Physiol Scand 1984; 121: 325–32. 187. Crowe R et al. An increase of neuropeptide Y but not nitric oxide synthase-immunoreactive nerves in the bladder neck from male patients with bladder neck dyssynergia. J Urol 1995; 154: 1231–6. 188. Dixon JS et al. A double-label immunohistochemical study of intramural ganglia from the human male urinary bladder neck. J Anat 1997; 190 (Pt 1): 125–34. 189. Gu J et  al. Peptide-containing nerves in human urinary bladder. Urology 1984; 24: 353–7. 190. Iwasa A. [Distribution of neuropeptide Y (NPY) and its binding sites in human lower urinary tract. Histological analysis]. Nippon Hinyokika Gakkai Zasshi 1993; 84: 1000–6. 191. Davis B et al. Lack of neuropeptide Y receptor detection in human bladder and prostate. BJU Int 2000; 85: 918–24. 192. Brown WW et  al. Prostaglandin E2 production by rabbit urinary bladder. Am J Physiol 1980; 239: F452–8. 193. Downie JW, Karmazyn M. Mechanical trauma to bladder epithelium liberates prostanoids which modulate neurotransmission in rabbit detrusor muscle. J Pharmacol Exp Ther 1984; 230: 445–9. 194. Jeremy JY et  al. Eicosanoid synthesis by human urinary bladder mucosa: Pathological implications. Br J Urol 1987; 59: 36–9. 195. Maggi CA. Prostanoids as local modulators of reflex micturition. Pharmacol Res 1992; 25(1): 13–20. 196. Andersson KE, Sjogren C. Aspects on the physiology and pharmacology of the bladder and urethra. Prog Neurobiol 1982; 19: 71–89. 197. Schroder A et al. Detrusor responses to prostaglandin E2 and bladder outlet obstruction in wild-type and Ep1 receptor knockout mice. J Urol 2004; 172: 1166–70. 198. Feng L et al. Cloning two isoforms of rat cyclooxygenase: Differential regulation of their expression. Arch Biochem Biophys 1993; 307: 361–8.

Pharmacology of the lower urinary tract 199. Pairet M, Engelhardt G. Distinct isoforms (COX-1 and COX-2) of cyclooxygenase: Possible physiological and therapeutic implications. Fundam Clin Pharmacol 1996; 10: 1–17. 200. Vane JR, Botting RM. Mechanism of action of anti-inflammatory drugs. Scand J Rheumatol Suppl 1996; 102: 9–21. 201. Park JM et al. Cyclooxygenase-2 is expressed in bladder during fetal development and stimulated by outlet obstruction. Am J Physiol 1997; 273: F538–44. 202. Lee THP, Newgreen D, Andersson KE. Urodynamic effects of a novel EP1-Receptor antagonist in normal rats and rats with bladder outlet obstruction. J Urol 2007; 177(4): 1562–7. 203. Chapple CR, Abrams P, Andersson K-E et al. Phase II study on the efficacy and safety of the EP-1 receptor antagonist, ONO-8539, for nonneurogenic overactive bladder syndrome. J Urol 2014; 191: 253–60. 204. Smet PJ et  al. Distribution of NADPH-diaphorase-positive nerves supplying the human urinary bladder. J Auton Nerv Syst 1994; 47: 109–13. 205. Persson K et  al. Nitric oxide synthase in pig lower urinary tract: Immunohistochemistry, NADPH diaphorase histochemistry and functional effects. Br J Pharmacol 1993; 110: 521–30. 206. James MJ et al. Partial mediation by nitric oxide of the relaxation of human isolated detrusor strips in response to electrical field stimulation. Br J Clin Pharmacol 1993; 35: 366–72. 207. Elliott RA, Castleden CM. Nerve mediated relaxation in human detrusor muscle. Br J Clin Pharmacol 1993; 36: 479. 208. Persson K et al. Effects of inhibition of the L-arginine/nitric oxide pathway in the rat lower urinary tract in vivo and in vitro. Br J Pharmacol 1992; 107: 178–84. 209. Persson K, Andersson KE. Non-adrenergic, non-cholinergic relaxation and levels of cyclic nucleotides in rabbit lower urinary tract. Eur J Pharmacol 1994; 268: 159–67. 210. Andersson KE. Pathways for relaxation of detrusor smooth muscle. Adv Exp Med Biol 1999; 462: 241–52. 211. Morita T et al. Regional difference in functional roles of cAMP and cGMP in lower urinary tract smooth muscle contractility. Urol Int 1992; 49: 191–5. 212. Wheeler MA et al. Regulation of cyclic nucleotides in the urinary tract. J Smooth Muscle Res 2005; 41: 1–21. 213. Sunahara RK et al. Complexity and diversity of mammalian adenylyl cyclases. Annu Rev Pharmacol Toxicol 1996; 36: 461–80. 214. Cooper DM, Crossthwaite AJ. Higher-order organization and regulation of adenylyl cyclases. Trends Pharmacol Sci 2006; 27: 426–31. 215. Dokita S et al. Involvement of nitric oxide and cyclic GMP in rabbit urethral relaxation. Eur J Pharmacol 1994; 266: 269–75. 216. Lucas KA et  al. Guanylyl cyclases and signaling by cyclic GMP. Pharmacol Rev 2000; 52: 375–414. 217. Conti M, Jin SL. The molecular biology of cyclic nucleotide phosphodiesterases. Prog Nucleic Acid Res Mol Biol 1999; 63: 1–38. 218. Francis SH et  al. Cyclic nucleotide phosphodiesterases: Relating structure and function. Prog Nucleic Acid Res Mol Biol 2001; 65: 1–52. 219. Beavo JA, Brunton LL. Cyclic nucleotide research—Still expanding after half a century. Nat Rev Mol Cell Biol 2002; 3: 710–8. 220. Rybalkin SD et al. Cyclic GMP phosphodiesterases and regulation of smooth muscle function. Circ Res 2003; 93: 280–91. 221. Francis SH, Blount MA, Corbin JD. Mammalian cyclic nucleotide phosphodiesterases: Molecular mechanisms and physiological functions. Physiol Rev 2011; 91(2): 651–90. 222. Truss MC et al. Initial clinical experience with the selective phosphodiesterase-I isoenzyme inhibitor vinpocetine in the treatment of urge incontinence and low compliance bladder. World J Urol 2000; 18: 439–43. 223. Truss MC et  al. Phosphodiesterase 1 inhibition in the treatment of lower urinary tract dysfunction: From bench to bedside. World J Urol 2001; 19: 344–50.

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224. Truss MC et al. Cyclic nucleotide phosphodiesterase (PDE) isoenzymes in the human detrusor smooth muscle. II. Effect of various PDE inhibitors on smooth muscle tone and cyclic nucleotide levels in vitro. Urol Res 1996; 24: 129–34. 225. Truss MC et al. Cyclic nucleotide phosphodiesterase (PDE) isoenzymes in the human detrusor smooth muscle. I. Identification and characterization. Urol Res 1996; 24: 123–8. 226. Truss MC et  al. Effects of various phosphodiesterase-inhibitors, forskolin, and sodium nitroprusside on porcine detrusor smooth muscle tonic responses to muscarinergic stimulation and cyclic nucleotide levels in vitro. Neurourol Urodyn 1996; 15: 59–70. 227. Qiu Y et al. Identification and functional study of phosphodiesterases in rat urinary bladder. Urol Res 2001; 29: 388–92. 228. Qiu Y et al. Cyclic nucleotide phosphodiesterases in rabbit detrusor smooth muscle. Urology 2002; 59: 145–9. 229. Morley DJ et  al. Distribution of phosphodiesterase I in normal human tissues. J Histochem Cytochem 1987; 35: 75–82. 230. Gillespie JI et  al. Expression of neuronal nitric oxide synthase (nNOS) and nitric-oxide-induced changes in cGMP in the urothelial layer of the guinea pig bladder. Cell Tissue Res 2005; 321: 341–51. 231. Longhurst PA et al. The role of cyclic nucleotides in guinea-pig bladder contractility. Br J Pharmacol 1997; 121: 1665–72. 232. Kaiho Y, Nishiguchi J, Kwon DD et al. The effects of a type 4 phosphodiesterase inhibitor and the muscarinic cholinergic antagonist tolterodine tartrate on detrusor overactivity in female rats with bladder outlet obstruction. BJU Int 2008; 101(5): 615–20. 233. Nishiguchi J, Kwon DD, Kaiho Y et al. Suppression of detrusor overactivity in rats with bladder outlet obstruction by a type 4 phosphodiesterase inhibitor. BJU Int 2007; 99(3): 680–6. 234. GillespieJI. Phosphodiesterase-linked inhibition of nonmicturition activity in the isolated bladder. BJU Int 2004; 93(9): 1325–32. 235. Martínez-Salamanca JI, Carballido J, Eardley I et  al. Phosphodiesterase type 5 inhibitors in the management of nonneurogenic male lower urinary tract symptoms: Critical analysis of current evidence. Eur Urol 2011; 60(3): 527–35. 236. Andersson KE, de Groat WC, McVary KT et  al. Tadalafil for the treatment of lower urinary tract symptoms secondary to benign prostatic hyperplasia: Pathophysiology and mechanism(s) of action. Neurourol Urodyn 2011; 30(3): 292–301. 237. Giuliano F, Ückert S, Maggi M et  al. The mechanism of action of phosphodiesterase type 5 inhibitors in the treatment of lower urinary tract symptoms related to benign prostatic hyperplasia. Eur Urol 2013; 63(3): 506–16. 238. Gacci M, Corona G, Salvi M et al. A systematic review and metaanalysis on the use of phosphodiesterase 5 inhibitors alone or in combination with alpha-blockers for lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol 2012; 61: 994–1003. 239. Tanagho EA, Miller ER. Initiation of voiding. Br J Urol 1970; 42: 175–83. 240. Persson K et al. Co-existence of nitrergic, peptidergic and acetylcholine esterase-positive nerves in the pig lower urinary tract. J Auton Nerv Syst 1995; 52: 225–36. 241. Persson K et  al. Nitrergic and cholinergic innervation of the rat lower urinary tract after pelvic ganglionectomy. Am J Physiol 1998; 274: R389–97. 242. Johns A. Alpha- and beta-adrenergic and muscarinic cholinergic binding sites in the bladder and urethra of the rabbit. Can J Physiol Pharmacol 1983; 61: 61–6. 243. Taki N et al. Evidence for predominant mediation of alpha1-adrenoceptor in the tonus of entire urethra of women. J Urol 1999; 162: 1829–32. 244. Persson CG, Andersson KE. Adrenoceptor and cholinoceptor mediated effects in the isolated urethra of cat and guinea-pig. Clin Exp Pharmacol Physiol 1976; 3: 415–26. 245. Andersson KE et  al. Effects of acetylcholine, noradrenaline, and prostaglandins on the isolated, perfused human fetal urethra. Acta Physiol Scand 1978; 104: 394–401.

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246. Ek A et  al. The effects of norephedrine and bethanechol on the human urethral closure pressure profile. Scand J Urol Nephrol 1978; 12: 97–104. 247. Ulmsten U, Andersson KE. The effects of emeprone on intravesical and intra-urethral pressure in women with urgency incontinence. Scand J Urol Nephrol 1977; 11: 103–9. 248. Mattiasson A et  al. Adrenoceptors and cholinoceptors controlling noradrenaline release from adrenergic nerves in the urethra of rabbit and man. J Urol 1984; 131: 1190–5. 249. Yamanishi T et  al. The role of M2 muscarinic receptor subtypes mediating contraction of the circular and longitudinal smooth muscle of the pig proximal urethra. J Urol 2002; 168: 308–14. 250. Gosling JA et al. The autonomic innervation of the human male and female bladder neck and proximal urethra. J Urol 1977; 118: 302–5. 251. Ek A et  al. Adrenergic and cholinergic nerves of the human urethra and urinary bladder. A histochemical study. Acta Physiol Scand 1977; 99: 345–52. 252. Alm P et al. Nitric oxide synthase-immunoreactive, adrenergic, cholinergic, and peptidergic nerves of the female rat urinary tract: A comparative study. J Auton Nerv Syst 1995; 56: 105–14. 253. Persson K et  al. Morphological and functional evidence against a sensory and sympathetic origin of nitric oxide synthase-containing nerves in the rat lower urinary tract. Neuroscience 1997; 77: 271–81. 254. Levin RM, Wein AJ. Quantitative analysis of alpha and beta adrenergic receptor densities in the lower urinary tract of the dog and the rabbit. Invest Urol 1979; 17: 75–7. 255. Latifpour J et al. Autonomic receptors in urinary tract: Sex and age differences. J Pharmacol Exp Ther 1990; 253: 661–7. 256. Ek A et al. Adrenoceptor and cholinoceptor mediated responses of the isolated human urethra. Scand J Urol Nephrol 1977; 11: 97–102. 257. Appell RA et al. The effects of epidural anesthesia on the urethral closure pressure profile in patients with prostatic enlargement. J Urol 1980; 124: 410–1. 258. Furuya S et  al. Alpha-adrenergic activity and urethral pressure in prostatic zone in benign prostatic hypertrophy. J Urol 1982; 128: 836–9. 259. Brading AF et  al. Alpha1-adrenoceptors in urethral function. Eur Urol 1999; 36(Suppl 1): 74–9. 260. Nasu K et al. Quantification and distribution of alpha1-adrenoceptor subtype mRNAs in human proximal urethra. Br J Pharmacol 1998; 123: 1289–93. 261. Daniels DV et  al. Human cloned alpha1A-adrenoceptor isoforms display alpha1L-adrenoceptor pharmacology in functional studies. Eur J Pharmacol 1999; 370: 337–43. 262. Fukasawa R et al. The alpha1L-adrenoceptor subtype in the lower urinary tract: A comparison of human urethra and prostate. Br J Urol 1998; 82: 733–7. 263. Chai TC et  al. Specificity of the American Urological Association voiding symptom index: Comparison of unselected and selected samples of both sexes. J Urol 1993; 150: 1710–3. 264. Lepor H, Machi G. Comparison of AUA symptom index in unselected males and females between fifty-five and seventy-nine years of age. Urology 1993; 42: 36–40. 265. Lepor H, Theune C. Randomized double-blind study comparing the efficacy of terazosin versus placebo in women with prostatism-like symptoms. J Urol 1995; 154: 116–8. 266. Nordling J et al. Effects of clonidine (Catapresan) on urethral pressure. Invest Urol 1979; 16: 289–91. 267. Werkstrom V et al. NANC transmitters in the female pig urethra— Localization and modulation of release via alpha 2-adrenoceptors and potassium channels. Br J Pharmacol 1997; 121: 1605–12. 268. Levin RM et al. Identification of receptor subtypes in the rabbit and human urinary bladder by selective radio-ligand binding. J Urol 1988; 139: 844–8. 269. Morita T et al. Function and distribution of beta3-adrenoceptors in rat, rabbit and human urinary bladder and external urethral sphincter. J Smooth Muscle Res 2000; 36: 21–32.

270. Laval KU et al. Effects of beta-adrenergic stimulating and blocking agents on the dynamics of the human bladder outlet. Urol Int 1978; 33: 366–9. 271. Rao MS et al. Clinical import of beta-adrenergic activity in the proximal urethra. J Urol 1980; 124: 254–5. 272. Vaidyanathan S et  al. Beta-adrenergic activity in human proximal urethra: A study with terbutaline. J Urol 1980; 124: 869–71. 273. Thind P et  al. The influence of beta-adrenoceptor and muscarinic receptor agonists and antagonists on the static urethral closure function in healthy females. Scand J Urol Nephrol 1993; 27: 31–8. 274. Ishiko O et  al. Beta(2)-adrenergic agonists and pelvic floor exercises for female stress incontinence. Int J Gynaecol Obstet 2000; 71: 39–44. 275. Morita T et al. Effects of clenbuterol on rabbit vesicourethral muscle contractility. J Smooth Muscle Res 1995; 31: 119–27. 276. Slack BE, Downie JW. Pharmacological analysis of the responses of the feline urethra to autonomic nerve stimulation. J Auton Nerv Syst 1983; 8: 141–60. 277. Burnett AL. Nitric oxide control of lower genitourinary tract functions: A review. Urology 1995; 45: 1071–83. 278. Schroder A et al. Carbon monoxide relaxes the female pig urethra as effectively as nitric oxide in the presence of YC-1. J Urol 2002; 167: 1892–6. 279. Peng W et al. Regulation of Ca(2+)-activated K+ channels in pulmonary vascular smooth muscle cells: Role of nitric oxide. J Appl Physiol 1996; 81: 1264–72. 280. Robertson BE et  al. cGMP-dependent protein kinase activates Ca-activated K channels in cerebral artery smooth muscle cells. Am J Physiol 1993; 265: C299–303. 281. Bolotina VM et al. Nitric oxide directly activates calcium-dependent potassium channels in vascular smooth muscle. Nature 1994; 368: 850–3. 282. Koh SD et al. Nitric oxide activates multiple potassium channels in canine colonic smooth muscle. J Physiol 1995; 489 (Pt 3): 735–43. 283. Warner TD et  al. Effects of cyclic GMP on smooth muscle relaxation. Adv Pharmacol 1994; 26: 171–94. 284. Ito Y, Kimoto Y. The neural and non-neural mechanisms involved in urethral activity in rabbits. J Physiol 1985; 367: 57–72. 285. Persson K et al. Functional characteristics of urinary tract smooth muscles in mice lacking cGMP protein kinase type I. Am J Physiol Regul Integr Comp Physiol 2000; 279: R1112–20. 286. Waldeck K et al. Mediators and mechanisms of relaxation in rabbit urethral smooth muscle. Br J Pharmacol 1998; 123: 617–24. 287. Smet PJ et al. Distribution of nitric oxide synthase-immunoreactive nerves and identification of the cellular targets of nitric oxide in guinea-pig and human urinary bladder by cGMP immunohistochemistry. Neuroscience 1996; 71: 337–48. 288. Sergeant GP et al. Role of IP(3) in modulation of spontaneous activity in pacemaker cells of rabbit urethra. Am J Physiol Cell Physiol 2001; 280: C1349–56. 289. McCloskey KD, Gurney AM. Kit positive cells in the guinea pig bladder. J Urol 2002; 168: 832–6. 290. Werkstrom V et al. Inhibitory innervation of the guinea-pig urethra; roles of CO, NO and VIP. J Auton Nerv Syst 1998; 74: 33–42 291. Werkström V, Svensson A, Andersson KE, Hedlund P. Phosphodiesterase 5 in the female pig and human urethra: Morphological and functional aspects. BJU Int 2006; 98(2): 414–23. 292. McVary KT et  al. Sildenafil citrate improves erectile function and urinary symptoms in men with erectile dysfunction and lower urinary tract symptoms associated with benign prostatic hyperplasia: A randomized, double-blind trial. J Urol 2007; 177: 1071–7. 293. McVary KT, Roehrborn CG, Kaminetsky JC et al. Tadalafil relieves lower urinary tract symptoms secondary to benign prostatichy perplasia. J Urol 2007; 177(4): 1401–7. 294. Werkstrom V et al. Carbon monoxide-induced relaxation and distribution of haem oxygenase isoenzymes in the pig urethra and lower oesophagogastric junction. Br J Pharmacol 1997; 120: 312–8.

Pharmacology of the lower urinary tract 295. Ho KM et al. Co-localization of carbon monoxide and nitric oxide synthesizing enzymes in the human urethral sphincter. J Urol 1999; 161: 1968–72. 296. Naseem KM et al. Relaxation of rabbit lower urinary tract smooth muscle by nitric oxide and carbon monoxide: Modulation by hydrogen peroxide. Eur J Pharmacol 2000; 387: 329–35. 297. Sjogren C et al. Effects of vasoactive intestinal polypeptide on isolated urethral and urinary bladder smooth muscle from rabbit and man. J Urol 1985; 133: 136–40. 298. Dalziel HH, Westfall DP. Receptors for adenine nucleotides and nucleosides: Subclassification, distribution, and molecular characterization. Pharmacol Rev 1994; 46: 449–66. 299. Callahan SM, Creed KE. Electrical and mechanical activity of the isolated lower urinary tract of the guinea-pig. Br J Pharmacol 1981; 74: 353–8. 300. Ohnishi N et al. Role of ATP and related purine compounds on urethral relaxation in male rabbits. Int J Urol 1997; 4: 191–7. 301. Pinna C et  al. ATP and vasoactive intestinal polypeptide relaxant responses in hamster isolated proximal urethra. Br J Pharmacol 1998; 124: 1069–74.

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302. Patacchini R, Santicioli P, Giuliani S, Maggi CA. Hydrogen sulfide (H2S) stimulates capsaicin-sensitive primary afferent neurons in the rat urinary bladder. Br J Pharmacol 2004; 142(1): 31–4. 303. Patacchini R, Santicioli P, Giuliani S, Maggi CA. Pharmacological investigation of hydrogen sulfide (H2S) contractile activity in rat detrusor muscle. Eur J Pharmacol 2005; 509(2–3): 171–7. 304. Streng T, Axelsson HE, Hedlund P et al. Distribution and function of the hydrogen sulfide-sensitive TRPA1 ion channel in rat urinary bladder. Eur Urol 2008; 53(2): 391–9. 305. Gratzke C, Streng T, Waldkirch E et al. Transient receptor potential A1 (TRPA1) activity in the human urethra—Evidence for a functional role for TRPA1 in the outflow region. Eur Urol 2009; 55(3): 696–704. 306. Fernandes VS, Ribeiro AS, Martínez MP et al. Endogenous hydrogen sulfide has a powerful role in inhibitory neurotransmission to the pig bladder neck. J Urol 2013; 189(4): 1567–73.

3 Integrated physiology of the lower urinary tract Naoki Yoshimura, Jeong Yun Jeong, Dae Kyung Kim, and Michael B. Chancellor

Introduction The urinary bladder and its outlet, the urethra, serve two main functions: (1) storage of urine without leakage and (2) periodic release of urine. These two functions are dependent on central as well as peripheral autonomic and somatic neural pathways.1–6 Since the lower urinary tract switches in an all-or-none manner between storage and elimination of urine, many of the neural circuits controlling voiding exhibit phasic patterns of activity rather than tonic patterns occurring in autonomic pathways to other viscera. Micturition is also a special visceral mechanism because it is dependent on voluntary control, which requires the participation of higher centers in the brain, whereas many other visceral functions are regulated involuntarily. Because of these complex neural regulations, the central and peripheral nervous control of the lower urinary tract is susceptible to a variety of neurologic disorders. This chapter summarizes clinical and experimental data to describe the complexity of the peripheral and central nervous systems controlling urine storage and elimination in the lower urinary tract.

Peripheral nervous system Efferent pathways of the lower urinary tract During urine storage, the bladder outlet is closed and detrusor (bladder smooth muscle) is quiescent, allowing intravesical pressure to remain low over a wide range of bladder volumes. On the other hand, during voluntary voiding, the initial event is a relaxation of striated urethral muscles, followed by a detrusor muscle contraction. These two different activities are mediated by three sets of peripheral nerves: parasympathetic (pelvic), sympathetic (hypogastric), and somatic (pudendal) nerves (Figure 3.1).7

Dorsal root ganglion

Th11 – L2

Inferior mesenteric ganglion

Hypogastric nerve (sympathetic) S2 – S4

Dorsal root ganglion

Pelvic nerve (parasympathetic) Pelvic ganglion Pudendal nerve (somatic)

Urinary bladder

Afferent Efferent

Bladder neck & internal sphincter (smooth muscle) External urethral sphincter (striated muscle)

Figure 3.1 Sympathetic, parasympathetic, and somatic innervation of the lower urinary tract. Sympathetic preganglionic pathways emerge from the thoracolumbar cord (Th11–L 2) and pass to the inferior mesenteric ganglia. Preganglionic and postganglionic sympathetic axons then travel in the hypogastric nerve to the pelvic ganglia and lower urinary tract. Parasympathetic preganglionic axons that originate in the sacral cord (S2–S 4) pass in the pelvic nerve to ganglion cells in the pelvic ganglia, and postganglionic axons innervate the bladder and urethral smooth muscle. Sacral somatic pathways are contained in the pudendal nerve, which provides an innervation to the external urethral sphincter striated muscles. Afferent axons from the lower urinary tract are carried in the abovementioned three nerves. (Reproduced from Yoshimura N, de Groat WC, Int J Urol, 4, 111–25, 1997. With permission.)

1. Pelvic parasympathetic nerves, which arise at the sacral level of the spinal cord, provide an excitatory input to the bladder and an inhibitory input to the urethral smooth muscle to eliminate urine.

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2. Hypogastric sympathetic nerves, which arise at the upper lumbar level of the spinal cord, excite the internal sphincter smooth muscle and inhibit the detrusor to store urine. 3. Pudendal somatic nerves, which arise at the sacral level of the spinal cord, elicit excitatory effects to the external sphincter striated muscle to facilitate urine storage in the bladder.

subtypes are found in bladder smooth muscle. Studies of subtype-selective receptor knockout mice revealed that the M3 subtype is the major receptor for bladder contractions.16,17 The postganglionic parasympathetic input to the urethra elicits inhibitory effects mediated at least in part via the release of nitric oxide (NO), which directly relaxes the urethral smooth muscle.18–24 Several neuropeptides, including vasoactive intestinal polypeptide (VIP) and neuropeptide Y (NPY), are also released at postganglionic neurons, which may function as modulators of neural transmission.25,26 Thus, the excitation of sacral parasympathetic efferent pathways induces a bladder contraction and urethral relaxation to promote bladder emptying during voiding (Figure 3.2).

Parasympathetic pathways Parasympathetic preganglionic neurons (PGNs) innervating the lower urinary tract are located in the lateral part of the sacral intermediate gray matter in a region termed sacral parasympathetic nucleus (SPN).1,8–11 Para­ sympathetic PGNs send axons through the ventral roots to peripheral ganglia, where they release the e­ xcitatory transmitter acetylcholine (ACh), which activates postsynaptic ganglionic-type nicotinic receptors.2,6,7 Parasympathetic postganglionic neurons in humans are located in the detrusor wall layer, and not as an independent ganglion, which is known as the major pelvic ganglion in the rodent. Parasympathetic postganglionic nerve terminals release ACh, which can excite various muscarinic receptors in bladder smooth muscles.12–15 Both M2 and M3 muscarinic

Sympathetic pathways Sympathetic outflow from the rostral lumbar spinal cord provides a noradrenergic excitatory and inhibitory input to the bladder and urethra18 to facilitate urine storage. The peripheral sympathetic pathways follow a complex route that passes through the sympathetic chain ganglia to the interior mesenteric ganglia and then via the hypogastric nerves to the pelvic ganglia (Figure 3.1).27 Sympathetic Efferent

Afferent Visceral/EUS Cutaneous perineal Muscle spindle Genital/visceral overlap

SPN Onuf’s nucleus MCP

Levator ani motor neurons

Lissauer’s tract LCP

Figure 3.2 Neuroanatomic distribution of primary afferent and efferent components of storage and micturition reflexes within the sacral spinal cord. Afferent components are shown on the left side, whereas efferent components are shown on the right side. Both components are distributed bilaterally and thus overlap extensively. Visceral afferent components represent bladder and urethral afferents contained in the pelvic nerve. External urethral sphincter (EUS) afferents have the same distribution as visceral afferents. Genital (glans penis/ clitoris) afferent fibers are contained in the pudendal nerves. Cutaneous perineal afferent components represent afferent fibers that innervate the perineal skin and that are contained in the pudendal nerve. Muscle spindle afferent components represent 1α/β afferent fibers contained in the levator ani nerve that innervates muscle spindles in the levator ani muscle. SPN, sacral parasympathetic nucleus; LCP, lateral collateral afferent projection; MCP, medial collateral afferent projection. (Reproduced from de Groat WC et al., Scand J Urol Nephrol Suppl, 35–43, 2001. With permission.)

Integrated physiology of the lower urinary tract PGNs make synaptic connections with postganglionic neurons in the inferior mesenteric ganglion as well as with postganglionic neurons in the paravertebral ganglia and pelvic ganglia.1,2,28,29 Ganglionic transmission in sympathetic pathways is also mediated by ACh acting on ganglionic-type nicotinic receptors. Sympathetic postganglionic terminals that release norepinephrine elicit contractions of bladder base and urethral smooth muscle and relaxation of the bladder body to facilitate urine storage.1,2,18,30

Somatic pathways Somatic efferent motor neurons that innervate the external striated urethral sphincter muscle and the pelvic floor musculature are located along the lateral border of the ventral horn in the sacral spinal cord, commonly referred to as the Onuf’s nucleus (Figure 3.2).31 Sphincter motor neurons also exhibit transversely oriented dendritic bundles that project laterally into the lateral funiculus, dorsally into the intermediate gray matter, and dorsomedially toward the central canal. Somatic nerve terminals release ACh, which acts on skeletal muscle–type nicotinic receptors to induce a muscle contraction (Figure 3.1). Combined activation of sympathetic and somatic pathways elevates bladder outlet resistance and contributes to urinary continence. This condition is usually found when one feels a strong desire to void in the storage phase, being evident with increased external sphincter electromyographic (EMG) activity in the urodynamic study.

myelinated Aδ-fiber afferents, which respond to bladder distension (Figure 3.3).4,33,35 Although sensing bladder volume is of particular relevance during urine storage, afferent discharges that occur during a bladder contraction have an important reflex function and appear to reinforce the central drive that maintains bladder contractions.36 Afferent nerves that respond to both distension and contraction, that is, in-series tension receptors, have been identified in the pelvic and hypogastric nerves of cats and rats.37–40 Afferents that respond only to bladder filling have been identified in the rat bladder,41 and appear to be volume receptors, possibly sensitive to stretch of the mucosa. In the cat bladder, some in-series tension receptors may also respond to bladder stretch.42 In rat, there is now evidence that many C-bladder afferents are volume receptors that do not Cortical diencephalic mechanisms (+/–) Pontine micturition center x Spinal tract neurons

Admyelinated afferent (Rat) Capsaicin block

Spinal efferent mechanisms

Afferent pathways of the lower urinary tract The pelvic, hypogastric, and pudendal nerves also contain afferent axons that transmit information from the lower urinary tract to the lumbosacral spinal cord.7,32,33 The primary afferent neurons of the pelvic and pudendal nerves are contained in sacral dorsal root ganglia, whereas afferent innervation in the hypogastric nerves arises in the rostral lumbar dorsal root ganglia (Figure 3.1). The central axons of the dorsal root ganglion neurons carry the sensory information from the lower urinary tract to second-order neurons in the spinal cord.10,11,31,32 Visceral afferent fibers of the pelvic11 and pudendal31 nerves enter the cord and travel rostrocaudally within Lissauer’s tract (Figure 3.2). Sensory information, including the feeling of bladder fullness or bladder pain, is conveyed to the spinal cord via afferent axons in the pelvic and hypogastric nerves.33,34 Pelvic nerve afferents, which monitor the volume of the bladder and the amplitude of the bladder contractions, consist of small myelinated Aδ and unmyelinated C axons. Electrophysiologic studies in cats and rats have revealed that the normal micturition reflex is mediated by

35

Cold stimulation Unmyelinated C-afferent

Bladder

Ganglia External urethral sphincter

Figure 3.3 The central reflex pathways that regulate micturition in the cat and rat. In animals such as cats and rats with an intact neuraxis, micturition is initiated by a supraspinal reflex pathway passing through the pontine micturition center (PMC) in the brainstem. The pathway is triggered by myelinated afferents (Aδ) connected to tension receptors in the bladder wall (Bladder). Spinal tract neurons carry information to the brain. PMC is controlled by excitatory and inhibitory pathways (+/−) in cortical and diencephalic mechanisms. In spinalized animals, connection of the brainstem and the sacral spinal cord is interrupted (X) and micturition is initially blocked. In animals with chronic spinal cord injuries (SCI), a spinal reflex mechanism emerges, which is triggered by unmyelinated (C-fiber) bladder afferents. The C-fiber reflex pathway is usually weak or undetectable in animals with an intact nervous system. Capsaicin blocks the C-fiber reflex in chronic SCI animals. Cold stimulation also activates the C-fiber-mediated micturition reflex. However, following SCI voiding, reflex in the rat is still triggered by myelinated Aδ afferents connecting to spinal efferent mechanisms (rat), whereas voiding reflex in the cat is totally abolished by capsaicin treatment.

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Textbook of the Neurogenic Bladder

respond to bladder contractions, a property that distinguishes them from in-series tension receptors.41 During inflammation and neuropathic conditions, there is recruitment of C-fiber bladder afferents, which form a new functional afferent pathway that can cause bladder overactivity and bladder pain (Figure 3.3).43 In cats, C-fiber afferents have high thresholds and are usually unresponsive to mechanical stimuli such as bladder distension and therefore have been termed silent C fibers. However, many of these fibers do respond to chemical, noxious, or cold stimuli.34,44,45 Previous studies in the rat using patch clamp techniques revealed that C-fiber afferent neurons are relatively unexcitable because of the presence of high-threshold, tetrodotoxin-resistant sodium channels and low-threshold A-type potassium channels.46 Activation of C-fiber afferents by chemical irritation induces detrusor overactivity, which is blocked by administration of capsaicin, a neurotoxin of C-fiber afferents.1,47,48 However, since capsaicin does not block normal micturition in cats as well as rats, it appears that C-fiber afferents are not essential for normal conscious voiding (Figure 3.3).1,47,49–51 Afferent fibers innervating the urethra are also important to modulate lower urinary tract function (Figure 3.4). Talaat52 has reported that in dogs urethral afferent fibers in the pelvic and pudendal nerves are sensitive to the passage of urine and that, during saline flow through the urethra, pudendal nerve afferents were activated at a much lower pressure in comparison to pelvic nerve afferents, discharges of which were induced by high-pressure flow that caused a distension of the urethra. High thresholds (over 60 cm H2O) for activation of urethral afferents in the pelvic nerves were also identified in rats.53 It has also been documented that conduction velocities of cat pudendal nerve afferent fibers responding to electrical stimulation of the urethra are approximately twice as fast (45 m/s) as pelvic nerve afferent fibers responding to the same stimulation (20 m/s).54 In addition, urethral afferents in the pudendal and pelvic nerves of the cat seem to have different receptor properties. Pudendal nerve afferents responding to urine flow, some of which may be connected to Pacinian corpuscle-like structures in the muscle layers and the deeper parts of urethral mucosa, exhibited a slowly adapting receptors firing pattern,55 whereas small myelinated or unmyelinated urethral afferents in the hypogastric nerves and myelinated urethral afferents in the pelvic nerves responding to urine flow or urethral distension are reportedly connected to rapidly adapting receptors.39,56 Nociceptive C fibers are also present in pelvic and pudendal nerves innervating the urethra.57,58 Previous studies have shown that C-fiber afferent fibers identified with positive staining of calcitonin gene-related peptide (CGRP) or substance P were found in the subepithelium, submucosa, and muscular layer in all portions of the urethra.59,60 Moreover, the activation of these urethral C

PMC (+) (+) (–)

(+) Detrusor

(+)

Urine flow Urethra

(+) (+)

EUS

Spinal cord

Electrical stimulation

Figure 3.4 Urethra-to-bladder reflexes. Activity in afferent nerves (dashed lines) from the urethra can facilitate parasympathetic efferent outflow to the detrusor via a supraspinal pathway passing through the pontine micturition center (PMC) as well as by a spinal reflex pathway. Afferent input from the external urethral sphincter (EUS) can inhibit parasympathetic outflow to the detrusor via a spinal reflex circuit. Electrical stimulation of motor axons in the S1 ventral root elicits EUS contractions and EUS afferent firing, which in turn inhibits reflex bladder activity; (+) excitatory and (−) inhibitory mechanisms. (Reproduced from de Groat WC et al., Scand J Urol Nephrol Suppl, 35–43, 2001. With permission.)

fibers induced by urethral capsaicin application elicited nociceptive behavioral responses, which disappeared after pudendal nerve transection,61 and increased EMG activity of pelvic floor striated muscle, including the external urethral sphincter (EUS).57,58 It is also known that urethral C-fiber activation by capsaicin suppressed reflex bladder contractions.62

Interaction between urothelium and afferent nerves There is increasing evidence that bladder epithelial cells play an important role in modulation of bladder activity by responding to local chemical and mechanical stimuli and then sending chemical signals to the bladder afferent nerves, which then convey information to the central nervous system (Figure 3.5).63 It has been shown that urothelial cells express nicotinic, muscarinic, tachykinin, and adrenergic receptors1,14 as well as vanilloid receptors,64 and can respond to mechanical as well as chemical stimuli and in turn release chemicals such as adenosine triphosphate (ATP), prostaglandins, and NO (Figure 3.5).63,65–67 These agents are known to have excitatory and inhibitory actions on afferent neurons that are located close to or in

Integrated physiology of the lower urinary tract

37

Bladder afferent nerve terminal High K+ low pH irritants

R

TRPV1 P2X3

trkA

trkA Ca2+ ATP NO NGF

Stretch

Force NGF

NOS

NO

ATP

R

Urine

Urothelium

Bladder mucosa

Smooth muscle

Figure 3.5 Interactions between chemical mediators released from bladder epithelial cells and smooth muscles and afferent nerve endings in the bladder mucosa. ATP and NO can be released from the urothelium, and may sensitize the mechanoreceptors via an activation of P2X 3 and TRPV1 receptors, respectively, which respond to stretch of the mucosa during bladder distension. This mechanism can be induced by the presence of high urinary potassium concentrations, and possibly by other sensitizing solutions within the bladder lumen, such as those with high osmolality or low pH; the presence of inflammatory mediators in the tissues may also sensitize the endings. The smooth muscle can generate force that may influence some mucosal endings, and the production of nerve growth factor (NGF) is another mechanism that can influence the mechanosensitivity of the sensory ending, via the trkA receptor. NOS, nitric oxide synthase.

the urothelium.7,68,69 Studies using P2X3, an ATP receptor, in knockout mice have revealed that urothelially released ATP during bladder distension can interact with P2X3 receptors in bladder afferent fibers to modulate bladder activity, and that a loss of P2X3 receptors resulted in bladder hypoactivity.65,70 It has also been demonstrated that vanilloid receptor (TRPV1)–knockout mice exhibited reduced NO and ATP release from urothelial cells, as well as alterations in bladder function.71 The urothelium also appears to modulate contractile responses of the detrusor smooth muscle to muscarinic and other stimulation. Hawthorn et  al.72 demonstrated that in the pig bladder, there is a greater muscarinic ­receptor density in the urothelium than in the detrusor smooth muscle. Contractions of urothelium-denuded muscle strip were inhibited in the presence of a second bladder strip with an intact urothelium, but not if the second strip was denuded. Thus, the detrusor smooth muscle is sensitive to a diffusible inhibitory factor released from the urothelium. Overall, it seems that urothelial cells exhibit specific signaling properties that allow them to respond to their chemical and physical environments and engage in reciprocal communication with neighboring nerves and smooth muscles in the bladder wall.

Reflex circuitry controlling micturition Coordinated activities of the peripheral nervous system innervating the bladder and urethra during urine storage and voiding depend on multiple reflex pathways organized in the brain and spinal cord. The central pathways controlling lower urinary tract function are organized as on–off switching circuits that maintain a reciprocal relationship between the urinary bladder and urethral outlet.1,69,73 The principal reflex components of these switching circuits are listed in Table 3.1 and illustrated in Figure 3.6.

Storage phase of the bladder The bladder functions as a low-pressure reservoir during urine storage. In both humans and animals, bladder pressures remain low and relatively constant when bladder volume is below the threshold for inducing voiding (Figure  3.7). The accommodation of the bladder to increasing volumes of urine is primarily a passive phenomenon dependent on the intrinsic properties of the vesical smooth muscle and the quiescence of the parasympathetic efferent pathway.1,4,7 The bladder-to-sympathetic

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Textbook of the Neurogenic Bladder Table 3.1 Reflexes to the lower urinary tract Afferent pathways

Efferent pathways

Central pathways

Urine storage Low-level vesical afferent activity (pelvic nerve)

1. External sphincter contraction (somatic nerves)

Spinal reflexes

2. Internal sphincter contraction (sympathetic nerves) 3. Detrusor inhibition (sympathetic nerves) 4. Ganglionic inhibition (sympathetic nerves) 5. Sacral parasympathetic outflow inactive

Micturition

High-level vesical afferent activity (pelvic nerve)

1. Inhibition of external sphincter activity

Spinobulbospinal

2. Inhibition of sympathetic outflow

Reflexes

3. Activation of parasympathetic outflow to the bladder 4. Activation of parasympathetic outflow to the urethra

(a) Storage reflexes

(b) Voiding reflexes

Pontine storage center

Pontine micturition center

+

Hypogastric nerve

+ Pelvic nerve

+ External sphincter

+

–

Hypogastric nerve + Contracts bladder oulet – Inhibits detrusor Urinary bladder

PAG

+

Pudendal nerve

Urinary bladder Internal sphincter

+ Pelvic nerve

–

+ Contracts detrusor – Inhibits bladder outlet External sphincter

reflex also contributes as a negative feedback for urine storage mechanism that promotes closure of the urethral outlet and inhibits neurally mediated contractions of the bladder during bladder filling (Table 3.1).74 Reflex activation of the sympathetic outflow to the lower urinary tract can be triggered by afferent activity induced by distension of the urinary bladder.1,74 This reflex response is organized in the lumbosacral spinal cord and persists after transection of the spinal cord at the thoracic levels (Figure 3.7).75 During bladder filling, the activity of the sphincter electromyogram also increases (see Figure 3.7), reflecting an

Pudendal nerve

Spinal reflex

Figure 3.6 Neural circuits controlling continence and micturition. (a) Storage reflexes. During urine storage, bladder distension produces lowlevel firing in bladder afferent pathways, which in turn stimulates (1) the sympathetic outflow to the bladder outlet (bladder base and urethra) and (2) pudendal outflow to the external sphincter muscle. These responses are elicited by spinal reflex pathways. Sympathetic firing also inhibits detrusor muscle and transmission in bladder ganglia. A region in the rostral pons (the pontine storage center) increases external urethral sphincter activity. (b) Voiding reflexes. During elimination of urine, intense bladder afferent firing activates spinobulbospinal reflex pathways passing through the pontine micturition center, which stimulate the parasympathetic outflow to the bladder and internal sphincter smooth muscle and inhibit the sympathetic and pudendal outflow to the bladder outlet. Ascending afferent input from the spinal cord may pass through relay neurons in the periaqueductal gray (PAG) before reaching the pontine micturition center. (Reproduced from Yoshimura N, de Groat WC, Int J Urol, 4, 111–25, 1997. With permission.)

increase in efferent firing in the pudendal nerve and an increase in outlet resistance that contributes to the maintenance of urinary continence. Pudendal motor neurons are activated by bladder afferent input (the guarding reflex).76 EUS motor neurons are also activated by urethral/perineal afferents in the pudendal nerve.77 This reflex may represent, in part, a continence mechanism that is activated by proprioceptive afferent input from the urethra/pelvic floor, which induces closure of the urethral outlet. These excitatory sphincter reflexes are organized in the spinal cord. It is also reported that a supraspinal urine storage center is located in the dorsolateral pons. Descending inputs

Integrated physiology of the lower urinary tract from this region activate the pudendal motor ­neurons to increase urethral resistance (see Figure 3.6).78,79

39

Normal EUS–EMG

Synergic sphincter relaxation

Cystometry

Voluntary bladder contraction Bladder volume (a)

Spinal cord injury EUS–EMG

Bladder pressure

During the urine storage phase, the bladder-to-EUS guarding reflex that triggers sphincter contractions during bladder filling could in turn activate sphincter muscle afferents, which initiate an inhibition of the parasympathetic excitatory pathway to the bladder.80 Previous studies in cats and monkeys have demonstrated that contractions of the EUS stimulate firing in muscle proprioceptive afferents in the pudendal nerve, which then activate central inhibitory mechanisms to suppress the micturition reflex (Figure 3.4).80 It is also known that stimulation of somatic afferent pathways projecting in the pudendal nerve to the caudal lumbosacral spinal cord can inhibit voiding function. The inhibition can be induced by activation of afferent input from various sites, including the penis, vagina, rectum, perineum, urethral sphincter, and anal sphincter.1,81 Electrophysiologic studies in cats showed that the inhibition was mediated by suppression of interneuronal pathways in the sacral spinal cord and also by direct inhibitory input to the parasympathetic PGNs.82 A similar inhibitory mechanism has been identified in monkeys by directly stimulating the anal sphincter muscle.83 In monkeys, at least part of the inhibitory mechanism is localized in the spinal cord because it persisted after chronic spinal cord injury (SCI).

Bladder pressure

Sphincter-to-bladder reflexes

Cystometry

Uninhibited bladder contraction Bladder volume

Emptying phase of the bladder The storage phase of the bladder can be switched to the voiding phase either involuntarily (reflexly) or voluntarily (Figure 3.7). The former is readily demonstrated in the human infant or in patients with neuropathic bladder. When bladder volume reaches the micturition threshold, afferent activity originating in bladder mechanoreceptors triggers micturition reflexes. The afferent fibers that trigger micturition in the rat and cat are small myelinated Aδ fibers (Figure 3.3).35,84,85 These bladder afferents in the pelvic nerve synapse on neurons in the sacral spinal cord, which then send their axons rostrally to a micturition center (the pontine micturition center [PMC]) in the dorsolateral pons (Figure 3.6).84–89 Activation of this center reverses the pattern of efferent outflow to the lower urinary tract, producing firing in the sacral parasympathetic pathways and inhibition of sympathetic and somatic pathways (Figure 3.6). The expulsion phase consists of an initial relaxation of the urethral sphincter followed in a few seconds by a contraction of the bladder, resulting in the flow of urine through the urethra. Relaxation of the urethral smooth muscle during micturition is mediated by activation of a parasympathetic pathway to the urethra, which triggers the release of NO,18,21 and by removal of excitatory inputs to the urethra (Figure 3.6).

Dyssynergic sphincter relaxation

(b)

Figure 3.7 Combined cystometry and external urethral sphincter electromyography (EUS–EMG) recordings comparing reflex voiding responses in a (a) normal adult and in a (b) spinal cord injury (SCI) patient. The abscissas represent bladder volume and the ordinates in cystometrograms represent bladder pressure. In panel (a), a slow infusion of fluid into the bladder induces a gradual increase of EMG activity, but no apparent changes in bladder pressure. When a voluntary voiding starts, an increase of bladder pressure (voluntary bladder contraction) is associated with a cessation of EUS–EMG activity (synergic sphincter relaxation). On the other hand, in an SCI patient (b), the reciprocal relationship between bladder and sphincter is abolished. During bladder filling, uninhibited bladder contraction occurs in association with an increase in sphincter activity (detrusor–sphincter dyssynergia). Loss of the reciprocal relationship between bladder and sphincter in SCI patients interferes with bladder emptying. (Reproduced from Yoshimura N, Progr Neurobiol, 57, 583–606, 1999. With permission.)

Studies in the rat and cat indicate that activity ascending from the spinal cord may pass through a relay center in the periaqueductal gray (PAG) before reaching the PMC (Figure 3.6).90–94 Thus, voiding reflexes depend on a spinobulbospinal pathway that passes through an integrative

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Textbook of the Neurogenic Bladder

center in the brain (Figure 3.6b). Secondary reflexes elicited by flow of urine through the urethra also facilitate bladder emptying.1,4,62 Inhibition of EUS reflex activity during micturition is dependent, in part, on supraspinal mechanisms because it is weak or absent in chronic spinal cord injured animals and humans, resulting in simultaneous contractions of bladder and urethral sphincter (i.e., detrusor sphincter dyssynergia) (Figure 3.7).75,95,96

Urethra-to-bladder reflexes It has been reported that myelinated afferents innervating the urethra could contribute to bladder emptying during the voiding phase. Barrington97,98 reported that urine flow or mechanical stimulation of the urethra with a catheter could excite afferent nerves that, in turn, facilitated reflex bladder contractions in the anesthetized cat (Figure 3.4). He proposed that this facilitatory urethra-to-bladder reflex could promote complete bladder emptying. A study in the anesthetized rat has provided additional support for Barrington’s findings.62 Measurements of reflex bladder contractions under isovolumetric conditions during continuous urethral perfusion (0.075 mL/min) revealed that the frequency of micturition reflexes was significantly reduced when urethral perfusion was stopped or following infusion of 1% lidocaine into the urethra. Intraurethral infusion of NO donors (S-nitroso-N-acetylpenicillamine [SNAP] or nitroprusside, 1–2 mmol) markedly decreased urethral perfusion pressure (≈30%) and decreased the frequency of reflex bladder contractions (45%–75%), but did not change the amplitude of bladder contractions. It was thus concluded that activation of urethral afferents during urethral perfusion could modulate the micturition reflex. Barrington also identified two components of this facilitatory urethra-to-bladder reflex during voiding. One component was activated by a somatic afferent pathway in the pudendal nerve and produced facilitation by a supraspinal mechanism involving the PMC.97 The other component was activated by a visceral afferent pathway in the pelvic nerve and produced facilitation by a spinal reflex mechanism.98 Afferent fibers that respond to urine flow in the urethra were found in the pelvic, hypogastric, and pudendal nerves, although it has been reported that the properties of urethral afferents in pelvic/hypogastric and pudendal nerves are different, as described earlier.

Spinal and supraspinal pathways involved in the micturition reflex Spinal cord In the spinal cord, afferent pathways terminate on second-order interneurons that relay information to the

brain or to other regions of the spinal cord. Since spinal reflex pathways controlling bladder and urethral activities are mediated by disynaptic or polysynaptic pathways, interneuronal mechanisms play an essential role in the regulation of lower urinary tract function. Electrophysiologic10,84,99,100 and neuroanatomic techniques101–104 have identified interneurons in the same regions of the spinal cord that receive afferent input from the bladder. As shown in Figure 3.2, horseradish peroxidase (HRP) labeling techniques in the cat revealed that afferent projections from the EUS and levator ani muscles (i.e., pelvic floor) project into different regions of the sacral spinal cord. The EUS afferent terminals are located in the superficial layers of the dorsal horn and at the base of the dorsal horn, whereas the levator ani afferents project into a region just lateral to the central canal and extending into the medial ventral horn. The EUS afferents overlap very closely with the central projections of visceral afferents in the pelvic nerve that innervate the bladder and urethra (Figure 3.2). Intracellular labeling experiments also showed that the dendritic patterns of EUS motor neurons105 and parasympathetic PGNs9 are similar. Pharmacologic experiments revealed that glutamic acid is the excitatory transmitter in these pathways. In addition, approximately 15% of interneurons located medial to the SPN in laminae V–VII make inhibitory synaptic connections with the PGN.10,106 These inhibitory neurons release γ-aminobutyric acid (GABA) and glycine. Reflex pathways that control the external sphincter muscles also utilize glutamatergic excitatory and GABAergic/glycinergic inhibitory interneuronal mechanisms. Central and spinal neural pathways controlling lower urinary tract function have also been identified by transneuronal tracing studies using neurotropic viruses such as pseudorabies virus (PRV) (Figure 3.8). PRV can be injected into a target organ and then move intra-axonally from the periphery to the central nervous system. Because PRV can be transported across many synapses it could sequentially infect all the neurons that connect directly or indirectly to the lower urinary tract.102–104 Interneurons identified by retrograde transport of PRV injected into the urinary bladder are located in the region of the SPN, the dorsal commissure (DCM), and the superficial laminae of the dorsal horn (Figure 3.8).10,102,104 A similar distribution of labeled interneurons has been noted after injection of virus into the urethra9 or the EUS,102 indicating a prominent overlap of the interneuronal pathways controlling various target organs of the lower urinary tract. The micturition reflex can be modulated at the level of the spinal cord by interneuronal mechanisms activated by afferent input from cutaneous and striated muscle targets. The micturition reflex can also be modulated by inputs from other visceral organs.1,4,7,73,84,107–110 Stimulation of afferent fibers from various regions (anus, colon/rectum,

Integrated physiology of the lower urinary tract

41

Cerebral cortex

Hypothalamus PVN MPOA Peri V.N.

Pontine micturition center Raphe nuclei

PAG

A5

VIRUS

LC

Redn.

VIRUS

DH INT PGN

Spinal interneurons

DCM

PGN

Preganglionic n.

VIRUS Postganglionic n.

VIRUS

URINARY BLADDER

Figure 3.8 Transneuronal virus tracing of the central pathways controlling the urinary bladder of the rat. Injection of pseudorabies virus (PRV) into the wall of the urinary bladder leads to retrograde transport of virus (dashed arrows) and sequential infection of postganglionic neurons, preganglionic neurons, and then various central neural circuits synaptically linked to the preganglionic neurons. At long survival times, virus can be detected with immunocytochemical techniques in neurons at specific sites throughout the spinal cord and brain, extending to the pontine micturition center in the pons (i.e., Barrington’s nucleus or the laterodorsal tegmental nucleus) and to the cerebral cortex. Other sites in the brain labeled by virus are (1) the paraventricular nucleus (PVN), medial preoptic area (MPOA), and periventricular nucleus (PVN) of the hypothalamus; (2) periaqueductal gray (PAG); (3) locus coeruleus (LC) and subcoeruleus; (4) red nucleus (Red n.); (5) medullary raphe nucleus; and (6) the noradrenergic cell group designated A5. L6 spinal cord section showing the distribution of virus labeled parasympathetic preganglionic neurons (D) and interneurons (•) in the region of the parasympathetic nucleus 72 hours after injection of the virus into the bladder. Interneurons (INT) in the dorsal commissure and the superficial laminae of the dorsal horn (DH) are also shown. The left side shows the entire population of preganglionic neurons (PGN) labeled by axonal tracing with fluorogold injected into the pelvic ganglia. The right side shows the distribution of PRV-labeled bladder PGN (D) among the entire population of FG-labeled PGN (D). Bladder PGN were labeled with PRV and FG. Composite diagram of neurons in 12 spinal sections (42 μm) is shown. (Reproduced from de Groat WC et al., Behav Brain Res, 92, 127–40, 1998. With permission.)

vagina, uterine cervix, penis, perineum, and pudendal nerve) can inhibit the firing of sacral interneurons evoked by bladder distension.83 This inhibition may occur as a result of presynaptic inhibition at primary afferent terminals or because of direct postsynaptic inhibition of the second-order neurons. Direct postsynaptic inhibition of bladder PGN can also be elicited by stimulation of somatic afferent axons in the pudendal nerve or by visceral afferents from the distal bowel.108,111

Pontine micturition center The dorsal pontine tegmentum has been firmly established as an essential control center for micturition in normal subjects. First described by Barrington,112 it has

subsequently been called “Barrington’s nucleus,” the “pontine micturition center” (PMC),113 or the “M region”78,92,114 because of its medial location. Studies in animals using brain-lesioning techniques revealed that neurons in the brainstem at the level of the inferior colliculus have an essential role in the control of the parasympathetic component of micturition.1,4,7 Removal of areas of brain above the colliculus by inter-collicular decerebration usually facilitates micturition by elimination of inhibitory inputs from more rostral centers, whereas transections at any point below the colliculi abolish micturition.115 In addition, bilateral lesions in the region of the locus coeruleus in cat or the d ­ orsolateral tegmental nucleus in rat abolish micturition, whereas electrical or chemical stimulation of this region induces a bladder contraction and a

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reciprocal relaxation of the u ­ rethra, leading to bladder emptying.78,86–89,116 In addition to providing axonal inputs to the locus coeruleus and the sacral spinal cord,117–119 neurons in the PMC also send axon collaterals to the paraventricular thalamic nucleus, which is thought to be involved in the limbic system modulation of visceral behavior.119 Some neurons in the PMC also project to the PAG region,120 which regulates many visceral activities as well as pain pathways.121 Thus, neurons in the PMC communicate with multiple supraspinal neuronal populations that may coordinate micturition with other functions. Although the circuitry in humans is uncertain, brain imaging studies have revealed increased blood flow in this region of the pons during micturition.122 In addition, it has been reported that in a case study of a multiple sclerosis patient, coordinated bladder contraction and urethral relaxation was induced by ectopic activation of a region in the dorsolateral pontine tegmentum.123 Thus the PMC appears critical for the normal micturition reflex across species. Neurons in the PMC provide direct synaptic inputs to sacral PGN, as well as to GABAergic neurons in the sacral DCM.113 The former neurons carry the excitatory outflow to the bladder, whereas the latter neurons are thought to be important in mediating an inhibitory influence on EUS motor neurons during voiding.120 As a result of these reciprocal connections, the PMC can promote coordination between the bladder and urethral sphincter.

Central pathways modulating the micturition reflex Transneuronal tracing studies using PRV injected into the lower urinary tract also identified various areas in the brain (Figure 3.8).102–104,124 Thus, central control of voiding is likely to be complex. Injection of PRV into the rat bladder labeled many areas of the brainstem, including the laterodorsal tegmental nucleus (the PMC); the medullary raphe nucleus, which contains serotonergic neurons; the locus coeruleus, which contains noradrenergic neurons; PAG; and noradrenergic cell group A5. Several regions in the hypothalamus and the cerebral cortex also exhibited virus-infected cells (Figure 3.8). Neurons in the cortex were located primarily in the medial frontal cortex. Similar brain areas were labeled after injection of virus into the urethra and urethral sphincter, suggesting that coordination between different parts of the lower urinary tract is mediated by a similar population of neurons in the brain.102–104,124 Studies in humans indicate that voluntary control of voiding is dependent on connections between the

frontal cortex and the septal/preoptic region of the hypothalamus as well as connections between the paracentral ­lobule and the brainstem.1 Lesions to these areas of cortex appear to directly increase bladder activity by ­removing cortical inhibitory control. Brain imaging studies in human volunteers have implicated both the frontal cortex and the anterior cingulate gyrus in control of m ­ icturition and have indicated that micturition is controlled predominately by the right side of the brain.113,125 Positron emission tomography (PET) scans were also used to examine which brain areas are involved in human micturition.126 In a study, when 17 right-handed male volunteers were scanned, 10 volunteers were able to micturate during scanning. Micturition was associated with increased blood flow in the right dorsomedial pontine tegmentum, the PAG, the hypothalamus, and the right inferior frontal gyrus. Decreased blood flow was found in the right anterior cingulate gyrus when urine was withheld. The other seven volunteers were not able to micturate during scanning, although they had a full bladder and tried vigorously to micturate. In this group, during these unsuccessful attempts to micturate, increased blood flow was detected in the right ventral pontine tegmentum. It has been reported that descending inputs from this area can activate the pudendal motor neurons to increase urethral resistance during urine storage in cats.80,114,127 Another study using PET scans in 11 healthy male subjects also revealed that increased brain activity related to increasing bladder volume was seen in the PAG, in the midline pons, in the mid-cingulate cortex, and bilaterally in the frontal lobe area, suggesting that the PAG receives information about bladder fullness and relays this information to areas involved in the control of bladder storage.128 The PAG has multiple connections with higher centers such as the thalamus, insula, cingulate, and prefrontal cortices. It seems that the influences from these higher centers have a role in determining when and where one may void safely. Increased blood flow also occurred in the right inferior frontal gyrus during unsuccessful attempts to micturate, and decreased blood flow occurred in the right anterior cingulate gyrus during the withholding of urine. The results suggest that the human brainstem contains specific nuclei responsible for the control of micturition, and that the cortical and pontine regions for micturition are predominantly on the right side. A PET study was also conducted in adult female volunteers to identify brain structures involved in the voluntary motor control of the pelvic floor.129 The results revealed that the superomedial precentral gyrus and the most medial portion of the motor cortex are activated during pelvic floor contraction, and the superolateral

Integrated physiology of the lower urinary tract precentral gyrus is activated during contraction of the abdominal musculature. In these conditions, significant activations were also found in the cerebellum, supplementary motor cortex, and thalamus. The right anterior cingulate gyrus was activated during sustained pelvic floor straining. Recently, functional magnetic resonance imaging (fMRI) has been popular in the study of brain activities. In the neurourologic applications, fMRI has been especially useful in studying functional brain changes associated with pelvic floor muscle contraction owing to its improved resolution compared to PET. Several fMRI studies reported strong activities of the supplementary motor area (SMA) in the motor cortex during repetitive pelvic muscle contractions in a full-bladder condition, whereas previous studies with PET were unable to record this in detail.130–132 SMA is known to be involved in motor timing and inhibition of motor control. An fMRI study combined with the MMPI (Minnesota Multiphasic Personality Inventory) reported that self-control, including self-inhibition, is related to the activity of SMA.133 In a recent series of 30 healthy volunteers (15 women, 15 men), Kuhtz-Buschbeck et  al.132 reported a strong and consistent recruitment of the SMA, with foci of peak activity located in the posterior portion of the SMA, suggesting involvement of this region in involuntary pelvic floor muscle control. They also found significant activation bilaterally in the frontal opercula, the right insular cortex, and the right supramarginal gyrus, and weaker signals in the primary motor cortex and dorsal pontine tegmentum. However, no significant gender-related difference was found. Overall, these results in animals and humans indicate that various regions in the central nervous system are necessary for voluntary control of lower urinary tract function.

Developmental changes of bladder reflexes The neural mechanisms involved in storage and elimination of urine undergo marked changes during postnatal development.134 In a postnatal period in humans, as well as animals, supraspinal neural pathways controlling lower urinary tract function are immature, and voiding is regulated by primitive reflex pathways organized in the spinal cord (Figure 3.9). In neonate animals such as rats and cats, voiding is dependent on an exteroceptive somato-bladder reflex mechanism triggered when the mother licks the genital or perineal region of the young animal. This exteroceptive perineal-to-bladder reflex is regulated by primitive reflex pathways organized in the sacral spinal

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cord (Figure 3.9). In humans, the neonatal bladder is more of a conduit of urine than a storage organ and, without control from the central nervous system, the bladder will reflexively empty into a diaper when it reaches functional capacity. Primitive reflex activities organized in the spinal cord such as perineal-to-bladder reflexes are also observed in infants.99 Previous studies have also reported that bladder-cooling reflexes are positive in neurologically normal infants and children about age 4 years.135 The bladder ice water cooling test is performed by quickly instilling up to 100 mL of 4°C sterile saline. The normal adult can maintain a stable bladder without uninhibited bladder contractions. The bladder cooling response is triggered by activation of cold receptors within the bladder wall supplied by unmyelinated C-fiber afferents, and organized by segmental spinal reflex pathways.45,136 Overall, it appears that during a postnatal period, primitive reflex activities organized in the spinal cord such as perineal-bladder reflexes or C-fiber-mediated cooling reflexes are dominant because of immature control of the central nervous system (Figure 3.9). However, transneuronal tracing studies using PRV have shown that micturition reflex pathways in the spinal cord and brain are already connected anatomically at birth, although voiding in neonatal rats does not depend on neural mechanisms in the brain.104 When PRV was injected into the bladder of 2- and 10-day-old rat pups, the labeled neurons were found in various sites in the brain, such as the PMC, the nucleus raphes magnus, A5 and A7 regions, parapyramidal reticular formation, the PAG, locus coeruleus, the lateral hypothalamus, medial preoptic area, and the frontal cortex (Figure 3.8).104 Thus, even in neonatal animals, supraspinal pathways may already be connected, but may either be nonfunctioning or functioning in an inhibitory manner to suppress the spinobulbospinal micturition reflex, allowing micturition to be induced by primitive spinal reflex mechanisms.134 As the central nervous system matures during the postnatal period, reflex voiding is brought under voluntary control, which originates in the higher center of the brain and, at the same time, primitive spinal reflex activities such as perineal-to-bladder reflexes or C-fibermediated cooling reflexes are masked (Figure 3.9).134 Electrophysiologic studies using patch-clamp recording techniques in rat spinal cord slice preparations indicate that developmental changes in sacral parasympathetic pathways are due in part to alterations in excitatory synaptic transmission between interneurons and PGNs.100 However, the primitive neonatal micturition reflexes such as positive bladder cooling responses and/or spinal perineal-to-bladder reflexes could be unmasked by pathologic processes that disturb the descending neuronal control of normal voiding, such as SCI (Figures 3.3 and 3.9).99,134

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(a)

At birth

• Human immature • Animals not functional

References

Cortical diencephalic mechanisms

Pontine micturition center

Spinal tract neurons Spinal efferent mechanisms

A afferent C afferent

Cold stimulation Perineal stimulation

Bladder

Ganglia

(b) Adults

Cortical diencephalic mechanisms

Maturation

Pontine micturition center

Spinal efferent mechanisms

Spinal tract neurons

A afferent C afferent

Cold stimulation Perineal stimulation Ganglia

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Figure 3.9 Organization of micturition reflex pathways in (a) postnatal and (b) adult periods. (a) Since in a postnatal period in humans, as well as animals, supraspinal neural pathways controlling lower urinary tract function are immature, voiding is regulated by primitive reflex pathways organized in the spinal cord. In neonate animals such as rats and cats, voiding is dependent on an exteroceptive somato-bladder reflex mechanism triggered when the mother licks the genital or perineal region of the young animal (perineal stimulation). Similar reflexes are also observed in infants. Bladder cooling reflexes mediated by C-fiber bladder afferents are positive in neurologically normal infants (cold stimulation). (b) When the central nervous system matures in adults (Maturation), reflex voiding is brought under voluntary control, which originates in the higher center of the brain and, at the same time, primitive spinal reflex activities such as perineal-bladder reflexes or C-fiber-mediated cooling reflexes are masked. However, the primitive neonatal micturition reflexes could be unmasked by pathologic processes that disturb the descending neuronal control of normal voiding, such as spinal cord injury (also see Figure 3.3).

307. de Groat WC, Booth AM, Yoshimura N. Neurophysiology of micturition and its modification in animal models of human disease. In: Maggi CA, ed. Nervous Control of the Urogenital System: The Autonomic Nervous System, Vol. 3. London, United Kingdom: Harwood Academic Publishers, 1993: 227–90. 308. de Groat WC, Booth AM. Synaptic transmission in pelvic ganglia. In: Maggi CA, ed. Nervous Control of the Urogenital System: The Autonomic Nervous System, Vol. 3. London, United Kingdom: Harwood Academic Publishers, 1993: 291–347. 309. Van Arsdalen K, Wein AJ. Physiology of micturition and continence. In: Krane RJ, Siroky M, eds. Clinical Neurourology. New York: Little, Brown and Company, 1991: 25–82. 310. Torrens M, Morrison JFB. The Physiology of the Lower Urinary Tract. Berlin, Germany: Springer-Verlag, 1987. 311. Chai TC, Steers WD. Neurophysiology of micturition and continence. Urol Clin North Am 1996; 23: 221–36. 312. Chancellor MB, Yoshimura N. Physiology and pharmacology of the bladder and urethra. In: Walsh PC, Retik AB, Vaughan C, Wein A, eds. Campbell’s Urology, Vol. 2. Philadelphia, PA: Saunders, 2002: 831–86. 313. Yoshimura N, de Groat WC. Neural control of the lower urinary tract. Int J Urol 1997; 4: 111–25. 314. Nadelhaft I, de Groat WC, Morgan C. Location and morphology of parasympathetic preganglionic neurons in the sacral spinal cord of the cat revealed by retrograde axonal transport of horseradish peroxidase. J Comp Neurol 1980; 193: 265–81. 315. Morgan CW, de Groat WC, Felkins LA, Zhang SJ. Intracellular injection of neurobiotin or horseradish peroxidase reveals separate types of preganglionic neurons in the sacral parasympathetic nucleus of the cat. J Comp Neurol 1993; 331: 161–82. 316. de Groat WC, Vizzard MA, Araki I, Roppolo JR. Spinal interneurons and preganglionic neurons in sacral autonomic reflex pathways. In: Holstege G, Bandler R, Saper C, eds. The Emotional Motor System, Progress in Brain Research. Amsterdam, The Netherlands: Elsevier Science Publishers, 1996: 97–111. 317. Morgan C, Nadelhaft I, de Groat WC. The distribution of visceral primary afferents from the pelvic nerve to Lissauer’s tract and the spinal gray matter and its relationship to the sacral parasympathetic nucleus. J Comp Neurol 1981; 201: 415–40. 318. Eglen RM, Hegde SS, Watson N. Muscarinic receptor subtypes and smooth muscle function. Pharmacol Rev 1996; 48: 531–65. 319. Maeda A, Kubo T, Mishina M, Numa S. Tissue distribution of mRNAs encoding muscarinic acetylcholine receptor subtypes. FEBS Lett 1988; 239: 339–42. 320. Kondo S, Morita T, Tashima Y. Muscarinic cholinergic receptor subtypes in human detrusor muscle studied by labeled and nonlabeled pirenzepine, AFDX–116 and 4DAMP. Urol Int 1995; 54: 150–3. 321. Yamaguchi O, Shishido K, Tamura K et  al. Evaluation of mRNAs encoding muscarinic receptor subtypes in human detrusor muscle. J Urol 1996; 156: 1208–13. 322. Matsui M, Motomura D, Karasawa H et  al. Multiple functional defects in peripheral autonomic organs in mice lacking muscarinic acetylcholine receptor gene for the M3 subtype. Proc Natl Acad Sci USA 2000; 97: 9579–84. 323. Matsui M, Motomura D, Fujikawa T et  al. Mice lacking M2 and M3 muscarinic acetylcholine receptors are devoid of cholinergic smooth  muscle contraction but still viable. J Neurosci 2002; 22: 10623–7. 324. Andersson K-E. Pharmacology of lower urinary tract smooth muscles and penile erectile tissues. Pharmacol Rev 1993; 45: 253–308. 325. Lundberg JM. Pharmacology of cotransmission in the autonomic nervous system: Integrative aspects on amines, neuropeptides, adenosine triphosphate, amino acids and nitric oxide. Pharmacol Rev 1996; 48: 113–78.

Integrated physiology of the lower urinary tract 326. Fraser MO, Flood HD, de Groat WC. Urethral smooth muscle relaxation is mediated by nitric oxide (NO) released from parasympathetic postganglionic neurons. J Urol 1995; 153: 461A. 327. Bennett BC, Kruse MN, Roppolo JR et al. Neural control of urethral outlet activity in vivo: Role of nitric oxide. J Urol 1995; 153: 2004–9. 328. Persson K, Igawa Y, Mattiasson A, Andersson K-E. Effects of inhibition of the L-arginine/nitric oxide pathway in the rat lower urinary tract in vivo and in vitro. Br J Pharmacol 1992; 107: 178–84. 329. Thornbury KD, Hollywood MA, McHale NG. Mediation by nitric oxide of neurogenic relaxation of the urinary bladder neck muscle in sheep. J Physiol 1992; 451: 133–44. 330. Takeda M, Lepor H. Nitric oxide synthase in dog urethra: A histochemical and pharmacological analysis. Br J Pharmacol 1995; 116: 2517–23. 331. Keast JR, de Groat WC. Immunohistochemical characterization of pelvic neurons which project to the bladder, colon or penis in rats. J Comp Neurol 1989; 288: 387–400. 332. Tran LV, Somogyi GT, de Groat WC. Inhibitory effects of neuropeptide Y on cholinergic and adrenergic transmission in the rat urinary bladder and urethra. Am J Physiol 1994; 266: R1411–17. 333. Kihara K, de Groat WC. Sympathetic efferent pathways projecting to the bladder neck and proximal urethra in the rat. J Auton Nerv Syst 1997; 62: 134–42. 334. Janig W, McLachlan EM. Organization of lumbar spinal outflow to distal colon and pelvic organs. Physiol Rev 1987; 67: 1332–404. 335. Lincoln J, Burnstock G. Autonomic innervation of the urinary bladder and urethra. In: Maggi CA, ed. Nervous control of the urogenital system: The Autonomic Nervous System, Vol. 3. London, United Kingdom: Harwood Academic Publishers, 1993: 33–68. 336. Levin RM, Ruggieri MR, Wein AJ. Identification of receptor subtypes in the rabbit and human urinary bladder by selective radioligand binding. J Urol 1988; 139: 844–8. 337. Thor KB, Morgan C, Nadelhaft I et al. Organization of afferent and efferent pathways in the pudendal nerve of the female cat. J Comp Neurol 1989; 288: 263–79. 338. de Groat WC. Spinal cord projections and neuropeptides in visceral afferent neurons. Progr Brain Res 1986; 67: 165–87. 339. Janig W, Morrison JFB. Functional properties of spinal visceral afferents supplying abdominal and pelvic organs, with special emphasis on visceral nociception. Progr Brain Res 1986; 67: 87–114. 340. Habler HJ, Janig W, Koltzenburg M. Activation of unmyelinated afferent fibres by mechanical stimuli and inflammation of the urinary bladder in the cat. J Physiol 1990; 425: 545–62. 341. Mallory B, Steers WD, de Groat WC. Electrophysiological study of micturition reflexes in rats. Am J Physiol 1989; 257: R410–21. 342. Kruse MN, Mallory BS, Noto H et al. Properties of the descending limb of the spinobulbospinal micturition reflex pathway in the cat. Brain Res 1991; 556: 6–12. 343. Iggo A. Tension receptors in the stomach and the urinary bladder. J Physiol 1955; 128: 593–607. 344. Floyd K, Hick VE, Morrison JF. Mechanosensitive afferent units in the hypogastric nerve of the cat. J Physiol 1976; 259: 457–71. 345. Bahns E, Ernsberger U, Janig W, Nelke A. Functional characteristics of lumbar visceral afferent fibres from the urinary bladder and the urethra in the cat. Pflugers Arch 1986; 407: 510–18. 346. Morrison JF. The physiological mechanisms involved in bladder emptying. Scand J Urol Nephrol Suppl 1997; 184: 15–18. 347. Morrison JFB. ATP may be a natural modulator of the sensitivity of bladder mechanoreceptors during slow distensions. First International Consultation on Incontinence, Monaco, 1998. 348. Downie JW, Armour JA. Mechanoreceptor afferent activity compared with receptor field dimensions and pressure changes in feline urinary bladder. Can J Physiol Pharmacol 1992; 70: 1457–67. 349. Yoshimura N, Seki S, Chancellor MB et al. Targeting afferent hyperexcitability for therapy of the painful bladder syndrome. Urology 2002; 59: 61–7.

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350. Janig W, Koltzenburg M. Pain arising from the urogenital tract. In: Maggi CA, ed. Nervous Control of the Urogenital System: The Autonomic Nervous System, Vol. 3. London, United Kingdom: Harwood Academic Publishers, 1993: 525–78. 351. Fall M, Lindström S, Mazieres L. A bladder-to-bladder cooling reflex in the cat. J Physiol 1990; 427: 281–300. 352. Yoshimura N, White G, Weight FF, de Groat WC. Different types of NA+ and A-type K+ currents in dorsal root ganglion neurons innervating the rat urinary bladder. J Physiol 1996; 494: 1–16. 353. Maggi CA. The dual, sensory and efferent function of the capsaicinsensitive primary sensory nerves in the bladder and urethra. In: Maggi CA, ed. Nervous Control of the Urogenital System: The Autonomic Nervous System, Vol. 3. London, United Kingdom: Harwood Academic Publishers, 1993: 383–422. 354. Birder LA, Roppolo JR, Erickson VE, de Groat WC. Increased c-fos expression in lumbosacral projection neurons and preganglionic neurons after irritation of the lower urinary tract in the rat. Brain Res 1999; 834: 55–65. 355. Cheng C-L, Ma C-P, de Groat WC. Effects of capsaicin on micturition and associated reflexes in the rat. Am J Physiol 1993; 265: R132–8. 356. de Groat WC, Kawatani M, Hisamitsu T et al. Mechanisms underlying the recovery of urinary bladder function following spinal cord injury. J Auton Nerv Syst 1990; 30(Suppl): S71–7. 357. Cheng C-L, Ma C-P, de Groat WC. Effect of capsaicin on micturition and associated reflexes in chronic spinal rats. Brain Res 1995; 678: 40–8. 358. Talaat M. Afferent impulses in the nerves supplying the urinary bladder. J Physiol (Lond) 1937; 89: 1–13. 359. Feber JL, van Asselt E, van Mastrigt R. Neurophysiological modeling of voiding in rats: Urethral nerve response to urethral pressure and flow. Am J Physiol 1998; 274: R1473–81. 360. Bradley W, Griffin D, Teague C, Timm G. Sensory innervation of the mammalian urethra. Invest Urol 1973; 10: 287–9. 361. Todd JK. Afferent impulses in the pudendal nerves of the cat. Q J Exp Physiol 1964; 49: 258–67. 362. Bahns E, Halsband U, Janig W. Responses of sacral visceral afferents from the lower urinary tract, colon and anus to mechanical stimulation. Pflugers Arch 1987; 410: 296–303. 363. Conte B, Maggi CA, Giachetti A et al. Intraurethral capsaicin produces reflex activation of the striated urethral sphincter in urethaneanesthetized male rats. J Urol 1993; 150: 1271–7. 364. Thor KB, Muhlhauser MA. Vesicoanal, urethroanal, and urethrovesical reflexes initiated by lower urinary tract irritation in the rat. Am J Physiol 1999; 277: R1002–12. 365. Hokfelt T, Schultzberg M, Elde R et al. Peptide neurons in peripheral tissues including the urinary tract: Immunohistochemical studies. Acta Pharmacol Toxicol (Copenh) 1978; 43: 79–89. 366. Warburton AL, Santer RM. Sympathetic and sensory innervation of the urinary tract in young adult and aged rats: A semi-quantitative histochemical and immunohistochemical study. Histochem J 1994; 26: 127–33. 367. Lecci A, Giuliani S, Lazzeri M et al. The behavioral response induced by intravesical instillation of capsaicin in rats is mediated by pudendal urethral sensory fibers. Life Sci 1994; 55: 429–36. 368. Jung SY, Fraser MO, Ozawa H et al. Urethral afferent nerve activity affects the micturition reflex: Implication for the relationship between stress incontinence and detrusor instability. J Urol 1999; 162: 204–12. 369. Ferguson DR, Kennedy I, Burton TJ. ATP is released from rabbit urinary bladder epithelial cells by hydrostatic pressure changes—A possible sensory mechanism? J Physiol 1997; 505: 503–11. 370. Birder LA, Kanai AJ, de Groat WC et al. Vanilloid receptor expression suggests a sensory role for urinary bladder epithelial cells. Proc Natl Acad Sci USA 2001; 98: 13396–401. 371. Vlaskovska M, Kasakov L, Rong W et  al. P2X3 knock-out mice reveal a major sensory role for urothelially released ATP. J Neurosci 2001; 21: 5670–7.

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372. Birder LA, Apodaca G, de Groat WC, Kanai AJ. Adrenergic- and capsaicin-evoked nitric oxide release from urothelium and afferent nerves in urinary bladder. Am J Physiol 1998; 275: F226–9. 373. Birder LA, Nealen ML, Kiss S et  al. Beta-adrenoceptor agonists stimulate endothelial nitric oxide synthase in rat urinary bladder urothelial cells. J Neurosci 2002; 22: 8063–70. 374. Bean BP, Williams CA, Ceelen PW. ATP-activated channels in rat and bullfrog sensory neurons: Current–voltage relation and singlechannel behavior. J Neurosci 1990; 10: 11–19. 375. Dmitrieva N, Burnstock G, McMahon SB. ATP and 2-methyl thioATP activate bladder reflexes and induce discharge of bladder sensory neurons. Soc Neurosci Abstr 1998; 24: 2088. 376. Cockayne DA, Hamilton SG, Zhu QM et al. Urinary bladder hyporeflexia and reduced pain-related behaviour in P2X3-deficient mice. Nature 2000; 407: 1011–15. 377. Birder LA, Nakamura Y, Kiss S et al. Altered urinary bladder function in mice lacking the vanilloid receptor TRPV1. Nat Neurosci 2002; 5: 856–60. 378. Hawthorn MH, Chapple CR, Cock M, Chess-Williams R. Urothelium-derived inhibitory factor(s) influences on detrusor muscle contractility in vitro. Br J Pharmacol 2000; 129: 416–19. 379. de Groat WC. Nervous control of the urinary bladder of the cat. Brain Res 1975; 87: 201–11. 380. de Groat WC, Theobald RJ. Reflex activation of sympathetic pathways to vesical smooth muscle and parasympathetic ganglia by electrical stimulation of vesical afferents. J Physiol 1976; 259: 223–37. 381. Yoshimura N. Bladder afferent pathway and spinal cord injury: Possible mechanisms inducing hyperreflexia of the urinary bladder. Progr Neurobiol 1999; 57: 583–606. 382. Park JM, Bloom DA, McGuire EJ. The guarding reflex revisited. Br J Urol 1997; 80: 940–5. 383. Fedirchuk B, Hochman S, Shefchyk SJ. An intracellular study of perineal and hindlimb afferent inputs onto sphincter motoneurons in the decerebrate cat. Exp Brain Res 1992; 89: 511–16. 384. Holstege G, Griffiths D, De Wall H, Dalm E. Anatomical and physiological observations on supraspinal control of bladder and urethral sphincter muscles in the cat. J Comp Neurol 1986; 250: 449–61. 385. Kohama T. [Neuroanatomical studies on the urine storage facilitatory areas in the cat brain. Part I. Input neuronal structures to the nucleus locus subcoeruleus and the nucleus radicularis pontis oralis.] Nippon Hinyokika Gakkai Zasshi 1992; 83: 1469–77. 386. de Groat WC, Fraser MO, Yoshiyama M et al. Neural control of the urethra. Scand J Urol Nephrol Suppl 2001: 35–43. 387. de Groat WC, Booth AM, Krier J et al. Neural control of the urinary bladder and large intestine. In: Brooks CM, Koizumi K, Sato A, eds. Integrative Functions of the Autonomic Nervous System. Tokyo, Japan: Tokyo University Press, 1979: 50–67. 388. de Groat WC, Booth AM, Milne RJ, Roppolo JR. Parasympathetic preganglionic neurons in the sacral spinal cord. J Auton Nerv Syst 1982; 5: 23–43. 389. McGuire EJ, Morrissey SG, Schichun Z, Horwinsk E. Control of reflex detrusor activity in normal and spinal injured non-human primates. J Urol 1983; 129: 197–9. 390. de Groat WC, Nadelhaft I, Milne RJ et al. Organization of the sacral parasympathetic reflex pathways to the urinary bladder and large intestine. J Auton Nerv Syst 1981; 3: 135–60. 391. Vera PL, Nadelhaft I. Conduction velocity distribution of afferent fibers innervating the rat urinary bladder. Brain Res 1990; 520: 83–9. 392. Kuru M. Nervous control of micturition. Physiol Rev 1965; 45: 425–94. 393. Nishizawa O, Sugaya K, Noto H et al. Pontine micturition center in the dog. J Urol 1988; 140: 872–4. 394. Mallory BS, Roppolo JR, de Groat WC. Pharmacological modulation of the pontine micturition center. Brain Res 1991; 546: 310–20. 395. Noto H, Roppolo JR, Steers WD, de Groat WC. Excitatory and inhibitory influences on bladder activity elicited by electrical stimulation in the pontine micturition center in rat. Brain Res 1989; 492: 99–115.

396. Noto H, Roppolo JR, Steers WD, de Groat WC. Electrophysiological analysis of the ascending and descending components of the micturition reflex pathway in the rat. Brain Res 1991; 549: 95–105. 397. Blok BF, Holstege G. Direct projections from the periaqueductal gray to the pontine micturition center (M-region). An anterograde and retrograde tracing study in the cat. Neurosci Lett 1994; 166: 93–6. 398. Blok BF, De Weerd H, Holstege G. Ultrastructural evidence for a paucity of projections from the lumbosacral cord to the pontine micturition center or M-region in the cat: A new concept for the organization of the micturition reflex with the periaqueductal gray as central relay. J Comp Neurol 1995; 359: 300–9. 399. Matsuura S, Allen GV, Downie JW. Volume-evoked micturition reflex is mediated by the ventrolateral periaqueductal gray in anesthetized rats. Am J Physiol 1998; 275: R2049–55. 400. Matsuura S, Downie JW, Allen GV. Micturition evoked by glutamate microinjection in the ventrolateral periaqueductal gray is mediated through Barrington’s nucleus in the rat. Neuroscience 2000; 101: 1053–61. 401. Blaivas JG. The neurophysiology of micturition: A clinical study of 550 patients. J Urol 1982; 127: 958. 402. Rossier AB, Ott R. Bladder and urethral recordings in acute and chronic spinal cord injury patients. Int J Urol 1976; 31: 49–59. 403. Barrington FJF. The component reflexes of micturition in the cat. Parts I and II. Brain 1931; 54: 177–88. 404. Barrington FJF. The component reflexes of micturition in the cat. Part III. Brain 1941; 64: 239–43. 405. de Groat WC, Araki I, Vizzard MA et al. Developmental and injury induced plasticity in the micturition reflex pathway. Behav Brain Res 1998; 92: 127–40. 406. Araki I, de Groat WC. Developmental synaptic depression underlying reorganization of visceral reflex pathways in the spinal cord. J Neurosci 1997; 17: 8402–7. 407. Birder LA, de Groat WC. Induction of c-fos gene expression of spinal neurons in the rat by nociceptive and non-nociceptive stimulation of the lower urinary tract. Am J Physiol 1993; 265: R643–8. 408. Nadelhaft I, Vera PL. Neurons in the rat brain and spinal cord labeled after pseudorabies virus injected into the external urethral sphincter. J Comp Neurol 1996; 375: 502–17. 409. Vizzard MA, Erickson VL, Card JP et al. Transneuronal labeling of neurons in the adult rat brainstem and spinal cord after injection of pseudorabies virus into the urethra. J Comp Neurol 1995; 355: 629–40. 410. Sugaya K, Roppolo JR, Yoshimura N et al. The central neural pathways involved in micturition in the neonatal rat as revealed by the injection of pseudorabies virus into the urinary bladder. Neurosci Lett 1997; 223: 197–200. 411. Sasaki M. Morphological analysis of external urethral and external anal sphincter motoneurones of cat. J Comp Neurol 1994; 349: 269–87. 412. Araki I. Inhibitory postsynaptic currents and the effects of GABA on visually identified sacral parasympathetic preganglionic neurons in neonatal rats. J Neurophysiol 1994; 72: 2903–10. 413. de Groat WC. Excitation and inhibition of sacral parasympathetic neurons by visceral and cutaneous stimuli in the cat. Brain Res 1971; 33: 499–503. 414. de Groat WC. Inhibitory mechanisms in the sacral reflex pathways to the urinary bladder. In: Ryall RW, Kelly JS, eds. Iontophoresis and Transmitter Mechanisms in the Mammalian Central Nervous System. Amsterdam, The Netherlands: Elsevier, 1978: 366–8. 415. Morrison JF, Sato A, Sato Y, Yamanishi T. The influence of afferent inputs from skin and viscera on the activity of the bladder and the skeletal muscle surrounding the urethra in the rat. Neurosci Res 1995; 23: 195–205. 416. McGuire EJ. Experimental observations on the integration of bladder and urethral function. Trans Am Assoc Genitourin Surg 1976; 68: 38–42.

Integrated physiology of the lower urinary tract 417. de Groat WC, Ryall RW. Reflexes to sacral parasympathetic neurones concerned with micturition in the cat. J Physiol 1969; 200: 87–108. 418. Barrington FJF. The relation of the hind-brain to micturition. Brain 1921; 4: 23–53. 419. Blok BFM, DeWeerd H, Holstege G. The pontine micturition center projects to sacral cord GABA immunoreactive neurons in the cat. Neurosci Lett 1997; 233: 109–12. 420. Blok BFM, Holstege G. Neuronal control of micturition and its relation to the emotional motor system. Progr Brain Res 1996; 107: 113–26. 421. Tang PC, Ruch TC. Localization of brain stem and diencephalic areas controlling the micturition reflex. J Comp Neurol 1956; 106: 213–45. 422. Sugaya K, Matsuyama K, Takakusaki K, Mori S. Electrical and chemical stimulations of the pontine micturition center. Neurosci Lett 1987; 80: 197–201. 423. Valentino RJ, Chen S, Zhu Y, Aston-Jones G. Evidence for divergent projections to the brain noradrenergic system and the spinal parasympathetic system from Barrington’s nucleus. Brain Res 1996; 732: 1–15. 424. Ding YQ, Takada M, Tokuno H, Mizuno N. Direct projections from the dorsolateral pontine tegmentum to pudendal motoneurons innervating the external urethral sphincter muscle in the rat. J Comp Neurol 1995; 357: 318–30. 425. Otake K, Nakamura Y. Single neurons in Barrington’s nucleus projecting to both the paraventricular thalamic nucleus and the spinal cord by way of axon collaterals: A double labeling study in the rat. Neurosci Lett 1996; 209: 97–100. 426. Blok BF, van Maarseveen JT, Holstege G. Electrical stimulation of the sacral dorsal gray commissure evokes relaxation of the external urethral sphincter in the cat. Neurosci Lett 1998; 249: 68–70. 427. Valentino RJ, Pavcovich LA, Hirata H. Evidence for corticotropinreleasing hormone projections from Barrington’s nucleus to the periaqueductal gray and dorsal motor nucleus of the vagus in the rat. J Comp Neurol 1995; 363: 402–22. 428. Blok BFM, Willemsen ATM, Holstege G. A PET study on the brain control of micturition in humans. Brain 1997: 111–21. 429. Yoshimura N, Nagahama Y, Ueda T, Yoshida O. Paroxysmal urinary incontinence associated with multiple sclerosis. Urol Int 1997; 59: 197–9.

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430. Marson L. Identification of central nervous system neurons that innervate the bladder body, bladder base, or external urethral sphincter of female rats: A transneuronal tracing study using pseudorabies virus. J Comp Neurol 1997; 389: 584–602. 431. Fukuyama H, Matsuzaki S, Ouchi Y et  al. Neural control of ­micturition in man examined with single photon emission computed tomography using 99mTc-HMPAO. Neuroreport 1996; 7: 3009–12. 432. Blok BF, Willemsen TM, Holstege G. A PET study on brain control of micturition in humans. Brain 1997; 120: 111–21. 433. Holstege JC, Van Dijken H, Buijs RM et  al. Distribution of dopamine immunoreactivity in the rat, cat and monkey spinal cord. J Comp Neurol 1996; 376: 631–52. 434. Athwal BS, Berkley KJ, Hussain I et al. Brain responses to changes in bladder volume and urge to void in healthy men. Brain 2001; 124: 369–77. 435. Blok BF, Sturms LM, Holstege G. A PET study on cortical and subcortical control of pelvic floor musculature in women. J Comp Neurol 1997; 389: 535–44. 436. Zhang H, Reitz A, Kollias S et  al. An fMRI study of the role of suprapontine brain structures in the voluntary voiding con­ trol induced by pelvic floor contraction. Neuroimage 2005; 24: 174–80. 437. Seseke S, Baudewig J, Kallenberg K et  al. Voluntary pelvic floor muscle control—An fMRI study. Neuroimage 2006; 31: 1399–407. 438. Kuhtz-Buschbeck JP, van der Horst C, Wolff S et  al. Activation of the supplementary motor area (SMA) during voluntary pelvic floor muscle contractions—An fMRI study. Neuroimage 2007; 35: 449–57. 439. Matsui M, Yoneyama E, Sumiyoshi T et al. Lack of self-control as assessed by a personality inventory is related to reduced volume of supplementary motor area. Psychiatry Res 2002; 116: 53–61. 440. de Groat WC, Araki I. Maturation of bladder reflex pathways during postnatal development. Adv Exp Med Biol 1999; 462: 253–63. 441. Geirsson G, Lindstrom S, Fall M. The bladder cooling reflex and the use of cooling as stimulus to the lower urinary tract. J Urol 1999; 162: 1890–6. 442. Chancellor MB, de Groat WC. Intravesical capsaicin and resiniferatoxin therapy: Spicing up the ways to treat the overactive bladder. J Urol 1999; 162: 3–11.

4 Physiology of normal sexual function Pierre Clément, Hélène Gelez, and François Giuliano

Introduction The lifting of the Victorian veil, which covered the Western world with prudishness and sexual taboos until the first half of the twentieth century, was followed by profound changes in social attitudes producing a socalled sexual revolution in the 1960s. As a result, rational approach of sexual physiology and sexual dysfunctions, developed by researchers from multiple scientific fields, progressively emerged and led to a better knowledge of human sexuality even if there is still significant progress to be made especially for female sexual physiology. In both genders, sexual behavior is divided into appetitive and consummatory components.1 Appetitive behaviors are associated with sexual desire, excitement, and arousal, whereas consummatory behaviors consist of genital stimulation leading to orgasm. Initially, the human sexual response was described by Masters and Johnson 2 as including four interactive phases: excitation, plateau, orgasm, and resolution. This definition has been subsequently revised by Kaplan3 and Levin4 to lead to a model commonly accepted, consisting of desire, excitation, orgasm, and resolution. Each of these phases is controlled by a complex and coordinated interplay of multiple components of the brain, spinal cord, and relevant peripheral organs. Much of the mechanisms of control of the different aspects of sexual function are not fully delineated although homologies and, most often analogies, with mammalian animal models have allowed the improvement of our understanding of the physiology of human sexual function.

Female sexual function Female sexual life phases consist of puberty, adulthood, pregnancy, and menopause. Puberty is defined as sexual maturation and refers to the process of physical and physiological changes by which a child’s body becomes an adult

body capable of reproduction. Then, adult females experience menstrual cycles consisting of different phases: menstruation, follicular phase, ovulation, and luteal phase. The ovarian cycle duration varies across species (4 days in rats, 17 days in sheeps, and 28 days in women), but in all species they are tightly controlled by steroid hormones. Women are able to express sexual desire and to engage in sexual intercourse at any time, contrary to females in most animal species that display sexual activity only during a precise period of the ovarian cycle, around ovulation. Female sexual behavior consists of proceptive components associated with sexual desire, excitement and arousal, and receptivity, commonly reflected by the lordosis reflex in female rodents.1,3,4 Each of these phases is controlled by both the autonomic and somatic nervous systems, and by their interconnections with different spinal and supraspinal centers.

Neuroanatomy Female genitalia Female genital sexual anatomy consists of the perineum, the external genitalia, and the vagina. The perineum is the short stretch of skin situated between the anus and the bottom of the vulva, extending from the inferior boundary of the pelvis to the symphysis pubis and the inferior edges of the pubic bone. The vagina is a muscular canal extending from the cervix to the exterior of the body. The vaginal opening is at the caudal end of the vulva, behind the opening of the urethra. The vaginal mucosa, which lines the vaginal walls, is thick and has a protective layer of stratified squamous, nonkeratinized epithelium. The vaginal walls are generally in contact with each other but are capable of major stretching during sexual intercourse as well as childbirth. The external genitalia of the female are collectively referred to as the vulva and include the mons veneris, labia

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majora, labia minora, clitoris, vulvovaginal glands (also called Bartholin’s glands), and the vestibule of the vagina (Figure 4.1a). The mons pubis, also called the mons veneris in females, is the soft tissue present in both sexes just above the genitals (above the vulva in females), raised above the surrounding area because of a pad of fat lying just beneath it, which protects the pubic bone. The labia majora are two prominent longitudinal cutaneous folds extend downward and backward from the mons pubis to the perineum. Each labium has two surfaces: an outer, pigmented and covered with hairs; and an inner, smooth and containing sebaceous glands, which render it moist. The labia minora are two smaller folds located medial to the labia majora and

anteriorly surrounding the clitoris. In the anterior, each labium divides into two portions: the upper division passes above the clitoris, forming a fold extending beyond the clitoral glans (glans clitoridis), and named the preputium clitoridis; the lower division passes under the clitoral glans and forms the frenulum clitoridis. The labia minora surround a space, called the vestibule, into which the vagina and urethra open. These labia lack hair but have a large supply of venous sinuses, sebaceous glands, and nerves. The clitoris is a multiplanar structure located near the anterior junction of the labia minora, above the opening of the urethra and vagina and consists of the glans, the body, and erectile bodies (the paired bulbs, crura and corpora).

Mons pubis

Clitoris Urethra Labia majora Labia minora Vestibule (or entrance to the vagina) Perineum Anus

(a)

Body of clitoris Ischiocavernosus Bulbospongiosus

Vagina

Sphincter urethrovaginalis

Smooth muscle Levator ani Anus

Sphincter ani externus

(b)

Figure 4.1 (a) Anatomy of female genitalia. (b) Muscular support of the female pelvic floor.

Physiology of normal sexual function The glans is the only visible external part of the clitoris and is entirely or partially protected by the clitoral hood or prepuce, a covering of tissue similar to the foreskin of the male penis. The clitoral body contains a pair of corpora cavernosa and extends several centimeters upward and to the back, before splitting into two arms, the clitoral crura. These crura extend around and to the interior of the labia majora. The pelvic floor is composed of muscles originating on the inner of the bony pelvis and inserting onto the caudal coccygeal vertebrae. The levator ani composed of two major muscles: pubococcygeus and iliococcygeus; and the coccygeus muscles form the pelvic diaphragm. The striated perineal muscles consist of sexually dimorphic bulbospongiosus and ischiocavernosus muscles, and regulate the external anal and urethral sphincters (Figure 4.1b). In addition, the vagina is surrounded by a circular layer of smooth muscles, as well as an important longitudinal smooth muscle layer (Figure 4.1b).

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female genital organs are not only innervated by the autonomic nervous system but also by somatic and sensory fibers. Afferent innervation  Sensory fibers from the pelvic, pudendal, and hypogastric nerves innervate the female genital organs and relay information to the spinal cord (in the thoracolumbar and lumbosacral segments) (Figure 4.2).5–8 Pelvic nerve sensory fibers innervate the vagina, the cervix, and the body of the uterus, with the ­g reatest ­concentration in the deepest portion of the vagina (fornix).9 The sensory fibers conveyed by the pelvic nerve enter the spinal cord via the S2–S3 dorsal roots in women, the L6–S1 dorsal roots in female rats, essentially in the Lissauer’s tract from which collaterals extend to the dorsal horn, the sacral parasympathetic nucleus (SPN) and the dorsal gray commissure (DGC).10,11 The pudendal nerve provides sensory innervation to the clitoris, perineum, and urethra; the major branch of the sensory pudendal nerve gives rise to the dorsal nerve of the clitoris, whereas other branches innervate the perineal skin and urethra. The pudendal afferent fiber terminals are located in the dorsal column, in the medial half

Peripheral innervation Peripheral innervation of female genital organs has not only been described in humans5,6 but also in different rodent species. Neuroanatomical studies show that

Paravertebral sympathetic chain

Spinal cord

Thoracolumbar levels (T12–L1)

HN

Genital tract

PP

Lumbosacral levels (S2–S3)

PN DRG (S2–S3)

PudN (sensory branch) Pelviperineal muscles

PudN (motor branch)

Figure 4.2 Neural pathways controlling female and male sexual responses. Sympathetic (hatched lines), parasympathetic (thin line), and somatic (thick line) nerves originating in lumbosacral spinal nuclei command the peripheral anatomical structures controlling female and male sexual responses. Sensory afferents (dotted lines) originating in genital areas are integrated at the spinal and brain levels. DRG, dorsal root ganglion; HN, hypogastric nerve; PudN, pudendal nerve; PN, pelvic nerve; PP, pelvic plexus.

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of Lissauer’s tract, in the extreme edge of the dorsal horn, and in the DGC in the L6–S1 segments.12,13 The dorsal nerves of the clitoris originate below the pubic bone and form two bundles that fan out laterally on the clitoral bodies, where they join to form the single clitoral body. The hypogastric nerve also contains some axons of afferent neurons originating in the uterus and the cervix, and reaches the thoracolumbar segments of the spinal cord.14 There is also evidence that vagal afferent fibers likely convey sensory information from the female genital organs directly to the nucleus of the tractus solitarius (NTS), bypassing the spinal cord. Indeed, it is noteworthy that women with complete upper spinal cord injury are still able to perceive genital sensation.15 Furthermore, in rat, it has been shown that afferent fibers in the vagus nerve are implicated in the responses to vaginocervical stimulation (VCS).16 Efferent innervation  The female genital organs receive parasympathetic, sympathetic, and somatic innervation via three nerves: pelvic, hypogastric, and pudendal (Figure 4.2). Parasympathetic fibers to the vagina and the clitoris are conveyed by the pelvic nerve originating from the sacral segments (S2–S4) of the spinal cord from the SPN.10 The neural fibers of the pelvic nerve travel in the pelvic plexus and send branches in the cavernous nerves that originate from the autonomic nerve plexus around the vagina and extend to the proximal urethra and the clitoral body. In rat, preganglionic neurons of the SPN are located almost exclusively (98%) within the L6–S1 spinal cord segment,11 corresponding to the sacral S2–S4 segments in humans. Autonomic sympathetic fibers destined to the vagina and the clitoris are conveyed by the paravertebral sympathetic chain and the hypogastric nerve. Sympathetic preganglionic neurons originate from the thoracolumbar segments of the spinal cord (T13–L2 in rats) from two separate nuclei, the DGC and the intermediolateral cell column, and represent the main sympathetic outflow to the genital tract.17 The pudendal nerve originates from the splanchnic branches of the sacral plexus and provides innervation to the pelvic floor and anal and urethral sphincters.12 The pudendal motor neurons are located in the ventral cord of the sacral spinal segments in the Onufrowicz’s (Onuf’s) nucleus. In rats, the Onuf’s nucleus is anatomically divided into the dorsomedial and the dorsolateral nuclei.12,18

Spinal and supraspinal centers: Neuroanatomical consideration In this section, details of the neuroanatomical connections between the spinal and brain centers involved in the control of female sexual responses are provided, whereas

their functional role is addressed in the Section “Central control of female sexual response.” Spinal centers  From tracing studies in the female rat, the major input to the clitoris has been found to originate from the lumbosacral segments of the spinal cord (L6– S1), in the SPN where the preganglionic neurons of the pelvic nerve are located and in the DGC.19 A secondary neuronal component was identified in other areas of the spinal cord, including the T13–L2 segments where the sympathetic preganglionic neurons of the hypogastric nerve and the lumbosacral paravertebral sympathetic chain are located. The spinal neurons destined to the uterus and cervix have been also identified in the female rat. Preganglionic neurons and putative interneurons were reported in the lumbosacral spinal cord (L6–S1) and the lower segments of the thoracic cord (T11–T13), mainly in the lateral horn area (SPN and intermediolateral nucleus), lateral aspect of the dorsal horn, intermediate gray, and the DGC.20 Sensory projections from the pelvic area and spinal neurons involved in different aspects of the female sexual response have been also examined by quantifying the Fos protein, a marker of neuronal activation, in response to genital stimulations. Activated neurons were detected primarily in the L6–S1 segments of the spinal cord, in the superficial dorsal horn, in the DGC, and in lateral laminae V–VII in the region of the SPN.21–24 Brain centers  Tracing techniques have evidenced two major ascending pathways in the rat: the spinothalamic and the spinoreticular pathways that relay sensory information to the brain.25 The spinothalamic pathway travels in the dorsal columns and dorsal lateral quadrant, crosses the brainstem, and reaches the specific nuclei of the thalamus. A last relay sends information to the somatosensory cortex. The spinoreticular fibers travel in the lateral spinal columns terminating in brainstem reticular formation and the nonspecific nuclei of the thalamus. The descending pathways from the brain to the female genital organs have been delineated in the rat.19,26,27 Brain neuronal network innervating the clitoris and the vagina includes several nuclei in the brainstem, the hypothalamus, and the amygdala.

Physiology of female sexual response The female sexual response consists of sexual desire, arousal, and orgasm. This includes genital and behavioral responses characterized by peripheral physiological events occurring mainly in genital organs and a central drive originating from spinal and supraspinal centers.

Physiology of normal sexual function It has always been difficult to define sexual desire and to dissociate sexual desire from sexual arousal. It is now commonly accepted that sexual arousal generally reflects increase in blood flow to genital organs and clitoral erectile tissues, whereas sexual desire refers to a psychological state characterizing sexual interest and motivation to engage in sexual contact.28 In women, central drive is crucial and constitutes the key element of the mechanisms controlling libido. Accordingly, it is crucial to emphasize that an increase of vaginal blood flow is not necessarily associated to the subjective feeling of sexual arousal.29

Peripheral physiological changes during female sexual response Genital arousal  Physiological sexual arousal in both humans and animals can be defined as an increase of autonomic activation that prepares the body for sexual activity and decreases the amount of sexual stimulation necessary to induce orgasm. In women, first studies focused on extragenital measures such as heart rate, respiration, blood pressure, sweat production, and body temperature, considered as indexes of sexual arousal.2 Then, methods measuring vaginal temperature30 and monitoring changes in clitoral and vaginal blood flow such as photoplethysmography measuring vaginal pulse amplitude,31 oxygenation-temperature method,32 and clitoral color Doppler ultrasonography33 have been developed. It has been shown that genital arousal results in an increase in blood flow to the vagina, clitoris, and labia mediated by the parasympathetic nervous system. The erectile tissue of the clitoris shows vasocongestion and tumescence, in the same way as does the penis. Sexual arousal is also associated with vaginal lubrication resulting from blood engorgement and increased epithelial capillary tufts permeability, also mediated by the parasympathetic nervous system. Some data suggested that female genital arousal is controlled, as in males, by a balance between facilitatory parasympathetic and inhibitory sympathetic inputs. However, a facilitatory effect of the sympathetic nervous system resulting in an increase in blood flow to striated and smooth muscles that participate in different sexual responses, such as increased heart and breathing rate, has been proposed.34 Electrical stimulation of the sacral roots in women increases vaginal blood flow.35 Analogous models have been developed in rats, rabbits, and dogs. In these in vivo experiments performed in various animal species, electrical stimulation of the pelvic nerve mimics the type of stimulation normally received by females during intromissive copulation and results in vaginal response and clitoral tumescence characterized by an increase in

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vaginal blood flow, vaginal wall pressure, vaginal length, clitoral and intracavernosal pressure and blood flow, and a decrease in vaginal luminal pressure.36–38 Orgasm  Orgasm is the third and probably the shortest phase of the human sexual response cycle. It is the most reinforcing component of sexual behavior and is followed by a feeling of euphoria and satisfaction during the resolution phase. In women, orgasm is usually obtained by stimulation of the clitoris and/or the vagina, although cervical stimulation may also be perceived as pleasurable during orgasm.39 Orgasm results in rhythmic contractions of the vagina, uterus, and anal sphincter and changes in vaginal and clitoral blood flow.40–43 Increases in heart rate, blood pressure, and respiration are also associated.2,44 Orgasmic responses are regulated by both the autonomic and somatic nervous systems. The pudendal nerve that conveys sensory information from the vulva and the striated pelvic perineal muscles play a critical role in the occurrence of clitoral orgasm. The pelvic and hypogastric nerve conveying sensory information from the internal pelvic organs may be involved in coital orgasm. Nevertheless, it must be emphasized that the exact physiological support for orgasm remains unknown. Some women have reported a dramatic increase in secretions during orgasm, described as female ejaculation by some authors. When female ejaculation occurs, it involves, as in males, the ejection of significant amounts of fluid in gushes through the urethra at the moment of sexual climax.45 However, it remains unclear if ejaculation in women consistently occurs and is associated with orgasm, and whether these secretions are different from urine.46 Orgasms are also associated with hormonal changes; especially an increase in circulating levels of prolactin, oxytocin (OT), vasopressin (AVP), adrenaline, and vasointestinal polypeptide (VIP) has been reported.47,48

Central control of female sexual response Spinal network  Functional approaches have demonstrated that local physiological changes associated with sexual arousal result mainly from spinal reflex mechanisms. Two main spinal sexual reflexes have been evidenced: the bulbocavernous reflex involving sacral segments S2–S4 and another reflex involving vaginal and clitoral cavernosal autonomic nerves stimulation and producing clitoral, labial,  and vaginal engorgement.48 Different data showed that the spinal cord is sufficient to generate female sexual responses, without functional connections to supraspinal centers. Women diagnosed with complete spinal cord injury retain the capacity of increased blood

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flow and/or lubrication on masturbation.46,49,50 Orgasm is also a reflex mediated by the spinal cord; women with complete spinal cord injury are still able to achieve orgasm during audiovisual erotic combined with manual genital stimulation.50 However, women with injury of the lower motor neurons and S2–S5 dermatomes are less likely to reach orgasm compared to women with injury at or above T11.51 This suggests that orgasmic responses require intact reflexes that relay in the sacral spinal cord. Experimental data in the female rat indicate that spinal reflexes are under a strong inhibitory tone originating in brainstem.52 Brain network  It is now commonly accepted that sexual desire is mainly controlled by brain mechanisms. Any individual, to engage sexual intercourse, must be able to respond to hormonal and neurochemical changes that signal sexual desire. Sexual arousal also includes a central component that increases neural tone or awareness to respond to sexual incentives, defined as arousability by Whalen.53 Contrary to the peripheral physiological changes that have been well identified in both humans and animals, the neural pathways involved in the control of female sexual desire and central arousal remain largely unknown. The majority of the data available have been obtained from animal studies, and there is an abundant literature regarding the central control of lordosis in female rodents. However, it remains difficult to extrapolate these data to human sexual behavior because there is no human counterpart of lordosis. Brain imaging studies have been conducted in humans to identify the brain centers activated during female sexual responses, but most of them focus on orgasmic reflexes. Positron emission tomography (PET) studies have evidenced that orgasm, compared to preorgasm arousal, enhances activation in the paraventricular nucleus (PVN), periaqueductal gray (PAG), amygdala, hippocampus, striatum, cerebellum, and different cortical areas.54 During self-masturbation, the NTS, thalamus, somatosensory and motor cortices, and sensory areas of the spinal medulla are activated. However, further studies are needed to identify the brain areas specifically activated during orgasm and to discriminate with those specifically activated during sexual arousal. This functional dissociation can be evaluated in animal models, by examining and comparing the neural pathways controlling appetitive and consummatory sexual responses. In females rats, mating with males results in neuronal activation in different hypothalamic nuclei (medial preoptic area [MPOA], ventromedial hypothalamic nucleus [VMN], PVN, arcuate nucleus), in structures belonging to the mesolimbic dopaminergic pathway (ventral tegmental area [VTA], medial amygdala [MeA], nucleus accumbens [Nac]), and also in the

lateral septum, striatum, BNST, and the medial central gray.55–57 A similar pattern of neuronal activation was obtained by manual VCS, 58,59 indicating that the brain structures stimulated in mating female rats are involved in relaying or integrating genital sensory information. These findings allow delineation of the brain circuitry dealing with consummatory aspects of the female sexual response. The MPOA plays a critical role in the control of female sexual desire. Neurochemical changes occurring in the MPOA have been measured in close association with sexual desire. Many neurotransmitters, neuropeptides, and pharmacological agents (dopamine (DA), OT, melanocortin, and opioids agonists) have been reported to exert facilitatory effects on proceptive behaviors, when microinfused into the MPOA. Furthermore, in anesthetized female rats, electrical stimulation of the MPOA resulted in an increase in vaginal blood flow and wall tension. 36 The MPOA does not directly innervate the spinal cord, and neuroanatomical data suggest that the major MPOA output relays in the PAG and nucleus paragigantocellularis (nPGi) before reaching the spinal circuits regulating female genital reflexes (Figure 4.3).60 Female sexual drive may also be controlled by other neural pathways. The mesolimbic dopaminergic pathway is involved in rewarding and motivational processes, including sexual motivation. In this pathway, neurons of the VTA project to the Nac and the MeA, two critical structures for the display of sexual desire. The MPOA, which sends direct outputs to the VTA and the Nac and receives neuronal inputs from the MeA, may modulate sexual responses through these central interconnections. Experimental evidences indicate that the ventromedial hypothalamus (VMH) contains neural mechanisms that facilitate female sexual behavior.61 The VMH is critical for lordosis and is the main site of action for steroids hormones.61–63 However, the role of the VMH in the control of genital responses has not been investigated yet. The PVN could also be involved in the control of female sexual response. The PVN is an important integrative site for the sympathetic nervous system and supplies OT to the peripheral circulation. Oxytocinergic neurons of the PVN, which directly projects to the lumbosacral neurons innervating clitoris and vagina (Figure 4.3), are activated after copulation or VCS.26,64,65 However, the exact role of the PVN in the control of female sexual function remains to be determined. The nPGi and the PAG are two other areas that project to spinal centers innervating genital areas and have direct connections with the MPOA (Figure 4.3).26 The nPGi regulates a variety of autonomic and somatic functions and could be involved in female sexual function, as a tonic inhibitory center. The PAG is known to be an important relay for sexually relevant stimuli and has extensive connections with brainstem and hypothalamic nuclei

Physiology of normal sexual function Brain

Cerebral cortex Nac

Striatum

Thalamus SPFp BNST PNpd

Somato sensory inputs

MeA

Hypothalamus MPOA PVN VMH (Female) Midbrain PAG Pons

T12–L1 (Sympathetic)

nPGi

L3–L4 LSt (Male)

L5–S1 (Parasympathetic, autonomic)

Genital areas

Spinal cord

Sensory receptors

Figure 4.3 Diagram of brain structures and putative central pathways involved in sexual responses. Hatched lines indicate sensory afferents. BNST, bed nucleus of stria terminalis; LSt, lumbar spinothalamic; MeA, medial amygdaloid nucleus; MPOA, medial preoptic area; Nac, nucleus accumbens; PAG, periaqueductal grey; nPGi, paragigantocellular nucleus; PNpd, posterodorsal preoptic nucleus; PVN, paraventricular hypothalamic nucleus; SPFp, parvicellular part of the subparafascicular thalamus; VMH, ventromedial hypothalamus.

involved in female sexual function.60 The PAG receives and integrates autonomic input from the MPOA and the PVN and appears to inhibit the nPGi, thereby disinhibiting sexual reflexes.

Hormonal control of female sexual response Role of sex steroids on physiological genital changes  Androgens, acting directly or through their conversion to estrogens in the central nervous system (CNS) and in periphery, are essential for the development of reproductive function and play a critical role in maintaining the structural and functional integrity of vaginal tissues, and modulating physiological changes occurring during sexual arousal.66,67 In addition, clinical and experimental studies suggested a role for estrogens in modulating genital

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blood flow. In women, the decline of circulating estrogen associated with menopause affect vaginal lubrication and can be responsible for clitoral fibrosis and diminished thinning of the vagina wall.68 Similarly, ovariectomized or estrogen-deprived female rats show low increase in vaginal and clitoral blood flow following pelvic nerve stimulation and vaginal lubrication significantly reduced in comparison to controls.66 In these females, normal physiological responses associated to sexual arousal can be restored by estrogen treatment. Vaginal smooth muscle contractility also seems to be regulated by estrogens.69 In contrast, the physiological changes that accompany orgasmic responses have been shown to be present even in the absence of steroid hormones.39 Role of steroid hormones on sexual behavior  In women, both estrogens and androgens are critical for sexual desire, arousal, and orgasm. The fluctuations of circulating hormones across the ovarian cycle are often associated with libido changes.70 The strong motivation for sexual activity at the time of ovulation may be due to the peak of steroid hormones. Furthermore, administration of androgens seems to enhance sexual interest.71 In animals also, both appetitive and consummatory sexual behaviors are tightly regulated by sex steroids. Estradiol and progesterone regulate different aspects of female sexual behavior, and must be present in a precise temporal sequence that varies across species.62 Ovariectomized females do not display any trait of sexual activity; and treatment with estradiol alone restores only receptive behaviors, whereas both sex steroids are necessary to induce proceptivity. The VMH plays a critical role in the hormonal regulation of lordosis. Neurons in the VMH, and particularly the ventrolateral region, concentrate both estradiol and progesterone receptors.61

Neurotransmitters and neuropeptides regulating female sexual response The presence of a variety of neurotransmitters has been demonstrated in the vagina and the clitoris but their physiological role at the peripheral level remains largely unknown. However, numerous animal studies have evidenced central mechanisms of action of different neurotransmitters and neuropeptides in the control of female sexual responses. Acetylcholine and noradrenaline  The respective role of the sympathetic (classical neurotransmitter, noradrenaline [NA]) and parasympathetic (classical neurotransmitter,

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acetylcholine [Ach]) systems in the control of female sexual response remains unclear. At the peripheral level, NA exerts an inhibitory effect on female sexual genital responses.37 Despite the rich cholinergic vaginal innervation, Ach appears to play a minor role in the control of vaginal blood flow, sexual arousal, and orgasm. Nonadrenergic–noncholinergic   neurotransmitters  Several nonadrenergic–noncholiner­ g ic (NANC) neurotransmitters/mediators have been identi­ fied in the female animal genital tract including VIP, nitric oxide (NO), neuropeptide Y (NPY), calcitonin gene-related ­peptide (CGRP), and substance P (SP). At the peripheral level, VIP and NO are generally considered as the most important facilitatory neurotransmitters of the genital arousal response, whereas NPY seems to produce inhibitory effects. In women, intravenous injection of VIP increases vaginal blood flow and elicits vaginal lubrication.72,73 In vivo experimental models have shown that NO can play a role in the control of vaginal blood flow, vaginal smooth muscles contractions, and clitoral erection.74–76 Clinically, sildenafil enhances vaginal vasocongestion during erotic stimulus in healthy premenopausal women but improves sexual arousal and orgasm in a minority of women suffering from sexual disorders.77–79 Dopamine  In rats, dopamine (DA) levels increase in the MPOA, Nac, and dorsal striatum during copulation but also in association with anticipatory aspects of sexual activity.80–82 Pharmacological studies showed that the effects of dopaminergic agonists or antagonists on female lordosis are variable and can have both facilitatory and inhibitory effects, according to the hormonal status of the females.83 Overall, the D1-like receptors, especially D5, play a critical role in the control of lordosis.84,85 However, which DA receptor subtypes control female appetitive behaviors remains unclear. A recent study conducted in humans showed an association between the D4 receptor gene and scores in scales measuring human sexual behavior including desire, arousal, and function.86 Serotonin (5-HT)  Selective serotonin reuptake inhibitors (SSRIs) are noted for their inhibitory effects on female sexual behavior. Decreased libido, arousal difficulties and delayed orgasm or anorgasmia are often reported by patients treated with antidepressant and antipsychotic drugs which directly or indirectly act on 5-HT  receptors.39,87 However, inhibitory side effects vary from some antidepressant to others. Fewer adverse sexual effects can be observed when the antidepressant drug interact

with dopaminergic or noradrenergic systems known as ­facilitatory effects on sexual behavior.88–90 In rats, the descending serotoninergic pathways originating in the nPGi inhibits spinal sexual reflexes.91,92 However, in female rat, sexual behavior can be both facilitated and inhibited by 5-HT, depending on which subtypes of 5-HT receptors are activated.93,94 5-HT1A receptors mediate inhibitory effects on female lordosis, whereas activation of 5-HT2A/2C receptors facilitate not only female receptivity but also appetitive behaviors.95–-97 Melanocortin  The melanocortin system is involved in the control of both appetitive and consummatory components of female sexual behavior. Administration of α-melanocyte stimulating hormone (α-MSH) in the lateral ventricle, MPOA, VMN, median eminence, or zona incerta enhances female lordosis.98–103 Melatonan-II and bremelanotide (PT-141), two peptides analogs of α-MSH, selectively increase proceptive behaviors, such as solicitation and hops and darts, without affecting lordosis.104,105 The facilitatory effect of these peptides on female sexual desire is located within the MPOA.106 A positive effect of bremelanotide, a nonselective agonist of MC receptors, on sexual desire in premenopausal women with sexual arousal disorder has been reported, and the clinical development of this compound is continued.107 Oxytocin and vasopressin  Data from human and animal studies suggested that OT might be involved in the control of sexual desire, arousal, and orgasm. In female rats, OT and AVP have opposite effects on female sexual behavior. Although OT enhances proceptivity, AVP, through 1a subtype vasopressin receptors, decreases it. Whereas injection of OT antagonist decreases proceptive behaviors and increases male-directed agonistic behavior.108–112 OT and AVP actions are localized in the MPOA suggesting that both neuropeptides can act synergistically between the MPOA, PVN and the VMH, to contribute to the regulation of female sexual behavior. OT may also be involved in the control of orgasm, and could act synergistically with sex hormones to facilitate muscle contractions. Opioids  In women, long-term opioids use has been associated with anorgasmia, absence of menstrual periods, elimination of sexual dreams, and infertility in some cases.113 The effects of acute opioid administration on sexual behavior are very different from long-term opioids use. For example, opioid users describe the acute administration of heroin as producing an instantaneous, orgasm-like rush of euphoria.114 Endogenous opioids

Physiology of normal sexual function appear to be released during genital stimulation and orgasm, and may play an important role in the euphoric feeling of orgasm by binding to opioid receptors in the amygdala, the MPOA, the PVN, the NST, and/or cingulate cortex and by mediating the activation of other brain structures that receive projections from these areas. Opioids receptors are differently involved in the control of female sexual behavior. In female rats, selective μ-opioid receptor agonists administrated in the lateral ventricle, MPOA, or VMN inhibit the lordosis reflex, whereas δ-opioid receptor agonists, when injected in the lateral ventricle but not in the MPOA, have a facilitatory effect on both proceptive and receptive behaviors.115–117

Male sexual function The different aspects of male sexual function include sexual desire, erection, ejaculation, and orgasm. Little is known about the physiology of male sexual desire, and this issue deserves a detailed paragraph in the present review. Sexual desire, also termed libido in humans, is defined as the biological need for sexual activity. It encompasses detection of a suitable mate, approach to it, and establishment of initial contact. Behaviors associated with sexual desire are highly variable and dependent of the context.

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Penile erection Neuroanatomy of the penis The penis is composed of three cylindrical spongy ­bodies, the paired corpora cavernosa and the corpus spongiosum, which surround the urethra (Figure 4.4). The corpora ­cavernosa lie side by side on the dorsal aspect of the penis, whereas the corpus spongiosum stands ventrally. At the level of the perineum, the corpora cavernosa split bilaterally to form the penile crura, each crus being attached to the p ­ elvis via the ischiopubic ramus. The distal part of the corpus spongiosum expands and covers the distal part of the corpora cavernosa to form the penile glans. The penile skin is continuous with that of the abdominal wall and c­ overs the glans of the penis as the prepuce to reattach at the coronal sulcus. Corpora cavernosa and corpus s­ pongiosum share common microscopic features. These formations consist of sinuses (trabeculae) lined by endothelium and separated by connective tissue septa. Surrounding the corpora cavernosa is the tunica albuginea. This multilayered structure of inner circular and outer longitudinal layers of connective tissue affords great flexibility, rigidity, and ­tissue strength to the penis. The inner coat contains the cavernous tissue and supports it by radiating throughout the ­cavernosum bodies. The outer coat extends from the penile glans to the proximal crura and provides strength to the tunica albuginea. The tunica albuginea is composed of fibrillar collagen in organized arrays interlaced with elastin fibers.

Superficial dorsal vein

Dorsal artery

Dorsal nerve

Deep dorsal vein Circumflex vein

Corpus cavernosum

Tunica albuginea

Cavernosal artery

Corpus spongiosum Urethra Urethral artery

Figure 4.4 Transverse section of the penis.

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The vascular components of the penis are of particular importance in erectile function (Figure 4.4). The blood supply to the penis is primarily provided by the internal pudendal artery, a branch of the internal iliac artery. Alternatively, main blood supply to the erectile tissue can be provided by accessory internal pudendal arteries. After passing through the Alcock’s canal, the internal pudendal artery becomes the common penile artery that, at the level of the perineum, gives off the bulbourethral, cavernosum, and dorsal penile arteries. The bulbourethral artery supplies the urethra and the glans. The cavernosal arteries, which run in the corpora cavernosa, furnish the trabecular erectile tissue with blood. The dorsal penile artery proceeds down the penis on its dorsal aspect to supply superficial components of the penis. The venous drainage system of the penis occurs at three levels. Superficially, on the dorsal aspect of the penis, the superficial dorsal vein drains the skin into the external pudendal veins. The intermediate system consists of the deep dorsal and circumflex veins. The deep dorsal vein receives blood from emissary veins, which arise from subtunical venules draining trabeculae and passing through the tunica albuginea, and circumflex veins. In the infrapubic region, the deep dorsal vein drains into the pelvic preprostatic venous plexus or the internal pudendal veins. The deep drainage system includes the crural and cavernosal veins that drain the deeper cavernous tissue and empty into the internal pudendal veins. The innervation of the penis is provided by ­sympathetic, parasympathetic, and somatic (motor and sensory) s­ ystems. Sympathetic preganglionic fibers arise from preganglionic neurons located from the twelfth thoracic to the second lumbar spinal cord segments (T12–L2) in humans. The sympathetic preganglionic fibers travel ­throughout the thoracic paravertebral sympathetic chain and then via the lumbar splanchnic nerves to the prevertebral ganglia in the inferior mesenteric and superior hypogastric plexi. From there, fibers reach pelvic plexus via the hypogastric nerves. In addition, sympathetic preganglionic axons synapse with ganglion cells in the sacral and caudal lumbar ganglia of the paravertebral sympathetic chain and then, postganglionic fibers reach the pelvic plexus via the pelvic nerves. The parasympathetic preganglionic fibers originate in neurons located in the second, third, and fourth sacral spinal cord segments (S2–S4) in humans. The parasympathetic preganglionic fibers traveling via the pelvic nerve join sympathetic nerves to form the pelvic plexus. One branch of the pelvic plexus that innervates the penis is the cavernous nerve. Autonomic fibers passing in the cavernous nerve provide innervation to cavernosal smooth muscle cells as well to the arterial supply of the penis. Sacral motor neurons (S2– S4) also send projections, via the pudendal nerves, to the ischiocavernosus muscles. Their rhythmic contractions reinforce penile erection by compression of the engorged corpora cavernosa. The somatic sensory pathway consists of the dorsal nerve of the penis, a sensory branch of the pudendal nerve. The dorsal nerve of the penis carries

impulses to the upper sacral segments of the spinal cord from sensory receptors harbored in the penile skin, prepuce, and glans. Encapsulated receptors (Krause-Finger corpuscles) have been found in the glans but the majority of afferent terminals are represented by free nerve endings.118

Local control of penile erection Penile erection corresponds to engorgement of the penis with blood and takes place when dilation of the penile arteries, mechanical occlusion of veins draining erectile tissue (emissary veins) because of the rigidity of the tunica albuginea, and relaxation of the smooth cells of the erectile tissue occur. (Figure 4.5). Both arterial and erectile tissue relaxations rely on a change in the tone of the arterial wall smooth muscle fibers and of the erectile tissue (trabeculae of the corpora cavernosa). It is the amount of intracellular, cytoplasm calcium that controls the tone of smooth muscle fibers. Increasing this amount, through releasing calcium from intracellular stores (sarcoplasmic reticulum) and/or facilitating its entry from the extracellular milieu leads to contraction. At the flaccid state, smooth muscle fibers of the penis and penile arteries are contracted. During erection, the smooth muscle fibers of the penis and penile arteries are relaxed. Depending on the smooth muscle fibers involved, intracellular calcium movements are either spontaneous or controlled by information from the extracellular milieu. With regards to the penis, this information is carried by a variety of chemical messengers that are released by both endothelial cells and autonomic nerve terminals. Chemical messengers either interact with specific receptors present at the surface of the smooth muscle fibers membrane, or cross the membrane to reach intracellular targets. Erection is mainly due to the increased synthesis of two intracellular second messengers, the cyclic nucleotides guanosine monophosphate (cGMP) and adenosine monophosphate (cAMP). cGMP and cAMP are degraded by phosphodiesterases. The proerectile chemicals facilitate synthesis or accumulation, or prevent degradation of cGMP and/or cAMP. Increasing the amounts of intracellular cGMP and cAMP leads to relaxation. Because smooth muscle fibers of the penis are connected with gap junctions, it is not required that chemical messengers reach all of the cells to elicit an effect. Indeed gap junctions allow for a rapid spread of electrotonic current and intercellular diffusion of second messengers and ions.119 The neurotransmitters released by the postganglionic nerve terminals of the sympathetic and parasympathetic pathways in the penis are of particular importance in the local control of erection. NA and NPY are released in the erectile tissue by the terminals of sympathetic fibers. NA is the major contractile agent of the cavernosal as well as penile arteries smooth muscle cells, and NPY enhances its effects. NA plays a role in flaccidity and detumescence.120 The terminals of parasympathetic fibers release Ach, VIP,

Physiology of normal sexual function Tunica albuginea

Helicine artery

Emissary vein

Sinus

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Constriction of vein

Dilatation of artery

Flaccidity

Expansion of sinus Erection

Figure 4.5 Vascular events occurring during erection. Vasodilatation of helicine arteries increase blood inflow in corpus cavernosum sinuses that, by expanding, press emissary veins against the rigid tunica albuginea resulting in decreased blood outflow. The final outcome is blood engorgement of the corpora cavernosa, resulting in increased volume and rigidity of the penis.

and NO. Ach contracts cavernosal smooth muscle in vitro; and erection is rather resistant to the cholinergic antagonist atropine. In fact, Ach activates the synthesis of NO by NO synthase in endothelial cells through muscarinic receptors located on endothelial cells. The relaxant effects of VIP121 and NO122,123 released by nerve terminals in the penis have been demonstrated. NO increases the production of cGMP in smooth muscle fibers, and it is recognized as the most important factor of the local relaxation of erectile tissue smooth muscle. The importance of this mechanism in humans is supported by the successful development of phosphodiesterase type-5 inhibitors, which prevent catabolism of cGMP, in the treatment of erectile dysfunctions.124

Spinal control of penile erection The spinal cord contains three sets of neurons (thoracolumbar sympathetic, sacral parasympathetic, and sacral somatic) that are anatomically linked with the penis and functionally involved in the erectile response elicited by any kind of sexual stimulation, i.e., peripheral and/or central. The majority of the sympathetic preganglionic cell bodies, whose axons run in the paravertebral sympathetic chain, are located in the intermediolateral cell column of T12–L2 spinal segments. Other sympathetic preganglionic neurons, which send axons into the hypogastric nerve, originate in the DGC.125 The cell bodies of the preganglionic parasympathetic neurons are located in the intermediolateral cell column of the S2–S4 segments of the spinal cord in an area referred to as the SPN. In humans, the sacral motor neurons are located in the ventral cord of the S2–S4 spinal segments in the Onuf’s nucleus. In rats, two distinct nuclei (dorsomedial and dorsolateral nuclei) constitute the Onuf’s nucleus;

the somatic motor neurons innervating ischiocavernosus muscles being found in the dorsolateral nucleus.126 The different spinal centers involved in the control of erection are reciprocally connected, allowing the synchronization of the peripheral events leading to erection.126 The spinal cord represents a key structure integrating excitatory and inhibitory information from the periphery and from supraspinal nuclei. Erection likely occurs when the convergence of peripheral and supraspinal information onto the spinal cord lowers the activity of the thoracolumbar sympathetic anti-erectile pathway and increases the activity of both the sacral parasympathetic and somatic pro-erectile pathways. There also may be a proerectile role for a component of the sympathetic innervation, which is responsible for vasoconstriction of nonpenile areas to divert blood to the penis.127 The primary role of afferent signals from genitalia in the induction of erection (i.e., reflexive erection) is well documented. In anesthetized rats, evoked potentials are recorded on the cavernous nerve in response to electrical stimulation of the dorsal nerve of the penis.128 In addition, stimulation of the dorsal nerve of the penis induces intracavernosal pressure rise and contraction of the perineal striated muscles.128,129 In humans too, genital stimulation elicits penile erection, an increased blood flow to the penis, and contraction of the perineal striated muscles.130,131 These data indicate that stimulation of penile sensory pathways is able to recruit the different autonomic and somatic nuclei of the spinal cord that control erection. Several lines of evidence indicate that the spinal cord contains the necessary circuitry for producing penile erection. In animals with a complete section of the spinal cord at the thoracic level, genital stimulation can

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elicit reflexive erection, contraction of the perineal striated muscles, and movements of the hind limbs, which are mediated by the spinal segments lower than the lesioned ones.132,133 Reflexive erections are also observed in patients with a lesion of the spinal segments upper than the sacral ones.134,135 Not only has the spinal cord to manage with the circuits of erection, but also it is responsible for the coordination of erection with other sexual responses such as ejaculation, and the inhibition of the activity of other pelvic functions such as micturition and defecation. The hyperreflexia, dyssynergia, altered erection, and/or ejaculation observed in patients with a lesion of the spinal cord reflect the important role of supraspinal structures in this coordination.

effect on erections during copulation, facilitate reflexive erections but depress noncontact erections.148 Among the supraspinal neurologic conditions that can cause erectile dysfunction through alteration of central pathways are brain tumor, stroke, encephalitis, Parkin­ son’s disease, dementias, olivopontocerebellar degeneration (Shy–Drager syndrome), and epilepsy of the temporal lobe.149 In contrast, erections occur after lesions of the pyriform cortex and amygdaloid complex (the Kluver– Bucy syndrome).

Supraspinal control of penile erection

The precise role of endogenous substances in the regulation of one sexual aspect is difficult to define because of the wide range of sexual parameters affected, species differences, conflicting results depending on the site ­ in the CNS where the substance acts, and the existence of receptor subtypes possibly with opposite action. An extensive review of the studies dealing with the central neurochemical regulation of sexual behavior is beyond the scope of the present review and has been proposed elsewhere.150,151 Here, we present briefly the data directly related to ­erectile and ejaculatory (in the Section “Central physiology of ejaculation”) functions. Depending on the site of action and the 5-HT receptor subtype activated, 5-HT enhances or inhibits erection. Activation of spinal 5-HT1A receptors inhibits reflexive erection,152 whereas spinal 5-HT2C receptors are thought to enhance erectile activity.153 The involvement of DA in penile erection was first suggested by the observation of enhanced erection in Parkinson’s patients treated with DA agonists.154 Later, it was demonstrated in rats that stimulation of D1 or D4 receptors in PVN155,156 and D1 or D2/3 receptors in spinal cord157 can produce erection. In addition, it was recently found that the microinjection of a D4 agonist into the PVN elicited penile erection in rats. The D1/D2-like agonist apomorphine has been registered in Europe for the treatment of erectile dysfunction, although its use is limited because of frequently occurring side effects as well as limited efficacy.158 Conversely to the periphery where it has been evidenced that adrenaline and NA can exert anti-erectile activity by acting on α1 adrenoreceptors,159 brain α2 adrenoreceptors stimulation was found to inhibit erections.160 OT can trigger erection in rats when injected into the PVN and hippocampus161 as well as by acting on OT receptors located in the lumbosacral spinal cord.162 Morphine, a preferential agonist for μ-opioid receptor subtypes, injected into the PVN prevents noncontact penile erections that occur in male rats in the presence of an inaccessible sexually receptive female.163 In addition to the primary proerectile role of NO locally produced in erectile tissue, this substance has been involved as an important proerectile messenger in

In humans and animals, penile erection occurs in several contexts, some of which are not related to sexual context (in utero or during paradoxical sleep). It is possible that several different areas of the brain contribute to the occurrence of erection in the different circumstances.136 Each context may reflect the contribution of a unique combination of several brain nuclei, and one brain nucleus may participate in the occurrence of erection in several contexts. The participation of each nucleus in erection depends on the amount of excitatory and inhibitory information it receives from the periphery and from other central nuclei, and in a lesser extent to its hormonal environment. The first candidates to a role in the supraspinal control of erection are those nuclei containing neurons that project directly onto the sacral spinal cord. Such neurons have been detected in a variety of areas of medulla oblongata (raphe nuclei, nPGi, locus coeruleus, and Barrington’s nucleus), pons (A5 noradrenergic cell group and PAG), and hypothalamic PVN in neuronal tracing experiments in rats.137 Investigation of the immediate early gene c-fos pattern of expression, which reflects neuronal activity at a given time, led to the identification of neurons in forebrain regions (MPOA, bed nucleus of stria terminalis [BNST], and MeA) that are activated following sexual behavior in male rats.55,138,139 Attempts to demonstrate the role of these brain structures in the control of erection have evidenced the MPOA as a key structure.140–142 MPOA is not a source of direct projections to the spinal cord, instead it integrates sensory and hormonal signals and projects to brain nuclei in direct connection with the spinal centers involved in the control of erection. One of these brain nuclei of particular importance is the PVN, more particularly the parvocellular part. It contains neurons that send direct oxytocinergic and vasopressinergic projections to the lumbosacral cord whose strong involvement in the control of erection has been reported.143–145 The nPGi provides descending serotoninergic fibers to the lumbosacral cord, which exert an inhibitory tone on spinal erection reflex.143,146,147 Finally, lesions of the MeA, which have no

Central neurochemical regulation of penile erection

Physiology of normal sexual function the CNS, and especially within the PVN.164,165 NO seems to play a pivotal role because DA and OT induce NO release in PVN; and NO-synthase inhibitors delivered within PVN reverse the proerectile effect of dopamine and OT.166 Adrenocorticotropic hormone (ACTH) and α-MSH are peptides derived from a common precursor, proopiomelanocortin. Both ACTH and α-MSH can trigger penile erection when injected in cerebral ventricles of rats167,168 by acting on melanocortin receptors.168 In erectile dysfunction patients, the use of the melanocortin 3/4 receptor subtypes agonist PT-141 (bremelanotide) has proven effective in restoring erectile function.169

Ejaculation Spermatozoa transported from the epididymis, secretions of the bulbourethral glands, prostate, and seminal vesicles compose the sperm. In the human male, the fluid is released from the glands in a specific sequence during ejaculation. The first portion of the ejaculate consists of a small amount of fluid from the bulbourethral glands. This is followed by a low-viscosity opalescent fluid from the prostate containing a few spermatozoa. Then the principal portion of the ejaculate is secreted, which contains the highest concentration of spermatozoa, along with secretions from the epididymis, and vas deferens, as well as prostatic and seminal vesicle fluids. The last fraction of the ejaculate consists of seminal vesicle secretions.

Anatomical organization of sexual organs involved in ejaculation The importance of the autonomic nervous system in regulating the ejaculatory response is well documented. All of these organs receive a dense autonomic innervation composed of sympathetic and parasympathetic axons mainly coming from the pelvic plexus. In addition to adrenergic and cholinergic mechanisms of regulation of ejaculation, NANC factors including ATP,170–172 NPY,173,174 VIP,175,176 and NO122,176 have been shown to have a direct participation in the peripheral control of ejaculation. Two main categories of anatomical structures involved in ejaculation can be distinguished depending on the phase they participate in. ••

Organs of emission synthesize, secrete, and/or transport to the urethra the different components of the semen. They include 1. The epididymis in which spermatozoa undergo final maturation and storage before ejaculation. 2. The ductus (or vas) deferens that exhibits peristaltic contractions during the emission phase to transport spermatozoa from the epididymis to the urethra. The ductus deferens widens as it enters the urethra to form the ampulla of the ductus deferens.

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3. The seminal vesicles, a pair of tubular glands, whose stroma is composed of smooth muscle layers and whose epithelial cells produce 50%–80% of the entire ejaculatory volume. 4. The prostate gland, which can be considered as a tangle of fibromuscular tissue and alveolar epithelium, secretes 15%–30% of the seminal fluid. 5. The bulbourethral glands, or Cowper’s glands, are closely invested by a layer of striated muscle, namely bulboglandularis, and produce a very small amount of fluid. ••

Organs and anatomical structures participating in expulsion allow forceful propelling of sperm in anterograde direction, to the urethra meatus. They include 1. The bladder neck, also known as the internal urethral sphincter, is composed of smooth muscle cells that firmly contract during expulsion to prevent sperm to flow backward into the bladder. 2. The urethra is a stratified epithelium surrounded, over about half of its length, by circular striated muscle forming the external urethral sphincter (or rhabdosphincter) that exhibits intense contractions interrupted by silence period during expulsion. 3. The perineal striated muscles, which include levator ani, ischiocavernosus and bulbospongiosus muscles, with the latest having a preponderant role, rhythmically contract during the expulsion phase to propel semen throughout the urethra.

Peripheral neural pathways Afferents  The dorsal nerve of the penis, a sensory branch of the pudendal nerve, carries impulses to the lower lumbar and upper sacral segments (sacral in human) of the spinal cord from sensory receptors harbored in the penile skin, prepuce, and glans (Figure 4.2).177,178 Encapsulated receptors (Krause-Finger corpuscles) have been found in the glans but the majority of afferent terminals are represented by free nerve endings.118 A second afferent pathway is constituted by fibers traveling along the hypogastric nerve and, after passing through the paravertebral lumbosacral sympathetic chain, enters the spinal cord via thoracolumbar dorsal roots.179 Sensory afferents terminate in the medial dorsal horn and the DGC of the spinal cord.11,12 Efferents  The soma of the preganglionic sympathetic neurons are located in the intermediolateral cell column and in the central autonomic region of the thoracolumbar segments of the spinal cord.180,181 The sympathetic fibers, emerging from the spinal column via the ventral roots,

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relay in the paravertebral sympathetic chain. In the majority of mammalian species, the fibers then proceed whether directly via the splanchnic nerves or after relaying in the coeliac superior mesenteric ganglia via the intermesenteric nerves to the inferior mesenteric ganglia.182 Emanating from the inferior mesenteric ganglia are the hypogastric nerves that form, after joining the parasympathetic pelvic nerve, the pelvic plexus from which fibers arise innervating the anatomical structures involved in ejaculation (Figure 4.2). The cell bodies of the preganglionic parasympathetic neurons are located in the intermediolateral cell ­column of the lumbosacral segments of the spinal cord, i.e., SPN.11 The SPN neurons send projections, traveling in the pelvic nerve, to the postganglionic cells located in the pelvic plexus. Efferents of somatic motor neurons, whose cell b ­ odies are found at the lumbosacral spinal level (sacral level in man) in the Onuf’s nucleus, exit the ventral horn of the medulla and proceed via the motor branch of the pudendal nerve to the pelvic floor striated muscles, ­ including b ­ ulbospongiosus and ischiocavernosus muscles (Figure 4.2).183

Functional considerations Sensory nervous system Sensory inputs originating in genital area have been shown sufficient to provoke ­ expulsion reflex or even complete ejaculatory response (forceful expulsion of semen). Contractions of ­ bulbospongiosus muscles measured in a man with electromyographic electrodes were evidenced following electrostimulation of the penile dorsal nerve, mechanical distension of the posterior urethra, and magneto­ stimulation of the sacral root.184–186 These procedures are currently used in routine to evaluate the integrity of neural pathways controlling ejaculation and have also served as basis for developing a method that produces ejaculation in patient with n ­ eurogenic ­anejaculation. This method, namely penile vibratory stimulation, consists in placing a vibration-delivering device on the glans of the penis, either the dorsum or frenulum, and applying mechanical ­v ibrations.187,188 Penile vibratory stimulation allowed to obtain complete ­ejaculatory response in a significant number of men with spinal cord injury.187 Autonomic nervous system  Both sympathetic and parasympathetic tones act in a synergistic manner to initiate seminal emission by activating smooth muscle contraction and epithelial secretion, respectively, throughout the seminal tract. From experimental studies carried out in different ­animal species, it has been demonstrated that activation of the sympathetic nervous system, whether by stimulating sympathetic nerves (hypogastric or splanchnic) or

using sympathomimetic agents, elicited strong contractile response in the ducti deferens,189 seminal vesicles,190 prostate,191 and urethra.191 Secretions by prostate and ­seminal vesicles are under control of cholinergic mechanism, although it is not clear whether parasympathetic fibers conveyed by the pelvic nerves are involved. It was suggested  that, contrary to the conventional view of the organization of pelvic autonomic pathways, sympathetic innervation to the prostate includes both adrenergic and cholinergic components. In addition to adrenergic and cholinergic commands, peptidergic (VIP and NPY)192,193 and purinergic (ATP)194,195 regulation of NA action on genital tract have been demonstrated in laboratory animals. In humans, disruption of sympathetic pathways supplying the bladder neck, ductus deferens, and prostate is widely accepted to be the cause of postoperative anejaculation or retrograde ejaculation.196,197 The essential role of sympathetic innervation is best illustrated by surgical strategies that, by sparing sympathetic efferents, successfully preserve normal ejaculatory function in patients who have undergone retroperitoneal lymphadenectomy for testicular cancer or resection for rectal cancer.198,199 In addition, in paraplegic men whose ability to ejaculate is commonly severely impaired, semen was obtained on electrical stimulation of the hypogastric plexus.200 As far as we know, there is no clear clinical evidence for a functional role of parasympathetic innervation in the ejaculatory process. Somatic nervous system The expulsion phase of ejaculation is under the sole control of the somatic nervous system. Forceful propulsion of semen out of the urethra via the glans meatus is caused by rhythmic contractions of perineal muscles and smooth muscles and sphincter of the urethra. Owing to the fact that relatively noninvasive measurement of perineal muscles activity is possible in humans, expulsion phase has been shown to be characterized by synchronous activation of ischiocavernosus, bulbospongiosus, and levator ani muscles and anal and urethral external sphincters.201,202 In case of lesion of the pudendal nerves, as it may occur after trauma203 or neuropathy related to diabetes,204 retrograde and/or dribbling ejaculation is observed.

Central physiology of ejaculation As described previously, the sympathetic and parasympathetic nervous systems, closely interconnected in the pelvic plexus, which represents an integrative peripheral crossroad site, act in synergy to command physiological events occurring during ejaculation. Both sympathetic and parasympathetic tones are under the influence of sensory genital and/or cerebral erotic stimuli integrated and processed at the spinal cord level.

Physiology of normal sexual function Spinal network  The thoracolumbar sympathetic and lumbosacral parasympathetic spinal ejaculatory nuclei play a pivotal role in ejaculation as they integrate peripheral and cerebral signals and send coordinated outputs to pelvic organs that allow a normal ejaculation to occur. Integrity of these spinal nuclei is necessary and sufficient for the expression of ejaculation as demonstrated by the induction of ejaculatory reflex after peripheral stimulation in animals with spinal cord transection and humans after spinal cord lesion.52,187 The conversion of sensory information into secretory and motor outputs involves spinal interneurons, which have been recently identified in rats.205 The presence of these cells, named lumbar spinothalamic (LSt) cells, has been shown in laminae X and VII of the spinal lumbar segments 3 and  4. Immunohistochemical investigations have shown that LSt neurons contain galanin, cholecystokinin, enkephalin, and gastrin-releasing peptide.206 They also express receptors for SP, glutamate, and androgens. LSts have been found sexually dimorphic in rats, with males possessing a great number of these neurons.207 In rat, spinal cord fibers of the sensory branch of the pudendal nerve terminate close to

T13–L2 (rat) T12–L1 (human)

L3–L4 (rat) L3–L5 ? (human)

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LSt,12 although a direct connection has not been proved yet. Brain neurons sending direct projections onto  LSt have been detected in caudal raphé and gigantocellular nuclei, and in lateral hypothalamus (LH) in rat.208,209 LSt neurons project to the sympathetic and parasympathetic preganglionic neurons innervating the pelvis as well as the motor neurons of the dorsomedial nucleus innervating the bulbospongiosus muscles (Figure 4.6).210 In addition, LSt neurons send direct projection to the parvocellular subparafascicular nucleus of the thalamus.211 Finally, electrical microstimulation focused on LSt can trigger ejaculation in anesthetized rats with intact or sectioned (thoracic level) spinal cord.212 All these data support a crucial role for LSt in coordinating the spinal control of ejaculation. The existence of LSt is not demonstrated in humans although clinical observations, especially in spinal cord injured men, suggest its presence in L3–L5 segments. The current understanding of LSt neurons functioning is that both peripheral and brain stimulatory and inhibitory outputs are summated in the LSt neurons and, once an excitatory threshold is reached, a programmed

DGC

IML

Seminal tract

LSt

BS muscle

SPN L6–S1 (rat) S2–S3 (human) DM

Figure 4.6 Schematic view of the spinal network of ejaculation. The lumbar spinothalamic neurons (LSt) projects to (i) thoracolumbar sympathetic centers including dorsal gray column (DGC) and intermediolateral nucleus (IML), (ii) lumbosacral parasympathetic centers including sacral parasympathetic nucleus (SPN), (iii) lumbosacral somatic centers including dorsomedial nucleus (DM). These autonomic and somatic spinal centers control seminal tract and bulbospongiosus (BS) muscle. Note that the location of LSt neurons in L3–L5 segments in humans is putative.

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sequence is generated and activates autonomic and somatic spinal centers commanding ejaculation. LSt neurons present features specific to central pattern generator213 in that they 1. Determine appropriate sequences of smooth followed by striated muscles activation 2. Provide a rigidly fixed action pattern, not subject to adaptation 3. Are sets of interneurons that assemble themselves into ordered network capable of controlling the activity of spinal preganglionic and motor neurons 4. Possess a high degree of autonomy in output Brain network  As a centrally integrated and highly coordinated process, ejaculation involves cerebral sensory areas and motor centers that are tightly interconnected (Figure 4.3). Recent findings, based on studies investigating c-fos pattern of expression, have revealed, in distinct species, brain structures specifically activated when the animals ejaculate.139,214 As a whole, these data strongly suggest the existence of a cerebral network specifically related to ejaculation, which is activated whatever be the preceding sexual activity, i.e., mounts and intromissions in rats. The brain structures belonging to this cerebral network comprise discrete regions lying within the posteromedial BNST (BNSTpm), the posterodorsal medial amygdaloid (MeApd) nucleus, the posterodorsal preoptic nucleus (PNpd), and the parvicellular part of the subparafascicular thalamus (SPFp). Reciprocal connections between those substructures and the MPOA of the hypothalamus, a brain area known as essential in controlling sexual behavior,215 has been reported in anatomical and functional studies.214,216 The pivotal role of MPOA in ejaculation has been documented in several experiments where both phases of ejaculation were abolished after MPOA lesion217 or elicited after chemical218,219 or electrical220 stimulations of this brain area. Neuroanatomical studies have shown that MPOA do not project to spinal cord but do project to other brain regions involved in ejaculation such as the PVN,221 the PAG,222 and the nPGi.223 The PVN has long been known as a key site for neuroendocrine and autonomic integration.224 Parvocellular neurons of the PVN directly innervate autonomic preganglionic neurons in the lumbosacral spinal cord and pudendal motor neurons located in the L5–L6 spinal segment in rats.225 Retrograde and antegrade tracing studies have shown that SPFp sends projections to BNST, MeA, and MPOA 226 and receives inputs from LSt cells.205 These data suggest a pivotal role for SPFp although functional investigations are lacking. The other forebrain structures that have been proposed, based on c-fos pattern of expression, to take part in regulation of the ejaculatory process in rat are MeA, BNST, and PNpd.139,216 Their precise roles remain unclear but they

may be involved in the relay of genital sensory signals to the MPOA. In the brainstem, a strong inhibitory role for nPGi, which projects to pelvic efferents and interneurons in the lumbosacral spinal cord,91,227 on ejaculation in rats has been suggested from investigations using an experimental model mimicking the expulsion reflex.91,228 In addition, PAG, which constitutes a relay between MPOA and nPGi, was found important in controlling expulsion reflex.216,229 Clearly, midbrain structures exert a regulating function on ejaculation but further investigations are required for revealing the details of the mechanism. Recently, study using PET to investigate increases in regional cerebral blood flow in humans during ejaculation showed that the strongest activation occurs in mesodiencephalic transition zone including VTA, medial and ventral thalamus, and SPFp.230 Regarding the role of neocortex in ejaculation, several studies have shown the intense activation of the parietal cortex during ejaculation by PET and functional magnetic resonance imaging (fMRI) techniques.230,231 This brain area is considered as a site that receives sensory information from pudendal sensory nerve fibers.232 Neurochemical regulation Similar to the erectile function, various neurotransmitters and neurohormones participate in the control of ejaculation. However, less is known about the neurochemical regulation of ejaculation despite the recent progress in this field. Several lines of experimental evidence support the involvement of dopamine in ejaculation. It was shown that D2/D3 receptors stimulation promotes seminal emission and ejaculation in conscious rats and trigger ejaculation in anesthetized rats likely by acting in MPOA.233,234 A great body of evidence supports the inhibitory role of cerebral 5-HT on ejaculation in the rat model. The stimulation of somatodendritic 5-HT1A autoreceptors regulating 5-HT neurons firing has been demonstrated to shorten the ejaculatory latency time.235 However, as suggested by Rehman et al.,236 5-HT1A receptors at different locations (brain, raphe nuclei, spinal cord, and autonomic ganglia) may modulate ejaculation in opposing ways. Stimulation of postsynaptic 5-HT2C receptors was responsible for inhibition of male rat ejaculatory behavior.237 In humans, as well, 5-HT tone is major in the control of ejaculation with, globally, an inhibitory action. Lengthened ejaculation latency is a frequent side effect of the antidepressants SSRIs, which increase 5-HT bioavailability within the CNS.238 This led to the development of dapoxetine, the first authorized medicine for the treatment of premature ejaculation effective on demand. Activation of the cholinergic muscarinic receptors in MPOA has been shown to reduce the ejaculatory threshold in copulating male rats.239 Delivered either systemically or centrally, OT decreases ejaculation latency and postejaculatory interval (i.e., refractory period) in copulating male rats.240

Physiology of normal sexual function Orgasm  The orgasm is undoubtedly one of the most pleasurable sensations known to humankind and has been associated with reward in rats,241 although very little is known about the underlying physiological mechanisms that control orgasmic responses. Orgasm is a cerebral process that usually follows a series of peripheral physical events comprising contraction of accessory sexual organs and urethral bulb, buildup and release of pressure in distal urethra. It is noteworthy that orgasm is reported by patients who do not ejaculate anymore, e.g., after radical prostatectomy.242,243 Furthermore, orgasmic sensations generated cerebrally without input from genitals or without ejaculation have been reported in humans.244 These clinical data indicate that the emission of sperm as well as its expulsion are not mandatory for orgasm to occur and support a distinction between ejaculation and orgasm from a physiological perspective.

Conclusion Although individuals may differ in their experience of pleasure and subjective feeling during sexual ­intercourse, a common human sexual response, consisting of four interactive phases (excitement, arousal, orgasm, and resolution), has been defined and refers to both men and women. Indeed, in both sexes, sexual behavior occurs as a sequence of behavioral events including appetitive and consummatory components that are, according to the incentive sequence model,245 the same for both sexes. Interestingly, the physiological correlates and the neural mechanisms controlling these sexual responses also

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share numerous commonalities between male and female (reviewed by McKenna246) (Table 4.1): 1. Male and female genitalia are anatomically very different, but the clitoris can be viewed as somewhat analogous of the penis, with comparable neuroanatomical organization and similar vasocongestion during sexual arousal. 2. Peripheral innervation of the genital organs is comparable between male and female, with sensory afferents conveyed by the pudendal, pelvic, and hypogastric nerves, and efferent outflows arising from multiple segments of the spinal cord. 3. The multisynaptic circuitry controlling sexual responses is remarkably similar between males and females, with the likely exception of the vagus nerve for females. Neuronal activation induced by copulation or PRV injection in the vagina and clitoris or in the penis results in a very comparable labeling in the lumbosacral segments of the spinal cord and neurons within the hypothalamus, midbrain, and brainstem. 4. In both sexes, genital sexual arousal and orgasm are controlled by a coordinated regulation between the sympathetic, parasympathetic, and somatic systems and are mainly the product of spinal reflexes. Studies in spinal cord injured patients or animals with spinal cord transection have shown that with adequate genital stimulation, the spinal cord can generate sexual responses. 5. In both sexes, spinal centers involved in the control of sexual responses are under excitatory and inhibitory inputs from the brain.

Table 4.1  C  omparison of genital peripheral physiological changes, neuroanatomical pathways, and neurotransmitters involved in the control of sexual responses in female and male Female

Male

Vagina, clitoris, pelvic striated muscles

Penis, organs of emission (epididymis, ductus deferens, seminal vesicles, prostate, and bulbourethral glands), organs of expulsion (bladder neck, urethra, pelvic striated muscles)

Afferent

Pelvic, hypogastric, pudendal (dorsal nerve of the clitoris), vagal

Pelvic, hypogastric, pudendal (dorsal nerve of the penis)

Efferent

Pelvic (parasympathetic), hypogastric (sympathetic), pudendal (somatic)

Pelvic (parasympathetic), hypogastric (sympathetic), pudendal (somatic)

Neuroanatomy Genital organs

Peripheral innervation

(Continued)

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Table 4.1  C  omparison of genital peripheral physiological changes, neuroanatomical pathways, and neurotransmitters involved in the control of sexual responses in female and male (Continued) Female

Male

Increased blood flow to vagina and clitoris

Erection:

Clitoral erection

Increased blood flow to the penis

Vaginal lubrication

Decreased outflow from the penis

Peripheral physiologic changes Genital arousal

Erectile tissue relaxation Orgasm

Rhythmic contractions of vagina, uterus and anal sphincter

Ejaculation: Emission: contraction of ductus deferens, seminal vesicles, prostate, urethra Expulsion: rhythmic contractions of perineal muscles and smooth muscles of the urethra

Spinal and supraspinal centers involved in sexual responses (identified by PRV injection in genital organs or Fos activation after copulation) Spinal

L5–S1: medial and lateral dorsal horn, SPN, DGC, Onuf ’s nucleus

T12–L1: IML, DGCL3–L4: LSt cells L5–S1: dorsal horn, SPN, Onuf ’s nucleus

Brain

MPOA, VMN, PVN, LH, arcuate nucleus, MeA, Nac, VTA, BNST, lateral septum, PAG, nPGi, Barrington’s nucleus, raphe magnus, raphe pallidus, A5 region

MPOA, VMN, PVN, LH, MeA, Nac, VTA, BNST, lateral septum, PAG, nPGi, SPFp, Barrington’s nucleus, raphe magnus, raphe pallidus, A5 region

DA

DA

5-HT

5-HT

OT

Androgens

Neurochemical control of sexual responses Sexual desire (central drive)

Melanocortin Estradiol, progesterone Genital arousal

DA (central)

DA (central)

5-HT (central)

5-HT (central)

OT (central)

NA (central and peripheral)

Opioids (central)

OT (central)

NO (central and peripheral)

Opioids (central)

Melanocortin (central)

NO (central and peripheral)

Estrogens

Melanocortin (central) Androgens (central and peripheral)

6. The MPOA and PVN play a critical role in the ­control of sexual responses and regulate both male and female sexual desire and genital arousal. These structures have numerous interconnections with PAG, MeA, which probably participate in sexual function.

In  females, the VMN is clearly involved in the  control of consummatory sexual behaviors, while its role in males remains to be investigated. 7. In males, descending serotonergic pathways from the brainstem, especially from the nPGi, exert an

Physiology of normal sexual function inhibitory control on spinal sexual reflexes. It seems probable that the same mechanism also occurs in female, although it has not been clearly evidenced. 8. Among the diversity of neurotransmitters and neuropeptides that can affect sexual responses, DA, 5-HT, OT, are believed to play a major role in both male and female sexual function. This chapter stated numerous similarities in the mechanisms controlling normal sexual function in male and female, and in particular a similar neural and neurochemical organization. However, it is important to notice a main discrepancy coming from the implication of the central drive that fundamentally differs between both sexes. In men, physiological performance, such as obtaining and maintaining a good erection, is sufficient to consider themselves as a good sexual partner and to enjoy sexual intercourse. In contrast, in women, the feeling of subjective arousal results more from central mechanisms, cognitive processes, and psychological changes than peripheral vasocongestive feedback. Further investigation and major advances need to be achieved in the future to help male and female patients complaining about sexual dysfunctions.

References 443. Beach FA. Sexual attractivity, proceptivity, and receptivity in female mammals. Horm Behav 1976; 7: 105–38. 444. Masters W, Johnson V. Human Sexual Response. Boston, MA: Little Brown, 1966. 445. Kaplan H. Disorders of Sexual Desire. New York: Simon and Schuster, 1979. 446. Levin RJ. Normal sexual function. In: Gelder MG, Lopez-Ibor JJ, Andreasen N, eds. New Oxford Textbook of Psychiatry. Oxford, United Kingdom: Oxford University Press, 2000: 875–82. 447. Bell C. Autonomic nervous control of reproduction: Circulatory and other factors. Pharmacol Rev 1972; 24(4): 657–736. 448. Janig W, McLachlan EM. Organization of lumbar spinal outflow to distal colon and pelvic organs. Physiol Rev 1987; 67(4): 1332–404. 449. Berkley KJ, Robbins A, Sato Y. Functional differences between ­afferent fibers in the hypogastric and pelvic nerves innervating female reproductive organs in the rat. J Neurophysiol 1993; 69(2): 533–44. 450. Peters LC, Kristal MB, Komisaruk BR. Sensory innervation of the external and internal genitalia of the female rat. Brain Res 1987; 408(1–2): 199–204. 451. Langworthy OR. Innervation of the pelvic organs of the rat. Invest Urol 1965; 2: 491–511. 452. Morgan C, Nadelhaft I, de Groat WC. The distribution of visceral primary afferents from the pelvic nerve to Lissauer’s tract and the spinal gray matter and its relationship to the sacral parasympathetic nucleus. J Comp Neurol 1981; 201(3): 415–40. 453. Nadelhaft I, Booth AM. The location and morphology of preganglionic neurons and the distribution of visceral afferents from the rat pelvic nerve: A horseradish peroxidase study. J Comp Neurol 1984; 226(2): 238–45. 454. McKenna KE, Nadelhaft I. The organization of the pudendal nerve in the male and female rat. J Comp Neurol 1986; 248(4): 532–49. 455. Ueyama T, Arakawa H, Mizuno N. Central distribution of efferent and afferent components of the pudendal nerve in rat. Anat Embryol (Berl) 1987; 177(1): 37–49.

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456. Berkley KJ, Robbins A, Sato Y. Afferent fibers supplying the uterus in the rat. J Neurophysiol 1988; 59(1): 142–63. 457. Komisaruk BR, Gerdes CA, Whipple B. ‘Complete’ spinal cord injury does not block perceptual responses to genital self-­stimulation in women. Arch Neurol 1997; 54(12): 1513–20. 458. Cueva-Rolon R, Sansone G, Bianca R et al. Vagotomy blocks responses to vaginocervical stimulation after genitospinal neurectomy in rats. Physiol Behav 1996; 60(1): 19–24. 459. Nadelhaft I, Roppolo J, Morgan C, de Groat WC. Parasympathetic preganglionic neurons and visceral primary afferents in monkey sacral spinal cord revealed following application of horseradish peroxidase to pelvic nerve. J Comp Neurol 1983; 216(1): 36–52. 460. Schroder HD. Onuf ’s nucleus X: A morphological study of a human spinal nucleus. Anat Embryol (Berl) 1981; 162(4): 443–53. 461. Marson L. Central nervous system neurons identified after injection of pseudorabies virus into the rat clitoris. Neurosci Lett 1995; 190(1): 41–4. 462. Papka RE, Williams S, Miller KE, Copelin T, Puri P. CNS location of uterine-related neurons revealed by trans-synaptic tracing with pseudorabies virus and their relation to estrogen receptor-­ immunoreactive neurons. Neuroscience 1998; 84(3): 935–52. 463. Birder LA, Roppolo JR, Iadarola MJ, de Groat WC. Electrical stimulation of visceral afferent pathways in the pelvic nerve increases c-fos in the rat lumbosacral spinal cord. Neurosci Lett 1991; 129(2): 193–6. 464. Chinapen S, Swann JM, Steinman JL, Komisaruk BR. Expression of c-fos protein in lumbosacral spinal cord in response to vaginocervical stimulation in rats. Neurosci Lett 1992; 145(1): 93–6. 465. Ghanima A, Bennis M, Rampin O. c-fos expression as endogenous marker of lumbosacral spinal neuron activity in response to ­vaginocervical-stimulation. Brain Res Brain Res Protoc 2002; 9(1): 1–8. 466. Lee JW, Erskine MS. Vaginocervical stimulation suppresses the expression of c-fos induced by mating in thoracic, lumbar and sacral segments of the female rat. Neuroscience 1996; 74(1): 237–49. 467. Cliffer KD, Burstein R, Giesler GJ Jr. Distributions of spinothalamic, spinohypothalamic, and spinotelencephalic fibers revealed by anterograde transport of PHA-L in rats. J Neurosci 1991; 11(3): 852–68. 468. Marson L, Murphy AZ. Identification of neural circuits involved in female genital responses in the rat: A dual virus and anterograde tracing study. Am J Physiol Regul Integr Comp Physiol 2006; 291(2): R419–R428. 469. Marson L. Identification of central nervous system neurons that innervate the bladder body, bladder base, or external urethral sphincter of female rats: A transneuronal tracing study using pseudorabies virus. J Comp Neurol 1997; 389(4): 584–602. 470. Goldstein I, Giraldi A, Kodigliu A et al. Physiology of female sexual function and pathophysiology of female sexual dysfunction. In: Lue TF, Basson R, Rosen R, Giuliano F, Khoury S, Montorsi F, eds. Sexual Medicine: Sexual Dysfunctions in Men and Women. Paris, France: Health Edition, 2004: 683–748. 471. Laan E, Everaerd W, van d, V, Geer JH. Determinants of ­subjective experience of sexual arousal in women: Feedback from genital arousal and erotic stimulus content. Psychophysiology 1995; 32(5): 444–51. 472. Fisher S, Osofsky H. Sexual responsiveness in women. Psychological correlates. Arch Gen Psychiatry 1967; 17(2): 214–26. 473. Sintchak G, Geer JH. A vaginal plethysmograph system. Psychophysiology 1975; 12(1): 113–5. 474. Levin RJ, Wagner G. Human vaginal fluid-ionic composition and modification by sexual arousal [proceedings]. J Physiol 1977; 266(1): 62P–63P. 475. Goldstein I, Berman JR. Vasculogenic female sexual dysfunction: Vaginal engorgement and clitoral erectile insufficiency syndromes. Int J Impot Res 1998; 10(Suppl 2): S84–S90. 476. Meston CM, Gorzalka BB. The effects of sympathetic activation on physiological and subjective sexual arousal in women. Behav Res Ther 1995; 33(6): 651–64.

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477. Levin RJ, Macdonagh RP. Increased vaginal blood flow induced by implant electrical stimulation of sacral anterior roots in the conscious woman: A case study. Arch Sex Behav 1993; 22(5): 471–5. 478. Giuliano F, Allard J, Compagnie S et al. Vaginal physiological changes in a model of sexual arousal in anesthetized rats. Am J Physiol Regul Integr Comp Physiol 2001; 281(1): R140–R149. 479. Park K, Goldstein I, Andry C et al. Vasculogenic female sexual dysfunction: The hemodynamic basis for vaginal engorgement insufficiency and clitoral erectile insufficiency. Int J Impot Res 1997; 9(1): 27–37. 480. Vachon P, Simmerman N, Zahran AR, Carrier S. Increases in clitoral and vaginal blood flow following clitoral and pelvic plexus nerve stimulations in the female rat. Int J Impot Res 2000; 12(1): 53–7. 481. Meston CM, Levin RJ, Sipski ML, Hull EM, Heiman JR. Women’s orgasm. Annu Rev Sex Res 2004; 15: 173–257. 482. Bohlen JG, Held JP, Sanderson MO, Ahlgren A. The female orgasm: Pelvic contractions. Arch Sex Behav 1982; 11(5): 367–86. 483. Gillan P, Brindley GS. Vaginal and pelvic floor responses to sexual stimulation. Psychophysiology 1979; 16(5): 471–81. 484. Levin RJ. Sex and the human female reproductive tract—What really happens during and after coitus. Int J Impot Res 1998; 10(Suppl 1): S14–S21. 485. Kratochvil S. [Vaginal contractions in female orgasm]. Cesk Psychiatr 1994; 90(1): 28–33. 486. Bohlen JG, Held JP, Sanderson MO, Patterson RP. Heart rate, ratepressure product, and oxygen uptake during four sexual activities. Arch Intern Med 1984; 144(9): 1745–8. 487. Kratochvil S. [Orgasmic expulsions in women]. Cesk Psychiatr 1994; 90(2): 71–7. 488. Hines TM. The G-spot: A modern gynecologic myth. Am J Obstet Gynecol 2001; 185(2): 359–62. 489. Carmichael MS, Warburton VL, Dixen J, Davidson JM. Relationships among cardiovascular, muscular, and oxytocin responses during human sexual activity. Arch Sex Behav 1994; 23(1): 59–79. 490. Munarriz R, Kim NN, Goldstein I, Traish AM. Biology of female sexual function. Urol Clin North Am 2002; 29(3): 685–93. 491. Sipski ML, Alexander CJ, Rosen RC. Physiologic parameters associated with sexual arousal in women with incomplete spinal cord injuries. Arch Phys Med Rehabil 1997; 78(3): 305–13. 492. Sipski ML, Alexander CJ, Rosen RC. Sexual response in women with spinal cord injuries: Implications for our understanding of the able bodied. J Sex Marital Ther 1999; 25(1): 11–22. 493. Sipski ML, Alexander CJ, Gomez-Marin O, Grossbard M, Rosen R. Effects of vibratory stimulation on sexual response in women with spinal cord injury. J Rehabil Res Dev 2005; 42(5): 609–16. 494. McKenna KE, Chung SK, McVary KT. A model for the study of sexual function in anesthetized male and female rats. Am J Physiol 1991; 261(5 Pt 2): R1276–R1285. 495. Whalen RE. Sexual motivation. Psychol Rev 1966; 73(2): 151–63. 496. Whipple B, Komisaruk BR. Brain (PET) responses to vaginal-­ cervical self-stimulation in women with complete spinal cord injury: Preliminary findings. J Sex Marital Ther 2002; 28(1): 79–86. 497. Coolen LM, Peters HJ, Veening JG. Fos immunoreactivity in the rat brain following consummatory elements of sexual behavior: A sex comparison. Brain Res 1996; 738(1): 67–82. 498. Erskine MS, Hanrahan SB. Effects of paced mating on c-fos gene expression in the female rat brain. J Neuroendocrinol 1997; 9(12): 903–12. 499. Pfaus JG, Heeb MM. Implications of immediate-early gene induction in the brain following sexual stimulation of female and male rodents. Brain Res Bull 1997; 44(4): 397–407. 500. Pfaus JG, Marcangione C, Smith WJ, Manitt C, Abillamaa H. Differential induction of Fos in the female rat brain following different amounts of vaginocervical stimulation: Modulation by steroid hormones. Brain Res 1996; 741(1–2): 314–30. 501. Tetel MJ, Getzinger MJ, Blaustein JD. Fos expression in the rat brain following vaginal-cervical stimulation by mating and manual probing. J Neuroendocrinol 1993; 5(4): 397–404.

502. Marson L, Foley KA. Identification of neural pathways involved in genital reflexes in the female: A combined anterograde and retrograde tracing study. Neuroscience 2004; 127(3): 723–36. 503. Pfaff DW. Estrogens and Brain Function. New York: Springer, 1980. 504. Rubin BS, Barfield RJ. Induction of estrous behavior in ovariectomized rats by sequential replacement of estrogen and progesterone to the ventromedial hypothalamus. Neuroendocrinology 1983; 37(3): 218–24. 505. Rubin BS, Barfield RJ. Progesterone in the ventromedial hypothalamus facilitates estrous behavior in ovariectomized, estrogen-primed rats. Endocrinology 1983; 113(2): 797–804. 506. Flanagan LM, Pfaus JG, Pfaff DW, McEwen BS. Induction of FOS immunoreactivity in oxytocin neurons after sexual activity in female rats. Neuroendocrinology 1993; 58(3): 352–8. 507. Luiten PG, Ter Horst GJ, Karst H, Steffens AB. The course of paraventricular hypothalamic efferents to autonomic structures in medulla and spinal cord. Brain Res 1985; 329(1–2): 374–8. 508. Min K, Munarriz R, Kim NN et al. Effects of ovariectomy and estrogen replacement on basal and pelvic nerve stimulated vaginal lubrication in an animal model. J Sex Marital Ther 2003; 29(Suppl 1): 77–84. 509. Park K, Ahn K, Lee S, Ryu S, Park Y, Azadzoi KM. Decreased circulating levels of estrogen alter vaginal and clitoral blood flow and structure in the rabbit. Int J Impot Res 2001; 13(2): 116–24. 510. Bachmann GA. Androgen cotherapy in menopause: Evolving benefits and challenges. Am J Obstet Gynecol 1999; 180(3 Pt 2): S308–S311. 511. Kim HW, Kim SC, Seo KK, Lee MY. Effects of estrogen on the relaxation response of rabbit clitoral cavernous smooth muscles. Urol Res 2002; 30(1): 26–30. 512. Slob AK, Ernste M, van der Werff ten Bosch JJ. Menstrual cycle phase and sexual arousability in women. Arch Sex Behav 1991; 20(6): 567–77. 513. Dorfman RI, Shipley RA. Androgens: Biochemistry, Physiology and Clinical Significance. New York: Wiley, 1956. 514. Ottesen B, Gerstenberg T, Ulrichsen H et al. Vasoactive intestinal polypeptide (VIP) increases vaginal blood flow and inhibits uterine smooth muscle activity in women. Eur J Clin Invest 1983; 13(4): 321–4. 515. Ottesen B, Pedersen B, Nielsen J et al. Vasoactive intestinal polypeptide (VIP) provokes vaginal lubrication in normal women. Peptides 1987; 8(5): 797–800. 516. Angulo J, Cuevas P, Cuevas B, Bischoff E, Saenz de, I. Vardenafil enhances clitoral and vaginal blood flow responses to pelvic nerve stimulation in female dogs. Int J Impot Res 2003; 15(2): 137–41. 517. Min K, Kim NN, McAuley I et al. Sildenafil augments pelvic nervemediated female genital sexual arousal in the anesthetized rabbit. Int J Impot Res 2000; 12(Suppl 3): S32–S39. 518. Park JK, Kim JU, Lee SO et al. Nitric oxide-cyclic GMP signaling pathway in the regulation of rabbit clitoral cavernosum tone. Exp Biol Med (Maywood) 2002; 227(11): 1022–30. 519. Berman JR, Berman LA, Lin H et al. Effect of sildenafil on subjective and physiologic parameters of the female sexual response in women with sexual arousal disorder. J Sex Marital Ther 2001; 27(5): 411–20. 520. Kaplan SA, Reis RB, Kohn IJ et al. Safety and efficacy of sildenafil in postmenopausal women with sexual dysfunction. Urology 1999; 53(3): 481–6. 521. Laan E, van Lunsen RH, Everaerd W et al. The enhancement of vaginal vasocongestion by sildenafil in healthy premenopausal women. J Womens Health Gend Based Med 2002; 11(4): 357–65. 522. Becker JB, Rudick CN, Jenkins WJ. The role of dopamine in the nucleus accumbens and striatum during sexual behavior in the female rat. J Neurosci 2001; 21(9): 3236–41. 523. Matuszewich L, Lorrain DS, Hull EM. Dopamine release in the medial preoptic area of female rats in response to hormonal manipulation and sexual activity. Behav Neurosci 2000; 114(4): 772–82. 524. Pfaus JG, Damsma G, Wenkstern D, Fibiger HC. Sexual activity increases dopamine transmission in the nucleus accumbens and striatum of female rats. Brain Res 1995; 693(1–2): 21–30.

Physiology of normal sexual function 525. Paredes RG, Agmo A. Has dopamine a physiological role in the control of sexual behavior? A critical review of the evidence. Prog Neurobiol 2004; 73(3): 179–226. 526. Apostolakis EM, Garai J, Fox C et al. Dopaminergic regulation of progesterone receptors: Brain D5 dopamine receptors mediate induction of lordosis by D1-like agonists in rats. J Neurosci 1996; 16(16): 4823–34. 527. Mani SK, Allen JM, Clark JH, Blaustein JD, O’Malley BW. Convergent pathways for steroid hormone—and neurotransmitterinduced rat sexual behavior. Science 1994; 265(5176): 1246–9. 528. Ben Zion IZ, Tessler R, Cohen L et al. Polymorphisms in the dopamine D4 receptor gene (DRD4) contribute to individual differences in human sexual behavior: Desire, arousal and sexual function. Mol Psychiatry 2006; 11(8): 782–6. 529. Ashton A, Hamer R, Rosen RC. Serotonin reuptake inhibitorinduced sexual dysfunction and its treatment: A large retrospective study of 596 psychiatric outpatients. J Sex Marital Ther 1997; 23: 165–75. 530. Alcantara AG. A possible dopaminergic mechanism in the serotonergic antidepressant-induced sexual dysfunctions. J Sex Marital Ther 1999; 25(2): 125–9. 531. Kennedy SH, Eisfeld BS, Dickens SE, Bacchiochi JR, Bagby RM. Antidepressant-induced sexual dysfunction during treatment with moclobemide, paroxetine, sertraline, and venlafaxine. J Clin Psychiatry 2000; 61(4): 276–81. 532. Montejo-Gonzalez AL, Llorca G, Izquierdo JA et al. SSRI-induced sexual dysfunction: Fluoxetine, paroxetine, sertraline, and ­fluvoxamine in a prospective, multicenter, and descriptive ­clinical study of 344 patients. J Sex Marital Ther 1997; 23(3): 176–94. 533. Marson L, McKenna KE. A role for 5-hydroxytryptamine in descending inhibition of spinal sexual reflexes. Exp Brain Res 1992; 88(2): 313–320. 534. Marson L, McKenna KE. Stimulation of the hypothalamus initiates the urethrogenital reflex in male rats. Brain Res 1994; 638(1–2): 103–8. 535. Gorzalka BB, Mendelson SD, Watson NV. Serotonin receptor subtypes and sexual behavior. Ann N Y Acad Sci 1990; 600: 435–44. 536. Mendelson SD, Gorzalka BB. 5-HT1A receptors: Differential involvement in female and male sexual behavior in the rat. Physiol Behav 1986; 37(2): 345–51. 537. Ahlenius S, Fernandez-Guasti A, Hjorth S, Larsson K. Suppression of lordosis behavior by the putative 5-HT receptor agonist 8-OH-DPAT in the rat. Eur J Pharmacol 1986; 124(3): 361–3. 538. Wolf A, Jackson A, Price T et al. Attenuation of the lordosis-­ inhibiting effects of 8-OH-DPAT by TFMPP and quipazine. Brain Res 1998; 804(2): 206–11. 539. Wolf A, Caldarola-Pastuszka M, Uphouse L. Facilitation of female rat lordosis behavior by hypothalamic infusion of 5-HT (2A/2C) receptor agonists. Brain Res 1998; 779(1–2): 84–95. 540. Cragnolini A, Scimonelli T, Celis ME, Schioth HB. The role of melanocortin receptors in sexual behavior in female rats. Neuropeptides 2000; 34(3–4): 211–5. 541. Gonzalez MI, Celis ME, Hole DR, Wilson CA. Interaction of oestradiol, alpha-melanotrophin and noradrenaline within the ventromedial nucleus in the control of female sexual behaviour. Neuroendocrinology 1993; 58(2): 218–26. 542. Gonzalez MI, Vaziri S, Wilson CA. Behavioral effects of alpha-MSH and MCH after central administration in the female rat. Peptides 1996; 17(1): 171–7. 543. Nocetto C, Cragnolini AB, Schioth HB, Scimonelli TN. Evidence that the effect of melanocortins on female sexual behavior in preoptic area is mediated by the MC3 receptor: Participation of nitric oxide. Behav Brain Res 2004; 153(2): 537–41. 544. Scimonelli T, Medina F, Wilson C, Celis ME. Interaction of alpha-­ melanotropin (alpha-MSH) and noradrenaline in the median eminence in the control of female sexual behavior. Peptides 2000; 21(2): 219–23.

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545. Thody AJ, Wilson CA, Everard D. Alpha-melanocyte stimulating hormone stimulates sexual behaviour in the female rat. Psychopharmacology (Berl) 1981; 74(2): 153–6. 546. Pfaus JG, Shadiack A, Van Soest T, Tse M, Molinoff P. Selective facilitation of sexual solicitation in the female rat by a melanocortin receptor agonist. Proc Natl Acad Sci USA 2004; 101(27): 10201–4. 547. Rossler AS, Pfaus JG, Kia HK et al. The melanocortin agonist, melanotan II, enhances proceptive sexual behaviors in the female rat. Pharmacol Biochem Behav 2006; 85: 514–21. 548. Gelez H, Jacubovich M, Ismail N et al. Melanocortin agonists facilitate solicitation in female rats through a central mechanism of action. Proceedings of Tenth Annual Meeting of the Society for Behavioral Neuroendocrinology, Pittsburgh, PA, 2006. 549. Diamond LE, Earle DC, Heiman JR et al. An effect on the subjective sexual response in premenopausal women with sexual arousal disorder by bremelanotide (PT-141), a melanocortin receptor agonist. J Sex Med 2006; 3(4): 628–38. 550. Caldwell JD, Jirikowski GF, Greer ER, Pedersen CA. Medial preoptic area oxytocin and female sexual receptivity. Behav Neurosci 1989; 103(3): 655–62. 551. Caldwell JD, Johns JM, Faggin BM, Senger MA, Pedersen CA. Infusion of an oxytocin antagonist into the medial preoptic area prior to progesterone inhibits sexual receptivity and increases rejection in female rats. Horm Behav 1994; 28(3): 288–302. 552. Witt DM, Insel TR. A selective oxytocin antagonist attenuates progesterone facilitation of female sexual behavior. Endocrinology 1991; 128(6): 3269–76. 553. Pedersen CA, Boccia ML. Vasopressin interactions with oxytocin in the control of female sexual behavior. Neuroscience 2006; 139(3): 843–51. 554. Sodersten P, Henning M, Melin P, Ludin S. Vasopressin alters female sexual behaviour by acting on the brain independently of alterations in blood pressure. Nature 1983; 301(5901): 608–10. 555. Pfaus JG, Gorzalka BB. Opioids and sexual behavior. Neurosci Biobehav Rev 1987; 11(1): 1–34. 556. Pfaus JG, Gorzalka BB. Selective activation of opioid receptors differentially affects lordosis behavior in female rats. Peptides 1987; 8(2): 309–17. 557. Acosta-Martinez M, Etgen AM. The role of delta-opioid receptors in estrogen facilitation of lordosis behavior. Behav Brain Res 2002; 136(1): 93–102. 558. Pfaus JG, Pfaff DW. Mu-, delta-, and kappa-opioid receptor agonists selectively modulate sexual behaviors in the female rat: Differential dependence on progesterone. Horm Behav 1992; 26(4): 457–73. 559. Sinchak K, Mills RH, Eckersell CB, Micevych PE. Medial preoptic area delta-opioid receptors inhibit lordosis. Behav Brain Res 2004; 155(2): 301–6. 560. Halata Z, Munger BL. The neuroanatomical basis for the protopathic sensibility of the human glans penis. Brain Res 1986; 371(2): 205–30. 561. Christ GJ. K+ channels and gap junctions in the modulation of corporal smooth muscle tone. Drug News Perspect 2000; 13(1): 28–36. 562. Andersson KE. Pharmacology of penile erection. Pharmacol Rev 2001; 53(3): 417–50. 563. Hedlund P, Alm P, Ekstrom P et al. Pituitary adenylate cyclase-­ activating polypeptide, helospectin, and vasoactive intestinal polypeptide in human corpus cavernosum. Br J Pharmacol 1995; 116(4): 2258–66. 564. Burnett AL, Lowenstein CJ, Bredt DS, Chang TS, Snyder SH. Nitric oxide: A physiologic mediator of penile erection. Science 1992; 257(5068): 401–3. 565. Ignarro LJ, Bush PA, Buga GM et al. Nitric oxide and cyclic GMP formation upon electrical field stimulation cause relaxation of corpus cavernosum smooth muscle. Biochem Biophys Res Commun 1990; 170(2): 843–50. 566. Steers WD. Viagra—After one year. Urology 1999; 54(1): 12–17. 567. Hancock MB, Peveto CA. A preganglionic autonomic nucleus in the dorsal gray commissure of the lumbar spinal cord of the rat. J Comp Neurol 1979; 183(1): 65–72.

70

Textbook of the Neurogenic Bladder

568. Schroder HD. Organization of the motoneurons innervating the pelvic muscles of the male rat. J Comp Neurol 1980; 192(3): 567–87. 569. Giuliano F, Bernabe J, Brown K et al. Erectile response to hypothalamic stimulation in rats: Role of peripheral nerves. Am J Physiol 1997; 273(6 Pt 2): R1990–R1997. 570. Steers WD, Mallory B, de Groat WC. Electrophysiological study of neural activity in penile nerve of the rat. Am J Physiol 1988; 254(6 Pt 2): R989–1000. 571. McKenna KE, Nadelhaft I. The pudenda-pudendal reflex in male and female rats. J Auton Nerv Syst 1989; 27(1): 67–77. 572. Lavoisier P, Proulx J, Courtois F. Reflex contractions of the ischiocavernosus muscles following electrical and pressure stimulations. J Urol 1988; 139(2): 396–9. 573. Ertekin C, Reel F. Bulbocavernosus reflex in normal men and in patients with neurogenic bladder and/or impotence. J Neurol Sci 1976; 28(1): 1–15. 574. Hart BL. Hormones, spinal reflexes, and sexual behaviour. In: Hutchison JB, ed. Biological Determinants of Sexual Behaviour. Chichester, United Kingdom: Wiley, 1978: 319–47. 575. Beach FA. Cerebral and hormonal control of reflexive mechanisms involved in copulatory behavior. Physiol Rev 1967; 47(2): 289–316. 576. Kuhn RA. Functional capacity of the isolated human spinal cord. Brain 1950; 73(1): 1–51. 577. Chapelle PA, Durand J, Lacert P. Penile erection following complete spinal cord injury in man. Br J Urol 1980; 52(3): 216–9. 578. Sachs BD. Contextual approaches to the physiology and classification of erectile function, erectile dysfunction, and sexual arousal. Neurosci Biobehav Rev 2000; 24(5): 541–60. 579. Marson L, Platt KB, McKenna KE. Central nervous system innervation of the penis as revealed by the transneuronal transport of pseudorabies virus. Neuroscience 1993; 55(1): 263–80. 580. Coolen LM, Peters HJ, Veening JG. Distribution of Fos immunoreactivity following mating versus anogenital investigation in the male rat brain. Neuroscience 1997; 77(4): 1151–61. 581. Hamson DK, Watson NV. Regional brainstem expression of Fos associated with sexual behavior in male rats. Brain Res 2004; 1006(2): 233–40. 582. Giuliano F, Rampin O, Brown K et al. Stimulation of the medial preoptic area of the hypothalamus in the rat elicits increases in intracavernous pressure. Neurosci Lett 1996; 209(1): 1–4. 583. Stefanick ML, Davidson JM. Genital responses in noncopulators and rats with lesions in the medical preoptic area or midthoracic spinal cord. Physiol Behav 1987; 41(5): 439–44. 584. Shimura T, Yamamoto T, Shimokochi M. The medial preoptic area is involved in both sexual arousal and performance in male rats: Re-evaluation of neuron activity in freely moving animals. Brain Res 1994; 640(1–2): 215–22. 585. Monaghan EP, Arjomand J, Breedlove SM. Brain lesions affect penile reflexes. Horm Behav 1993; 27(1): 122–31. 586. Liu YC, Salamone JD, Sachs BD. Impaired sexual response after lesions of the paraventricular nucleus of the hypothalamus in male rats. Behav Neurosci 1997; 111(6): 1361–7. 587. Chen KK, Chan SH, Chang LS, Chan JY. Participation of paraventricular nucleus of hypothalamus in central regulation of penile erection in the rat. J Urol 1997; 158(1): 238–44. 588. Liu YC, Sachs BD. Erectile function in male rats after lesions in the lateral paragigantocellular nucleus. Neurosci Lett 1999; 262(3): 203–6. 589. Marson L, List MS, McKenna KE. Lesions of the nucleus paragigantocellularis alter ex copula penile reflexes. Brain Res 1992; 592(1–2): 187–92. 590. Kondo Y, Sachs BD, Sakuma Y. Importance of the medial amygdala in rat penile erection evoked by remote stimuli from estrous females. Behav Brain Res 1997; 88(2): 153–60. 591. Steers WD. Neural pathways and central sites involved in penile erection: Neuroanatomy and clinical implications. Neurosci Biobehav Rev 2000; 24(5): 507–16.

592. Argiolas A. Neuropeptides and sexual behaviour. Neurosci Biobehav Rev 1999; 23(8): 1127–42. 593. Pfaus JG. Neurobiology of sexual behavior. Curr Opin Neurobiol 1999; 9(6): 751–8. 594. Lee RL, Smith ER, Mas M, Davidson JM. Effects of intrathecal administration of 8-OH-DPAT on genital reflexes and mating behavior in male rats. Physiol Behav 1990; 47(4): 665–669. 595. Millan MJ, Peglion JL, Lavielle G, Perrin-Monneyron S. 5-HT2C receptors mediate penile erections in rats: Actions of novel and selective agonists and antagonists. Eur J Pharmacol 1997; 325(1): 9–12. 596. Uitti RJ, Tanner CM, Rajput AH, Goetz CG, Klawans HL, Thiessen B. Hypersexuality with antiparkinsonian therapy. Clin Neuropharmacol 1989; 12(5): 375–383. 597. Melis MR, Argiolas A, Gessa GL. Apomorphine-induced penile erection and yawning: Site of action in brain. Brain Research 1987; 415(1): 98–104. 598. Melis MR, Succu S, Mascia MS, Argiolas A. PD-168077, a selective dopamine D4 receptor agonist, induces penile erection when injected into the paraventricular nucleus of male rats. Neurosci Lett 2005; 379(1): 59–62. 599. Giuliano F, Allard J, Rampin O et al. Spinal proerectile effect of apomorphine in the anesthetized rat. Int J Impot Res 2001; 13(2): 110–115. 600. Heaton JP, Morales A, Adams MA, Johnston B, el Rashidy R. Recovery of erectile function by the oral administration of apomorphine. Urology 1995; 45(2): 200–206. 601. Kaplan SA, Reis RB, Kohn IJ, Shabsigh R, Te AE. Combination therapy using oral alpha-blockers and intracavernosal injection in men with erectile dysfunction. Urology 1998; 52(5): 739–743. 602. Bitran D, Hull EM. Pharmacological analysis of male rat sexual behavior. Neurosci Biobehav Rev 1987; 11(4): 365–389. 603. Melis MR, Argiolas A, Gessa GL. Oxytocin-induced penile e­ rection and yawning: Site of action in the brain. Brain Res 1986; 398(2): 259–265. 604. Giuliano F, Bernabe J, McKenna K, Longueville F, Rampin O. Spinal proerectile effect of oxytocin in anesthetized rats. Am J Physiol Regul Integr Comp Physiol 2001; 280(6): R1870–R1877. 605. Melis MR, Succu S, Spano MS, Argiolas A. Morphine injected into the paraventricular nucleus of the hypothalamus prevents noncontact penile erections and impairs copulation: Involvement of nitric oxide. Eur J Neurosci 1999; 11(6): 1857–1864. 606. Melis MR, Argiolas A. Nitric oxide donors induce penile erection and yawning when injected in the central nervous system of male rats. Eur J Pharmacol 1995; 294(1): 1–9. 607. Melis MR, Argiolas A. Role of central nitric oxide in the control of penile erection and yawning. Prog Neuropsychopharmacol Biol Psychiatry 1997; 21(6): 899–922. 608. Argiolas A, Melis MR. The role of oxytocin and the paraventricular nucleus in the sexual behaviour of male mammals. Physiol Behav 2004; 83(2): 309–317. 609. Serra G, Fratta W, Collu M, Gessa GL. Hypophysectomy prevents ACTH-induced yawning and penile erection in rats. Pharmacol Biochem Behav 1987; 26(2): 277–279. 610. Vergoni AV, Bertolini A, Mutulis F, Wikberg JE, Schioth HB. Differential influence of a selective melanocortin MC4 receptor antagonist (HS014) on melanocortin-induced behavioral effects in rats. Eur J Pharmacol 1998; 362(2–3): 95–101. 611. Diamond LE, Earle DC, Rosen RC, Willett MS, Molinoff PB. Double-blind, placebo-controlled evaluation of the safety, pharmacokinetic properties and pharmacodynamic effects of intranasal PT-141, a melanocortin receptor agonist, in healthy males and patients with mild-to-moderate erectile dysfunction. Int J Impot Res 2004; 16(1): 51–59. 612. Andersson KE, Wagner G. Physiology of penile erection. Physiol Rev 1995; 75(1): 191–236.

Physiology of normal sexual function 613. Hoyle CHV. Transmission: Purines. In: Burnstock G, Hoyle CHV, eds. Autonomic Neuroeffector Mechanisms. Chur, Switzerland: Harwood Academic, 1992: 367–408. 614. Morris JL, Gibbins IL. Co-transmission and neuromodulation. In: Burnstock G, Hoyle CHV, eds. Autonomic Neuroeffector Mechanisms. Chur, Switzerland: Harwood Academic, 1992: 31–117. 615. Grundemar L, Hakanson R. Effects of various neuropeptide Y/peptide YY fragments on electrically-evoked contractions of the rat vas deferens. Br J Pharmacol 1990; 100(1): 190–2. 616. Zoubek J, Somogyi GT, de Groat WC. A comparison of inhibitory effects of neuropeptide Y on rat urinary bladder, urethra, and vas deferens. Am J Physiol 1993; 265(3 Pt 2): R537–R543. 617. Dail WG, Moll MA, Weber K. Localization of vasoactive intestinal polypeptide in penile erectile tissue and in the major pelvic ganglion of the rat. Neuroscience 1983; 10(4): 1379–86. 618. Domoto T, Tsumori T. Co-localization of nitric oxide synthase and vasoactive intestinal peptide immunoreactivity in neurons of the major pelvic ganglion projecting to the rat rectum and penis. Cell Tissue Res 1994; 278(2): 273–8. 619. Johnson RD, Halata Z. Topography and ultrastructure of sensory nerve endings in the glans penis of the rat. J Comp Neurol 1991; 312(2): 299–310. 620. Nunez R, Gross GH, Sachs BD. Origin and central projections of rat dorsal penile nerve: Possible direct projection to autonomic and somatic neurons by primary afferents of nonmuscle origin. J Comp Neurol 1986; 247(4): 417–29. 621. Baron R, Janig W. Afferent and sympathetic neurons projecting into lumbar visceral nerves of the male rat. J Comp Neurol 1991; 314(3): 429–36. 622. Morgan C, de Groat WC, Nadelhaft I. The spinal distribution of sympathetic preganglionic and visceral primary afferent neurons that send axons into the hypogastric nerves of the cat. J Comp Neurol 1986; 243(1): 23–40. 623. Nadelhaft I, McKenna KE. Sexual dimorphism in sympathetic preganglionic neurons of the rat hypogastric nerve. J Comp Neurol 1987; 256(2): 308–15. 624. Owman C, Stjernquist M. The peripheral nervous system. In: Bjorklund A, Hokfelt T, Owman C, eds. Handbook of Chemical Neuroanatomy. Amsterdam, The Netherlands: Elsevier Science, 1988: 445–544. 625. Schroder HD. Anatomical and pathoanatomical studies on the spinal efferent systems innervating pelvic structures. 1. Organization of spinal nuclei in animals. 2. The nucleus X-pelvic motor system in man. J Auton Nerv Syst 1985; 14(1): 23–48. 626. Nordling J, Andersen JT, Walter S et al. Evoked response of the bulbocavernosus reflex. Eur Urol 1979; 5(1): 36–8. 627. Opsomer RJ, Caramia MD, Zarola F, Pesce F, Rossini PM. Neurophysiological evaluation of central-peripheral sensory and motor pudendal fibres. Electroencephalogr Clin Neurophysiol 1989; 74(4): 260–70. 628. Shafik A, El Sibai O. Mechanism of ejection during ejaculation: Identification of a urethrocavernosus reflex. Arch Androl 2000; 44(1): 77–83. 629. Brackett NL, Ferrell SM, Aballa TC et al. An analysis of 653 trials of penile vibratory stimulation in men with spinal cord injury. J Urol 1998; 159(6): 1931–4. 630. Sonksen J, Biering-Sorensen F, Kristensen JK. Ejaculation induced by penile vibratory stimulation in men with spinal cord injuries. The importance of the vibratory amplitude. Paraplegia 1994; 32(10): 651–60. 631. Kolbeck SC, Steers WD. Neural regulation of the vas deferens in the rat: An electrophysiological analysis. Am J Physiol 1992; 263(2 Pt 2): R331–R338. 632. Terasaki T. Effects of autonomic drugs on intraluminal pressure and excretion of rat seminal vesicles in vivo. Tohoku J Exp Med 1989; 157(4): 373–79.

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633. Kontani H, Shiraoya C. Method for simultaneous recording of the prostatic contractile and urethral pressure responses in anesthetized rats and the effects of tamsulosin. Jpn J Pharmacol 2002; 90(3): 281–90. 634. Stjernquist M, Hakanson R, Leander S et al. Immunohistochemical localization of substance P, vasoactive intestinal polypeptide and gastrin-releasing peptide in vas deferens and seminal vesicle, and the effect of these and eight other neuropeptides on resting tension and neurally evoked contractile activity. Regul Pept 1983; 7(1): 67–86. 635. Moss HE, Crowe R, Burnstock G. The seminal vesicle in eight and 16 week streptozotocin-induced diabetic rats: Adrenergic, cholinergic and peptidergic innervation. J Urol 1987; 138(5): 1273–78. 636. Ventura S, Dewalagama RK, Lau LCL. Adenosine 5’-triphosphate (ATP) is an excitatory cotransmitter with noradrenaline to the smooth muscle of the rat prostate gland. Br J Pharmacol 2003; 138(7): 1277–84. 637. Allcorn RJ, Cunnane TC, Kirkpatrick K. Actions of alpha, betamethylene ATP and 6-hydroxydopamine on sympathetic neurotransmission in the vas deferens of the guinea-pig, rat and mouse: Support for cotransmission. Br J Pharmacol 1986; 89(4): 647–59. 638. May AG, DeWeese JA, Rob CG. Changes in sexual function following operation on the abdominal aorta. Surgery 1969; 65(1): 41–7. 639. Weinstein MH, Machleder HI. Sexual function after aorto-lliac ­surgery. Ann Surg 1975; 181(6): 787–90. 640. Pocard M, Zinzindohoue F, Haab F et al. A prospective study of sexual and urinary function before and after total mesorectal excision with autonomic nerve preservation for rectal cancer. Surgery 2002; 131(4): 368–72. 641. Sugihara K, Moriya Y, Akasu T, Fujita S. Pelvic autonomic nerve preservation for patients with rectal carcinoma. Oncologic and functional outcome. Cancer 1996; 78(9): 1871–80. 642. Brindley GS, Sauerwein D, Hendry WF. Hypogastric plexus stimulators for obtaining semen from paraplegic men. Br J Urol 1989; 64(1): 72–7. 643. Bohlen JG, Held JP, Sanderson MO. The male orgasm: Pelvic contractions measured by anal probe. Arch Sex Behav 1980; 9(6): 503–21. 644. Gerstenberg TC, Levin RJ, Wagner G. Erection and ejaculation in man. Assessment of the electromyographic activity of the bulbocavernosus and ischiocavernosus muscles. Br J Urol 1990; 65(4): 395–402. 645. Grossiord A, Chapelle PA, Lacert P, Pannier S, Durand J. The affected medullary segment in paraplegics. Relation to sexual function in men. Rev Neurol (Paris) 1978; 134(12): 729–40. 646. Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care 2003; 26(5): 1553–79. 647. Truitt WA, Coolen LM. Identification of a potential ejaculation generator in the spinal cord. Science 2002; 297(5586): 1566–9. 648. Giuliano F, Clement P. Pharmacology for the treatment of premature ejaculation. Pharmacol Rev 2012; 64(3): 621–44. 649. Newton BW, Phan DC. Androgens regulate the sexually dimorphic production of co-contained galanin and cholecystokinin in lumbar laminae VII and X neurons. Brain Res 2006; 1099: 88–96. 650. Coolen LM, Allard J, Pattij T, McKenna KE. The spinal ejaculation generator in male rats receives serotonergic inputs and expresses 5HT1B receptors. Neuroscience meeting planner 2004 San Diego, Society for Neuroscience, online: presentation number 998.1. 651. Clement P, Laurin M, Bernabe J, Giuliano F. Identification of brain structures projecting to the area of the spinal generator for ejaculation in the rat. Abstract number 167. J Sex Med 2010; 7. 652. Xu C, Yaici ED, Conrath M et al. Galanin and neurokinin-1 receptor immunoreactivity spinal neurons controlling the prostate and the bulbospongiosus muscle identified by transsynaptic labeling in the rat. Neuroscience 2005; 134(4): 1325–41. 653. Coolen LM, Veening JG, Wells AB, Shipley MT. Afferent connections of the parvocellular subparafascicular thalamic nucleus in the rat: Evidence for functional subdivisions. J Comp Neurol 2003; 463(2): 132–56.

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654. Borgdorff A, Bernabe J, Denys P, Alexandre L, Giuliano F. Ejaculation  elicited by microstimulation of lumbar spinothalamic neurons. Eur Urol 2008; 54(2): 448–56. 655. Grillner S. Biological pattern generation: The cellular and computational logic of networks in motion. Neuron 2006; 52(5): 751–66. 656. Heeb MM, Yahr P. Anatomical and functional connections among cell groups in the gerbil brain that are activated with ejaculation. J Comp Neurol 2001; 439(2): 248–58. 657. Meisel R, Sachs B. The physiology of male sexual behavior. In: Knobil E, Neill J, eds. The Physiology of Reproduction. New York: Raven, 1994: 3–105. 658. Coolen LM, Peters HJ, Veening JG. Anatomical interrelationships of the medial preoptic area and other brain regions activated ­following male sexual behavior: A combined fos and tract-tracing study. J Comp Neurol 1998; 397(3): 421–35. 659. Arendash GW, Gorski RA. Effects of discrete lesions of the sexually dimorphic nucleus of the preoptic area or other medial preoptic regions on the sexual behavior of male rats. Brain Res Bull 1983; 10(1): 147–54. 660. Hull EM, Eaton RC, Markowski VP et al. Opposite influence of medial preoptic D1 and D2 receptors on genital reflexes: Implications for copulation. Life Sci 1992; 51(22): 1705–13. 661. Pehek EA, Thompson JT, Hull EM. The effects of intracranial administration of the dopamine agonist apomorphine on penile reflexes and seminal emission in the rat. Brain Res 1989; 500(1–2): 325–32. 662. Larsson K, van Dis H. Seminal discharge following intracranial electrical stimulation. Brain Res 1970; 23(3): 381–6. 663. Simerly RB, Swanson LW. Projections of the medial preoptic nucleus: A Phaseolus vulgaris leucoagglutinin anterograde tracttracing study in the rat. J Comp Neurol 1988; 270(2): 209–42. 664. Rizvi TA, Ennis M, Shipley MT. Reciprocal connections between the medial preoptic area and the midbrain periaqueductal gray in rat: A WGA-HRP and PHA-L study. J Comp Neurol 1992; 315(1): 1–15. 665. Murphy AZ, Rizvi TA, Ennis M, Shipley MT. The organization of preoptic-medullary circuits in the male rat: Evidence for interconnectivity of neural structures involved in reproductive behavior, antinociception and cardiovascular regulation. Neuroscience 1999; 91(3): 1103–16. 666. Swanson LW, Sawchenko PE. Hypothalamic integration: Organization of the paraventricular and supraoptic nuclei. Annu Rev Neurosci 1983; 6: 269–324. 667. Saper CB, Loewy AD, Swanson LW, Cowan WM. Direct ­hypothalamo-autonomic connections. Brain Res 1976; 117(2): 305–12. 668. Canteras NS, Simerly RB, Swanson LW. Organization of projections from the medial nucleus of the amygdala: A PHAL study in the rat. J Comp Neurol 1995; 360(2): 213–45. 669. Marson L, McKenna KE. CNS cell groups involved in the control of the ischiocavernosus and bulbospongiosus muscles: A transneuronal tracing study using pseudorabies virus. J Comp Neurol 1996; 374(2): 161–79.

670. Marson L, McKenna KE. The identification of a brainstem site controlling spinal sexual reflexes in male rats. Brain Res 1990; 515(1–2): 303–8. 671. Marson L. Lesions of the periaqueductal gray block the medial preoptic area-induced activation of the urethrogenital reflex in male rats. Neurosci Lett 2004; 367(3): 278–82. 672. Holstege G, Georgiadis JR, Paans AMJ et al. Brain activation during human male ejaculation. J Neurosci 2003; 23(27): 9185–93. 673. Arnow BA, Desmond JE, Banner LL et al. Brain activation and sexual arousal in healthy, heterosexual males. Brain 2002; 125(Pt 5): 1014–23. 674. Perretti A, Catalano A, Mirone V et al. Neurophysiologic evaluation of central-peripheral sensory and motor pudendal pathways in primary premature ejaculation. Urology 2003; 61(3): 623–8. 675. Hull EM, Warner RK, Bazzett TJ et al. D2/D1 ratio in the medial preoptic area affects copulation of male rats. J Pharmacol Exp Ther 1989; 251(2): 422–7. 676. Clement P, Bernabe J, Denys P, Alexandre L, Giuliano F. Ejaculation induced by i.c.v. injection of the preferential dopamine D(3) ­receptor agonist 7-hydroxy-2-(di-N-propylamino)tetralin in anesthetized rats. Neuroscience 2007; 145(2): 605–10. 677. Hillegaart V, Ahlenius S. Facilitation and inhibition of male rat ejaculatory behaviour by the respective 5-HT1A and 5-HT1B receptor agonists 8-OH-DPAT and anpirtoline, as evidenced by use of the corresponding new and selective receptor antagonists NAD-299 and NAS-181. Br J Pharmacol 1998; 125(8): 1733–43. 678. Rehman J, Kaynan A, Christ G et al. Modification of sexual behavior of Long-Evans male rats by drugs acting on the 5-HT1A receptor. Brain Res 1999; 821(2): 414–25. 679. Foreman MM, Hall JL, Love RL. The role of the 5-HT2 receptor in the regulation of sexual performance of male rats. Life Sci 1989; 45(14): 1263–70. 680. Giuliano F, Clement P. Serotonin and premature ejaculation: From physiology to patient management. Eur Urol 2006; 50(3): 454–66. 681. Hull EM, Bitran D, Pehek EA et al. Brain localization of cholinergic influence on male sex behavior in rats: Agonists. Pharmacol Biochem Behav 1988; 31(1): 169–74. 682. Arletti R, Bazzani C, Castelli M, Bertolini A. Oxytocin improves male copulatory performance in rats. Horm Behav 1985; 19(1): 14–20. 683. Pfaus JG, Kippin TE, Centeno S. Conditioning and sexual behavior: A review. Horm Behav 2001; 40(2): 291–321. 684. Barnas JL, Pierpaoli S, Ladd P et al. The prevalence and nature of orgasmic dysfunction after radical prostatectomy. BJU Int 2004; 94(4): 603–5. 685. Koeman M, van Driel MF, Schultz WC, Mensink HJ. Orgasm after radical prostatectomy. Br J Urol 1996; 77(6): 861–4. 686. Newman HF, Reiss H, Northup JD. Physical basis of emission, ejaculation, and orgasm in the male. Urology 1982; 19(4): 341–50. 687. Pfaus JG. Frank A. Beach award. Homologies of animal and human sexual behaviors. Horm Behav 1996; 30(3): 187–200. 688. McKenna K. The brain is the master organ in sexual function: Central nervous system control of male and female sexual function. Int J Impot Res 1999; 11(Suppl 1): 48–55.

Part III Functional pathology of the lower urinary tract

5 Epidemiology of the neurogenic bladder Patrick B. Leu and Ananias C. Diokno

Introduction The neurogenic bladder is an entity with many different characteristics. It is not a disease in and of itself, but rather the manifestation of multiple different neurologic processes capable of exerting effects on the bladder by way of its innervation. The outward expression of these effects by the bladder is as varied as the conditions that cause them, ranging from essentially no detrusor activity at all to extreme detrusor overactivity. The long-term consequences cover a spectrum just as broad, ranging from little to no consequence to the patient to severe debility and even death. This chapter aims to outline for the reader the many neurologic processes that can serve as the risk factor for the development of neurogenic bladder. Although a brief description of some diseases is given, the main focus is the prevalence and type of neurogenic bladder involvement in many of these conditions. Prevalence of neurogenic bladder is the frequency with which bladder dysfunction is observed among the population of neurologically impaired patients at a given period. Incidence rate is the frequency of developing neurogenic bladder within a period. Unfortunately, there are very few reports of incidence rates on neurogenic bladder. Organization of this chapter is based on location of neurologic injury: above the brain stem, the spinal cord, and the peripheral nervous system.

Cerebrovascular accident Cerebrovascular accident (CVA) or stroke is a major cause of morbidity and mortality, especially among the elderly. Causes include cerebral embolus, atherosclerotic thrombus, and hemorrhage. Risk factors include hypertension, diabetes mellitus, smoking, high serum cholesterol, alcohol consumption, obesity, stress, and a sedentary lifestyle.1 CVAs can have profound effects on the genitourinary system. Voiding dysfunction can range from urinary

retention to total incontinence. Evaluation and management can be complicated because of associated comorbidities, which may also contribute to voiding dysfunction in this patient population. Many studies have demonstrated urologic findings as predictors of prognosis in stroke patients. In an analysis of 532 stroke patients, Wade and Hewer2 noted that of those with urinary incontinence within the first week after the event, half died within 6 months. They also noted an association between early incontinence and decreased chance of regaining mobility. Taub et  al.3 evaluated 639 CVA patients and found that initial incontinence was the best single indicator of future disability. Acute urinary retention, commonly known as cerebral shock, is often seen immediately after stroke. The neurophysiologic mechanism of this is unknown and it may not necessarily be the result of the stroke. It may be the consequence of inability to communicate the need to void, impaired consciousness, temporary overdistension, restricted mobility, associated comorbidities (i.e., diabetes, benign prostatic hyperplasia [BPH]), or medications. Urodynamic studies soon after unilateral CVA have demonstrated a 21% prevalence of overflow incontinence because of detrusor hyporeflexia; however, several of these patients were either diabetic or receiving anticholinergics.4 Urinary incontinence is common after stroke. It may be due to detrusor overactivity secondary to loss of cortical inhibition, cognitive impairment with normal bladder function, or overflow incontinence secondary to detrusor hyporeflexia that is secondary to neuropathy or medication. Underlying dementia, BPH, or stress urinary incontinence may also contribute.1 Incontinence after stroke is frequently transitory. Although the incidence of early poststroke urinary incontinence is 57%–83%, many of these patients have been found to recover continence with time, with as many as 80% being continent at 6 months post-CVA.5 Irritative voiding symptoms of frequency, urgency, and incontinence are most commonly seen after resolution of

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the cerebral shock. These are manifestations of detrusor overactivity. In a review of recent literature, Marinkovic and Badlani found that 69% of patients had detrusor overactivity, 10% had detrusor hypocontractility, 31% had uninhibited external sphincter relaxation, and 22% had detrusor–sphincter dyssynergia (DSD). Furthermore, they note that attempts at correlating either the site or mechanism (ischemic vs. hemorrhagic) of injury with urodynamic findings have been inconclusive.1

Cerebellar ataxia Ataxia refers to a heterogeneous spectrum of abnormal motor phenomena associated with cerebellar deficiency. Histologically, Purkinje’s cells are abnormal and less in number. The location of nervous system involvement may extend from the cerebellum to the brain stem, spinal cord, and dorsal nerve roots. The disease is classified based on etiologies. Acute ataxia is secondary to various intoxicants, cerebellar tumors, viral infections, hyperpyrexia, demyelinating diseases, and vascular accidents. Subacute ataxia may be secondary to alcohol abuse, paraneoplastic syndromes, or cerebellar tumors. Chronic childhood ataxia may include Friedreich’s ataxia, ataxia telangiectasia, and ataxias associated with inherited metabolic derangements. Adult forms include olivopontocerebellar atrophy and cortical cerebellar degeneration. Urodynamic evaluation by Leach et  al. of 15 ataxic patients, ranging in age from 8 to 58 years, found that 8 (53%) had overactivity with bladder-sphincteric coordination, 1 (7%) had overactivity without bladder-sphincteric coordination, 2 (13%) had normal bladder contraction without sphincteric coordination, and 4 (27%) had acontractile bladders.6 Machado–Joseph disease is an autosomal dominant spinocerebellar ataxia, which frequently causes autonomic dysfunction. A study of 15 patients found 67% to have at least three symptoms of autonomic dysfunction. Voiding problems (predominantly nocturia and incontinence) and thermoregulatory disturbances were the most common symptoms.7

Tumors of the cerebrum Incontinence of urine can occur in frontal tumors as part of a frontal lobe syndrome of indifference, disinhibition, and self-neglect. However, it can also present urinary frequency, urgency, and incontinence without signs of cognitive or intellectual impairment. This was first described by Andrew and Nathan in 1964, who reported this with a variety of frontal lobe lesions and concluded what is known to be true today: there exists a micturition control center in the superomedial part of the frontal lobes.8 Ten years later, seven further cases were reported by Maurice-Williams in

a series of 50 consecutive frontal lobe tumors (14%) over a 29-month timespan. After evaluation of 100 consecutive intracranial tumors, he observed that this constellation of symptoms was seen only with frontal tumors.9 Blaivas reported results of urodynamic studies on 550 patients. Of them, 27 (4.9%) had pathologic cystometric findings solely attributable to a focal suprapontine lesion. Thirteen of these patients had brain tumors and 14 of them had strokes. Incontinence was their only clinical manifestation, although not all of them were able to void.10 Lang et al. reported two cases of urinary retention and space-occupying lesions of the frontal cortex in 1996. The first case involved an 87-year-old woman who regained her ability to void with minimal postvoid residual after evacuation of a subdural hematoma. The second patient was a 63-year-old woman who presented with increasing difficulty in voiding over 2½ years. She was found to have detrusor hypocontractility and mild bilateral overactivity. She refused surgery for a large left frontal meningioma. During the 4-year follow-up, she eventually required suprapubic catheterization before dying of increasing intracranial pressure from the expanding tumors.11

Normal pressure hydrocephalus Normal pressure hydrocephalus (NPH) is a syndrome of progressive dementia and gait disturbance in patients with normal spinal fluid pressure yet distended cerebral ventricles. Although some patients can have an identifiable mechanical reason for dilation of cerebral ventricles (obstructing tumor, subarachnoid hemorrhage), the cause of this disease is not identifiable in many patients. In 1975, Jonas and Brown evaluated five NPH patients with urinary incontinence by performing cystometry. These patients had urinary frequency, urgency, and urge incontinence. Four of the patients exhibited pressure spikes from involuntary bladder contractions. The other patient exhibited low-volume involuntary voiding at 200  mL fluid. These findings are consistent with the ­so-called uninhibited neurogenic bladder, as described by Lapides. This is secondary to loss of cortical inhibition of primitive bladder reflex contractions.12

Cerebral palsy Cerebral palsy (CP) is a nonprogressive disorder of the brain, resulting in a variety of motor abnormalities often accompanied by intellectual impairment, convulsive disorders, or other cerebral dysfunction. Strict definitions exclude spinal cord involvement. Approximately one-third of children with CP have lower urinary tract symptoms. McNeal et  al. published urodynamic results of 50 patients between the ages of 8 and 29 years. They found enuresis in 28%, stress incontinence in 26%, urgency in

Epidemiology of the neurogenic bladder 18%, and dribbling in 6%. Overall, 36% had some form of voiding dysfunction and some had multiple symptoms.13 Decter et al. evaluated 57 children with cerebral palsy and lower urinary tract symptoms. Incontinence occurred in 49/57 (86%) patients. Eleven of the children had wetting limited to day or night, while the remaining 38 experienced wetting during both the day and the night. Of the eight who were totally continent, three suffered from severe urgency and frequency, two presented with urinary tract infections, two complained of difficulty initiating urination, and one was in urinary retention. General neurologic examination revealed only minor findings in some patients. Urodynamic s­ tudies ­identified definite abnormalities in a majority. On ­ urodynamic evaluation, 70% of the incontinent patients had ­ ­uninhibited contractions that could not be suppressed, 6% had overflow incontinence with incomplete emptying secondary to DSD, 4% had hypertonia causing intermittent leaking, and 2% had periodic relaxation of the e­ xternal sphincter d ­uring filling. Overall, 49 of the 57 (86%) patients (­continent and incontinent) were found to have purely upper motor ­neuron lesions. Urinary tract infection was seen in 11% patients. Four of the six had bladder outlet obstruction secondary to DSD and one had elevated residual volumes owing to poor detrusor contraction. Radiologic abnormalities were seen in all six children who had bladder outlet obstruction.14

Mental retardation Mental retardation may result from a heterogeneous group of disorders and is seldom the result of deficient ­intelligence alone.15 Etiologies include infection, toxin exposure (maternal overdose), perinatal injury, metabolic disturbances (hypercalcemia, hypoglycemia, phenylketonuria), malformations (hydrocephaly, microcephaly, and others), genetic disorders (Down’s syndrome), and cerebral palsy.16 In 1981, Mitchell and Woodthorpe published data on prevalence and disability of mentally handicapped people born between 1958 and 1963 in three London boroughs. They reported that nocturnal enuresis occurred in over a quarter of patients and 12% experienced both day- and nighttime incontinence.16 Another British study by Reid et al. evaluated behavioral syndromes in a sample of 100 severely (49) and profoundly (51) retarded adults. Sixtyfive percent patients in this study of hospitalized patients were incontinent.17 Hellstrom et  al. studied 21 mentally retarded patients (16 men, 5 women; average age 36 years) referred for longstanding urinary problems. The most common urinary symptoms were incontinence, nocturnal enuresis, and urinary retention/poor bladder emptying. The most common urodynamic findings were detrusor areflexia (seven) and detrusor overactivity (five). Four patients had normal

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urodynamic studies. High micturition pressure was found in three patients and large bladder capacity in one patient. Poor flow with high residual volume was seen in two patients. Some patients had more than one finding.15

Parkinson’s disease Parkinson’s disease is a leading cause of neurologic disability among the elderly population. The estimated prevalence of the disease in the United States is 100–150 per 100,000 population and the incidence per annum is 20 per 100,000. It manifests clinically as tremor, rigidity, and bradykinesia.18 Urinary symptoms associated with onset of tremor in some parkinsonian patients were described as early as 1936, and later studies in the 1960s and 1970s demonstrated a 37%–71% incidence of bladder dysfunction with Parkinson’s disease.19–21 Pavlakis et al.18 in 1983 reported urodynamic findings in 30 patients (22 men and 8 women) with Parkinson’s disease and voiding dysfunction. Fifty-seven percent complained of irritative symptoms, 23% obstructive symptoms, and 20% had a combination of the two. Ninety-three percent of the 30 CO2 cystometrographs (CMGs) performed demonstrated detrusor overactivity and 7% (women only) detrusor areflexia. No patient had a normal CMG. Of patients with detrusor overactivity, 75% demonstrated appropriate sphincter relaxation, 7% showed pseudodyssynergia (voluntary contraction of the perineal floor at the time of detrusor contraction in an attempt to prevent leakage), 11% showed sphincter bradykinesia (involuntary electromyographic [EMG] activity persisting through at least the initial part of the expulsive phase of the CMG), and 7% showed neuropathic sphincter potentials. In the two women with detrusor areflexia, there was neither evidence of detrusor denervation based on supersensitivity testing nor any evidence of sphincter denervation based on EMG studies. These two patients were on anticholinergics, and this may have been the etiology of their areflexia. Maximum flow rate was decreased in 10 of the 17 men who underwent uroflow analysis. All 10 had prostatic enlargement and 8 presented with obstructive symptoms. Eight of the 10 demonstrated detrusor overactivity with normal sphincter relaxation, and the other two had pseudodyssynergia.18 A more recent study from Araki et al.22 reported urodynamic findings on 70 patients (30 men and 40 women) with Parkinson’s disease. No male with evidence of prostatic enlargement based on transrectal ultrasound and retrograde urethrocystography was included. Detrusor overactivity was present in 67% patients and hyporeflexia or areflexia was seen in 16%. Other findings were overactivity with impaired contractile function in 9%, overactivity with DSD in 3%, and normal detrusor function in 6%. DSD and detrusor overactivity with impaired contractile function were observed only at

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advanced stages, whereas bladder function was normal only at mild or moderate stages. Abnormal urodynamic findings increased with disease severity.22 O’Sullivan published a case report of a 52-year-old male with initial presentation of urinary frequency and urgency. Urodynamics demonstrated bladder instability and obstruction although no visual obstruction was noted on cystoscopy. Two years later he developed stiffness, slowing of his movements, and shuffling gait and other parkinsonian signs. He also developed orthostatic hypotension. Repeat urodynamic studies demonstrated a hypocompliant bladder with further evidence of bladder instability and obstruction. He was diagnosed with multisystem atrophy Parkinsonism (MSA-P) but, on autopsy performed 8 years after his initial presentation, he was found to have Parkinson’s disease with involvement of Onuf’s nucleus, suggesting the bladder dysfunctions can herald the neurologic disease.23

Shy–Drager syndrome Shy–Drager syndrome is a rare syndrome, which manifests as orthostatic hypotension, urinary incontinence and retention, and associated neurologic dysfunction. The complete syndrome may also include rectal incontinence, anhidrosis, iris atrophy, external ocular palsies, rigidity, tremor, impotence, fasciculations, myasthenia, and anterior horn cell neuropathy. The disease mostly affects men. Urinary symptoms occur early and orthostatic hypotension appears later.24 Salinas et al. studied nine patients (seven men and two women; mean age 71 years) referred for urologic evaluation. Thirty-three percent of patients had difficulty or inability to void, 44% had stress urinary incontinence, 33% had urinary frequency, and 33% had urge incontinence. Two-thirds of patients had lax anal tone and 45% had absent voluntary anal control. EMG of the periurethral striated muscle revealed normal response to cough/ Valsalva in 56% and weak or absent activity in the remaining patients. Voluntary sphincter control, likewise, was present in 56% and weak or absent in 44%. Two of the three patients who were able to void had synchronous cessation of EMG activity and the other patient exhibited sporadic sphincteric activity. On CMG, 67% failed to demonstrate reflex or voluntary detrusor contractions. Poor bladder compliance was seen in four out of nine patients. Involuntary contractions were seen in one-third of patients.25

Multiple sclerosis Multiple sclerosis (MS), a demyelinating process affecting the central nervous system, is characterized by exacerbations and remissions, with associated changes in signs and symptoms. It affects 1 of 1000 Americans.26 Of patients

with MS, 80%–90% will have urologic manifestations, and as many as 10% will present with urologic dysfunction. Patients may exhibit symptoms of urgency, urge incontinence, frequency, and urinary retention. These are secondary to detrusor overactivity, DSD, and hypocontractility.27 Litwiller et al. performed a review of the literature on multiple sclerosis and the involvement of the genitourinary system. In evaluating 22 studies involving 1882 patients, they found urodynamic evidence of detrusor overactivity in 62% patients, DSD in 25%, and detrusor hypocontractility in 20% patients. Less than 1% patients had renal deterioration.28 The manifestations of the disease can also change during its course. Ciancio et al. published data on urodynamic pattern changes in MS. They evaluated 22 patients with MS who underwent at least 2 urodynamic evaluations with a mean follow-up interval of 42–45 months between the studies. Overall, 55% patients demonstrated a change in their urodynamic patterns and/or compliance. Sixtyfour percent patients had the same or worsening of the same symptoms and 36% had new urologic symptoms. Forty-three percent patients with no new symptoms and 75% patients with new symptoms had significant changes found in follow-up urodynamic testing.29

Myelodysplasia/spina bifida Myelodysplasia, also known as spina bifida, is the most common cause of neuropathic bladder in children. It occurs in approximately 1 in 1000 births in the United States. It can involve all levels of the spinal column, including the lumbar 26%, lumbosacral 47%, sacral 20%, thoracic 5%, and cervical spine 2%. Eighty-five percent of children have an associated Arnold–Chiari malformation. The neurologic lesion produced can be quite variable. The level of the bony defect gives little clue to the clinical manifestation of the patient. The height of the bony level and the highest extent of the neurologic lesion may vary from one to three vertebral levels in either direction. Furthermore, the differential growth rates between the vertebral bodies and the elongating spinal cord add a factor of dynamism in the developing child. Because of fibrosis surrounding the spinal cord at the site of meningocele closure, the cord can become tethered during growth, leading to changes in the bowel, bladder, and lower extremity function. Urodynamic evaluation of these patients is therefore a critical component of their management.30 Urodynamic studies in the newborn have shown that 57% of myelodysplastic infants have bladder contractions. In children with upper lumbar or thoracic lesions where the sacral cord is spared, 50% have bladder contractions.31 EMG studies of the external sphincter demonstrate 48% newborns with intact sacral reflex arcs and no lower motor neuron denervation, 23% with partial denervation, and 29% with complete loss of sacral cord function.32

Epidemiology of the neurogenic bladder In 1981, McGuire et  al. demonstrated the relation between intravesical pressure at the time of urethral leakage and presence/development of upper tract changes in myelodysplastic patients. No patient with an intravesical pressure less than 40 cmH2O at the time of urethral leakage developed vesicoureteral reflux and only 10% demonstrated ureteral dilatation on excretory urography. Sixty-eight percent of patients with higher leak point pressures developed vesicoureteral reflux, and 81% showed ureteral dilatation on excretory urography.33 A major problem and risk factor for developing upper urinary tract deterioration is the presence of dyssynergia between the external sphincter and the bladder. Urodynamic evaluation of 36 infants with myelodysplasia demonstrated 50% with dyssynergia, 25% with synergy, and 25% with no sphincter activity. Seventy-two percent of the group with dyssynergia was found to exhibit hydroureteronephrosis by 2 years of age. This was present in only 22% of those with synergy and 11% with absent activity. Of those patients with synergy who developed upper tract deterioration, hydroureteronephrosis occurred only after development of incoordination between the detrusor and external sphincter. The one patient with absent sphincter activity, who developed upper tract changes, had an elevated fixed urethral resistance at 1 year of age. This is felt to be secondary to fibrosis of the striated external urethral sphincter. Treatment by catheterization or cutaneous vesicostomy improved drainage of the urinary tract in each patient.34 The tethered cord syndrome, resulting from fibrosis around the cord and differential growth rates of vertebral bodies and the spinal cord, can be seen in children and adults after neurosurgical closure of the primary defect. Symptoms of bladder dysfunction may be seen in 56% patients at presentation.35 Adamson et  al. reported five adults with tethered cord syndrome revealing a full spectrum of bladder dysfunction ranging from retention in two and frequency and or urgency/incontinence in three patients.36 Flanigan et  al. reported urodynamic results of 24 children before operative cord release. Seventy-one percent had areflexia and 29% had overactive bladders.37 Pang and Wilberger reported preoperative urodynamic study results on eight patients. Five showed small capacity, spastic unstable bladders, while three had hypotonic bladders.35

Sacral agenesis Sacral agenesis is defined as the absence of all or part of two or more vertebral bodies at the lower end of the spinal column. The incidence of sacral agenesis is about 0.09%– 0.43% births. It occurs more frequently in children of diabetic mothers. Approximately 20% of children with sacral agenesis are not identified until they are 3–4 years old and present with difficulty in toilet training.38

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The urodynamic pattern in children with sacral agenesis is varied. Guzman et al. reported upper motor lesions at a rate of 35%, including detrusor overactivity, DSD, exaggerated sacral reflexes, and no voluntary control over sphincter function. Forty percent demonstrated lower motor lesions, including detrusor areflexia and absent sacral reflexes. The remaining 25% were unaffected.38 Another study by Koff and Deridder evaluated 13 patients with sacral agenesis. Urodynamic studies revealed that 31% had a rate of lower motor lesions (flaccid bladder), 23% had an upper motor lesion, and 31% had a mixed pattern.39

Spinal cord injury Spinal cord injury (SCI) affects over 200,000 persons in the United States, with an estimated 8,000–10,000 new cases occurring annually.40 Bladder dysfunction after SCI can be classified as either lower motor neuron (LMN) dysfunction or upper motor neuron (UMN) dysfunction.41 In patients with detrusor overactivity following spinal cord injury, it is imperative to know whether the external sphincter is coordinated (synergic) with the detrusor contraction or uncoordinated (dyssynergic) with the involuntary detrusor contraction. Diokno et al.42 reported a 66% rate of dyssynergia among 47 patients with a reflex neurogenic bladder. In 2000, Weld and Dmochowski reported urodynamic findings of 243 SCI patients. All but three patients were male. Of 196 patients with suprasacral injuries, 95% showed overactivity and/or DSD, 42% had low bladder compliance, and 40% had high detrusor leak point pressures. Of 14 patients with sacral injuries, 86% manifested areflexia, 79% had low compliance, and 86% had high leak point pressures. Of 33 patients with combined suprasacral and sacral injuries, 68% demonstrated overactivity and/or DSD, 27% exhibited areflexia, 58% had low compliance, and 61% had high leak point pressures. Overactivity was seen in 42%, 54%, 32%, 14%, and 33% of cervical, thoracic, lumbar, sacral, and multilevel cord injuries, respectively. DSD was seen in 68%, 50%, 39% 14%, and 45% of these same lesions. Areflexia was seen in 0%, 0%, 21%, 86%, and 27%, respectively. Normal urodynamic findings were found in 1%, 4%, 4%, 0%, and 3% of injuries at the aforementioned levels. These findings further reinforce that although general correlations between level of injury and the clinical manifestation exist, they are not exact or exclusive.43 The central cord syndrome is caused by incomplete cervical SCI and is characterized by incomplete quadriplegia with disproportionately worse impairment of the upper than the lower extremities. Central cord syndrome may involve 9%–16% of all SCIs and is more predominant in the elderly. Smith et al. reported video urodynamic testing results from 22 men with central cord syndrome. Studies

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were done for an average of 34.5 months after injury and after spinal shock had resolved. Results showed normal evaluations in 14%, detrusor areflexia in 18%, detrusor overactivity with synergy in 5%, DSD in 50%, and detrusor hypocontractility in 5%.44 Two cases of neurogenic bladder following imageguided transforaminal lumbar spine epidural steroid injection were reported in two patients, an 83-year-old and a 79-year-old. Both patients developed bilateral lower extremity paralysis with neurogenic bladder immediately after the procedure. MRI showed spinal cord infarction without intraspinal mass or hematoma.45 The status of innervation and function of the external sphincter or periurethral striated muscle is as important as the type of detrusor innervation and function following an SCI, or for that matter any neurologic condition affecting the lower urinary tract. A paralytic external sphincter due to total or partial injury to the anterior motor neuron will certainly cause reduction to the urethral resistance at the sphincteric level, predisposing the individual to stress incontinence. In patients with areflexic bladder, Diokno et al.42 reported 60% patients with complete denervation of the external sphincter and the rest had partial denervation.

Diabetes Diabetes is the most common metabolic disease and affects  over 5 million people in the United States. Neuropathy is the most frequent of the many complications associated with the disease. The cause is thought to be due to a combination of ischemic nerve injury secondary to vasculopathy associated with the disease, as well as nerve injury secondary to deranged metabolic function. Tests of autonomic function have shown impairment in roughly 20%–40% of diabetic patients.46 Diabetic cystopathy is the constellation of clinical and urodynamic findings associated with long-term diabetes mellitus. Classically, it has been described as decreased bladder sensation, increased bladder capacity, and impaired detrusor contractility. It is frequently insidious in onset and progression, and many patients may have minimal symptoms. Impaired bladder sensation is the most common initial presentation. Patients may void only once or twice a day. Eventually, they may have difficulty initiating and maintaining voiding. Urodynamic testing of unselected diabetics reveals diabetic cystopathy in 26%–87% patients. The finding of cystopathy correlates directly with the duration of symptoms, which generally occur about 10 years after the onset of diabetes. It frequently coexists with signs of peripheral neuropathy. Many diabetics have other coexisting urologic problems such as benign prostatic hyperplasia, stress incontinence, bladder or prostate cancer, or infection causing voiding symptoms that may be similar to or different from the classically described diabetic bladder.47

Kaplan et  al. reported urodynamic findings of 115 male and 67 female consecutive diabetic patients referred for evaluation of voiding symptoms. Mean duration of diabetes was 58 months and mean duration of voiding symptoms was 27 months. The most common symptoms were nocturia greater than two times in 87%, urinary frequency in 78%, urinary hesitancy in 62%, decreased force of stream 52%, and sensation of incomplete emptying in 45%. No differences between men or women in the above symptoms were noted. The mean volume of urine at which sensation of filling was first felt was 298 mL. Mean bladder capacity was 485 mL. Fifty-two percent of patients had detrusor instability, 23% had impaired detrusor contractility, 11% had indeterminate findings, 10% had detrusor areflexia, 24% had poor compliance, and 1% were normal. Of the 47 patients with peripheral neuropathy, 70% had detrusor instability, 57% had bladder outlet obstruction, 13% had indeterminate findings, 30% had detrusor areflexia, and 66% had evidence of sacral cord signs. Bladder outlet obstruction was present in 36% of men. Nine percent patients (13) had urinary retention, which in men was secondary to bladder outlet obstruction (seven) and detrusor areflexia (five). All four women with retention had areflexia.48 Kitami performed urodynamic studies on 173 diabetics. Patients in this study did have classic findings of increased volume at first desire and decreased maximum vesicle pressure (67%), but they also demonstrated overactive bladder (14.5%), low-compliance bladder (11%), and ­detrusor–external sphincter dyssynergia (32%).49 Frimodt-Moller, who coined the term “diabetic cystopathy,” reported 124 patients with diabetes. Thirty-eight ­percent had what are now recognized as classic cystopathic findings and 26% had bladder outlet obstruction.50 Pediatric diabetes can be associated with neurogenic bladder as well. Goksen et al. reported a 6-year-old child with neonatal diabetes mellitus that became permanent. She was diagnosed at birth. She has subsequently been found to have neurogenic bladder, immune deficiency, constipation, and ichthyosis. Urodynamic testing demonstrated decreased capacity, detrusor instability, and ­dysfunctional voiding.51

Disc disease Symptoms from lumbar disc protrusion are most often secondary to posterolateral protrusion, occurring frequently at the L4–L5 and L5–S1 levels. However, more central (posterior) protrusion may disturb nerves leading to the bladder, perineal floor, and cavernous tissue of the penis. Dong et al. reviewed urodynamic reports of 30 patients with neurogenic bladder dysfunction secondary to disc disease and found differences in urodynamics are indispensable in the evaluation and treatment of intervertebral disc hernia.52

Epidemiology of the neurogenic bladder Fanciullacci et al.53 studied 22 patients with lumbar central disc protrusion and neuropathic bladder. All patients except two women with urinary incontinence had urinary retention at presentation. Urodynamic studies performed at the onset revealed areflexia with normal compliance in all patients. Bladder sensation was absent in 16 (73%) and reduced in 6 (27%). EMG showed signs of severe denervation. Postoperative urodynamic evaluation in 17 patients revealed 65% had persistent areflexia, 29% had normoreflexia, and 6% had areflexia; and all had normal compliance. Bladder sensation was absent in 35%, reduced in 47%, and normal in 18%. EMG studies of the periurethral muscles showed good recovery of voluntary contraction in 76% of patients.53 O’Flynn et al. reviewed the records of 30 patients with lumbar disc prolapse and bladder dysfunction who underwent laminectomy and disc removal. Preoperatively, 87% of the patients developed urinary symptoms. Fifty-three percent required catheterization for urinary retention. Postoperative urodynamics revealed 37% of patients had areflexic bladders and voided by straining, 13% exhibited detrusor overactivity with urinary incontinence, and 7% had low compliance with opening of the bladder neck during filling. Thirty-seven percent demonstrated genuine stress incontinence at bladder volumes greater than 300 mL. Only one patient regained normal detrusor activity postoperatively.54 Bartolin et  al. evaluated bladder function after disc surgery. Ninety-eight patients underwent urodynamic evaluation before and after surgery. Twenty-eight percent patients exhibited detrusor areflexia preoperatively. Only 22% of these patients had a return to normal function after surgery. Of the 71 patients with normal urodynamic findings preoperatively, 4 (6%) developed detrusor overactivity and 3 (4%) developed areflexia postoperatively.55

Cauda equina syndrome The cauda equina syndrome is a relatively rare constellation of symptoms for herniated lumbar discs. It is characterized by bilateral sciatica, lower extremity weakness, saddle-type hypesthesia, and bowel and bladder dysfunction. Cauda equina syndrome occurs in approximately 1%–10% cases of lumbar disc herniation. Early operative decompression is advocated, but may not always restore normal function. Chang et  al. evaluated the incidence and long-term outcome of patients with this condition. They identified 4 of 144 (2.8%) consecutive surgical cases of lumbar disc herniation with urinary retention. All patients regained voluntary voiding within 6 months, 1, 3, and 4 years of surgery.56 Podner et  al. reported urinary function in 65 patients with chronic cauda equina syndrome. Symptoms of disturbed bladder emptying were the most common

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followed by urinary incontinence and overactive bladder. Urodynamic findings varied and included overactive bladder in 21% men, 0% women; reduced bladder capacity in 9% men and 15% women; and during voiding an acontractile detrusor or detrusor underactivity were found in 59% men and 89% women. There was a poor correlation between patient symptoms and urodynamic findings.57

Infectious diseases Acquired immune deficiency syndrome Patients with acquired immune deficiency syndrome (AIDS) have not made up a large portion of most urologists’ practices. However, because of the large number of people with this disease and increased survival with new medications, urologists can expect to see more patients with AIDS. Neurologic involvement occurs in 30%–40% of patients with AIDS, and involves the central and peripheral nervous systems.58–60 Neurologic involvement may be the result of infection, immunologic injury to target organs, or neoplasia. Khan et al. performed urodynamic studies on 11 of 677 AIDS patients. Voiding dysfunction secondary to neurogenic bladder was found in 9 of 11 (82%) patients. Urinary retention in 6 of the 11 (55%) patients was the most common presenting symptom. Three patients (27%) presented with urinary incontinence, 1 (9%) with urinary frequency, 1 (9%) with poor urinary flow. Urodynamic study demonstrated areflexia in 4 (36%) patients, overactivity in 3 (27%), hyporeflexia in 2 (18%), and urinary outflow obstruction without evidence of neurologic involvement in 2 (18%). EMG studies of the urinary sphincter were done in eight of the patients. Only two of them had abnormalities: one with myelopathy exhibited poor recruitment of neuronal activity and the one with equina syndrome had many fibrillatory potentials.61 Menendez et  al. reported urodynamic evaluations of three patients with AIDS and neurogenic bladder. Two of the patients had areflexic bladder secondary to ascending myelitis by herpes simplex virus type II in one patient, and cerebral abscess from toxoplasmosis in the other patient. A third patient with AIDS dementia complex exhibited a hyperreflexic detrusor. Voiding symptoms improved in all three patients with institution of antiviral, antibiotic, and anticholinergic medications, respectively.62

Encephalitis Sasaki et  al. reported on three males diagnosed with meningo-radiculo encephalitis presenting with acute urinary retention. On urodynamics all three showed features

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of atonic bladder with or without detrusor hyperactivity. At 3-year follow-up, two continued to use intermittent self-catheterization.63

Guillain–Barré syndrome Guillain–Barré syndrome is an idiopathic polyradiculopathy frequently related to viral illnesses or vaccination. Lesions of the motor neuron in the spinal nerve are seen on pathological examination. Clinically, it is characterized by motor paralysis initially in the lower extremities and progressing cephalad. Kogan et al. first reported urodynamic findings in two patients with Guillain–Barré syndrome in 1981. Both the patients were found to have motor paralytic bladders on cystometrogram evaluation.64 Wheeler et  al. reported urodynamic findings in seven patients with Guillain–Barré syndrome. Impaired voiding with namic studies revealed four patients with detrusor areflexia and nonrelaxation of the perineal muscles with a positive bethanechol supersensitivity test. Three of these four patients had abnormal perineal EMG studies that demonstrated a decreased interference pattern with polyphasic potentials, which is characteristic of motor denervation. Three of the seven patients had detrusor overactivity with appropriate sphincter relaxation. Intravesical sensation, although decreased, was present in six patients and completely absent in one patient.65 Another study by Sakakibara et  al. described urologic findings in 28 patients with Guillain–Barré syndrome. Micturitional symptoms were seen in 25% patients and included voiding difficulty in six, transient urinary retention in three, nocturnal urinary frequency in three, urinary urgency in three, diurnal urinary frequency in two, urge incontinence in two, and stress incontinence in one. Urodynamic evaluation in four patients revealed disturbed sensation in one patient, bladder areflexia in one, and absence of bulbocavernosus reflex in others. Cystometry showed decreased bladder volume in two and bladder overactivity in two, one of whom had urge urinary incontinence and the other urinary retention.66

Herpes Herpes zoster infection is a viral syndrome characterized by a painful vesicular eruption involving one or more dermatomes and inflammation of the corresponding dorsal root ganglia. Both sensory and motor neurons can be affected. Cohen et  al. reviewed the literature of herpes zoster associated with bladder and/or bowel dysfunction and reported 32 cases. Urinary retention was present in 28 (88%), symptoms of cystitis (dysuria, frequency, hesitancy)

in 13 (41%), symptoms of both retention and cystitis in 11 (34%), and constipation and/or fecal incontinence in 20 (63%) patients. Sacral dermatomes (S2–S4) were involved in 78% of cases; lumbar and thoracic dermatomes were affected in 16% and 2% patients, respectively. Men were affected more commonly than women (66% vs. 34%). Patients tended to present in the sixth to eighth decades of life, although some women in their twenties have been reported. Cystometrograms typically show absent detrusor spikes or flaccid neurogenic bladders.67 Brosetta et al. published urologic findings of 57 patients diagnosed with and treated for herpes zoster infection. Fifty-four percent of the patients were men and the mean age was 51 years. Thirty-seven percent patients had some type of immunodeficiency (HIV, hepatic disease, lymphoproliferative disorder). Fifteen of the 57 (26%) had urologic manifestations. Two of the 15 (13%) exhibited urinary retention and were found to have detrusor areflexia on CMG. Three of the 15 (20%) exhibited incontinence and detrusor overactivity on CMG.68

Human T-lymphotropic virus Human T-lymphotropic virus (HTLV-I)–associated myelopathy (HAM) is a slowly progressive spastic paraparesis caused by infection with HTLV-I and less frequently with HTLV type II. Clinical manifestations result from demyelination and eventual atrophy of the thoracic spinal cord. The myelopathy has a peak incidence in HTLV-infected patients aged 40–50 years, and women are affected more than men. Coinfection with HIV results in an increased rate of myelopathy among those with HTLV infection. Murphy et al. performed a cross-sectional analysis of HTLV-seropositive subjects who were detected from five blood donor centers in the United States. Myelopathy was confirmed in 4 of 166 (2.4%) HTLV-I-positive subjects and in 1 of 404 (0.25%) HTLV-II-positive subjects. All five patients diagnosed with HAM underwent urodynamic evaluation and all were found to have dyssynergic bladder contractions. In fact, urinary urgency and incontinence were the most common presenting symptoms and two of the patients had undergone urodynamic evaluation before enrollment in the study.69

Lyme disease Lyme disease is caused by the spirochete Borrelia burgdorferi. It is the most common tick-borne disease in the United States and is associated with a variety of neurologic sequelae. Chancellor et  al. evaluated seven patients with confirmed Lyme disease and associated lower urinary tract dysfunction. Most of the patients had paraparesis with partial sensory loss and one was temporarily in coma. Two patients had urinary retention, four patients had one or

Epidemiology of the neurogenic bladder more irritative symptoms (frequency, urge incontinence, nocturia), and one patient had enuresis. On urodynamic evaluation, five patients showed detrusor overactivity and two had detrusor areflexia. DSD was not observed in any patient. Of the five patients with detrusor overactivity, two were aware of the involuntary contractions but could not inhibit them and three were unaware of the involuntary contractions. With follow-up after intravenous antibiotics ranging from 6 months to 2 years, urologic symptoms resolved completely in four patients, whereas in three patients, symptoms improved but with residual urgency and frequency.70

Poliomyelitis Acute poliomyelitis is often associated with urinary retention owing to detrusor areflexia, although bladder function is generally recovered. Uninhibited detrusor contractions with urge incontinence or an atonic bladder with weak, ineffective detrusor contractions may also be seen.71 Howard et al. reported an 11% prevalence of retention in 23 of 203 patients during the acute polio episode, whereas 69/203 (34%) had chronic urinary symptoms persisting after resolution of the acute episode.72 Progressive functional deterioration occurring years after an acute episode of poliomyelitis is termed post-polio syndrome (PPS). It manifests as new-onset or progressive motor or visceral dysfunction, or as joint or limb deterioration. The mechanism is not known but may be secondary to premature or accelerated loss of anterior horn cells that innervate large numbers of muscle fibers, loss of neuronal cell terminals that had sprouted to innervate muscle fibers, reactivation of the virus, deterioration of the immune system, and intercurrent neurologic or nonneurologic diseases.72 Johnson et al. evaluated 330 completed questionnaires mailed randomly to subjects in West Texas with a history of polio. Eighty-seven percent of women and 74% of males reported symptoms of PPS. The mean age of responders was 55 years. The mean age at acute attack was 10 years and the mean interval between the acute episode and the development of PPS was 33 years for females and 36 years for males. Three hundred and six (93%) patients reported urologic symptoms that included change in bladder function, change in sexual function, frequency (8 voids/day), nocturia (2 voids/night), hesitancy, urgency, intermittency, postvoid dribbling, and decreased force of stream. Thirty-five patients (10.6%) reported detrusor instability. Only a few had symptoms compatible with hypocontractile or areflexic bladders, requiring catheterization. The prevalence of incontinence among females was similar among those with and without PPS (72% vs. 77%, respectively); however, the severity of incontinence was worse in those with PPS. Incontinence in men was limited

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to postvoid dribbling or urge incontinence. These symptoms were worse in men with PPS.73

Syphilis Voiding dysfunction related to neurosyphilis had a high prevalence in the prepenicillin era. Voiding dysfunction caused by decreased vesical sensation resulted in large residual urine and bladder decompensation. Fortunately, improvements in medical care have made neurosyphilis a rare entity. Roughly 10% patients infected with primary syphilis later develop neurosyphilis. Lumbosacral meningomyelitis with involvement of the dorsal cord and/or spinal roots (tabes dorsalis) results in bladder dysfunction. This manifests as decreased bladder sensation, large bladder capacity, and high postvoid residuals. In some patients, typically those with general paresis of the insane, incontinence can occur, which is usually functional or possibly the result of uninhibited detrusor activity as seen in upper motor neuron lesions.74 Brodie et  al. reported 13 patients with neurosyphilis and bladder involvement. Of the 13 patients, 12 had classic detrusor areflexia and decreased bladder sensation, leading to overdistension. One patient had detrusor overactivity.75 Garber et al. reported three patients with tertiary syphilis. All three were found to have hypocompliant bladders with detrusor overactivity, DSD, and elevated residual volumes on video CMG. This small group of patients demonstrates how tertiary syphilis can manifest with upper motor neuron bladder dysfunction.76

Tuberculosis Tuberculosis can affect the spine. Spinal tuberculosis is more severe, dangerous, and disabling in children than in adults. Mushkin and Kovalenko studied 32 patients under the age of 16 years with thoracic and lumbar spinal tuberculosis who underwent antibiotic and surgical treatment. Paraplegia occurred in eight patients and was always associated with bladder and bowel dysfunction. Three other patients without paraplegia also had bladder and bowel dysfunction (34% overall). Eight of the 11 recovered bladder and bowel function postoperatively. Urodynamic evaluations were not included in this report.77 Kiran et  al. reported 59 patients from India who suffered from spinal involvement of tuberculosis and severe motor deficits and who underwent surgical management. Thirty-four of 48 patients who had follow-up presented with bladder involvement. Thirty (88%) of these 34 patients recovered complete function postoperatively. One patient experienced incontinence, and an indwelling catheter

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had been placed, and the remaining three complained of straining to urinate.78

Radical pelvic surgery Rectal carcinoma/resection Urinary dysfunction as a consequence of damage to important neuroanatomic structures remains a common complication of radical pelvic surgery, particularly in abdominoperineal resection (APR) for rectal carcinoma. The extent of primary resection and lymphadenectomy are major determinants of degree of postoperative urologic morbidity. The incidence of de-novo urinary dysfunction following APR has been reported to be as high as 70%. Urinary retention caused by detrusor denervation is the most common type of voiding dysfunction after APR, and is the result of disruption of detrusor branches of the pelvic nerve. Less commonly, stress urinary incontinence secondary to denervation of the external sphincter or direct injury to the muscle itself can occur.79 Voiding dysfunction is more severe after APR than after rectal sphincter–preserving procedures, such as low anterior resection (LAR), and the degree of dysfunction is related to the extent of dissection. In a report by Hojo et al., 22 of 25 patients (88%) who underwent preservation of the autonomic nerves were voiding spontaneously by postoperative day 10, whereas 28 of 36 patients (78%) with complete resection of the pelvic autonomic nerves still have urinary retention and were dependent on indwelling catheter drainage by postoperative day 60.80 Similar studies by Mitsui et  al. and Sugihara et  al. demonstrated that 100% patients undergoing bilateral nerve sparing with radical resection for rectal carcinoma regained spontaneous voiding postoperativley.81,82 When unilateral pelvic plexus preservation is performed, over 90% are able to void spontaneously. Thirty percent patients undergoing complete resection of pelvic autonomic nerves in Sugihara’s study required self-­catheterization. In Mitsui’s investigation series, only 30% patients in the nonpreserved group voided normally. Interestingly, they noted no significant difference in lower urinary tract function between patients receiving LAR versus APR. Cosimelli et al. reported minimal urologic morbidity in 57 male patients undergoing LAR and limited lumboaortic lymphadenectomy. Less than 3% had urinary incontinence and 4.2% experienced urinary retention.83

Radical hysterectomy Voiding dysfunction after radical hysterectomy and pelvic lymphadenectomy for carcinoma of the cervix has typically manifested as bladder atonia. An early report by Ketcham et al. revealed an 8% rate of atonia requiring Foley catheter drainage postoperatively.84

Seski and Diokno prospectively studied 10 patients before and after radical hysterectomy. Results suggest that a hypertonic phase immediately postoperatively is transient and secondary to myogenic tonicity. By 6–8 weeks postoperatively, bladder capacity and compliance returned to the preoperative level. Only 1/10 (10%) developed significant detrusor denervation, as demonstrated by a positive bethanechol supersensitivity test.85 A more recent report by Lin et al. reported urodynamic results on patients who underwent either radical hysterectomy, pelvic radiation, or both and compared them to a control group of patients with cervical cancer before treatment. Detrusor instability or low bladder compliance was found in 57%, 45%, 80%, and 24% patients, respectively. Each group was found to have decreased bladder capacity. The frequency of abdominal strain voiding was 100% in all treatment groups, but was 0% in the pretreatment group. Abnormal residual urine was seen in 41%, 27%, 40%, and 24% patients, respectively.86

Spinal stenosis Lumbar spinal stenosis does not often cause chronic bladder dysfunction. However, when it does, it is considered to be an advanced form and is related to compression of the cauda equina. Kawaguchi et al. evaluated 37 patients with lumbar spinal stenosis before and after decompressive laminectomy. Twenty-nine patients had subjective urinary complaints. Preoperative CMG studies revealed 23 patients (62%) with neuropathic bladders (18 underactive, 5 overactive). Thirty-eight percent had normal CMG studies. Postoperative CMG studies in nine patients with neuropathic bladders showed a normal pattern in six patients, with three exhibiting a persistent underactive bladder.87 Cervical spondylosis is a generalized disease process, which can affect all levels of the cervical spine. When the pathology is located laterally, spondylosis causes only radicular symptoms, whereas a central or paracentral location can cause cord compression in addition to root lesions. Lower urinary tract sphincter disturbances and bladder dysfunction (frequency, urgency, and urge incontinence) can be seen along with lower extremity signs such as gait disturbance, lower extremity spasticity, and hyperactive tendon reflexes. Tammela et  al. performed urodynamic studies on 30 consecutive patients with clinically and radiologically verified cervical spondylosis causing radiculopathy and/or myelopathy. Sixty-one percent of patients complained of irritative bladder symptoms, and detrusor hyperactivity was demonstrated urodynamically in 46%. Twenty-five percent had hyperreflexic detrusor contractions with ice water provocation. Sensitivity to cold was lacking in 39%. Eleven percent described difficulty emptying the bladder, and all were found to have hypotonic detrusors.88

Epidemiology of the neurogenic bladder

Spine surgery The incidence of voiding dysfunction after spinal surgery has been shown to be as high as 60%.89 Boulis et al. reported an incidence of 38% in 503 patients undergoing routine cervical or lumbar laminectomy or diskectomy. Neither the rate nor the duration of retention between men and women was significantly different. Patients undergoing cervical or lumbar laminectomy were found to have longer duration of retention than those undergoing cervical or lumbar diskectomy. Preoperative use of beta-­blockers was associated with increased risk of urinary retention postoperatively. Patients who developed urinary retention were older on average than those who did not develop retention (51.9 vs. 48.4 years). The rate of retention did not differ significantly between groups who did and did not have intraoperative Foley catheters placed.90 Brooks et  al. performed urodynamic evaluations of 74  patients who complained of new onset (69) voiding symptoms or exacerbation of underlying voiding symptoms (5) after undergoing lumbosacral laminectomy, diskectomy, or both. Sixty percent were found to have pathologic urodynamic findings. Sixteen percent were found to have a hypoesthetic bladder and 24% demonstrated a hyperesthetic bladder. Fourteen percent had bladder capacities less than 200 mL, whereas another 14% had capacities greater than 500 mL.89

Other causes of neurogenic bladder Nonneurogenic neurogenic bladder Nonneurogenic bladder, also known as Hinman’s syndrome is a functional bladder outlet obstruction caused by voluntary contractions of the external urethral sphincter during voiding. It is a learned voiding dysfunction developed early in life by children in response to uncontrolled bladder contractions. Typically, patients present with frequency, urgency, urinary incontinence, recurrent urinary tract infections, or occasionally encopresis. The voiding dysfunction is usually acquired after toilet training and tends to resolve after puberty.91,92 The syndrome is rare in children. Reports on the prevalence of Hinman’s syndrome in adults vary. Jorgensen et al. reported a 0.5% prevalence rate among patients referred for urodynamic evaluation.93 In scanning a urodynamic database of 1015 consecutive adults referred for evaluation of voiding dysfunction, Groutz et al. identified 21 (2%) patients (13 women, 8 men) who met criteria for Hinman’s syndrome. Ninety-five percent of the patients exhibited obstructive symptoms and more than half had frequency, nocturia, and urgency. On noninvasive uroflow evaluation, all patients exhibited an intermittent flow pattern. On urodynamic study, first

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sensation volume was significantly lower in women than in men (123 vs. 272 mL). This trend was also seen in first urge, strong urge, and bladder capacity volumes. Fourteen percent (3) were also found to have detrusor instability. Detrusor pressure at maximum flow and maximum detrusor pressure during voiding were both found to be significantly higher in men than in women. The authors concluded that the prevalence of this condition among the adult population may actually be higher than 2%.92

Myasthenia gravis Myasthenia gravis (MG) is an autoimmune disorder whereby antibodies against the nicotinic cholinergic receptors of neuromuscular transmission result in muscle weakness and easy fatigability. It typically affects striated muscle, although antibodies against smooth muscle muscarinic receptors have been identified as well. Voiding dysfunction in association with the disease is rare.94 There are reports in the literature that note an association between MG and incontinence in men with prostatic bladder outlet obstruction. It has been hypothesized that thorough resection led to injury to a sphincter already compromised by the underlying neurologic disorder, and the authors recommended incomplete resection to prevent this complication.95 Another small group of eight men with MG and prostatic resection, who underwent transurethral resection of the prostate (TURP) with blended current all became incontinent, but men who underwent TURP with either high-frequency unblended current, partial proximal resection, or open prostatectomy remained dry.96 Khan and Bhola published a report of one patient who underwent open prostatectomy and remained dry. EMG studies revealed that although his sphincter functioned normally, it did demonstrate easy fatigability.97 There are four reports in the literature of voiding dysfunction in patients with no history of TURP. Howard et al. reported a 31-year-old female with recurrent incontinence after undergoing bladder neck suspension for stress incontinence. She was found to have an open bladder neck, inability to sustain a pelvic floor contraction, and overactivity which occurred concomitantly with deterioration of her MG.98

References 689. Marinkovic SP, Badlani G. Voiding and sexual dysfunction after cerebrovascular accidents. J Urol 2001; 165: 359–70. 690. Wade DT, Hewer RL. Outlook after an acute stroke: Urinary incontinence and loss of consciousness compared in 532 patients. Q J Med 1985; 56: 601–8. 691. Taub NA, Wolfe CD, Richardson E, Burney PG. Predicting the disability of first-time stroke sufferers at 1 year. 12-month follow-up of a ­population-based cohort in Southeast England. Stroke 1994; 25: 352–7. 692. Gelber DA, Good DC, Laven LJ, Verhulst SJ. Causes of urinary incontinence after acute hemispheric stroke. Stroke 1993; 24: 378–82.

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693. Brocklehurst JC, Andrews K, Richards B, Laycock PJ. Incidence and correlates of incontinence in stroke patients. J Am Geriatr Soc 1985; 33: 540–2. 694. Leach GE, Farsaii A, Kark P, Raz S. Urodynamic manifestations of cerebellar ataxia. J Urol 1982; 128: 348–50. 695. Yeh T, Lu C, Chou Y et  al. Autonomic dysfunction in MachadoJoseph disease. Arch Neurol 2005; 62: 630–6 696. Andrew J, Nathan PW. Lesions of the anterior frontal lobes and disturbances of micturition and defaecation. Brain 1964; 87: 233–62. 697. Maurice-Williams RS. Micturition symptoms in frontal tumors. J Neurol Neurosurg Psychiatr 1974; 37: 431–6. 698. Blaivas JG. The neurophysiology of micturition: A clinical study of 550 patients. J Urol 1982; 127: 958–63. 699. Lang EW, Chestnut RM, Hennerici M. Urinary retention and space occupying lesions of the frontal cortex. Eur Neurol 1996; 36: 43–7. 700. Jonas S, Brown J. Neurogenic bladder in normal pressure hydrocephalus. Urology 1975; 5: 44–50. 701. McNeal DM, Hawtrey CE, Wolraich ML, Mapel JR. Symptomatic neurogenic bladder in a cerebral-palsied population. Dev Med Child Neurol 1983; 25: 612–6. 702. Decter RM, Bauer SB, Khoshbin S et al. Urodynamic assessment of children with cerebral palsy. J Urol 1987; 138: 1110–2. 703. Hellstrom PA, Jarvelin M, Kontturi MJ, Huttunen NP. Bladder function in the mentally retarded. Br J Urol 1990; 66: 475–8. 704. Mitchell SJF, Woodthorpe J. Young mentally handicapped adults in three London boroughs: Prevalence and degree of disability. J Epidemiol Comm Health 1981; 35: 59–64. 705. Reid AH, Ballinger BR, Heather BB. Behavioral syndromes identified by cluster analysis in a sample of 100 severely and profoundly retarded adults. Psychol Med 1978; 8: 399–412. 706. Pavlakis AJ, Siroky MB, Goldstein I, Krane RJ. Neurourologic findings in Parkinson’s disease. J Urol 1983; 129: 80–3. 707. Langworthy OR, Lewis LG, Dees JE, Hesser FH. Clinical study of control of bladder by central nervous system. Bull Johns Hopkins Hosp 1936; 58: 89. 708. Murnaghan GF. Neurogenic disorders of the bladder in parkinsonism. Br J Urol 1961; 33: 403–9. 709. Porter RW, Bors E. Neurogenic bladder in parkinsonism: Effect of thalamotomy. J Neurosurg 1971; 34: 27–32. 710. Araki I, Kitahara M, Oida T, Kuno S. Voiding dysfunction and Parkinson’s disease: Urodynamic abnormalities and urinary symptoms. J Urol 2000; 164: 1640–3. 711. O’Sullivan SS, Holton JL, Massey LA et al. Parkinson’s disease with Onuf ’s nucleus involvement mimicking multiple system atrophy. J Neurol Neurosurg Psychiatry 2008; 79: 232–4. 712. Shy GM, Drager GA. A neurological syndrome associated with orthostatic hypotension: A clinico-pathologic study. Arch Neurol 1960; 2: 511–27. 713. Salinas JM, Berger Y, De La Rocha RE, Blaivas JG. Urological evaluation in the Shy Drager syndrome. J Urol 1986; 135: 741–3. 714. Fingerman JS, Finkelstein LH. The overactive bladder in multiple sclerosis. JAOA 2000; 100: S9–S12. 715. Rashid TM, Hollander JB. Multiple sclerosis and the neurogenic bladder. Phys Med Rehabil Clin N Am 1998; 9: 615–29. 716. Litwiller SE, Frohman EM, Zimmern PE. Multiple sclerosis and the urologist. J Urol 1999; 161: 743–57. 717. Ciancio SJ, Mutchnik SE, Rivera VM, Boone TB. Urodynamic pattern changes in multiple sclerosis. Urology 2001; 57: 239–45. 718. Selzman AA, Elder JS, Mapstone TB. Urologic consequences of myelodysplasia and other congenital abnormalities of the spinal cord. Urol Clin N Am 1993; 20: 485–504. 719. Pontari MA, Keating M, Kelly M et al. Retained sacral function in children with high level myelodysplasia. J Urol 1995; 154: 775–7. 720. Spindel MR, Bauer SB, Dyro FM et al. The changing neurourologic lesion in myelodysplasia. JAMA 1987; 258: 1630–3.

721. McGuire EJ, Woodside JR, Borden TA, Weiss RM. Prognostic value of urodynamic testing in myelodysplastic patients. J Urol 1981; 126: 205–9. 722. Bauer SB, Hallett M, Khoshbin S et  al. Predictive value of urodynamic evaluation in newborns with myelodysplasia. JAMA 1984; 252: 650–2. 723. Pang D, Wilberger JE. Tethered cord syndrome in adults. J Neurosurg 1982; 57: 32–47. 724. Adamson AS, Gelister J, Hayward R, Snell ME. Tethered cord syndrome: An unusual cause of adult bladder dysfunction. Br J Urol 1993; 71: 417–21. 725. Flanigan RC, Russell DP, Walsh JW. Urological aspects of tethered cord. Urology 1989; 33: 80–2. 726. Guzman L, Bauer SB, Hallet M et al. Evaluation and management of children with sacral agenesis. Urology 1983; 22: 506–510. 727. Koff SA, Deridder PA. Patterns of neurogenic dysfunction in sacral agenesis. J Urol 1977; 118: 87–9. 728. Waites KB, Canupp KC, DeVivo MJ et al. Compliance with annual urologic evaluations and preservation of renal function in persons with spinal cord injury. J Spinal Cord Med 1995; 18: 251–4. 729. Burns AS, Rivas DA, Ditunno JF. The management of neurogenic bladder and sexual dysfunction after spinal cord injury. Spine 2001; 26: S129–S136. 730. Diokno AC, Koff SA, Anderson W. Combined cystometry and perineal electromyography in the diagnosis and treatment of neurogenic urinary incontinence. J Urol 1976; 115: 161–3. 731. Weld KJ, Dmochowski RR. Association of level of injury and bladder behavior in patients with post-traumatic spinal cord injury. Urology 2000; 55: 490–4. 732. Smith CP, Kraus SR, Nickell KG, Boone TM. Video urodynamic findings in men with the central cord syndrome. J Urol 2000; 164: 2014–7. 733. Kennedy DJ, Dreyfuss P, Aprill CN et al. Paraplegia following imageguided transforaminal lumbar spine epidural steroid injection: Two case reports. Pain Medicine 2009; 10(8): 1389–94. 734. Ross MA. Neuropathies associated with diabetes. Med Clin N Am 1993; 77: 111–24. 735. Kaplan SA, Blaivas JG. Diabetic cystopathy. J Diabet Complications 1988; 2: 133–9. 736. Kaplan SA, Te AE, Blaivas JG. Urodynamic findings in patients with diabetic cystopathy. J Urol 1995; 153: 342–4. 737. Kitami K. Vesicourethral dysfunction of diabetic patients. Nippon Hinyokika Gakkai Zasshi 1991; 82: 1074–83. 738. Moller CF. Diabetic cystopathy. I: A clinical study of the frequency of bladder dysfunction in diabetics. Dan Med Bull 1976; 23: 267–78. 739. Goksen D, Darcan S, Coker M et al. Permanent neonatal diabetes with arthrogryposis multiplex congenital and neurogenic bladder – A new syndrome? Pediatr Diabetes 2006; 7: 279–83. 740. Dong D. Xu Z, Shi B et  al. Urodynamic study in the neurogenic bladder dysfunction caused by intervertebral disk hernia. Neurourol Urodyn 2006; 25: 446–50. 741. Fanciullacci F, Sandri S, Politi P, Zanollo A. Clinical, urodynamic and neurophysiological findings in patients with neuropathic bladder due to a lumbar intervertebral disc protrusion. Paraplegia 1989; 27: 354–8. 742. O’Flynn KJ, Murphy R, Thomas DG. Neurogenic bladder dysfunction in lumbar intervertebral disc prolapse. Br J Urol 1992; 69: 38–40. 743. Bartolin Z, Vilendecic M, Derezic D. Bladder function after surgery for lumbar intervertebral disk protrusion. J Urol 1999; 161: 1885–7. 744. Chang HS, Nakagawa H, Mizuno J. Lumbar herniated disc presenting with cauda equina syndrome: Long-term follow-up of four cases. Surg Neurol 2000; 53: 100–5. 745. Podnar S, Trsinar B, Vodusek DB. Bladder dysfunction in patients with cauda equine lesions. Neurourol Urodyn 2006; 25: 23–31. 746. Britton CB, Miller JR. Neurologic complications in acquired immunodeficiency syndrome (AIDS). Neurol Clin 1984; 2: 315–39.

Epidemiology of the neurogenic bladder 747. Levy RM, Bredesen DE, Rosenblum ML. Neurological manifestations of acquired immunodeficiency syndrome: Experiences at UCSF and review of the literature. J Neurosurg 1985; 62: 475–95. 748. Snider WD, Simpson DM, Nielsen S et al. Neurological complications of acquired immune deficiency syndrome: Analysis of 50 patients. Ann Neurol 1983; 14: 403–18. 749. Khan Z, Singh VK, Yang WC. Neurogenic bladder in acquired immune deficiency syndrome (AIDS). Urology 1992; 40: 289–91. 750. Menendez V, Valls J, Espuna M et al. Neurogenic bladder in patients with acquired immunodeficiency syndrome. Neurourol Urodyn 1995; 14: 253–7. 751. Sasaki M, O’Hara S, Hayashi R et al. Aseptic meningo-radiculoencephalitis presenting initially with urinary retention. A variant of acute disseminated encephalomyelitis. J Neurol 2006; 253: 908–13. 752. Kogan BA, Solomon MH, Diokno AC. Urinary retention secondary to Landry–Guillain–Barré syndrome. J Urol 1981; 126: 643–4. 753. Wheeler JS, Siroky MB, Pavlakis A, Krane RJ. The urodynamic aspects of the Guillain–Barré syndrome. J Urol 1984; 131: 917–9. 754. Sakakibara R, Hattori T, Kuwabara S et  al. Micturitional disturbance in patients with Guillain–Barré syndrome. J Neurol Neurosurg Psychiatr 1997; 63: 649–53. 755. Cohen LM, Fowler JF, Owen LG, Callen JP. Urinary retention associated with herpes zoster infection. Int J Dermatol 1993; 32: 24–6. 756. Broseta E, Osca JM, Morera J et al. Urological manifestations of herpes zoster. Eur Urol 1993; 24: 244–7. 757. Murphy EL, Fridey J, Smith JW et  al. HTLV-associated myelopathy in a cohort of HTLV-I and HTLV-II-infected blood donors. Neurology 1997; 48: 315–20. 758. Chancellor MB, McGinnis DE, Shenot PJ et al. Urinary dysfunction in Lyme disease. J Urol 1993; 149: 26–30. 759. Timmermans L, Bonnet F, Maquinay C. Urological complications of poliomyelitis and their treatment. Acta Urol Belg 1965; 33: 409–26. 760. Howard RS, Wiles CM, Spencer GT. The late sequelae of poliomyelitis. Q J Med 1988; 66: 219–32. 761. Johnson VY, Hubbard D, Vordermark JS. Urologic manifestations of post-polio syndrome. JWOCN 1996; 23: 218–23. 762. Wheeler JS, Culkin DJ, O’Hara RJ, Canning JR. Bladder dysfunction and neurosyphilis. J Urol 1986; 136: 903–5. 763. Brodie EL, Helfert I, Phifer IA. Cystometric observations in asymptomatic neurosyphilis. J Urol 1940; 43: 496–510. 764. Garber SJ, Christmas TJ, Rickards D. Voiding dysfunction due to neurosyphilis. Br J Urol 1990; 66: 19–21. 765. Mushkin AY, Kovalenko KN. Neurological complications of spinal tuberculosis in children. Int Orthop 1999; 23: 210–2. 766. Kiran NA, Vaishya S, Kale SS et al. Surgical results in patients with tuberculosis of the spine and severe lower extremity motor deficits: A retrospective study of 48 patients. J Neurosurg Spine 2007; 6: 320–6. 767. Hollabaugh RS, Steiner MS, Sellers KD et  al. Neuroanatomy of the pelvis: Implications for colonic and rectal resection. Dis Colon Rectum 2000; 43: 1390–7.

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768. Hojo K, Vernava AM, Sugihara K, Katumata K. Preservation of urine voiding and sexual function after rectal cancer surgery. Dis Colon Rectum 1991; 34: 532–9. 769. Mitsui T, Kobayashi S, Matsuura S et al. Vesicourethral dysfunction following radical surgery for rectal carcinoma: Change in voiding pattern on sequential urodynamic studies and impact of nerve-­ sparing surgery. Int J Urol 1998; 5: 35–8. 770. Sugihara K, Moriya Y, Akasu T, Fujita S. Pelvic autonomic nerve preservation for patients with rectal carcinoma: Oncologic and functional outcome. Cancer 1996; 78: 1871–80. 771. Cosimelli M, Mannella E, Giannarelli D et al. Nerve-sparing surgery in 302 resectable rectosigmoid cancer patients: Genitourinary morbidity and 10-year survival. Dis Colon Rectum 1994; 37: S42–S46. 772. Ketcham AS, Hoye RC, Taylor PT et  al. Radical hysterectomy and pelvic lymphadenectomy for carcinoma of the uterine cervix. Cancer 1971; 28: 1272–7. 773. Seski JC, Diokno AC. Bladder dysfunction after radical abdominal hysterectomy. Am J Obstet Gynecol 1977; 128: 643–51. 774. Lin HH, Sheu BC, Lo MC, Huang SC. Abnormal urodynamic findings after radical hysterectomy or pelvic irradiation for cervical cancer. Int J Gynaecol Obstet 1998; 63: 169–74. 775. Kawaguchi Y, Kanamori M, Ishihara H et al. Clinical symptoms and surgical outcome in lumbar spinal stenosis patients with neuropathic bladder. J Spinal Disord 2001; 14: 404–10. 776. Tammela TLJ, Heiskari MJ, Lukkarinen OA. Voiding dysfunction and urodynamic findings in patients with cervical spondylotic spinal stenosis compared with severity of the disease. Br J Urol 1992; 70: 144–8. 777. Brooks ME, Moreno M, Sidi A, Braf ZF. Urologic complications after surgery on lumbosacral spine. Urology 1985; 26: 202–4. 778. Boulis NM, Mian FS, Rodriguez D et al. Urinary retention following routine neurosurgical procedures. Surg Neurol 2001; 55: 23–8. 779. Hinman F. Non-neurogenic neurogenic bladder (the Hinman syndrome): 15 years later. J Urol 1986; 136: 769–77. 780. Groutz A, Blaivas JG, Pies C, Sassone AM. Learned voiding dysfunction (non-neurogenic, neurogenic bladder) among adults. Neurourol Urodynam 2001; 20: 259–68. 781. Jorgensen TM, Djurhuus JC, Schroder HD. Idiopathic detrusor sphincter dyssynergia in neurologically normal patients with voiding abnormalities. Eur Urol 1982; 8: 107–10. 782. Sandler PM, Avillo C, Kaplan SA. Detrusor areflexia in a patient with myasthenia gravis. Int J Urol 1998; 5: 188–90. 783. Greene LF, Ghosh MK, Howard FM. Transurethral prostatic resection in patients with myasthenia gravis. J Urol 1974; 12: 226–7. 784. Wise GJ, Gerstenfeld JN, Brunner N, Grob D. Urinary incontinence following prostatectomy in patients with myasthenia gravis. Br J Urol 1982; 54: 369–71. 785. Khan Z, Bhola A. Urinary incontinence after transurethral resection of prostate in myasthenia gravis patients. Urology 1989; 34: 168–9. 786. Howard JF, Donovan MK, Tucker MS. Urinary incontinence in myasthenia gravis: A single-fiber electromyographic study. Abstract. Ann Neurol 1992; 32: 254.

6 Ultrastructure of neurogenic bladders Axel Haferkamp

Introduction Functional pathology of the detrusor has evolved as a new  paradigm for the clinical study of voiding dysfunction.1,2 It defines altered microstructure of the detrusor and how it impacts on abnormalities of its function, as a corollary to the premise that normal detrusor microstructure and function are closely interrelated, if not ­interdependent.3 This approach has led to a better understanding of various voiding dysfunctions, including incontinence in the elderly, and promises to be equally valuable in ­similar disorders in younger patients. Three distinctive ultrastructural patterns occurring separately or in combination have been described: the degeneration, dysjunction, and myohypertrophy patterns associated with impaired detrusor contractility (IDC), detrusor overactivity (DO), and detrusor with bladder outlet obstruction (BOO), respectively. A fourth so-called dense-band pattern with depleted caveolae and elongated intervening dense bands of muscle cell membranes (sarcolemmas) appears to be characteristic of the aged detrusor, whether it is normal or dysfunctional. To date, intrinsic structural defects in neurogenic bladder dysfunction (NBD) have been described in feline models, and proposed as the structural basis of the dysfunction associated with lower motor neuron injury or deficit.4–6 Intrinsic structural defects of longstanding NBD because of an upper motor neuron lesion (spinal cord injury [SCI], brain disorder [BD]) or from a combined lower and upper motor neuron deficit (­meningomyelocele [MMC]) have been investigated in humans.7–10

Tissue preparation for ultrastructural evaluation An endoscopic cold cup biopsy should be obtained outside of the trigone from the bladder wall. The open

biopsy from the bladder wall should be excised by scalpel to obviate tissue destruction and artifacts because of electrocautery. Each biopsy should be placed immediately in chilled fixative (2.5% glutaraldehyde in 0.1 M phosphate buffer containing 0.02% magnesium sulfate heptahydrate), and later processed for electron microscopy by a standardized procedure.1,2,11 Specimen processing includes trimming of each specimen to yield 5–10 tissue blocks (~1 mm3), postfixation in 1% osmium tetroxide, dehydration in ascending concentrations of ethanol, and embedment in Epon® or Araldite®. Semithin sections (1–2 μm) can be stained, for example, with toluidine blue, and examined by light microscopy to select from each biopsy two blocks best suitable for electron microscopy (ample diagonally and longitudinally sectioned smooth muscle). Ultrathin sections (60 nm thick) of the selected blocks can be obtained by a diamond knife, mounted on uncoated 150-mesh copper grids, and stained by a standard uranyl acetate/lead citrate sequence. Between 8 and 12 sections on two grids from each tissue block should be examined and photographed by an electron microscope. Following the MIN approach for structural study of the detrusor,3 the ultrastructure of smooth muscle (M), interstitium (I), and intrinsic nerves (N) should be examined at various magnifications (×2,500–100,000), both qualitatively and quantitatively.

Criteria for ultrastructural evaluation Smooth muscle The detrusor should be examined for grouping ­arrangement of the muscle cells as compact, intermediate, or loose fascicles2 (Figure 6.1), and the various ultrastructural ­patterns of nonneuropathic vesical dysfunction.1,2,12

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Figure 6.1 Fascicular arrangement of detrusor smooth muscle. (a) Compact (near-normal) fascicles with closely packed muscle cells: shortest intercellular distance 90 nm (Neg. # 45296; ×4109). (b) Intermediate fascicles with mild muscle cell separation: shortest intercellular distance 285 nm (Neg. # 46551; ×3897). (c) Loose fascicles; arrangement of widely separated muscle cells with lots of intercellular ­collagen fibrils: intercellular distance up to 1 μm or more (Neg. # 68816; ×4141).

Three distinctive ultrastructural patterns occurring separately or in combination have been described as follows: 1. IDC is characterized structurally by a widespread marked degeneration of intrinsic muscle cells and axons (full degeneration pattern).2,13 2. BOO presents with muscle cell hypertrophy and increased collagen content of widened spaces between individual cells (myohypertrophy pattern).14 3. Geriatric and obstructive DO has been associated with altered muscle cell junctions. Intermediate junctions (IJs) of muscle cells predominate in normal detrusor, and mediate contraction coupling of muscle cells mechanically.15 The IJ consists of strictly parallel sarcolemmas with paired symmetric dense plaques in the subsarcolemmal sarcoplasm, separated by a 25–60-nm junctional gap containing a central linear density (Figure 6.2). The overactive detrusor has a distinctive ultrastructural pattern (complete dysjunction) of three essential components.1,2,10,12,16 These are reduction or loss of IJs, abundance (or exclusive presence) of new cell junctions with very close separation gaps, introduced as protrusion junctions and ultraclose abutments and collectively designated as intimate cell appositions (ICAs) (Figure 6.2), and chain-like linkage of five or more muscle cells by these close junctions (Figure 6.3). With very close gaps (6–12 nm) between apposed sarcolemmas, these junctions were suggested as the myogenic basis of involuntary contractions during bladder filling (DO), mediating electrical coupling of muscle cells.17

A fourth (dense-band) pattern with depleted caveolae and elongation of intervening dense bands of muscle cell membranes (sarcolemmas) was recognized as characteristic of the aged detrusor, be it normal or dysfunctional.12 Disruptive muscle cell degeneration is recognized by the disarray of sarcoplasmic myofilaments and dense bodies, sarcoplasmic vacuolation, sequestration or blebbing, and cell shrinkage or fragmentation (Figure 6.4).1,2,12 The degeneration is considered rare when observed in onequarter or less of the examined microscopic fields, focal when in one-quarter to one-half of the fields, widespread when in one-half to all the fields, and generalized when observed in every muscle cell – generally with condensation, intensified electron density, or disruption of its sarcoplasm. Muscle cells were also examined for features of regeneration, including nucleoli, expanded endoplasmic reticulum, and abundant mitochondria.

Intrinsic neural elements The ultrastructural morphology and content of axon terminals at neuroeffector junctions (axon–muscle cell contacts) and Schwann cells, together with their ensheathed unmyelinated and myelinated axons (axon preterminals and nonvaricose segments), should be evaluated. Profiles of unmyelinated axon terminals and preterminals can be defined as normal, degenerated, or regenerated. Normal axon terminals within the detrusor (Figure 6.5) are unmyelinated and bare (without a Schwann cell sheath),  are packed with small vesicles (SVs) (~60 nm

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Figure 6.2 Muscle cell junctions. (a) Normal intermediate junctions (white arrows); note strictly parallel sarcolemmas with uniform 56-nm-wide cell separation containing central linear density (Neg. # 45688; ×15 790). (b) Finger-like intimate cell apposition (ICA) (black arrow) (Neg. # 47271; ×27 900). (c) Finger-like ICAs (white arrows) (Neg. # 46718; ×17 860).

M1

M3

M2 M6

M5

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Figure 6.3 Muscle cell chain: six muscle cells (M1–6) chain linked by fingerlike protrusion junctions (white arrows) (Neg. # 45295; ×7425).

diameter), contain one to three rodlet-shaped mitochondria  with defined cristae, and contact muscle cells with 15–25, >25–40, or >40–80 nm gaps at close, almost close, or en passant neuroeffector junctions, respectively.9,18 Cholinergic axons contain clear (empty) and adrenergic axons contain dense-cored (granular) SVs.

The latter vesicles are often indiscernible in tissues fixed in vitro because of the rapid release of the neurotransmitter ­norepinephrine (responsible for the dense cores); t­herefore, the content of adrenergic axons in human ­biopsies ­processed routinely in vitro tends to be underestimated. Unfortunately, corrective procedures ­ to intensify the dense cores ensuring their visualization (e.g., i­njection of 5-hydroxydopamine in vivo before biopsy4–6) are ­inapplicable to human. Axon terminal profiles often contain one or two large dense-cored vesicles (LDCVs) (~120 nm diameter) that are believed to store purinergic and/or peptidergic neurotransmitters in the same ­terminals containing acetylcholine in cholinergic or norepinephrine in adrenergic SVs.5,19 Preterminal axons resemble normal axon terminals but have Schwann cell sheaths and lack contact with muscle cells (Figure  6.5). More, central n ­ ormal unmyelinated and myelinated nonvaricose axon segments within nerve bundles are also ensheathed, but their axoplasms abound in neurotubules and neurofilaments, and contain few SVs but no LDCVs (Figure 6.5). Degenerated axon terminal profiles have much fewer to depleted SVs (Figure 6.5), often with neuroeffector junctional gaps >80 nm–even exceeding 200 nm. Wide gaps alone, however, cannot be considered a sign of ­ a xonal degeneration. Globoid (empty) mitochondria with ­d istorted cristae20 were an ancillary feature of axonal degeneration when not attributable to artifacts of ­ bladder/tissue manipulation at open surgery,

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Figure 6.4

Disruptive muscle cell degeneration. (a) Vacuolated sarcoplasm: arrows (Neg. # 45803; ×7425). (b) Intensely electron-dense sarcoplasm of shrunken muscle cells: arrows (Neg. # 46694; ×7965).

causing similar involvement of other tissue elements. Degeneration of myelinated axons (within nerve bundles) can be identified by changes resembling Wallerian degeneration, including collapse of nonvaricose axon segments, and angulated, bean-shaped, or split myelin sheaths (Figure 6.5).7,9,21 The cardinal feature of growing and regenerating axons  is a general increase in axoplasmic organelles. Sprouting axons have been characterized ultrastructurally by having abundant mitochondria and LDCVs, in addition to increased neurofilaments and neurotubules in the axoplasm. In the absence of available standards, abundant mitochondria have been defined in the studies presented by Elbadawi et al.7 and Haferkamp et al.9 as ≥4, and abundant LDCV as ≥3 per axon profile. Profiles with both features were considered as axon sprouts (Figure 6.6), and those with abundant LDCVs only (i.e., with ≤3 mitochondria) as copeptidergic axons (Figure 6.6). Sprouts were assumed to represent active, ongoing regeneration. Terminal profiles designated as copeptidergic were considered normal (representing stable regeneration) when also packed with SVs, or degenerating (presumably representing regressed regeneration) when SVs were reduced or depleted. Abundant neurotubules/neurofilaments were discounted when observed as the only axoplasmic change in single cross-sectioned profiles of nonvaricose axon segments since these are indistinguishable from crosssectioned processes of activated Schwann cells containing abundant ultrastructurally similar microtubules and microfilaments.22

Schwann cells can be evaluated for changes similar to those following peripheral nerve transection22–24 occurring in conjunction with axonal degeneration and regeneration. Normal cells contain few mitochondria, underdeveloped endoplasmic reticulum, and few ribosomes.25 Activated Schwann cells (Figure 6.6) have abundant mitochondria, ribosomes, microfilaments, microtubules, dilated endoplasmic reticulum, cell processes mimicking axon profiles,22 and outlying dense collagen deposits.26 Gap widths at neuroeffector junctions were based on the measurement of the shortest distances between axon ­terminals and adjacent muscle cells.

Short- and long-term ultrastructural changes in lower motor neuron neurogenic bladder dysfunction in a feline model Elbadawi et al.4,6 and Atta et al.5 evaluated the ultrastructural changes of the detrusor muscle and its cholinergic and adrenergic innervation in a feline animal model. All animals had undergone bladder decentralization by unilateral sacral ventral rhizotomy (deterioration of the preganglionic peripheral axon). In a short-term evaluation (2–4 weeks after surgery), in all samples, a widespread transsynaptic degeneration of cholinergic axon terminals

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Figure 6.5 Intrinsic nerve profiles. (a) Normal axon terminal (cholinergic) (white arrow), partially ensheated by a Schwann cell (S) at a neuroeffector junction with a muscle cell (M) (Neg. # 45304; ×21 649). (b) Axon terminal partially ensheathed by a Schwann cell (S) with a very small neuroeffector junctional gap (Neg. # 45368; ×25 200). (c) Degenerated axon terminal with reduced (black arrow) clear SVs at a neuroeffector junction (Neg. # 45646; ×26 069). (d) Schwann cell ensheathed (S) axon preterminals: degenerated with reduced (black arrow) or nearly depleted (white arrow) vesicles. (Neg. # 45269; ×29 077). (e) Degenerated axon terminal: bloated disrupted mitochondria (arrow) (Neg # 45562; ×16 614). (f) Nonvaricose segment of myelinated axon within nerve bundle, with features of degeneration: irregularly split myelin sheath, and collapsed axoplasm (Neg. # 46729; ×15 007).

and varicosities occurred together with a loss of neuroeffector junctions, characterized by a w ­ idening of the axon terminal to a muscle cell cleft (up to ± 500 nm). The herein observed degenerative changes in (postganglionic) axons of the decentralized bladder represent the first example of transsynaptic degeneration in an autonomically innervated mammalian smooth muscle system. This was associated with a preservation of most adrenergic axons, and especially starting in the 4-week samples with concurrent early regeneration or sprouting in many cholinergic and adrenergic axons. In the long-term evaluation (8–10 weeks after surgery), there was a widespread

regeneration of cholinergic axons that ­ displayed initial transsynaptic degeneration shortly after operation, with reformation of cholinergic neuroeffector junctions. This was associated with reactive sprouting of adrenergic axons leading to adrenergic hyperinnervation, as well as the emergence of a population of cholinergic and adrenergic axons containing strikingly abundant LDCV. These findings suggest that the degeneration of cholinergic axons occurring after rhizotomy is reversible, and is c­ ompensated by the development of adrenergic hyperinnervation and by an emergent probable p­eptidergic ­a xonal influence.

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Figure 6.6

Regenerated nerve profiles. (a) and (b) Axon sprout replete with mitochondria and LDCV (Neg. # 45361, 47197; ×41 850). (c) Copeptidergic axon profile with few mitochondria and abundant LDCVs (black arrow) (Neg. # 45184; ×36 260). (d) Activated Schwann cell ensheathing myelinated axon segment with abundant neurotubules; cytoplasm contains abundant mitochondria (arrow) (Neg. # 45711; ×26 460).

These neural changes were associated with both degenerative and regenerative ultrastructural changes in smooth muscle cells, indicating transjunctional changes in an effector tissue. Degenerative muscle cell profiles ­presented with myofilament disruption with reduced e­ lectron density, granular disintegration, flocculent degeneration, vacuolar degeneration, or generalized increase of sarcoplasmic electron density with aggregation of myofilaments were much more frequent in short-term than in long-term samples. Although the muscle cell changes had no constant relationship with neural changes in their spatially close axon bundles, most degenerative profiles were observed next to degenerating cholinergic neuroeffector junctions. In contrast, regenerative muscle cell profiles were much more frequent and widespread in the long-term samples. These profiles were recognized by their overall intact ultrastructure with active nuclei and proliferation of some organelles.

Long-term ultrastructural changes in human upper motor neuron neurogenic bladder dysfunction Haferkamp et al.8,9 undertook the ultrastructural evaluation of detrusor biopsies of 9 patients with MMC, 25 patients with SCI, and 12 patients with different BDs. In these patients, the neurogenic hyperreflexic bladder dysfunction had been present for between 3 months and 43 years. The most frequent fascicle structure was compact; it tended to be more common in biopsies of the SCI group than those of either the MMC (p = .011) or the BD group (p = .026). Biopsies from four patients with BOO (BD group) displayed the ultrastructural myohypertrophy pattern, with broadly undulated or crenelated cell contours.

Ultrastructure of neurogenic bladders This observation confirms the previously described ultrastructural myohypertrophy patterns in outlet obstruction. In contrast, detrusor–sphincter–dyssynergia, which is tantamount to functional obstruction of the outlet, was not associated with the myohypertrophy pattern in the present study. The dense-band pattern of aged detrusor was identified in 14 biopsies obtained from 65- to 96-year-old patients (2  SCI, 12 BD group). None of the MMC group biopsies had this pattern, but a similar pattern was also observed in a patchy distribution in four more SCI group biopsies from 50- to 65-year-old patients. The complete dysjunction pattern of DO with chain-like linkage of ≥5 muscle cells was observed in all biopsies. One BD group biopsy had dominant IJs with a 0.8 ICA:IJ ratio. This ratio was elevated (range: 2–45) in other 45 biopsies. An ICA:IJ ratio ≥3 thus had 91% sensitivity as an ultrastructural marker of neurogenic DO. Our observations confirm abnormal junctions (protrusion and other forms of similarly close ICA) as a constant feature of DO, be it nonneuropathic idiopathic or obstructive or neuropathic. Some degree of disruptive muscle cell degeneration was observed in all biopsies. The degree of degeneration in SCI group biopsies had no association with the anatomic level of SCI or its degree (complete versus incomplete). Nor it had any association with IDC in collective analysis of all biopsies – unlike previously reported findings in nonneuropathic dysfunctional detrusor. The observed neural changes comprised widespread axonal degeneration, far in excess of concomitant muscle cell degeneration, and restricted regeneration related with activated Schwann cells. Most evaluated axon profiles (64%) had features of axonal degeneration, 20% had features of axonal regeneration, and 16% normal ultrastructural morphology. Axonal degeneration and regeneration coexisted in 75% biopsies, of which 57% also had admixed axon profiles of normal morphology. Regeneration was not identified or was indeterminate in 24% biopsies. Reduction/depletion of SVs was the dominant feature of  transsynaptic axonal degeneration in MMC (median 87%  of axon terminals) and SCI (median 84%) group ­biopsies, but was less prominent in BD (median 60%) group biopsies. This may be attributed to the greater number of synaptic relays (at least three) in neural pathways in biopsies of the BD than in the other two groups. Another feature of ­axonal degeneration, i.e., widening of axon/muscle cell ­separation gaps at neuroeffector junctions, was very frequently observed (71% of junctions), with clefts often exceeding 200 nm, but does not indicate whether the ­ ­degeneration was present at the time of biopsy or had happened some time before and persisted, since gaps between regenerating axons and related muscle cells were also widened. Distorted axonal mitochondria were observed in 38 biopsies (90.5%). Seven mixed nerve bundles contained

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degenerated myelinated axons. Axonal collapse and irregularities of myelin sheaths were present in all, and split sheaths in five biopsies. Axon sprouts and/or copeptidergic axons were restricted, but observed in 76% of the 45 biopsies with discernible neural elements. The prevalence of regeneration was rather similar in the three biopsy groups, and it had no association with the duration of NBD. Axon sprout profiles were identified in 17 biopsies (38%), and copeptidergic axon profiles in 34 biopsies. A characteristic component of the regeneration was the obvious increase in copeptidergic axons (median: 18% of axons vs. only 10 years duration of NBD. The lack of a relationship of axonal degeneration to duration of NBD, despite its wide range, together with the associated restricted regeneration, suggests a persistent – or continuing – degenerative process. Activated Schwann cells were observed within nerve bundles and around ensheathed preterminals in 44 of the 45 biopsies with discernible neural elements. Their presence had no association with the biopsy groups, duration of NBD, or axonal regeneration. Abundant mitochondria were present in 13 (29%), dilated endoplasmic reticulum in 6 (13%), and increased microfilaments and microtubules in all 44 biopsies (98%). Abundant outlying collagen was observed within the perineurium of the eight identified nerve bundles.

Summary Characteristic ultrastructural findings have been described for lower and upper motor neuron bladder dysfunction in animal models or human specimens. These findings represent morphologic markers to indicate not only the presence of such dysfunction, but also the anatomic level of its causative neural deficit, i.e., spinal versus supraspinal (cephalic).

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The possible contribution of an occult neurologic factor to clinically nonneurogenic vesical dysfunction in both the young and the elderly has so far eluded clinical and urodynamic recognition. The usefulness of the suggested morphologic markers in the clinical management of vesical dysfunction, whether overtly neurogenic or nonneurogenic, remains to be investigated in future studies.

References 787. Elbadawi A. Functional pathology of urinary bladder muscularis: The new frontier in diagnostic uropathology. Semin Diagn Pathol 1993; 10: 314–54. 788. Hailemariam S, Elbadawi A, Yalla SV, Resnick NM. Structural basis of geriatric voiding dysfunction. V. Standardized protocols for routine ultrastructural study and diagnosis of endoscopic detrusor biopsies. J Urol 1997; 157: 1783–801. 789. Elbadawi A. Microstructural basis of detrusor contractility. The MIN approach to its understanding and study. Neurourol Urodyn 1991; 10: 77–85. 790. Elbadawi A, Atta MA, Franck JI. Intrinsic neuromuscular defects in the neurogenic bladder. I. Short-term ultrastructural changes in muscular innervation of the decentralized feline bladder base following unilateral sacral ventral rhizotomy. Neurourol Urodyn 1984; 3: 93–113. 791. Atta MA, Franck JI, Elbadawi A. Intrinsic neuromuscular defects in the neurogenic bladder. II. Long-term innervation of the unilaterally decentralized feline bladder base by regenerated cholinergic, increased adrenergic and emergent probable “peptidergic” nerves. Neurourol Urodyn 1984; 3: 185–200. 792. Elbadawi A, Atta MA. Intrinsic neuromuscular defects in the neurogenic bladder. III. Transjunctional, short- and long-term ultrastructural changes in muscle cells of the decentralized feline bladder base following unilateral sacral ventral rhizotomy. Neurourol Urodyn 1984; 3: 245–70. 793. Elbadawi A, Resnick NM, Dorsam J, Yalla SV, Haferkamp A. Structural basis of neurogenic bladder dysfunction. I. Methods of prospective ultrastructural study and overview of the findings. J Urol 2003; 169: 540–6. 794. Haferkamp A, Dorsam J, Resnick NM, Yalla SV, Elbadawi A. Structural basis of neurogenic bladder dysfunction. II. Myogenic basis of detrusor hyperreflexia. J Urol 2003; 169: 547–54. 795. Haferkamp A, Dorsam J, Resnick NM, Yalla SW, Elbadawi A. Structural basis of neurogenic bladder dysfunction. III. Intrinsic detrusor innervation. J Urol 2003; 169: 555–62. 796. Haferkamp A, Dorsam J, Elbadawi A. Ultrastructural diagnosis of neuropathic detrusor overactivity: Validation of a common myogenic mechanism. Adv Exp Med Biol 2003; 539: 281–91.

797. Elbadawi A, Yalla SV, Resnick NM. Structural basis of geriatric voiding dysfunction. I. Methods of a prospective ultrastructural/ urodynamic study and an overview of the findings. J Urol 1993; 150: 1650–6. 798. Elbadawi A, Hailemariam S, Yalla SV, Resnick NM. Structural basis of geriatric voiding dysfunction. VI. Validation and update of diagnostic criteria in 71 detrusor biopsies. J Urol 1997; 157: 1802–13. 799. Elbadawi A, Yalla SV, Resnick NM. Structural basis of geriatric voiding dysfunction. II. Aging detrusor: Normal versus impaired contractility. J Urol 1993; 150: 1657–67. 800. Elbadawi A, Yalla SV, Resnick NM. Structural basis of geriatric voiding dysfunction. IV. Bladder outlet obstruction. J Urol 1993; 150: 1681–95. 801. Elbadawi A. Functional anatomy of the organs of micturition. Urol Clin N Am 1996; 23: 177–210. 802. Elbadawi A, Yalla SV, Resnick NM. Structural basis of geriatric voiding dysfunction. III. Detrusor overactivity. J Urol 1993; 150: 1668–80. 803. Elbadawi A. The neostructural myogenic mechanism of detrusor overactivity. Urology 1997; 50(Suppl 6A): 71–2. 804. Elbadawi A. Autonomic muscular innervation of the vesical outlet and its role in micturition. In: Hinman F Jr, ed. Benign Prostatic Hypertrophy. New York: Springer, 1983: 330–48. 805. Daniel EE, Cowan W, Daniel VP. Structural bases for neural and myogenic control of human detrusor muscle. Can J Physiol Pharmacol 1983; 61: 1247–73. 806. Mugnaini E, Friederich VL. Electron microscopy. Identification and study of normal and degenerating neural elements by electron microscopy. In: Heimer L, Robards MJ, eds. Neuroanatomical TractTracing Methods. New York: Plenum Press, 1981: 377–406. 807. Friede RL, Martinez AJ. Analysis of axon-sheath relations during early Wallerian degeneration. Brain Res 1970; 19: 199–212. 808. Payer AF. An ultrastructural study of Schwann cell response to axonal degeneration. J Comp Neurol 1979; 183: 365–84. 809. Lampert PW. A comparative electron microscopic study of reactive, degenerating, regenerating and dystrophic axons. J Neuropathol Exper Neurol 1967; 26: 345–68. 810. Knoche H, Terwort H. Elektronenmikroskopischer Beitrag zur Kenntnis von Degenerationsformen der vegetativen Endstrecke nach Durch-schneidung postganglionärer Fasern. Z Zellforsch 1973; 141: 181–202. 811. Blümcke S, Niedorf HR. Elektronenoptische Untersuchungen an Wachstumsendkolben regenerierenden peripherer Nervenfasern. Virchows Arch Pathol Anat 1965; 340: 93–104. 812. Nathaniel EJH, Pease DC. Collagen and basement membrane formation by Schwann cells during nerve regeneration. J Ultrastruct Res 1963; 9: 550–60.

7 Pathophysiology of neurogenic detrusor overactivity Alexandra McPencow and Toby C. Chai

Introduction The bladder is a unique organ in that it requires both central nervous system (CNS) and peripheral nervous system (PNS) input for its proper function – storing and emptying urine. When disorders of the CNS and/or PNS occur, dysfunction of both storing and emptying can arise. This condition is termed “neurogenic bladder” (NGB). Symptoms arising from NGB range from urinary incontinence (­storage dysfunction) to urinary retention (emptying dysfunction). These symptoms may not be mutually exclusive, so patients may suffer from both incontinence and retention simultaneously. Although the urinary incontinence of NGB may at times be secondary to high-volume urinary retention with resultant overflow, the prototypical etiology of urinary incontinence in NGB is neurogenic detrusor overactivity (NDO) due to a neurologic lesion superior (rostral) to the sacral spinal cord. Throughout this chapter on NDO, anytime spinal cord injury (SCI) is mentioned, it is synonymous to suprasacral SCI. Diagnosis of NGB is predicated on two criteria: bladder symptoms and a neurologic diagnosis, with the presumption that these two conditions are related. Appearance of detrusor overactivity (DO) on urodynamics in a patient with an NGB is then termed “NDO.” However, when a neurologic diagnosis has not already been established in a patient with bladder symptoms, whether or not DO is present on urodynamics, one cannot confidently say that the patient has NGB and/or NDO. Another confounding situation that often arises is when patients with neurologic conditions have other disease/conditions that give rise to similar bladder symptoms and/or urodynamic findings. For example, in an older male patient with Parkinson’s and benign prostatic hyperplasia (BPH), DO is the result of his neurologic condition of Parkinson’s or bladder outlet obstruction? Or, in a female with history of strokes who is a diabetic, is the increased post-void residual the

result of the stroke or the diabetes? Or, in the female patient with multiple sclerosis (MS) complaining of urinary frequency, is the DO related to the MS or idiopathic overactive bladder (OAB)? Admittedly, there is no objective clinical tool, instrument, or biomarker to effectively and completely resolve these confounding issues. It is useful to equate the micturition reflex to a neuromuscular reflex to conceptualize NDO pathophysiology. NDO might be caused by a lack of inhibition of motor (efferent) pathway, by augmented sensory (afferent) input, and/or augmented motor output. This chapter is organized to review the pathophysiology of NDO, starting within the  bladder urothelium and ending at the brain. Some NDO mechanisms may be common regardless of the site of the neurologic lesion, whereas some NDO mechanisms are neurologic lesion specific. The anatomic sites covered in this chapter include urothelium/suburothelium/afferent nerve (urothelial-afferent junction), detrusor smooth muscle/efferent nerve (neuroeffector junction), spinal cord, and brain. Data from investigations supporting alterations at these sites are discussed. By understanding these alterations, future treatments for NDO could be developed, which target the abnormalities.

Urodynamics tracing of neurogenic detrusor overactivity A urodynamics study depicting NDO in a male patient with multiple sclerosis is shown in Figure 7.1. Oscillatory DO with occasional peak detrusor pressures >100 cm water without urethral flow is exhibited in this tracing. Although this urodynamics study is representative of NDO, clinical situations exist where it might be difficult to distinguish between NDO and idiopathic detrusor overactivity (IDO). Investigators have studied which urodynamic variables might help discriminate between NDO

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Figure 7.1 Urodynamic tracing of NDO.

and IDO in MS patients.1 Compared to IDO, NDO had greater peak detrusor pressures and greater first DO contraction pressure. These authors concluded that if amplitude of the first DO contraction was greater than 30 cm H2O, and there was a positive predictive value of 88% in identifying NDO. Figure 7.1 provides a clinical point of reference for this chapter, which details basic pathophysiologic mechanisms leading to the appearance of this urodynamic tracing.

Changes in urothelium and suburothelium Beyond simply acting as a barrier between urine and bladder stroma, the urothelium is now thought to be an active participant in bladder sensory and afferent signaling function. The normal microarchitecture of the bladder urothelium is polarized – meaning there is an apical layer (in contact with the urine) and a basal layer (in contact with

suburothelium/lamina propria) (Figure 7.2a). The basal urothelial cells are in close approximation to suburothelial myofibroblasts and bladder afferent fibers located in the lamina propria. The myofibroblasts have been studied from human bladders and are shown to generate spontaneous electrical activity,2 thus these myofibroblasts are thought to be important in regulating bladder activity. The urothelial-afferent junction (Figure 7.2b) is composed of urothelial cells, suburothelial cells (myofibroblasts), and afferent nerve fibers. The possible interactions at this junction are shown in Figure 7.2b. Augmentation of the afferent signaling function within this junction can contribute to NDO.3 The urothelial cells and myofibroblasts have been shown to be altered after neurologic lesions, which lead to NDO, and these alterations are discussed in this section. Bladder urothelial cells contain many receptors and ion channels, which can be mechano- and chemosensitive, including receptors for bradykinin, neurotrophins, purines (P2X, P2Y), protease activated receptors, amiloride/mechanosensitive epithelial sodium channels

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(ENaC), and transient receptor potential (TRP) channels.4 In addition, the urothelial cells release a variety of chemical mediators, thus communicating with other surrounding cell types, such as afferent nerves and myofibroblasts. One such mediator, adenosine triphosphate (ATP), can be released from urothelial cells on bladder distension.5 ATP can excite suburothelial myofibroblasts and or afferent nerves via purinergenic receptors, P2X3, triggering

bladder overactivity. Afferent nerve fibers and myofibroblasts might release ATP in response to stretch as well, which can interact with bladder urothelial cells. Apodaca et al.6 showed significant changes in both urothelial morphology and impermeability function ­ acutely within 2 hours of SCI. These changes were localized to the apical urothelial cell (umbrella cell). When given before SCI, the ganglionic blocker, hexamethonium,

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inhibited acute urothelial disruption, whereas capsaicin worsened the acute effects of SCI on the urothelium. These findings paint an image of a web of communication occurring from nerves all the way to apical urothelial cells.7 Several weeks after SCI, when NDO developed, the impermeability function of the urothelium returned to normal, but the umbrella cells were significantly smaller possibly indicating increased turnover of surface lining cells. Thus, alteration in urothelial structure (size of apical cells) was chronically affected after SCI. In NDO bladder urothelial tissues from SCI and MS patients, ATP was significantly elevated by mechanical stretch and electrical field stimulation (EFS) compared to control urothelial tissues.8 Several things should be noted about this study. First, the dissected urothelium included myofibroblasts and afferent nerves (i.e., consistent with urothelial-afferent tissue as depicted in Figure 7.2b). Stretch of this urothelial-afferent tissue triggered release of ATP from urothelial cells, myofibroblasts, and/or afferent nerves, whereas EFS of tissue would trigger release of ATP only from nerves since nonneuronal cells are not electrically excitable. To determine neural contribution to ATP release, tetradotoxin (TTx) (a sodium channel blocker that prevents release of neurotransmitters) was used to treat the urothelial-afferent junction before EFS or mechanic stretch stimuli. This study found that both stretch and EFS caused urothelial-afferent tissue from NDO to release significantly more ATP than controls. It also appeared that in NDO, ATP released by mechanical and EFS stimuli was primarily from afferent nerves suggesting that nerve function within the urothelial-afferent junction was altered in NDO. Urothelial release of ATP was further studied by Smith et  al.9 In their rat model, SCI bladders had increased ­urothelial release of ATP under both basal and hypoosmotic stimulus conditions (which was equivalent to stretch stimulus because hypoosmolality caused cell swelling). However, in this study, the entire bladder was used, not just the urothelial-afferent tissue as in Kumar’s work.8 The whole bladder was split open and mounted in two hemichambers (Ussing chamber) so that the urothelial and serosal sides of the bladder were bathed separately. Buffer collected from the urothelial side was analyzed for ATP, either in the basal state (non-stimulated) or with hypoosmotic solution (stretch). The increased ATP measured from the urothelial side was presumed to come from the urothelium, though the exact source (urothelial cells, myofibroblasts, and afferent nerves) was not determined. The investigators also showed release of urothelial ATP returns to normal values after treatment of SCI bladder with intradetrusor injections of onabotulinumtoxinA (oBTxA), suggesting that this agent may work on urothelial-afferent signaling in addition to the neuroeffector junction. Another observation from this study was that urothelial release of nitric oxide (NO) was exactly opposite of ATP in all experimental conditions, leading these authors to hypothesize that urothelial-afferent junction ATP and

NO provide complementary functions, namely, ATP was a excitatory factor whereas NO as an inhibitory factor in SCI. This same investigative group measured in vivo ATP release into the bladder lumen in SCI rats.10 They found that SCI bladders released significantly more ATP into lumen of bladder in response to increase in bladder pressure. The contribution to NDO by the myofibroblasts within suburothelial lamina propria of the bladder has also been studied. Investigators have found increased gap junction protein, Cx43 (connexin 43), expression in NDO.11 Gap junction proteins connect membranes between two adjacent cells and allow ions to freely pass between them. Therefore, increased Cx43 could promote NDO by facilitating spread of spontaneous electrical activity to surrounding myofibroblasts. Another junctional protein, cadherin-11, was shown to be upregulated in NDO myofibroblasts.12 Cadherin-11 is a member of the adherens junctional protein family. Adherens junctions (or zona adherens) are proteins that provide structure to adjoining cells. Because both cadherin-11 and Cx43 are co-localized on the myofibroblasts, and both are upregulated in NDO, these investigators theorized that these two proteins might interact to form a functional unit that mediates increased myofibroblast activity in NDO.

Changes in type, structure, and function of afferent nerves Although the urothelial and suburothelial component of the urothelial-afferent junction has drawn interest recently, the importance of afferent C fibers in development of NDO was demonstrated years ago.13 In the normal micturition reflex, afferent signals are carried by myelinated Aδ-nerve fibers and travel through the pelvic nerve to the dorsal root ganglia (DRG). The DRG is where the neuronal bodies of the afferent nerve fibers reside. The usually silent unmyelinated C fibers are activated after SCI. Thus in NDO, bladder afferent signals change from being carried from Aδ to C fibers. The micturition reflex mediated by the C-fiber afferents is of a shorter latency (less time from start of afferent signal to reflex bladder contraction) compared to the normal reflex. Therefore, this short latency micturition reflex is similar to what one would expect in NDO. This was demonstrated by de Groat.13 His findings in the SCI cat supported studies of human SCI bladders.14 Because activity in C fibers can be blocked by capsaicin and resiniferatoxin (RTX), these agents have been studied as a way to treat NDO.15,16 Interest in these C-fiber blockers has diminished recently probably because of FDA approval of oBTxA for treatment for NDO incontinence. The changes in the electrophysiologic functional properties of the C-fiber neurons within the DRG have also been studied. These studies involve dissecting out neuronal cell bodies from the DRG, after retrograde labeling (by injecting the bladder wall with fluorescent dye) of afferent

Pathophysiology of neurogenic detrusor overactivity neurons innervating the bladder. Several changes in the afferent neurons after SCI were noted. There was enlargement of the bladder afferent neuron bodies in the DRG. The dissected out primary afferent neurons from the DRG, which were specifically labeled by bladder retrograde dye, exhibited a shift from high-threshold TTx-resistant excitability to low-threshold TTx-sensitive excitability.17 This was due to increases in expression of TTx-sensitive sodium channel. This lowered threshold for afferent excitability can help explain the shortened latency micturition reflex of NDO. It was interesting that colonic afferent neuronal function, measured using the same electrophysiologic methods, was not affected from SCI suggesting that colon reflex function is less altered following SCI.18 Although NDO secondary to SCI is dependent on C-fiber function, NDO from middle cerebral artery occlusion (MCAO) in a rat model does not seem to depend on C-fiber afferent activity.19 This was shown by the fact that MCAO-induced NDO occurred in both untreated and RTX-treated rats. Since RTX treatment desensitizes (inactivates) C fibers, the fact NDO still occurred after MCAO and RTX suggested that C fibers are not involved in development of NDO in this model. However, these investigators found another interesting mechanism. They found that α1-adrenergic blockade was effective in suppressing NDO secondary to MCAO. But for α1-adrenergic blockade to work, C-fiber ­f unction was necessary because α1-blockers did not work in RTX-treated rats. These findings showed that even if C fibers did not play a direct role in the evolution to NDO, they did play a role in mediating beneficial effects of α1-adrenergic blockers. It is unclear why the authors concluded that α1-blocker worked by suppressing C-fiber afferents, since C-fiber activity was not involved in NDO. α1-adrenergic blockers may quell NDO through non-C-fiber mechanisms. An ultrastructural electron microscopic study of the nerve fibers/axons in the lamina propria of NDO bladders has been published.20 These investigators measured nerve fiber dimensions in lamina propria of bladders from patients with tropical spastic paraparesis (a neurologic disease secondary to human T-lymphotropic virus [HTLV-1] infection also known as chronic progressive myelopathy), MS, and various spinal cord diseases. They found that nerve fiber diameter varied among these different neurologic conditions. This suggested an inconsistent change in nerve fiber sizes within the lamina propria in NGBs. The changes in the expression of P2X3 and TRPV1 receptors in suburothelial nerve fibers in NDO has also been studied.21 These investigators biopsied NDO bladders before oBTxA treatment and stained them for P2X3 and TRPV1 immunoreactivity. They found that NDO subjects had greater P2X3 and TRPV1 expression in the nerves (compared to controls) and that after successful oBTxA treatment, the expression levels decreased toward normal levels. These findings were similar to a prior publication,9 and showed that the urothelial-afferent

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alterations, whether augmented luminal side ATP release or augmented P2X3 and TRPV1 expression on suburothelial nerves, can be abrogated by oBTxA. This concept was further supported by direct measurement of afferent neural activity in SCI animals.22 Afferent firing was significantly increased from SCI bladders and decreased after oBTxA treatment. Therefore, oBTxA’s mechanism of action, in addition to blocking the neuroeffector junction, also blocks the activity of the urothelial-afferent junction. In summary, afferent nerves can be altered structurally and functionally in NDO. In SCI, the type of nerve relaying afferent signals changed from Aδ to C fibers. However, in MCAO-induced NDO, C fibers appeared to be uninvolved in mediating NDO. Although NDO occurred as a result of both of these neurologic lesions, the afferent pathophysiology appeared to be different. Treatment modalities targeting the afferent limb of the NDO reflex will need to take this difference into account.

Changes in spinal cord The bladder afferent fibers are bipolar with one end terminating in the lamina propria of the urothelial-afferent junction and the other end terminating in the dorsal horn of the spinal cord at the thoracolumbar and sacral levels (Figure 7.3). The afferent fibers travel in the dorsal horn and synapse with the preganglionic parasympathetic motor neuron located in the intermediolateral cell column (IMLCC) and interneurons in the gray matter in the spinal cord. This anatomy is depicted in Figure 7.3. After SCI, several changes can occur within the spinal cord, which promote NDO. The afferent fibers, near the IMLCC, expressed vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase–activating polypeptide PACAP.23 Both VIP and PACAP are pro-micturition reflex agents, and PACAP is upregulated after SCI in rats and contributes to NDO.24 Other neurotransmitters within the spinal cord may contribute to NDO. Spinal glutamate is an excitatory neurotransmitter for the micturition reflex. In contrast, spinal glycine and γ-aminobutyric acid (GABA) are inhibitory neurotransmitters for the micturition reflex. After SCI, it was determined that the expression of the synthetic enzyme for GABA, glutamic acid decarboxylase (GAD) was significantly decreased and that GABA-receptor agonists can suppress NDO.25 This mechanism for NDO was correlated with the clinical findings that intrathecal baclofen can reduce NDO.26,27 Spinal ATP has also been measured in SCI animals.10 These investigators found that ATP release, measured by microdialysis probes implanted into L6–S1 dorsal spinal cords of rats, was significantly higher in the SCI animal compared to controls. This finding showed that the bladder afferents neurons, after SCI, release significantly more ATP at the urothelial end and the dorsal horn of the spinal cord end. Since ATP is an excitatory neurotransmitter, these findings

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Dorsal horn gray matter

DRG

Afferent neuron Pre‐ganglionic autonomic motor neuron Interneuron IMLCC

Ventral horn gray matter

support that after SCI, there was increased excitability from the bladder afferent pathways contributing to NDO. Tachykinins, such as substance P and neurokinin A, are released within the spinal cord by C-fiber afferents. These neurotransmitters can interact with second-order neurons (interneurons), via the NK1 receptor, within the spinal cord. It has been shown that NK1 receptor antagonists can reduce NDO.28 Electrical stimulation of the dorsal interneurons (blue neuron, Figure 7.3) elicited excitatory postsynaptic currents in the parasympathetic preganglionic neurons (green neuron, Figure 7.3).29 Because the interneurons also receive inputs from the afferent neurons (red neuron, Figure 7.3), activity in these interneurons modulate the excitatory input into the micturition reflex. The synapses between the interneurons and the afferent neurons and preganglionic motor neurons can be altered by SCI because of synaptic plasticity. It has been theorized that after SCI, because of descending axonal degeneration, axonal sprouting in interneurons occurs.30 This synaptic plasticity promotes more communication between afferent neurons and the parasympathetic preganglionic neurons leading and promoting NDO.

Changes at efferent nerve: Detrusor smooth muscle level (neuroeffector level) The use of harvested detrusor smooth muscle (DSM) from human and animal NGB to study NDO ­pathophysiology has been ongoing for many years. The earliest investigations of bladder physiology comprised mainly of studying DSM as the basis for understanding bladder function and dysfuntion. This is understandable, that per weight, the largest cellular component of the bladder is the DSM

Figure 7.3 Thoracolumbar and sacral spinal cord.

compartment. Furthermore, the active function of the bladder is the force generated by the coordinated contraction of the bladder resulting in effective emptying of urine out of the bladder. Therefore studying mechanisms underlying DSM contractions seems apropos. Thus, much of the work in understanding of the pathophysiology of NDO focused on DSM studies. Since the DSM is autonomically innervated, the contribution of the postganglionic efferent nerve (i.e., neural dysfunction) can also contribute to NDO. However, many studies on DSM have examined in vitro rhythmic contractions of the DSM without neural input and/or response of DSM to exogenously added neurotransmitters such as carbachol (muscarinic agonist) or ATP (purinergic agonist). These experiments would not address the efferent nerve contribution to DSM function. However, EFS, which causes neural release of neurotransmitters (see Section “Changes in urothelium and suburothelium” on EFS and urothelialafferent t­issue), can be used to determine contribution of efferent nerve to NDO at the neuroeffector junction. The paradigm used to understand DSM’s contribution to NDO is extended from our understanding of DO secondary to bladder outlet obstruction (BOO). On the basis of the BOO model construct, DO was described to be caused by postjunctional DSM supersensitivity resulting from partial bladder denervation.31,32 What this means is that the autonomic motor innervation to the bladder was reduced (bladder denervation) and that DSM responded to excitatory neurotransmitters (such as acetycholine or ATP) in an exaggerated (supersensitive) manner because of intrinsic DSM (postjuctional) pathology. It was thought that this myogenic aberration also occurred in NDO secondary to neurologic lesions. Studies on human NDO DSM suggested that indeed denervation postjunctional supersensitivity also underlies NDO.33–35 This supersensitivity was manifested by increased sensitivity of NDO detrusor muscle strips to muscarinic agonist. The normal and SCI neuroeffector junctions are

Pathophysiology of neurogenic detrusor overactivity Post-ganglionic parasympathetic efferent nerve

BK channels

Neuroeffector junction

Vesicle containing ACh

103

ACh Muscarinic receptors Purinergic receptors ATP

Vesicle containing ATP

Detrusor smooth muscle

(a) KATP channels

Post-junctional supersensitivity

SKCa channels

Patchy denervation

(b)

Figure 7.4 (a) Normal neuroeffector junction; (b) changes in neuroeffector junction after SCI.

depicted in Figures 7.4a and b, respectively. Another event that can occur at the NDO neuroeffector junction is change in the neurotransmitter released. Investigators found that in SCI rabbits, the excitatory neurotransmitter mechanism changed from a purinergic (e.g., ATP) to a ­cholinergic (e.g., acetylcholine) mechanism.36 Other investigators have shown that cholinergic agonism suppressed purinergic-mediated contractions after rat SCI.37 Another study examined

contractile responses of NDO, IDO, and control DSM from humans.38 These investigators found that there was increased sensitivity of NDO, compared to control, to carbachol and that the M3 muscarinic receptor subtype mediated the contraction in all types of bladders suggesting that there was no switch in excitatory neurotransmitter in NDO. Several things should be kept in mind when interpreting different studies. First, there appears to be species

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differences in which neurotransmitter mediate both normal and pathologic bladder contractions. So, although animal models can help us test in vivo mechanisms, the findings in animals at the very least need to be verified in human tissues. In humans, it appears that the certain DSM alterations were similar whether the NDO DSM tissues were obtained from patients with congenital lesions (e.g., spinal dysraphism) or acquired lesions (SCI). However, in NDO secondary to brain injury, such as in the cerebral ischemia rat model (MCAO as described in Section “Changes in type, structure, and function of afferent nerves”), the DSM showed no evidence of supersensitivity nor changes from cholinergic to purinergic neurotransmission.39 A lack of change in DSM denervation after brain lesions was supported by electron microscopy studies,40 which showed DSM from brain-lesioned neurologic individuals had significantly more normal postganglionic efferent innervation than DSM from SCI individuals. Whether or not detrusor supersensitivity is present in NDO DSM from human brain injured or brain lesioned patients has not been explored yet. This is probably because DSM specimens are usually obtained from augmentation cystoplasties, and this procedure is less common in brain-lesioned patients compared to SCI patients. Second, in older studies, before the role of the urothelium in regulating DSM contractility was appreciated, urothelium was probably not removed in organ bath experiments. Urothelial contribution to DSM contractility was first shown by investigators in 2000.41 This finding has been supported by other publications.42,43 Therefore, whether these NDO DSM

contractility studies would have shown different results had the urothelium been stripped remains uncertain. The large conductance of calcium-activated potassium channel (BK) has been shown to be important regulator of normal human and mouse DSM contractility.44,45 When BK is open (activated by increased intracellular calcium and/or cellular depolarization), potassium flows out of the cell, thus hyperpolarizing the cell and reducing the ability of the cell to contract and/or generate spontaneous activity. The depiction of BK morphology is shown in Figure 7.5. Each BK channel is composed of 4 units (tetramer) of BK protein. Each BK protein unit has an α-subunit (pore-forming unit) and a β-subunit (regulatory unit). Each α-subunit has seven transmembrane domains, whereas each β-subunit has two transmembrane domains. Alternative splicing of the BK gene (KCNMA1) can further regulate the properties of the BK channel. The role of BK in mediating human NDO was examined by comparing spontaneous contractile activity (SCA) from DSM obtained from NDO and non-NDO patients.46 These investigators found that SCA, measured in an organ muscle bath, was increased in NDO bladder strips. However, the urothelium/suburothelium neither affected the SCA in NDO DSM nor control DSM, which was an unexpected finding since it conflicted with prior studies mentioned earlier. Furthermore, BK regulated SCA only in control DSM, but not in NDO DSM, suggesting a change in type of potassium channel regulating DSM contractility after SCI. In fact, KATP and SKCa potassium channels, and not BK channels, were determined to be the channels that were regulating SCA in NDO DSM. KATP channels in the DSM

K+

Extracellular

Membrane Lipid bilayer Cytosolic

K+ pore K+

Opening of channel pore regulated by membrane potential (voltage gated) and intracellular calcium concentrations (calcium gated). These gating properties are contained within amino acid sequences of the α-subunit.

Figure 7.5 Calcium-activated potassium channel (BK) channel morphology.

β-Subunit (regulatory unit). Each β-subunit has 2 transmembrane loops

α-Subunit (pore forming unit) Each α-subunit has 7 transmembrane loops

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SUR 1 regulatory subunit with 3 transmembrane domains

(a)

K+ pore

Kir 6.1  pore-forming subunit has 2 transmembrane domains

SK pore-forming subunit has 6 transmembrane domains

(b)

Calmodulin

Figure 7.6 (a) K ATP channel morphology; (b) SKCa channel morphology.

were first characterized electrophysiologically in guinea pig DSM.47 KATP is a potassium channel that has been shown to be important in pancreatic function and is the target of the oral hypoglycemic sulfonylurea drug, glibenclamide. KATP’s morphology is shown in Figure 7.6a. The potassium pore is composed of a tetramer of the Kir6.1 (inward rectifying) proteins. This channel is regulated by the SUR1 protein that surrounds the pore forming core. Glibenclamide targets the regulatory subunit, SUR1, of the KATP channel. SKca is a small conductance potassium channel that is activated (opened) by increases in intracellular calcium, though its function is independent of cell membrane potential (voltage). The unique aspect of SKca channel, compared to the other potassium channels, is that it interacts with calmodulin, a calcium-binding second messenger protein, to regulate its activity. The morphology of SKCa is shown in Figure 7.6b. The complexities underlying regulation of detrusor contraction due to the presence of multiple different potassium channels was reviewed.48 Furthermore, changes in potassium channels after NDO may depend on location of neurologic lesion. In Oger’s study,46 DSM from both brain lesion (multiple sclerosis 21%, encephalomyelitis 11%) and SCI (SCI 61%, spinal bifida 7%) subjects were considered as one phenotype. Although all of these conditions may give rise to NDO, the heterogeneity in pathophysiology may manifest as different potassium channels regulating DSM contractility.

Changes at brain level The portion of brain neuroplasticity, post-SCI, specifically contributing to NDO has not been described to date in the literature. However, overall brain plasticity as a result of SCI, utilizing functional magnetic resonance imaging (fMRI) and neurophysiological studies, has been recently reviewed.49 The summary of these studies is that the cortical topographical representation of the somatosensory projections within the cortex changed significantly after SCI. This review paper hypothesized that this reorganization of the cerebral cortex could have clinical consequences such as phantom pain or neuropathic pain. Although autonomic function of the bladder is different than locomotion (somatic function), it should not be difficult to propose that similar plasticity occurs with the cortical mapping of bladder function after SCI. Investigators who study NGB have proposed to study brain signaling changes after SCI.50 However, in this review, these investigators described a different technique than fMRI to study brain signaling, They used an anesthetized animal and after craniotomy, performed cortical surface optical microfluorimetry (with calcium dyes) to generate a spectral map of areas of the cortical activation (reflected by increases in intracellular calcium concentration) with bladder stimulation. This technique however cannot image brain locations deeper than the cerebral cortex. It remains to be seen whether brain areas

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that were mapped using fMRI in patients with IDO51,52 will remain areas of interest in SCI patients with NDO. Although the study of post-SCI brain plasticity contributing to NDO is still nascent, the study of NDO secondary to post-MCAO has been ongoing since 1999.53 Depending on which animal model is used (SCI versus MCAO), the brain’s contribution to NDO pathophysiology should be interpreted differently. After SCI, brain neuroplasticity contributing to NDO would necessarily be secondary downstream effects. However, in the MCAO model, since the brain is the primary target of injury, subsequent changes would be a mixture of primary and secondary effects. Whether or not brain changes that drive NDO are similar between MCAO and SCI models remains to be seen. Given this caveat, using MCAO rat model, investigators have found that the forebrain input contributes to the maintenance of NDO.54 This was because decerebration (disconnecting cerebrum from midbrain at the superior colliculus) reduced the degree of NDO as evidenced by

increased bladder capacity. MCAO augmented the excitatory descending pathway and at the same time inhibited the inhibitory pathway for NDO.

Conclusions NDO can be a consequence of various neurologic diseases and conditions. Studies into pathophysiologic mechanisms contributing to, or as a result of, NDO utilized both human and animal bladder tissues. Because human tissues are more difficult to obtain, investigators have usually considered NDO mechanisms to be generally similar, regardless of the clinical neurologic conditions. The two most common animal models for NDO are SCI and MCAO injuries. These animal models have revealed both similarities and dissimilarities in NDO mechanisms. The anatomic sites where abnormalities have been described include urothelial-afferent junction, afferent nerves, spinal cord, and brain. A summary of these changes are shown in Table 7.1.

Table 7.1  Anatomic sites with corresponding etiologic mechanisms for NDO Anatomic site

Type of neurologic injury

Alterations

SCI

Increased permeability (acute), decreased size (chronic)

SCI/MS

Increased ATP releasea

SCI

Increased ATP releasea

Urothelial-afferent junction Urothelial cell

Myofibroblasts

Increased gap junction (Cx43) Increased zona adherens (cadherin-11) Afferent nerves

SCI

Change to C fibers Lower threshold to fire Change in sodium channels Increased afferent firing Increased ATP releasea

SCI/MS/tropical paraparesis

Variable changes in nerve diameters

SCI

Increased VIP, PACAP

Spinal cord Dorsal horn and IMLCC

Decreased GAD Increase NK1 signaling Interneuron sprouting Brain Cerebral cortex

SCI

Changes in sensory projections

Forebrain

MCAO

Forebrain augmentation

Efferent nerve

SCI

Denervation

Detrusor smooth muscle

SCI

Supersensitivity, changes in which potassium channels are active

Neuroeffector junction

a

Specific site within urothelial-afferent junction was not determined, so could be from urothelial cells, myofibroblasts, and/or afferent nerves.

Pathophysiology of neurogenic detrusor overactivity

References 813. Lemack GE, Frohman EM, Zimmern PE, Hawker K, Ramnarayan P. Urodynamic distinctions between idiopathic detrusor overactivity and detrusor overactivity secondary to multiple sclerosis. Urology 2006; 67: 960–4. 814. Sui GP, Wu C, Fry CH. Electrical characteristics of suburothelial cells isolated from the human bladder. J Urol 2004; 171: 938–43. 815. Fowler CJ, Griffiths D, de Groat WC. The neural control of micturition. Nat Rev Neurosci 2008; 9: 453–66. 816. Birder L. Urinary bladder urothelium: Molecular sensors of ­chemical/thermal/mechanical stimuli. Vasc Pharm 2006; 45: 221–6. 817. Ferguson DR, Kennedy I, Burton TJ. ATP is released from rabbit urinary bladder epithelial cells by hydrostatic pressure changes—A possible sensory mechanism? J Physiol 1997; 505: 503–511. 818. Apodaca G, Kiss S, Ruiz W et al. Disruption of bladder epithelium barrier function after spinal cord injury. Am J Physiol Renal Physiol 2003; 284: F966–76. 819. Apodaca G, Balestreire E, Birder LA. The uroepithelial-associated sensory web. Kidney Int 2007; 72: 1057–64. 820. Kumar V, Chapple CR, Rosario D, Tophill PR, Chess-Williams R. In vitro release of adenosine triphosphate from the urothelium of human bladders with detrusor overactivity, both neurogenic and idiopathic. Eur Urol 2010; 57: 1087–92. 821. Smith CP, Gangitano DA, Munoz A et al. Botulinum toxin type A normalizes alterations in urothelial ATP and NO release induced by chronic spinal cord injury. Neurochem Int 2008; 52: 1068–75. 822. Salas NA, Somogyi GT, Gangitano DA, Boone TB, Smith CP. Receptor activated bladder and spinal ATP release in neurally intact and chronic spinal cord injured rats. Neurochem Int 2007; 50: 345–50. 823. Roosen A, Datta SN, Chowdhury RA et al. Suburothelial myofibroblasts in the human overactive bladder and the effect of botulinum neurotoxin type A treatment. Eur Urol 2009a; 55: 1440–8. 824. Roosen A, Apostolidis A, Elneil S et al. Cadherin-11 up-regulation in overactive bladder suburothelial myofibroblasts. J Urol 2009b; 182: 190–5. 825. de Groat WC, Kawatani M, Hisamitsu T et al. Mechanisms underlying the recovery of urinary bladder function following spinal cord injury. Auton Nerv Syst 1990; 30(Suppl): S71–7. 826. Geirsson G, Fall M, Sullivan L. Clinical and urodynamic effects of intravesical capsaicin treatment in patients with chronic traumatic spinal detrusor hyperreflexia. J Urol 1995; 154: 1825–9. 827. de Sèze M, Wiart L, de Sèze MP et al. Intravesical capsaicin versus resiniferatoxin for the treatment of detrusor hyperreflexia in spinal cord injured patients: A double-blind, randomized, controlled study. J Urol 2004; 171: 251–5. 828. Lazzeri M, Spinelli M, Zanollo A, Turini D. Intravesical vanilloids and neurogenic incontinence: Ten years experience. Urol Int 2004; 72: 145–9. 829. Yoshimura N, de Groat WC. Plasticity of Na+ channels in afferent neurones innervating rat urinary bladder following spinal cord injury. J Physiol 1997; 503: 269–76. 830. de Groat WC, Krier J. The sacral parasympathetic reflex pathway regulating colonic motility and defaecation in the cat. J Physiol 1978; 276: 481–500. 831. Yokoyama O, Yusup A, Oyama N et al. Improvement of bladder storage function by alpha1-blocker depends on the suppression of C-fiber afferent activity in rats. Neurourol Urodyn 2006; 25: 461–7. 832. Wiseman OJ, Brady CM, Hussain IF et al. The ultrastructure of bladder lamina propria nerves in healthy subjects and patients with detrusor hyperreflexia. J Urol 2002; 168: 2040–5. 833. Apostolidis A, Popat R, Yiangou Y et al. Decreased sensory receptors P2X3 and TRPV1 in suburothelial nerve fibers following intradetrusor injections of botulinum toxin for human detrusor overactivity. J Urol 2005; 174: 977–82.

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834. Ikeda Y, Zabbarova IV, Birder LA et al. Botulinum neurotoxin serotype A suppresses neurotransmitter release from afferent as well as efferent nerves in the urinary bladder. Eur Urol 2012; 62: 1157–64. 835. Kawatani M, Erdman SL, de Groat WC. Vasoactive intestinal polypeptide and substance P in primary afferent pathways to the sacral spinal cord of the cat. J Comp Neurol 1985; 241: 327–47. 836. Zvarova K, Dunleavy JD, Vizzard MA. Changes in pituitary adenylate cyclase activating polypeptide expression in urinary bladder pathways after spinal cord injury. Exp Neurol 2005; 192: 46–59. 837. Miyazato M, Sasatomi K, Hiragata S et al. GABA receptor activation in the lumbosacral spinal cord decreases detrusor overactivity in spinal cord injured rats. J Urol 2008; 179: 1178–83. 838. Mertens P, Parise M, Garcia-Larrea L et al. Long-term clinical, electrophysiological and urodynamic effects of chronic intrathecal baclofen infusion for treatment of spinal spasticity. Acta Neurochir Suppl 1995; 64: 17–25. 839. Steers WD, Meythaler JM, Haworth C, Herrell D, Park TS. Effects of acute bolus and chronic continuous intrathecal baclofen on genitourinary dysfunction due to spinal cord pathology. J Urol 1992; 148: 1849–55. 840. Zhang X, Douglas KL, Jin H et al. Sprouting of substance P-expressing primary afferent central terminals and spinal micturition reflex NK1 receptor dependence after spinal cord injury. Am J Physiol Regul Integr Comp Physiol 2008; 295: R2084–96. 841. Araki I, de Groat WC. Unitary excitatory synaptic currents in preganglionic neurons mediated by two distinct groups of interneurons in neonatal rat sacral parasympathetic nucleus. J Neurophysiol 1996; 76: 215–26. 842. Araki I, de Groat WC. Developmental synaptic depression underlying reorganization of visceral reflex pathways in the spinal cord. J Neurosci 1997; 17: 8402–7. 843. Sibley GN. An experimental model of detrusor instability in the obstructed pig. Br J Urol 1985; 57: 292–8. 844. Speakman MJ, Brading AF, Gilpin CJ et al. Bladder outflow ­obstruction—A cause of denervation supersensitivity. J Urol 1987; 138: 1461–6. 845. Kinder RB, Mundy AR. Pathophysiology of idiopathic detrusor instability and detrusor hyper-reflexia. An in vitro study of human detrusor muscle. Br J Urol 1987; 60: 509–15. 846. German K, Bedwani J, Davies J, Brading AF, Stephenson TP. Physiological and morphometric studies into the pathophysiology of detrusor hyperreflexia in neuropathic patients. J Urol 1995; 153: 1678–83. 847. Drake MJ, Gardner BP, Brading AF. Innervation of the detrusor muscle bundle in neurogenic detrusor overactivity. BJU Int 2003; 91: 702–10. 848. Yokota T, Yamaguchi O. Changes in cholinergic and purinergic neurotransmission in pathologic bladder of chronic spinal rabbit. J Urol 1996; 156: 1862–6. 849. Lai HH, Munoz A, Smith CP, Boone TB, Somogyi GT. Plasticity of non-adrenergic non-cholinergic bladder contractions in rats after chronic spinal cord injury. Brain Res Bull 2011; 86: 91–6. 850. Stevens LA, Chapple CR, Chess-Williams R. Human idiopathic and neurogenic overactive bladders and the role of M2 muscarinic receptors in contraction. Eur Urol 2007; 52: 531–8. 851. Yokoyama O, Komatsu K, Ishiura Y et al. Change in bladder contractility associated with bladder overactivity in rats with cerebral infarction. J Urol 1998; 159: 577–80. 852. Haferkamp A, Dörsam J, Resnick NM, Yalla SV, Elbadawi A. Structural basis of neurogenic bladder dysfunction. III. Intrinsic detrusor innervation. J Urol 2003; 169: 555–62. 853. Hawthorn MH, Chapple CR, Cock M, Chess-Williams R. Urothelium-derived inhibitory factor(s) influences on detrusor muscle contractility in vitro. Br J Pharmacol 2000; 129: 416–9.

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854. Santoso AG, Sonarno IA, Arsad NA, Liang W. The role of the urothelium and ATP in mediating detrusor smooth muscle contractility. Urology 2010; 76: 1267.e7–12. 855. Munoz A, Gangitano DA, Smith CP, Boone TB, Somogyi GT. Removal of urothelium affects bladder contractility and release of ATP but not release of NO in rat urinary bladder. BMC Urol 2010; 10: 10. 856. Petkov GV, Bonev AD, Heppner TJ et al. Beta1-subunit of the Ca2+activated K+ channel regulates contractile activity of mouse urinary bladder smooth muscle. J Physiol 2001; 537: 443–52. 857. Hristov KL, Chen M, Kellett WF, Rovner ES, Petkov GV. Largeconductance voltage- and Ca2+-activated K+ channels regulate human detrusor smooth muscle function. Am J Physiol Cell Physiol 2011; 301: C903–12. 858. Oger S, Behr-Roussel D, Gorny D et al. Effects of potassium channel modulators on myogenic spontaneous phasic contractile activity in human detrusor from neurogenic patients. BJU Int 2011; 108: 604–11. 859. Bonev AD, Nelson MT. ATP-sensitive potassium channels in smooth muscle cells from guinea pig urinary bladder. Am J Physiol 1993; 264: C1190–200.

860. Petkov GV. Role of potassium ion channels in detrusor smooth muscle function and dysfunction. Nat Rev Urol 2011; 9: 30–40. 861. Nardone R, Höller Y, Brigo F et al. Functional brain reorganization after spinal cord injury: Systematic review of animal and human studies. Brain Res 2013; 1504: 58–73. 862. Kanai A, Zabbarova I, Ikeda Y et al. Sophisticated models and methods for studying neurogenic bladder dysfunction. Neurourol Urodyn 2011; 30: 658–67. 863. Griffiths D, Tadic SD, Schaefer W, Resnick NM. Cerebral control of the bladder in normal and urge-incontinent women. Neuroimage 2007; 37: 1–7. 864. Tadic SD, Griffiths D, Schaefer W, Resnick NM. Abnormal ­connections in the supraspinal bladder control network in women with urge urinary incontinence. Neuroimage 2008; 39: 1647–53. 865. Yokoyama O, Yoshiyama M, Namiki M, de Groat WC. Glutamatergic and dopaminergic contributions to rat bladder hyperactivity after cerebral artery occlusion. Am J Physiol 1999; 276: R935–42. 866. Yokoyama O, Yoshiyama M, Namiki M, de Groat WC. Role of the forebrain in bladder overactivity following cerebral infarction in the rat. Exp Neurol 2000; 163: 469–76.

8 Pathophysiology of detrusor underactivity/acontractile detrusor Dae Kyung Kim and Michael B. Chancellor

Introduction According to the standardization of terminology from the International Continence Society,1 detrusor underactivity (DU) is urodynamically defined as a contraction of reduced strength and/or duration, resulting in prolonged bladder emptying and/or a failure to achieve complete bladder emptying within a normal time span. Acontractile detrusor (AD) is one that cannot be demonstrated to contract during urodynamic studies. DU or AD (DU/AD) can be developed from various kinds of conditions, when afferent and/or efferent pathways innervating the bladder are mainly damaged. Various myogenic factors in detrusor muscles also cause AD as well as DU.

Mechanism of micturition reflexes Pelvic afferent pathways Efferent outflow to the lower urinary tract can be activated reflexively by spinal afferent pathways as well as by input from the brain. Afferent input from the pelvic visceral organs and somatic afferent pathways from the perineal muscle and skin are very important.2 Somatic afferent pathways in the pudendal nerves, which transmit noxious or nonnoxious information from the genital organs, urethra, prostate, vagina, anal canal, and skin can modulate voiding function.3–5 Bladder afferent nerves are critical for sending signals of bladder fullness and discomfort to the brain and for i­nitiating the micturition reflex. The bladder

afferent pathways are composed of two types of axons: large/medium diameter myelinated Aδ fibers and unmyelinated C fibers.6 Aδ fibers transmit signals mainly from mechanoreceptors that detect bladder fullness or wall tension. C fibers, on the other hand, mainly detect noxious signals and initiate painful sensations. The bladder C fiber nociceptors perform a similar function, and signal the central nervous system (CNS) when there is an infection or irritative condition in the bladder. C-fiber bladder afferents also have reflex functions to facilitate or trigger voiding.7–9 This can be viewed as a defense mechanism to eliminate irritants or bacteria from the body. C-fiber bladder afferents have been implicated in the triggering of reflex bladder overactivity associated with neurologic disorders such as spinal cord injury and multiple sclerosis.

Micturition reflexes Normal micturition is completely dependent on neural pathways in the CNS. These pathways perform three major functions: amplification, coordination, and timing. 3 The nervous control of the lower urinary tract must be able to amplify weak smooth muscle activity to provide sustained increases in intravesical pressure sufficient to empty the bladder. The bladder and urethral sphincter function must be coordinated to allow the sphincter to open during micturition but to be closed at all other times. Timing represents the voluntary control of voiding in the normal adult and the ability to initiate voiding over a wide range of bladder volumes (Figure 8.1). In this regard, the bladder is a unique visceral organ, which exhibits predominantly voluntary rather than

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Brain

Pons

T10

Bladder afferent

L2

(+) (+)

(+)

(−)

(+)

Somatic efferent

Sympathetic S2

Pelvic

S4 A Pudendal

Afferent

Figure 8.2 The guarding reflex prevents urinary incontinence. When there is a sudden increase in intravesical pressure, such as cough, the urinary sphincter contracts via the spinal guarding reflex to prevent urinary incontinence. The spinal guarding reflex can be turned off by the brain to urinate.

Efferent

Figure 8.1 Micturition requires positive feedback to ensure complete bladder emptying. As the bladder fills, myelinated Aδ tension receptors are activated. This afferent signal must reach the pontine micturition center with subsequent activation of parasympathetic efferent outflow.

involuntary (autonomic) neural regulation. Several important reflex mechanisms contribute to the storage or elimination of urine and modulate the voluntary control of micturition. 5

Guarding reflexes (guarding against stress urinary incontinence) There is an important bladder to urethral reflex that is mediated by sympathetic efferent pathways to the ­u rethra. This is an excitatory reflex that contracts the urethral smooth muscle and therefore is called a guarding reflex.10,11 The positive reflex is not activated during micturition but when bladder pressure is increased such as during a cough or exercise. A second guarding reflex is triggered by the bladder afferents, which synapse with sacral interneurons that in turn activate urethral external sphincter efferent neurons that send axons into the pudendal nerves.12 The activation of pudendal urethral efferent pathways contracts the external urinary sphincter, and prevents stress urinary incontinence (Figure 8.2). The brain inhibits the guarding reflexes during micturition.

Conditions or diseases developing detrusor underactivity/ acontractile detrusor DU/AD is usually observed when the following mechanisms are damaged:13 •• •• •• ••

Bladder peripheral afferent pathways Bladder peripheral efferent pathways Lumbosacral spinal cord (micturition center) Myogenic failure

These four factors are often mixed in the condition of DU/AD. In this section, several kinds of diseases that develop DU/AD, including the pathogenesis, urodynamic findings, and treatments are discussed. Future treatment strategies are also presented.

Diabetes mellitus (diabetic cystopathy) Bladder dysfunction associated with the complication of diabetes mellitus (DM), classically called diabetic cystopathy, has been described as impaired sensation of bladder fullness, increased bladder capacity, reduced bladder contractility, and increased residual urine.14–16

Pathophysiology of detrusor underactivity/acontractile detrusor However, these classic symptoms are not always observed in diabetic patients and symptom presentations are quite variable. Moreover, common concomitant diseases such as urinary tract infection, benign prostatic hyperplasia (BPH), and stress urinary incontinence may obscure underlying diabetic cystopathy. Therefore, it is important to discern the major factor from the complex presentation of symptoms in an individual patient. It has also been reported that diabetic cystopathy can occur silently and early in the course of diabetes.17 In such cases, it is rare to detect bladder dysfunction induced by diabetes without careful questions and/or urodynamic testing. The sex and age of patients are not the factors related to prevalence, whereas the duration of diabetes is bound up with the prevalence rate of diabetic cystopathy.17

Pathogenesis of diabetic cystopathy Pathophysiology of diabetic cystopathy has multifocal aspects. Traditionally, diabetic cystopathy was thought to result from polyneuropathy that predominantly affects sensory and autonomic nerve fibers.18,19 Some of the proposed pathogenesis includes altered metabolism of glucose, ischemia, superoxide-induced free radical formation, impaired axonal transport, and metabolic derangement of the Schwann cells.20,21 In addition to neuronal changes, many recent studies suggest that diabetic cystopathy can result from an alteration in the physiology of the detrusor smooth muscle cell, or urothelial dysfunction.21 Detrusor smooth muscle function has shown altered physiology in streptozotocin (STZ)- or alloxan-induced DM animal models. Major physiologic alterations are changes in sensitivity and contractile forces. Although there is some controversy on the responsiveness to muscarinic agonists, most agree on the increased responsiveness of DM bladder strip to electrical field stimulation.22,23 These changes are suggested to reflect increased calcium channel activity and enhanced calcium sensitivity.23 Myocytes from DM rats have also shown increased depolarization to externally applied acetylcholine and decreased spontaneous activity, presumably related to altered purinergic transmission.24 Changolkar et al.25 reported that diabetes induced a decrease in detrusor smooth muscle contractility; an increase in oxidative stress factors, lipid peroxidase/sorbitol; and concomitant overexpression of the aldose reductase/polyol pathway activation. They also reported increased expression of thin-filament proteins, calponin, tropomyosin, and caldesmon, in DM rabbit bladder, which might alter the contractile and cytoskeletal structure.26 The changes in tissue neurotrophic factors such as nerve growth factor (NGF) have been focused on as a convincing pathogenesis of diabetic neuropathy.27–32 In

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STZ-DM rats, the decrease in tissue NGF levels in the bladder and bladder afferent pathways is associated with diabetic cystopathy. 33 Changes in another neurotrophic factor, neurotrophin-3 (NT-3), have also been reported.34–36 It is promising for future treatment strategies in that the changes in tissue neurotrophic factor could play a critical role in inducing diabetic cystopathy. Studies have shown that the urothelium is not a passive barrier but rather it can take an active role in bladder physiology. 21 The urothelium can release many mediators including ATP, NO, and prostaniod. 37,38 Pinna et al. 39 reported that, in isolated urothelial layer preparations from STZ-DM rats, levels of endogenous prostaglandins E2 and F2α were higher than in preparations from normal rats. ATP and bradykinin significantly increased the endogenous release of prostaglandins E2 and F2α from the urothelium when compared with the basal release level. This time-dependent increase was higher in diabetic tissues than in controls. Prostaglandins may have a role in the sensitization of sensory nerves and may increase the sensitivity of DM bladder to contractile stimuli. The formation of nitric oxide synthase (NOS) and reactive nitrogen species also change during DM-related bladder remodeling. Poladia and Bauer40 reported that endothelial NOS is significantly upregulated in the lamina propria; neuronal NOS is upregulated in the urothelium, lamina propria, and smooth muscle; whereas inducible NOS is upregulated only in the urothelium. They suggested that impaired NO control is an early event leading to increased oxidative stress and proteasomal activation in the pathogenesis of diabetic cystopathy.

Urodynamic testing on diabetic cystopathy In most typical cases with diabetic cystopathy, cystometry shows a long curve with lack of sensation, often until bladder capacity is reached, with a low detrusor pressure.16,41,42 However, it has been reported that this classical type of underactive diabetic cystopathy is sometimes modified by concomitant lesions such as bladder outlet obstruction (BOO) or a history of cerebrovascular disease. For example, previous studies have reported a high incidence of detrusor overactivity (DO), of up to 50%–60%, when bladder function was examined in a selected population of diabetic patients presenting with positive lower urinary tract symptoms (LUTSs) or with a history of stroke.43,44 BOO should also be considered as a differential diagnosis for DO in diabetic patients.41 BOO is documented by measuring a high or normal pressure in the presence of an impaired urinary flow rate. Some patients with both diabetic cystopathy and BOO exhibit DO and elevated detrusor pressure during low-flow voiding.

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Figure 8.3 Acontractile detrusor in a 62-year-old insulin-dependent diabetic woman. The patient is on intermittent catheterization approximately 4 times per 24 hours. Pves, intravesical pressure; Pabd, abdominal pressure; Pdet, detrusor pressure.

Qmax = 29.1 mL/s Qmean = 11.5 mL/s Volume = 380 mL

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However, despite reports of a relatively high incidence of DO in symptomatic diabetic patients,43 one should be aware that autonomic and sensory neuropathy with diminished bladder sensation and bladder contractility is the predominant urologic manifestation of diabetic cystopathy when unselected diabetic patients are examined14–16 (Figures 8.3 and 8.4). Electromyography (EMG) is usually normal but sometimes exhibits sphincter denervation and uninhibited sphincter relaxation. Uroflowmetry shows low peak flow and prolonged duration of flow associated with increased residual urine. Urethral pressure profiles have not been well studied or validated in diabetic cystopathy.16,45

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Figure 8.4

Treatment of diabetic cystopathy The first and most important step in the management of diabetes is to control the blood glucose level. Hyperglycemia has been proved to be related to neuropathy and other complications of diabetes. However, the control of blood glucose level does not mean the prevention of diabetic cystopathy.17 Other preventive general management techniques include hypertension and hyperlipidemia control and education on nonsmoking. The main goal in treatment for diabetic cystopathy is basically to avoid overdistension of the bladder and to decrease residual urine. Because diabetic cystopathy usually has an insidious onset, scheduled voiding should be recommended to all diabetic patients regardless of symptom presence. If needed, double or triple voiding may also be recommended.46 Manual compression

Straining uroflowmetry of the diabetic woman in Figure 8.3. The patient complained of a sensation of incomplete emptying postmicturition, occasional incontinence, and straining to urinate. Although her maximum flow rate (Qmax) is normal (29.1 mL/s), the voiding pattern is classic for Valsalva voiding without true detrusor contractility.

of the lower abdomen (Credé’s maneuver) or abdominal straining (Valsalva maneuver) may be helpful to decrease residual urine in selected patients. However, these maneuvers are contraindicated in the presence of increased intravesical pressure, vagal reflux, and vesicoureteral reflux. Alpha (α)-blockers have some benefit in diabetic cystopathy concomitant with BOO. Cholinergic receptor agonists such as bethanechol chloride or urecholine have been used with inconsistent results in diabetic cystopathy.47

Pathophysiology of detrusor underactivity/acontractile detrusor Loss of bladder sensation is irreversible in diabetes and long-term follow-up is necessary. In addition, many patients with diabetic cystopathy may delay in seeking urologic evaluation because of the insidious development of diabetic cystopathy that induces diminished sensation and increased bladder capacity. Thus, careful surveillance for voiding symptoms and screening for elevated residual urine, including urodynamic studies, should be done regularly to prevent long-term complications secondary to diabetic cystopathy.

Future treatment strategies Conservative treatments for diabetic cystopathy are limited and cannot restore bladder function, as mentioned earlier. Recently, new treatment approaches for diabetic polyneuropathy, including diabetic cystopathy, have been reported in both the basic and clinical fields. Following the efficacy of NGF treatment in basic studies,48–50 the efficacy of NGF treatment in the clinical field has been reported.51–53 The feasibility of gene therapy using replication-­ deficient herpes simplex virus (HSV) encoding rhNGF genes has been reported. Four weeks after HSV–rhNGF injection into the STZ-DM rat bladder, a significant increase of NGF ­levels in the bladder and the L6 dorsal root ganglion (DRG) was detected. DM rats on HSV-NGF gene therapy also had a smaller bladder capacity and less residual urine than untreated DM rats.54,55 Studies using neurotrophic factors other than NGF, such as glial cell line–derived neurotrophic factor (GDNF) or NT-3, have also shown significant efficacy in restoring nerve function in diabetic animals.56,57 Thus, in future, neurotrophic factors or other growth factors combined with targeted gene therapy techniques may be beneficial for the therapy of patients with diabetic cystopathy.

Conclusions Diabetic cystopathy, which is characterized by loss of bladder sensation and DU/AD, is common and can develop insidiously. Tests, including urodynamic studies in the early stages of diabetes, are needed. Exciting new approaches to the treatment of diabetic cystopathy are being investigated.

Injury to the spinal cord, cauda equina, and pelvic plexus Any injury to the spinal cord, such as blunt, degenerative, developmental, vascular, infectious, traumatic, and idiopathic injury, can cause voiding dysfunction. In  this

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section, we discuss the urodynamic manifestations of some common spinal and cauda equina neurologic processes. Injury to the cauda equina or peripheral sacral nerves can have a devastating effect on bladder and urethral sphincter function. The resulting urinary dysfunction can be a major cause of morbidity in these cases. Lumbosacral spinal cord injury and herniated ­intervertebral disc are the two most common etiologic factors.58,59 Other etiologic causes include lumbar spinal stenosis, myelodysplasia, spinal arachnoiditis, arteriovenous malformation, and primary or metastatic tumors of the lumbar spine. It is also a rare complication of regional anesthesia. Injury to the pelvic plexus is not common. It is usually iatrogenic, most often occurring after major abdominal and pelvic surgery such as abdominoperineal resection or radical hysterectomy. Sometimes the problem may result from a pelvic fracture, or the trauma may be intentional (e.g., transvesical phenol injection) to abolish neurogenic DO in patients who have failed standard treatment regimens.

Neuroanatomy and pathophysiology Although it is well established that the pelvic plexus is derived from the ventral rami of S2–S4 nerves,58–60 there is contradictory information on sacral nerve c­ onnections and collateralization.59–61 The precise branching and interconnections among the sacral plexus are important because of increasing interest in dorsal rhizotomy and functional electrical stimulation for bladder control. The pelvic plexus lies deep in the pelvis, oriented in a parasagittal plane alongside the rectum. On most occasions, injury to this structure is iatrogenically induced following major pelvic ablative surgery. A malignant process involving the pelvis or invasive rectal neoplasms in the lateral and posterior or rectal wall may infiltrate the adjacent pararectal autonomic nerves, thus causing pelvic plexus injury.62–64 Marani et al.61 reported the surgical dissection of the cauda equina and pelvic plexus of 10 human cadavers (5  males and 5 females). In 9 (4 males and 5 females), a branch connecting the ventral rami of the second and third sacral spinal nerves was found. Electron microscopy showed the presence of thick myelinated fibers in this branch. This may contribute to the interaction between detrusor and sphincter contractions. The branches contributing to the pelvic plexus have individual and intersexual differences. It is important to be aware of the wide range of branches when decisions have to be made concerning the strategy of neurostimulation or dorsal rhizotomy. Voiding dysfunction after major pelvic surgery is usually caused by intraoperative injury to pelvic,

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hypogastric, and pudendal nerves.64,65 The neuroanatomic basis for the denervation of the bladder has been described on the basis of detailed anatomic dissections.66 Direct damage to the parasympathetic nerves and the p ­ osterior part of the pelvic plexus may occur during dissection on the anterolateral aspect of the lower rectum. In addition, traction injury may occur during mobilization of the lower rectum because of the relationship of the pelvic nerves with the fascial capsule investing the rectum.67 During hysterectomy, the main factor producing bladder denervation appears to be extensive dissection inferolateral to the cervix.63 Damage to the sympathetics in the hypogastric plexus may occur at the pelvic brim medial to the ureters and also in the region lateral to the rectum. Extensive dissection in the vicinity of the cardinal ligaments at the time of radical hysterectomy may also produce sympathetic denervation.64 During an abdominoperineal resection of perineal portion at the time of mobilization of the anus, injury to the pudendal nerve may occur. It is therefore apparent that varying degrees of damage to parasympathetic, sympathetic, and somatic nerves may occur, which can range from neural traction injury, to incomplete or complete nerve ablation.

Pelvic surgery The incidence of vesicoureteral dysfunction has been reported to be 20%–68% in patients after abdominal perineal resection, 16%–80% after radical hysterectomy, 10%–20% after proctocolectomy, and 20%–25% after anterior resection.64,65,67–70 However, the true incidence of lower urinary tract dysfunction after pelvic plexus injury is still unknown, mainly because it is very difficult to make prospective studies with pre- and postoperative neurourologic evaluation of the patients. Three additional factors make the issue more complex. First, most patients in the age group requiring treatment for abdominal or pelvic malignancy may have preexisting BOO or another pathology responsible for the functional derangement of the lower urinary tract. Second, in a significant percentage of patients, recovery of bladder function may occur as time goes on. Up to 80% of the patients with bladder dysfunction resulting from major pelvic surgery resume normal voiding within 6 months from the procedure. Finally, in most early series, the technical means for a comprehensive urodynamic evaluation were not available at that time. Regarding the complexity of neural injuries in these cases, which can involve parasympathetic, sympathetic, as well as somatic nerve fibers, it is evident that only modern urodynamic techniques can provide the exact information on the nature and the extent of an individual case.62,65

Pelvic and sacral fractures Pelvic trauma can result in cauda equina and pelvic plexus injury. The frequency of neurologic injury after pelvic fractures is estimated to be between 0.75% and 11%.71–73 Autopsy findings and clinical studies have shown that neurologic injury accompanying sacral fractures occurs either intradurally or extradurally within the sacral canal. Sacral fractures are associated with pelvic fractures in 90% of the cases.71,72 Approximately 25% of sacral fractures result in permanent neurologic deficit.74,75 Transverse fractures are most closely correlated with neurologic injury. Approximately two-thirds of these patients have neurogenic bladder.76 Because most of the injuries are incomplete, the majority of patients with neurourologic injury after pelvic and sacral fractures notice improvement with time. However, delayed neurologic deficits may occur after sacral fracture as a late complication.77,78 These delayed deficits result from various causes: scarring, hematoma formation at the fracture site, and untreated spinal instability.

Herniated disk Some reports indicate that the incidence of voiding dysfunction as a result of disk prolapse may approach 20% patients.79,80 Because the data represented that detrusor recovery was rare after treatment once patients showed bladder dysfunction following lumbar disk prolapse, cauda equina syndrome from lumbar disk herniation might be a diagnostic and surgical emergency.81,82

Lesions of the pudendal nerve The pudendal nerve arises from anterior primary rami of S2–S4, leaves the pelvis through the greater sciatic foramen below the piriformis muscle, and passes forward into the ischiorectal fossa. The nerve is occasionally injured in fractures of the pelvis. Damage produces sensory loss in the perineum and scrotum on the side of the lesion. Bilateral lesions produce bladder disturbances, with urinary retention and overflow incontinence.

Clinical findings Patients with known or suspected neurologic injury because of pelvic or sacral injury should have a careful physical examination. The integrity of the sacral dermatomes is tested by assessing perianal sensation, anal sphincter tone, and the bulbocavernosus reflex. The type of the resulting functional disturbance depends on the nature and extent of nerve injury. Parasympathetic denervation causes AD, whereas sympathetic damage will produce loss of proximal urethral

Pathophysiology of detrusor underactivity/acontractile detrusor pressure as a result of the compromised α-mediated innervations to the smooth muscle fibers of the bladder neck and urethra.83,84 Many patients complain of straining to urinate, incontinence, and a sensation of incomplete emptying. The urinary stream may be diminished and interrupted, as many of these patients rely on abdominal straining to urinate. On occasions, symptoms of voiding dysfunction can be the only initial clinical manifestation of a cauda equina lesion.85 The varied and mixed symptomatologies emphasize the need for a complete neurourologic evaluation. The physical examination may reveal a distended bladder, but the most characteristic features are elicited on a careful neurologic examination. Sensory loss in the perineum or perianal area is associated with S2–S4 dermatomes. The extent of perineal anesthesia can be a useful predictive clinical index in patients with lumbar disk prolapse. If saddle anesthesia of the S2–S4 dermatomes continues after surgical laminectomy and decompression, the urinary bladder rarely recovers.86 On the contrary, a unilateral or mild sensory disturbance indicates a better prognosis. Deep tendon reflexes in the lower extremities, clonus, and plantar responses, as well as the bulbocavernosus reflex, should be routinely evaluated. In a series of patients with cauda equina injury of various etiologies, the bulbocavernosus reflex was absent or significantly diminished in 84% cases, whereas the perineal sensation and muscle stretch reflexes were compromised in 77% patients.76 In addition, it was noted that absence of the reflex correlated well with perineal floor denervation.87 It is of interest that parasympathetic denervation itself may actually increase adrenergic activity by unmasking already existing α-receptors or inducing α-receptors. It has been demonstrated by histochemical fluorescence studies that the adrenergic nerve terminals of denervated human detrusors were thicker and denser than those of neurologically normal detrusors. A complete injury of both pelvic plexuses disrupts the nerve supply to the bladder and the urethra, but most injuries are incomplete. Because most ganglia lie close to or within the bladder wall, and large numbers of postganglionic neurons remain intact, any denervation is followed by reinnervation88 so that some residual lower tract activity remains. Sensation may be preserved, but, if it is lost, the resultant symptoms are usually urinary retention and overflow incontinence. Peripheral sympathetic injury results in an open, nonfunctional bladder neck and proximal urethra. Although this could occur as an isolated injury, it typically occurs in association with partial detrusor denervation, but with preservation of sphincter function.84 The combination of decreased compliance, open bladder neck, and fixed external sphincter resistance results in the paradoxic symptomatology of both leaking across the distal sphincter and the inability to empty the bladder. Under these circumstances, the optimal management is a combination of anticholinergics and intermittent catheterization.

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Urodynamic findings The typical cystometrogram (CMG) finding of cauda equina injury is loss of detrusor contraction.62,76 On the uroflowmetry, an abdominal straining sawtooth pattern is generally seen when the patients claim they can urinate. Urodynamic abnormalities may be the only aberration documented without other overt neurologic manifestations in some patients with cauda equina injury. On herniated disk, which is not induced by trauma or acute conditions, the protrusion is usually slow and progressive. In these cases, it may result in nerve irritation and consequently detrusor DO.89 Sphincter denervation—as documented on EMG by a decreased interference pattern, fibrillation, positive sharp waves, and polyphasic potentials—has also been reported.76 This observation can be attributed to the different location of the detrusor and pudendal motor nuclei within the sacral cord,90 as well as to the fact that the dominant segment of the pelvic nerve usually arises one segment higher than that of the pudendal nerve.91 The predominant CMG/EMG pattern is AD associated with sphincter neuropathy. Bladder sensation, however, is preserved in a significant number of patients because there are numerous exteroceptive sensory nerves in the bladder trigone and bladder neck entering the thoracolumbar spinal segments, thus bypassing the sacral cord.92 The integrity of the sacral reflex may be further studied with the evaluation of the latency time of the sacral-evoked potentials by stimulating the penile skin and recording the response with a needle electrode in the bulbocavernosus muscle.66,93 In patients with complete cauda equina lesions, the sacral-evoked response is either absent or significantly prolonged,94 and this represents a more sensitive indicator of neuropathy than the classic EMG changes. Rockswold and Bradley 95 reported the use of evoked EMG responses in diagnosing lesions of the cauda equina in 110 patients and correlated the results with clinical myelographic and operative findings. Absent evoked EMG responses were consistently correlated with urinary retention. Delayed evoked EMG responses were less consistently associated with urinary retention and lesions along this reflex pathway. However, normal responses do not exclude significant pathology of the cauda equina. Four patients with normal preoperative evoked EMG responses had arachnoiditis, a congenital lipoma, or a myelomeningocele at the time of the operation. Therefore, the technique cannot be considered in isolation. The technique does provide information regarding lesions involving the sacral nerves distal to the dural sac that were not accessible to myelography. Routine magnetic resonance imaging (MRI) was not available for that study. In conclusion, the major ­urodynamic features in patients with cauda equina injury are an absent or diminished ­bulbocavernosus reflex, AD, neuropathic changes on perineal floor EMG, and absent evoked EMG responses.

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Treatment Individualization of treatment is necessary according to the underlying abnormality. Indwelling or intermittent catheterization should be instituted in the postoperative period. Urodynamic evaluation should be performed after a few weeks. It is better to perform a urodynamic study after the patients have had a chance to recover from the major pelvic injury. If the bladder is acontractile, clean intermittent self-catheterization is recommended. If bladder compliance diminishes or DO develops, anticholinergics should be started to prevent upper tract damage.62,84 If the DO or poor filling compliance is unresponsive to aggressive anticholinergic trials, bladder augmentation using a detubularized bowel segment can be performed. Prostatectomy in a man who develops urinary retention immediately after a major pelvic operation must be avoided. Not only does resection of the prostate not help a man to urinate, but it may also result in stress urinary incontinence when there is underlying denervation of the external sphincter.53 In case of documented BPH, when surgical treatment is contemplated in patients with cauda equina syndrome, extreme caution must be taken because of the risk of postoperative incontinence. Urodynamic assessment to confirm obstruction is highly recommended in these cases and the patient has to be properly informed of the risks of surgery. The most commonly used pharmacologic agent in the treatment of AD is the cholinergic agent bethanechol chloride. Although the drug increases intravesical pressure, it has not been shown beneficial in promoting adequate bladder emptying.96,97 In fact, there are no single prospective randomized studies that show any clinical efficacy of bethanechol chloride in AD. Bethanechol chloride is especially contraindicated in patients with AD and BOO such as BPH, urethral stricture, or sphincter dyssynergia. In this scenario, increasing intravesical pressure with the existing increased outlet resistance may hasten vesicoureteral reflux, urinary sepsis, and renal damage. Similarly, the performance of Credé’s maneuver for AD may trigger a reflex contraction of the perineal floor, thus increasing bladder outlet resistance, a phenomenon that can also impede renal function. An adequate Credé’s maneuver or abdominal straining voiding is only effective when both smooth and skeletal muscle resistance are significantly reduced. This is feasible in some women but rarely effective or safe in men. Finally, external stimulation with implantable electrodes has met with many problems, making its routine use impractical. Stress urinary incontinence secondary to pelvic floor denervation may be difficult to manage. In men, the application of an external condom-type collecting device is the most common solution. In women, however, no external urinary collection device has ever proven effective. Many

women choose an indwelling Foley catheter, but this is associated with bladder irritation, chronic bacterial colonization, destruction of the sphincter mechanism, and even squamous cell carcinoma of the bladder with prolonged indwelling bladder catheterization. Treatment options for the destroyed urethral sphincter require major reconstructive urologic surgery such as the artificial urinary sphincter implantation, pubovaginal sling procedures, or supravesical urinary diversion such as the ileocystostomy, bladder chimney procedure. Finally, in patients with detrusor and perineal floor denervation but preservation of urethral smooth muscle function, the combination of bladder augmentation with a continent stoma and intermittent catheterization provides a reasonable therapeutic alternative.

Conclusions Neurourologic dysfunction secondary to injury to the cauda equina and pelvic plexus can result in devastating urologic dysfunction, the loss of volitional micturition, and the risk of upper tract damage. Fortunately, most of the initial bladder and urethral dysfunction recover within 6–12 months unless the injury is severe and bilateral. Conservative bladder management such as clean intermittent self-catheterization guided by urodynamic evaluation is the preferred management. Permanent solutions should be deferred until after the recovery or stabilization of the general neurologic status.

Infectious neurologic problems Acquired immune deficiency syndrome The acquired immune deficiency syndrome (AIDS) is caused by human immunodeficiency virus (HIV) and commonly associated with neurologic dysfunction. Neurologic involvement occurs in as many as 40% patients with AIDS.98 It involves both central and peripheral nervous systems, causing various neurologic manifestations: HIV dementia, encephalopathy, myelopathy, and peripheral neuropathy. Voiding symptoms are very common in AIDS patients, especially at the late stages of the disease or when associated with neurologic manifestations. Urodynamic evaluation in a series of 18 AIDS patients with voiding symptoms revealed neurogenic bladder in 11 patients.99 Urinary retention was the most common presenting symptom, and was seen in 6 of the 11 patients (55%). Urodynamic study revealed AD in 36%, DO in 27%, and BOO in 18% patients. The remaining 19% had normal urodynamic findings.

Pathophysiology of detrusor underactivity/acontractile detrusor

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Neurosyphilis (tabes dorsalis)

Lyme disease

Neurosyphilis has long been recognized as a cause of central and peripheral nerve abnormalities. Voiding dysfunction related to neurosyphilis was common in the era before penicillin use. Hattori et al.100 reported decreased bladder sensation in tabes dorsalis. Out of eight patients, six had increased bladder capacity at first desire to void, and three also had an increased maximum cystometric capacity. The most common urodynamic finding in neurosyphilis is AD. Sphincteric EMG activity is generally normal, as the corticospinal tracts are not involved in the disorder.101

Lyme disease, caused by the spirochete Borrelia ­burgdorferi, is associated with a variety of neurologic sequelae. The  ­urologic manifestation of Lyme disease can be the primary or late manifestation of the disease a­ffecting both sexes and all ages. Urinary urgency, nocturia, and urge incontinence are the most common urological symptoms.106 Urodynamic evaluation in a series of seven patients revealed DO in five patients and AD in two patients.107 Detrusor-external sphincter dyssynergia was not noted on EMG in any patient. The urinary tract may be involved in two different ways in the course of Lyme disease. There may be neurogenic voiding dysfunction as a part of neuroborreliosis and there may also be direct invasion of the urinary tract by the spirochete. This is analogous to voiding dysfunction secondary to other neurologic diseases such as multiple sclerosis. Only one patient had direct bladder invasion by the spirochete and he was an unusual case of Lyme disease with a fulminate presentation and multisystem involvement.

Herpes zoster and herpes simplex Herpes zoster is an acute, painful mononeuropathy associated with a vesicular eruption in the distribution of the affected nerve. The viral activity is predominantly located in the dorsal root ganglia or sensory ganglia of the cranial nerves. However, sacral nerve involvement may be associated with loss of bladder and anal sphincter control.102 When viral invasion of the lumbosacral dorsal roots occurs there may be visible skin vesicles along the corresponding dermatome, and cystoscopy may reveal a similar grouping of vesicles in the urethral and bladder mucosa. The early stages of lower urinary tract involvement with herpes are manifested as symptomatic detrusor instability with urinary frequency and urgency, but the latter stages include decreased sensation of filling and elevated residual urine or urinary retention.103 On the positive side, the problem is only temporary and generally recovers spontaneously over several months.

Guillain–Barré syndrome Guillain–Barré syndrome, also known as postinfectious polyneuritis, is an acute symmetric ascending polyneuropathy occurring 1–4 weeks after an acute infection. The syndrome is characterized by rapidly progressive signs of motor weakness and paresthesia progressing from the lower to upper extremities. Paralysis may progress for about 10 days and then remains relatively unchanged for about 2 weeks. The recovery is gradual and may take from 6 months to 2 years for completion. Autonomic disorders are not unusual. The inflammatory process may involve the afferent sensory neurons as well and produce loss of position and vibration sense. This may explain the urodynamic findings of detrusor motor and sensory deficits with Guillain– Barré syndrome.104 Retention of urine may occur in the early stages and require bladder catheterization.105 Longterm urologic dysfunction is uncommon.

Other conditions causing detrusor underactivity/ acontractile detrusor Acute cerebrovascular accidents Cerebrovascular accident (CVA) is a serious neurologic event and it can cause temporary or permanent voiding dysfunction to the victims. It is generally accepted that the most common urodynamic finding in CVA patients is DO. However, most reports in CVA patients have been done in a retrospective analysis and often months to years after the acute episode.108–110 After the initial stroke episode, patients are in a state of cerebral shock and urinary retention commonly occurs. Burney et al.111 reported urodynamic evaluations in 60  CVA patients, performed within 72 hours from the accident. In their series, 47% patients had urinary retention, mainly because of AD (75%). AD was found more commonly in patients with hemorrhagic infarcts (85%), compared to only in 10% with ischemic infarct. Although most cortical and internal capsular lesions resulted in DO, all cerebellar infarcts resulted in AD.

Multiple sclerosis Multiple sclerosis (MS) is a chronic disease with focal demyelinization of the CNS at various levels, causing a wide spectrum of neurologic manifestation. Urologic problems are reported in up to 90% patients, and represent the most troublesome and socially disabling feature of the

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disease course.112 The storage symptoms such as frequency, urgency, and urge incontinence are more common, but voiding symptoms such as weak stream, straining, and large residual urine are also common manifestations in MS patients. In MS patients, large residual urine generally means inefficient voiding from either detrusor contraction problems or sphincteric dyssynergia. It may be caused by concomitant BOO such as BPH. Therefore, thorough urodynamic evaluation is mandatory in MS patient management. Because cervical lesions predominate in MS, DO with/without dyssynergia is the most common urodynamic finding in 50%–80% cases. DU/AD has been reported up to 30% in cases when the plaques involve lumbosacral lesions.113,114

Parkinson’s disease Parkinson’s disease is a degenerative disorder of the CNS characterized by muscle rigidity, tremor, and a slow physical movement. These symptoms result from decreased stimulation of the motor cortex by the basal ganglia, usually caused by the insufficient formation and action of dopamine, which is produced in the dopaminergic neurons of the brain. Most patients with Parkinson’s disease complain of LUTSs, and the degree of symptoms reported correlates with the severity and duration of the disease.115 The most common finding in a urodynamic study is DO, which reflects the involvement of the CNS in this condition. However, DU/AD has also been reported in up to 16% patients.116 These findings may result from deterioration in bladder contractile function in the late stages of Parkinson’s disease, or from possible adverse effects of anticholinergic agents, which are commonly used in these patients for CNS symptom control.

Systemic sclerosis Systemic sclerosis is a connective tissue disease characterized by thickening and fibrosis of the skin. It also shows abnormalities of the small arteries involving the gastrointestinal tract, heart, lung, and kidney. Typical histopathologic findings are arteritis and periarteritis with leukocyte infiltrates and deposition of fibrous tissues. Although bladder involvement in systemic sclerosis is an uncommon manifestation, there are some reports of DU/AD from systemic sclerosis patients with LUTS. In a series of nine patients, urodynamic evaluation revealed normal findings in five patients and AD in four patients.117 Bladder biopsies from acontractile patients showed a derangement of the capillary bed of the muscle tissue, atrophy of the muscularis, and fibrotic replacement of the smooth muscle with attenuation of the lumen of the small arteries.

Sacral nerve stimulation Sacral afferent input–modifying micturition reflexes The guarding and voiding reflexes are activated at different times under completely different clinical scenarios. However, anatomically they are located in close proximity in the S2–S4 levels of the human spinal cord.118 Both sets of reflexes are modulated by several centers in the brain. Thus, these reflexes can be altered by a variety of neurologic diseases, some of which can unmask involuntary bladder activity mediated by C fibers. It is possible to modulate these reflexes via sacral nerve stimulation (SNS) and restore voluntary micturition. Experimental data from animals indicate that somatic afferent input to the sacral spinal cord can modulate the guarding and bladder–bladder reflexes. Sacral preganglionic outflow to the urinary bladder receives inhibitory inputs from various somatic and visceral afferents, as well as a recurrent inhibitory pathway.119 Electrical stimulation of somatic afferents in the pudendal nerve elicits inhibitory mechanisms.120 This is supported by the finding that interneurons in the sacral autonomic nucleus exhibiting firing were correlated with bladder activity and were inhibited by activation of somatic afferent pathways. This electrical stimulation of somatic efferent nerves in the sacral spinal roots could inhibit reflex of DO mediated by spinal or supraspinal pathways. In neonatal kittens and rats, micturition as well as defecation are elicited when their mother licks the perineal region.120 This reflex appears to be the primary stimulus for micturition, because urinary retention occurs when the young kittens and rat pups are separated from their mother. To induce micturition, the perineal afferents must activate the parasympathetic excitatory inputs to the bladder and also suppress the urethral sympathetic and sphincter somatic guarding reflexes. A suppression of guarding reflexes by SNS contributes to the enhancement of voiding in patients with urinary retention. The perineal-to-bladder reflex is very prominent during the first 4 postnatal weeks and then becomes less effective and usually disappears in kittens by the age of 7–8 weeks, which is the approximate age of weaning. In adult animals and humans, perineal stimulation or mechanical stimulation of the sex organs (vagina or penis) inhibits the micturition reflex.5,10,11 Besides the strong animal research that identified somatic afferent modulation of bladder and urethral reflexes, there are also data from clinical physiologic studies supporting the view that stimulation of sacral afferents can modify bladder and urethral sphincter reflexes. Functional electrical stimulation appears to be a favorable nonsurgical treatment for many patients with detrusor instability.

Pathophysiology of detrusor underactivity/acontractile detrusor

Hypotheses of sacral nerve stimulation mechanisms How do sacral somatic afferents alter lower urinary tract reflexes to promote voiding? To understand this mechanism, it should be recognized that, in adults, brain pathways are necessary to turn off sphincter and urethral guarding reflexes to allow efficient bladder emptying. Thus, spinal cord injury produces bladder sphincter dyssynergia and inefficient bladder emptying by eliminating the brain mechanisms (Figure 8.5). This may also occur after more subtle neurologic lesions in patients with idiopathic urinary retention, such as after a bout of prostatitis or urinary tract infection. Before the development of brain control of micturition, at least in animals, stimulation of somatic afferent pathways passing through the pudendal nerve to the perineum can initiate efficient voiding by activating bladder efferent pathways and turning off the excitatory pathways to the urethral outlet.3,4,8 Tactile stimulation of the perineum in the cat also inhibits the bladder–sympathetic reflex component of the guarding reflex mechanism. With the hypothesis that SNS can elicit similar responses in patients with urinary retention and turn off excitatory outflow to the urethral outlet and promote bladder emptying, Tanagho and Schmidt121 demonstrated the efficacy of SNS for AD, not only in animal studies but also in clinical studies. Jonas et al.122 reported the efficacy of SNS for idiopathic urinary retention in a prospective, randomized multicenter trial, which is the largest one so far. At 6 months after implantation, 69% patients treated eliminated catheterization and an additional 14% had a 50% or greater reduction in catheter volume per catheterization. However, patients in this trial were a mixed

Brain

SNS

Bladder afferent

(+) (+) (−)

(+)

(+)

Somatic efferent

Figure 8.5 In cases of neurologic diseases, the brain cannot turn off the guarding reflex and retention can occur. Sacral nerve stimulation restores voluntary micturition in cases of voiding dysfunction and urinary retention but inhibits the guarding reflex.

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population with DU, AD, or functional outlet obstruction because of urethral overactivity, and no subgroup analysis was reported. The methods for nerve stimulation also vary, including intraspinal transplantation, nerve root implantation, and transcutaneous stimulation.121,123,124 Because sphincter activity can generate afferent input to the spinal cord that can, in turn, inhibit reflex bladder activity, an indirect benefit of suppressing sphincter reflexes would be a facilitation of bladder activity. This may also be useful in this patient population.

Myogenic sections Degeneration of or damage to bladder smooth muscle is also an important factor that induces DU/AD. Diabetes is the most common disease that shows these conditions. Chronic overdistension can result in detrusor myogenic failure even if the neurologic disease is treated or reversed. Bladder management to avoid overdistension, such as institution of intermittent catheterization after spinal cord injury, may protect the bladder from permanent myogenic damage. At the present time, detrusor myogenic failure has been impossible to treat or reverse. This is why catheterization, either intermittent or indwelling, has been the most commonly used management. There is potential hope for the future, however, of transplanting muscle stem cells to repair the damaged bladder with or without ex-vivo gene therapy. The aim of ex-vivo cell therapy is to replace, repair, or enhance the biologic function of damaged tissue or organs. An ex-vivo process involves harvesting cells from patients or donors, in vitro manipulation to enhance the therapeutic potential of the harvested cells (ex-vivo gene therapy), and subsequent injection or implantation of the cells into the patient. One particular advantage of cellularbased ex-vivo gene therapy is that the manufactured cells act like bioreactors. At any stage of the process, cells can be cryopreserved so that therapy can be scheduled according to the patient’s requirements.125 A safety feature of the ex-vivo approach is that all genetic manipulation involving viral vectors is performed in vitro in a controlled fashion. Therefore, the patients are not directly exposed to the viral vectors. In addition, the amount of gene product expression can be quantitated, leading to controlled protein production at specific sites with decreased system side effects.126 Cell transplantation is not a new concept; however, the field of urologic tissue engineering has just recently grown to new and exciting levels. Because there is a general lack of regenerative ability in the bladder and urethral smooth muscle, research has centered on tissue repair by using ­pluripotent stem cells derived from other ­lineages. Our laboratory has focused on the isolation and characterization of a small population of these pluripotent stem cells

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that were derived from skeletal muscle. Using the preplate technique, we can purify and isolate cells that are highly capable of surviving posttransplantation and differentiating into other lineages.127 The rationale for using skeletal muscle for cellular-based gene therapy for the urinary tract is two-fold. In contrast to smooth muscle, skeletal muscle is constantly undergoing repair of its damaged tissue because of the presence of satellite cells.128 These cells are fusion-competent skeletal muscle precursors and, when differentiated, fuse to form myofibers capable of muscle contraction. Second, some purified satellite cells behave like pluripotent stem cells that may differentiate into another lineage. We and other investigators have previously demonstrated the ability to harvest muscle-derived cells (MDCs), which contain satellite cells and stem cells, from a skeletal muscle biopsy.127,129–131 MDCs have been used for the delivery of secretory nonmuscle protein products, such as human growth hormone and coagulation factor IX, to the circulation.132,133 In addition, when MDCs differentiate, they form myofibers that become postmitotic and consequently exhibit long-term transgene persistence.134 We have also demonstrated that MDC transplantation increased muscle contractility in a cryo-injured detrusor model and nerve, or a sphincter-injured incontinence model.135–139 Thus, transplantation of MDCs from skeletal muscle might be a promising treatment strategy for DU or AD.

Summary DU/AD can be observed in many neurologic conditions. Careful neurologic and urodynamic examinations are necessary for the diagnosis. Proper management is focused on prevention of upper tract damage, avoidance of overdistension, and decrease of residual urine. Scheduled voiding, double voiding, α1-blockers, and intermittent self-catheterization are the typical conservative treatment options. Sacral nerve stimulation may be an effective treatment option for DU/AD. New promising concepts such as stem cell therapy and neurotrophic gene therapy are being explored.

References 867. Abrams P, Cardozo L, Fall M et al. The standardisation of terminology in lower urinary tract function: Report from the standardisation sub-committee of the International Continence Society. Urology 2003; 61: 37–49. 868. de Groat WC, Theobald RJ. Reflex activation of sympathetic pathways to vesical smooth muscle and parasympathetic ganglia by electrical stimulation of vesical afferents. J Physiol 1976; 259: 223–37. 869. de Groat WC. Central nervous system control of micturition. In: O’Donnell PD, ed. Urinary Incontinence. St Louis, MO: Mosby, 1997: 33–47.

870. Yoshimura N, de Groat WC. Neural control of the lower urinary tract. Int J Urol 1997; 4: 111–25. 871. de Groat WC, Araki I, Vizzard MA et al. Developmental and injury induced plasticity in the micturition reflex pathway. Behav Brain Res 1998; 92: 127–40. 872. Yoshimura N, Chancellor MB. Current and future pharmacological therapy for overactive bladder. J Urol 2002; 168: 1897–913. 873. Cheng CL, Ma CP, de Groat WC. Effect of capsaicin on micturition and associated reflexes in rats. Am J Physiol 1993; 265: R132–138. 874. Kruse MN, de Groat WC. Spinal pathways mediate coordinated bladder/urethral sphincter activity during reflex micturition in normal and spinal cord injured neonatal rats. Neurosci Lett 1993; 152: 141–4. 875. Cheng CL, Ma CP, de Groat WC. Effect of capsaicin on micturition and associated reflexes in chronic spinal rats. Brain Res 1995; 678: 40–8. 876. de Groat WC, Nadelhaft I, Milne RJ et al. Organization of the sacral parasympathetic reflex pathways to the urinary bladder and large intestine. J Auton Nerv Syst 1981; 3: 135–60. 877. de Groat WC, Vizzard MA, Araki I, Roppolo JR. Spinal interneurons and preganglionic neurons in sacral autonomic reflex pathways. In: Holstege G, Bandler R, Saper C, eds. The Emotional Motor System. Progress in Brain Research. New York: Elsevier Science, 1996; 107: 97. 878. de Groat WC. Inhibitory mechanisms in the sacral reflex pathways to the urinary bladder. In: Ryall RW, Kelly JS, eds. Iontophoresis and Transmitter Mechanisms in the Mammalian Central Nervous System. Holland, The Netherlands: Elsevier, 1978: 366–8. 879. Chancellor MB, Blaivas JG. Classification of neurogenic bladder disease. In: Chancellor MB, eds. Practical Neuro-urology. Boston, MA: Butterworth-Heinemann, 1995: 25–32. 880. Frimodt-Moller C. Diabetic cystopathy: I. A clinical study of the frequency of bladder dysfunction in diabetics. Dan Med Bull 1976; 23: 267–78. 881. Ellenburg M. Development of urinary bladder dysfunction in diabetes mellitus. Ann Intern Med 1980; 92: 321–3. 882. Ueda T, Yoshimura N, Yoshida O. Diabetic cystopathy: Relationship to autonomic neuropathy detected by sympathetic skin response. J Urol 1997; 157: 580–4. 883. Frimodt-Moller C. Diabetic cystopathy: Epidemiology and related disorders. Ann Intern Med 1980; 92: 318–21. 884. Mastri AR. Neuropathology of diabetic neurogenic bladder. Ann Intern Med 1980; 92: 316–18. 885. van Poppel H, Stessens R, van Damme B et al. Diabetic cystopathy: Neuropathological examination of urinary bladder biopsy. Eur Urol 1988; 15: 128–31. 886. Apfel SC. Neurotrophic factors and diabetic peripheral neuropathy. Eur Neurol 1999; 41(Suppl): 27–34. 887. Yoshimura Y, Chancellor MB, Andersson KE et al. Recent advances in understanding the biology of diabetes-associated bladder complications and novel therapy. BJU Int 2004; 95: 733–8. 888. Longhurst PA, Kauer J, Levin RM. The ability of insulin treatment to reverse or prevent the changes in urinary bladder function caused by streptozotocin-induced diabetes mellitus. Gen Pharmacol 1991; 22: 305–11. 889. Waring JV, Wendt IR. Effect of streptozotocin-induced diabetes mellitus on intracellular calcium and contraction of longitudinal smooth muscle from rat urinary bladder. J Urol 2000; 163: 323–30. 890. Hashitani H, Suzuki H. Altered electrical properties of bladder smooth muscle in streptozotocin-induced diabetic rats. Br J Urol 1996; 77: 798–804. 891. Changolkar AK, Hypolite JA, Disanto M et al. Diabetes induced decrease in detrusor smooth muscle force is associated with oxidative stress and overactivity of aldose reductase. J Urol 2005; 173: 309–13. 892. Mannikarottu AS, Changolkar AK, Disanto ME et al. Overexpression of smooth muscle thin filament associated proteins in the bladder wall of diabetics. J Urol 2005; 174: 360–4.

Pathophysiology of detrusor underactivity/acontractile detrusor 893. Kasayama S, Oka T. Impaired production of nerve growth factor in the submandibular gland of diabetic mice. Am J Physiol 1989; 257: E400–4. 894. Hellweg R, Hartung HD. Endogenous levels of nerve growth factor (NGF) are altered in experimental diabetes mellitus: A possible role of NGF in the pathogenesis of diabetic neuropathy. J Neurosci Res 1990; 26: 258–67. 895. Fernyhough P, Diemel LT, Brewster WJ, Tomlinson DR. Deficits in sciatic nerve neuropeptide content coincide with a reduction in target tissue nerve growth factor messenger RNA in streptozotocin-­ diabetic rats: Effects of insulin treatment. Neuroscience 1994; 62: 337–44. 896. Steinbacher BC, Nadelhaft I. Increased level of nerve growth factor in the urinary bladder and hypertrophy of dorsal root ganglion neurons in the diabetic rat. Brain Res 1998; 782: 255–60. 897. Diemel LT, Cai F, Anand P et al. Increased nerve growth factor mRNA in lateral calf skin biopsies from diabetic patients. Diabet Med 1999; 16: 113–18. 898. Schmid H, Forman LA, Cao X et al. Heterogenous cardiac ­sympathetic denervation and decreased myocardial nerve growth factor in streptozotocin-induced diabetic rats: Implications for cardiac sympathetic dysinnervation complicating diabetes. Diabetes 1999; 48: 603–8. 899. Sasaki K, Chancellor MB, Phelan MW et al. Diabetic cystopathy ­correlates with long-term decrease in nerve growth factor (NGF) levels in the bladder and lumbosacral dorsal root ganglia. J Urol 2002; 168: 1259–64. 900. Ihara C, Shimatsu A, Mizuta H. Decreased neurotrophin-3 expression in skeletal muscles of streptozotocin-induced diabetic rats. Neuropeptides 1996; 30: 309–12. 901. Fernyhough P, Diemel LT, Tomlinson DR. Target tissue production and axonal transport of neurotrophin-3 are reduced in streptozotocin diabetic rats. Diabetologia 1998; 41: 300–6. 902. Cai F, Tomlinson DR, Fernyhough P. Elevated expression of neurotorophin-3 mRNA in sensory nerve of streptozotocin-diabetic rats. Neurosci Lett 1999; 263: 81–4. 903. Vlaskovska M, Kasakov L, Rong W et al. P2X3 knock-out mice reveal a major sensory role for urothelially released ATP. J Neurosci 2001; 21: 5670–7. 904. Birder LA, Nealen ML, Kiss S et al. Beta-adrenocepter agonists stimulate endothelial nitric oxide synthase in rat urinary bladder urothelial cells. J Neurosci 2002; 15: 8063–70. 905. Pinna C, Zanardo R, Puglisi L. Prostaglandin-release impairment in the bladder epithelium of streptozotocin-induced diabetic rats. Eur J Pharmacol 2000; 388: 267–73. 906. Poladia DP, Bauer JA. Early cell-specific changes in nitric oxide synthase, reactive nitrogen species formation, and ubiquitinylation during diabetes-related bladder remodeling. Diabetes Metab Res Rev 2003; 19: 313–19. 907. Frimodt-Moller C. Diabetic cystopathy: A review of the urodynamic and clinical features of neurogenic bladder dysfunction in diabetes mellitus. Dan Med Bull 1978; 25: 49–60. 908. Blaivas JG. Neurogenic dysfunction. In: Yalla SU, McGuire EJ, Elbadawi A, Blaivas JG, eds. Neurourology and Urodynamics: Principles and Practice. New York: Macmillan, 1988: 347–50. 909. Kaplan SA, Te AE, Blaivas JG. Urodynamic findings in patients with diabetic cystopathy. J Urol 1995; 153: 342–4. 910. Starer P, Libow L. Cystometric evaluation of bladder dysfunction in elderly diabetic patients. Arch Intern Med 1990; 150: 810–13. 911. Bradley WE. Diagnosis of urinary bladder dysfunction in diabetes mellitus. Ann Intern Med 1980; 92: 323–6. 912. Kaplan SA, Blaivas JG. Diabetic cystopathy. J Diabet Compl 1988; 2: 133–9. 913. Hunter KF, Moore KN. Diabetes-associated bladder dysfunction in the old adult. Geriatr Nurs 2003; 24: 138–47. 914. Apfel SC, Arezzo JC, Brownlee M et al. Nerve growth factor administration protects against experimental diabetic sensory neuropathy. Brain Res 1994; 634: 7–12.

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915. Delcroix JD, Michael GJ, Priestley JV et al. Effect of nerve growth factor treatment on p75NTR gene expression in lumbar dorsal root ganglia of streptozotocin-induced diabetic rats. Diabetes 1998; 47: 1779–85. 916. Unger JW, Klitzsch T, Pera S, Reiter R. Nerve growth factor (NGF) and diabetic neuropathy in the rat: Morphological investigation of the sural nerve, dorsal root ganglion, and spinal cord. Exp Neurol 1998; 153: 23–34. 917. Petty BG, Comblath DR, Adornato BT et al. The effect of systemically administered recombinant human nerve growth factor in healthy human projects. Ann Neurol 1994; 36: 244–6. 918. Apfel SC, Kessler JA, Adomato BT et al. The NGF study group: Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy. Neurology 1998; 51: 695–702. 919. Apfel SC, Schwartz S, Adomato BT et al. The rhNGF clinical investigator group: Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy. A randomized control trial. JAMA 2000; 284: 2215–21. 920. Goins WF, Yoshimura N, Phelan MW et al. Herpes simplex virus mediated nerve growth factor expression in bladder and afferent neurons: Potential treatment for diabetic bladder dysfunction. J Urol 2001; 165: 1748–54. 921. Sasaki K, Chancellor MB, Goins WF et al. Gene therapy using replication defective herpes simplex virus (HSV) vectors expressing nerve growth factor (NGF) in a rat model of diabetic cystopathy. Diabetes 2004; 53: 2723–30. 922. Akkina SK, Patterson CL, Wright DE. GDNF rescues nonpeptidergic unmyelinated primary afferents in streptozotocin-treated diabetic mice. Exp Neurol 2001; 167: 173–82. 923. Pradat PF, Kennel P, Naimi-Sadaoui S et al. Continuous delivery of neurotrophin 3 by gene therapy has a neuroprotective effect in experimental models of diabetic and acrylamide neuropathies. Hum Gene Ther 2001; 12: 2237–49. 924. Bradley WE, Andersen JT. Neuromuscular dysfunction of the lower urinary tract in patients with lesions of the cauda equina and conus medullaris. J Urol 1976; 116: 620–1. 925. Hellstrom P, Kortelainen P, Kontturi M. Late urodynamic findings after surgery for cauda equina syndrome caused by a prolapsed lumbar intervertebral disk. J Urol 1986; 135: 308–12. 926. Gray H. The urinary organs. In: Williams PL, Warwick R, eds. Gray’s Anatomy, 36th ed. Edinburgh, Scotland: Churchill Livingstone, 1984: 1110–23. 927. Marani E, Pijl ME, Kraan MC et al. Interconnections of the upper ventral rami of the human sacral plexus: A reappraisal for dorsal rhizotomy in neurostimulation operations. Neurourol Urodyn 1993; 12: 585–98. 928. Woodside JR, Crawford ED. Urodynamic features of pelvic plexus injury. J Urol 1980; 124: 657–8. 929. Forney JP. The effect of radical hysterectomy on bladder physiology. Am J Obstet Gynecol 1980; 138: 374–82. 930. Yalla SV, Andriole GL. Vesicourethral dysfunction following pelvic visceral ablative surgery. J Urol 1984; 132: 503–9. 931. Blaivas JG, Barbalias GA. Characteristics of neural injury after abdominoperineal resection of the rectum. J Urol 1983; 129: 84–7. 932. Siroky MB, Sax DS, Krane RJ. Sacral signal tracing: The electrophysiology of the bulbocavernosus reflex. J Urol 1979; 122: 661–4. 933. Smith PH, Ballantyne B. The neuroanatomical basis for denervation of the urinary bladder following major pelvic surgery. Br J Surg 1968; 55: 929–33. 934. McGuire EJ. Urodynamic evaluation after abdominal-perineal resection and lumbar intervertebral disc herniation. Urology 1975; 6: 63–70. 935. Seski JC, Diokno AC. Bladder dysfunction after radical abdominal hysterectomy. Am J Obstet Gynecol 1977; 128: 643–51. 936. Mundy AR. An anatomical explanation for bladder dysfunction following rectal and uterine surgery. Br J Urol 1982; 54: 501–4. 937. Patterson FP, Morton KS. Neurologic complications of fractures and dislocations of the pelvis. Surg Gynecol Obstet 1961; 112: 702.

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938. Brynes DP, Russo GL, Dunker TB, Cowley RA. Sacrum fractures and neurological damage. J Neuorsurg 1977; 47: 459–62. 939. Heckman JD, Keats PK. Fracture of the sacrum in children. J Bone Joint Surg Am 1978; 60: 404–5. 940. Goodell CL. Neurological deficit associated to pelvic fractures. J Neurosurg 1966; 24: 837–42. 941. Fountain SS, Hamilton RD, Jameson RM. Transverse fractures of the sacrum: A report of six cases. J Bone Joint Surg Am 1977; 59: 486–9. 942. Pavlakis AJ. Cauda equina and pelvic plexus injury. In: Krane RJ, Siroky MB, eds. Clinical Neuro-urology. Boston, MA: Little Brown, 1991: 333–4. 943. Dewey P, Browne PSH. Fractures and dislocation of the lumbosacral spine with cauda equina lesion. J Bone Joint Surg Br 1968; 50: 635–8. 944. Fardon DF. Displaced fractures of the lumbosacral spine with delayed cauda equina deficit. Clin Orthop 1976; 120: 155–8. 945. Scott PJ. Bladder paralysis in cauda equina lesions from disc prolapse. J Bone Joint Surg 1965; 47: 244. 946. Bartolin Z, Vilendecic M, Derezic D. Bladder function after surgery for lumber intervertebral disk protrusion. J Urol 1999; 161: 1885–7. 947. O’Flynn KJ, Murphy R, Thomas DG. Neurogenic bladder dysfunction in lumbar intervertebral disc prolapse. Br J Urol 1992; 69: 38–40. 948. Shapiro S. Medical realities of cauda equina syndromes secondary to lumbar disc herniation. Spine 2000; 25: 348–52. 949. Albert NE, Sparks FC, McGuire EJ. Effect of pelvic and retroperitoneal surgery on the urethral pressure profile and perineal floor electromyogram in dogs. Invest Urol 1977; 15: 140–2. 950. McGuire EJ, Wagner FC. The effects of sacral denervation on bladder and urethral function. Surg Gynecol Obstet 1977; 144: 343–6. 951. Blaivas JG, Scott MR, Labib KB. Urodynamic evaluation as neurologic test for sacral cord function. Urology 1979; 8: 682–7. 952. Scott M. Surgery of the spinal column. Prog Neurol Psychiatry 1965; 20: 509–23. 953. Lapides J, Babbitt JM. Diagnostic value of bulbocavernosus reflex. JAMA 1956; 162: 971. 954. Neal DE, Boguc PRI, Williams RE. Histological appearances of the nerves of the bladder in patients with denervation of the bladder after excision of the rectum. Br J Urol 1982; 54: 658–66. 955. Jones DL, Moore T. The types of neuropathic bladder dysfunction associated with prolapsed lumbar intervertebral discs. Br J Urol 1973; 45: 39–43. 956. Kuru M. Nervous control of micturition. Physiol Rev 1965; 45: 425. 957. Bradley WE, Teague C. Spinal cord representation of the peripheral neural pathways of the micturition reflex. J Urol 1969; 101: 220–3. 958. Bradley WE, Timm GM, Scott FB. Cystometry: V. Bladder sensation. Urology 1975; 6: 654–8. 959. Blaivas JG, Zaved AAH, Labib KB. The bulbocavernosus reflex in urology: A prospective study of 299 patients. J Urol 1981; 126: 197–9. 960. Krane RJ, Siroky MB. Studies on sacral evoked potentials. J Urol 1980; 124: 872–6. 961. Rockswold GL, Bradley WE. The use of evoked electromyographic responses in diagnosing lesions of the cauda equina. J Urol 1977; 118: 629–31. 962. Blaivas JG, Labib KB, Michalik SJ, Zayed AA. Failure of bethanechol denervation supersensitivity as a diagnostic aid. J Urol 1980; 123: 199–201. 963. Wein A, Raezer D, Malloy T. Failure of the bethanechol supersensitivity test to predict improved voiding after subcutaneous bethanechol administration. J Urol 1980; 123: 302–3. 964. Levy R, Janssen R, Bush T et al. Neuroepidemiology of acquired immunodeficiency syndrome. In: Rosenblum ML, ed. AIDS and the Nervous System. New York: Raven Press, 1998: 13–40. 965. Kahn Z, Singh VK, Yang WE. Neurogenic bladder in acquired immune deficiency syndrome (AIDS). Urology 1992; 40: 289–91. 966. Hattori T, Yasuda K, Kita K, Hirayama K. Disorders of micturition in tabes dorsalis. Br J Urol 1990; 65: 497–9. 967. Wheeler JS Jr, Culkin DJ, O’Hara RJ, Canning JR. Bladder dysfunction and neurosyphilis. J Urol 1986; 136: 903–5.

968. Cohen LM, Fowler JF, Owen LG, Callen JP. Urinary retention ­associated with herpes zoster infection. Int J Dermatol 1993; 32: 24–6. 969. Yamanishi T, Yasuda K, Sakakibara R et al. Urinary retention due to herpes virus infections. Neurol Urodyn 1998; 17: 613–19. 970. Wheeler JS Jr, Siroky MB, Pavlakis A, Krane RJ. The urodynamic aspects of the Guillain–Barré syndrome. J Urol 1984; 137: 917–19. 971. Kogan BA, Solomon MH, Diokno AC. Urinary retention secondary to Landry Guillain–Barré syndrome. J Urol 1981; 126: 643–4. 972. Chancellor MB, McGinnis DE, Shenot PJ et al. Lyme cystitis and neurogenic bladder dysfunction. Lancet 1992; 339: 1237–8. 973. Chancellor MB, McGinnis DE, Shenot PJ et al. Urinary dysfunction in Lyme disease. J Urol 1993; 149: 26–30. 974. Tsuchida S, Noto H, Yamaguchi O, Itoh M. Urodynamic studies on hemiplegic patients after cerebrovascular accident. Urology 1983; 21: 315–18. 975. Gelber DA, Good DC, Laven LJ, Verhulst SJ. Causes of urinary incontinence after acute hemispheric stroke. Stroke 1993; 24: 378–82. 976. Khan Z, Starer P, Yang WC, Bhola A. Analysis of voiding disorders in patients with cerebrovascular accidents. Urology 1990; 35: 265–70. 977. Burney TL, Senapati M, Desai S et al. Acute cerebrovascular accident and lower urinary tract dysfunction: A prospective correlation of the site of brain injury with urodynamic findings. J Urol 1996; 156: 1748–50. 978. Haensch CA, Jorg J. Autonomic dysfunction in multiple sclerosis. J Neurol 2006; 253(Suppl 1): i3–i9. 979. Wheeler JS Jr. Multiple sclerosis. In: Krane RJ, Siroky MB, eds. Clinical Neuro-urology. Boston, MA: Little Brown, 1991: 353–63. 980. Barbalias GA, Nikiforidis G, Liatsikos EN. Vesicourethral dysfunction associated with multiple sclerosis: Clinical and urodynamic perspectives. J Urol 1998; 160: 106–11. 981. Araki I, Kuno S. Assessment of voiding dysfunction in Parkinson’s disease by the international prostate symptom score. J Neurol Neurosurg Psychiatry 2000; 68: 429–33. 982. Araki I, Kitahara M, Oida T, Kuno S. Voiding dysfunction and Parkinson’s disease: Urodynamic abnormalities and urinary symptoms. J Urol 2000; 164: 1640–3. 983. Lazzeri M, Beneforti P, Benaim G et al. Vesical dysfunction in systemic sclerosis. J Urol 1995; 153: 1184–7. 984. Chancellor MB, Chartier-Kastler EJ. Principles of sacral nerve stimulation (SNS) for the treatment of bladder and urethral sphincter dysfunctions. Neuromodulation 2000; 3: 16–26. 985. de Groat WC. Nervous control of the urinary bladder of the cat. Brain Res 1975; 87: 201–11. 986. de Groat WC. Changes in the organization of the micturition reflex pathway of the cat after transection of the spinal cord. In: Veraa RP, Grafstein B, eds. Cellular mechanisms for recovery from nervous systems injury: A conference report. Exp Neurol 1981; 71: 22. 987. Tanagho EA, Schmidt RA. Electrical stimulation in the clinical management of the neurogenic bladder. J Urol 1988; 140: 1331–9. 988. Jonas U, Fowler CJ, Chancellor MB et al. Efficacy of sacral nerve stimulation for urinary retention: Results 18 months after implantation. J Urol 2001; 165: 15–19. 989. Heine JP, Schmidt RA, Tanagho EA. Intraspinal sacral root stimulation for controlled micturition. Invest Urol 1977; 15: 78–82. 990. Crocker M, Doleys DM, Dolce JJ. Transcutaneous electrical nerve stimulation in urinary retention. South Med J 1985; 78: 1515–16. 991. Huard J, Acsadi G, Jani A et al. Gene transfer into skeletal muscles by isogenic myoblasts. Hum Gene Ther 1994; 5: 949–58. 992. Schindhelm K, Nordon R. Ex vivo Cell Therapy. San Diego, CA: Academic Press, 1999: 1–4. 993. Lee JY, Qu-Petersen Z, Cao B et al. Clonal isolation of musclederived cells capable of enhancing muscle regeneration and bone healing. J Cell Biol 2000; 150(5): 1085–100. 994. Campion DR. The muscle satellite cell: A review. Int Rev Cytol 1984; 87: 225.

Pathophysiology of detrusor underactivity/acontractile detrusor 995. Rando TO, Blau HM. Primary mouse myoblast purification, characterization, and transplantation for cell-mediated gene therapy. J Cell Biol 1994; 125: 1275–87. 996. Qu Z, Balkir L, van Deutekom JC et al. Development of approaches to improve cell survival in myoblast transfer therapy. J Cell Biol 1998; 142: 1257. 997. Yokoyama T, Huard J, Yoshimura N et al. Muscle derived cells transplantation and differentiation into the lower urinary tract smooth muscle. Urology 2001; 57: 826–31. 998. Dhawan J, Pan LC, Pavlath GK et al. Systemic delivery of human growth hormone by injection of genetically engineered myoblasts. Science 1991; 254: 1509. 999. Dai Y, Schwarz EM, Gu D et al. Cellular and humoral immune responses to adenoviral vectors containing factor IX gene: Tolerization of factor IX and vector antigens allow for long-term expression. Proc Natl Acad Sci USA 1995; 92: 1401. 1000. Jiao S, Guerich V, Wolffe JA. Long-term correction of rat model of Parkinson’s disease by gene therapy. Nature 1993; 362: 450.

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1001. Chancellor MB, Yokoyama T, Tirney S et al. Preliminary results of myoblast injection into the urethra and bladder wall: A possible method for the treatment of stress urinary incontinence and impaired detrusor contractility. Neurourol Urodyn 2000; 19: 279–87. 1002. Yokoyama T, Dhir R, Qu Z et al. Persistence and survival of autologous muscle derived cells versus bovine collagen as possible treatment of stress urinary incontinence. J Urol 2001; 165: 271–6. 1003. Lee JY, Cannon TW, Pruchnic R et al. The effects of periurethral muscle-derived stem cell injection on leak point pressure in a rat model of stress urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct 2003; 14(1): 31–7. 1004. Cannon TW, Lee JY, Somogyi G et al. Improved sphincter contractility after allogenic muscle-derived progenitor cell injection into the denervated rat urethra. Urology 2003; 62(5): 958–63. 1005. Kwon D, Kim Y, Pruchnic R et al. Periurethral cellular injection: Comparison of muscle-derived progenitor cells and fibroblasts with regard to efficacy and tissue contractility in an animal model of stress urinary incontinence. Urology 2006; 68(2): 449–54.

9 Pathophysiology of the low-compliant bladder Véronique Phé, Emmanuel Chartier-Kastler, Jean-Marc Soler, and Pierre Denys

Definition and physiology Bladder compliance is defined by the ratio of the increase in intravesical pressure over the increase in bladder volume (ΔV/ΔP). It reflects the capacity of the detrusor to allow bladder filling at low pressure to maintain the functional properties of the urinary system and to avoid deterioration of these properties (vesicorenal reflux, deterioration of the bladder wall, incontinence). It is dependent on both the physical reservoir qualities and the qualitative and quantitative innervation of the bladder (autonomic nervous system). The urodynamic definition of bladder compliance was proposed by the International Continence Society (ICS) and its various clinical study reports.1 The individual definition of compliance has been shown to vary as a function of bladder volume at the time of measurement, the filling rate,2,3 the technique used to measure compliance,4 repetition of urodynamic investigations,5 and filling conditions (physiological vs. artificial).6 The detrusor is normally composed of 70% elastic tissue, consisting of smooth muscle cells, and 30% viscous tissues, consisting of collagen fibers. Smooth muscle fibers behave like elastic elements, i.e., they are able to return to their initial state as soon as the stretching force is removed. Smooth muscle fiber lengthening is proportional to the tension applied (Hooke’s law: T [tension] = f [elastic module] × L [lengthening]). Collagen fibers present the property of being able to delay deformation in response to stretch. Linear viscosity is governed by Newton’s law, which states that the deformity of a fiber is directly proportional to the rate of tension. For more than 25 years, there has been an ongoing debate concerning whether bladder tone is determined by the passive properties of the bladder wall or by the autonomic nervous system. Figure 9.1 represents the physiological factors influencing bladder compliance. In this chapter, we see that arguments derived from clinical experience

of neurogenic bladder and its natural history, as well as our knowledge of detrusor innervation, now explain the important role of the nervous system in disorders of compliance. In 1994, in an editorial devoted to this subject, McGuire7 summarized the history of these concepts. The interaction between reflex detrusor contraction and failure of sphincter opening mechanisms inevitably leads to the appearance of disorders of compliance. Introduction of self-catheterization to the management of neurogenic bladder, in which there is no longer any detrusor– sphincter synergy, has demonstrated the positive effect on improvement of bladder compliance. An increase in intravesical pressure, for whatever reason, is universally accepted to be a major factor in disorders of compliance. Various diseases can be responsible for increased intra­ vesical pressure, including myelomeningocele, spinal cord injury, multiple sclerosis, obstructive uropathy, benign prostatic hyperplasia, and radiotherapy-induced lesions. All of the treatments proposed below are designed to decrease intravesical pressures, as clinical practice has demonstrated the major role of raised intravesical pressure in deterioration of the upper tract and the appearance of voiding disorders with severe repercussions on quality of life. Indeed, a decrease in the bladder compliance is known to be correlated with deterioration of renal function.8,9

Natural history of compliance in neurogenic bladder: Prognostic factors related to the mode of drainage and to the etiologic disease Clinical practice provides pathophysiological information about disorders of compliance in neurogenic bladder.

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Reservoir properties

Autonomous nervous system - Qualitative innervation - Quantitative innervation

Elasticity

Viscosity

70% elastic tissue: Smooth muscle cells

30% viscous tissue: Collagen fibers

Bladder compliance

Measurement Depends on:

Bladder volume Filling rate Technique used Filling conditions Repeated investigations

Figure 9.1 Physiological factors responsible for bladder compliance.

Mode of drainage A review of large cohorts analyzed according to the level of the spinal cord lesion and the treatment used demonstrates a correlation between high intravesical pressure and disorders of compliance. In a series of 316 patients, Weld et al.10 showed that patients treated by self-catheterization had a significantly higher incidence of normal bladder compliance than those with indwelling catheter, regardless of the level of the lesion. With a follow-up ranging between 16 and 20 years, 75% patients treated by self-catheterization had normal compliance (>12.5 cc/ cm H2O) versus 20% patients with an indwelling catheter and 60% patients with reflex voiding. The rate of clinical complications was also proportional to the state of compliance.

Level of lesion The level of the lesion also influences the incidence of lowcompliant bladder, which is less frequent in the case of a suprasacral versus sacral lesion, or an incomplete versus complete lesion. These data were confirmed by other cohort studies.11–14 Particular attention must be paid to cauda equina lesions, which may be associated with low compliance in up to 55% of cases,15 representing a major threat for the upper urinary tract and requiring strict surveillance and screening. More recently, Beric and Light16 emphasized the need

to clearly distinguish between cauda equina lesions and conus lesions, especially by neurological or electrophysiological examinations. Pure conus lesions without detrusor areflexia may present various abnormalities of compliance in urodynamic studies (five patients), including decreased compliance with a high risk of functional impairment. This finding has also been reported by Shin et al.17

Particular case of myelomeningocele Myelomeningocele must also be considered separately. Although the extent of the neurological lesions can vary considerably, 40%–48%18 patients develop upper urinary tract lesions over a period of 7 years. A correlation has been shown between the level of the malformation, as 57% patients present upper urinary tract dilatation in the case of thoracolumbar lesion and 90% in the case of thoracic lesion. This is particularly true during early childhood, while puberty and growth period constitute the second high-risk period for the appearance of a major compliance disorder, even despite the well-conducted treatment, especially self-catheterization. Boys are more particularly concerned (65%) and the presence of a tethered spinal cord, destabilized by growth, must be detected and treated if necessary, but this does not always prevent the risk of deterioration of probably acquired low bladder compliance. This problem must be carefully assessed

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before treatment of sphincter incompetence, especially by artificial urinary sphincter. De Badiola et al.19 demonstrated the importance of precise preoperative assessment of compliance, which, when abnormal (100 ml was noted in 3. Decreased urinary flow was noted in all of the five patients who underwent flowmetry. DO was revealed in five of the seven patients undergoing EMG cystometry: a low compliance detrusor in two (storage phase), an underactive detrusor in four, an acontractile detrusor in one, and detrusor–sphincter dyssynergia in one (voiding phase). Bethanechol supersensitivity of the bladder was noted in two  patients with low-compliance detrusor. Neurogenic changes were revealed in two of the three patients undergoing motor unit potential analysis. These peripheral features may need differential diagnosis from multiple system atrophy. Sphincter EMG also revealed uninhibited sphincter relaxation (USR) in the patients. When USR occurs together with DO, incontinence becomes more prominent, which is thought to be a feature of cerebral diseases. The pathology of Alzheimer’s disease involves the medial frontal lobe, which receives various inputs from another brain area. Of particular importance is the cholinergic pathway that originates from the nucleus basalis­ of Meynert (Ch4  cell group). In experimental studies, lesions in this small nucleus give rise to DO, suggesting cortical cholinergic neurons have an inhibitory role in the micturition reflex.66 Sakakibara et  al.67 examined

Dementia and lower urinary tract dysfunction 19 patients with multi-infarct dementia. All of them had nocturnal f­requency and urgency, and 70% had urinary incontinence of the urgency and stress types. Urodynamic studies revealed DO in 70% and a low-­compliance curve in 10%. Sakakibara et al.21 urodynamically studied 22 elderly s­ubjects with white matter multi-­infarction and 11 subjects without. DO was significantly more prevalent

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in those with white matter lesions (82%) than in those with normal MRI (9%). Although the difference was not statistically significant, USR was more common in subjects with white matter lesions. Thus, according to these reports, DO contributes to urinary frequency and urgency incontinence more in multi-infarct dementia than in Alzheimer’s disease.

Detrusor overactivity after forebrain lesion Forebrain Disinhibition

D1 dopaminergic ACh

Increased facilitation D2 dopaminerg NMDA

Brainstem (PAG, PMC)

Aδ fiber

Spinal afferent

Spinal efferent

Bladder de Groat 2006 Yokoyama 2005

Spinal ganglia

Micturition circuit preserved & facilitated

(a)

PET H215O-PET

Urinary storage in normal volunteers Thalamus

Anterior Cingulate

SMA

PAG Prefrontal Cortex

Insula

Pons

Cerebellum

(b)

Figure 16.9 Neural mechanism of overactive bladder. (a) Micturitional reflex circuit is preserved in brain disease. Mainly disinhibition of this circuit by frontal/basal ganglia disease leads to facilitation of the reflex. (b) Brain areas activated by urinary storage in normal volunteers. (From Kavia, RBC et al., J Comp Neurol, 493, 27–32, 2005.) (Continued)

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Low activation of Parkinson’s brain when urinary+: [123I]-2β-carbomethoxy-3β-(4-iodophenyl) tropane (β-CIT) SPECT βCIT

PD n = 11

9

Dopamine transporter imaging: visualizing dopamine neuronal terminal

p < 0.01

p < 0.05

p < 0.05

8 7 6

Urinary dysfunction No

Yes

5 4 Decreased accumulation in post. Putamen in PD

3 2 1

Basal ganglia

0

RCD u- RCD u+ Caudate head

RAP u- RAP u+ Ant. putamen

RPP u- RPP u+ Post. putamen

(c)

Figure 16.9 (Continued) (c) Marked depletion of basal ganglia activity in parkinsonian brain when urinary dysfunction was present. (From Sakakibara, R et al., J Neurol Sci, 187, 55–9, 2001.)

Bladder underactivity Resnick and Yalla68 reported that a subgroup of incontinent elderly individuals with DO, most of whom were women, had bladder underactivity that led to post-micturition residuals (PMR) with an average volume of 95 mL; they called this detrusor hyperactivity with impaired contractile function (DHIC). Although Eastwood and Lord69 were not able to replicate these findings, Elbadawi et al.70 found that patients with DHIC could be differentiated from those with DO and normal contractility on the basis of the detrusor ultrastructure. Another important finding by Resnick and Yalla68 was that sphincter EMG of patients with DHIC did not show detrusor–sphincter dyssynergia. We performed pressure-flow analysis in eight patients with Alzheimer’s disease who had neither PMR nor d ­ etrusor–sphincter dyssynergia. However, the mean voiding pressure of the patients was 54 cmH2 O (range 20–101 cmH2 O), and 5 of the 8 had weak detrusor. Sakakibara et al.21 also found that persons with multiinfarction were more likely to have PMR with an average ­volume of 93 mL than those without (50% vs. 9%, respectively). Correctly diagnosing the impaired contractility

group with urodynamic testing is of therapeutic importance, because such patients may be at risk of acute urinary retention if anticholinergic medication is given.68 Kuwabara et al.71 studied PMR volumes by portable echography (BV5000) in 82 institutionalized dementia patients; 45 had Alzheimer’s disease, 19 had multi-infarct dementia, 5 had normal pressure hydrocephalus, 2 had Pick’s disease, and 11 had other causes. Eighty-three percent of the patients had urinary urgency or incontinence. They found PMR >100 mL in 6 patients (8%), consisting of Alzheimer’s disease in 5 and multi-infarct dementia in 1. However, the cause of the high PMR in those patients was assumed to be drug induced in one, prostate hypertrophy in one, frontal lobectomy for preexisting schizophrenia in one, and unknown in two. DHIC is recognized in various brain diseases (parkinsonian syndrome, Alzheimer’s disease, etc.) and spinal cord diseases (cervical spondylotic myelopathy, etc.).72 However, the exact pathophysiology of DHIC is still uncertain. In brain diseases, one explanation is that two separate brain areas (the facilitatory and inhibitory brain sites for micturition) might be involved that lead to DHIC. In contrast, in spinal cord lesions, a single partial lesion in the spinal autonomic pathways could cause DHIC, since it disrupts the

Dementia and lower urinary tract dysfunction spino-bulbo-spinal micturition reflex arc, and could cause the emergence of a C-fiber-mediated novel sacral micturition reflex arc below the lesion.54,55 In the clinical context, the prevalence of a combination of multiple diseases, such as multiple cerebral infarction and diabetic neuropathy, or cervical and lumbar spondylotic radiculopathy, seems to be high. These combinations can lead to DHIC by lesions in the central (mostly inhibitory) and peripheral (facilitatory) nervous systems. Among comorbid conditions, ­lumbar spondylosis and diabetic polyneuropathy are common in the elderly. Examination of the lower extremities for sensation and deep tendon reflexes may provide clues to suspect these disorders. These issues are particularly problematic in patients who have undergone prostate hypertrophy for large PMR or retention since impaired detrusor contractility during voiding is a significant factor that may lead to an unsuccessful surgical outcome.68

Stress urinary incontinence It is important to evaluate patients for comorbid stress incontinence since it is a very common condition due to pelvic floor weakness in older women and is potentially treatable. In an older incontinent population, Payne73 found that half of the patients suffered from pure stress incontinence, 10%–20% had pure urge incontinence, and the remaining patients had both. Resnick et al.60 noted that a significant proportion of women with dementia also had stress urinary incontinence. Although the reliability of stress incontinence diagnoses decreased as the severity of dementia increased, 80% of those with MMSE scores of 10–23 and 66% of those with scores of 9 or lower were still able to perform a stress maneuver.

Nocturnal polyuria Nocturnal polyuria is a common reason for nocturia in the elderly and is potentially treatable. Nocturnal polyuria in older individuals seems to be multifactorial. It may result from congestive heart failure or liver cirrhosis, but may also have a cerebral etiology. Cerebrovascular disease may cause nocturnal polyuria, particularly when it involves the hypothalamic region that contains arginine vasopressin (AVP) neurons. We had such patients; they lost the circadian rhythm of plasma AVP that normally rises at night. Diabetes is also a common cause of polyuria.

Drug-induced incontinence and retention Drugs that may affect either the central nervous system (CNS) or the LUT are potential cause of transient incontinence. In a study of 84 elderly, incontinent, female nursing home residents, Keister and Creason74 found that 70% of subjects were taking a drug that could potentially cause

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incontinence. Antipsychotic medications, antidepressants, benzodiazepines, and sedatives are frequently used to treat agitation, insomnia, and depression, and may cause incontinence through increased confusion, sedation, ­ parkinsonism, and immobility. Urinary retention and ­ overflow may result from the anticholinergic side effects of tricyclic antidepressants and antipsychotic medications.

Management In general, management for LUT dysfunction in dementia patients needs to be individualized, and the risk/benefit ratio of these procedures, particularly invasive or irreversible treatments, needs to be carefully considered.

Treatment of transient causes The first step in management is to identify and treat transient acute causes of incontinence. Acute causes may be recalled from the mnemonic “DIAPPERS” ­(delirium, infection, atrophic vaginitis, pharmaceuticals, psychological factors, endocrine conditions, restricted mobility, stool impaction).75 Some factors are derived from the dementing illness, but others are from comorbid medical conditions, inappropriate environment, and medication. There are also interrelationships among these factors. An elderly patient’s delirium may be secondary to, for example, a pharmacological or infectious outcome.

Toileting/behavioral therapy Toileting regimens (behavioral therapy) have been used to manage functional incontinence in elderly individuals. Patients with decreased motivation, cognitive disability, and gait disorder are highly likely to be incontinent. With prompted voiding, patients who have decreased motivation are asked on a regular schedule if they need toileting assistance, but are given such assistance only if they request it. Prompted voiding is usually combined with positive reinforcement, in the form of praise, for making appropriate toileting requests and for keeping themselves dry. On most occasions, patients require physical assistance with toileting because of comorbid gait disorder and cognitive disability. According to Skelly and Flint,76 who carefully reviewed seven studies, patients were dry 64% of the time at baseline on average when they were checked every 1–2 hours during waking hours. After treatment, this figure rose to 76%. This translated into a 32% mean relative reduction in wet episodes. A better response to the treatment was obtained in less demented patients, i.e., those who could recognize the need to void and who experienced incontinence fewer than 4 episodes per 12-hour period. As expected, normal bladder function also predicted better response. With scheduled toileting, patients who had little or no motivation were toileted on a regular schedule

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(fixed schedule), usually every 2 hours, or on a schedule that matched the patient’s own voiding pattern (individualized schedule). Ouslander et al.77 examined the effects of a fixed, 2-hourly toileting schedule on 15 cognitively impaired patients with DO, of whom 53% needed physical assistance. Toileting significantly reduced the incidence of incontinence, from 43% to 32%. Flint and Skelly78 reported that 55% ambulatory dementia patients became dry or had a significant improvement in incontinence with a t­ oileting schedule. However, Jirovec79 reported that 6  weeks of scheduled toileting did not improve incontinence in a group of demented and dependent nursing home residents, although poor staff compliance with the toileting program contributed to the negative outcome. The results suggest that more severely demented and less mobile individuals with bladder abnormalities are the least likely to benefit from toileting programs. Cost/benefit studies have indicated that the labor costs of toileting programs may be higher than the savings in laundry costs to the nursing home.80 However, carefully selecting patients who can most benefit from toileting regimens is one possible way of reducing conflict between the cost and dryness. Environmental settings are also important for man­ aging functional incontinence. Chanfreau-Rona et al.81 assessed whether enhanced visual cues, such as painting the toilet doors bright orange and displaying large ­pictures of a lady sitting on a toilet, would have an impact on incontinence in severely demented women in a psychogeriatric ward. However, when environmental changes were the only treatment intervention, incontinence did not improve. Nevertheless, recommended toilet settings may include mobility aids such as hallway handrails, canes, walkers, and wheelchairs; easy toilet access and visibility; improvements to toilet facilities such as better lighting, grab bars, and toilet seat height; automatic washing devices for the buttocks and lift-up commodes; and, finally, well-designed clothes to make disrobing easier. Also, to maximize continence, alternatives to physical restraints need to be sought.

Medication Cognitive impairment and decreased motivation Although the etiology of Alzheimer’s disease remains uncertain, the cognitive deficits in Alzheimer’s disease patients are thought to be due, at least in part, to a decrease in cholinergic innervation of the cerebral cortex and basal forebrain. The loss of cholinergic nerve terminals in Alzheimer’s disease is detected in vivo by PET using acetylcholinesterase (AChE) activities.87 Central cholinergic agents are widely used in the treatment of cognitive decline in Alzheimer’s disease. There are several central cholinomimetic agents, including donepezil hydrochloride and rivastigmine, both of which are central AChE inhibitors

that decrease degradation of acetylcholine, thus increasing the concentration of acetylcholine in the synaptic cleft. These agents inhibit AChE selectively in the brain,82 and this action reverses cognitive decline in ­mild-to-moderate Alzheimer’s disease patients for at least 6–12 months.83 Clinicians must be aware that these agents may cause adverse gastrointestinal effects as peripheral nervous system (PNS) effects. As mentioned earlier, a subgroup of Alzheimer’s disease patients have urge incontinence and DO even at an early stage. Hashimoto et al.84 reported that 7% patients taking 5 mg/day of donepezil showed urinary incontinence as a potential initial adverse effect. However, we recently showed that donepezil could ameliorate cognitive function without serious adverse effects on the LUT function in patients with Alzheimer’s disease.85 In regards to changes in urodynamic parameters, DO appeared to be augmented after donepezil treatment, which is reasonably attributed to the PNS effects as seen with other cholinergic drugs. However, our patients with Alzheimer’s disease showed a slight increase in bladder capacity, which cannot be explained by PNS effects alone. Although it is unknown to what extent the central cholinergic circuit may participate in the regulation of micturition, recent experimental studies showed that lesions in the nucleus basalis of Meynert in the basal forebrain (central cholinergic nucleus projecting fibers to the frontoparietal cortex) lead to decreased bladder capacity.86 In addition, improved cognitive status and alertness may well give the patient sufficient initiative to hold urine. Therefore central AChE inhibitors, including donepezil hydrochloride, may have complex effects on the LUT function (Figure 16.10a). Cognitive impairment in patients with DLB also responded well to central cholinergic agents.27 In patients with mild-to-moderate dementia, decreased motivation can be treated with 200–300 mg/day of amantadine hydrochloride. However, it has not been determined whether these drugs could improve patients’ disability scale scores in toileting and functional incontinence. Aniracetam is a pyrrolidinone derivative and is thought to facilitate cholinergic neurotransmission. In an open study of 52 senile poststroke patients, some of whom had dementia, Kumon et al.88 found that 600 mg/day of aniracetam improved urinary and fecal incontinence in 46% patients.

Gait disorder Gait disorder is a symptom of parkinsonian syndrome in multi-infarct dementia and DLB, but it also occurs mildly in Alzheimer’s disease. Although levodopa seems less effective in Alzheimer’s than in Parkinson’s disease, 200–300 mg/day (usually coupled with peripheral ­dopa-decarboxylase inhibitor) ameliorates gait disorder in dementia patients, and may be of benefit in treating functional incontinence. Levodopa is better prescribed in conjunction with rehabilitation programs, since Jirovec89

Dementia and lower urinary tract dysfunction

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Figure 16.10 Cholinergic neural pathways, cognition and bladder. (a) Effect of donepezil (central cholinergic drug) on the micturition function in Alzheimer’s disease. (b) Receptor binding of four cholinergics to hippocampus (pRO50) and human muascarine M3 receptors (pKiM). Oxibutynin has more binding to hippocampus as compared with propiverine, solifenacin and tolterodine. (c) Addition of propiverine (a peripheral anticholinergic) to donepezil (a central cholinesterase inhibitor) ameliorated OAB without worsening cognitive function in elderly OAB patients with dementia.

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found that, in cognitively impaired nursing home residents, a daily exercise program designed to improve walking significantly reduced daytime incontinence. Physicians should also be aware of the potential adverse effects of levodopa, such as postural hypotension and hallucinations. Although levodopa seems to ameliorate urinary urgency in early, untreated Parkinson’s disease patients,90,91 it may augment DO in a 1-hour time-window in early 92 or advanced Parkinson’s disease patients.93

Overactive bladder and detrusor overactivity Medications used to treat OAB and DO include anticholinergic agents such as propantheline, oxybutynin, and propiverine, tolterodine, darifenacin, trospiumn and smooth muscle relaxants such as flavoxate. Mori et al.63 performed urodynamic studies in 46 dementia patients, and found DO in 58% Alzheimer’s patients and 91% multi-infarct dementia patients. They conducted an open trial with 20 mg/day of propiverine hydrochloride for 2 weeks irrespective of the presence of DO, and found increased bladder capacity or lessened frequency of incontinence in 40% patients. Both types of dementia groups responded almost equally, and patients with DO showed more satisfactory response. Tobin and Brocklehurst94 used a combination of propantheline bromide (15 mg/day) and flavoxate hydrochloride (200 mg/day) to treat urinary incontinence in a cognitively impaired nursing home population, of whom 95% were clinically diagnosed with OAB. There was a significant reduction in nocturnal but not daytime incontinence compared with controls. Burgio et al.95 found that, in 197 cognitively intact elderly women with predominantly urge incontinence, either 7.5–15 mg/day of oxybutynin hydrochloride (68.5%) or behavioral treatment (80.7%) was more effective than placebo (39.4%) in randomized controlled trials. However, in dementia patients with DO, Zorzitto et al.96 found that 15 mg/day of propantheline was no more effective than placebo. When the dose of propantheline was increased to 30 mg, there was a statistically significant improvement, but the clinical benefit was outweighed by the presence of adverse effects in 50% subjects. Although DO seems to be the cause of OAB-wet in those patients, the study’s negative findings contrast with the reported efficacy of anticholinergic medications in approximately 50% cognitively intact, independently mobile older outpatients with incontinence. Therefore, treatment for OAB/ DO may be of benefit only in ­mild-to-moderate dementia without marked immobility. The use of medications with anticholinergic side effects in older persons is a concern, particularly when there is a risk of exacerbating cognitive impairment. After they are ingested and absorbed from the intestine, anticholinergic drugs are systemically circulated. If they cross the blood– brain barrier (BBB), they reach the CNS and block cholinergic receptors, particularly M1-muscarinic receptors in

the cerebral cortex, or M4 receptors in the basal ganglia. Previous data suggested that a centrally acting anticholinergic, trihexyphenidyl (for ameliorating Parkinson’s disease), exacerbated cognitive function in experimental animals and humans. The same was reported for atropine (before endoscopy/surgery) and scopolamine (hyoscine) (for colicky pain or motion sickness). Although oxybutynin has been developed as a peripherally acting drug, recent research suggests that it has some adverse effects on cognitive function.97 To a much lesser extent, tolterodine98 also affect cognitive function99,100 (Figure 16.10b). Factors underlying the cognitive effects of these medications include (1) central muscarinic receptor affinity, e.g., high M1-receptor selectivity and (2) easy penetration of the BBB, e.g., high lipid solubility (water vs. oil partition coefficient [LogP] once a month

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(b)

Figure 18.1 Urinary symptoms in patients with multiple system atrophy (MSA) compared to age-matched controls estimated by questionnaire. (a) Storage symptoms and (b) voiding symptoms. Both storage and voiding symptoms in patients with MSA were significantly worse than age-matched controls. They had a significantly higher prevalence of voiding symptoms, particularly, retardation in initiating ­urination (hesitancy) than the controls. (From Yamamoto, T et al., Mov Disord, 24, 972–8, 2009.)

significantly higher prevalence of daytime frequency (45% of women, 43% of men), nighttime frequency (65%  of women, 69% of men), urinary urgency (64% of men), urgency incontinence (75% of women, 66% of men) than did the controls. Symptom of urinary urgency/frequency is also referred to as overactive bladder (OAB).12 They also had more hesitancy of micturition (62% of women, 73% of men), prolonged, poor (71%  of women, 81% of men), or intermittent stream (61% of women, 47% of men), or the need to strain to void (48% of women, 55% of men). Of particular importance is that the quality of life (QOL) index in MSA group was significantly higher (i.e., worse)

in MSA patients for bladder dysfunction (70% of women, 76% of men) than that in controls. Many of them show large postvoid residual (PVR) urine volume > 100 mL. Therefore, both OAB and large PVR are common in MSA.

Urinary dysfunction precedes postural hypotension Of various symptoms of AF (erectile dysfunction, urinary dysfunction, postural hypotension, and respiratory stridor) in patients with MSA, urinary dysfunction

Urinary dysfunction in multiple system atrophy has attracted less attention than postural hypotension, although urinary dysfunction may result in recurrent urinary tract infection and cause morbidity. In addition, urinary incontinence results in impaired self-esteem, stress on the caregiver, and considerable financial cost. Postural hypotension was pointed out first in AF-MSA, which turned out to be a marker of autonomic involvement in this disorder. Both of the original two patients discussed by Shy and Drager had urinary frequency, incontinence, and urinary retention.4 Other variants (MSA-P and MSA-C) rarely develop postural hypotension in their ­ early stage. However, in the original reports, three of four patients with MSA-P showed voiding difficulty, retention, and urinary incontinence,2 and both patients with MSA-C had voiding difficulty and urinary incontinence.3 Thus, what are the most common and earliest autonomic features of MSA? In our previous study of 121 patients with MSA,13 urinary symptoms (96%) were more common than orthostatic symptoms (43%) (p < .01) (Figure 18.2). The most

frequent urinary symptom was difficulty voiding in 79% of the patients, followed by nocturnal urinary frequency in 74%. Other symptoms included sensation of urgency in 63%, urgency incontinence in 63%, diurnal urinary frequency in 45%, nocturnal enuresis in 19%, and urinary retention in 8%. The most frequent orthostatic symptom was postural faintness in 43%, followed by blurred vision in 38% and syncope in 19%. These figures are similar to those of Wenning et al.,14 who noted urinary incontinence in 71%, urinary retention in 27%, postural faintness in 53%, and syncope in 15% of 100 patients with MSA; these figures were recently confirmed by a larger study.15 In our previous study mentioned earlier, among 53 patients with both urinary and orthostatic symptoms, those who had urinary symptoms first (48%) were more common than those who had orthostatic symptoms first (29%), and some patients developed both symptoms simultaneously (23%).13 These findings indicate that urinary dysfunction is a more common and often earlier manifestation than

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Figure 18.2 Urinary dysfunction and postural hypotension in multiple system atrophy (MSA). (From Sakakibara, R et al., J Neurol Neurosurg Psychiatry, 68, 65–9, 2000.)

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Textbook of the Neurogenic Bladder Urinary and orthostatic symptoms in MSA

11 10 9

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Erectile dysfunction

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Figure 18.3

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Autonomic and motor disorders in multiple system atrophy (MSA). Left bar indicates an interval (years) between the first-, second-, and third-­appearing symptoms. Right horizontal line indicates each case (no. of the case). The majority of patients presented with urinary dysfunction (square) first, followed by orthostatic hypotension (triangle) and/or gait disturbance (circle). Erectile dysfunction (swoosh) may appear together with urinary dysfunction.

postural hypotension in MSA. Many factors might be involved in this phenomenon. Reports of focal lesions have shown that postural hypotension occurs in lesions below the medulla, whereas urinary dysfunction occurs in lesions at any sites in the neuraxis. MSA lesions involve the pons, hypothalamus, and basal ganglia, all of which might affect the lower urinary tract function as described earlier.

on “Parkinson’s disease and the bladder” might inadvertently include patients with MSA. The prevalence rate of urinary dysfunction in MSA is higher than the 58%–71% rate reported in IPD13,17–19; similarly, the rate of urgency incontinence in MSA is higher than the 33% rate reported in IPD. In addition, urinary dysfunction is never the initial presentation in IPD.

Urinary dysfunction also precedes motor disorder

Videourodynamic and sphincter electromyography assessments

Looking at both urinary and motor disorders, we see that approximately 60% of patients with MSA develop urinary symptoms either prior to or at the time of presentation with the motor disorder12,13 (Figure 18.3). This indicates that many of these patients seek urological advice early in the course of their disease. Because the severity of urinary symptoms is severe enough for surgical intervention, male patients with MSA may undergo urological surgery for prostatic outflow obstruction before the correct diagnosis has been made. The results of such surgery are often transient or unfavorable because of the progressive nature of this disease. Male erectile dysfunction is often the first presentation,12,13,16 possibly preceding the occurrence of urinary dysfunction in MSA. The urologist confronted with a patient showing these features should be cautious about embarking on an operative approach. The neurologist encountering a patient with marked urinary symptoms might consider future investigation by brain magnetic resonance imaging (MRI) and sphincter EMG. Since motor disorders in MSA mostly mimic those in IPD, the urogenital distinction between these two diseases is worth considering, although a number of earlier studies

Since MSA is a neurodegenerative disease that affects multiple brain regions, patients with the disease may have a wide range of urodynamic abnormalities that change with progression of the illness. Videourodynamics and sphincter EMG also enable us to assess the lumbosacral cord functions, which help us distinguish MSA from other parkinsonian disorders.

Bladder overactivity Filling phase abnormalities included bladder overactivity in 33%–100% and uninhibited external sphincter relaxation in 33% of MSA,12,19–21 figures similar to those reported in IPD10,12–16 (Figure 18.4). Bladder overactivity is urodynamically defined as an involuntary phasic increase in detrusor pressure (naïve bladder pressure— abdominal pressure) >10 cm⋅H2O during bladder filling, which is commonly associated with decreased bladder volumes at first sensation and bladder capacity. It is bladder overactivity that seems to be the major cause of urgency incontinence in patients with MSA. But when

Urinary dysfunction in multiple system atrophy

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coupled with uninhibited sphincter relaxation, incontinence may worsen (Figure 18.4).22 It is well known that cerebral diseases can lead to a loss of the brain’s inhibitory influence on the ­spino-bulbospinal micturition reflex. The information that arises from the lower urinary tract reaches the periaqueductal gray ­matter (PAG), then goes down to the pontine micturition ­center (PMC), an area identical or just adjacent to the locus c­ eruleus, which then activates the descending pathway to the sacral preganglionic neurons innervating the bladder.23 The basal ganglia are thought to be one of the higher centers for micturition, since lesions of this area lead to bladder overactivity.24–27 Recent positron emission tomography (PET) studies have shown that the hypothalamus, PAG, midline pons, and cingulate cortex are activated during urinary filling.28,29 The central pathology of MSA includes neuronal loss of neuromelanin-containing cells in the locus ceruleus30,31 as well as in the nigrostriatal dopaminergic system (putaminal slit sign)6,27 and cerebellum, and to a lesser extent in the ponto-medullary raphe (pontine cross sign)6,32 and the frontal cortex.33,34 Recent experimental studies have suggested that the raphe modulates micturition function.35 Experimental studies have also suggested that the cerebellum controls micturition function.36 A single-photon emission computed tomography (SPECT) study has shown that in the urinary storage and micturition phases, but not in the resting phase, activation of the cerebellar vermis was significantly lower in MSA patients than in control subjects (Figure 18.5).37 These areas seem to be responsible for the occurrence of bladder overactivity and uninhibited sphincter relaxation in MSA patients.

Redraw

6

Figure 18.4 Bladder overactivity.

Bladder underactivity and detrusor-sphincter dyssynergia Incomplete bladder emptying is a significant feature in MSA. In fact, 47% of patients with MSA had PVR > 100 mL, whereas no patients with IPD had such ­levels (p 40 means outflow obstruction in men.39 The mean AG numbers were smaller in patients with MSA (12 in women, 28 in men) than in those with IPD (40 in women, 43 in men).19 However, a subset of patients with MSA may have an obstructive pattern, the reason for which is unknown. Detrusor–external sphincter dyssynergia is a factor contributing to neurogenic

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Mechanism of bladder overactivity

Radioactivity of ECD (% uptake)

Low activation of MSA brain in urinary storage and micturition: [99mTc]-L, L-ethyl cysteinate dimer (ECD)-SPECT 100

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urethral relaxation failure,41 which is noted in 47% of MSA patients.19,42 Therefore, it is likely that bladder underactivity accounts mostly for voiding difficulty and elevated PVR in MSA. A subset of patients with MSA has bladder overactivity during storage and underactivity during voiding (detrusor hyperactivity with impaired contractile function, DHIC).43 The exact mechanism of this phenomenon has yet to be ascertained. However, it

Figure 18.5 Reduced cerebellar vermis activation in urinary storage and micturition phases in multiple system atrophy (MSA). (From Sakakibara, R et al., Eur J Neurol 2004; 11: 705–8.)

has been recognized that the central mechanisms underlying bladder filling and voiding are distinct from each other; i.e., the area promoting micturition is located in the PMC and the frontal cortex, whereas that promoting urinary storage is in the pontine storage center, basal ganglia, raphe, and frontal cortex.23 Lesions in these areas may cause various combinations of urinary filling and voiding disorders, such as DHIC.

Urinary dysfunction in multiple system atrophy Disease Duration and Residual Urine Volume

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Figure 18.6 Incomplete bladder emptying in multiple system atrophy (MSA). (From Ito, T et al., Mov Disord, 21(6), 816–23, 2006.)

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Role of the sympathetic system Open bladder neck suggesting sympathetic denervation The bladder neck, also known as the internal (smooth) ­urethral sphincter, is a component in the maintenance of continence that is innervated by the sympathetic hypogastric nerve. Videourodynamic study is an established method for evaluating bladder neck function. It is a combination of visualizing the lower urinary tract

Redraw

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Figure 18.7 Open bladder neck.

simultaneously with EMG-cystometry; urethral pressure at the external urethral sphincter (EUS) can be obtained with visual guidance using a radiopaque marker. In normal subjects, the bladder neck is closed throughout filling so as to avoid leaking. However, an open bladder neck is found in 4­ 6%–100% of MSA patients and in 23%–31% of Parkinson’s disease (PD) patients, and an open bladder neck at the start of bladder filling, even without the accompaniment of bladder overactivity, was noted in no PD patients but in 53% of MSA patients (p < .01) (Figure 18.7).19 Because open bladder neck is common in patients

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with myelodysplasia or a lower thoracic cord lesion at T12–L2 (where sympathetic thoracolumbar intermediolateral [IML] nuclei are located) and is reproduced by systemic or intraurethral application of alpha1-adrenergic blockers,44 it is likely that an open bladder neck reflects the loss of sympathetic innervation. This seems to be one of the exceptions to primary preganglionic pathology in MSA. An open bladder neck is usually considered asymptomatic, but may cause incontinence and reduce bladder capacity.

Role of the somatic system Neurogenic changes in sphincter EMG suggesting somatic denervation A distinguishing pathology in MSA is neuronal cell loss in the Onuf’s nucleus, a group of anterior horn cells in the sacral spinal cord.6 The first reports on neurogenic changes of external anal sphincter (EAS)-EMG in MSA are attributed to Sakuta et al.45,51 Since then, EAS-EMG results for over 600 MSA patients have been reported, with abnormality rates of more than 70% in many studies.46,47 EAS-EMG is better tolerated and yields identical results to those from EUS investigation.48 Abnormalities have also been recorded in the bulbocavernosus muscles in MSA.58 Figure 18.8 shows the method of sphincter EMG in clinical practice. A particular importance is not to miss the late components.49 In our study of 84 probable MSA cases, 62% ­exhibited neurogenic change.50 The prevalence was relatively low presumably because up to 25% of our patients had a disease duration of 1 year or less. In such early cases, the diagnosis of MSA should be made with extreme caution. In addition to the clinical diagnostic criteria, we usually add an imaging study and we perform gene analysis to the extent possible. The prevalence of neurogenic change was 52% in the first year after disease onset, which increased to 83% by the fifth year (p < .05) (Figure 18.9a). Therefore, as expected, it is apparent that the involvement of Onuf’s nucleus in MSA is time dependent; and EAS-MUP abnormalities can distinguish MSA from IPD and other diseases in the first 5 years after disease onset. Receiver-operating characteristic analysis of sphincter EMG showed high diagnostic power in terms of the duration of motor unit potential (MUP) analysis (Figure 18.9b).47 In contrast, in the early stages of illness, the prevalence of neurogenic change in MSA does not seem to be high. In only two patients who underwent repeated studies, the EAS-EMG findings tended to remain normal. We do not know whether some MSA patients never develop neurogenic change during the course of their illness. However, Wenning et al.14 reported three patients with normal EASEMG and a postmortem confirmation of MSA. Therefore, a negative result cannot exclude a diagnosis of MSA. Paviour et al.51 reported that among 30 sets of clinical

data and postmortem confirmation in MSA cases with a duration of more than 5 years, 24 (80%) had abnormal EAS-EMG, 5 (17%) had a borderline result, and only 1 had a normal EMG. It has been reported that neurogenic change does not correlate directly with a clinically obvious functional deficit, although urinary incontinence was more severe in the patients with neurogenic change than in those without it (p < .05). The prevalence of neurogenic change also increased with the severity of gait disturbance (wheelchair bound) (p < .05) in our study.50 However, neurogenic change was not related to postural hypotension (reflecting adrenergic nerve dysfunction); erectile dysfunction in men (presumably reflecting cholinergic and nitrate oxidergic nerve dysfunction); detrusor overactivity (reflecting the central type of detrusor dysfunction); constipation (presumably reflecting both peripheral and central types of autonomic and somatic dysfunction); or gender.50 The neurogenic change in EAS-MUP was slightly more common in those with detrusor-sphincter dyssynergia (DSD). Recently, it is suggested that not only suprasacral pathology but also sacral/peripheral lesions can produce DSD.52 Although denervation can be found in the other skeletal muscles in MSA, it occurs much earlier in the external sphincter muscles.53 This is in clear contrast to the case in amyotrophic lateral sclerosis, where denervation occurs in most advanced cases (respirator bound).

Changes of bladder patterns Bladder patterns change from central to peripheral The sites responsible for cardiovascular AF in MSA are mostly central, in contrast to the peripheral lesions in PAF.10 However, 31%–45% of patients with MSA also had low-compliance detrusor, defined as a maximum bladder capacity/tonic detrusor pressure increase < P= 130 SI

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Figure 19.4 Detrusor hyperreflexia without bladder outlet obstruction.

testing, emphasizing the need for periodically repeating urodynamic studies, even in patients with persistent stable symptomatology.52,53

Management of urinary manifestations of multiple sclerosis The aim of treatment of the neurogenic patient is management of lower urinary tract symptoms, prevention of UTIs, preservation of the upper urinary tract, and improvement of the quality of life. The choice of treatment should be based on a clear understanding of the pathology and on objective parameters, as well as on the patient’s disability, autonomy, manual dexterity, and motivation. Since symptoms of MS can change over time due to its remission–exacerbation pattern, treatment modalities should preferably be reversible and permanent surgical procedures should be avoided as much as possible. Table 19.5 is a summary of the different therapeutic options.

Detrusor overactivity without bladder outlet obstruction Behavioral modifications and pelvic floor rehabilitation Voiding symptoms can often be improved by simple behavioral manipulations, but the success of voiding mostly relies on the patient’s motivation. Regular voiding may reduce hyperreflexic contraction by emptying the bladder before a critical state of filling is reached. Limitation of fluids may help prevent irritative symptoms, as well as avoidance of ­beverages such as coffee, tea, cola, and alcohol that  may cause  diuresis or irritation of the bladder.54 Although ­behavioral modification is a conservative treatment modality, objective evaluation should not be overlooked. Empirical treatment trials without proper evaluation should be avoided, as it may lead to improper care and complications.11 Suppression of an involuntary detrusor contraction by stimulation of the perineal musculature is the physiologic principle underlying pelvic floor rehabilitation. This modality has already been part of the treatment of many problems, such as stress incontinence, urgency,

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Figure 19.5 Detrusor hyperreflexia with bladder outlet obstruction.

sexual dysfunction, and fecal incontinence. Pelvic floor rehabilitation has been reported to be of some value in the treatment of detrusor instability and urgency by influencing the sacral micturition reflex arc and thus inhibiting detrusor overactivity. De Ridder et al.55 have noted a subjective improvement in 76.7% of patients, with significant improvement in functional bladder capacity, frequency, and incontinence, as evaluated by urodynamic study.

with detrusor overactivity should be considered only after all the treatment options have been evaluated since indwelling catheters have been associated with multiple problems such as urethral erosion in males, bladder neck and urethral damage in females, and UTIs.56 Use of antibiotic prophylaxis to prevent symptomatic infections has limited role in this setting and may lead to increased ­antimicrobial-resistant strains.

Clean intermittent catheterization and catheter drainage

Pharmacologic therapy

Clean intermittent catheterization (CIC) is a simple and very effective treatment modality for neurogenic voiding dysfunction, either in patients with primary emptying difficulties or after pharmacologic therapy in patients with detrusor overactivity.41,45 Urodynamic evaluation is required to define bladder storage capabilities and to select the optimum catheterization interval. Chronic catheter drainage after pharmacologic therapy in patients

Since almost two-thirds of patients with MS have detrusor overactivity, treatment often involves pharmacologic therapy to suppress uninhibited bladder contractions. Traditionally, oxybutynin chloride has been among the most widely used drugs. It binds competitively to the muscarinic receptor, thus suppressing bladder contractions. Response rates in MS patients have been reported in the range of 65%–80%.1 However, because of the anticholinergic profile of its side effects—namely, decreased salivation,

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86 100

pves 100

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39 33 43 35

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220 243 249 243 4:30 5:002495:30 6:00 249

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Figure 19.6 Detrusor hyperreflexia.

Table 19.5  Management options of multiple sclerosis patients based on urologic dysfunction Detrusor overactivity without bladder outlet obstruction: •• Behavioral modification and pelvic floor rehabilitation •• Clean intermittent catheterization/catheter drainage •• Pharmacologic therapy •• Surgical management −− Denervation procedures −− Augmentation cystoplasty •• Neuromodulation •• Botulinum toxin Detrusor overactivity with bladder outlet obstruction: •• Clean intermittent catheterization/catheter drainage •• External sphincterotomy •• Augmentation cystoplasty •• Ileal conduit •• Cutaneous ileovesicostomy •• Neuromodulation •• Botulinum toxin Hypocontractile detrusor: •• Clean intermittent catheterization/catheter drainage •• Credé’s maneuver (women) •• Urinary diversion

C. Vol 1000 9:00

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constipation, and blurred vision—discontinuation of treatment was reported in as many as 50% of patients.55 Tolterodine, a potent antimuscarinic agent, was specifically developed for the treatment of the overactive bladder (OAB). It is a selective muscarinic receptor blocker with efficacy proven equivalent to oxybutynin but with a more favorable tolerability profile.57,58 In patients who tolerate these medicines, recent research indicates that additional benefit can be achieved (decreased incontinence episodes, increased cystometric capacity) by doubling the recommended dosages.59 In a prospective study of 30 patients suffering with MS, Rey and Heesakkers60 demonstrated that solifenacin significantly improved frequency, severity of urgency, volume voided, and number of pads used per 24 hours. Darifenacin has not been studied specifically in the MS population but remain potential treatment options due to its lack of cognitive impairment when compared to oxybutynin.61 A novel class of pharmacologic therapy targeting the human beta-3 adrenergic receptor (AR) was approved by U.S. Food and Drug Administration (FDA) in 2012 for the treatment of OAB. Mirabegron (Myrbetriq®) relaxes the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle by activation of beta-3 AR increasing bladder capacity and improving symptoms of OAB.62–64 The role mirabegron in the treatment paradigm of MS patients is yet to be defined. In certain patients with combined storage and emptying failure, CIC may be used in concert with anticholinergic therapy. In these patients, urinary retention is promoted by anticholinergics and the “paralyzed” bladder is hence drained by CIC. Experimental treatment with sublingually delivered cannabis extracts have also been demonstrated to alleviate urinary symptoms in MS patients.65 Urinary urgency, number and volume of incontinence episodes, frequency, and nocturia episodes all decreased in the cannabis extract group, and patients also reported decreased pain and spasticity with improved quality of sleep on the drug.65 This remains an area of future study. Intravesical instillation of oxybutynin is another treatment option for detrusor overactivity and is reported to alleviate side effects of oral medication.66,67 Capsaicin and resiniferatoxin, the newer intravesical agents, are thought to exert a selective neurotoxic action on axons of C sensory fibers. These fibers appear to play an important role in bladder reflex pathways following spinal cord insult. Intravesical capsaicin and resiniferatoxin are known to reduce the amplitude of hyperreflexic contractions and have been used in selective research centers for the treatment of intractable detrusor overactivity.68,69 Nocturia and enuresis are common problems in MS and the effect of sleep disturbance may be detrimental to the patient’s functional level. Desmopressin, a synthetic analogue of vasopressine, has been proven efficacious and safe in the management of these problems in that population.70,71

Surgical management The role of surgical intervention in the management of patients with neurogenic dysfunction secondary to MS has been dramatically reduced with the increased adoption of CIC. As a general guiding principle in the management of MS patients, nonoperative treatments should be utilized as long as possible. As the course of the disease is dynamic and progressive, permanent procedures should be performed only after stabilization of the neurologic status and after all other conservative options have been exhausted. Evaluation of manual dexterity, disability, life expectancy, and social support should be undertaken as well as a thorough urodynamic characterization of the neurogenic voiding dysfunction. Denervation procedures of the bladder have been reported for the treatment of detrusor overactivity and include selective dorsal rhizotomy, subtrigonal injection of phenol or alcohol, and bladder myotomy and transection. These techniques, although displaying good short-term results, have not proven to produce satisfactory long-term effects.72 Augmentation cystoplasty with or without a catheterizable limb (using the ileocecal valve or intussuscepted portion of the small bowel) is usually reserved for the patient with refractory detrusor overactivity in whom all other nonoperative options have failed. Bladder augmentation will allow attainment of large volumes of urine in the bladder with low-filling pressures. Excellent results can be expected in at least 80% of patients, but most will require CIC; thus, the ability to perform CIC is mandatory if one is to consider this type of procedure.73,74 Careful evaluation of sphincteric competence may also obviate the need for a concomitant outlet procedure such as pubovaginal sling or sphincter prosthesis.

Neuromodulation Neuromodulation has proven efficacy in relieving neurogenic OAB symptoms secondary to MS, especially in detrusor overactivity with or without DESD. Commonly used approaches include sacral neuromodulation, pudendal nerve stimulation and posterior tibial nerve stimulation.75 Sacral nerve stimulation (SNS) modulates dysfunctional voiding behavior in patients by a mechanism not fully understood but comprising detrusor inhibition via afferent and/or efferent stimulation of sacral nerves.76 Although the FDA approved indications for SNS are urge incontinence, urgency–frequency syndrome, and nonneurogenic urinary retention, SNS has been evaluated as a reversible treatment option for neurogenic refractory urge incontinence related to detrusor overactivity. Chartier-Kastler et al.77 have reported a 43.6-month long-term efficacy of this technique in 7 out of 9 patients

Multiple sclerosis with urodynamically demonstrable detrusor overactivity, with or without DESD. Although sacral neuromodulation seems to be a promising therapy for neurogenic disease, further studies and long-term results with an extended cohort of SCI and MS patients are yet to be obtained. Additional means of neuromodulation to control voiding symptoms are being evaluated. Transcutaneous electrical nerve stimulation (TENS) has been evaluated in MS patients with improvement in irritative voiding symptoms, diminished 24-hour micturition frequency and incontinence episodes.78 Placement of TENS units on either the sacral dermatomes or dorsal nerve of the penis or clitoris has been successful.78,79 However, placement of the TENS unit on the dorsal nerve of the penis or clitoris may have the added benefit of inhibiting detrusor contractions.80 Additional study is required to place this method into everyday clinical practice.80

Botulinum-A toxin Botulinum toxin, the neurotoxin produced by Clostridium botulinum, comprises seven different subtypes of which botulinum toxin A has longest duration of action. Botulinum-A toxin inhibits calcium-mediated release of acetylcholine vesicles at the neuromuscular junction, which results in reduced muscle contractility and atrophy at the injection site.81 Injections into the detrusor muscle seem to be a safe conservative treatment for detrusor overactivity in SCI patients. In 2011, onabotulinumtoxinA was approved by the U.S. FDA for the treatment of neurogenic detrusor overactivity. In January 2013, it received approval of treatment of OAB. In a study of 21 patients, Schurch et al.82 found that 19 of them underwent complete continence at 6 weeks and 11 out of 22 at 36 weeks. Schulte-Baukloh83 evaluated 16 MS patients with frequency, urgency, and urge incontinence who were refractory to anticholinergics. Botulinum-A toxin was injected into 40 sites of the detrusor muscle for a total dose of 300 U. Patients had an increase in PVR urine with one woman needing to perform CIC for an extended period of time. Both daytime and nighttime micturition frequency decreased to a statically significant lower amount. Incontinence was improved as well as patients required fewer pads per day at the 3-month visit. Urodynamic parameters were also measured and demonstrated increased reflex volume, mean cystometric capacity, and decrease in mean detrusor pressure. Patient satisfaction was evaluated with validated questionnaires. Patients indicated improvement in quality of life and overall satisfaction, and all patients indicated a willingness to undergo repeated procedures.83 Other studies evaluating botulinum-A toxin in neurogenic patients typically include patients with MS and show good results but do not stratify the results as to cause of the dysfunction.84,85

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Detrusor overactivity with bladder outlet obstruction Behavioral modifications and pelvic floor rehabilitation Pelvic floor spasticity and DESD are both predictors of poor prognosis, and behavioral modifications and pelvic floor rehabilitation should be reserved for mildly symptomatic patients. Some women may be guided in voiding by Credé’s maneuver, but this may put the upper urinary tract at risk.41 Although the maneuver appears easier and less invasive, in women, with time, a significant number of patients develop daytime and nighttime frequency and stress incontinence. Consequently, CIC should be the method of choice.

Clean intermittent catheterization and catheter drainage Patients with detrusor overactivity have higher treatment failures and more upper tract damage.32 The most reasonable treatment is CIC. The alternative, in the male, if he cannot perform CIC is external sphincterotomy, which is discussed below. The other alternative for both sexes is indwelling catheter but those patients, as mentioned earlier, have a higher incidence of upper tract changes.32

Pharmacologic therapy Symptoms of neurogenic voiding dysfunction complicated by bladder outlet obstruction may be treated by alpha antagonists (terazosin, doxazosin, tamsulosin) or muscle relaxants (diazepam, baclofen, dantrolene). Alpha antagonists aim at blockage of the sympathetic receptors of the smooth muscle component of the proximal urethra and bladder neck, thereby decreasing the sphincter tone and relieving bladder outlet obstruction. These treatments have had mixed results in MS patients.86 Commonly encountered side effects include orthostatic hypotension, dizziness, and lassitude.

Surgical management Patients with DESD are at higher risk of upper tract damage.32 In those males who cannot be treated with conservative measures, outlet reducing procedures such as transurethral external sphincterotomy, self-expandable urethral stents, or balloon dilatation may be necessary. The  conventional and most-used technique is external sphincterotomy, which typically involves transurethral incision of the external sphincter. These procedures allow for total urinary incontinence, which can afterward be ­managed by condom catheter drainage. They are best

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reserved for the patient with limited hand function for whom CIC is not an option or for patients who do not have caretakers that can provide this service.87,88 The performance of supravesical diversion (ileal conduit) has decreased with the widespread acceptance of augmentation cystoplasty. The latter, constructed with or without a continent stoma, is the preferred method. These procedures should be reserved for patients with failure of conservative therapy who lack the fine motor skills to do CIC.74 Cutaneous ileovesicostomy has been used successfully for storage or emptying abnormalities. In this procedure, a segment of ileum is used to construct a “chimney” from the bladder to allow cutaneous drainage to an external collection device.89 Such procedure should be reserved for individuals who cannot have CIC performed, either by themselves or by others, and who wish to avoid chronic indwelling catheter drainage.

Botulinum-A toxin

and urinary incontinence.77 Long-term results have to be carefully evaluated, particularly in the light of an evolving disease such as MS. However, it could become a minimally invasive therapy used in the armamentarium of modalities for the disease.

Hypocontractile detrusor Behavioral modifications and pelvic floor rehabilitation In certain patients with high PVRs, behavioral modifications such as bladder emptying maneuvers (Credé’s), double-voiding, and Valsalva can all assist with bladder emptying. Also, timed voiding may also be helpful by avoidance of overdistention of the bladder. Pelvic floor stimulation in the hyporeflexic bladder has been proven to play a very limited role.92

Phelan et al. prospectively evaluated 22 SCI patients with DESD who were voiding by indwelling catheters or by CIC. After botulinum-A toxin injection in the external sphincter, all patients except two were able to void without catheterization.81 For treatment of DESD, the duration of botulinum effect has been reported to be approximately 3 months for a single injection,81,90 but monthly intervals for 3 months resulted in clinical effects up to 9 months.81 Hence, botulinum-A toxin may be an alternative to external sphincterotomy for men with neuropathic DESD. It produces a reversible chemical sphincterotomy, which avoids the risks associated with the surgical procedure. However, the main disadvantage is the need for repeated injections to maintain results. This treatment has to be considered in cases of failure of more traditional conservative modalities and before definitive surgery. A recent multi-institutional placebo-controlled trial of 86 patients recruited from 6 centers in Europe randomized patients with MS and urodynamically proven DESD to injection of the striated sphincter with placebo or ­botulinum-A toxin.91 The authors found no difference in PVR volumes between the treatment and placebo groups (p = .45) However, the botulinum-A toxin group had significantly increased voided volumes (197 mL vs. 128 mL) and decreased maximal detrusor pressures (52 vs. 66 cm water pressure). No serious side adverse events were attributable to the botulinum-A toxin.91 Further study is warranted in this patient population.

Clean intermittent catheterization and catheter drainage

Neuromodulation

Surgical management

Chartier-Kastler et al. have evaluated the use of SNS for patients with detrusor overactivity. They implanted a sacral neurostimulator into nine patients, of whom five had detrusor overactivity with DESD. Four of these patients had improvement in frequency, volume voided,

When MS patients present symptoms, have urologic complications, or cannot perform CIC, urinary diversion is to be considered. However, the risks and benefits of this major surgical procedure must be carefully evaluated, especially in those patients with advanced disease.

For some patients with more advanced disease and/or poor hand dexterity, catheterization may be a problem. These patients may require an indwelling catheter or suprapubic cystostomy. The latter is an attractive option as it has several advantages over a conventional indwelling catheter: urethral erosion and traumatic hypospadias may be avoided and personal hygiene and catheter care are simplified because of the accessibility of the catheter and its position remote from perineal or vaginal soilage. Also, the external genitalia can be free of foreign bodies and may render sexual activity possible.72,92 Chronic catheter drainage should be considered only after all the treatment options have been exhausted. The risks of bladder calculi, infection, and squamous cell carcinoma92–94 should be weighed against the advantages for the patient.

Pharmacologic therapy There is no proven pharmacologic therapy for hypocontractile detrusor or areflexia. Bethanechol chloride, a cholinergic agonist, was used in the past but no prospective placebo-controlled trial has ever demonstrated its efficacy in MS.95

Multiple sclerosis

Neuromodulation Detrusor areflexia or hypocontractile detrusor, i.e., impaired detrusor function of neurogenic origin as a cause of voiding dysfunction, is a contraindication for sacral neuromodulation therapy. Destruction of the peripheral innervation will not allow neuromodulation therapy to be effective.76

Conclusion Urinary tract dysfunction is the fate of the majority of patients suffering from MS with the advancing course of their disease. Due to the poor correlation between subjective symptoms and objective parameters, a thorough evaluation of the urinary tract is mandatory in patients with and without urinary symptoms. Although many options exist for treatment of the neurogenic bladder, a stepwise approach with conservative and initially reversible therapy is important considering the waxing and waning course of the disease. Long-term follow-up aims at preserving renal function while minimizing symptoms and enhancing quality of life.

References 1643. Charcot M. Histologie de la sclerose en plaques. Gaz Hop Paris 1868; 141: 554. 1644. McDonald WI. The dynamics of multiple sclerosis. The Charcot Lecture. J Neurol 1993; 240: 28. 1645. Compston A, Coles A. Multiple sclerosis. Lancet 2002; 359: 1221–31. 1646. Shibasaki H, McDonald WI, Kurojwa Y. Racial modifications of clinical picture of multiple sclerosis: Comparison between British and Japanese patients. J Neurol Sci 1981; 49: 253–71. 1647. Kira J, Kanai T, Nishimura Y et al. Western versus Asian types of multiple sclerosis: Immunogenetically and clinically distinct disorders. Ann Neurol 1996; 40: 569–74. 1648. Compston A. Risks factors for multiple sclerosis: Race or place? J Neurol Neurosurg Psychiatry 1990; 53: 821–3. 1649. Poser CM. The epidemiology of multiple sclerosis: A general overview. Ann Neurol 1994; 36(Suppl 2): S180–93. 1650. Sadovnick A, Eberg G, Dyment D, Rish N, Canadian Collaborative Study Group. Evidence for genetic basis of multiple sclerosis. Lancet 1996; 347: 1728–30. 1651. Hinson JL, Boone TB. Urodynamics and multiple sclerosis. Urol Clin N Am 1996; 23(3): 475–81. 1652. Keegan BM, Noseworthy JH. Multiple sclerosis. Annu Rev Med 2002; 53: 285–302. 1653. Litwiller SE, Frohman EM, Zimmern PE. Multiple sclerosis and the urologist. J Urol 1999; 161: 743–57. 1654. Zhang J, Markovic-Plese S, Lacet B et al. Increased frequency of interleukin 2-responsive T cells specific for myelin basic protein and proteolipid protein in peripheral blood and cerebrospinal fluid of patients with multiple sclerosis. J Exp Med 1994; 179: 973–84. 1655. Archelos JJ, Storch MK, Hartung HP. The role of B cells and autoantibodies in multiple sclerosis. Ann Neurol 2000; 47: 694–706. 1656. Genain CP, Cannella B, Hauser SL, Raine CS. Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nat Med 1999; 5: 170–5. 1657. Ebers G, Sadovnick A, Rish N, Canadian Collaborative Study Group. A genetic basis for familial aggregation in multiple sclerosis. Nature 1995; 377: 150–1.

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1658. Sawcer S, Meranian M, Setakis E et al. A whole genome screen for linkage disequilibrium in multiple sclerosis confirms disease associations with regions previously linked to susceptibility. Brain 2002; 125: 1337–47. 1659. Compston A. The genetic epidemiology of multiple sclerosis. Philos Trans R Soc Lond B Biol Sci 1999; 354: 1623–34. 1660. Hunter SF, Hafler DA. Ubiquitous pathogens – links between infection and autoimmunity in MS? Neurology 2000; 55: 164–5. 1661. Albert LJ, Inman RD. Molecular mimicry and autoimmunity. N Engl J Med 1999; 341: 2068–74. 1662. Wandinger KB, Jabs W, Siekhaus A et al. Association between clinical disease activity and Epstein–Barr virus reactivation in MS. Neurology 2000; 55: 178–84. 1663. Challoner P, Smith K, Parker J et al. Plaque–associated expression of human herpesvirus 6 in multiple sclerosis. Proc Natl Acad Sci USA 1995; 92: 7440–4. 1664. Sriram S, Stratton C, Yao S et al. Chlamydia pneumoniae infection of the central nervous system in multiple sclerosis. Ann Neurol 1999; 46: 6–14. 1665. McDonald WI, Compston A, Edan G et al. Recommended diagnostic criteria for multiple sclerosis: Guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001; 50: 121–7. 1666. Weinshenker B, Lucchinetti C. Acute leukoencephalopathies: Differential diagnosis and investigation. Neurologist 1998; 4: 148–66. 1667. Lublin FD, Reingold SC. Defining the clinical course of mutiple sclerosis: Results of an international survey. Neurology 1996; 46: 907–11. 1668. Werring DJ, Bullmore ET, Toosy AT et al. Recovery from optic neuritis is associated with a change in the distribution of cerebral response to visual stimulation: A functional magnetic resonance imaging study. J Neurol Neurosurg Psychiatry 2000; 68: 441–9. 1669. Weinshenker BG, Rice GPA, Noseworthy JH et al. The natural history of multiple sclerosis: A geographically based study. III. Multivariate analysis of predictive factors and models of outcome. Brain 1991; 114: 1045–56. 1670. O’Riordan JI, Thompson AJ, Kingsley DP et al. The prognostic value of brain MRI in clinically isolated syndromes of the CNS. A 10-year follow-up. Brain 1998; 121: 495–503. 1671. Griffiths D, Holstege G, de Wall H, Dalm E. Control and coordination of bladder and urethral function in the brain stem of the cat. Neurourol Urodyn 1990; 9: 63–82. 1672. Blok B, Willemsen T, Holstege G. A pet study of brain control of micturition in humans. Brain 1997; 129: 111–21. 1673. Oppenheimer DR. The cervical cord in multiple sclerosis. Neuropathol Appl Neurobiol 1978; 4:151–162. 1674. Blaivas JG, Barbalias GA. Detrusor external sphincter dyssynergia in men with multiple sclerosis: An ominous urologic condition. J Urol 1984; 131: 91–4. 1675. Philip T, Read DJ, Higson RH. The urodynamic characteristics of multiple sclerosis. Br J Urol 1981; 53: 672–5. 1676. Mayo ME, Chetner MP. Lower urinary tract dysfunction in multiple sclerosis. Urology 1992; 39: 67–70. 1677. Fernandez O. Mechanisms and current treatments of urogenital dysfunction in multiple sclerosis. J Neurol 2002; 249: 1–8. 1678. Hennessey A, Robertson NP, Swingker R et al. Urinary, faecal and sexual dysfunction in patients with multiple sclerosis. J Neurol 1999; 246: 1027–32. 1679. Beck RP, Warren KG, Whitman P. Urodynamic studies in female patients with multiple sclerosis. Am J Obstet Gynecol 1981; 139: 273–6. 1680. Goldstein I, Siroky MB, Sax DS, Krane RJ. Neurourologic abnormalities in multiple sclerosis. J Urol 1982; 128: 541–5. 1681. Ukkonen M, Elovaara I, Dastidar P, Tammela TLJ. Urodynamic findings in primary progressive multiple sclerosis are associated with increased volumes of plaques and atrophy in the central nervous system. Acta Neurol Scand 2004; 109: 100–5. 1682. Koldewijn EL, Hommes OR, Lemmens AJG et al. Relationship between lower urinary tract abnormalities and disease-related parameters in multiple sclerosis. J Urol 1995; 154: 169–73.

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1683. McGuire EJ, Savastano JA. Urodynamic findings and long-term outcome management of patients with multiple sclerosis induced lower urinary tract dysfunction. J Urol 1984; 132: 713–5. 1684. Sirls LT, Zimmern PE, Leach GE. Role of limited evaluation and aggressive medical management in multiple sclerosis: A review of 113 patients. J Urol 1994; 151: 946–50. 1685. Betts CD, D’Mellow MT, Fowler CJ. Urinary symptoms and the neurological features of bladder dysfunction in multiple sclerosis. J Neurol Neurosurg Psychiatry 1993; 56: 245–0. 1686. Awad SA, Gajewski JB, Sogbein SK et al. Relationship between neurological and urological status in patients with multiple sclerosis. J Urol 1984; 132: 499–502. 1687. Chancellor MB, Blaivas JG. Urological and sexual problems in multiple sclerosis. Clin Neurosci 1994; 2: 189–95. 1688. Lee KH, Hashimoto SA, Hooge JP et al. Magnetic resonance imaging of the head in the diagnosis of multiple sclerosis: A prospective 2-year follow-up with comparison of clinical evaluation, evoked potentials, oligoclonal banding, and CT. Neurology 1991; 41: 657–60. 1689. Goodkin DE, Rudick RA, Ross JS. The use of brain magnetic resonance imaging in multiple sclerosis. Arch Neurol 1994; 51: 505–16. 1690. Prineas JW, Barnard RO, Kwon EE et al. Multiple sclerosis: Remyelination of nascent lesions. Ann Neurol 1993; 33: 137–51. 1691. Kim YH, Goodman C, Omessi E et al. The correlation of urodynamic findings with cranial magnetic resonance imaging findings in multiple sclerosis. J Urol 1998; 159: 972–6. 1692. Lemack GE, Hawker K, Frohman E. Incidence of upper tract abnormalities in patients with neurovesical dysfunction secondary to multiple sclerosis: Analysis of risk factors at initial urologic evaluation. Urology 2005; 65(5): 854–7. 1693. Bemelmans BL, Hommes OR, Van Kerrebroek PEV et al. Evidence for early lower urinary tract dysfunction in clinically silent multiple sclerosis. J Urol 1991; 145: 1219–24. 1694. Gonor SE, Carroll DJ, Metcalfe JB. Vesical dysfunction in multiple sclerosis. Urology 1985; 25: 429–31. 1695. Ciancio SJ, Mutchnik SE, Rivera VM, Boone TB. Urodynamic pattern changes in multiple sclerosis. Urology 2001; 57: 239–45. 1696. McClurg D, Ashe RG, Marshall K, Lowe-Strong AS. Comparison of pelvic floor muscle training, electromyography biofeedback, and neuromuscular electrical stimulation for bladder dysfunction in people with multiple sclerosis: A randomized pilot study. Neurourol Urodyn 2006; 25: 337–48. 1697. De Ridder D, Vermeulen C, Ketelaer P et al. Pelvic floor rehabilitation in multiple sclerosis. Acta Neurol Belg 1999; 99: 61–4. 1698. De Ridder D, Ost D, Van der Aa F et al. Conservative bladder management in advanced multiple sclerosis. Mult Scler 2005; 11: 694–9. 1699. Thuroff JW, Bunke B, Ebner A et al. Randomized, double-blind, multicenter trial on treatment of frequency, urgency and incontinence related to detrusor hyperactivity: Oxybutynin versus propantheline versus placebo. J Urol 1991; 145: 813–7. 1700. Abrams P, Freeman R, Anderstrom C, Mattiasson A. Tolterodine, a new antimuscarinic agent: As effective but better tolerated than oxybutynin in patients with an overactive bladder. Br J Urol 1998; 81(6): 801–10. 1701. Horstmann M, Schaefer T, Aguilar Y, Stenzl A, Sievert KD. Neurogenic bladder treatment by doubling the recommended antimuscarinic dosage. Neurourol Urodyn 2006; 25: 441–5. 1702. Rey Fv, Heesakkers J. Solifenacin in multiple sclerosis patients with overactive bladder: A prospective study. Adv Urol 2011; 2011: 834753. 1703. Kay GG, Ebinger U. Preserving cognitive function for patients with overactive bladder: Evidence for a differential effect with darifenacin. Int J Clin Pract 2008; 62(11): 1792–800. 1704. Nitti VW, Auerbach S, Martin N et al. Results of a randomized phase III trial of mirabegron in patients with overactive bladder. J Urol 2013; 189(4): 1388–95.

1705. Khullar V, Amarenco G, Angulo JC et al. Efficacy and tolerability of mirabegron, a β(3)-adrenoceptor agonist, in patients with overactive bladder: Results from a randomised European-Australian phase 3 trial. Eur Urol 2013; 63(2): 283–95. 1706. Van Kerrebroeck P, Barkin 2, Castro-Diaz D et al. Randomised, double-blind, placebo-controlled phase III study to assess the efficacy and safety of mirabegron 25 mg and 50 mg once daily in overactive bladder (OAB). 42nd Annual Meeting of the International Continence Society, Beijing, China, October 15–19, 2012. 1707. Brady CM, DasGupta R, Dalton C et al. An open-label pilot study of cannabis-based extracts for bladder dysfunction in advanced multiple sclerosis. Mult Scler 2004; 10: 425–33. 1708. Madersbacher H, Jilg G. Control of detrusor hyperreflexia by the intravesical instillation of oxybutynin hydrochloride. Paraplegia 1991; 29: 84–90. 1709. Weese DL, Roskamp DA, Leach GE, Zimmern PE. Intravesical oxybutynin chloride: Experience with 42 patients. Urology 1993; 41(6): 527–30. 1710. de Ridder D, Chandiramani V, Dasgupta P et al. Intravesical capsaicin as a treatment for refractory detrusor hyperreflexia: A dual center study with long-term follow up. J Urol 1997; 158: 2087–92. 1711. Lazzeri M, Beneforti P, Spinelli M et al. Intravesical resiniferatoxin for the treatment of hypersensitive disorder: A randomized placebo controlled study. J Urol 2000; 164: 676–9. 1712. Valiquette G, Herbert J, Meade–D’Alisera P. Desmopressin in the management of nocturia in patients with multiple sclerosis. Arch Neurol 1996; 53: 1270–5. 1713. Eckford SD, Swami KS, Jackson SR, Abrams PH. Desmopressin in the treatment of nocturia and enuresis in patients with multiple sclerosis. Br J Urol 1994; 74(6): 733–5. 1714. Chancellor MB, Blaivas JG. Multiple sclerosis. Probl Urol 1993; 7(1): 15–33. 1715. Goldwasser B, Webster GD. Augmentation and substitution enterocystoplasty. J Urol 1986; 135: 215–24. 1716. Luangkhot R, Peng BCH, Blaivas JG. Ileocecocystoplasty for the management of refractory neurogenic bladder: Surgical technique and urodynamic findings. J Urol 1991; 146: 1340–4. 1717. Le NB, Kim JH. Expanding the role of neuromodulation for overactive bladder: New indications and alternatives to delivery. Curr Bladder Dysfunct Rep 2011; 6(1): 25–30. 1718. Scheepens WA, van Kerrebroeck PEV. Indications and predictive factors. In: Udo J, Grunewald V, eds. New Perspectives in Sacral Nerve Stimulation. London, United Kingdom: Martin Dunitz, 2002: 89–98. 1719. Chartier-Kastler E, Ruud Bosch JLH, Perrigot M et al. Long–term results of sacral nerve stimulation (S3) for the treatment of neurogenic refractory urge incontinence related to detrusor hyperreflexia. J Urol 2000; 164: 1476–80. 1720. Skeil D, Thorpe AC. Transcutaneous electrical nerve stimulation in the treatment of neurological patients with urinary symptoms. BJU Int 2001; 88: 899–908. 1721. Fjorback MV, Van Rey FS, Riijkhoff NJM et al. Electrical stimulation of sacral dermatomes in multiple sclerosis patients with neurogenic detrusor overactivity. Neurourol Urodyn 2007; 1–7. 1722. Fjorback MV, Riijkhoff N, Petersen T, Nohr M, Sinkjaer T. Event driven electrical stimulation of the dorsal penile/clitoral nerve for management of neurogenic detrusor overactivity in multiple sclerosis. Neurourol Urodyn 2006; 25: 349–55. 1723. Phelan MW, Franks M, Somogyi GT et al. Botulinum toxin urethral sphincter injection to restore bladder emptying in men and women with voiding dysfunction. J Urol 2001; 165: 1107–10. 1724. Schurch B, Stohrer M, Kramer G et al. Botulinum-A toxin for treating detrusor hyperreflexia in spinal cord injured patients: A new alternative to anticholinergic drugs? Preliminary results. J Urol 2000; 164: 692–7.

Multiple sclerosis 1725. Schulte-Baukloh H, Schobert J, Stolze T et al. Efficacy of botulinumA toxin bladder injections for the treatment of neurogenic detrusor overactivity in multiple sclerosis patients: An objective and subjective analysis. Neurourol Urodyn 2006; 25: 110–5. 1726. Schurch B, de Seze M, Deys P et al. Botulium toxin type A is a safe and effective treatment for neurogenic urinary incontinence: Results of a single treatment, randomized, placebo controlled 6-month study. J Urol 2005; 174: 196–200. 1727. Smith CP, Nishiguchi J, O’Leary M, Yoshimura N, Chancellor MB. Single-institution experience in 110 patients with botulinum toxin A injection into bladder or urethra. Urology 2005; 65(1): 37–41. 1728. O’Riordan JI, Doherty C, Javed M et al. Do alpha-blockers have a role in lower urinary tract dysfunction in multiple sclerosis? J Urol 1995; 153: 1114–6. 1729. Lockhart JL, Vorstman B, Weinstein D, Politano VA. Sphincterotomy failure in neurogenic bladder disease. J Urol 1986; 135: 86–9. 1730. Sauerwein D, Gross AJ, Kutzenberger J, Ringert RH. Wallstents in patients with detrusor–sphincter dyssynergia. J Urol 1995; 154: 495–7.

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1731. Schwartz SL, Kennely MJ, McGuire EJ, Farber GJ. Incontinent ileovesicostomy urinary diversion in the treatment of lower urinary tract dysfunction. J Urol 1994; 152: 99. 1732. Schurch B, Hauri D, Rodic B et al. Botulinum-A toxin as a treatment of detrusor–sphincter dyssynergia: A prospective study in 24 cord injury patients. J Urol 1996; 155: 1023–29. 1733. Gallien P, Reymann J-M, Amarenco G et al. Placebo controlled, randomized, double blind study of the effects of botulinum A toxin on detrusor sphincter dyssynergia in multiple sclerosis patients. J Neurol Neurosurg Psychiatry 2005; 76: 1670–6. 1734. Rashid TM, Hollander JB. Multiple sclerosis and the neurogenic bladder. Phys Med Rehab Clin N Am 1998; 9(3): 615–29. 1735. Broecker BH, Klein FA, Hackler RH. Cancer of the bladder in spinal cord injury patients. J Urol 1981; 125: 196–7. 1736. Bejany DE, Lockhart JL, Rhamy RK. Malignant vesical tumors following spinal cord injury. J Urol 1987; 138: 1390–2. 1737. Finkbeiner AE. Is bethanechol chloride clinically effective in promoting bladder emptying? A literature review. J Urol 1985; 134: 443–9.

20 Other diseases (transverse myelitis, tropical spastic paraparesis, progressive multifocal leukoencephalopathy, Lyme’s disease) Tomáš Hanuš

Transverse myelitis Incidence Acute transverse myelitis (ATM) has an incidence of one to four new cases per million people per year affecting individuals of all ages with bimodal peaks between the ages of 10 and 19 years and 30 and 39 years. There is no sex or familial predisposition to ATM. Characteristics and natural history, particularly in relation to neurological outcome, have already been described in a pediatric population in last years as well; however, it is a relatively rare condition in children.

Etiology and pathogenesis Transverse myelitis (TM) is a clinical syndrome, where an immune-mediated process causes a neural injury to the spinal cord, resulting in varying degrees of weakness, sensory alterations, and autonomic dysfunction. TM may exist as part of a multifocal disease of central nervous system (CNS) (e.g., multiple sclerosis [MS]), multisystemic disease (e.g., systemic lupus erythematosus [SLE]) or as an isolated, idiopathic entity. ATM is commonly parainfectious. Recurrent ATM occurs in connective tissue diseases, infective myelitis, and idiopathic inflammatory demyelinating disorders including MS and neuromyelitis optica. With improved understanding of the underlying neurophysiology, only true spinal inflammatory processes are designated myelitis. Myelitis is classified either according to the speed of symptoms progression (acute, subacute, or chronic) or according to the etiology (viral, bacterial, parasitic, tuberculosis, and idiopathic). These disorders may selectively affect different parts of the nervous system, spinal cord

and meninges (meningomyelitis), or meninges and roots (meningoradiculitis). The inflammatory distribution is termed poliomyelitis when it is confined to the gray matter and leukomyelitis if it affects the white matter. When the entire thickness of the spinal cord is involved, it is called TM.

Diagnosis ATM is characterized clinically by acute or subacute onset of symptoms and signs of neurologic dysfunction in motor, sensory, and autonomic nerves and nerve tracts of the spinal cord. There is often a clearly defined upper border of sensory dysfunction, and spinal magnetic resonance imaging (MRI) and lumbar puncture often show signs of acute inflammation. When the maximal level of deficit is reached, approximately 50% of patients lose all movements of their legs, virtually all patients have bladder dysfunction, and 80%–94% of patients have numbness, paresthesias, or band-like dysesthesias. Autonomic symptoms consist variably of increased urinary urgency, bowel or bladder incontinence, difficulty or inability to void, incomplete evacuation, or constipation. The Transverse Myelitis Consortium Working Group1 suggested a set of uniform diagnostic criteria and nosology for ATM, which is a focal inflammatory disorder of the spinal cord, resulting in motor, sensory, and autonomic dysfunction. This set was proposed to avoid the confusion that inevitably results when investigators use differing criteria. This set will ensure a common language of classification, reduce diagnostic confusion, and will lay the groundwork necessary for multicenter clinical trials. In addition, a framework is suggested for evaluation of individuals presenting with signs and symptoms of ATM. The best treatment often depends on a timely and accurate

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diagnosis. Because acute transverse myelopathies are relatively rare, delayed and incomplete work-up often occurs. Rapid and accurate diagnosis will ensure that not only compressive lesions are detected and treated but also an idiopathic ATM is distinguished from ATM secondary to known underlying disease. Identification of etiologies may suggest medical treatment, whereas no clearly established medical treatment currently exists for idiopathic ATM. Establishment of a diagnostic algorithm will likely lead to improved care, although it is recognized that the entire evaluation may not be performed for every patient. The diagnostic criteria for idiopathic ATM are listed in Table 20.1. Diagnosis of idiopathic ATM should require

Table 20.1  C  riteria for idiopathic acute transverse myelitis A. Inclusion criteria Development of sensory, motor, or autonomic dysfunction attributable to the spinal cord Bilateral signs and/or symptoms (though not necessarily symmetric) Clearly defined sensory level Exclusion of extra-axial compressive etiology by neuroimaging (magnetic resonance imaging [MRI] or myelography; computerized tomography of spine not adequate) Inflammation within the spinal cord demonstrated by cerebrospinal fluid pleocytosis or elevated immunoglobulin G index or gadolinium enhancement. If none of the inflammatory criteria is met at symptom onset, repeat MRI and lumbar puncture evaluation between 2 and 7 days following symptom onset Progression to nadir between 4 hours and 21 days following the onset of symptoms B. Exclusion criteria History of previous radiation to the spine within the last 10 years Clear arterial distribution clinical deficit consistent with thrombosis of the anterior spinal artery Abnormal flow voids on the surface of the spinal cord c/w arteriovenous malformation Serologic or clinical evidence of connective tissue disease (sarcoidosis, Behçet’s disease, Sjögren’s syndrome, systemic lupus erythematosus, mixed connective tissue disorder, etc.) Central nervous sysytem manifestations of syphilis, Lyme disease, human immunodeficiency virus, human T-cell lymphotropic virus type 1, Mycoplasma, other viral infection (e.g., human simplex virus 1, human simplex virus 2, varicella-zoster virus, Epstein–Barr virus, cytomegalovirus, human herpesvirus 6, enteroviruses) Brain MRI abnormalities suggestive of multiple sclerosis History of clinically apparent optic neuritis

that all of the inclusion criteria and none of the exclusion criteria are fulfilled. Diagnosis of disease-associated ATM should require that all the inclusion criteria are met and that the patient is identified as having an underlying condition listed in the disease-specific exclusions.

Voiding dysfunctions in transverse myelitis TM has various neurological manifestations. Bladder dysfunction is common and may be the only sequel. The neurological events during normal micturition that culminate in a detrusor contraction and urethral relaxation are integrated in the rostral brainstem in the area designated as pontine micturition center. Any lesion within the spinal cord, such as trauma, MS, myelodysplasia, and myelitis, which causes a disruption of this pathway, may result in detrusor external sphincter dyssynergia (DESD). If the disease involves the sacral (S2 to S4) cord or roots, a lower motor neuron lesion may occur as well, with pudendal or parasympathetic dysfunction. In case the thoracolumbar cord is affected, sympathetic dysfunction may occur. Urodynamic study is helpful in evaluating the bladder dysfunction and also in its management. Ganesan and Borzyskowski2 described characteristics and course of urinary tract dysfunction after ATM in 10 children, with ages ranging from 8 months to 16 years. Patients were studied with videourodynamics and followed at a pediatric neurourology clinic. Nine of 10 children had obstructive urinary tract symptoms at presentation and all developed irritative urinary tract symptoms (frequency and urgency) about 1 month after the initial presentation. Videourodynamics showed a combination of irritative (detrusor overactivity) and obstructive (detrusor sphincter dyssynergia [DSD]) abnormalities in most patients and enabled management to be specifically directed toward these. Patients’ progress was followed for a median duration of 36 months. All had residual bladder dysfunction, and only four were asymptomatic on treatment. The degree of recovery of bladder function was not related to the degree of motor recovery. In the study of Cheng et al.,3 the long-term urological outcome of children with ATM was assessed. Medical records of children with ATM over last 15 years were reviewed. Median age of the five children with ATM at the time of onset was 6 years (range 2–12). The median length of follow-up was 5 years (2–10 years). Four children recovered completely from paraparesis; two had no urinary symptoms with normal voiding. However, videourodynamic studies 3 years after the acute onset revealed that four out of the five children, including one without any urinary symptom, suffered from residual bladder dysfunction—two from contractile neurogenic bladder and two from intermediate type of neurogenic bladder.

Other diseases Leroy-Malherbe4 studied retrospectively the records of 21 children admitted at the mean age of 8 years 5 months (2 to 14 years and 8 months) for acute transverse myelopathy. Bladder sphincter dysfunction occurred on the first days of disease in 85% of these patients. Abnormal perception of micturition was one of the most constant and specific symptoms. Anorectal function was also impaired. Complete regressive course was noted in 38% of patients, minor sequelae in 39%, and major sequelae after 6 months in 23%. No upper tract deterioration was noted after 3  years. Factors of favorable prognosis were early motor function recovery (especially recommencement of walking before 20 days) and early management of bladder dysfunction (inability to void had better prognosis than urinary incontinence). Early systematic bladder drainage in case of inability to void might be essential for improved prognosis. Voiding dysfunction secondary to schistosomal myelopathy was described by Gomes et  al. Schistosomiasis mansoni is an endemic fluke infection in South America, the Caribbean, and Africa. In the United States and Europe, people may become infected mainly after traveling to endemic areas and immigration of infected individuals. Clinical involvement of the spinal cord is a well-recognized complication of the disease. The typical presentations are those of an ATM, with sudden onset of lower extremity neuropathy associated with bladder and bowel dysfunction. The authors reviewed records and urodynamic studies of 14 consecutive patients (10 men and 4 women, aged 23–49 years) with schistosomal myelopathy confirmed by cerebrospinal fluid (CSF) serology for S. mansoni, who were referred for evaluation of voiding dysfunction during a 2-year period. At the time of the urologic evaluation, nine patients had chronic neurologic and urinary symptoms and five had recent onset of acute symptoms. History of voiding function, urologic complications, and outcomes after therapy for schistosomiasis were also reviewed. Of the patients with acute disease (five patients), the urologic symptoms included urinary retention (three patients) and incontinence (two patients). Three of them had concurrent lower back pain and lower extremity neurologic deficits. Urodynamic studies were performed in three patients and revealed bladder contractility in two patients and detrusor overactivity with external sphincter dyssynergia in one patient. The patients were started on clean intermittent catheterization (CIC) and received praziquantel and corticosteroids. Three patients had complete resolution of their symptoms, one recovered normal voiding function but the neurologic deficits persisted, and one had no clinical improvement. All patients with chronic schistosomal myelopathy presented with lower limb neurologic deficits of varying degrees and urinary symptoms, including difficulty in bladder emptying (seven patients), urinary incontinence (six patients), and urgency and frequency (two patients). Laboratory and radiographic investigations of patients with chronic disease revealed urinary tract

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infection in five patients, hydronephrosis in two patients, and bladder calculi in two patients. Urologic management consisted of antibiotics, CIC, anticholinergic medication, and stone removal, as appropriate. In one patient, conservative treatment failed and patient required ileocystoplasty. Schistosomal myelopathy is a potential cause of severe voiding dysfunction secondary to spinal cord disease. High index of suspicion is of paramount importance because early medical intervention can abort the progression of neurologic deterioration. Kalita et  al.5 evaluated voiding abnormalities in ATM and correlated these with evoked potentials, MRI, and urodynamic findings. Of 18 patients with ATM aged 4–50 years, 15 had a paraparesis and 3 quadruparesis. Patients with ATM had a neurological examination and tibial somatosensory evoked potential (SSEP) and motor evoked potential studies in the lower limbs. Spinal MRI was carried out using 1.5 T scanner. Urodynamic studies were done using Dantec UD 5500 machine. Neurological outcome was classified on the basis of Barthel index score at 6 months as poor, partial, or complete. In some patients, urodynamic studies were repeated at 6 and 12 months. Spinal MRI in 14 of 18 patients revealed T2 hyperintense signal changes, extending over at least three spinal segments in 13. One patient had normal MRI. In the acute phase, 17 patients had a history of urinary retention and one had urge incontinence. At 6 months’ follow-up, two patients regained normal voiding, retention persisted in six, and storage symptoms developed in 10, of whom five also had emptying difficulties. Urodynamic studies showed an acontractile or hypocontractile bladder in 10, detrusor overactivity with poor compliance in two, and DSD in three. Early abnormal urodynamic findings commonly persisted at the 6- and 12-month examinations. Persistent abnormalities included detrusor overactivity, dyssynergia, and acontractile bladder. The urodynamic abnormalities correlated with muscle tone and reflex changes but not with sensory or motor evoked potentials, muscle power, MRI signal changes, sensory level, or 6-month outcome. Sakakibara et  al.6 reported 10 patients with ATM. Seven patients had urinary retention and three patients had voiding difficulties within 1 month after the onset of the disease. Five patients with retention became able to void. After the mean follow-up of 40 months, nine still had urinary symptoms including difficult voiding in five and urinary frequency, urgency, and incontinence in four patients. Four patients had urinary disturbance as a sole sequel of ATM. Urodynamic studies performed on nine patients revealed that all of the three patients with the urgent incontinence had detrusor overactivity, all of the four patients with retention had acontractile cystometrogram as well as sphincter overactivity, and three of five patients with voiding difficulty had DSD. Acontractile cystometrogram tended to change to a low compliance bladder, followed by detrusor overacivity or a normal cystometrogram. Analysis of the motor unit potentials

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of the external sphincter revealed that two of the three patients had high-amplitude or polyphasic neurogenic changes. Supranuclear as well as nuclear types of parasympathetic and somatic nerve dysfunctions seemed to be responsible for voiding disturbances in our patients with ATM. Chan et al.7 reported a case of the 63-year-old Chinese man who presented with quadruparesis and urinary incontinence. The initial diagnosis was a cord compression from cervical spondylosis. The patient relapsed 3 months after cervical laminectomy. The TM picture, left optic atrophy, and suggestive brainstem evoked potentials led to treatment of a presumptive demyelinating process. The presence of vitiligo, however, led to the detection of high titers of antinuclear antibodies (ANAs) and presence of antinonhistone antibodies. The patient was then diagnosed to have a lupus (SLE)-like disease, which has not fully developed. He was prescribed pulsed cyclophosphamide and prednisolone with significant gains both neurologically and functionally up to 1 year of follow-up. It can occur in men in the seventh decade of life, heightening the need for awareness in our approach to the myelopathic patient. Chan and Boey8 published clinical features of nine lupus patients who presented with transverse myelopathy and documented functional outcomes of early treatment with high-dose corticosteroids and/or cyclophosphamide. These nine patients who developed a total of 14 episodes of TM were retrospectively reviewed. All patients were females aged 21 to 59 years. Nine episodes of paraparesis, three of quadruparesis, one of numbness, and one of neurogenic bladder were reported early in the diagnosis of SLE (median of 2 years). Neurogenic bowel and bladder and presence of antibodies ANA and anti-ds-DNA were invariable. Berger et al.9 found abnormal detrusor function in all six patients with TM. Computerized tomography scans and myelograms were inconclusive and CSF studies were normal. Erythrocyte sedimentation rate and complement levels were insensitive as markers of disease activity. The  treatment regimens included pulses of methylprednisolone and/or cyclophosphamide followed by prednisolone and high-dose prednisolone from the onset. The functional outcomes were uniformly good, with independent ambulation in all except three (who needed assistive devices) and improvement of motor scores. Acute hospital stay was short (range 3–45 days) and only two were referred for inpatient rehabilitation. Bladder abnormalities persisted despite motor recovery. Six men and two women with a history of TM and persistent lower urinary tract symptoms underwent neurourological evaluation. Of the patients, four were neurologically intact, while the remainder had residual neurological deficits. Urodynamic studies revealed DESD in six patients. Two patients had detrusor overactivity, of whom one also had an incompetent sphincter. Erectile or ejaculatory dysfunction was reported by three men. They concluded

that prolonged bladder and sexual dysfunction, caused by spinal cord inflammatory insult, may persist despite a systemic neurological recovery. Therefore, bladder management guided by initial and follow-up urodynamics is recommended. Chartier-Kastler et  al.10 assessed clinical and urodynamic results of sacral nerve stimulation for patients with neurogenic (spinal cord diseases) urge incontinence and detrusor overactivity resistant to parasympatholytic medications. Nine women with a mean age of 42.6 years (range 26–53) were treated since 1992 for refractory neurogenic urge incontinence with sacral nerve stimulation. Neurological spinal diseases included viral and vascular myelitis in one patient each, MS in five, and traumatic spinal cord injury in two. Mean time since neurological diagnosis was 12 years. All patients had incontinence with chronic pad use related to neurogenic detrusor overactivity. Intermittent self-catheterization for external DSD was used by five patients. Social life was impaired and these patients were candidates for bladder augmentation. A sacral (S3) lead was surgically implanted and connected to a subcutaneous neurostimulator after a positive stimulation trial. Mean follow-up was 43.6 months (range 7–72). All patients had clinically significant improvement of incontinence and five were completely dry. Average number of voids per day decreased from 16.1 to 8.2. Urodynamic parameters at 6 months after implant improved significantly from baseline, including maximum bladder capacity from 244 to 377 mL and volume at first uninhibited contraction from 214 to 340 mL. Maximum detrusor pressure at first uninhibited contraction increased in three, stabilized in two, and decreased in four patients. Urodynamic results returned to baseline when stimulation was inactivated. All patients subjectively reported improved visual analog scale results by at least 75% at last follow-up. Conclusions: Sacral nerve stimulation can be used as a reversible treatment option for refractory urge incontinence related to detrusor overactivity in selected patients with spinal lesions. Das and Jaykumar11 reported a case of TM with urinary retention in Nepal following typhoid vaccination. The prognosis is unsatisfactory and tends to linger for prolonged period with residual paralysis. Tsiodras et  al.12 reviewed all available literature on cases of Mycoplasma spp. associated ATM with dominant spinal cord pathology and classified those cases according to the strength of evidence implicating Mycoplasma pneumoniae as the cause. Wide range of data on diagnosis, epidemiology, immunopathogenesis, clinical picture, laboratory diagnosis, neuroimaging, and treatment of this rare entity has been presented. The use of highly sensitive and specific molecular diagnostic techniques may assist to clearly elucidate the role of M. pneumoniae in ATM/acute disseminated encephalomyelitis syndromes in the near future. Myelitis is one of the most severe CNS complications seen in association with M. pneumoniae infections,

Other diseases and ATM has been observed. Immunomodulating therapies may have a role in treatment of such cases. A  case of TM with urinary retention in 16-year-old man caused by M. pneumoniae was also reported. He was discharged from the hospital after 2 months. However, since urinary frequency, urge incontinence, and weak urinary stream persisted, he was referred to a pressure flow study examination showing overactive detrusor and DSD. He is improved after 8 months of oral propiverin hydrochloride and imipramine hydrochloride treatment but still has nighttime incontinence. Another case described a 9-yearold girl with urinary retention 16 days after measles and rubella vaccination. Her illness was diagnosed as TM. She was treated with steroids and discharged with only mild lower limb weakness. Krishnan et al.13 described the clinical manifestations of TM as a consequence of a dysfunction of motor, sensory, and autonomic pathways. At peak deficit, 50% of patients with TM were completely paraplegic (with no volitional leg movements), virtually all had some degree of bladder dysfunction, and 80%–94% had numbness, paresthesias, or band-like dysesthesias. Recent studies have shown that the cytokine interleukin-6 may be a useful biomarker, as the levels of interleukin-6 in the CSF of acute TM patients c­ orrelate strongly with and are highly predictive of d ­ isability. Clinical trials testing the efficacy of promising axonoprotective agents in combination with intravenous (i.v.) ­steroids in the treatment of TM are currently underway.

Prognosis Longitudinal case series of ATM reveal that approximately one-third of patients recovered with little to no sequelae, one-third are left with moderate degree of permanent disability, and one-third has severe disabilities. Rapid progression of symptoms, back pain, and spinal shock predict poor recovery. Paraclinical findings such as absent central conduction on evoked potential testing and the presence of 14-3-3 protein, a marker of neuronal injury, in the CSF during the acute phase predict a poor outcome. Some authors reported that the recovery rate is generally complete. Bourre14 published a follow-up study on a series of patients with acute partial TM. The authors included 85 cases of first-episode acute partial TM prospectively and retrospectively collected at three neurologic centers in France and examined the rate of conversion to MS as well as predictive factors of long-term disability during a mean follow-up of 8.7 years. They confirmed the wellknown relevance of oligoclonal bands in the CSF and brain MRI abnormalities in increasing the risk for conversion to MS, while none of the explored clinical, MRI, CSF, and neurophysiological variables showed prognostic value for neurologic disability.

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Long-term follow-up of urological function in all patients with TM is recommended.14

Tropical spastic paraparesis Etiopathogenesis and epidemiology Tropical spastic paraparesis (TSP) is a condition associated with and probably caused by the retrovirus human T-cell lymphotropic virus type 1 (HTLV-1).15,16 HTLV-1 is a retrovirus with affinity for CD-4 cells. It is a common cause of paraparesis in the West Indies,17 where it was formerly known as Jamaican neuropathy or myelopathy, and in the southern islands of Japan, where it is called HTLV-1 associated myelopathy or HAM,18 but it is also found widely in the tropics and subtropics and in immigrants to northern Europe from endemic areas.16,19 The first description of the HTLV-1 was made in 1980, followed closely by the discovery of HTLV-2 in 1982. Since then, the main characteristics of these viruses, commonly referred to as HTLV-1/2, have been thoroughly studied. Central and South America and the Caribbean are areas of high prevalence of HTLV-1 and HTVL-2 and have clusters of infected people. The major modes of transmission have been through sexual contact, blood, and mother to child via breast-feeding. HTLV-1 is associated with adult T-cell leukemia/lymphoma (ATL), HAM/TSP, and HTLVassociated uveitis as well as infectious dermatitis of children. More clarification is needed in the possible role of HTLV in rheumatologic, psychiatric, and infectious diseases. Since cures for ATL and HAM/TSP are lacking and no vaccine is available to prevent HTLV-1 and HTLV-2 transmission, these illnesses impose enormous social and financial costs on infected individuals, their families, and healthcare systems. For this reason, public health interventions aimed at counseling and educating high-risk individuals and populations are of vital importance. In the Americas this is especially important in the areas of high prevalence.20 Cooper et al.21 and Goncalves et al.22 considered HTLV-1 as a significant global health problem, fortunately, still remaining largely confined to endemic areas and risk groups. However, increasing migration may mean that the virus will be encountered more frequently in areas traditionally thought of as virtually free of HTLV-1.

Pathology Meningomyelitis with demyelination and axonal loss, particularly affecting the corticospinal tracts is usually present. These findings are most prominent in lower thoracic and upper lumbar regions.16,17,23

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Symptoms

Urodynamic findings

This infection may give rise to a broad spectrum of disorders including T-cell leukemia/lymphoma, the myelopathy/TSP complex (M/TSP), and to a lesser extent, uveitis, arthritis, polymyositis, and peripheral neuropathy. M/ TSP is a progressive, chronic myelopathy characterized by spasticity, hyperreflexia, muscle weakness, and sphincter disorders. Much less frequently it may precede, or give rise to, a cerebellar syndrome with ataxia and intention tremor. The widespread nature of the pathological changes within the nervous system results in a complex variety of urodynamic and neurophysiological features. Gait disturbance is a main symptom of HAM; however, bladder dysfunction is one of the major symptom characteristic to HAM and these patients complaint of voiding disturbances frequently. Fujiki et al.24 reported a 75-year-old woman with HAM presenting with cerebellar signs. She was admitted because of walking unsteadiness, which initially appeared 3 years ago with gradual worsening. Neurological examination revealed limb and truncal ataxia, cerebellar type dysfunction of eye movements, pyramidal sign, diminished vibration sense, and neurogenic bladder. Serum and CSF titers of anti-HTLV-1 antibody were markedly elevated. MRI revealed abnormal signals in cerebral white matter, mild cerebellar atrophy, and thoracic cord atrophy. Cerebellar signs and symptoms were initial and main neurological manifestations in this patient, which were improved by steroid therapy. They considered this case was unique among HAM, because cerebellum was considered to be the main site of her lesions. The presence of a cerebellar syndrome or neuropathy of uncertain origin, in endemic areas, should lead to the inclusion of HTLV-1 infection in the differential diagnosis, even in the absence of pyramidal symptoms or defined M/TSP. Maternal seropositivity supports the hypothesis of mother–daughter transmission during breast-feeding. Anti-HTLV-1 antibodies and ATL-like cells can be present in the peripheral blood of patients with HAM. Clinical case with a cerebellar syndrome and peripheral neuropathy as manifestations of infection by HTLV-1 was described by Carod-Artal et al.25 This was the case of a 13-year-old adolescent girl who presented with a neurological syndrome which had started with head and limbs tremor, ataxia, dysmetria, frequent falls, and sphincter disorders. During the two and a half years that she had had this illness, she developed spastic paraparesis of the legs and had repeated urinary infections. Blood and CSF serology was positive for HTLV-1 using the enzymelinked immunoabsorbent assay (ELISA) technique and confirmed by Western blot. Electromyography (EMG) showed predominantly axonal sensomotor neuropathy. Neurogenic bladder was detected on urodynamic studies. MRI revealed moderate atrophy of the thoracic spinal cord and slight alterations of the subcortical white matter.

The condition is characterized by a progressive paraparesis associated with back pain and voiding disturbances. Although there have been many reports concerning the clinical and immunological features of this condition, little attention has been paid to the bladder dysfunction, which commonly accompanies it. Most patients had urodynamic evidence of detrusor overactivity and DSD. Supranuclear type of voiding dysfunctions seems to be in accordance with the known pathological lesions of this disease. Sakiyama et  al.26 evaluated symptoms and urodynamic examinations in untreated 31 patients with HAM. Although two cases (11%) had no urinary symptom, 19 cases (89%) suffered from dysuria, frequency, incontinence, or urgency. The combination of irritative and obstructive urinary disturbance was a characteristic symptom in the HAM patients. In three cases, the urinary symptoms preceded the gait disturbance, which is the main symptom of HAM. Urodynamics revealed bladder overactivity in 14 cases (66%), although three cases (15%) showed underactive or acontractile bladder with decrease in urinary sensation. Urethral pressure profile was normal, but DSD was found frequently at EMG. This typical dysfunction of the HAM patients was thought to be caused by destruction of the lateral column of the spinal cord. Eardley et  al.27 reported the clinical features, urodynamic results, and neurophysiological findings in six patients with urinary symptoms related to tropical spastic paraplegia. Voiding dysfunction was also evaluated in 26 patients (9 males and 17 females) with HAM by Yamashita and Kumazawa28 Of 26 patients, 22 (85%) had voiding difficulties, 15 (58%) had urinary frequency, and 9 (35%) had urge incontinence. Cystograms showed trabeculated bladder in five patients, vesicoureteral reflux in three, and bladder neck obstruction in five. In 25 patients (96%), urodynamic studies showed detrusor overactivity with normal urethral function during storage. Of these patients, 17 had detrusor underactivity with DSD during micturition. One patient had normal detrusor function during storage and detrusor contractility during voiding. In 1991, Imamura et  al.29 performed clinical surveys and urodynamic examinations in 25 untreated patients with HAM. Although four cases (16%) were entirely aware of urinary symptoms, the onset of urinary symptoms preceded other pyramidal symptoms in six cases (24%). All cases suffered from dysuria. The cause of dysuria was thought mainly to be DESD, but in some cases underactive detrusor and poor opening of the bladder neck at voiding were also the causes of dysuria. In 1994, again Imamura30 evaluated 50 patients with untreated HAM by urodynamic studies to clarify the nature of urinary disturbance and to find out suitable urological treatment. Both irritative and obstructive symptoms coexisted in the HAM patients. Thirty-eight percent of patients experienced urinary symptoms only throughout the affected period. The main cause of frequency was

Other diseases neurogenic detrusor overactivity during filling phase, which was found in 58% of patients. However, decreased effective bladder capacity due to large amount of residual urine was possibly another cause of frequency. DSD was the main cause of voiding symptoms, but in some cases underactive detrusor at voiding phase was also present. Hydronephrosis was observed in only 5 kidneys, although as many as 30 out of 46 cases (65.2%) showed bladder deformities. Seventeen patients (34%) had urinary tract infection at first visit. As the activities of daily living were deteriorated, the mean postvoid residual volume, incidence of detrusor hyperreflexia, and DSD were all increased. Medical treatment was effective to relieve subjective symptoms, but urodynamic examination did not necessarily confirmed improvement. Intermittent catheterization was needed and successful in 64% of all cases. Walton and Kaplan31 presented urodynamic findings in four females and one male with TSP. Of the five patients, four presented with DESD and one had detrusor overactivity with coordinated sphincter contraction. Hattori et  al.32 reported the findings of voiding histories and urodynamic studies in five patients with HTLV-1 associated myelopathy. Histories showed that all patients had obstructive as well as irritative voiding symptoms, and symptoms were present from the onset of the disease in four patients. Urodynamic studies showed that four patients had residual urine (average 170 mL), all had detrusor overactivity and two had DSD. No patient had neurogenic changes in external urethral sphincter EMG. Supranuclear type of voiding dysfunctions seemed to be in accordance with the known pathological lesions of this disease. Matsumoto et al.33 performed clinical and electrophysiological studies in nine cases of HAM (seven females and two males). Spastic paraparesis and neurogenic bladder were present in eight patients and sensory disturbances were detected only in four. The conduction velocities of the posterior tibial and sural nerves were reduced in two cases. Median nerve SSEP revealed a delay of N11, N13, N14, N20 peak latencies and an increase of N9–N20, N13– N14, and N13–N20 interpeak latencies. The electrophysiological studies are the most accurate indicators of the diffuse involvement not only of central motor and sensory pathways but also of the peripheral nervous system. Mori et al.34 recommended in patients with HAM/TSP ultrasound (US) and video-urodynamic studies as the usual methods to define the common diagnosis of neurogenic bladder. Many kidney disturbances can occur due to HAM/TSP neurogenic bladder. US evaluation determines the renal size and parenchyma detail, enlargement of the ureters, hydronephrosis, and kidney stones. Neurogenic bladder leads to incomplete emptying and chronic inflammation of the bladder. Stone formation and acquired diverticula are possible complications. The study of urodynamics is useful for establishing the bladder pattern and choosing the best therapeutic approach. This evaluation

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identifies the storage pressures, the residual volume, and voiding dysfunctions, which are important for the planning of treatment strategies. Cystoscopy is a method that complements bladder evaluation, since it allows a direct view of its contents and mucosa aspect.34

Complications Lower urinary symptoms associated with HAM/TSP are common, but have been regarded as “neurogenic” due to spinal involvements. However, in some cases, these symptoms are persistent, progressive, and do not correlate directly with the severity of other neurologic symptoms of the lower spinal cord. These findings prompted Nomata et al.35 to locate organic lesions in the lower urinary tract and to correlate them with HTLV-1 infection. Among 35 HAM patients with lower urinary symptoms, they found 4 cases with persistent and progressive symptoms, 3 with contracted bladder, and another with persistent prostatitis. Histologic or cytologic investigations indicated local lymphocyte infiltrations in the lower urinary tract in all cases, with bladder infiltration in three cases and high lymphocyte concentration in expressed prostatic secretions in others. Of three cases whose urine samples were available, urinary concentration of anti-HTLV-1 immunoglobulin A (IgA) antibodies were significantly increased in two cases. The urinary IgA antibodies were not elevated in the third case, but the sample had been obtained after resection of the affected bladder. None of the control cases showed significant levels of anti-HTLV-1 IgA antibodies in urine except for a case of gross hematuria due to chemotherapy for ATL. They suggested inclusion of these processes into the spectrum of complications for HAM/TSP. The elevated level of anti-HTLV-1 IgA antibodies in the urine may be an indicator of these complications. There is a tendency for urinary dysfunction to become worse as the primary disease progresses.

Treatment Idiopathic or HTLV-1 associated progressive spastic paraparesis does not have a clear treatment. Cartier et  al.36 assessed the effects of a medication containing cytidine monophosphate (CMP), uridine triphosphate, and vitamin B12 in the treatment of progressive spasticity. Patients with the disease were randomly assigned to receive the Nucleus CMP forte (containing disodium CMP 5 mg, trisodium uridine triphosphate 3 mg, and hydroxocobalamin 2 mg) three times a day or placebo for 6 months. Gait, spasticity, degree of neurogenic bladder, and SSEPs were assessed during treatment. Results: Forty-six patients aged 25 to 79 years old were studied, 24 were females and 29 were HTLV-1 positive. Twenty-two were treated with the drug and the rest with placebo. Gait and spasticity

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improved in 7 of 22 patients receiving the drug and 1 of 24 receiving placebo (p < .05). Neurogenic bladder improved in 10 of 22 receiving the drug and 4 of 24 receiving placebo (normal saline). SSEPs improved in four of seven patients treated with the drug and in two of seven treated with placebo. The medication resulted in a modest improvement in patients with progressive spastic paraparesis and was free of side effects. Harrington et  al.37 used danazol for the treatment of urinary incontinence in TSP. Saito et  al.38 reported four patients (three females and one male) diagnosed by neurologists to have HAM with spastic gait disturbance and increased titer of antiHTLV-1 antibodies. They complained of urge incontinence, bed wetting, voiding difficulties, and/or frequency. Urodynamically, severe uninhibited detrusor contractions were observed in three of them. On the other hand, in one case, detrusor contractility during voiding was completely lost. Bladder sensation was well preserved in all patients. Corticosteroids and interferon could not improve their urological symptoms. CIC in three patients with a significant amount of postvoid residual urine volume relieved their urinary incontinence. They believed that HAM in patients suffering from severe voiding disturbances is a good indication for CIC. Namima et al.39 reported two cases with HAM. Case 1 (24-year-old female) had complained of slowly progressive urinary incontinence (since 14 years old) and gait disturbance (since 18 years old). Marked pyramidal disorder was observed, and anti-HTLV-1 antibodies (1:640) were present in her peripheral blood. She was diagnosed as having HAM. Repeated urodynamic studies revealed exacerbation of overactive bladder and DSD with progression of the disease. Case 2 (48-year-old male) had complained of gait disturbance (since 32 years old) and progressive urinary hesitancy (since 46 years old). Physical examination revealed significant pyramidal disorder. Anti-HTLV-1 antibodies (1:200) and ATL-like cells were present in his peripheral blood. He was diagnosed as having HAM. Voiding cystourethrography demonstrated an abnormal change of the bladder wall. Urodynamic studies revealed overactive bladder and marked DESD. Medications based on adrenocortical steroids and urological care have improved urinary disturbance, in both cases.

Conclusions In summary, TSP is a spinal cord disorder caused by the retrovirus HTLV-1. Patients commonly have urinary symptoms that usually begin simultaneously with complaints of limb weakness. This process must be distinguished from MS. Patients suffering from symptoms due to TSP are mostly (in up to 80%) affected by DESD. Thus, it seems justifiable that patients with TSP who have urinary symptoms are evaluated aggressively. These patients are at

high risk for DESD and they should undergo urodynamic evaluation before instituting appropriate therapy. This is particularly true in men with TSP to prevent the potential deleterious effects of untreated and unrecognized DESD on the upper tract. Patients with HAM must be carefully followed by urologist to prevent a deterioration of the urinary tract.

Progressive multifocal leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) is an infectious demyelinating brain disease caused by the JC virus (JCV), which is associated with significant morbidity and mortality in the immunocompromised host. Polyomaviruses (BK virus [BKV], JCV, and simian virus 40) have been known to be associated with diseases in humans for over 30 years. BKV-associated nephropathy and JCV-induced PML were rare diseases for many years occurring only in patients with underlying severe impaired immunity. Over the past decade, the use of more potent immunosuppression (IS) in transplantations and acquired immune deficiency syndrome (AIDS) have coincided with a significant increase in the prevalence of these viral complications. PML is an infectious demyelinating brain disease caused by the JCV that is associated with significant morbidity and mortality in the immunocompromised host. It is a destructive demyelinating infection which vitiates oligodendrocytes. The dramatic increase in the incidence of PML that occurred as a consequence of the AIDS pandemic and the recent association of PML with the administration of natalizumab, a monoclonal antibody against α4 integrin that blocks entry of inflammatory cell into the brain, has stimulated a great deal of interest in this previously obscure viral demyelinating disease. The etiology of this disorder is JCV (JCV) observed in 80% of the population worldwide. Seroepidemiological studies indicate that infection with this virus typically occurs before the age of 20 years. No primary illness owing to JCV infection has been recognized and the means of spread from person to person remains obscure. Following infection, the virus becomes latent in bone marrow, spleen, tonsils, and other tissues. Periodically, the virus reactivates during which time it can be demonstrated in circulating peripheral lymphocytes. The latter is significantly more commonly observed in immunosuppressed populations compared to normal subjects. Despite the large pool of people infected with JCV, PML remains a relatively rare disease. It is seldom observed in the absence of an underlying predisposing illness, typically one that results in impaired cellular immunity. Variety of factors are likely responsible for the unique increase in frequency of PML in human immunodeficiency virus (HIV) infection relative to other underlying immunosuppressive disorders. Preliminary data suggest that natalizumab appears

Other diseases to distinctively predispose recipients to PML relative to other infectious complications. Studies in these populations will be invaluable in understanding the mechanisms of disease pathogenesis.40 Bratt et al.,41 during 6 years, investigated approximately 400 CSF samples from immunosuppressed individuals with neurological symptoms by polymerase chain reaction (PCR) for the presence of polyomaviruses at the Gay Men’s Health Clinic in Sweden. The two widespread human polyomaviruses, BKV and JCV establish latency in the urinary tract and can be reactivated in AIDS. JCV might cause PML, but although up to 60% of AIDS patients excrete BKV in the urine, there have been few reports of BKV-related renal and/or neurological diseases. BKV could be demonstrated in the brain, CSF, eye tissues, kidneys, and peripheral blood mononuclear cells. BKV DNA has, so far, only been found in one case. They also analyzed brain, eye tissue, CSF, urine, and peripheral blood mononuclear cells by nested PCR for polyomavirus DNA. Macroscopic and microscopic examinations were performed of the renal and brain tissue obtained postmortem. Immunohistochemical staining for the two BKV proteins, the VP1, and the agnoprotein, was performed on autopsy material and virus-infected tissue culture cells. Although reports of BKV infections in the nervous system are rare, there is now evidence for its occurrence in immunocompromised patients and the diagnosis should be considered in such patients with neurological symptoms and signs of renal disease. It is easy to verify and also important to establish this diagnosis. Robinson et al.42 reported a case of PML treated successfully with highly active antiretroviral therapy and cidofovir in an adolescent patient perinatally infected with HIV causing PML. Aksamit43 described PML in patients treated with natalizumab. MRI scan imaging of the brain gives clues to ­diagnosis but is nonspecific in distinguishing MS from PML. Spinal fluid detection of JCV is specific but has insufficient sensitivity. Associated IS is typically of the cell-mediated type but can be poorly defined on clinical grounds. It is apparent that natalizumab is a predisposing factor for developing PML from the three cases of natalizumab-treated patients. There is no reliable presymptomatic way to detect PML or JCV infection of the brain by virologic or imaging surveillance techniques. One patient with MS and natalizumab treatment has survived, indicating that withdrawal of antibody, possibly in combination with antiviral therapy, may permit survival. However, immune reconstitution disease is a risk after immune restoration and withdrawal of natalizumab. PML deficits would be expected to be permanent. Estimated incidence of PML in natalizumab-treated patients is 1 per 1000. The duration of natalizumab treatment may be an independent risk factor for development of PML. PML, usually fatal neurologic infection, should be considered as a risk factor when using natalizumab. The treatment of MS patients

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with natalizumab is a matter of informed risk, individualized for each MS patient. Prophylactic and therapeutic interventions for human polyomavirus diseases are limited by our current understanding of polyomaviral pathogenesis. Clinical trials are limited by small numbers of patients affected with clinically significant diseases, lack of defined risk factors and disease definitions, no proven effective treatment, and the overall significant morbidity and mortality associated with these diseases.44 Baldwin et al.45 described that PML—as a rare opportunistic infection of the CNS—has been recently associated with selective IS in patients with MS. Treatment of MS with natalizumab first involves risk stratifying patients. Clinicians can use new tools for risk stratification including JC virus–antibody status, prior IS, and length of natalizumab treatment. These tools can help to minimize the risk of developing PML.

Lyme disease Etiology and epidemiology Lyme disease (LD) is a multisystemic, tick-borne infectious disease caused by Borrelia burgdorferi, the type of bacterium called a spirochete that is carried by deer ticks. Infected tick can transmit the spirochete to humans and animals by its bites. Untreated, the bacterium travels through the bloodstream, gets into various body tissues and can cause a number of symptoms, of which some being severe. Lyme borreliosis is a multiorgan infection caused by spirochetes of the Borrelia burgdorferi sensu lato group with its species B. burgdorferisensu stricto, Borrelia garinii, and Borrelia afzelii, which are transmitted by ticks of the species Ixodes. This multisystemic infection may cause skin, neurological (including neurogenic bladder), cardiac, or rheumatologic disorders. Manifestations of what we now call Lyme disease were first reported in the medical literature in Europe in 1883. Over the years, various clinical signs of this illness have been noted as separate medical conditions: acrodermatitis chronica atrophicans, lymphadenosis benigna cutis, erythema migrans (EM), and lymphocytic meningoradiculitis (Bannwarth’s syndrome). However, these diverse manifestations were not recognized as indicators of a single infectious illness until 1975, when LD was described following an outbreak of apparent juvenile arthritis, preceded by a rash, among residents of Lyme, CT. Lyme borreliosis caused by the spirochete B. burgdorferi is now the most common vector-borne disease in North America, Europe, and Asia. It is potentially serious infection common in many countries of the world, but little data about its incidence, distribution, and clinical manifestations are available. Since very little is known about the clinical expression of Lyme borreliosis in Western Europe,

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a 3-year prospective study was conducted by Attali et al.46 studying disease expression of Lyme borreliosis in northeastern France. It included all patients seen for suspected Lyme borreliosis at the Strasbourg University Hospital in northeastern France. The diagnosis of Lyme borreliosis was made on the basis of the presence of EM or on the basis of another suggestive clinical manifestation and laboratory confirmation. A total of 132 patients, 70 women and 62 men, mean age 54 years, had Lyme borreliosis according to these criteria. Within this study group, 77% of the patients were regularly exposed to tick bites and 64% could remember one. EM, the most frequent clinical manifestation, occurred in 60% of the patients and was the only sign of Lyme borreliosis in 40%. Lymphocytoma and acrodermatitis chronica atrophicans were rare (one and three patients, respectively). Nervous system involvement (mainly radiculoneuropathy), the second most common clinical manifestation, was found in 40% of the patients and was the only sign of Lyme borreliosis in 22%. Musculoskeletal involvement was present in 26% of the patients and was an isolated finding in 14%. During the study period, no patient was diagnosed with Lyme carditis. There was serological evidence of Lyme borreliosis in 75% of the cases and direct evidence of borrelial infection in 10 (7.5%). The results show that the clinical expression of Lyme borreliosis in northeastern France is similar to that in other European countries but different from that in North America. Data on disease expression and epidemiological characteristics of Lyme borreliosis in southeastern Europe are scarce. To reveal features of Lyme borreliosis in Bulgaria, clinical data and epidemiological characteristics of 1257 patients reported between 1999 and 2002 were analyzed by Christova and Komitova.47 The most affected age group was 5–9 years, followed by 45–49 years, 50–54 years, and 10–14 years. Most of the patients (68%) lived in rural area or were attacked by ticks during activities in rural area. Lyme borreliosis cases occurred throughout the year with two peaks—one in June and second smaller one in September. The most common clinical manifestation was EM, diagnosed in 868 (69.1%) of the patients. Rashes had a median diameter of 11 cm and were predominantly located on lower extremities. Forty-four percent of the rashes consisted of homogenous erythema and 56% had central clearing. Multiple EM was detected in 4.3% of the EM cases. Neuroborreliosis including voiding disorders was the second most common presentation of Lyme borreliosis and was diagnosed in 19% of the patients. Lyme arthritis was found in 8% of the patients. Cardiac and ocular manifestations were recorded in 1.1% and 0.9% of the patients, respectively. Borrelial lymphocytoma and acrodermatitis chronica atrophicans were very rare (0.3%). Twenty-seven patients (2.1%) had multiple organ involvement. The results of study show that epidemiology and clinical manifestations of Lyme borreliosis in Bulgaria are similar to those in the majority European countries but possess some distinguishing characteristics.

To improve the notification in Germany, 6 of Germany’s 16 states—Berlin, Brandenburg, MecklenburgVorpommern, Sachsen, Sachsen-Anhalt, and Thuringen— have enhanced notification systems, which include Lyme borreliosis. The efforts made in these states to monitor confirmed cases through notification are therefore an important contribution to understanding of Lyme b ­ orreliosis epidemiology in Germany. The report of Mehnert and Krause48 summarizes the analysis of Lyme borreliosis cases sent to the Robert Koch Institute during 2002–2003. The average incidence of Lyme borreliosis of the six East German states was 17.8 cases per 100,000 people in 2002 and increased by 31% to 23.3 cases in 2003, respectively. Patient ages were bimodally distributed, with a peak incidence among children aged 5–9 years and elderly patients, aged 60–64 in 2002, and 65–69 in 2003. For both years, 55% of patients were females. Around 86% of notified cases occurred from May to October. EM affected 2697 patients (89.3%) in 2002 and 3442 (86.7%) in 2003. For a vectorborne disease, like Lyme borreliosis, the risk of infection depends on the degree and duration of contact between humans and ticks harboring B. burgdorferi. As infected ticks probably occur throughout Germany, it is likely that the situation in the remaining 10 German states is similar to that of the states in this study. Nygarg et  al.49 from Norway confirmed in their study that Lyme borreliosis is also the most common tickborne infection in Norway. All clinical manifestations of Lyme borreliosis other than EM are notifiable to Folkehelseinstituttet, the Norwegian Institute of Public Health. During the period 1995–2004, a total of 1506 cases of disseminated and chronic Lyme borreliosis were reported. Serological tests were the basis for laboratory diagnosis in almost all cases. Annual statistics showed no clear trend over the period, but varied each year between 120 and 253 cases, with the highest number of cases reported in 2004. Seventy-five percent of cases with information on time of onset were in patients who fell ill during the months of June to October. There was marked geographical variation in reported incidence rates, with the highest rates reported from coastal counties in southern and central Norway. Fifty-six percent of the cases were in males and 44% in females. The highest incidence rate was found in children aged between 5 and 9 years. Neuroborreliosis was the most common clinical manifestation (71%), followed by arthritis/arthralgia (22%) and acrodermatitis chronica atrophicans (5%). Forty-six percent of patients were admitted to hospital. Prevention of borreliosis in Norway relies on measures to prevent tick bites, such as use of protective clothing and insect repellents, early detection, and removal of ticks. Antibiotics are generally not recommended for prophylaxis after tick bites in Norway. Kim et  al.50 reported—despite the fact that Korea is not an endemic area of LD—a case of a 32-year-old man with rapidly progressive bilateral ptosis, dysphagia, spastic

Other diseases paraparesis, and voiding difficulty in whom LD was diagnosed through serologic tests for antibodies and Western blot testing. A urodynamic study demonstrated detrusor areflexia and bulbocavernosus reflex tests showed delayed latency, indicating demyelination at S2–S4 levels. He received a 4-week course of i.v. ceftriaxone (2 g/day). The  patient has recovered from the bilateral ptosis and spastic paraparesis but still suffers from neurogenic bladder. The urodynamic study showed no voluntary or involuntary detrusor contraction on filling to 300 mL.50

Pathophysiology of voiding dysfunction in Lyme disease Micturition disorders in LD can occur by several mechanisms. First, Lyme cystitis can occur because the spirochete directly invades the urinary bladder. The second mechanism is related to neuroborreliosis, such as meningoencephalopathy, TM, myeloradiculitis, and demyelinating lesions of the spinal cord. Micturition disorders can appear in diverse forms such as detrusor hyperreflexia, DSD, and detrusor areflexia. Voiding dysfunction can appear as an initial symptom or as a later-stage symptom of LD. Micturition disorder generally develops after other neurological symptoms appear; however, it does sometimes appear in the early stage in a small number of cases.

Symptoms Although voiding dysfunction is a rarely reported symptom in patients with LD, it is one of the most disabling complications of LD. LD presents as a multisystemic inflammatory disease that affects skin in its early, localized stage and spreads to the joints, nervous system and, to a lesser extent, other organ systems in its later, disseminated stages. Early symptoms of LD can be mild and easily overlooked. People who are aware of the risk of LD in their communities and who do not ignore the sometimes subtle early symptoms are most likely to seek medical attention and treatment early enough to be assured of a full recovery. The first symptom is usually an expanding rash (called EM), which is thought to occur in 80% to 90% of all LD cases. As the LD spirochete continues disseminating through the body, a number of other symptoms including severe fatigue, a stiff, aching neck, and peripheral nervous system involvement such as tingling or numbness in the extremities or facial palsy (paralysis) can occur. The more severe, potentially debilitating symptoms of later stage LD may occur weeks, months, or in few cases years after a tick bite. These can include severe headaches, painful arthritis and swelling of joints, cardiac abnormalities, and CNS involvement leading to cognitive (mental) disorders.

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The following is a checklist of common symptoms seen in various stages of LD: •• ••

••

Localized early (acute) stage: Solid red or bull’s-eye rash, usually at site of bite, swelling of lymph glands near tick bite, generalized achiness, and headache Early disseminated stage: Two or more rashes not at site of bite, migrating pains in joints/tendons, headache, stiff, aching neck, facial palsy (facial paralysis similar to Bell’s palsy), tingling or numbness in extremities, multiple enlarged lymph glands, abnormal pulse, sore throat, changes in vision, fever of 100–102°F, severe fatigue Late stage: Arthritis (pain/swelling) of one or two large joints, disabling neurological disorders (disorientation, confusion, dizziness, short-term memory loss, inability to concentrate, finish sentences, or follow conversations; mental “fog”), numbness in arms/ hands or legs/feet

It was observed that the urinary tract may be involved in two respects in the course of LD: (1) voiding dysfunction may be part of neuroborreliosis and (2) the spirochete may directly invade the urinary tract. Several neurological manifestations of LD, both central and peripheral, have been described. Associated neurologic symptoms fall broadly into three syndromes: (1) encephalopathy, (2) polyneuropathy, and (3) leukoencephalitis. Common skin manifestations of Lyme borreliosis include EM, lymphocytoma, and acrodermatitis chronica atrophicans. The last two conditions are usually caused by B. garinii and B. afzelii, respectively, which are seen more frequently in Europe than in America. Late extracutaneous manifestations of Lyme borreliosis are characterized by carditis, neuroborreliosis, and arthritis.51

Diagnostic methods Laboratory testing of Lyme borreliosis includes culture, antibody detection using ELISA with whole extracts or recombinant chimeric borrelia proteins, immunoblot, and PCR with different levels of sensitivity and specificity for each test. The EM rash, which may occur in up to 90% of the reported cases, is a specific feature of LD, and treatment should begin immediately. Even in the absence of an EM rash, diagnosis of early LD should be made solely on the basis of symptoms and evidence of a tick bite, not blood tests, which can often give false results if performed in the first month after initial infection (later on, the tests are considered more reliable). If early symptoms are undetected or ignored, it is recommended to use the ELISA and Western blot blood tests. These tests are considered more reliable and accurate when performed at least a month after initial infection, although no test is 100% accurate. If neurological symptoms or swollen joints are present, in

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addition, a PCR test via a spinal tap or withdrawal of synovial fluid from an affected joint can be performed. This test amplifies the DNA of the spirochete and will usually indicate its presence. The aims of the thesis presented by Lebech52 were: (1) to develop PCR assay for direct detection of B. burgdorferi DNA and to evaluate the diagnostic utility of PCR in clinical specimens from patients with Lyme borreliosis and (2) to study the taxonomic classification of B. burgdorferi isolates and its implications for epidemiology and clinical presentation. Laboratory diagnosis of Lyme borreliosis by direct demonstration of B. burgdorferi in clinical specimens compared to current serology would allow (1) optimal specificity, (2) increased sensitivity during the first weeks of infection, when the antibody response is not yet detectable, and (3) discrimination between ongoing and past infection.52 Due to the extreme paucity of spirochetes in clinical specimens, neither in vitro culture nor antigen detection had yielded a sufficient diagnostic sensitivity. Thus, the recently introduced highly sensitive PCR methodology could be a solution and was thus studied. Assays for PCR amplification and subsequent identification of B. burgdorferi-specific sequences were established and used. For all assays, the analytical sensitivity was a few genome copies using purified DNA as template. The efficacy of PCR was initially evaluated using tissue samples from experimentally infected gerbils to start with biological samples a priori known to contain B. burgdorferi. B. burgdorferi DNA was detectable in 88% of the specimens. Thus, the diagnostic sensitivity of PCR was comparable to and even higher than in vitro culture. PCR was significantly more sensitive than in histological B. burgdorferispecific immunophosphatase staining method. The utility of the PCR was then tested for the identification of B. burgdorferi DNA in skin biopsies from 31 patients with EM. The sensitivity of PCR was 71%, which was superior to culture and serology. Based on our own and other published results, there is clear evidence for PCR being the most sensitive and specific test for detection of B. burgdorferi in skin biopsies from patients with both early and late dermatoborreliosis. However, since the clinical diagnosis of dermatoborreliosis in most instances is easy, an invasive procedure as skin biopsy will only be justified in patients with atypical clinical presentation. The most frequent and serious manifestation of disseminated Lyme borreliosis is neuroborreliosis. PCR was used in 190 patients with untreated and confirmed neuroborreliosis. B. burgdorferi DNA was detectable in 17%–21% of CSF samples from patients with neuroborreliosis. In patients with very early neuroborreliosis (6 months after stroke)

Success: continue therapy

Failure: urodynamic evaluation

Intravesical botulinum toxin or sacral neuromodulation

Figure 21.6 Proposed treatment algorithm for post–cerebrovascular accident incontinence.

strokes. Urodynamics is recommended in this patient population prior to any incontinence surgery, and the sur­ gery should be delayed for at least 6 months. Suburethral bulking agents may also be a valid option for a patient with primarily stress incontinence. Patients with brain tumors will often show improve­ ment in urinary symptoms after surgical excision or radiotherapy. Komei Ueki11 found that 5 out of 10 patients treated with radiotherapy for pontine tumors showed remarkable improvement in voiding complaints after therapy. In addition, the majority of patients with urinary symptoms who underwent surgical resection also saw improvement. Overall, patients with brain tumors can be treated in a similar fashion to stroke patients.

Conclusion Patients with intracranial pathologies such as CVAs and brain tumors often develop a disturbance in their voiding and sexual habits. Incontinence usually occurs in the early periods after an acute event. Subsequently, the typical pre­ sentation is an overactive detrusor that results in urgency and urge incontinence. Incontinence after a CVA is a very

important prognostic factor for the mortality, severity of stroke, and recovery of the patient. Though management can be challenging in these patients, social continence should be the ultimate goal, as this can affect their over­ all sense of well-being and quality of life. Through a thor­ ough understanding of the anatomy and behavior of brain lesions, the urologist should be able to understand and anticipate the needs of these often disabled patients.

References 1803. Calabro RS, Bramanti P. Post-stroke sexual dysfunction: An over­ looked and under-addressed problem. Disabil Rehabil 2014; 36(3): 263–4. 1804. Ovbiagele B, Goldstein LB, Higashida RT et al. Forecasting the future of stroke in the United States: A policy statement from the American Heart Association and American Stroke Association. Stroke 2013; 44(8): 2361–75. 1805. Rosamond W, Flegal K, Friday G et al. Heart disease and stroke sta­ tistics –2007 update: A report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007; 115: e69–171. 1806. Towfighi A, Saver JL. Stroke declines from third to fourth leading cause of death in the United States: Historical perspective and chal­ lenges ahead. Stroke 2011; 42: 2351–5.

Cerebrovascular accidents, intracranial tumors, and urologic consequences 1807. May DS, Kittner SJ. Use of Medicare claims data to estimate national trends in stroke incidence, 1985–1991. Stroke 1994; 25: 2343–7. 1808. Burney TL, Senapati M, Desai S et al. Effects of cerebrovascular acci­ dent on micturition. Urol Clin North Am 1996; 23: 483–90. 1809. Bondy ML, Scheurer ME, Malmer B et al. Brain tumor epidemiol­ ogy: Consensus from the Brain Tumor Epidemiology Consortium. Cancer 2008; 113: 1953–68. 1810. Nelson N. Recent studies show cell phone use is not associated with increased cancer risk. J Natl Cancer Inst 2001; 93: 170–2. 1811. Central Brain Tumor Registry of the United States. Analyses of the NPCR, IARC and SEER data, 2005–2009. Available at: http://www .cbtrus.org/factsheet/factsheet.html, accessed May 17, 2013. 1812. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer J Clin 2012; 62: 10–29. 1813. Ueki K. Disturbances of micturition observed in some patients with brain tumor. Neurologia Medico-Chirurgica 1960; 2: 25–33. 1814. Brittain KR, Perry SI, Peet SM et al. Prevalence and impact of uri­ nary symptoms among community-dwelling stroke survivors. Stroke 2000; 31: 886–91. 1815. Marinkovic SP, Badlani G. Voiding and sexual dysfunction after cerebrovascular accidents. J Urol 2001; 165: 359–70. 1816. Pfisterer MH-D, Griffiths DJ, Rosenberg L et al. The impact of detru­ sor overactivity on bladder function in younger and older women. J Urol 2006; 175: 1777–83. Discussion 1783. 1817. Abeloff DMD, Armitage JO, Niederhuber JE. Abeloff ’s Clinical Oncology. New York, NY: Churchill Livingstone, 2008. 1818. Plum F, Posner JB. The Diagnosis of Stupor & Coma. New York, NY: Oxford University Press, 1982. 1819. Carlsson CA. The supraspinal control of the urinary bladder. Acta Pharmacol Toxicol (Copenh) 1978; 43(Suppl 2): 8–12. 1820. Siracusa G, Sparacino A, Lentini V. Neurogenic bladder and disc disease: A brief review. Curr Med Res Opin 2013; 29(8): 1025–31. 1821. Bradley WE, Sundin T. The physiology and pharmacology of uri­ nary tract dysfunction. Clin Neuropharmacol 1982; 5: 131–58. 1822. Kavia RBC, Dasgupta R, Fowler CJ. Functional imaging and the cen­ tral control of the bladder. J Comp Neurol 2005; 493: 27–32. 1823. Blok BF, Holstege G. Direct projections from the periaqueductal gray to the pontine micturition center (M-region). An anterograde and retrograde tracing study in the cat. Neurosci Lett 1994; 166: 93–6. 1824. Sacco RL. Risk factors, outcomes, and stroke subtypes for ischemic stroke. Neurology 1997; 49: S39–44. 1825. Blok BF, Willemsen AT, Holstege G. A PET study on brain control of micturition in humans. Brain 1997; 120(Pt 1): 111–21. 1826. de Groat WC. Nervous control of the urinary bladder of the cat. Brain Res 1975; 87: 201–11. 1827. Sakakibara R, Hattori T, Yasuda K et al. Micturitional disturbance and the pontine tegmental lesion: Urodynamic and MRI analyses of vascular cases. J Neurol Sci 1996; 141: 105–10. 1828. Fukuyama H, Matsuzaki S, Ouchi Y et al. Neural control of mic­ turition in man examined with single photon emission computed tomography using 99mTc-HMPAO. Neuroreport 1996; 7: 3009–12. 1829. Tadic SD, Tannenbaum C, Resnick NM et al. Brain responses to bladder filling in older women without urgency incontinence. Neurourol Urodyn 2013. 1830. Griffiths D. Clinical studies of cerebral and urinary tract function in elderly people with urinary incontinence. Behav Brain Res 1998; 92: 151–5. 1831. Borrie MJ, Campbell AJ, Caradoc-Davies TH et al. Urinary inconti­ nence after stroke: A prospective study. Age Ageing 1986; 15: 177–81. 1832. Burney TL, Senapati M, Desai S et al. Acute cerebrovascular acci­ dent and lower urinary tract dysfunction: A prospective correlation of the site of brain injury with urodynamic findings. J Urol 1996; 156: 1748–50. 1833. Gelber DA, Good DC, Laven LJ et al. Causes of urinary inconti­ nence after acute hemispheric stroke. Stroke 1993; 24: 378–82.

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1834. Kong KH, Young S. Incidence and outcome of poststroke urinary retention: A prospective study. Arch Phys Med Rehabil 2000; 81: 1464–7. 1835. Patel M, Coshall C, Lawrence E et al. Recovery from poststroke uri­ nary incontinence: Associated factors and impact on outcome. J Am Geriatr Soc 2001; 49: 1229–33. 1836. Rees JH. Diagnosis and treatment in neuro-oncology: An oncologi­ cal perspective. Br J Radiol 2011; 84(Spec No 2): S82–9. 1837. Grant R. Overview: Brain tumour diagnosis and management/ Royal College of Physicians guidelines. J Neurol Neurosurg Psychiatr 2004; 75(Suppl 2): ii18–23. 1838. Renier WO, Gabreels FJ. Evaluation of diagnosis and non-surgical therapy in 24 children with a pontine tumour. Neuropediatrics 1980; 11: 262–73. 1839. Yaguchi H, Soma H, Miyazaki Y et al. A case of acute urinary retention caused by periaqueductal grey lesion. J Neurol Neurosurg Psychiatr 2004; 75: 1202–3. 1840. Tsuchida S, Noto H, Yamaguchi O et al. Urodynamic studies on hemiplegic patients after cerebrovascular accident. Urology 1983; 21: 315–8. 1841. Kalra L, Smith DH, Crome P. Stroke in patients aged over 75 years: Outcome and predictors. Postgrad Med J 1993; 69: 33–6. 1842. Brittain KR, Peet SM, Castleden CM. Stroke and incontinence. Stroke 1998; 29: 524–8. 1843. Brocklehurst JC, Andrews K, Richards B et al. Incidence and cor­ relates of incontinence in stroke patients. J Am Geriatr Soc 1985; 33: 540–2. 1844. Anderson CS, Jamrozik KD, Broadhurst RJ et al. Predicting survival for 1 year among different subtypes of stroke. Results from the Perth Community Stroke Study. Stroke 1994; 25: 1935–44. 1845. Rotar M, Blagus R, Jeromel M et al. Stroke patients who regain uri­ nary continence in the first week after acute first-ever stroke have better prognosis than patients with persistent lower urinary tract dysfunction. Neurourol Urodyn 2011; 30: 1315–8. 1846. Pettersen R, Wyller TB. Prognostic significance of micturition dis­ turbances after acute stroke. J Am Geriatr Soc 2006; 54: 1878–84. 1847. Hartman-Maeir A, Soroker N, Oman SD et al. Awareness of disabili­ ties in stroke rehabilitation –a clinical trial. Disabil Rehabil 2003; 25: 35–44. 1848. Pohjasvaara T, Leskelä M, Vataja R et al. Post-stroke depression, executive dysfunction and functional outcome. Eur J Neurol 2002; 9: 269–75. 1849. Turhan N, Atalay A, Atabek HK. Impact of stroke etiology, lesion location and aging on post-stroke urinary incontinence as a predic­ tor of functional recovery. Int J Rehabil Res 2006; 29: 335–8. 1850. Thommessen B, Bautz-Holter E, Laake K. Predictors of outcome of rehabilitation of elderly stroke patients in a geriatric ward. Clin Rehabil 1999; 13: 123–8. 1851. Tilling K, Sterne JA, Rudd AG et al. A new method for predicting recovery after stroke. Stroke 2001; 32: 2867–73. 1852. van Kuijk AA, van der Linde H, van Limbeek J. Urinary inconti­ nence in stroke patients after admission to a postacute inpatient rehabilitation program. Arch Phys Med Rehabil 2001; 82: 1407–11. 1853. Samanci N, Dora B, Kizilay F et al. Factors affecting one year mor­ tality and functional outcome after first ever ischemic stroke in the region of Antalya, Turkey (a hospital-based study). Acta Neurol Belg 2004; 104: 154–60. 1854. Barer DH. Continence after stroke: Useful predictor or goal of ther­ apy? Age Ageing 1989; 18: 183–91. 1855. Haacke C, Althaus A, Spottke A et al. Long-term outcome after stroke: Evaluating health-related quality of life using utility mea­ surements. Stroke 2006; 37: 193–8. 1856. Ween JE, Alexander MP, D’Esposito M et al. Incontinence after stroke in a rehabilitation setting: Outcome associations and predic­ tive factors. Neurology 1996; 47: 659–63.

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1857. Edwards DF, Hahn M, Dromerick A. Post stroke urinary loss, ­incontinence and life satisfaction: When does post-stroke urinary loss become incontinence? Neurourol Urodyn 2006; 25: 39–45. 1858. Williams AM. Caregivers of persons with stroke: Their physical and emotional well-being. Qual Life Res 1993; 2: 213–20. 1859. Noelker LS. Incontinence in elderly cared for by family. Gerontologist 1987; 27: 194–200. 1860. Hunskaar S. A systematic review of overweight and obesity as risk factors and targets for clinical intervention for urinary incontinence in women. Neurourol Urodyn 2008; 27: 749–57. 1861. Korpelainen JT, Nieminen P, Myllyla VV. Sexual functioning among stroke patients and their spouses. Stroke 1999; 30: 715–9. 1862. Hayder D. The effects of urinary incontinence on sexuality: Seeking an intimate partnership. J Wound Ostomy Continence Nurs 2012; 39: 539–44. 1863. Sims J, Browning C, Lundgren-Lindquist B et al. Urinary incon­ tinence in a community sample of older adults: Prevalence and impact on quality of life. Disabil Rehabil 2011; 33: 1389–98. 1864. Coyne KS, Sexton CC, Thompson C et al. The impact of OAB on sexual health in men and women: Results from EpiLUTS. J Sex Med 2011; 8: 1603–15. 1865. Sakakibara R, Hattori T, Yasuda K et al. Micturitional disturbance after acute hemispheric stroke: Analysis of the lesion site by CT and MRI. J Neurol Sci 1996; 137: 47–56. 1866. Zhang H, Reitz A, Kollias S et al. An fMRI study of the role of supra­ pontine brain structures in the voluntary voiding control induced by pelvic floor contraction. Neuroimage 2005; 24: 174–80. 1867. Kuroiwa Y, Tohgi H, Ono S et al. Frequency and urgency of micturi­ tion in hemiplegic patients: Relationship to hemisphere laterality of lesions. J Neurol 1987; 234: 100–2. 1868. Andrew J, Nathan PW. Lesions on the anterior frontal lobes and dis­ turbances of micturition and defaecation. Brain 1964; 87: 233–62.

1869. Wein A, Barrett DM. Etiologic possibilities for increased pelvic floor electromyography activity during cystometry. J Urol 1982; 127: 949–52. 1870. Khan Z, Hertanu J, Yang WC et al. Predictive correlation of urody­ namic dysfunction and brain injury after cerebrovascular accident. J Urol 1981; 126: 86–8. 1871. Tibaek S, Gard G, Jensen R. Pelvic floor muscle training is effec­ tive in women with urinary incontinence after stroke: A ran­ domised, controlled and blinded study. Neurourol Urodyn 2005; 24: 348–57. 1872. Bottiggi KA, Salazar JC, Yu L et al. Long-term cognitive impact of anticholinergic medications in older adults. Am J Geriatr Psychiatry 2006; 14: 980–4. 1873. Hunsballe JM, Djurhuus JC. Clinical options for imipramine in the management of urinary incontinence. Urol Res 2001; 29: 118–25. 1874. Natsume O, Yasukawa M, Yoshii M et al. Transurethral resection of the prostate in the urological management for patients with stroke. Hinyokika Kiyo 1992; 38: 1123–7. 1875. Lum SK, Marshall VR. Results of prostatectomy in patients follow­ ing a cerebrovascular accident. Br J Urol 1982; 54: 186–9. 1876. Kuo H-C. Therapeutic effects of suburothelial injection of botuli­ num a toxin for neurogenic detrusor overactivity due to chronic cerebrovascular accident and spinal cord lesions. Urology 2006; 67: 232–6. 1877. Kennelly M, Dmochowski R, Ethans K et al. Long-term efficacy and safety of onabotulinumtoxinA in patients with urinary inconti­ nence due to neurogenic detrusor overactivity: An interim analysis. Urology 2013; 81: 491–7. 1878. Amundsen CL, Romero AA, Jamison MG et al. Sacral neuromodu­ lation for intractable urge incontinence: Are there factors associated with cure? Urology 2005; 66: 746–50.

22 Intervertebral disk prolapse Patrick J. Shenot and M. Louis Moy

Introduction Intervertebral disk degeneration leading to disk prolapse is a leading cause of chronic disability in both sexes. Symptoms of disk prolapse may vary depending on the location of the herniation. Clinical symptoms can range from little or no pain if the disk is the only tissue involved to severe back pain associated with sensory or motor deficits in regions served by affected nerve roots that are irritated or compressed by the prolapsed disk. The frequency of lumbar disk prolapse is highest at L4/L5 and L5/SI levels, representing approximately 90% of symptomatic cases. The association of intervertebral disk prolapse with voiding dysfunction has long been recognized and typically results from the impact of spinal nerve root compression by the protruding disk.1 Nerve root compression may result in axonal dysfunction, ischemia, inflammation, and biochemical sensitization of afferent nerves. The true incidence of lower urinary tract dysfunction in patients with disk prolapse, however, is unclear as many reported series on this subject describe findings only in patients with the cauda equina syndrome who present with urologic symptoms.

Anatomy of the intervertebral disk The intervertebral disk in the adult is a complex avascular structure (Figure 22.1). The nucleus pulposus is composed of embryologically distinct chondrocyte-like cells and a loose collagen framework embedded in a gelatinous matrix of various glycosaminoglycans, water, and salts. In a healthy intervertebral disk, this material is under significant pressure and is restrained by dense collagenous annulus fibrosis. The annulus fibrosus is composed of numerous concentric layers of fibrocartilaginous tissue. Collagen fibers extend from the annulus to the surrounding tissues into both the longitudinal ligaments and the hyaline cartilage vertebral endplates superiorly and

inferiorly. At the cranial and caudal ends of each disk, the vertebral endplates separate the vertebral bone from the disk and prevent the nucleus pulposus from bulging into the adjacent vertebrae. The disk absorbs the considerable hydrostatic pressure that results from mechanical loading of the spine. Endplate tissue is rich hyaline cartilage, which acts to bind the disk to the overlying vertebral bones. The endplates are typically less than 1 mm thick and are often thinnest in the central region adjacent to the nucleus.2–4 Herniated disks in the lower lumbar spine most often result from avulsion of the vertebral endplate junction between the disk and the spinal bone, rather than rupture of the annulus fibrosus itself.5 The annulus fibrosus may also undergo progressive radial tearing, which can result in a focal asymmetry in the outer circumference of the annulus fibrosus, allowing for a localized disk bulge (contained herniation) or even frank extrusion (noncontained herniation) of disk material. This distinction is not always clinically apparent as a disk bulge may contribute significantly to symptomatic neural compression, and a true focal disk herniation may be asymptomatic. Disk herniations can also be classified by the ­anatomic location within zones along the circumference of  the ­annulus fibrosus in which the protrusion occurs. Pos­ terolateral herniations are most common and result in prolapsed disk material impinging on the anterolateral aspect of the traversing nerve root.6 A herniation that occurs in the central zone in the midline posteriorly may affect the traversing nerve roots bilaterally as well as all of the roots caudal to the herniation. Intervertebral disk prolapse may occur anywhere in the spine but is much more common in the lumbar spine. Lumbar disk protrusion appears to be highly prevalent in the adult population. A magnetic resonance imaging (MRI) study of asymptomatic individuals revealed that 27% of subjects had a protrusion (focal or asymmetric extension of the disk beyond the interspace) and 1% had an extrusion (more extreme extension of the disk beyond the interspace). Findings were similar in men and women.7

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Vertebral endplate Nucleus pulposus

Annulus fibrosus Vertebral endplate

Figure 22.1 Anatomy of the intervertebral disk.

Asymptomatic thoracic disk herniation is also common, with a prevalence of 7%–15%.8,9 However, symptomatic thoracic disk herniation is rare, accounting for only 0.25%–0.57% of all disk symptomatic herniations.9–11 A  study of 497 asymptomatic subjects found that posterior disk prolapse was noted in 27% of subjects.12 Posterior disk prolapse is potentially of great clinical significance because it may lead to radiculopathy and myelopathy. Spinal cord compression from posterior disk prolapse was found in 7.2% of asymptomatic subjects in this study, suggesting that mild cord compression does not necessarily result in myelopathy.

Pathophysiology of intervertebral disk disease Parasympathetic innervation via pelvic nerve originates in the motor nuclei within the intermediolateral columns of the sacral cord segments S2–S4 and provides the major excitatory input to the urinary bladder.13 Somatic innervation originates from the ventromedial aspect of the ventral gray matter of the third and fourth sacral segments via the pudendal nerve to provide innervation to the external urinary sphincter and the reminder of the pelvic floor musculature.14 Sympathetic innervation of the lower urinary tract originates from T11–L2 (sympathetic nucleus; intermediolateral column of gray matter) and follows pathways of the hypogastric nerves to provide inhibitory input to the bladder body as well as excitatory input to the urethra and bladder outlet. The pelvic, hypogastric, and pudendal nerves also carry sensory information in afferent fibers

from the lower urinary tract to the lumbosacral spinal cord. Sensory nerves initiate the micturition reflex and modulate the drive that maintains bladder contraction. In the adult, sacral segments of the spinal cord are located in the conus medullaris, the tapered distal tip of the spinal cord. Anatomically, this is usually at the level of the first and second lumbar vertebral bodies. Spinal cord segments in the thoracic and lumbar spine are named for the vertebral body at which its nerve roots exit the spinal canal. Thus, although the first sacral segment of the spinal cord is located at L1/L2, its nerve roots run in the subarachnoid space posterior to the L2 to L5 vertebral bodies until reaching the first sacral body at which point they exit the canal. This results in disk pathology most commonly affecting the nerve root one segment caudal (e.g., an L4 disk herniation would be expected to cause L5 root symptoms and findings). Because disk prolapse most commonly occurs in a posterolateral direction, it does not generally affect a significant portion of the cauda equina. Rarely, however, a large posterolateral disk prolapse may migrate medially and cause cauda equina compression. Central disk prolapse is less common and may occur in 1%–15% of cases.6 Central prolapse may result in more widespread compression of nerve roots arising from multiple spinal cord levels with the potential to cause the conus medullaris or cauda equina syndromes. Spinal root compression in the lower lumbar (L4–5 or L5–S1) disk space is a leading cause of the cauda equina syndrome. The mechanisms and pathways for the degenerative process in the intervertebral disk are not completely understood. Histological studies have demonstrated that one of the initial events triggering intervertebral disk degeneration is a decrease in the number of viable cells in the nucleus pulposus.15,16 The process of disk degeneration as well as its resulting symptoms may have, in part, a biochemical basis. The pain accompanying disk herniation may be caused by direct pressure on the nerve root or may be induced by breakdown products from a degenerated nucleus pulposus or by an autoimmune reaction. Disk material is a direct source of chemically irritative substances such as phospholipase A2, prostaglandin E2, substance P, and lactic acid. The chemical mediators contributing to progressive disk degeneration may also have a direct role in the sensitization of afferent nerve endings in the innervated structures surrounding the spinal canal as well as direct effects on the spinal nerve root and dorsal root ganglion.17 Spinal nerve roots, unlike peripheral nerves, lack appreciable epineurium and perineurium, making them more susceptible to symptomatic compression injury than peripheral nerves resulting from activation of primary sensory pathways, increased tissue swelling and tension from fluid accumulation, and presence of inflammatory mediators. Herniated disk material has been shown to elicit a

Intervertebral disk prolapse foreign body–type macrophage inflammatory response. Displaced disk material may have direct neurotoxic and vascular effects on spinal nerve roots, which is unrelated to compressive effects. A prolapsing disk can also affect the sacral nerves by compromising blood flow to and from the cauda equina.18 In an animal model, compression of veins around the cauda equina leads to congestion and ischemia of the nerve roots. Fifty percent constriction resulted in no significant cystometric changes but did cause venous congestion of the nerve roots and ganglia. Seventy-five percent constriction caused detrusor areflexia and markedly increased bladder capacity and overflow incontinence, as well as arterial narrowing and venous congestion of the nerve roots and ganglia.

Clinical findings Compression of nerve roots will typically result in lower back pain and pain that radiates along the lumbar dermatomes of the affected nerve roots.19 The true incidence of lower urinary tract dysfunction in patients with disk prolapse is unknown. It is important to remember that most patients with lumbar disk prolapse do not have the cauda equina syndrome or progressive weaknesses are initially managed medically. A distinct minority of patients presenting with lumbar disk protrusion will have clinical signs and symptoms of bladder dysfunctions. Many reported series on this subject describe findings only in patients who present with urologic symptoms. Multiple studies indicate that the patient will usually complain of urinary hesitancy and intermittency, straining to urinate, and sometimes a sensation of incomplete bladder emptying. Incontinence is much less common and implies a more severe insult resulting in diminished bladder sensation resulting in overflow incontinence, sphincteric dysfunction from pelvic floor denervation, or a combination of both processes. Changes in perineal and lower extremity motor function, sensation, and reflexes may be appreciated on physical examination. Characteristic findings are useful in

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determining which nerve roots are affected (Table 22.1). The most characteristic findings on physical examination are sensory loss in the perineum or perianal area (S2-4 dermatomes) and sensory loss on the lateral foot (S1-2 dermatomes).20 Unilateral and less severe sensory loss may portend a more favorable prognosis, while persistent sensory deficits suggest that bladder contractility may not completely recover because normal bladder function requires an intact sensory sacral visceral reflex arc.21,22 Somatic nerve involvement may be assessed by compression of glans penis in the male or clitoris in the female. The  increase in anal sphincter tone, known as the bulbocavernosus reflex (BCR), assesses pudendal (somatic) nerve function from which external sphincter function can be surmised. It is important to note that although this reflex is expected to be absent in all patients with complete lower motor neuron lesions of the sacral cord, 19% of healthy female subjects do not have a detectable BCR on physical examination.23 In one study of patients with cauda equina and conus injuries, BCR was absent or significantly diminished in 84% of the patients and perineal sensation and muscle-stretch reflexes were absent or diminished in 77% of patients.24 These findings showed significant correlations between a compromised BCR and neuropathic pelvic floor dysfunction. Many neurologic insults from intervertebral disk prolapse are incomplete and slowly progressive. Jones and Moore25 first postulated that neuropathic insult could result in a range of symptoms depending on the degree of nerve irritation and compression. A slow, progressive disk protrusion may result in nerve irritation and detrusor overactivity that progresses to detrusor areflexia as the degree of compression increases. A more acute compression of nerve roots, as may occur with acute traumatic disk rupture and herniation, interrupts nerve transmission and may result not only in detrusor areflexia from the impact on autonomic parasympathetic innervation of the bladder but also in sphincteric dysfunction from the effect on the somatic nerve roots supplying the pudendal nerve. In contrast, Ross suggested that the first manifestation of such bladder dysfunction was actually impaired sensation.26

Table 22.1  Clinical features of lumbar nerve root compression Disk

Nerve root

Pain

Sensory

Motor

Reflex

L3/L4

L4

Anterior thigh

Anterior thigh to medial ankle

Knee extension

Patellar

L4/L5

L5

Posterolateral leg

Dorsum of foot

Dorsiflexion, foot drop

Medial hamstring

L5/S1

S1

Posterior calf and plantar surface of foot

Lateral and plantar foot

Plantar flexion and eversion

Achilles

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Evaluation Lumbar spine MRI with gadolinium contrast is useful in the evaluation of symptomatic patients with lower urinary tract dysfunction presumed secondary to lumbar disk disease. It provides a more complete radiographic assessment of the spine than other imaging studies. Spinal nerve roots, conus medullaris, and cauda equina can be evaluated in great detail (Figure 22.2). Clinical findings often correlate well with MRI findings. Because of the high rate of disk degeneration noted in asymptomatic individuals, MRI findings are nonspecific and must always be correlated with clinical findings. Bladder dysfunction secondary to disk prolapse has been reported in two women who presented with painless urinary retention and no other neurological findings.27 MRI revealed lumbar central disk prolapse, suggesting that a prolapsed intervertebral disk may result in relatively isolated injury to the autonomic parasympathetic nervous input to the lower urinary tract. Urodynamic testing is invaluable to fully evaluate the type of voiding dysfunction. Assessment of the patient’s

postvoid residual volume should be made by catheterization or bladder ultrasound. A cystometrogram with simultaneous pelvic floor electromyography will provide the urodynamic diagnosis, whereas pressure flow studies are helpful in cases where obstruction may be present. Symptomatic prolapse is most common in middle-aged males who may have coexisting bladder outlet obstruction from benign prostatic hyperplasia. The primary urodynamic findings in symptomatic disk disease are diminished or absent detrusor contractility, often with impaired external sphincter activity and function. Normal bladder compliance is usually preserved. In cases of somatic preservation, the external sphincter is often nonrelaxing during straining to void creating a functional obstruction to limit bladder emptying. Incontinence may be secondary to overflow or to diminished outlet resistance from impaired sphincter function. In symptomatic patients, historical rates of voiding dysfunction as high as 92% have been noted.28 These studies have come into question as they measured intravesical pressure alone and made the diagnosis of decreased detrusor activity if the voiding reflex could not be elicited during examination. A prospective study of 114 patients complaining of lower back pain and disk protrusion who required surgical intervention found that 27% of subjects had detrusor areflexia while detrusor activity was normal in the remaining 83%.29 Clinical symptoms correlated well with urodynamic findings as all patients with detrusor areflexia complained of straining to void. A more recent study of patients with cervical, thoracic, and lumbar disk prolapse not only confirmed the finding of diminished detrusor contractility in lumbar disease but also showed, as expected, detrusor overactivity with or without sphincter dyssynergia in thoracic and cervical lesions.30

Treatment

Figure 22.2 Sagittal T2 weighted image of the lumbar spine. The conus medullaris (indicated by the arrow) ends at the L1/L2 interspace. The nerve roots forming the cauda equina are visible traveling from the cauda to the conus.

Laminectomy addresses the underlying cause and is often performed in patients but may not improve bladder function. Preoperative urodynamic evaluations may provide prognostic information. O’Flynn et al.6 followed 30 patients for 1 year following decompressive surgery for lumbar intervertebral disk prolapse. The most consistent urodynamic finding reported has been a normally compliant areflexic bladder associated with normal innervation or incomplete denervation of perineal floor muscles. In that study, only 1 of 26 patients with incontinence prior to laminectomy had normal postoperative bladder function. As the outlook for the return of normal detrusor function in such patients with detrusor areflexia is poor, prelaminectomy urodynamic evaluation is offered as it is difficult postoperatively in these cases to separate causation of voiding dysfunction owing to the disk from the sequelae of laminectomy such as spinal stenosis or arachnoiditis.

Intervertebral disk prolapse A study by Shapiro of 14 patients who presented with cauda equina syndrome secondary to lumbar disk herniation found that all 7 patients operated on within 48 hours regained continence, whereas only 2 of 6 patients operated on at lengths greater than 48 hours from presentation regained continence.31 It is unknown if detrusor function normalized in these patients. Bartolin et al.32 reported on the results of surgery in a group of patients with lumbar disk protrusion and lower urinary tract dysfunction. Detrusor function returned to normal in only 6 of 27 patients with detrusor areflexia preoperatively. Of the 71 patients with normal preoperative urodynamic findings, 4 patients developed detrusor overactivity and 3 developed detrusor areflexia postoperatively. Bladder management is guided by urodynamic findings to allow adequate bladder emptying while maintaining satisfactory continence and preserving upper urinary tract function. Most cases of disk prolapse resulting in lower urinary tract dysfunction occur in the lower lumbar region, below the level of the spinal cord. This results in a lower motor neuron–type lesion characterized by impaired detrusor contractility or detrusor areflexia with normal compliance. Intermittent catheterization is usually offered in patients with poor bladder contractility. Impaired bladder compliance, if present, is usually associated with conus injuries and myelopathy. Many patients with symptomatic disk disease, however, have preserved detrusor function but are plagued by frequency, urgency, and urge urinary incontinence. Anticholinergic medications can be given in such patients after assurance of adequate bladder emptying. Sacral neuromodulation (SNM) has also been utilized in managing these symptoms, although there is a lack of randomized controlled trials. The published studies have small numbers of patients with significant heterogeneity. Evidence primarily comes from retrospective case series with significant methodological flaws. In one trial of SNM, 17 of 32 patients were diagnosed with urge incontinence, of whom 52.9% reported a successful outcome at a mean of 2.3 years of follow-up compared to an 80.3% success rate in patients with no history of spinal surgery.33 Sixteen of 32 carried a diagnosis of urgency/frequency with 62.5% success at last follow-up, compared to 73.9% of those without a history of spinal surgery or neurological disease. Thirteen of 32 patients diagnosed with urinary retention experienced a 61.5% long-term success rate, compared with 63.6% for those without spinal surgery and urinary retention. The authors concluded that clinical success can be achieved using SNM in patients with voiding dysfunction and a history of spinal surgery; however, those with urge incontinence are less likely to report significant improvement. A systematic review and meta-analysis of 357 patients with neurogenic lower urinary tract dysfunction identified 30 patients with disk disease.34 Success of test stimulation

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in patients with disk disease was reported in 60% of subjects, whereas success of permanent implant disk disease was only 56% in those with a successful trial. Clearly, well-designed and adequately powered studies are needed before more widespread use of SNM for neurogenic lower urinary tract dysfunction can be recommended.

Conclusion Intervertebral disk disease can be associated with significant neurogenic lower urinary tract dysfunction. Disturbances in both bladder and sphincter function are well recognized. Characterization of the resulting voiding dysfunction mandates a thorough clinical evaluation correlated with findings on imaging studies and urodynamic testing. Clinical management of resulting urologic symptoms should strive for adequate bladder emptying and preservation of upper urinary tract function while relieving bothersome symptoms.

References 1879. Shephard RH. Diagnosis and prognosis of cauda equina syndrome produced by protrusion of lumbar disc. Br Med J 1959; 2: 1434–9. 1880. Pitzen T, Schmitz B, Georg T, Barbier D, Beuter T, Steudel WI, Reith W. Variation of endplate thickness in the cervical spine. Eur Spine J 2004; 13: 235–40. 1881. Grant JP, Oxland TR, Dvorak MF et al. The effects of bone density and disc degeneration on the structural property distributions in the lower lumbar vertebral endplates. J Orthop Res 2002; 20: 1115–20. 1882. Ochia RS, Tencer AF, Ching RP. Effect of loading rate on endplate and vertebral body strength in human lumbar vertebrae. J Biomech 2003; 36: 1875–81. 1883. Rajasekaran S, Bajaj N, Tubaki V et al. ISSLS Prize winner: The anatomy of failure in lumbar disc herniation: An in vivo, multimodal, prospective study of 181 subjects. Spine 2013; 38: 1491–500. 1884. O’Flynn KJ, Murphy R, Thomas DG. Neurogenic bladder dysfunction in lumbar intervertebral disc prolapse. Br J Urol 1992; 69: 38–40. 1885. Jensen MC, Brant-Zawadzki MN, Obuchowski N et al. Magnetic resonance imaging of the lumbar spine in people without back pain. N Engl J Med 1994; 331: 69–73. 1886. Abbott KH, Retter RH. Protrusions of thoracic intervertebral discs. Neurology 1956; 6: 1–10. 1887. Arseni C, Nash F. Thoracic intervertebral disc protrusion: A clinical study. J Neurosurg 1960; 17: 418–30. 1888. Carson J, Gumpert J, Jefferson A. Diagnosis and treatment of thoracic intervertebral disc protrusions. J Neurol Neurosurg Psychiatry 1971; 34: 68–77. 1889. Stillerman CB, Chen TC, Couldwell et al. Experience in the surgical management of 82 symptomatic herniated thoracic discs and review of the literature. J Neurosurg 1998; 88: 623–33. 1890. Matsumoto M, Fujimura Y, Suzuki N et al. MRI of cervical intervertebral discs in asymptomatic subjects. J Bone Joint Surg Br 1998; 80: 19–24. 1891. de Groat WC, Booth AM, Milne RJ, Roppolo JR. Parasympathetic preganglionic neurons in the sacral spinal cord. J Auton Nerv Syst 1982; 5: 23–43. 1892. de Groat WC. Neuroanatomy and neurophysiology: Innervation of the lower urinary tract. In: Raz S, Rodriguez LV, eds. Female Urology. Philadelphia, PA: WB Saunders, 2008: 26–46.

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1893. Antoniou J, Steffen T, Nelson F et al. The human lumbar intervertebral disc: Evidence for changes in the biosynthesis and denaturation of the extracellular matrix with growth, maturation, ageing, and degeneration. J Clin Invest 1996; 98: 996–1003. 1894. Buckwalter JA. Aging and degeneration of the human intervertebral disc. Spine 1995; 20: 1307–14. 1895. Lotz JC, Ulrich JA. Innervation, inflammation, and hypermobility may characterize pathologic disc degeneration: Review of animal model data. J Bone Joint Surg Am 2006; 88: 76–82. 1896. Delamarter RB, Bohlman HH, Bodner D et al. Urologic function after experimental cauda equina compression-cystometrograms versus cortical evoked potentials. Spine 1990; 15: 864–70. 1897. Bradley WE. Neurologic disorders affecting the urinary bladder. In: Krane RJ, Siroky MB, eds. Clinical Neuro-Urology. 1st edn. Boston, MA: Little, Brown, 1978: 245–55. 1898. Appell RA. Voiding dysfunction and lumbar disc disorders. Problems Urol 1993; 7: 35–40. 1899. Scott PJ. Bladder paralysis in cauda equina lesions from disc prolapse. J Bone Joint Surg 1965; 47: 224–7. 1900. Susset JG, Peters ND, Cohen SI et al. Early detection of neurogenic bladder dysfunction caused by protruded lumbar disc. Urology 1982; 20: 461–3. 1901. Blaivas JG, Zayed AAH, Labib KB. The bulbocavernosus reflex in urology: A prospective study of 299 patients. J Urol 1981; 126: 197–9. 1902. Pavlakis AJ, Siroky MB, Goldstein I, Krane RJ. Neurourologic findings in conus medullaris and cauda equina injury. Arch Neurol 1983; 40: 570–3.

1903. Jones D, Moore T. The types of neuropathic bladder dysfunction associated with prolapsed lumbar intervertebral discs. Br J Urol 1973; 45: 39–43. 1904. Ross JC, Jameson RM. Vesical dysfunction due to prolapsed disc. BMJ 1971; 3: 752–4. 1905. Sylvester PA, McLoughlin J, Sibley GN et al. Neuropathic urinary retention in the absence of neurological signs. Postgrad Med J 1995; 71: 747–8. 1906. Rosomoff HL, Johnston JD, Gallo AE et al. Cystometry in the evaluation of nerve compression in lumbar spine disorders. Surg Gynecol Obstet 1963; 117: 263–70. 1907. Bartolin Z, Gilja I, Bedalov G, Savic I. Bladder function in patients with lumbar intervertebral disc protrusion. J Urol 1998; 159: 969–71. 1908. Dong D, Xu Z, Shi B, Chen J et al. Clinical significance of urodynamic studies in neurogenic bladder dysfunction caused by intervertebral disk hernia. Neurourol Urodyn 2006; 25: 446–50. 1909. Shapiro S. Cauda equina syndrome secondary to lumbar disc herniation. Neurosurgery 1993; 32: 743–7. 1910. Bartolin Z, Vilendecic M, Derezic D. Bladder function after surgery for lumbar intervertebral disk protrusion. J Urol 1999; 161: 1885–7. 1911. Arlen AM, Powell CR, Kreder KJ. Sacral neuromodulation for refractory urge incontinence is less effective following spinal surgery. Scientific World Journal 2011; 11: 142–6. 1912. Kessler TM, La Framboise D, Trelle S et al. Sacral neuromodulation for neurogenic lower urinary tract dysfunction: Systematic review and meta-analysis. Eur Urol 2010; 58: 865–74.

23 Cauda equina injury Patrick J. Shenot and M. Louis Moy

Introduction Cauda equina and conus medullaris are injuries that may result in profound functional compromise of both the urinary bladder and the pelvic floor musculature. The resulting lower urinary tract dysfunction can be a significant cause of morbidity in these cases. Numerous causes of cauda equina syndrome have been reported, including traumatic injury, disc herniation, spinal tumors, spinal stenosis, inflammatory conditions, infectious conditions, and iatrogenic causes by medical intervention.1,2 Intervertebral disc protrusion is the second most common offender, with spinal root compression usually in the L4–L5 or L5–S1 disc space.1,3,4 Classically, cauda equina syndrome is characterized by a constellation of symptoms including low back pain, unilateral or bilateral lower extremity pain, weakness, or parasthesia, bowel disturbance, bladder and sexual dysfunction, and saddle or perineal parasthesias. It results from the simultaneous compression of multiple lumbosacral nerve roots below the level of the conus medullaris. Although the lesion technically involves nerve roots and represents a peripheral or lower motor neuron nerve injury, damage may result in devastating and permanent loss of function. Conus medullaris injuries are similar in many respects in that they also result in significant lower extremity and lower urinary tract dysfunction. It is important to remember that the conus medullaris constitutes part of the spinal cord and is in proximity to the nerve roots forming the cauda equina. Thus, injuries to this area may yield a combination of upper motor neuron and lower motor neuron symptoms with signs in the dermatomes and myotomes of the affected segments.

Anatomy and pathophysiology The conus medullaris is the tapered caudal end of the spinal cord. In the adult, it is usually located at the lower edge of the first lumbar vertebra. The ventral and dorsal lumbar and sacral nerve roots that arise from the conus

medullaris form a bundle of nerve roots, the cauda equina, which branch out diagonally from the conus medullaris. These paired lumbar and sacral spinal nerves exit laterally through the nerve root foramina. The nerves that compose the cauda equina innervate the pelvic floor, pelvic organs, the urinary and anal sphincters, and the lower extremities. In addition, the cauda equina carries sensory innervation to these areas as well as parasympathetic innervation to the bladder. The cauda equina, like the spinal cord, is invested by the meninges. The arachnoid membrane envelops the cauda equina loosely as the thecal sac surrounded by the thicker and more superficial dura mater. The principle excitatory input to the urinary bladder is parasympathetic innervation via the pelvic nerves, which originate in the motor nuclei within the intermediolateral columns of the sacral cord segments S2–S4.5 Somatic innervation originates from the ventromedial aspect of the ventral gray matter of the third and fourth sacral segments and travels via the pudendal nerve to provide innervation to the external urinary sphincter and the remainder of the pelvic floor musculature.6 Sympathetic innervation of the lower urinary tract originates in dorsal root ganglia at thoracolumbar segments from the T11–L2 (sympathetic nucleus; intermediolateral column of gray matter) and follows pathways of the hypogastric nerves to provide inhibitory input to the bladder body as well as excitatory input to the urethra and bladder outlet. Afferent nerves carry sensory information in afferent fibers from the lower urinary tract to the lumbosacral spinal cord via the pelvic, hypogastric, and pudendal nerves.7–9 Sensory nerves initiate the micturition reflex and modulate the drive that maintains bladder contractions. Spinal cord segments are named for the vertebral body at which its nerve roots exit the spinal canal. Thus, though the motor nucleus of the first sacral segment of the spinal cord is located at L1, its nerve roots run in the subarachnoid space posterior to the L2 to L5 vertebral bodies before exiting the fused sacrum between the S1 and S2 segments. As sacral roots pass multiple levels of lumbar disc, it is not surprising that spinal root compression in the lower

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lumbar (L4–L5 or L5–S1) disc space is a leading cause of the cauda equina syndrome.1,3,4

Etiology of cauda equina syndrome Disc herniations usually occur in a dorsolateral direction, thereby leading to compression of individual spinal nerve roots after they have separated from the cauda equina (Figure 23.1). Central disc herniations comprise less than 3% of all disc herniations but result in a disproportionate number of cases that result in severe lower urinary tract dysfunction. The signs and symptoms resulting from central disc prolapse vary depending on the rate and extent of the herniation, the size of the spinal canal, and the number of nerve roots involved. Sacral roots travel closest to the midline in the cauda equina and consequently the

Annulus fibrosus

Nucleus pulposus

Paracentral disc protrusion resulting in compression of nerve root

Nerve

Spinal cord

Figure 23.1 Disc herniations most commonly occur in a dorsolateral direction leading to compression of individual spinal nerve root.

nerve roots are most likely to be damaged by central disc herniations. Complete injury to the conus or sacral roots (from cauda equina injuries) results in detrusor areflexia. Although there are some similarities in terms of clinical presentation of these two syndromes, there are important differences as well (Table 23.1). Pure chronic conus injuries generally have a more profound effect on the autonomic rather than somatic function. As a result, changes in bladder function resulting in impaired bladder contractility are more common than is sphincteric weakness resulting from impairment of somatic innervation. Patients with conus injuries may initially present with impairment of the external urinary and anal sphincters, but chronic conus medullaris injuries often result in intact pelvic floor muscle and preserved external sphincter function despite the impairment of detrusor contractility. Typically, conus medullaris injuries result in symmetric, hyperreflexic distal paresis of lower limbs rather than the asymmetric areflexic paraplegia seen in cauda equina injuries. In either syndrome, the bladder may completely or partially empty in the absence of detrusor contractility if there is a sufficient increase in abdominal pressure from Valsalva or Credé’s maneuvers to exceed bladder outflow resistance. Voiding in this manner is dependent on the absence of any outflow obstruction. Voiding efficiency is often diminished even when some detrusor function returns as detrusor contractility, which is frequently still impaired and unable to overcome the relatively preserved resistance of the bladder outlet.

Clinical findings Disorders affecting the cauda equina are characterized by weakness and sensory loss in the lower limbs, buttocks and perineum, usually with functional abnormalities of

Table 23.1  Symptoms and signs of cauda equina and conus medullaris syndromes Cauda equina syndrome

Conus medullaris syndrome

Presentation

Sometimes gradual and unilateral. May be acute

Sudden and bilateral

Reflexes

Both ankle and knee jerks affected

Knee jerks preserved, ankle jerks affected

Sensory symptoms and signs

Numbness tends to be more localized to saddle area; asymmetrical and patchy, may be unilateral; loss of sensation in specific dermatomes in lower extremities with numbness and paresthesia; possible numbness in pubic area, including glans penis or clitoris

Numbness tends to be more localized to perianal area; symmetrical and bilateral

Motor strength

Asymmetric areflexic paraplegia that is more marked; fasciculations rare; atrophy more common

Typically symmetric, hyperreflexic distal paresis of lower limbs that is less marked; fasciculations may be present

Cauda equina injury bladder, bowel, and sexual function. The functional integrity of sacral dermatomes should be evaluated by assessing perineal and genital sensation, anal sphincter tone, and the presence or absence of the bulbocavernosus reflex. Functional deficits will depend on the extent and severity of nerve injury. The most consistent urodynamic finding reported is a normally compliant, areflexic bladder associated  with normal innervation or incomplete denervation of the ­perineal floor muscles. O’Flynn et al.6 followed 30 patients for 1  year following decompressive surgery for lumbar intervertebral disc prolapse. In this study, only 1 of 26 patients with incontinence prior to laminectomy had normal postoperative bladder function. In more retrospective series of patients with cauda equina syndrome and either urinary incontinence or retention, over 90% regained continence without requiring intermittent catheterization. Recovery of function was not related to the time to surgical intervention.10 Prospective studies are needed to clarify the effect of surgery on ultimate lower urinary tract function. The physical examination may reveal a distended bladder or a positive cough test for incontinence. Examination usually shows weakness in muscles innervated by S1 and S2 (gastrocnemius, hamstrings, gluteal muscles) and sensory loss extending from the soles of the feet to the perianal region that may be variable and patchy. There may be laxity of the anal sphincter and loss of the bulbocavernosus reflex. The pattern of sensory loss restricted to the medial buttocks and perianal area is termed saddle anesthesia. Smaller, less extensive disc herniation produces a more limited syndrome consisting mainly of incomplete saddle anesthesia, often combined with bladder and sphincter dysfunction. A unilateral or mild sensory deficit portends a more favorable prognosis as normal bladder function predisposes an intact visceral reflex arc of the sacral nerve roots.3,10 Patients with voiding symptoms may present with obstructive voiding symptoms including urinary hesitancy, intermittency, diminished urinary flow rate straining to void, elevated residual urine volume, and incontinence. These symptoms are primarily due to the diminished detrusor contractility. On occasion, symptoms of voiding dysfunction can be the only initial clinical manifestation of a cauda equina lesion.11 The incontinence, however, may result from either overflow due to poor or absent detrusor contractility or due to diminished lack of resistance at the level of the external sphincter. In a series of patients with conus medullaris and cauda equina injury of various etiologies, the bulbocavernosus reflex was absent or significantly diminished in 84% of the cases, whereas the perineal sensation and muscle stretch reflexes were compromised in 77% of the patients.2 In addition, it was noted that absence of the reflex correlated well with perineal floor denervation.12

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Diagnostic studies Assessment of the patient’s postvoid residual volume should be made by catheterization or an ultrasound bladder scanning device. Further urodynamic testing, including pressure flow cystometry with sphincter electromyography (EMG) is usually required to fully evaluate the voiding dysfunction. In some cases, somatic innervation remains intact and the external sphincter is nonrelaxing when the patient strains to void, thus creating a functional obstruction. Simultaneous pressure flow studies are invaluable if there is a question of outlet obstruction from preserved external sphincter function or in male patients with coexisting outflow obstruction from benign prostatic hyperplasia (BPH). Confirmation that intravesical pressure elevation on voiding cystometry is due to abdominal straining, and not a true detrusor contraction, can be inferred by using subtracted pressure measurements and simultaneous perineal EMG. The predominant urodynamic pattern found in cauda equina syndrome is detrusor areflexia associated with neuropathic sphincter dysfunction.1,2 Bladder compliance can be normal or decreased, regardless of the cause of cauda equina syndrome.13 Uroflow tracings are characterized by the saw-toothed abdominal straining pattern commonly noted in patients with impaired bladder contractility. Sphincter denervation may be documented on electromyogram (EMG) by fibrillation, positive sharp waves, and polyphasic potentials, which is noted in approximately two-thirds of the patients.2 It is important to stress, however, that neuropathic EMG changes do not always correlate with clinically meaningful functional compromise as the sphincter may still be capable of contraction. Anderson noted a high incidence of neurogenic dysfunction of the detrusor muscle was found in patients with disc prolapse and with continued symptoms following laminectomy, whereas impaired function of the striated external urethral sphincter was rare.14 A significant number of patients will also demonstrate preserved bladder sensation because of the presence of numerous exteroceptive sensory nerves in the bladder trigone and vesical neck that bypass the sacral spinal cord by entering thoracolumbar spinal segments.9,15 There appears to be a poor correlation between patients’ symptoms and urodynamic findings leading some to propose urodynamic studies in all patients with significant lower urinary tract dysfunction.16 Sacral reflex arc integrity may be further studied with the evaluation of the latency time of the sacral evoked potentials by stimulating the penile skin and recording the response with a needle electrode in the bulbocavernosus muscle. Complete cauda equina lesions result in a sacral evoked response that is either absent or greatly prolonged.17 This is likely a more sensitive and practical indicator of neuropathy than EMG.

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Figure 23.2 T2-weighted sagittal magnetic resonance imaging (MRI) of the lumbar spine showing a large central disc prolapse with extrusion at L5–S1 resulting in acute cauda equina syndrome in a 23-year-old female.

Magnetic resonance imaging (MRI) precisely shows the spinal cord, nerve roots, and surrounding areas and should be performed in cases where cauda equina syndrome is the suspected cause of voiding dysfunction. MRI is also invaluable in the diagnosis of other causes of cauda equina syndrome including tumors, hematoma, and infectious processes such as an epidural abscess. An MRI performed with a high magnetic field strength usually provides the most conclusive evidence for the diagnosis of a disc herniation. T2-weighted images allow for clear visualization of protruded disc material in the spinal canal (Figure 23.2). In conclusion, the major urodynamic features in patients with cauda equina injury are an absent or diminished bulbocavernosus reflex, detrusor areflexia, neuropathic changes on perineal floor EMG, and absent evoked EMG responses.

Urologic management of cauda equina syndrome Urologic management of patient with cauda equina syndrome should be guided by the patient’s symptoms and in accordance with sound urologic principles. In patients with significant obstructive lower urinary tract symptoms, intermittent catheterization is generally ­preferred since most of these patients do not have compromised upper extremity function. Selected patients with

moderately bothersome symptoms and modest postvoid residual ­volumes may be offered a trial of an α-adrenergic ­antagonist after a complete urologic evaluation. Bethanechol chloride is a commonly used ­muscarinic agonist in the treatment of detrusor areflexia. Cholinergic agents, although potentially helpful as diagnostic aids, have  not been proven beneficial in promoting bladder emptying in patients with chronic detrusor areflexia. They ­continue to be used despite the lack of high quality, ­ ­ randomized trials demonstrating any clinical efficacy of this agent in the management of detrusor areflexia. Bethanechol chloride is ­ considered contraindicated in patients with detrusor areflexia ­ and bladder o ­utlet ­ obstruction such as BPH, urethral ­structure, or d ­ etrusor–­external sphincter dyssynergia as it may increase ­intravesical p ­ ressure and potentially lead to vesicoureteral reflux and ultimately to renal damage. In  patients with preserved outlet resistance, the utilization of the Credé’s m ­ aneuver for bladder emptying may trigger a reflex ­contraction of the pelvic floor and external sphincter resulting in increased bladder outlet resistance and elevated intravesical pressures. Abdominal straining to void or Credé’s maneuvers are only effective when both smooth and skeletal muscle resistance are significantly reduced and can only be safely recommended after a thorough and accurate urodynamic evaluation. Prostatectomy is usually contraindicated, even in cases where BPH is clearly documented prior to the cauda equina injury. Resection of the bladder neck and prostate, the “internal sphincter,” in the face of a poorly functional external sphincter can convert a patient suffering from urinary retention to one who is still empties poorly but is now also incontinent. Injecting 50–100 U of botulinum toxin A into the external sphincter has been shown to decrease voiding pressures, increase maximum flow rate, and decrease postvoid residual. This can be performed with minimal morbidity.18 Sacral nerve stimulation has also been reported to be successful in improving urinary symptoms in patients with cauda equina syndrome with urinary and fecal incontinence and perineal pain.19 A trial with a n ­ eurostimulator lead can be performed and if the patient has a positive response a peripheral neurostimulator generator can be placed. Neuromodulation techniques appear to be ­minimally invasive and promising treatment options, but ­f urther studies are needed. Management of incontinence should be guided by ­diagnostic findings. When the symptom is due to urine overflow, it can be dealt with easily if the bladder is emptied in regular intervals by intermittent catheterization. On the contrary, incontinence secondary to pelvic floor denervation is more difficult to manage. In men, the application of an external, “condom”-type collecting device is a common solution, but often fails to be an acceptable option in ambulatory men. In women, however, no external urinary collection device has ever proven effective.

Cauda equina injury Unfortunately, some women chose an indwelling Foley catheter, a management option that is associated with bladder irritation, chronic bacterial colonization, urethral erosion and destruction of the sphincter mechanism, and even squamous cell carcinoma of the bladder with prolonged indwelling bladder catheterization. Surgical options for sphincteric incontinence may require major reconstructive urologic surgery. Supravesical urinary diversion is rarely used in this patient population although the creation of a continent catheterizable abdominal stoma may allow intermittent catheterization in carefully selected women with difficulty catheterizing via the urethra. Bladder neck slings have been used to increase outlet resistance in patients with neurogenic lower urinary tract dysfunction with mixed results.20,21 There are no studies specifically addressing the use of this technique in adults with cauda equina syndrome. Implantation of an artificial sphincter has achieved excellent results in small series of men with neurogenic sphincteric incontinence.22–24 We generally prefer that the artificial sphincter cuff be placed at the bladder neck to minimize the chance of erosion, particularly in patients on intermittent catheterization. In adult males, the dissection necessary to place this device may be technically challenging. Recent reports suggest that laparoscopic and robotic-assisted laparoscopic placement of bladder neck artificial sphincter in adult neurogenic patients may simplify the lateral and posterior dissection needed for bladder neck placement. In some patients, particularly whom with significant obesity, placement of the cuff around the bulbar urethra is preferred. In women, a pubovaginal sling procedure will generally afford excellent continence and may be combined with intermittent catheterization to completely empty the bladder. The implantation of the artificial sphincter is more technically challenging in women because of lack of adequate tissue between the urethra and the vagina. Reports to the U.S. Food and Drug Administration suggest a much higher rate of infection and malfunction leading to a high revision and removal rate in the female patients.

Conclusion Bladder and sphincter dysfunction secondary to injury to the cauda equina can result in devastating urologic impairment including the loss of volitional voiding and marked urinary incontinence. Fortunately, some patients initially suffering from urinary retention and neurogenic incontinence will eventually recover acceptable lowered urinary tract function. Conservative management, particularly intermittent catheterization, should be the initial intervention. Bladder management should address bothersome symptoms and be guided by urodynamic evaluation. Surgical intervention should be deferred until such a time that a reasonable chance of functional recovery is unlikely.

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References 1913. Andersen JT, Bradley WE. Neurogenic bladder dysfunction in protruded lumbar disc and after laminectomy. Urology 1976; 8: 94–6. 1914. Pavlakis AJ, Siroky MB, Goldstein I, Krane RJ. Neurourologic findings in conus medullaris and cauda equina injury. Arch Neurol 1983; 40: 570–3. 1915. Scott PJ. Bladder paralysis in cauda equina lesions from disc prolapse. J Bone Joint Surg 1965; 47: 224–7. 1916. O’Flynn KJ, Murphy R, Thomas DG. Neurogenic bladder dysfunction in lumbar intervertebral disc prolapse. Br J Urol 1992; 69: 38–40. 1917. de Groat WC, Booth AM, Milne RJ et al. Parasympathetic preganglionic neurons in the sacral spinal cord. J Auton Nerv Syst 1982; 5: 23–43. 1918. de Groat WC. Neuroanatomy and neurophysiology: Innervation of the lower urinary tract. In: Raz S, Rodriguez LV, eds. Female Urology. Philadelphia, PA: WB Saunders, 2008: 26–46. 1919. Yoshimura N, Kaiho Y, Miyazato M et al. Therapeutic receptor targets for lower urinary tract dysfunction. Naunyn Schmiedebergs Arch Pharmacol 2008; 377: 437–48. 1920. Susset JG, Peters ND, Cohen SI etal. Early detection of neurogenic bladder dysfunction caused by protruded lumbar disc. Urology 1982; 20: 461–3. 1921. Reitz A. Afferent pathways arising from the lower urinary tract after complete spinal cord injury or cauda equina lesion: Clinical observations with neurophysiological implications. Urol Int 2012; 89: 462–7. 1922. Olivero WC, Wang H, Hanigan WC et al. Cauda Equina syndrome (CES) from lumbar disc herniations. J Spinal Disord Tech 2009; 22: 202–6. 1923. Sylvester PA, McLoughlin J, Sibley GN et al. Neuropathic urinary retention in the absence of neurological signs. Postgrad Med J 1995; 71: 747–8. 1924. Lapides J, Babbitt JM. Diagnostic value of bulbocavernosus reflex. JAMA 1956; 162: 971–2. 1925. Shin JC, Park C, Kim HJ, Lee IY. Significance of low bladder compliance in cauda equine syndrome. Spinal Cord 2002; 40: 650–5. 1926. Andersen JT, Bradley WE. Neurogenic bladder dysfunction in protruded lumbar disc and after laminectomy. Urology 1976; 8: 94–6. 1927. Bradley WE, Timm GW, Scott FB. Cystometry. V. Bladder sensation. Urology 1975; 6: 654–8. 1928. Podnar S, Trsinar B, Vodusek DB. Bladder dysfunction in patients with cauda lesions. Neurourol Urodyn 2006: 25: 23–31. 1929. Krane RJ, Siroky MB. Studies on sacral evoked potentials. J Urol 1980; 124: 872–6. 1930. Kuo HC. Botulinum A toxin urethral injection for the treatment of lower urinary tract dysfunction. J Urol 2003; 170(5): 1908–12. 1931. Kim JH, Hong JC, Kim MS, Kim SH. Sacral nerve stimulation for treatment of intractable pain associated with cauda equine syndrome. J Korean Neurosurg Soc 2010; 47(6): 473–6. 1932. Castellan M, Gosalbez R, Labbie A et al. Bladder neck sling for treatment of neurogenic incontinence in children with augmentation cystoplasty: Long-term follow-up. J Urol 2005; 173: 2128–31. 1933. Barthold JS, Rodriguez E, Freedman AL et al. Results of the rectus fascial sling and wrap procedures for the treatment of neurogenic sphincteric incontinence. J Urol 1999; 16: 272–4. 1934. Bersch U, Göcking K, Pannek J. The artificial urinary sphincter in patients with spinal cord lesion: Description of a modified technique and clinical results. Eur Urol 2009; 55: 687–93. 1935. Chartier Kastler E, Genevois S, Gamé X et al. Treatment of neurogenic male urinary incontinence related to intrinsic sphincter insufficiency with an artificial urinary sphincter: A French retrospective multicentre study. BJU Int 2011; 107: 426–32. 1936. Yates DR, Phé V, Rouprêt M et al. Robot-assisted laparoscopic artificial urinary sphincter insertion in men with neurogenic stress urinary incontinence. BJU Int 2013; 111: 1175–9.

24 Tumors of the spinal cord Homero Bruschini, J. Pindaro P. Plese, and Miguel Srougi

Introduction Tumors compromising the neural transmission at the spinal cord can originate in the bone structures or tissue extensions involving the spinal cord and in the neural structures existing inside the bone framework. Spinal cord tumors constitute 15% of the central nervous system neoplasias. They are divided according to their relation to the duramater into extradural, intradural but extramedullary, and intramedullary1 (Figure 24.1). Intradural spinal cord tumors are less common.2 In a few cases, an intramedullary and an extramedullary component may coexist, with communication through the entrance of the nerve root or at the conus medullaris–filum terminale transition. Some intradural tumors extend through the nerve root sheaths to the extradural space. Intradural extramedullary tumors comprise about 45% of intradural tumors in children.3 An accurate diagnosis is crucial to determine the prognosis and direct therapy. Magnetic resonance imaging (MRI) has revolutionized the diagnosis of intraspinal tumors, allowing for early detection and improved anatomic localization.4 It has also become fundamental for staging primary and metastatic neoplasms. Association of MRI with diffusion tractography allows improvement to the understanding of normal tracts involved.5 Bladder and sphincter dysfunctions are rarely the first symptoms in these patients, but they may coexist with other complaints, usually as a late presentation. Scientific communications specifically on this topic are scarce in the literature.

Intradural extramedullary tumors About two-thirds of the so-called adult spinal cord tumors are extramedullary (Table 24.1). Schwannomas, meningiomas, and ependymomas comprise 95% of the extraspinal tumors. The other 5% are intradural metastases, inclusion

cysts, paragangliomas, and melanocystic neoplasias. With few exceptions, intradural extramedullary tumors are benign and surgically excisable. Recent revision of Japanese population showed similar distribution.6

Types of tumor Tumors derived from the neural sheath These consist of neurinomas or schwannomas. They constitute about 25% of all the intradural adult tumors and the annual incidence is 0.3 to 0.4 per 100,000 of the population. The most frequent presentation is as a single lesion in the vertebral channel, in the fourth to sixth decades of life, with no gender differentiation (Figure 24.2). The most affected regions are the dorsal roots, with 30% growing through the vertebral foramina in an hourglass shape. About 10% can be exclusively extradural. Only 1% originate from the perivascular neural sheaths of the penetrating medullary circulation vessels. Malignant tumors comprise only 2.5%, mostly associated with neurofibromatosis, and they have a poor prognosis, with an average survival of 1 year.

Meningiomas These originate from the arachnoid cells close to the nerve exit, which explains its lateral localization. They occur in a frequency similar to the neural sheath tumors. They can affect people of any age; however, most arise in the fifth to seventh decade, with 80% in the thoracic segment (Figure 24.3). They sometimes occur in the high cervical area and at the craniovertebral junction, such as the magnum foramina. About 90% of spinal meningiomas are intradural. They are more suitable for surgical excision than the intracranial meningiomas, since they do not invade the pia mater. This is due to the presence of a leptomeningeal cellular layer between the pia mater and the arachnoid in the spinal area, different from the cranial region.

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(c) (a)

(b) (d)

Figure 24.1

(e)

Table 24.1  Incidence of tumors in adults Extramedullary (two-thirds of cases)

%

Intramedullary (one-third of cases)

%

Nerve sheath tumors

40

Ependymoma

45

Meningioma

40

Astrocytoma

40

Filum ependymoma

15

Hemangioblastoma

Miscellaneous

5

Miscellaneous

5 10

Source: Schwartz H, McCormick PC. Spinal cord tumors in adults. In: Winn HR, ed. Neurological Surgery, 5th edn, Vol 4. Philadephia, PA: WB Saunders Co, 2004: 4817–34.

Ependymomas The filum terminale ependymomas correspond to 40% of spinal ependymomas (Figure 24.4). Other rare presentations of filum terminale tumors are astrocytomas, paragangliomas, and oligodendrogliomas. The usual histologic pattern is a benign myxopapillary ependymoma, which is more aggressive in young patients.

Other tumors Less common tumors are those derived from embryologic disorders, such as dermoid cysts, lipomas, teratomas, and neuroenteric cysts. They occur mainly in the lumbar and thoracolumbar areas. Other causes are malformations

Anatomic relationship of spinal tumors with other spine structures: (a) intramedullary tumor; (b) filum terminale ependymoma; (c) extradural neurofibroma; (d) intradural extramedullary meningioma; (e) schwannoma growing through the vertebral foramina.

such as spina bifida and occult rachischisis. Some nonneoplastic lesions can simulate tumors, such as arachnoid cysts7 and dural inflammations such as sarcoidosis and tuberculosis.

Clinical findings and treatment These tumors grow slowly. The clinical findings are mainly a consequence of compression and depend on its localization. The usual complaint is pain and some enervation impairment of the corresponding area. Tumors of the craniovertebral junction and magnum foramina are mostly ventral, causing suboccipital pain and weakness of the arm, with atrophy of the intrinsic muscular components of the hands. The physiopathology may be related to local venous insufficiency. Tumors in a high cervical position may cause hydrocephaly due to higher levels of protein and decreased liquor absorption. Segmental motor deficiency together with signs and symptoms of the involvement of the spinothalamic and corticospinal tracts suggests lesions of the medium and low cervical segments. They generally cause premature and asymmetric symptoms. Thoracic tumors particularly compromise the corticospinal tract. This is usually signaled by complaints of rigidity and spasticity together with distal weakness of the arms, as a consequence of the initial participation of the peripheral fibers. Tumors of the dorsal median line initially cause gait ataxia due to compression and loss of

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Figure 24.2 Magnetic resonance imaging (MRI) of a large neurinoma.

sensitivity of the posterior column. Bladder and sphincter dysfunction is unusual and may present only as a late symptom. Filum terminale ependymomas usually present as lumbar pain, with irradiation to the legs. In these cases, worsening of symptoms when taking the horizontal dorsal position is indicative of large extramedullary tumors, especially at the cauda equina. Intraoperative monitoring of bladder function during spinal cord surgery in a few cases including ependymoma of the cauda equina and cervical intramedullary tumors has been reported.8 This method proved unsuitable for intramedullary tumors, but is an effective tool for identifying bladder efferent nerves at the cauda equina. The practical use of this approach has yet to be tested.

Intramedullary tumors Around 80% of spinal cord intramedullary tumors are glials (originating from the central nervous system) and histologically benign. They include astrocytomas, ependymomas, and, less frequently, gangliogliomas, oligodendrogliomas, and subependymomas. Hemangioblastomas comprise 3%–8% of intramedullary tumors. Less than 5% of these tumors are metastatic lesions, usually from primary tumors of the lung and breasts. The other 10%–15%

Figure 24.3 MRI of an extramedullary intradural thoracic meningioma.

of these tumors are inclusion cysts, tumors from the neural sheath, neurocytomas, and melanocytomas. Some lesions, such as tuberculosis, bacterial abscesses, sarcoidosis, and multiple sclerosis, can simulate neoplasia. Differential diagnosis is suggested by the rapid course of symptoms in the real tumors. A recent series of 48 patients with intramedullary tumors presented ependymoma in 67% of cases, followed by lipomas, gangliomas, astrocytomas, and hemangioblastomas.9 Three percent of all astrocytomas are located at the spinal cord. They can be found at any age, being more frequent in the first three decades of life. Ninety percent of the pediatric intramedullary tumors in the first 10 years of life are astrocytomas. They are associated with syringomyelia in 20% of cases. Around 60% of them occur at the cervical or cervicothoracic transition. It is known that intramedullary astrocytomas tend to be associated with neurofibromatosis type 1. Malignancy varies from low-grade pyelocystic astrocytomas to anaplastic astrocytoma or glioblastomas. Malignant tumors are more frequent in the pediatric population.

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Clinical findings and treatment

(a)

(b)

Figure 24.4 (a) MRI of an ependymoma of cauda equina. (b) Surgical aspect of the tumor.

In adults, 25% of tumors are malignant, while ependymomas are the most frequent tumor, with equal gender commitment. They occur in association with syringomyelia in 65% of patients, especially in those tumors located at the cervical area. Mutations of gene NF2 are associated with ependymomas. Most of the wide variety of histologic

Clinical manifestations of these tumors are quite variable. Initial complaints are nonspecific and start 3 to 4 years before the diagnosis. There have been cases diagnosed at a chiropractic clinic after intermittent backache for some years, without any other symptom or with mild and irrelevant bowel and bladder dysfunction.10 In adults, pain and weakness are the most frequent initial symptoms. Malignant neoplasias have a shorter evolutionary course. A sudden neurologic impairment suggests intratumoral bleeding, being more frequent in ependymomas (Figure 24.5). The pain is usually in accordance with the level of the lesion. Upper extremity symptoms predominate in cervical lesions. Thoracic tumors cause spasticity and sensorial problems due to involvement of the posterior portion of the medulla and thalamo-spinal tracts. Lumbar tumors promote pain in the posterior areas of the thighs and feet, simulating radicular pain. Bladder and sphincter symptom participation is unusual, occurring most in advanced stages of medullary and cauda equina compression. A review of 48 patients showed pain as the first symptom in 50%, sensory alterations such as paresthesias and dysesthesias in 35%, and gait problems in 15%, with no urinary or bowel complaints as first manifestation.9 MRI is the method of choice to detect these tumors. Early detection favors a curative therapeutic approach. Subtotal aggressive surgical excision seems feasible in two-thirds of cases, and should be the target when possible, with an improved or stable situation resulting in over 65% of patients.9 The use of neurophysiological monitoring at surgical approach can improve the outcome.11 Maintenance of more than 50% of the original motor evoked potentials amplitude sustain that tumor removal can be continued safely.12

Metastatic spinal lesions The spinal muscular and bone structures are the third most common place for metastasis, after the lungs and liver. Vertebral bone metastasis occurs in 10% of malignancies, being the most common spinal tumors. Extradural

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Figure 24.6 Breast neoplasia causing bone metastasis to T10 and invading the medullary space.

Clinical findings and treatment

Figure 24.5 MRI of an intramedullary cervical ependymoma. Bleeding of the tumor, as seen in the upper portion of the figure, caused a sudden worsening of symptoms.

compression represents 97% of spinal cord metastatic lesions.13 Metastasis usually arises in the posterior aspect of the vertebral body, with later invasion of the epidural space (Figure 24.6). Pathophysiologically, vascular insufficiency is more important than direct spinal cord compression.14 Neoplastic cells reach the spine through the arterial or venous hematogenic pathway or through direct extension. The vertebral venous plexus of Batson is the main route for dissemination of breast, intrathoracic, intra-abdominal, and pelvic tumors to this area. The absence of valves in these blood vessels allows neoplastic cells to disseminate to the bone, without passing through lung and liver filters. The most frequent primary tumors to give metastasis to this area are breast,15 lung,16–18 uterus,19 kidney, and prostate.20 In around 10% of metastases, a primary tumor is not immediately found. Recently, with the evolution of neoplasia, 50% of undetectable primary tumors show a lung origin. Anecdotal cases of primary nervous system tumors such as multiform glioblastomas causing vertebral metastasis have been reported.21

Insidious and progressive pain is the first complaint in vertebral metastasis in 90% of patients, followed by weakness, sensory complaints, and loss of voluntary control of sphincters. In a study of symptoms carried out in 153 patients with metastatic compression of the spinal cord or cauda equina,22 radicular pain was predominant in cases with metastases located in the lumbar area, while the severity of motor symptoms was positively correlated with thoracic metastases. The most frequent initial symptom was radicular pain, followed with decreasing frequency by motor weakness, sensory complaints, and bladder dysfunction. The nocturnal worsening of symptoms is very characteristic. A sudden aggravation of pain suggests pathologic fractures and additional compressions. Increased pain with movement means vertebral instability. Around 87% of the patients receive an initial diagnosis of fibromuscular pain. Recent dorsal pain in oncologic patients should be investigated as potential metastasis. Early diagnosis is related to better treatment evolution. Concomitant activation of Herpes zoster, the Brown-Sequard syndrome, or ataxia at the level of medullary compression is unusual. Surgery for treatment of intramedullary spinal cord metastasis is controversial. Sporadic cases have been reported, with pain relief and improvement in bladder dysfunction.23 This procedure was recommended by Faillot et al. in selected cases, which might benefit from an improvement in the quality and comfort of life, although it does not seem to affect the duration of survival. A retrospective analysis of clinical data concerning 140 patients with spinal cord compression compared those

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submitted to surgical decompressive laminectomy followed by radiation therapy (127 cases) to those treated by primary radiation alone (26 cases).24 Combined therapy offered sphincter function improvement in 68% of cases, compared to an improvement in 33% with radiation alone. It seems that the treatment of choice for each patient must take into account his general condition, life expectancy, and the origin of the primary tumor.25

Conclusions Bladder and sphincter complaints are seldom the first and sole symptom of spinal tumors.26 Usually other signs of neural impairment, such as pain or sensory or motor weakness, precede it. The urinary dysfunction is initially overlooked in these patients and total attention is in general directed to the tumor itself and its treatment. The urologists rarely see these patients before the neurosurgical approach. When urinary dysfunction results, it is related to the localized area involved rather than to the tumor type. Urodynamic examination should be used to identify the level of the lesion and the urotherapeutic approach. Underlying disease and life expectancy should establish the type of bladder management in patients with neoplastic spinal cord involvement.27 Those with stabilized sequel lesions and potentially curative disease should be submitted to a full bladder rehabilitation program, as described in other chapters of this book. Those with spinal tumors not eligible for bladder rehabilitation and needing only temporary urinary care may be managed with a transurethral, or preferably a suprapubic catheter.

References 1937. Schwartz H, McCormick PC. Spinal cord tumors in adults. In: Winn HR, ed. Neurological Surgery, 5th edn, Vol 4. Philadelphia, PA: WB Saunders, 2004: 4817–34. 1938. Duong LM, McCarthy BJ, McLendon RE et al. Descriptive epidemiology of malignant and nonmalignant primary spinal cord, spinal meninges, and cauda equina tumors. Cancer 2012; 118: 4220–7. 1939. Jallo GI, Kothbauer KF, Epstein FJ. Intraspinal tumors in infants and children. In: Neurological Surgery, 5th edn, Vol 3. Philadelphia, PA: WB Saunders, 2004: 3707–15. 1940. Bloomer CW, Ackerman A, Bhatia RG. Imaging for spine tumors and new applications. Top Magn Reson Imaging 2006; 17(2): 69–87. 1941. Mechtler L, Nandingam K. Spinal cord tumors—new views and future directions. Neuro Clin 2013; 31: 241–68. 1942. Hirano K, Imagama S, Sato K et al. Primary spinal cord tumors: Review of 678 surgically treated patients in Japan. A multicenter study. Eur Spine J 2012; 21: 2019–26.

1943. Dulou R, Blondet E, Dutertre G et al. [Spinal cord compression by arachnoid cysts]. Neurochirurgie 2006; 52(4): 381–6. 1944. Schaan M, Boszczyk B, Jaksche H et al. Intraoperative urodynamics in spinal cord surgery: A study of feasibility. Eur Spine J 2004; 13(1): 39–43. 1945. Taricco MA. Post-operative follow-up of the intramedullary tumors evolution. PhD thesis, University of Sao Paulo School of Medicine, 2006. 1946. Lensgraf AG, Young KJ. Ependymoma of the spinal cord presenting in a chiropractic practice: 2 case studies. J Manipul Physiol Ther 2006; 29(8): 676–81. 1947. Sala F, Bricolo A, Facioli F et al. Surgery for intramedullary spinal cord tumors. The role of intraoperative (neurophysiological) monitoring. Eur Spine J 2007; 16(Suppl 2): 130–9. 1948. Chatterjee S, Chatterjee U. Intramedullary tumors in children. J Pediatr Neurosci 2011; 6(Suppl 1): 86–90. 1949. Spinazze S, Careceni A, Schrijvers D. Epidural spinal cord compression. Crit Rev Oncol Hematol 2005; 56(3): 397–406. 1950. Mut M, Schiff D, Shaffrey ME. Metastasis to nervous system: Spinal epidural and intramedullary metastases. J Neurooncol 2005; 75(1): 43–56. 1951. Luvin R, Cornu P, Philippon J et al. Isolated cervical intramedullary metastasis from breast cancer. Value of magnetic resonance imaging. Rev Neurol (Paris) 1988; 144(1): 40–2. 1952. Wada H, Ieki R, Ota T et al. [Intramedullary spinal cord metastasis of lung adenocarcinoma causing Brown–Sequard syndrome]. Nihon Kokyuki Gakkai Zasshi 2001; 39(8): 590–4. 1953. Takahima M, Ono N, Noguchi T et al. [Two cases of intramedullary spinal cord metastasis of lung cancer detected with MRI]. Nihon Kokyuki Gakkai Zasshi 2003; 41(4): 320–3. 1954. Kato A, Katayama H, Nagao T et al. [A case of small cell lung cancer with intramedullary spinal cord metastasis]. Nippon Ronen Igakkai Zasshi 2005; 42(5): 567–70. 1955. Sakuma S, Iwasaki Y, Isu T et al. [A case of intramedullary spinal cord metastasis from adenocarcinoma of corpus uteri]. No Shinkei Geka 1990; 18(7): 653–7. 1956. Maranzano E, Latini P, Beneventi S et al. Comparison of two different radiotherapy schedules for spinal cord compression in prostate cancer. Tumori 1998; 84(4): 472–7. 1957. Slowik F, Balogh I. Extracranial spreading of glioblastoma multiforme. Zentralbl Neurochir 1980; 41(1): 57–68. 1958. Helweg-Larsen S, Sorensen PS. Symptoms and signs in metastatic spinal cord compression: A study of progression from first symptom until diagnosis in 153 patients. Eur J Cancer 1994; 30(3): 396–8. 1959. Faillot T, Roujeau T, Dulou R, Blanc JL, Chedru F. [Intramedullary spinal cord metastasis: Is there a place for surgery? Case report and review of literature]. Neurochirurgie 2002; 48(6): 533–6. 1960. Landmann C, Hunig R, Gratzi O. The role of laminectomy in the combined treatment of metastatic spinal cord compression. Int J Radiat Oncol Biol Phys 1992; 24(4): 627–31. 1961. Byrne TN, Borges LF, Loeffler JS. Metastatic epidural spinal cord compression: Update on management. Semin Oncol 2006; 33(3): 307–11. 1962. Perea J, Romero Maroto J, Ruiz C, Fernandez A, Perales Cabanas L. [Urologic symptoms as first clinical manifestation of tumors of the nervous system. Apropos of 2 cases]. Actas Urol Esp 1989; 13(1): 71–4. 1963. Reitz A, Haferkamp Am, Wagener N, Gerner HJ, Hohenfellner M. Neurogenic bladder dysfunction in patients with neoplastic spinal cord compression: Adaptation of the bladder management strategy to the underlying disease. NeuroRehabilitation 2006; 21(1): 65–9.

25 Tethered cord syndrome Shokei Yamada, Brian S. Yamada, and Daniel J. Won

Introduction Tethered cord syndrome (TCS) is a stretch-induced functional disorder of the spinal cord caused by the anchoring of its caudal end by an inelastic structure. The neurologic dysfunction with TCS can be attributed to lumbosacral cord lesions and is reversible if cord-untethering surgery is done at an appropriate time. Clinical and basic research has indicated that oxidative metabolism is impaired in the tethered spinal cord and that there is a link between recovery from the neurologic dysfunction and oxidative metabolism when the stretched cord is released.1 This chapter seeks to increase urologists’ understanding of TCS and the importance of early diagnosis and treatment in patients with associated urinary incontinence. The discussion includes pathophysiology, symptomatology, treatment, and prognosis of TCS patients. Because TCS is associated with anatomic abnormalities, many clinicians still believe erroneously that congenital dysraphic anomalies are synonymous with TCS. This misunderstanding of TCS is accentuated by the terms derived from visual impressions of anatomic abnormalities, such as “cord tethering” and “tethered cord.” To clarify these expressions, the authors formulate three categories and define those patients in category 1 as clearly representing TCS.2

History of tethered cord syndrome In the early twentieth century, several surgeons and radiologists suggested the concept of a tethering-induced spinal cord lesion.3–8 In 1940, Lichtenstein9 attributed paraplegia and Chiari malformation to the downward spinal cord traction by the caudally located spinal dysraphism (e.g., myelomeningocele [MMC]). This hypothesis was not accepted by Barry et al.,10 Barson,11 and Gardner

et  al.12 Two major questions were unanswered: first, if ­tethering-induced symptoms exist, what part of the nervous system is affected? Second, what is the pathophysiological basis for any reversible lesion? In 1976, Hoffman et  al.13 localized reversible lesions in the lumbosacral cord anchored by an inelastic thickened filum and adopted the term “tethered spinal cord.” In 1981, Yamada et  al.1 demonstrated that oxidative metabolism was impaired in the lumbosacral cord of TCS patients and that neurologic improvement from untethering was accompanied by parallel metabolic improvement. Since then, articles referring to TCS and tethered spinal cord have increasingly appeared in the neurosurgical literature.14,15

Categorization of tethered cord syndrome and similar disorders Yamada and Won2 divided the conditions visually ­described by “cord tethering” or “tethered cord” into four pathophysiological categories: ••

••

Category 1: The mechanical tethering site is located at the caudal end of the spinal cord. Lumbosacral cord dysfunction can be reversible. Patients with an inelastic filum, a sacral MMC, and a caudal lipomyelomeningocele (LMMC) belong to this category. Category 2: The small anomalies are attached or c­ontinuous to the dorsal aspect of the caudal lumbosacral cord. Many MMCs and some of the ­ ­dorsal or transitional LMMCs belong to this category. The ­symptomatology may be partly the ­manifestation of TCS and partly due to local lesion caused by fibrous or fibroadipose tissue invasion. Impaired ­cerebrospinal fluid circulation may accentuate local cord d ­ ysfunction. Accordingly, signs and symptoms are only partially reversible. Some cases often require

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repeated surgery, sometimes resulting in progressive neurologic worsening, but not as a sign of TCS. Category 3: This category includes patients with large MMC or LMMC covering the entire lumbosacral cord and no stretch-induced signs or symptoms of TCS. Category 4: This category includes paraplegic and totally incontinent patients associated with higher lumbar or thoracic MMCs or occasionally LMMCs. No functional neurons exist in the lumbosacral cord. Another subgroup includes asymptomatic patients with an elongated cord and a thick filum because the syndrome is meant to be a special neurologic complex.

Embryology The anomalies related to TCS originate in two developmental stages.14–21 The first stage is complicated by incomplete neurulation during the third to fourth week of gestation. Failure to connect two neural crests for the formation of the neural tube results in spinal dysraphism.15,21 The 9th to 11th week of the gestation period corresponds to the second stage. At the ninth week, the permanent spinal cord forms, with its caudal end located in the coccygeal canal. Further caudally, the coccygeal medullary vestige is formed and then separated from the conus–filum complex.16 If the vestige, which is surrounded by mesenchymal tissue, is not isolated, fibrous tissue may continue to grow into the filum, resulting in an inelastic filum.

Epidemiology The epidemiology of TCS is not clear, although the incidence of midline dorsal anomalies has been reported. Demographic studies in the United States have shown that MMCs and other midline dorsal anomalies occur in 1 out of 1000 births.14,22 A child with a sibling who was born with spinal dysraphism has a higher probability of this anomaly. No generally accepted statistics are available for the incidence of TCS. From our experiences, less than 10% of category 1 patients are found in the spina bifida clinic among newborns. It is not possible to determine whether neurologic deficits of newborns with category 2 patients are related to TCS at the MMC repair. Patients with LMMC are found less frequently than those with MMC, and the incidence of TCS is higher than that of MMC. Fifty percent of adult and late teenage patients with TCS associated with an inelastic filum (with or without filum thickening) were referred to our clinic as the diagnosis of failed back surgery syndrome (S. Yamada, unpublished data). We believe that institutional studies are needed to collect systematically arranged data, based on populations of three categories.

Pathophysiology of tethered cord syndrome The link between neurologic function and metabolic activity is not surprising because the central nervous system relies absolutely on oxidative metabolism to produce adenosine triphosphate, which is the energy-donating molecule necessary for neuronal function and cell survival.23 Experimental tethered spinal cords have shown that impairment of oxidative metabolism parallels that of glucose metabolism, and diminished interneuron activities in the spinal cord, 24 and blood flow decreases.25–28 Of relevance to the impaired oxidative metabolism in human TCS, 29 mild to moderate spinal cord stretching had effects similar to mild hypoxemia, 30 whereas severe stretching had the effects expected from prolonged ischemia.31 Experimental cord traction studies also indicated that, with increasing traction weight, there was greater cord elongation that paralleled greater metabolic changes. Such metabolic changes were more prominent in the caudal segments than in the cephalic segments (Figure 25.1a and b) and were not found above the lowest pair of dentate ligaments (attachments to the L5–L6 cord segments in cats, where the lowest pair of dentate ligaments is attached).32 Accordingly, the human conus medullaris is most vulnerable to traction at the caudal end.1,33,34

Symptomatology Various authors have described signs and symptoms in children1,13,35 and adults.36–38 In infants, the signs and symptoms of TCS include dribbling of urine (constant wetting of diapers), foot deformity, skin stigmata, and a dysraphic dorsal midline spine or spinal cord. Skin abnormalities include a tuft of hair, fatty swelling, dimple, hemangioma, and dermal sinus in lumbosacral areas. Young children with TCS show progression of the following signs and symptoms: (1) stumbling after walking normally for months or years, (2) dribbling urine after successful toilet training, (3) foot drop, (4) painless sore, and (5) scoliosis and exaggerated lumbosacral lordosis. Early teenagers with TCS present with only a few mild symptoms, such as scoliosis, difficulty in bending over, or difficulty in running, often associated with thinning of lower limb muscles. A complaint of back and leg pain is more frequently found in this group than in younger children, usually aggravated by exercises that include flexion–extension of the spine. For diagnostic and prognostic purposes, Yamada et al.38,39 divided adults and late teenage patients with TCS into two groups. Group 1 patients have a prior history of spinal dysraphism associated with stabilized neurologic signs and symptoms from childhood. They usually present with subtle progression of the signs and symptoms in adulthood. Group 2 patients present with new subtle

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Figure 25.1 (a) By caudad traction of the filum, elongation of the filum and cord segments was measured in experimental cats. The graph shows the elongation rate of the filum (with a steep rise) and slow rise of the spinal cord segment (Div. 2 being the lowest and Div. 6 being the highest lumbar cord segment). Viscoelasticity of the filum is much greater than that of the spinal cord. This experimental model simulates the normal lumbosacral cord that is protected from overstretching when an intense vertical traction force is exerted. (b) By caudad traction of the spinal cord tip, the lowest cord segment elongated much more than when the filum was tractioned, but less than the filum in (a). The other cord segments also elongate more than in the case of filum traction. This model simulates the human tethered spinal cord, in which the conus is most vulnerable to stretching force exerted in the causal direction. (Reproduced from the American Association of Neurological Surgeons, Rolling Meadows, Illinois. With permission.)

neurologic symptoms in adulthood without associated neuronal spinal dysraphism. Group 2 patients are easily overlooked because they present with subtle, specific symptomatology and radiologic findings. In particular, MRI studies show neither cord elongation nor filum thickening in 50% of the patients. To properly diagnose group 2 TCS patients, signs and symptoms common to the patients of this group were tabulated. More than 90% of signs and symptoms were positive in all the adult TCS patients.40 Common symptoms are as follows: ••

Back and leg pain, particularly aggravated by postural changes and by other activities such as the following: −− Sitting with legs crossed in a Buddha pose −− Bending over the sink

−− Holding a baby at waist level −− Lying supine −− Sitting in a slouching position •• ••

Increasing difficulty in urination and bowel control Physical stress–related complaints, such as decreased tolerance to running or walking and driving a car, especially on bumpy roads. Common signs of TCS in adults are as follows:

••

••

Weakness of distal muscles, e.g., extensor hallucis ­longus, or extensive muscle weakness in the lower limbs in scattered myotomes and hypotrophic leg muscles Hyporeflexia in the lower limbs

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Sensory deficits in the distal lower limbs and perianal area, or extensive hypalgesia in lower limbs with patchy distribution Increases in postvoid residual urine Diminished sphincter tone: reflex (digital insertion, voluntary contraction, and wink reflex) Musculoskeletal deformities such as the following: −− Spinal: Exaggerated lumbosacral lordosis and thoracolumbar scoliosis −− Leg or foot: High-arched feet, hammertoes

The important differential diagnostic issue in TCS is that the neurological lesion is located cephalic to the ­attachment of an anomaly to the spinal cord. Negative signs and symptoms such as no pain aggravation in lower limbs on coughing and straight leg raising are important for differential diagnosis from herniated lumbar disk. Reflex changes are important signs for the diagnosis of TCS. Somatic reflex activities have been clearly explained by the facilitation and inhibition of reflex arcs.41,42 Patients with TCS usually show hypoactive tendon reflexes in the lower limbs, because the lesions are located in the gray matter and the reflex arcs are inactivated. If hyperactive tendon reflexes are noted, another lesion must be suspected above the L2 cord segment, including diastomatomyelia, congenital spinal diplegia, and cerebral anomalies (e.g., Chiari malformation). Bladder control relies on complex reflex mechanisms through the parasympathetic, sympathetic, and somatic systems.

Imaging diagnosis MRI is the most effective, noninvasive diagnostic technology for TCS, although radiography, computed tomography (CT) scan, and ultrasound studies provide useful background information on the anomalies that may be related to TCS.8,43–46 CT myelography is useful for patients with claustrophobia, or a cardiac pacemaker, and ultrasonography is useful for detecting an inelastic filum in newborns. It is important, however, to clinically assess imaging studies for correlation with the signs and symptoms of TCS. Common MRI findings are as follows: •• ••

•• ••

An elongated cord8 or thickened filum (>2 mm) is frequently noted.35,43 A consistent finding in TCS patients is the posterior displacement of conus and filum, indicative of its inelastic nature.38 The filum touches the posterior arachnoid membrane usually at the L5 or S1 lamina. Detailed axial T1 and T2 weighted views are mandatory. Spinal dysraphism, such as MMC, LMMC, and lipomas. A fat signal in the filum helps to confirm its posterior displacement.

Table 25.1  C  ombination of spinal cord tip location and filum thickness 1. Normal range of caudal end (above L2–L3 interspace) and filum thickness 35 mL, and the remaining two required intermittent ­catheterization after surgery. The 14 patients who did not experience incontinence had little or no PVR both ­preand postoperatively. All 50 had decreased anal sphincter tone on exam, which was improved after the surgery.75.

Voiding symptoms and incontinence after surgical untethering The majority of patients regained control of bladder function after untethering procedures, as described earlier by Khoury69 and by Fukui and Kakizaki76 who showed

Tethered cord syndrome resolution of incontinence associated with detrusor-external urethral sphincter dyssynergia. However, the baseline bladder function in patients who develop TCS is often abnormal, whereas 30%–40% of patients do not respond to cord release.61 A significant number of patients will have residual neurogenic bladder dysfunction. The surgical outcome of Kondo et al.70 supports this data. From our experience, those cases probably belonged to category 2, for example, with a large transitional LMMC.2 Another logical explanation is drawn from our experimental studies,24,77 suggesting that neuronal degeneration develops in the conus after sudden cord stretching caused by extreme spinal flexion and extension in TCS patients. Addressing their urologic problems in terms of the storage and emptying functions of the bladder facilitates management of these patients. In emptying failure due to detrusor areflexia, the most common pattern seen in these patients, an intermittent catheterization program is often most effective.

Conclusion TCS is defined as a stretch-induced functional disorder of the spinal cord with its caudal part anchored by inelastic structures. Clinical findings such as motor and sensory deficits in the lower limbs, incontinence, and musculoskeletal deformities allow for the localization of the lesions in the lumbosacral cord. These clinical impressions are compatible with findings of spinal cord traction in experimental animals. In TCS patients and in experimental animals, impaired oxidative metabolism and electrophysiological activities within the lumbosacral cord were linked to neurologic dysfunction. These changes occurred without observable histologic damage to neurons. Many patients with TCS have associated voiding dysfunction and incontinence. In some patients, urinary incontinence is the sole complaint. The urologist must have a high index of suspicion for a neurologic etiology for the urinary incontinence. Prompt recognition of the neurologic disorder is of paramount importance. With early intervention, neurosurgical untethering of the spinal cord in category 1 patients can result in complete resolution of neurologic deficit, including urinary symptoms. The surgical results for category 2 patients are not as good as in the former patients. Nevertheless, the diagnosis and treatment must not be delayed or irreversible urinary tract dysfunction may occur.

Acknowledgment The authors acknowledge Dr. Myron Rosenthal, professor of physiology and neurology at the University of Miami School of Medicine, for his continued support and advice for our research on tethered cord syndrome.

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References 1964. Yamada S, Zinke DE, Sanders D. Pathophysiology of “tethered cord syndrome.” J Neurosurg 1981; 54: 494–503. 1965. Yamada S, Won DJ. What is the true tethered cord syndrome? Childs’ Nerv Syst 2007; 23: 371–5. 1966. Fuchs A. Über Beziehungen der Enuresis nocturna zu Rudimentarformen der Spina bifida occulta (myelodysplasie). Wien Med Wochenschr 1910; 80: 1569–73. 1967. Garceau GJ. The filum terminale syndrome (the cord-traction syndrome). Bone Joint Surg (Am) 1953; 35: 711–6. 1968. Hoffmann GT, Hooks CA, Jackson IJ, Thompson IM. Urinary incontinence in myelomeningoceles due to a tethered spinal cord and its surgical treatment. Surg Gynecol Obstet 1956; 103: 618–24. 1969. Jones PH, Love JG. Tight filum terminale. Arch Surg 1956; 73: 556–66. 1970. James CCM, Lassman LP. Spinal dysraphism. The diagnosis and treatment of progressive lesions in spina bifida occulta. J Bone Joint Surg (Br) 1962; 44: 828–40. 1971. Fitz C, Harwood-Nash DC. Tethered conus. Am J Roentgenol 1975; 125: 515–23. 1972. Lichtenstein BW. Distant neuroanatomic complications of spina bifida (spinal dysraphism), hydrocephalus, Arnold–Chiari deformity, stenosis of the aqueduct of Sylvius, etc; pathogenesis and pathology. Arch Neurol Psychiatry 1940; 47: 195–214. 1973. Barry A, Pattern BM, Stewart BH. Possible factors in the development of the Arnold–Chiari malformation. J Neurosurg 1957; 14: 285–301. 1974. Barson AJ. The vertebral level of termination of the spinal cord during normal and abnormal chemical development. J Anat 1970; 106: 489–97. 1975. Gardner WJ, Smith JL, Padget DH. The relationship of Arnold– Chiari and Dandy–Walker malformations. J Neurosurg 1972; 36: 481–9. 1976. Hoffman HJ, Hendrick EB, Humpreys RJ. The tethered spinal cord: Its protean manifestations, diagnosis and surgical correction. Childs Brain 1976; 2: 145–55. 1977. Reigel DH. Spinal bifida. In: McLaurin RL, Schut L, Venes JL, Epstein F, eds. Pediatric Neurosurgery, 2nd edn. Philadelphia, PA: WB Saunders, 1989: 35–52. 1978. McLone DG, Naidich TP. The tethered spinal cord. In: McLaurin RL, Schut I, Venes JL, Epstein F, eds. Pediatric Neurosurgery, 2nd edn. Philadelphia, PA: WB Saunders, 1989: 76–96. 1979. Kunitomo K. The development and reduction of the tail and of the caudal end of the spinal cord. Contrib Embryol Carnegie Inst 1978; 8: 161–98. 1980. Streeter GI. Factors involved in the formation of the filum terminale. Am J Anat 1919; 25: 1–12. 1981. Lemire RI, Shepard TH, Ellsworth CA Jr. Caudal myeloschisis (lumbo-sacral spina bifida cystica) in five millimeter (Horizen XIV) human embryo. Anat Rec 1965; 192: 9–16. 1982. French BN. The embryology of spinal dysraphism. Clin Neurosurg 1983; 3: 295–340. 1983. Marin Padilla M. The tethered cord syndrome: Developmental consideration. In: Holtzman RNN, Stein BM, eds. The Tethered Spinal Cord. New York, NY: Thieme-Stratton, 1985: 1–13. 1984. Newgreen DF, McKeown ASJ. The neural crest: A model developmental EMT. In: Savagner P, ed. Rise and Fall of Epithelial Phenotype: Concepts of Epithelial Mesenchymal Transition. New York, NY: Kluwer Academic/Academic/Plenum, 2005: 29–39. 1985. Shurtleff DB, Lemire RL. Epidemiology, etiologic factors, and prenatal diagnosis of open spinal dysraphism. Neurosurg Clin North Am 1995; 6: 183–93. 1986. Rosenthal M, LaManna J, Yamada S, Somjen G. Oxidative metabolism, extracellular potassium and sustained potential shifts in cat spinal cord in situ. Brain Res 1979; 162: 113–27.

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1987. Yamada S, Iacono R, Yamada BS. Pathophysiology of tethered cord syndrome. In: Yamada S, ed. Tethered Cord Syndrome. Park Ridge, IL: American Association of Neurological Surgeons, 1996: 29–48. 1988. Turnbull IM, Breig A, Hassler O. Blood supply of cervical spinal cord in man. A microangiographic cadaver study. J Neurosurg 1966; 24: 951–65. 1989. Yamada S, Knierim D, Yonekura M, Schultz R, Maeda G. Tethered cord syndrome. J Am Paraplegia Soc 1983; 6: 58–61. 1990. Kang JK, Kim MC, King DS, Song JU. Effects of tethering on regional spinal cord blood flow and sensory-evoked potentials in growing cats. Childs Nerv Syst 1987; 3: 35–9. 1991. Schneider SJ, Rosenthal AD, Greenberg VM, Danto J. A preliminary report on the use of laser-Doppler flowmetry during tethered spinal cord release. Neurosurgery 1983; 32: 214–7. 1992. Yamada S, Won DJ, Yamada SM. Pathophysiology of tethered cord syndrome and clinical correlation. Neurosurg Forum 2004; 16: 1–5. 1993. Yamada S, Sanders DC, Haugen GE. Functional and metabolic responses of the spinal cord to anoxia and asphyxia. In: Austin GM, ed. Contemporary Aspects of Cerebrovascular Disease. Dallas, TX: Professional Information Library, 1976: 239–46. 1994. Yamada S, Sanders DC, Maeda G. Oxidative metabolism during and following ischemia of cat spinal cord. Neurol Res 1981; 3: 1–16. 1995. Yamada S, Perot PL, Ducker TB, Lockard I. Myelotomy for control of mass spasms in paraplegia. J Neurosurg 1976; 45: 681–3. 1996. Tani S, Yamada S, Knighton R. Extensibility of the lumbar and sacral spinal cord—Pathophysiology of tethered spinal cord. J Neurosurg 1987; 66: 116–23. 1997. Yamada S, Won DJ, Pezeshkpour G et al. Pathophysiology of tethered cord syndrome and similar disorders. Neurosug Focus 2007; 23(2): E6: 1–10. 1998. Pang D, Tethered cord syndrome. In: Hoffman HJ, ed. Advances in Neurosurgery. Vol 1, No 1. Philadelphia, PA: Hanley & Belfus, 1986: 45–79. 1999. Pang D, Wilberger JE Jr. Tethered cord syndrome in adults. J Neurosurg 1982; 57: 32–47. 2000. Yamada S, Lonser RR. Adult tethered cord syndrome. J Spinal Disord 2000; 13: 319–23. 2001. Yamada S, Won DJ, Kido DK. Adult tethered cord syndrome: New classification correlated with symptomatology, imaging and pathophysiology. Neurosurg Q 2001; 11: 260–75. 2002. Yamada S, Iacono R, Douglas C, Lonser RR, Shook J. Tethered cord syndrome in adults. In: Yamada S, ed. Tethered Cord Syndrome. Park Ridge, IL: American Association of Neurological Surgeons, 1996: 149–65. 2003. Yamada S, Siddiqi J, Won DJ et al. Symptomatic protocols for adult tethered cord syndrome. Neurol Res 2004; 26: 741–4. 2004. Grew TJ. Spinal cord II: Reflex action. In: Kandel EP, Schwartz JH, eds. Principles of Neural Science. New York, NY: Elsevier/North Holland, 1981: 293–304. 2005. Haines DE, Mihailoff GA, Yerzierski RP. The spinal cord. In: Haines DE, ed. Fundamental Neuroscience, 2nd edn. New York, NY: Churchill Livingston, 2002: 294–357. 2006. Harwood-Nash D. Neuroradiology A: Computed tomography. In: Holtzman RNN, Stein BM, eds. The Tethered Spinal Cord. New York, NY: Thieme-Stratton, 1985: 41–6. 2007. Naidich P, McLone DG. Neuroradiology B: Ultrasonography. In: Holtzman RNN, Stein B, eds. The Tethered Spinal Cord. New York, NY: Thieme-Stratton, 1985: 47–58. 2008. Hinshaw DB Jr., Engelhart JA, Kaminsky CK. Imaging of the tethered spinal cord. In: Yamada S, ed. Tethered Cord Syndrome. Park Ridge, IL: American Association of Neurological Surgeons, 1996: 55–70. 2009. Nelson MD. Ultrasonic evaluation of the tethered cord syndrome. In: Yamada S, ed. Tethered Cord Syndrome. Park Ridge, IL: American Association of Neurological Surgeons, 1996: 71–8.

2010. Tubbs RS. Oakes WJ. Can the conus medullaris in normal position be tethered? Neurol Res 2004; 26: 727–31. 2011. Wehby MC, O’Hollaren PS, Abtin K, Hune JL, Richards BJ. Occult tight filum terminale syndrome: Results of surgical untethering. Pediatr Neurosurg 2004; 40: 51–7. 2012. Pang D. Split cord malformation. In: Pang D, ed. Disorders of the Pediatric Spine. New York, NY: Raven Press, 1995: 203–52. 2013. Yamada S, Yamada SM, Mandybur GM, Yamada BS. Conservative versus surgical treatment and tethered cord syndrome prognosis. In: Yamada S, ed. Tethered Cord Syndrome. Park Ridge, IL: American Association of Neurological Surgeons, 1996: 183–202. 2014. Guthkelch AN, Hoffmann GT. Tethered spinal cord in association with diastematomyelia. Surg Neurol 1981; 15: 352–4. 2015. Hoffman HJ. Indication and treatment of the tethered spinal cord. In: Yamada S, ed. Tethered Cord Syndrome. Park Ridge, IL: American Association of Neurological Surgeons, 1996: 29–48. 2016. Till K. Spinal dysraphism. A study of congenital malformations of the lower back. J Bone Joint Surg (Br) 1969; 51: 415–22. 2017. Till K. Occult spinal dysraphism. The value of prophylactic surgical treatment. In: Sano K, Ishii S, Le Vay D, eds. Recent Progress in Neurological Surgery. New York, NY: Elsevier, 1973: 61–6. 2018. Hoffman HJ, Taecholarn C, Hendrick EB, Humphreys RP. Management of lipomyelomeningoceles. Experience at the Hospital for Sick Children. Toronto J Neurosurg 1985; 62: 1–8. 2019. Yamada S, Lonser RR, Yamada SM, Iacono RP. Tethered cord syndrome associated with myelomeningoceles and lipomyelo­ meningoceles. In: Yamada S, ed. Tethered Cord Syndrome. Park Ridge, IL: American Association of Neurological Surgeons, 1996: 103–23. 2020. Sakamoto H, Hakuba A, Fujitani K, Nishimura S. Surgical treatment of the tethered spinal cord after repair of lipomyelomeningocele. J Neurosurg 1991; 74: 709–14. 2021. Ruch TC. The urinary bladder. In: Ruch TC, Fulton JF, eds. Medical Physiology and Biophysics. Philadelphia, PA: WB Saunders, 1960: 955–62. 2022. Blaivas JG. Urological abnormalities in the tethered spinal cord. In: Holtzman RNN, Stein BM, eds. The Tethered Spinal Cord. New York, NY: Thieme-Stratton, 1985: 41–6. 2023. Hadley R, Holevas RE. Lower urinary tract dysfunction in tethered cord syndrome. In: Yamada S, ed. Tethered Cord Syndrome. Park Ridge, IL: American Association of Neurological Surgeons, 1996: 79–88. 2024. Khoury AE, Balcom A, LcLorie GA, Churchill BM. Clinical experience in urological involvement with tethered cord syndrome. In: Yamada S, ed. Tethered Cord Syndrome. Park Ridge, IL: American Association of Neurological Surgeons, 1996: 89–98. 2025. Fuse T, Patrickson J, Yamada S. Axonal transport of horseradish peroxidase in the experimental tethered spinal cord. Pediatr Neurosci 1989; 15: 296–301. 2026. Murphy JJ, Wein AJ. Urologic aspects of surgery. In: Austin GM, ed. The Spinal Cord, 3rd edn. New York, NY: Igaku-Shoin, 1983: 664–76. 2027. Hardy SGP, Naftel JP. Viscerosensory pathway. In: Haines DE, ed. Fundamental Neuroscience. New York, NY: Churchill Livingstone, 2002: 293–322. 2028. Kuru M. Nervous control of micturition. Physiol Rev 1965; 45: 425–94. 2029. McGuire EJ, Woodside JR, Borden TA, Weiss RM. Prognostic value of urodynamic testing in myelodysplastic patients. J Urol 1981; 126: 205–9. 2030. Helstrom WJG, Edwards MSB, Kogan BA. Urological aspects of the tethered cord syndrome. J Urol 1986; 135: 317–20. 2031. Pippi Salle JL, Capolicchi Edwards MSB, Kogan BA. Urological aspects of the tethered cord syndrome. J Urol 1986; 135: 317–20.

Tethered cord syndrome 2032. Khoury AE, Hendrick EB, McLorie GA, Kulkami A, Churchill BM. Occult spinal dysraphism: Clinical and urodynamic outcome after division of the filum terminale. J Urol 1990; 144: 426–9. 2033. Kondo A, Kato K, Kanai, Sakakibara T. Bladder dysfunction secondary to tethered cord syndrome in adults: Is it curable? J Urol 1986; 135: 313–6. 2034. Drake JM. Occult tethered cord syndrome: Not an indication for surgery. J Neurosurg 2006; 104(Suppl 5 Pediatrics): 305–8. 2035. Selden NR. Occult tethered cord syndrome: The case for surgery. J Neurosurg 2006; 104(Suppl 5 Pediatrics): 302–4. 2036. Steinbok P, Garton HJL, Gupta N. Occult tethered cord syndrome: A survey of practice pattern. J Neurosurg 2006; 104(Suppl 5 Pediatrics): 309–13.

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2037. Yamada S, Won DJ. Neurosurgical forum, letters to the editor. Occult tethered cord syndrome. J Neurosurg 2007; 106: 411–4. 2038. Hadley HR, Ruckle HC, Yamada BS, Gideon DR. Urologic aspect of tethered cord syndrome I: Lower tract dysfunction in tethered cord syndrome. In: Yamada S, ed, Tethered Cord Syndrome In Children and Adults, 2nd Edition, New York, NY: Thieme, and Rolling Meadow, IL: American Association of Neurological Surgeons, 2010, 74–85. 2039. Fukui J, Kakizaki TL. Urodynamic evaluation of tethered cord ­syndrome including tight filum terminale. Urology 1980; 16: 539–52. 2040. Yamada S, Schultz RL, Mandybur GT et  al. Axonal degeneration after sudden forceful traction of the spinal cord: Is it the cause of permanent neurological deficit? J Neurosurg 2003; 98: 681.

26 Spinal cord injury and cerebral trauma Jerzy B. Gajewski

Introduction Disturbances of micturition are very common with head and spinal cord injuries. The range of bladder symptoms caused by neurologic lesions is wide and determined by whether the lesion primarily affects supraspinal control, the pontine–sacral neural circuit, or the sacral nerves and whether these lesions are predominantly motor, sensory, or both (Figure 26.1).

Head injury Coma Head injury can cause temporary dysfunction (coma) or permanent lesion. Unconsciousness after cerebral injury relates to compression, hemorrhage, or ischemia. The brainstem can be displaced downwards or the temporal lobe herniates through the tentorial opening. Classification of the different stages of coma is best described by the Glasgow Scale.1 In most cases of coma, spontaneous micturition is possible and there seems to be some perception of bladder fullness in lighter stages.2 Because only the suprapontine area is affected, coordination between the detrusor and sphincter remains. Voiding is synergistic, with no residual. Some patients, however, show decreased detrusor compliance (ability of the bladder to accommodate a larger volume with low pressure), which depends on both neural and non-­neural factors. An indwelling Foley catheter, which patients usually have, may cause detrusor irritation and may explain increased stiffness of the bladder. Lack of sympathetic inhibition of bladder activity by the cerebrum, as in progressive autonomic and multiple system failure,3,4 can be another explanation. In some comatose patients, however, there is temporary bladder retention. It is not clear whether this is related to bladder overstretching immediately after the accident or to active

cerebral bladder inhibition. The possibility of temporary pontine shock similar to spinal shock cannot be excluded.

Suprapontine neurogenic detrusor overactivity If the amount of cortical inhibition running in descending pathways is reduced by a suprapontine injury, there will be diminished ability to inhibit the micturition reflex. This results in an uninhibited detrusor contraction, with synergistic relaxation of the proximal and distal sphincter. Animal studies showed that injury above the inferior ­colliculus eliminated the inhibitory effect on the micturition center, whereas a lesion below this point abolished the normal micturition reflex.5 Human positron emission tomography study showed that the control areas of micturition are  mostly located on the right side of the brain (Figure 26.2).4,5 Some clinical reports indicate that urgency incontinence or detrusor overactivity (DO) is more commonly associated with right-sided damage,6 whereas impaired contractility was associated with left hemispheric damage.7 Other clinical observations suggest that unilateral right cortical lesions (prefrontal damage) produce transient dysfunction, whereas bilateral lesions produce permanent dysfunction.8 Some finding suggests a central mechanism sensitive to nitric oxide for bladder overactivity after cerebral infarction.9 During the filling phase, when the bladder ­contains a comparatively small volume of urine, inhibition of the suprapontine reflex arc will fail and the detrusor muscle will  contract. There is no resistance from the urethra because of adequate relaxation of the sphincters due to the preserved sacropontine reflex arc. Patients with suprapontine DO will complain of frequency, urgency, and urgency incontinence and, in severe cases of complete lesion, lack of sensory or motor c­ontrol of the micturition reflex. They have no residual urine and thus are not prone to bladder i­nfections. Urodynamic studies may show

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PMC

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Sensory C fibers

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PLN S2 S3 S4

Figure 26.1

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Innervation of the lower urinary tract. HGN, hypogastric nerve (sympathetic); PDN, pudendal nerve (somatic); PLN, pelvic nerve (parasympathetic); PMC, pontine micturition center.

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Figure 26.2 Significant differences in regional cerebral blood flow in the cortical areas after the comparison between the conditions “­successful ­micturition” (scan 2) and “urine withholding” (scan 1). Note the activation of the right anterior cingulated gyrus (acg) in z planes +8 to +16, and the right inferior frontal gyrus (gfi) in z planes 0 to +12. (Reproduced with permission from Blok BFM, Willemsen ATM, Holstege G. Brain 1997; 120: 111–121.)

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5 Qura [mL/s] 0

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Figure 26.3 Pressure flow study in a patient with a suprapontine lesion. The patient has no sensation; however, voiding is coordinated between the detrusor (Pdet) and external sphincter electromyography (EMG). EMG activity decreases during detrusor contraction. Qura, flow rate; P ves, bladder pressure; Pabd, abdominal pressure.

early (small-volume) detrusor contractions, no detrusor–­ sphincter dyssynergia (DSD) (the sphincter relaxes during detrusor contraction), and voiding without residual (Figure 26.3).

myotomes to determine the level and completeness of the sensory and motor functions and distinguishes four classes of spinal cord injury based on the Frankel system and five clinical syndromes:

Spinal cord injury Classification

••

The most comprehensive classification is that developed by the American Spinal Injury Association (ASIA) (Figure 26.4). It uses the examination of dermatomes and

Central cord syndrome is a result of hemorrhagic necrosis of the central gray matter and some of the medial white matter and is most commonly due to hyperextension injury. More caudal fibers of the corticospinal and spinothalamic tract are localized in the spine more lateral (from the center), and hence are better protected from the central necrosis; consequently,

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Textbook of the Neurogenic Bladder ASIA IMPAIRMENT SCALE A = Complete: No motor or sensory function is preserved in the sacral segments S4–S5. B = Incomplete: Sensory but not motor function is preserved below the neurological level and includes the sacral segments S4–S5. C = Incomplete: Motor function is preserved below the neurological level, and more than half of key muscles below the neurological level have a muscle grade less than 3. D = Incomplete: Motor function is preserved below the neurological level, and at least half of key muscles below the neurological level have a muscle grade of 3 of more. E = Normal: Motor and sensory function are normal.

CLINICAL SYNDROMES Central cord Brown-Séquard Anterior cord Conus medullaris Cauda equina

STANDARD NEUROLOGICAL CLASSIFICATION OF SPINAL CORD INJURY R

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C2 C3 C4 Elbow flexors C5 Wrist extensions C6 Elbow extensions C7 Finger flexors (distal phalanx of middle finger) C8 T1 Finger abductors (little finger) T2 0 = total paralysis T3 1 = palpable or visible contraction T4 2 = active movement T5 gravity eliminated T6 3 = active movement T7 against gravity T8 4 = active movement T9 against some resistance T10 5 = active movement T11 against full resistance T12 NT = not testable L1 L2 Hip flexors L3 Knee extensors L4 Ankle dorsiflexors L5 Long toe extensors S1 Ankle planfar flexors S2 S3 Voluntary anal contraction (Yes/No) S4-5

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ZONE OF PARTIAL PRESERVATION Caudal ankle of partially incompleted segments

SENSORY MOTOR

R

L

Figure 26.4 Classification developed by the American Spinal Injury Association (ASIA).

••

arms are more affected than legs. Bladder dysfunction is also less common. Brown–Séquard syndrome is a rare unilateral cord condition that can result from penetrating injury or asymmetric disc herniation. It presents as ipsilateral motor weakness and sense impairment of fine touch

••

and position and contralateral sensory impairment of pain and temperature. Bladder dysfunction in the pure condition is uncommon. Anterior cord syndrome is characterized by injury to the anterior aspects of the cord, with preservation of the posterior columns and dorsal horns. There is a

Spinal cord injury and cerebral trauma

••

motor deficit and loss of pain and temperature sensation below the level of the injury. Conus medullaris and cauda equina syndrome result from damage to the conus and spinal nerve roots, leading to flaccid paraplegia and sensory loss. Sacral reflexes can be partially or totally lost.

The bladder in “spinal shock” Following an acute spinal cord injury (the first 2 weeks to 3 months) at a level above the sacral segments, the central synapses between the afferent and efferent arms of the micturition reflex will be rendered inactive with total depression of the interneuronal activity due to release of inhibitory transmitters. The detrusor will be underactive (acontractile detrusor), and there will be no conscious awareness of bladder fullness. However, the bladder neck and proximal urethra remains closed and the bladder will continue to distend because the reflex arc does not function. The resulting retention of urine is followed by dribbling incontinence as a consequence of an overflow. This retention cannot be avoided or managed by muscarinic stimulation with bethanechol.10,11 Infection resulting from the large amount of residual urine may become a serious recurrent problem. The only reflex activity which is preserved or returns almost immediately is anal and bulbocavernosus reflex. Bladder reflex activity recovers usually within 2–3 months. It has been shown that sacral root stimulation during spinal shock facilitates recovery of the reflex activity of the detrusor;12 however, transdermal amplitude-modulated signal, similar to neuromodulator, caused a reduction in neurogenic detrusor overactivity (NDO) by inhibiting C-fiber activity.13 We have also found that perineal and urethral stimulation is necessary for recovery of bladder reflex activity in spinally transected cats.14

Upper motor neuron lesion Suprasacral neurogenic detrusor overactivity This follows the stage of spinal shock resulting from a cord injury above the S1 level. Reflex bladder function eventually occurs in experimental animals and in man after suprasacral cord injury. This function is different from normal in that •• •• •• ••

It involves different afferent fibers (C-fibers in the cat).15 Bladder contractions are poorly sustained.16 The urethra and bladder become discoordinated.17 Previously “irrelevant” stimuli influence the bladder18 and/or external sphincter activity.19

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Consciousness of bladder sensation may not be totally absent, but voluntary inhibition of the micturition reflex arc is lost. The initial retention of urine with accompanying overflow incontinence during the stage of spinal shock gives way to the effects of an augmented reflex arc and results in a small, spastic, and overactive bladder. The bladder empties incompletely because of the dyssynergic contraction of the external sphincter, reflex inhibition from the dyssynergic sphincter, and primary detrusor failure (discoordinated contraction).20 Overall, this alteration in central organization results in a high voiding pressure, residual urine, and incontinence. These subsequently lead to recurrent infection, hydronephrosis, and finally to renal failure. In some instances of an incomplete suprasacral lesion, synergistic relaxation of the external sphincter is preserved. In these patients, given time, reflex bladder contraction in response to skin stimulation may be learned, thus allowing the patient some voluntary control.

Afferent fibers Normal micturition reflex involves Aδ-fiber afferents. Only in inflammatory states are C-fiber afferents involved (chemosensitivity). After spinal cord injury, C-fiber afferents mediate (mechanosensitivity) the abnormal sacral segmental bladder reflex.15 The mechanism of this change from chemosensitivity to mechanosensitivity of C-fibers is unclear. In rats, the timing of recovery of bladder contractile activity after spinal cord injury coincides with sacral primary afferent terminal sprouting.21

Detrusor underactivity The normal micturition reflex is controlled by spinal (sacral) and supraspinal centers.22 After suprasacral spinal cord injury, some reflex bladder function persists. However, the bladder contractions are ineffective and poorly sustained,16 and the urethra and bladder become uncoordinated.17 It has been assumed that poor detrusor function is primarily due to reflex inhibition from the ­dyssynergic sphincter.23 There are suggestions that primary detrusor failure might also be of significance.24 In some instances of cervical and high thoracic spinal cord injury (10%–20%), detrusor acontractility and external sphincter denervation are present, indicating a distinct and separate lesion in the sacral area.25–27

Detrusor–sphincter dyssynergia (internal and external) The pons coordinates the micturition reflex. Any lesion between the sacral and pontine level may produce discoordinated voiding, which results in increased external

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sphincter activity during detrusor contraction. DSD correlates with completeness but not with the level of the upper motor neuron lesion.28 DSD is responsible for the bladder outlet obstruction and, in combination with NDO, for high, sustained intravesical pressure, which is the most common cause of upper tract complications in spinal cord injury.29,30 Diagnosis of DSD is based on electromyography (EMG) recording during cystometography and voiding or during videourodynamics. There is an increased EMG activity during bladder contraction. In true DSD, increased EMG activity correlates with an ascending portion of the detrusor contraction curve, as opposed to dysfunction voiding, in which the EMG increase is more random (Figure 26.5).31 A normal constant increase in the activity of the smooth and striated urethral sphincter accompanies bladder filling in response to the activation of bladder afferents.28,32 This reflex is mainly driven by afferents conveyed through the pelvic nerves; it is lost in patients with complete upper motor neuron lesions and 0

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correlates well with DSD.31 The sympathetic system controls the bladder neck and proximal urethra from the T10 to L2 spinal cord segments.33 A spinal cord lesion above T10 removes supraspinal inhibitory control of the sympathetic vesicourethral neurons, resulting in bladder neck functional obstruction (smooth muscle dyssynergia).34 Urologic manifestations of smooth muscle dyssynergia are the same as with detrusor–external sphincter dyssynergia. Outflow obstruction is at the level of the bladder neck and proximal urethra and adds to the obstruction at the level of the external sphincter.35

Abnormal reflex activity after spinal injury Bladder activity can be influenced not only by its own sensory inputs but also by those from the colon and anal sphincter,36,37 and from somatic structures (e.g., 6:40 Cough VH2O = 300 ml Strong Desire V VV 20

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0

Figure 26.5 Pressure flow study in a patient with a suprasacral complete lesion. The patient has detrusor–sphincter dyssynergia (DSD). Increase in external sphincter EMG activity is during the ascending phase of detrusor contraction (Pdet)—shaded area. There is an interrupted flow because of severe bladder outlet obstruction due to DSD. Qura, flow rate; P ves, bladder pressure; Pabd, abdominal pressure.

Spinal cord injury and cerebral trauma perineum).38 Visceral afferents can also have effects on somatic reflexes, particularly polysynaptic ones.37 Sacral spinal interneurons appear to be one site for these interactions.39,40 After acute suprasacral spinal transection, the external urethral sphincter quickly recovers its response to bladder distension. However, the absence of the normal suppression of this reflex during bladder contraction creates inefficient voiding. In chronic suprasacral spinal injury, previously “irrelevant” stimuli to the penis, perineal skin, etc., can cause bladder contraction18,38 and/or external sphincter activity19 in both man and animals. The “skin–central nervous system–bladder reflex,” in animal experiments, is effective in initiating bladder contractions after acute transection of the lumbar spinal cord. It is suggested that somatic motor axons can innervate bladder parasympathetic ganglion cells and thereby transfer somatic reflex activity to the bladder smooth muscle.41

Autonomic dysreflexia In the patient with a neurologic midthoracic or higher spinal lesion, autonomic dysreflexia may occur.42,43 This syndrome is secondary to loss of supraspinal inhibitory control of a thoracolumbar sympathetic outflow and results from massive discharge of the sympathetic system. Systemic manifestation of the autonomic dysreflexia (usually with a lesion above T6) includes sweating below and cutaneous flushing above the level of the neurologic lesion, pounding headache, nasal congestion, and piloerection.44,45 Splanchnic vasoconstriction occurs rapidly, causing hypertension which may be life-threatening due to intracranial hemorrhage. There is a bradycardia, mediated through vagus nerves (Figure 26.6). Autonomic dysreflexia can be triggered by a noxious stimulus below the level of the spinal cord injury and includes bladder

distension, urologic manipulations, constipation, and skin irritation.46 The severity of the dysreflexia depends on the sprouting of myelinated and unmyelinated primary afferents below the injury. Although there is no evidence that sprouting reaches directly autonomic or motor neurons, an increased pool of interneurons contributes to exaggerated autonomic reflexes (dysreflexia).47 An animal study showed that blocking intraspinal sprouting minimized dysreflexia.48 In the case of so-called malignant autonomic dysreflexia, supraspinal autonomic control is also lost.49

Lower motor neuron lesion Spinal cord injury to the sacral paths at S1–S4 results in parasympathetic decentralization of the bladder detrusor and somatic denervation of the external urethral sphincter, and loss of some afferent pathways. In a complete lesion, conscious awareness of bladder fullness will be lost and the micturition reflex is absent. Some pain sensation can be preserved because the hypogastric (sympathetic) nerve is intact.

Bladder Parasympathetic decentralization results in degeneration and regeneration changes in the muscle cells of the bladder detrusor as well as in their innervating axons,50 and that can account for the abnormal physiologic and pharmacologic behavior observed. In the chronic decentralized human and feline bladder, an increase ­ in adrenergic innervation to the detrusor has been reported.51–53 This results in the outgrowth of sympathetic fibers in the detrusor and the conversion of their

Headaches and cerebral hemorrhages

Stimulation of baroreceptors in aortic arch and carotid

e erv

n us

Reflex bradycardia

Vag

T6 Lack of supraspinal inhibition

Reflex vasodilation Flashing piloerection and diaphoresis above the injury

Bo we l

Uninhibited splanchnic vasoconstriction below lesion and hypertension

Bladder Nociceptive and proprioceptive stimuli

305

Figure 26.6 Autonomic dysreflexia.

306

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functional role from β-adrenoreceptor-mediated relaxation to α-adrenoreceptor-mediated contraction.50,51,54 This change in sympathetic function appeared only after complete lesions.55 On the other hand, de Groat and Kawatani55 postulated that unilateral parasympathetic preganglionic denervation of the detrusor leads to a reinnervation of the denervated cholinergic ganglions by sympathetic preganglionic pathways. This new pathway provides a means for eliciting excitatory bladder muscle responses. It has been suggested that an altered sympathetic pathway could explain the decrease in detrusor compliance associated with lower motor neuron (LMN) lesions in monkeys56 and dogs.57 McGuire and Morrissey56 demonstrated in monkeys that complete intradural sacral rhizotomy produced hypertonic areflexic bladder, whereas selective dorsal root damage produced hypotonic areflexic detrusor. Further studies showed that α-adrenergic blockade partially reversed the effect of chronic denervation on detrusor compliance in these animals58 and in dogs.56 Gunasekera et al.59 reported decreased bladder compliance in more than half of patients with acquired LMN lesions. More than 70% of patients with myelodysplasia have bladders with low compliance.60 In our study61 of patients with LMN lesions, all of whom were on intermittent catheterization and we could not demonstrate any changes in detrusor compliance, regardless of whether the lesion was complete or incomplete. This is in agreement with a laboratory study62 in which compliance was not decreased 3 months after sacral root injury in cats. These findings imply that ongoing activity from the sacral cord or pelvic afferent nerve traffic is not required for the maintenance of normal detrusor compliance in this situation. The role of the sympathetic system, however, in the parasympathetically decentralized bladder detrusor is still unclear. The chronic complete parasympathetically decentralized bladder develops supersensitivity to muscarinic stimulants,63 which can be demonstrated as a marked increase in the intravesical pressure in response to subcutaneous bethanechol. In partial LMN lesions, supersensitivity was not detected in rats64 or dogs.65 Using an alternative way of performing the bethanechol test (reduction in threshold dose of bethanechol rather than an increase in bladder pressure used as an indicator), El-Salmy et  al.66 demonstrated supersensitivity of the detrusor in cats with partial sacral rhizotomies. In our study,60 patients with complete or incomplete lesions responded to bethanechol injection with bladder pressure increase, although the more dramatic response was seen in patients with complete lesions. These findings dispute the validity of the bethanechol test in differentiating between complete and incomplete lesions.

Urethra and external urinary sphincter The urethra is mainly innervated by the sympathetic system and only sparsely by the parasympathetic system.

Maximum urethral pressure (MUP) values were low, however, in our patients 60 when compared with our normal values or other67 standards. There was no significant difference between complete and incomplete lesions. Mattiasson et  al.68 also reported that MUP was significantly lower in patients with parasympathetic decentralization than in volunteers. Loss of somatic innervation to the external sphincter may account for this finding. Phentolamine had little effect on MUP in our study, in contrast to the finding in volunteers with normal lower urinary tracts.66 There is a possibility that sympathetic influence over urethral closure pressure has been lost in this situation. Other researchers have reported variable urethral pressure profile responses to α-adrenergic blockers in LMN lesions.69 In a complete LMN lesion due to somatic denervation of the external sphincter, striated muscle activity is abnormal. EMG is characterized by individual action potentials which are of increased amplitude and duration, and are polyphasic with some abnormal spontaneous activity in the form of positive waves and fibrillation potentials.70 Conscious control is lost; however, some muscle tone is preserved. Narrowing in the region of the external urethral sphincter is not an uncommon finding. Proposed mechanisms include •• •• ••

Fibrosis of the urethral sphincter71 Sympathetic dyssynergia72 Denervation supersensitivity73 or autonomic reinnervation of the rhabdosphincter74,75

Bladder neck and proximal urethra The bladder neck and proximal urethra receive a dual cholinergic and adrenergic innervation from the pelvic and hypogastric nerve, respectively.50,76–78 Laboratory studies have demonstrated a predominance of α-adrenergic receptors in that area.79–81 Normally, the bladder neck should remain closed except during voiding.82 Neurogenic and non-neurogenic factors influence competence of the bladder neck. The hydromechanical effect of Credé’s maneuver has been shown to reduce proximal urethral closure pressure in cats with a sacral injury.83 It is not clear whether an open bladder neck in an LMN lesion is a primary neurologic defect or is secondary to associated detrusor dysfunction (increased stiffness or autonomous waves) or treatment. There are conflicting reports regarding which neurologic lesion causes an open bladder neck.59,84,85 McGuire and Wagner85 found that a complete, isolated sacral decentralization of the parasympathetic and pudendal nerves did not result in an open bladder neck, which conflicts with our results.60 We have shown that bladder neck incompetence is related to completeness of the LMN lesion and that sympathetic blockade (phentolamine) had an effect on the bladder neck closing mechanism only in incomplete lesions. The data imply that, in addition to sympathetic function,

Spinal cord injury and cerebral trauma some sacral root activity takes part in the maintenance of bladder neck closure, either through efferent parasympathetic activity or by providing an afferent link to a sympathetic reflex. Kirby et al.86 found the bladder neck open in all patients with pelvic nerve injury or cauda equina lesion. Open bladder neck was also found in almost 90% of children with myelodysplasia.59 Extensive autonomic system damage (after abdominoperineal resection) was found to be associated with open bladder neck, probably due to sympathetic denervation.87 However, a contribution from the increased intravesical pressure cannot be ruled out. Neurogenic bladder dysfunction is more common than was previously diagnosed. A report by Ahlberg et  al.88 showed that up to 82% of patients with “idiopathic bladder” dysfunction have pathologic neurologic findings, which indicates that patients with voiding dysfunction should be considered to have a neurologic underlying condition unless proven otherwise.

References 2041. Born JD. The Glasgow–Liege Scale. Prognostic value and evolution of motor response and brain stem reflexes after severe head injury. Acta Neurochir (Wien) 1988; 91(1–2): 1–11. 2042. Wyndaele JJ. Urodynamics in comatose patients. Neurourol Urodyn 1990; 9: 43–52. 2043. Kirby RS. Autonomic failure and the role of the sympathetic nervous system in the control of the lower urinary tract function. Clin Sci 1986; 70(Suppl 14): 45s–50s. 2044. Shy GM, Drager GA. A neurological syndrome associated with orthostatic hypotension: A clinical-pathologic study. Arch Neurol (Chicago) 1960; 2: 511–27. 2045. Tang PC. Levels of brain stem and diencephalon controlling micturition reflex. J Neurophysiol 1955; 18: 583–95. 2046. Kuroiwa Y, Tohgi H, Ono S, Itoh M. Frequency and urgency of micturition in hemiplegic patients: Relationship to hemisphere laterality of lesions. J Neurol 1987; 234: 100–2. 2047. Giannantoni A, Slivestro D, Siracusano S, Azicnuda E, D’Ippolito M, Rigon J, Sabatini U, Bini V, Formisan R. Urologic dysfunction and neurologic outcome in coma survivors after severe traumatic brain injury in the postacute and chronic phase. Arch Phys Med Rehab 2011; 92: 1134–8. 2048. Mochizuki H, Saito H. Mesial frontal lobe syndrome: Correlations between neurological deficits and radiological localizations. Tohoku J Exp Med 1990; 161(Suppl): 231–9. 2049. Kodama K, Yokoyama O, Komatsu K et al. Contribution of cerebral nitric oxide to bladder overactivity after cerebral infarction in rats. J Urol 2002; 167: 391–6. 2050. Twiddy DA, Downie JW, Awad SA. Response of the bladder to bethanechol after acute spinal cord transection in cats. J Pharmacol Exp Ther 1980; 215: 500–6. 2051. Downie JW. Bethanechol chloride in urology: A discussion of issues. Neurourol Urodyn 1984; 3: 211–22. 2052. Hassuna M, Li JS, Sawan M et al. Effect of early bladder stimulation on spinal shock: Experimental approach. Urology 1992; 40: 563–73. 2053. Elkelini MS, Pravdivyi I, Hassouna MM. Mechanism of action of sacral nerve stimulation using a transdermal amplitude-modulated signal in a spinal cord injury rodent model. Can Urol Assoc J 2012; 6(4): 227–30. 2054. Downie JW, Espey MJ, Gajewski JB. Contribution of perineal stimulation to the emergence of distension-evoked bladder contractions in spinal cats. Soc Neurosci Abstracts 1995; 21: 1201.

307

2055. De Groat WC, Kawatani M, Hisamitsu T et al. Mechanisms underlying the recovery of urinary bladder function following spinal cord injury. J Auton Nerv System 1990; 30: S71–7. 2056. Blaivas JG. The neurophysiology of micturition: A clinical study of 550 patients. J Urol 1982; 127: 958–63. 2057. Galeano C, Jubelin B, Germain L, Guenette L. Micturitional reflexes in chronic spinalized cats: The underactive detrusor and detrusor sphincter dyssynergia. Neurourol Urodyn 1986; 5: 45–63. 2058. De Groat WC, Ryall RW. Reflexes to sacral parasympathetic neurones concerned with micturition in the cat. J Physiol (Lond) 1969; 200: 87–108. 2059. Downie JW, Awad SA. The state of urethral musculature during the detrusor areflexia after spinal cord transection. Invest Urol 1979; 17: 55–9. 2060. Nagatomi J, Toosi KK, Grashow JS, Chancellor MB, Sacks MS. Quantification of the bladder smooth muscle orientation in normal and spinal cord injured rats. Ann Biomed Eng 2005; 33: 1078–89. 2061. Zinck NDT, Rafuse VF, Downie JW. Sprouting of CGRP primary afferents in lumbosacral spinal cord precedes emergence of bladder activity after spinal injury. Exp Neurol 2007; 204: 777–90. 2062. Barrington FJF. The nervous mechanism of micturition. Q J Exp Physiol 1915; 8: 33–71. 2063. Yalla SV, Blunt KJ, Fam BA et al. Detrusor-urethral sphincter dyssynergia. J Urol 1977; 118: 1026–9. 2064. Griffiths DJ. Residual urine, underactive detrusor function and the nature of detrusor/sphincter dyssynergia. Neurourol Urodyn 1983; 2: 289–94. 2065. Dimitrijevic MR, Larsson LE, Lehmkuhl D, Sherwood AM. Evoked spinal cord and nerve root potentials in human using a non-invasive recording technique. Electroencephalogr Clin Neurophysiol 1978; 45: 331–40. 2066. Beric A, Dimitrijevic MR, Light JK. A clinical syndrome of rostal and caudal spinal injury: Neurological, neurophysiological and urodynamic evidence for occult sacral lesion. J Neurol Neurosurg Psychiatry 1987; 50(5): 600–6. 2067. Beric A, Light JK. Correlation of bladder dysfunction and lumbosacral somatosensory evoked potential S wave abnormality in spinal cord injured patients. Neurourol Urodyn 1988; 7: 131–40. 2068. Siroky MB, Krane RJ. Neurologic aspects of detrusor sphincter dyssynergia, with reference to the guarding reflex. J Urol 1982; 127: 953–7. 2069. McGuire EJ, Savastano JA. Long term follow-up of spinal cord injury patients managed by intermittent catheterization. J Urol 1983; 129: 775–6. 2070. Wang SC, McGuire EJ, Bloom DA. A bladder pressure management system for myelodysplasia—Clinical outcome. J Urol 1988; 140: 1499–502. 2071. Rudy DC, Woodside JR. Non-neurogenic neurogenic bladder. The relationship between intravesical pressure and external sphincter electromyogram. Neurourol Urodyn 1991; 10: 169–76. 2072. Rudy DC, Awad SA, Downie JW. External sphincter dyssynergia: An abnormal continence reflex. J Urol 1988; 140: 105–10. 2073. De Groat WC, Lalley PM. Reflex firing in the lumbar sympathetic outflow to activation of vesical afferent fibres. J Physiol 1972; 226: 289–309. 2074. Schurch B, Yasuda K, Rossier AB. Detrusor bladder neck dyssynergia—Revisited. J Urol 1994; 152: 2066–70. 2075. Awad SA, Downie JW, Kiruluta HG. Alpha-adrenergic agents in urinary disorders of proximal urethra. Part II. Urethral obstruction due to “sympathetic dyssynergia.” Br J Urol 1978; 50: 336–9. 2076. Pedersen E. Regulation of bladder and colon–rectum in patients with spinal lesions. J Auton Nerv Syst 1983; 7(3–4): 329–38. 2077. Floyd K, Hick VE, Morrison JF. The influence of visceral mechanoreceptors on sympathetic efferent discharge in the cat. J Physiol Lond 1982; 323: 65–75. 2078. Sato A, Sato Y, Sugimoto H, Terui N. Reflex changes in the urinary bladder after mechanical and thermal stimulation of the skin at various segmental levels in cats. Neuroscience 1977; 2: 111–17.

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2079. McMahon SB, Morrison JFB. Two groups of spinal interneurons that respond to stimulation of the abdominal viscera of the cat. J Physiol 1982; 322: 21–34. 2080. Coonan EM, Downie JW, Du H-J. Sacral spinal cord neurons responsive to bladder pelvic and perineal inputs in cats. Neurosci Lett 1999; 260: 137–40. 2081. Xiao CG, De Groat WC, Godec CJ et al. “Skin–CNS–bladder” reflex pathway for micturition after spinal cord injury and its underlying mechanisms. J Urol 1999; 162: 936–42. 2082. Head H, Riddoch G. The autonomic bladder, excessive sweating and some other reflex conditions, in gross injuries of the spinal cord. Brain 1917; 40: 188. 2083. Guttmann L, Whitteridge D. Effects of bladder distention on autonomic mechanisms after spinal cord injuries. Brain 1947; 70: 361. 2084. Rossier A, Bors E. Urological and neurological observations following anesthetic procedures for bladder rehabilitation of patients with spinal cord injuries. I. Topical anesthesias. J Urol 1962; 87: 876–82. 2085. Perkash I. An attempt to understand and to treat voiding dysfunction during rehabilitation of the bladder in spinal cord injury patients. J Urol 1976; 115: 36–40. 2086. Yalla SV. Spinal cord injury. In: Krane RJ, Siroky MB, eds. Clinical Neuro-urology. Boston, MA: Little, Brown, 1979: 229–43. 2087. Krenz NR, Weaver LC. Sprouting of primary afferent fibers after spinal cord transection in the rat. Neuroscience 1998; 85: 443–58. 2088. Krenz NR, Meakin SO, Krassioukov AV, Weaver LC. Neutralizing intraspinal nerve growth factor blocks autonomic dysreflexia caused by spinal cord injury. J Neurosci 1999; 19: 7405–14. 2089. Elliott S, Krassioukov A. Malignant autonomic dysreflexia in spinal cord injured men. Spinal Cord 2006; 44: 386–92. 2090. Elbadawi A, Atta MA, Franck JI. Intrinsic neuromuscular defects in the neurogenic bladder. I. Short-term ultrastructural changes in muscular innervation of the decentralized feline border base following unilateral sacral ventral rhizotomy. Neurourol Urodyn 1984; 3: 93–113. 2091. Sundin T, Dahlstrom A, Norlen LJ, Svedmyr N. The sympathetic innervation and adrenoreceptor function of the human lower urinary tract in the normal state and after parasympathetic denervation. Invest Urol 1977; 14: 322–8. 2092. Norlen LJ, Dahlstrom A, Sundin T, Svedmyr N. The adrenergic innervation and adrenergic receptor activity of the feline urinary bladder and urethra in the normal state and after hypogastric and/or parasympathetic denervation. Scan J Urol Nephrol 1976; 10:177–84. 2093. Atta MA, Franck JI, Elbadawi A. Intrinsic neuromuscular defects in the neurogenic bladder. II. Long-term innervation of the unilaterally decentralized feline bladder base by regenerated cholinergic, increased adrenergic and emergent probable ‘peptidergic’ nerves. Neurourol Urodyn 1984; 3: 185–200. 2094. Sundin T, Dahlstrom A. The sympathetic innervation of the urinary bladder and urethra in the normal state and after parasympathetic denervation at the spinal root level. An experimental study in cats. Scand J Urol Nephrol 1973; 7: 131–49. 2095. de Groat WV, Kawatani M. Reorganization of sympathetic preganglionic connections in cat bladder ganglia following parasympathetic denervation. J Physiol 1989; 409: 431–49. 2096. McGuire EJ, Morrissey SG. The development of neurogenic vesical dysfunction after experimental spinal cord injury or sacral rhizotomy in non-human primates. J Urol 1982; 128: 1390–3. 2097. Ghoniem GM, Regnier HC, Biancani P et al. Effect of bilateral sacral decentralization on detrusor contractility and passive properties in dog. Neurourol Urodyn 1984; 3: 23–33. 2098. McGuire EJ, Savastano JA. Effect of alpha-adrenergic blockade and anticholinergic agents on the decentralized primate bladder. Neurourol Urodyn 1985; 4: 139–42. 2099. Gunasekera WSL, Richardson AE, Seneviratne KN, Eversden ID. Significance of detrusor compliance in patients with localized partial lesions of the spinal cord and cauda equina. Surg Neurol 1983; 20: 59–62.

2100. McGuire EJ, Woodside JR, Borden TA, Weiss RM. Prognostic value of urodynamic testing in myelodysplastic patients. J Urol 1981; 126: 205–9. 2101. Gajewski JB, Awad SA, Heffernan LPH et  al. Neurogenic bladder in lower motor neuron lesion: Long-term assessment. Neurourol Urodyn 1992; 11: 509–18. 2102. Skehan AM, Downie JW, Awad SA. Control of bladder stiffness in normal and chronic decentralized feline bladder. J Urol 1993; 149: 1165–73. 2103. Lapides J, French CR, Ajemian EP, Reus WF. A new method for diagnosis of the neurogenic bladder. Univ Mich Med Bull 1962; 28: 166–80. 2104. Carpenter FG, Rubin RM. The motor innervation of the rat urinary bladder. J Physiol 1967; 192: 609–17. 2105. Diokno AC, Davis R, Lapides J. Urecholine test for denervated bladders. Invest Urol 1975; 13: 233–5. 2106. El-Salmy S, Downie JW, Awad SA. Bladder and urethral function and supersensitivity to subcutaneously administered bethanechol in cats with chronic cauda equina lesions. J Urol 1985; 134: 1011–18. 2107. Donker PJ, Ivanovici F, Noach EL. Analysis of the urethral pressure profile by means of electromyography and the administration of drugs. Br J Urol 1972; 44: 180–93. 2108. Mattiasson A, Andersson K-E, Sjogren C. Urethral sensitivity to alpha-adrenoceptor stimulation and blockade in patients with parasympathetically decentralised lower urinary tract and in healthy volunteers. Neurourol Urodyn 1984; 3: 223–33. 2109. Clarke SJ, Thomas DG. Characteristics of the urethral pressure profile in flaccid male paraplegics. Br J Urol 1981; 53: 157–61. 2110. Blaivas JG. A critical appraisal of specific diagnostic techniques. In: Krane RJ, Siroky MB, eds. Clinical Neuro-urology. Boston, MA: Little, Brown, 1979: 69–109. 2111. Bauer SB, Labib KB, Dieppa RA, Retik AB. Urodynamic evaluation of the boy with myelodysplasia. Urology 1977; 10: 354–62. 2112. Awad SA, Downie JW. Sympathetic dyssynergia in the region of the external sphincter: A possible source of lower urinary tract obstruction. J Urol 1977; 118: 636–40. 2113. Parsons KF, Turton MB. Urethral supersensitivity and occult urethral neuropathy. Br J Urol 1980; 52: 131–37. 2114. Elbadawi A, Atta MA. Intrinsic neuromuscular defect in the neurogenic bladder. V. Autonomic re-innervation of the male feline rhabdosphincter following somatic denervation by bilateral sacral ventral rhizotomy. Neurourol Urodyn 1986; 5: 65–85. 2115. Flood HD, Downie JW, Awad SA. Urethral function after chronic cauda equina lesion in cats. II. The role of autonomicallyinnervated smooth and striated muscle in distal sphincter dysfunction. J Urol 1990; 144: 1029–35. 2116. Kluck P. The autonomic innervation of the human urinary bladder, bladder neck and urethra. A histochemical study. Anat Rec 1980; 198: 439–47. 2117. Elbadawi A. Neuromorphological basis of vesicourethral function I. Histochemistry, ultrastructure and function of intrinsic nerves of the bladder and urethra. Neurourol Urodyn 1982; 1: 3–50. 2118. Awad SA, Downie JW, Kiruluta HG. Alpha adrenergic agents in urinary disorders of the proximal urethra. Part I. Sphincteric incontinence. Br J Urol 1978; 50: 332–5. 2119. Awad SA, Downie JW. The adrenergic component in the proximal urethra. Urol Int 1977; 32: 192–7. 2120. Nergardh A. The functional role of adrenergic receptors in the outlet region of the bladder. An in vitro and in vivo study in the cat. Scand J Urol Nephrol 1974; 8: 100–7. 2121. Caine M, Raz S, Zeigler M. Adrenergic and cholinergic receptors in prostate, prostatic capsule and bladder neck. Br J Urol 1975; 47: 193–202. 2122. Stephenson TP, Wein AJ. The interpretation of urodynamics. In: Mundy AR, Stephenson TP, Wein AJ, eds. Urodynamics: Principles, Practice and Application. London: Churchill-Livingstone, 1984: 93–115.

Spinal cord injury and cerebral trauma 2123. Flood HD, Downie JW, Awad SA. Urethral function after chronic cauda equina lesions in cats. I. The contribution of the mechanical factors and sympathetic innervation to proximal sphincter dysfunction. J Urol 1990; 144: 1022–8. 2124. Barbalias GA, Blaivas JG. Neurologic implication of the pathologically open bladder neck. J Urol 1983; 129: 780–2. 2125. McGuire EJ, Wagner FC. The effects of sacral denervation on bladder and urethral functions. Surg Gynecol Obstet 1977; 144: 343–6.

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2126. Kirby RS, Flower C, Gilpin S et al. Non-obstructive detrusor failure. A urodynamic, electromyographic, neurohistochemical and autonomic study. Br J Urol 1983; 55: 652–9. 2127. Blaivas JG, Barbalias GA. Characteristics of neural injury after abdominoperineal resection of the rectum. J Urol 1983; 129: 84–7. 2128. Ahlberg J, Edlund C, Wikkelsö C et al. Neurological signs are common in patients with urodynamically verified “idiopathic” bladder overactivity. Neurourol Urodyn 2002; 21: 65–70.

27 Cerebral palsy, cerebellar ataxia, AIDS, phacomatosis, neuromuscular disorders, and epilepsy Christopher Kobylecki, Ling K. Lee, and Mark W. Kellett

Introduction In previous chapters, authors have described neurologic disorders that are frequently associated with or produce characteristic neurogenic bladder disturbances. In this chapter, the authors review a number of miscellaneous conditions in which neurogenic disorders of the bladder may infrequently occur, either as a manifestation of the primary disease or sometimes as a complication of disease treatment. Although urinary disturbance is well recognized in many of the conditions discussed, in others such as neuromuscular disorders cases are rare and reports are largely anecdotal.

Cerebral palsy Cerebral palsy is becoming increasingly common as more premature low birthweight infants are surviving in neonatal intensive care units and are prone to insults to their central nervous system (CNS). Adverse events such as infection, cerebrovascular accident, or anoxia, in the prenatal and perinatal period, can permanently damage areas in the brain, which leads to the nonprogressive disorders of motor function seen in cerebral palsy. The most common manifestation is muscle spasticity (70%–80%), with athetoid, hypotonic, and ataxic motor disorders making up the rest. Intellectual capacity is directly related to the severity of physical impairment. The combination of mental, neurologic, and physical handicap results in urinary symptoms and incontinence being commoner in patients with cerebral palsy. Roijen et al.t sent a continence questionnaire to the parents of 601 children (aged between 4 and 18 years) with cerebral palsy and received a response from 459 (76%). The prevalence for primary urinary incontinence in this

study was 23.5%. Daytime continence usually preceded nocturnal continence and 85% of children gained nocturnal continence within the year of achieving daytime continence. In this study, 96% of all cerebral palsy children with normal intelligence (intelligence quotient [IQ] > 65) were continent, demonstrating the importance of comprehension and communication skills for continence training. The ability to achieve continence was related to the extent of both physical and mental handicap (Table 27.1) and, not surprisingly, children with spastic tetraplegia and low intelligence (IQ < 65) were the least likely to become continent. The majority of children with cerebral palsy (89%) who were continent became so before 12 years age, but others gained control spontaneously later in their teens. Although urinary incontinence is the commonest reason for a urologic referral (Table 27.2), a significant number of patients with cerebral palsy have other lower urinary tract symptoms (LUTS).2–6 Over a 7-month Table 27.1  Th  e percentage of children aged 6 years old with cerebral palsy (CP) of different severity who were continent compared to normally developing children1 At age 6 years old

Percent continent

Normally developing

92

Spastic hemiplegia

80

Spastic diplegia

84

Spastic tetraplegia

54

CP with IQ > 65

80

CP with IQ < 65

38

Spastic tetraplegia with IQ < 65

33

IQ, intelligence quotient.

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Table 27.2  Th  e distribution of the common lower urinary tract symptoms in patients with cerebral palsy undergoing urological assessment McNeal et al.5

Decter et al.4

Mayo7

Reid and Borzyskowski2

50

57

33

27

 Incontinencea

54%

86%

48%

74%

 Urgency

18%

Number of patients Symptoms

 Frequency  Dribbling

51%

56%

6%

  Hesitancy/voiding difficulties  Retention a

37%

3.5%

46%

11%

2%

6%

7%

Incontinence includes urge/stress/day, and/or enuresis.

Note: Some patients had multiple symptoms.

period, McNeal et  al.5 interviewed 50 patients (between 8  and 29 years old) with cerebral palsy who attended outpatient clinics and actively sought out symptoms of urinary dysfunction. More than a third (36%) had two or more urinary symptoms prompting referral for further urologic assessment. In reality, the overall incidence of LUTS could be higher, as McNeal’s study excluded patients with IQs < 40. Mayo7 found an unusually high incidence of voiding difficulty in 17 of the 33 patients who underwent videocystometrogram. The patients predominantly had difficulty initiating a urinary stream and two adult patients were using catheters for urinary retention. His group of patients was older (10 patients > 20 years old, 3 patients > 55 years old) and Mayo postulated that obstructive symptoms might become more prevalent as patients with cerebral palsy progress into adult life. This, he felt, was due to lack of voluntary control over a “spastic” pelvic floor. Murphy et al.8 recently reported a large study of 214 patients with cerebral palsy (median age 9 years 7 months, range 5–66 years), aiming to determine the prevalence of symptomatic neurogenic bladder disturbance, which was seen in 35 patients (16.4%). The highest percentage of those presenting with symptomatic neurogenic bladder (31%) was seen in the 6- to 10-year age group, with 26% presenting at the age of 30 or older; bladder dysfunction was seen at all levels and patterns of motor disability.8 A hyperreflexic bladder consistent with an upper motor neuron injury was the commonest urodynamic finding in symptomatic patients with cerebral palsy2–5,8,9 (Table 27.3). Symptoms of urgency and frequency appear to correlate well with an overactive detrusor. Mayo demonstrated hyperreflexia in 14 of the 16 patients with urge ± incontinence compared to only 8 out of the 17 with voiding difficulties. Reduced bladder capacity was also a common finding, and occasionally a noncompliant bladder with end-fill instability was found to be responsible for the patient’s symptoms.

A voiding study was more difficult to obtain, bearing in mind that a proportion of patients were wheelchair bound and had learning disabilities. Therefore, it is difficult to estimate the incidence of detrusor under activity or bladder outlet obstruction in patients with cerebral palsy. Excluding 2 patients who were in retention and 1 with detrusor–sphincter dyssynergia, Mayo found the remaining 14 of 17 patients with voiding difficulties had low postvoid residual volumes, and none had significant trabeculation to suggest obstruction.7 During urodynamic evaluation on 57 children with cerebral palsy, Decter et  al.4 also carried out electromyography (EMG) on the external sphincter using needle electrodes. They identified 11 patients with incomplete lower motor neuron injury to the sphincter, defined as a partially denervated sphincter with reduced motor unit recruitment and reduced amplitude and duration of action potential during voiding simulating dyssynergia.4 However, Decter did not comment as to whether these patients had outflow obstruction. Although uncommon, the finding of detrusor–sphincter dyssynergia and lower motor neuron lesions (acontractile bladder) implies that the perinatal injury that caused the abnormal neurology in cerebral palsy may also involve the spinal cord. Another urodynamic study on children (age range 4–18 years, mean age 8.2 years) with cerebral palsy also identified detrusor–sphincter dyssynergia in 4 children out of 36 (11%) with high voiding pressures of 90 cm H2O.6 The reported incidence of vesicoureteric reflux on videourodynamics varies from 1.8% to 35%,2–4,6,9 but none of the authors commented on renal impairment or the presence of reflux nephropathy. In the study of Murphy et al.,8 urodynamic studies in those with symptomatic neurogenic bladder identified neurogenic detrusor overactivity in the majority of 35 patients, which was slightly more common with greater levels of functional disability. Neurogenic pelvic floor overactivity on voiding was additionally seen

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Cerebral palsy, cerebellar ataxia, AIDS, phacomatosis, neuromuscular disorders, and epilepsy Table 27.3  Urodynamic findings in patients with cerebral palsy

Number of patients Hyperreflexic

Reid and Borzyskowski2

Mayo7

Decter et al.4

McNeal et al.5

Drigo et al.9

Karaman et al.6

27

33

57

13

9

36

21 (78%)

22 (67%)

35 (61%)

4 (31%)

9 (100%)

17 (47%)

2 (22%)

4 (11%)

End-fill instability Detrusor sphincter dyssynergia Acontractile bladder

2 (15%) 5 (19%)

1 (3%)

2

in 12 cases, whereas neurogenic detrusor underactivity was only observed in 2 cases.8 Given the risk of upper tract damage in neurogenic voiding dysfunction, Brodak et  al.10 used ultrasound to prospectively screen 90 patients (age 1 to 25 years old), with or without urologic symptoms, in an attempt to determine whether urinary tract screening was necessary for patients with cerebral palsy. On first ultrasound, 7 of the 90 patients had renal abnormalities, which were hydronephrosis in 3, renal asymmetry in 2, and nonvisualization in 2. On a follow-up ultrasound, only two of the three had persistent hydronephrosis and had ultrasound evidence of a neurogenic bladder. The authors concluded that routine urinary tract screening was not justified because urinary tract abnormalities were only detected in 2% of the patients studied. More recent work supports this view, as only 1 patient in a series of 35 was found to have upper urinary tract pathology (vesiscoureteric reflux and hydronephrosis).8 Although there is little to support routine screening in asymptomatic patients, patients with UTIs may require investigation although the frequency of abnormalities varies between studies. Decter et al.4 found that all six children with UTIs (single episode or recurrent) had radiologic and urodynamic abnormalities, four had detrusor–sphincter dyssynergia, and one had chronic retention due to detrusor failure. In contrast, the study by Reid and Borzyskowski2 involved 13 patients with a history of UTIs, but vesicoureteric reflux was demonstrated in only 1 patient who had hyperreflexia and detrusor– sphincter dyssynergia. Thus, it seems reasonable to recommend ultrasound imaging of kidneys, bladder, and postmicturition residual volume11 and a plain kidney, ureter, and bladder X-ray is useful, although renal tract stones are uncommon.12 In the presence of abnormalities, further evaluation with videourodynamics, micturating cystourethrography, and renogram should be performed. Treatment for patients with overactive bladders and symptoms of urge and frequency consists primarily of anticholinergic drugs. Postmicturition bladder residuals should then be closely monitored, as clean intermittent catheterization may be necessary with increasing residuals. Prophylactic antibiotics are used for urinary tract

7 (17%) 1

infections (UTIs) and reflux nephropathy. Adrenergic drugs may be effective for a weak bladder neck causing stress incontinence.2 Mayo advocated muscle relaxants (e.g., diazepam, baclofen) for his patients with voiding difficulties due to spasticity of their pelvic floor muscles.3 Using a combination of medication and behavioral modification (e.g. frequent voiding schedule), Decter et al.4 were able to improve the incontinence in 21 of the 27 cerebral palsy patients (78%) who had adequate follow-up data. Murphy et  al.8 instigated a functional toileting review in 35 patients with neurogenic bladder, 26 of whom also required oxybutynin therapy, with the addition of desmopressin and pseudoephedrine hydrochloride in 3. Positive continence outcomes were seen in 32 (91%), with no apparent relationship to motor severity or mobility status. Cerebral palsy patients with detrusor–sphincter dyssynergia are most at risk of developing hydronephrosis and renal deterioration and should have long-term upper tract monitoring. Karaman et  al.6 advocated early intermittent catheterization with or without anticholinergics for increased residual urine and voiding biofeedback in four children with detrusor–sphincter dyssynergy on urodynamic studies. In patients with worsening renal function and in whom intermittent catheterization is not a realistic alternative, a vesicostomy or urinary diversion (ileal conduit or continent diversion) should be considered.2–5,13 Long-term catheterization for neuropathic bladders is generally not recommended because of the high complication rates of stone formation, urinary bypassing, and upper tract dilation.14,15 Selective sacral dorsal rhizotomy for controlling lower limb spasticity in cerebral palsy patients may result in a lower motor neuron lesion of the bladder. Abbott noted urinary retention in 7% of the 200 patients who underwent this procedure, although it was transient in all but 1 of the 13 patients.16 Houle et  al.17 demonstrated an increase in bladder capacity (p 100 mL was only seen in one. Sphincter EMG revealed neurogenic abnormalities in six of nine patients studied.27 Impaired bladder sensation was seen in three SCA3 patients but is not commonly seen in other neurodegenerative forms of cerebellar ataxia such as multiple system atrophy (MSA).28 Abnormalities on somatosensory evoked potentials were seen in these three patients, suggesting spinal sensory tract damage as a potential mechanism although the authors also considered the role of subcortical regions involved by SCA3, such as the globus pallidus, in detrusor overactivity.27 Reports of urinary dysfunction in rarer autosomal dominant forms of SCA are less commonly published. A case report of a patient with cerebellar ataxia and prominent urge incontinence was initially diagnosed as MSA-C but was subsequently found to have SCA17. Urodynamic studies showed decreased bladder capacity of 140 mL, with marked detrusor overactivity but no residual postmicturition volume, sphincter dyssynergia, or neurogenic sphincter change; oxybutynin improved urinary symptoms.29 Urinary symptoms had not hitherto been

Cerebral palsy, cerebellar ataxia, AIDS, phacomatosis, neuromuscular disorders, and epilepsy identified as a feature of SCA17, expanding the phenotype of this condition and indicating the importance of further investigations in the differential diagnosis between MSA-C and inherited SCAs. Sakakibara et al.30 have also reported a 54-year-old man diagnosed with dentatorubral pallidoluysian atrophy with urinary incontinence, in whom urodynamic studies showed detrusor hyperactivity during filling, and underactive detrusor on voiding with ­detrusor–sphincter dyssynergia. The authors speculated that involvement of the dentatorubral and pallidoluysian systems could explain detrusor overactivity, while pathology in the spinal cord, including Clarke’s nucleus, could explain detrusor underactivity and detrusor–sphincter dyssynergia.30,31 Urinary incontinence was present in seven of a series of nine patients with autosomal recessive spastic ataxia of Charlevoix–Saguenay, together with other autonomic features, suggesting that the recognized phenotype in this condition could be wider than previously reported.32 Treatment for urgency and urge incontinence in patients with ataxia ideally should be specific to the urodynamic findings. However, the likelihood is an underlying overactive bladder and these patients could be treated empirically with anticholinergics if they do not carry large residual volumes. Patients with underactive detrusor can be treated with intermittent catheterization. Leach et al.19 successfully treated their three patients with sphincter dyssynergia with a combination of α-sympathetic blockade (phenoxybenzamine), diazepam, and baclofen. Nonhereditary ataxias with a multitude of etiologies, e.g., alcohol intoxication, neurosarcoidosis, CNS infection, superficial siderosis, can present acutely or subacutely, with urinary incontinence as a common copresenting symptom.33–37 Urodynamic studies are not commonly performed in the investigation of such patients, but when they have been done, an overactive detrusor has typically been identified.33,34,37 Treatment will depend on the etiology and prognosis of the underlying condition. In some cases, improvements in urinary control will occur as the underlying disease responds to specific treatment.33,34,37

Human immunodeficiency virus (HIV) infection and acquired immunodeficiency syndrome (AIDS) LUTS in the well HIV-positive patient is uncommon and if present is usually due to UTI.38 However, at the time of seroconversion to HIV, the patient may experience a variety of neurologic syndromes including acute urinary retention and sacral sensory loss.39 Impaired micturition becomes more common with disease progression and can occur as part of a global neurologic dysfunction or due

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to infection.38,40 Hermieu et  al.41 undertook urodynamic and neurologic evaluation in 39 HIV-positive patients presenting with LUTS. A urodynamic abnormality, either an overactive or underactive detrusor or detrusor–sphincter dyssynergia, was identified in 87% of patients. Of these, 61% had AIDS-related neurologic problems such as cerebral toxoplasmosis, HIV demyelination disorders, motor dysfunction, and AIDS-related dementia. This heralded a poor prognosis as 43% in this group died after 2–24 months (mean 8 months). Urinary sphincter abnormalities leading to either urinary incontinence or retention can occur as a result of spinal cord compression (e.g., metastatic lymphoma, tuberculoma), or infection of the spinal cord (myelitis) or nerve roots (radiculitis) by opportunistic infections such as cytomegalovirus (CMV), toxoplasmosis, and herpes. Diagnosis of the underlying cause for the neurologic complication requires magnetic resonance imaging (MRI) of the spine, biopsies of abnormal spinal lesions, cerebrospinal fluid analysis, and also the identification of concurrent opportunistic infections.42 CMV polyradiculopathy is very rare but eminently treatable and reversible if caught early. The patient presents with back and sciatica pain with bladder or bowel dysfunction. Cerebrospinal fluid examination typically shows a polymorphonuclear cell-predominant pleocytosis with CMV found on polymerase chain reaction testing. Detrusor failure due to a lower motor lesion is uncommon and usually caused by malignancy or infection such as herpes. These patients should be taught clean intermittent self-catheterization. Long-term indwelling catheters are best avoided in HIV-infected patients because of their vulnerability to Staphylococcus aureus bacteremia. Infection with the other retroviruses such as human T-cell lymphotropic virus type 1 (HTLV-1) has also been associated with development of bladder symptoms, which would be expected due to its tendency to cause a myelopathy.34,36 Bladder symptoms in HTLV-1 infected patients are often attributed to UTIs, which are thought to occur more commonly in this condition. In a series of 21 HTLV-1 infected patients with urinary symptoms and negative urine cultures, urodynamic studies were abnormal in over 90%.43 In most cases, the findings were of detrusor overactivity and dyssynergia, and the strongest clinical predictor of urinary symptomatology was neurological disability as measured by the Expanded Disability Status Scale.43

Neurocutaneous syndromes (phacomatosis) Neurocutaneous syndromes encompass a number of congenital or hereditary conditions featuring involvement of nervous system, eyeball, retina, and skin. They present in childhood and slowly progress through adolescence, with

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many conditions demonstrating a propensity to malignant transformation. Most cases are genetically determined, although sporadic cases can occur.44,45 Minor features are often present from birth, but with age neoplasia can often develop. Bladder disorders are unusual in many of these conditions, but the reported cases are discussed below. In some phacomatoses, such as tuberous sclerosis complex, bladder disorders have not been reported. Neurogenic bladder abnormalities have most commonly been reported in neurofibromatosis types 1 and 2.

Neurofibromatosis types 1 and 2 Neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2) are inherited neurocutaneous disorders.46–48 The NF1 gene is on chromosome 17q11.2 and encodes a protein product termed neurofibromin;49,50 the gene for NF2 is on chromosome 22q11.2 and encodes a protein called merlin.51 Both merlin and neurofibromin act as tumor suppressor genes that control cell growth and proliferation. Mutations in another tumor suppressor gene called SMARCB1 is responsible for 45% of familial and 7% of sporadic cases of Schwannomatosis, a condition resembling NF2 but without the vestibular schwannomas.48,52,53 NF1 is characterized by café au lait patches, skinfold freckling, lisch nodules on the iris, bony dysplasia, and benign nerve sheath tumors called neurofibromas.47 Neurofibromas are the hallmark lesion and can be located on peripheral nerves, spinal nerves, and the spinal cord. Malignant peripheral nerve sheath tumors can occur in up to 10% of patients, typically in the second or third decades with a risk of metastasizing; they often originate in plexiform neurofibromas.47 Gliomas are the most common brain tumor and are mainly located in the optic pathway and brainstem. Spinal nerve or spinal cord neurofibromas can occur at all levels and cause sphincter disturbance and sexual dysfunction. Various NF1-associated tumors have been reported to affect the urinary system and particularly the bladder. They are usually derived from nerves of the pelvic, vesical, and prostatic plexuses, 54 and include benign and, less commonly, malignant neurofibromas, 54–74 paragangliomas,75 and other occasional malignant tumors.76 Plexifirm neurofibromas, which can form diffuse lesions that spread along individual or multiple nerves, can involve the perineal region leading to local urinary tract involvement. These should be suspected when patients with neurofibromatosis develop any urinary symptoms, as they may present in a multitude of ways. LUTS, enuresis, flank pain, incontinence, or symptoms related to urinary tract obstruction may occur, as can localized pain, low back pain, and lower limb dysesthesia.77 These symptoms may result from the tumor size and/or neurogenic involvement.78–81 A conservative management

approach to tumors causing urinary symptoms has been suggested due to likely damage to adjacent organs on attempted removal. However, careful follow-up is necessary to detect signs of upper tract obstruction, which may be a sign of tumor progression or malignant transformation.78 NF2 is characterized by the presence of bilateral vestibular schwannomas.46 Other tumors seen in NF2 include multiple meningiomas, ependymoma, glioma, neurofibroma, or peripheral nerve schwannomas.46,82 Spinal schwannomas are characteristic of Schwannomatosis and may lead to upper motor neuron syndromes due to spinal cord compression.48,83 Other tumors seen in NF2 and schwannomatosis that can involve the spinal cord include ependymomas, meningiomas, or hamartomas.83–89 Neurofibromas or schwannomas,89,90 or other tumors,91 may involve the conus or cauda equina and may present with mixed upper and/or lower motor neuron bladder symptoms. The typical presentation of conus and cauda equina lesions and the effects on the bladder have been described in earlier chapters.

Cobb syndrome Cobb syndrome is a rare neurocutaneous syndrome manifest by cutaneous nevi and spinal angiomas within the same dermatome.92 Wakabayashi et  al.93 reported an 8-year-old boy presenting with difficulty initiating micturition, constipation, low back pain, and a mild spastic paraparesis. Multiple angiokeratomas were present over dermatomes of the cervical region and lower sacral region on the right and over the lumbar and sacral areas on the left. Multiple angiomas were present in the cervicothoracic spinal cord and conus medullaris, with evidence of bleeding from an upper thoracic angioma that had probably produced his presenting symptoms. His symptoms gradually improved without surgical intervention. This phenotype most closely resembles Cobb syndrome, but unusually he also had cerebral angiomas that are rare in this condition.

Klippel–Trenaunay– Weber syndrome In Klippel–Trenaunay–Weber syndrome, intracranial and intraspinal angiomas may occur in association with hypertrophy of skeletal muscles and visceral involvement.94–96 Urinary symptoms would be expected if symptomatic spinal cord pathology occurred due to pressure or bleeding from large spinal angiomas. Kojima et  al.97 reported one such case with a nevus flammeus, varices, hypertrophy, and elongation of the left leg. The patient presented with a progressive paraparesis and urinary retention due to an extensive spinal arteriovenous malformation

Cerebral palsy, cerebellar ataxia, AIDS, phacomatosis, neuromuscular disorders, and epilepsy extending from T11 to L2. The arteriovenous malformation was treated surgically with an initial deterioration in bladder function; however, 6 months later her motor junction improved to the preoperative state and the bladder dysfunction disappeared. Various other non-neurogenic genitourinary manifestations may occur in Klippel– Trenaunay syndrome. They tend to occur in more severe cases and usually involve cutaneous vascular malformations of the trunk, pelvis, and genitalia, sometimes with intra-abdominal and intrapelvic extension of the vascular malformations.98

Proteus syndrome Proteus syndrome has numerous manifestations. It is characterized by massive tissue overgrowth and asymmetry. Frequent features include partial gigantism of hands and feet, nevi, and hemihypertrophy, as well as other multisystem involvement.44 Neurogenic bladder symptoms are not a reported feature of this condition,44 but urinary tract involvement may occur. In one case presenting with renal tract stones, left-sided ureterovesical reflux was found on the same side as hemihypertrophy. The authors postulated that the unilateral involvement was a feature related to hemihypertrophy 99; however, similar cases have not been reported to further corroborate this. In another case, leiomyoma of the urinary bladder has been reported.100

Neurocutaneous melanosis Neurocutaneous melanosis is a form of phacomatosis in which there is a proliferation of melanocytes in skin and meninges. The most common skin lesion is a giant pigmented hairy naevus but diffuse pigmentation can also occur. Infiltration of the pia and arachnoid by melanocytes can usually be seen macroscopically. There is an approximate 2%–13% risk of malignant change in skin and a 50% risk of malignant change in the meninges. Typical neurologic abnormalities include hydrocephalus (probably due to vascular obstruction of the fourth ventricle), epilepsy, intracranial hemorrhage, cranial nerve palsies, and psychiatric disturbance. Neurogenic bladder has not been a feature except in one case reported by Sawamura et al.101 The 13-year-old subject of their report presented with signs attributable to a large right frontal malignant leptomeningeal melanoma. Among his other clinical features was a neurogenic bladder, although, as there was no direct spinal involvement from the neurocutaneous melanosis, it was more likely to be attributable to his coexisting spina bifida. In 28 additional cases reviewed from the literature, neurogenic bladder disturbance was not reported, suggesting that it is unlikely to be a disease feature.101

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Neuromuscular disorders Neuromuscular junction disorders Myasthenia gravis Myasthenia gravis is an autoimmune disorder due to the presence of anti-acetylcholine receptor antibodies that bind to the nicotinic cholinergic receptors at the motor endplate of the neuromuscular junction. It typically affects striated muscle, causing weakness with fatiguability. In 15% of patients, its effects are confined to the ocular and facial muscles, causing ptosis and diplopia; however, more generalized weakness occurs in the majority of remaining patients. Although the antibodies act on nicotinic cholinergic receptors, antibodies have also been demonstrated against muscarinic cholinergic receptors. Bladder disturbance attributable to myasthenia gravis is unusual, but a number of individual case reports have been published.102–107 The clinical, urodynamic, and neurophysiologic findings in these cases are summarized in Table 27.5. The bladder dysfunction in all cases resembled a lower motor neuron pattern with variable degrees of detrusor areflexia/atonia. In the patient reported by Sandler et  al.,106 the voiding dysfunction was complete and prolonged, and the patient required long-term intermittent catheterization. Unfortunately, the authors do not report on the response of the original myasthenia gravis symptoms. In other patients, urinary symptoms have responded to medical therapy directed at the myasthenia gravis.103,105 In some rare cases, voiding dysfunction may be the initial presenting symptom,102,104 and in others may be associated with an exacerbation of generalized myasthenia gravis.104,106 The detrusor muscle is predominantly under control of the parasympathetic nervous system with muscarinic innovation. Detrusor failure suggests involvement of acetylcholine receptor antibodies at muscarinic receptors on the detrusor muscle itself or in the pelvic ganglia. The fluctuation in severity related to drug treatment of myasthenia gravis suggests a causal relationship in some cases. Urinary symptoms in myasthenia gravis have also been reported in male patients who have undergone prostatic surgery. Greene et  al.108 reported six men with bladder outflow obstruction who underwent a transurethral resection of the prostate (TURP) and subsequently developed urinary incontinence. They hypothesized that the resection led to some form of injury to the external sphincter that had already been compromised by the underlying myasthenia gravis. They therefore recommended an incomplete resection to leave distal tissue that they felt would prevent trauma to the sphincter. They later reported a seventh man with myasthenia gravis who underwent an incomplete resection who initially remained dry, but 3 months later developed urge incontinence. Subsequently,

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Table 27.5  The clinical, urodynamic, and neurophysiological findings of myasthenia gravis (MG) patients with bladder disturbance Reference

Age, sex

Myasthenia characteristics

Urinary symptoms

Urodynamic and EMG findings

103

59,

Generalized MG

Difficulty voiding

Normal bladder capacity (430 mL).

Incomplete bladder emptying

Normal filling sensation

Frequency

Atonic detrusor (pressure < 8 cm H2O) during attempted void

Severity related to treatment with pyridostigmine

Voiding by abdominal pressure with poor flow and interrupted flow pattern

Stress incontinence

Open bladder neck

Bladder neck suspension 8 months before MG diagnosed

Inability to sustain pelvic floor contraction

female

104

31,

Generalized MG

female

Bladder hyperreflexia Associated with deterioration in MG condition 105

102

20,

Seronegative

“Urinary disturbance”

female

Generalized MG

Symptoms responded to treatment with steroids and thymectomy

Elderly,

Generalized MG

Urgency and urge incontinence

male 106

39, female

Atonic bladder

Detrusor hyporeflexia

Uncontrollable flatus and fecal incontinence on sneezing and coughing Seropositive Generalized MG

Incontinence followed by retention with constipation at time of myasthenic crisis

Bladder capacity 662 mL Areflexic detrusor Unable to generate detrusor contraction and unable to void EMG—low intensity unchanged during bladder filling

107

61,

Generalized MG

female

Frequency

Residual volume 100 mL

Difficulty voiding

Detrusor underactivity

Incomplete bladder voiding

Poor flow rates and voided by abdominal straining

Recurrent UTIs EMG, electromyography; UTI, urinary tract infection.

Wise et  al.109 found that incontinence after  TURP was associated with the use of blended current and that patients treated with either high-frequency unblended current, partial proximal resection, or open prostatectomy remained dry. Unfortunately, urodynamic or EMG studies were not made in these cases and therefore the pathophysiologic mechanism is unclear. However,  Khan and Bhola110 reported another patient who remained continent after an open prostatectomy; p ­ reoperative EMG of the external urinary sphincter revealed fatiguability and abnormal motor units, s­uggesting an underlying neurogenic weakness of the c­ ontinence mechanism. The authors postulated that electrical current could further damage this mechanism, possibly by damaging residual acetylcholine receptors.110

Lambert–Eaton myasthenic syndrome Lambert–Eaton myasthenic syndrome (LEMS) is characterized by muscle weakness as well as autonomic dysfunction; it is associated with small cell lung cancer in approximately 60% of cases and is often associated with the  presence of anti-P/Q-type voltage-gated ­calcium ­channel antibodies.111–113 Dysautonomia is frequent in LEMS and involves cholinergic and adrenergic ­systems,114–117 but ­neurogenic bladder involvement is rare. In one series of 50 patients, autonomic symptoms occurred in 80% of patients, with dry mouth and impotence being the most frequently experienced symptoms, followed by constipation, blurred vision, and sweating abnormalities; there were no reports of bladder

Cerebral palsy, cerebellar ataxia, AIDS, phacomatosis, neuromuscular disorders, and epilepsy dysfunction.118 Another study involving 30 patients had similar findings.115 Bladder dysfunction has been reported in five cases,114,119,120 although detailed features, including urodynamic findings, have only been reported in one case.120 In this report, Satoh et  al. described a 71-year-old Japanese woman with neurophysiologically and serologically confirmed LEMS. She was initially treated with anticholinesterase drugs, corticosteroids, and plasma exchange. Four years after presentation, her condition deteriorated and she was unable to stand or walk. She complained of a dry mouth and urinary frequency greater than 15 times per day. Urodynamic studies consisting of uroflowmetry, cystometry, and urethral pressure recordings were made before and after treatment with 3,4-diaminopyridine. Maximum urinary flow rate was decreased at 12.8 mL/s, suggestive of an underactive detrusor. Bladder emptying was reasonable, with postvoid residual volumes of 37, 170, and 70 mL on three separate measurements. After treatment with 10 mg of 3,4-diaminopyridine, muscle weakness and dry mouth dramatically improved and was associated with reduced urinary frequency. Post-treatment anal sphincter EMG and detrusor and abdominal pressures also increased markedly during voiding, and the maximum urine flow rate normalized from 12.8 to 17.9 mL/s. The presentation with frequency is a little unusual in disorders manifest by detrusor underactivity; however, this patient’s urinary symptoms undoubtedly improved with better detrusor contractility. Detrusor muscle pressure and abdominal muscle pressure were reduced in voiding, suggesting that the neurogenic bladder was caused by defective neurotransmission in both autonomic detrusor muscle and skeletal abdominal muscle. Furthermore, the response to 3,4-diaminopyridine suggests that the neurogenic bladder was directly attributable to the dysautonomia of LEMS. The authors speculated that this was due to the action of anti-P/Q-type voltage-gated calcium channel antibodies on the bladder. In support of this theory, they cited a number of animal studies suggesting an important role for these antibodies in mediating neurotransmitter release in the urinary bladder of mice, rats, and guinea pigs.117,121,122

Muscular dystrophies Myotonic dystrophy Myotonic dystrophy is a disorder characterized by myotonia (sustained contraction of muscle in response to electrical or percussive stimuli) and dystrophy (progressive loss of skeletal muscle with fibrosis and fatty infiltration). However, it is a multisystem disorder with the most prominent manifestations in skeletal muscle, the cardiac conduction system, brain, smooth muscle, and lens. It is inherited as an autosomal dominant trait with variable

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penetrance and phenotypic expression that results from a variable (CTG) triplet repeat of a gene named myotonin.123 Smooth muscle abnormalities are well recognized in myotonic dystrophy but predominantly affect the gastrointestinal tract. Urinary tract dysfunction is much less commonly encountered.124 Urinary retention without evidence of other pathologic conditions was noted in a number of early reports.125–127 Bundschu et al.128 described two brothers with myotonic dystrophy who developed dilatation of the renal pelvis, ureter, and bladder due to presumed smooth muscle involvement. However, in a more systematic study of nine patients using cystometrography, Orndahl et  al.129 found normal bladder function in all cases. More recently, in two systematic studies symptomatic bladder dysfunction was found in 6 of 16 patients.130,131 Symptoms often occurred at a young age and included urinary urgency, frequency, and stress incontinence. Urodynamic investigation revealed reduced urethral pressures and abnormal motor units in the external sphincter. There was a suggestion that, in women in particular, pelvic floor muscle involvement may have been contributory. A recent case report documents stress incontinence as the presenting symptom of myotonic dystrophy in a 14-yearold girl.132 Histopathologic findings in myotonic dystrophy have been variable. The bladder was reported to be normal in one autopsied case;133 however in another case, Harvey et al.125 found slight vacuolization of the bladder smooth muscle syncytium and an increased number of nuclei. Furthermore, Pruzanski and Huvos,134 in another autopsy study, demonstrated muscle degeneration in the bowel and bladder. Histology of the bladder showed separation of myofibrils by edematous fibrous tissue, variation in muscle fiber size and shape, and longitudinal myofibers showed breakup with hypereosinophilia. Fibrous tissue replacement as seen in the bladder of the latter case is frequently seen in skeletal muscles of patients with myotonic dystrophy. However, it should be noted that this patient also had evidence of prostatic hyperplasia with some trabeculation of the bladder wall and thus the significance of these pathologic changes is uncertain.

Limb-girdle muscular dystrophy Limb-girdle muscular dystrophies (LGMDs) are a group of genetically heterogenous disorders that share similar presenting features.135 Their classification is based on mode of inheritance and chromosomal localization, with the gene product known in increasing numbers of subtypes.136,137 Limb-girdle dystrophies occur in both sexes, with onset between the second and sixth decade, usually in late childhood or early adulthood, although onset can occur at almost any age. Weakness in many cases begins in the pelvic girdle musculature and then spreads to the pectoral muscles, although the reverse is not unusual.

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The various phenotypes have been widely characterized and urinary symptoms are unusual. However, Dixon et al.138 reported a 48-year-old woman with clinical, laboratory, and neurophysiologic evidence of LGMD with urinary symptoms that appeared to be related to the presence of LGMD. The patient was nulliparous and had originally developed stress incontinence at the age of 12 years when jumping. This progressed over subsequent years until it was present on coughing and walking. Videocystometogram showed marked bladder descent and stress incontinence with no detrusor instability and normal urethral sphincter EMG. Histology of pelvic floor muscles revealed changes consistent with LGMD: large variability of fiber size with hypertrophied and atrophic fibers and type 1 fiber predominance, frequent internal nuclei, and disruption of the myofibrillar pattern. Unfortunately, at the time this report was made it was impossible to identify the specific phenotype although it may represent a subtype with early and predominant involvement of pelvic muscles. Although not directly neurogenic in etiology, the weak pelvic floor muscles may have  led to abnormal positioning of the ­vesicourethral junction and consequent incontinence. Pompe disease is a heterogeneous metabolic myopathy due to deficiency of acid maltase (acid α-glucosidase), which in its late-onset form may present with a LGMD phenotype, with typical features including respiratory failure.139 Chancellor et al.140 reported a 68-year-old man who presented with a 3-year history of leg weakness and more recent exercise-induced urinary incontinence; a videocystometrogram showed gross detrusor instability (maximum detrusor pressure 70 cm H2O), with total incontinence occurring at a bladder capacity of 250 mL. Acid α-glucosidase activity was reduced in leucocytes, as well as in a muscle biopsy specimen. The authors postulated that exercise-induced fatiguing of striated pelvic floor muscles may have caused inability to withstand increases in detrusor pressure, but noted that neurogenic involvement in Pompe disease has also been postulated.140,141 Autopsy studies in late-onset Pompe disease have disclosed CNS involvement,142 while vacuolar change in the bladder is also reported.143

Duchenne muscular dystrophy Duchenne muscular dystrophy (DMD) is an X-linked disorder that is the most common muscular dystrophy in children. It is characterized by progressive weakness of skeletal muscle with onset in early childhood. The disorder is caused by loss-of-function mutations of an extremely large gene located on the X-chromosome (Xp21). The protein product of the gene, dystrophin, is absent or markedly deficient and leads to a chronic necrotizing myopathy with marked muscle wasting. The disease progresses over 20 years and is always associated with an inability to walk.144 Becker muscular dystrophy is also due

to mutations in dystrophin, but is associated with a milder clinical phenotype. Despite the fact that most patients with DMD have normal sphincter function, some patients will experience urinary incontinence. It is not uncommon for a short period of urinary and bowel incontinence to occur around the age of 12 years, as the child becomes wheelchair-­ dependent. This appears unrelated to structural pathology such as increasingly severe scoliosis and is thought to be a manifestation of depression. It usually resolves within a few months.145 Neurogenic bladder disorders in DMD are unusual, but reported. In one retrospective study from the Mayo Clinic in Rochester,146 33 patients with DMD, born between 1953 and 1983 and followed during their second decade of life, were studied. Urinary disturbance was described in only 2 of the 33 cases (6%); it occurred relatively late in the disease course and in both cases it was manifested by urinary retention. In one 12-year-old boy, acute urinary retention occurred several weeks following surgery for correction of scoliosis. In the other case, acute urinary retention appeared while the patient was undergoing an excretory cystourethrogram for nephrolithiasis. Although this settled, acute retention recurred several months later. Detailed urodynamic studies were not reported and the authors were unclear about the significance of these findings in view of the associated events.146 In another study, Caress et  al.147 identified seven boys with DMD who had undergone urodynamic tests at the Children’s Hospital of Boston during the years 1978–94. The clinical, urodynamic, and neurophysiologic findings are summarized in Table 27.6. Five of the boys complained  of  urinary incontinence and two had difficulty initiating voiding consistent with urinary retention. Five of the boys had undergone a spinal fusion procedure, and in two of these there was a temporal relationship between their spinal fusion surgery and the onset of urinary d ­ ysfunction, similar to the case reported by Boland et al.146 In one of these cases, acute urinary retention and left lateral thigh and testicular numbness occurred immediately following his T4–L5 spinal fusion. In another case, bladder and bowel incontinence was associated with paraplegia and a T10 sensory level following a spinal fusion procedure. None of the other six patients had upper motor neuron signs, although the severe muscle wasting and weakness could have obscured subtle signs. Sacral reflexes were preserved in all of the patients and bladder contractions were of normal or high pressures in all but one child. Urodynamic studies and EMG were abnormal in six cases, with five out of six exhibiting upper motor neuron dysfunction. There was no clear pattern of bladder size or postvoid residual volume in this group, but uninhibited contractions were a frequent finding (four/five), as was detrusor–sphincter dyssynergia (three/five). One patient had normal reflexes but enlarged motor units suggestive of reinnervation and was classified as

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Table 27.6  Clinical features and neurophysiologic findings in seven patients with Duchenne muscular dystrophy

Patient

Age (years)

History of spinal fusion

Symptoms

Urodynamic/ urethral EMG

Detrusor– sphincter dyssynergy

Uninhibited contractions

Motor unit appearance

1

17

Yes

Retention

Normal

No

No

Normal

2

14

Yes

Urgency, incontinence

UMN

No

Yes

Normal

3

11

Yes

Voiding difficulty

LMN

No

No

Long duration

4

17

Yes

Incontinence, frequent UTIs

UMN

Yes

Yes

Normal

5

8

No

Incontinence

UMN

No

Yes

Normal

6

16

?

Urgency, UTI. incontinence

UMN

Yes

Yes

Normal

7

16

Yes

Incontinence

UMN

Yes

Yes

Normal

LMN, lower motor neuron; UMN, upper motor neuron. Source: Adapted from Caress JB, Kothari MJ, Bauer SB, Shefner JM. Muscle Nerve 1996; 19: 819–22. With permission.

having lower motor neuron dysfunction. This 11-yearold had a normal capacity bladder and an initial postvoid residual urine volume of 250 mL.147 Despite the advanced disease course in most of the cases, unlike the previous case with LGMD,138 there was no evidence of myopathic motor units or abnormal spontaneous activity in the pelvic floor muscles. Furthermore, bladder pressures generated during voiding or during uninhibited contractions were normal or elevated, suggesting that there was no significant detrusor myopathy.147 More recent studies suggest a higher prevalence of neurogenic bladder disturbance in patients with mus­ cular dystrophies. MacLeod et  al.148 identified urinary symptoms in 46 of 74 DMD patients who responded to a questionnaire, occurring at a mean age of 10.8 years (range 3–25 years). Urodynamic studies were abnormal in all nine patients (mean age 9.4 years) who underwent formal investigation, showing detrusor hyperreflexia in all patients, with additional reduced bladder capacity in seven. One patient had also developed detrusor–sphincter dyssynergia postspinal surgery. Van Wijk et al.149 reported a questionnaire study of 199 patients with DMD, 85% of whom reported at least one LUTS, with 32% reporting urinary incontinence, and 27% reporting urge incontinence. The discrepancies between these two recent studies most likely relate to differences in recruitment and ascertainment and are summarized in Table 27.7. One case has been reported of urinary urge incontinence in a 20-year-old with Becker muscular dystrophy; urodynamic studies revealed a marked rise in pressure during the filling phase up to 120 cm H2O, confirming detrusor overactivity.150 No evidence of spinal pathology to explain these symptoms was identified. The mechanism

of neurogenic bladder symptoms in muscular dystrophies is unclear. Myopathic changes within the detrusor muscle would be expected to cause a large capacity, flaccid bladder, while pathology in skeletal pelvic floor muscles could account for stress incontinence, reported in only a minority of cases.148 The upper motor neuron lesions in older cases, and in the case of Boland et al.,146 are most likely to be due to progressive scoliosis, complications of surgical treatment, or both. The temporal nature of urinary disturbance to a surgical procedure in at least 3 of 9 reported cases suggests a direct causal relationship. In the other cases that had undergone surgery, the lack of a clear temporal relationship does not exclude a similar mechanism. However, the study of MacLeod et al.148 indicated upper motor neuron bladder dysfunction in younger patients with no history of previous spinal surgery, suggesting alternative mechanisms for neurogenic bladder dysfunction in DMD. In addition, other studies have shown no correlation between previous spinal surgery and LUTS.149 It has therefore been postulated that upper motor neuron dysfunction could result from the altered expression of dystrophin on the CNS.147,148 Dystrophin is present in the normal brain and its presumed absence in DMD patients may be related to the cognitive deficiencies seen in many affected individuals. Thus, they suggested that an absence of dystrophin in the brain or spinal cord could account for the upper motor neuron findings. A case of new urinary incontinence, associated with neurogenic bladder disturbance, in a 13-yearold boy with DMD associated with fatty infiltration of the filum terminale has been reported.151 Sectioning of the filum terminale resulted in recovery of urinary continence despite subsequent progression of his myopathic weakness; while occult spina bifida has not previously been reported

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Table 27.7  F  requency of urinary symptoms in studies in Duchenne muscular dystrophy Macleod et al.148

Van Wijk et al.149

46/74 (62)

170/199 (85)

Incontinence

22 (30)

63 (32)

Frequency

14 (19)

12 (6)

Urgency

18 (24)

37 (19)

Enuresis

21 (28)

37 (19)

Nocturia

22 (30)

10 (5)

Urinary symptom Lower urinary tract symptoms

Stress incontinence

5 (7)

10 (5)

Hesitancy

5 (7)

39 (20)

in association with DMD, the case illustrates the importance of considering alternative causes for new onset urinary incontinence in such conditions.151 The treatment of bladder disturbance in these cases ­followed standard therapy and all patients were subsequently treated with anticholinergic medicines, clean intermittent catheterization, or both. All 10 patients ­ treated with oxybutynin in the study of MacLeod et al.148 responded well to this therapy. The authors recommended that a trial of anticholinergic therapy should be considered in DMD patients with a history suggestive of detrusor hyperreflexia following pre- and postmicturition bladder ultrasound.

Epilepsy Seizure classification Seizures are symptoms of cerebral dysfunction, resulting from paroxysmal hyperexcitable and/or hypersynchronous discharges of neurones involving the cerebral cortex. Epilepsy is defined as a disorder characterized by recurrent epileptic seizures. The International Classification of Epileptic Seizures divides the clinical manifestations into partial seizures, which begin in a part of one hemisphere, and generalized seizures, which begin in both hemispheres simultaneously. The clinical manifestations of simple partial seizures are determined by the function of the cortical area involved and are divided by the International Classification into motor, sensory, autonomic, and psychic phenomena.152

Cortical bladder control and seizure localization A number of regions within the brain are implicated in cortical control of urinary function. Functional studies using positron emission tomography and single-photon

emission computed tomography (SPECT) suggest lateralization to the right hemisphere for cortical bladder control and more specifically involvement of the right medial temporal gyrus, right anterior cingulate gyrus, right inferior frontal gyrus, right frontal operculum, dorsomedial pontine tegmentum, periaqueductal gray, and rostral hypothalamus.153–155 Furthermore, in patients with structural pathology, urinary incontinence usually correlates with right hemisphere involvement,156,157 and in elderly patients, urge incontinence with reduced bladder filling sensation is associated with right frontal abnormalities on SPECT scanning.158 Thus, given that semiology of partial seizures is dependent on the cortical function involved, it is not surprising that disorders of micturition are seen during seizures arising from the above regions of the brain. One report describes urinary incontinence following resection of a seizure focus in the supracallosal portion of the left medial frontal gyrus, with urodynamic features of reduced bladder sensation and increased bladder capacity, with involuntary detrusor contraction.159 This region has been reported to contain one of the suprapontine micturition centers.

Urinary symptoms in epilepsy Urinary incontinence is a common and well-recognized feature of epileptic seizures. Indeed, enquiry into loss of continence during seizures or blackouts is a routine aspect of history taking. Incontinence during episodes of loss of consciousness is, however, not diagnostic of seizures and must always be considered along with other ictal phenomena as incontinence can also occur in simple faints, and micturition can induce syncope in some patients.

Incontinence in seizures During typical absence seizures, pressure recordings with catheterization reveal increased intravesicular pressure secondary to detrusor muscle contraction.160 Enuresis following generalized tonic–clonic seizures is due to relaxation of the external sphincter.161 During absence status, urinary incontinence occurs as a result of either micturitional automatism or neglect. Isolated ictal enuresis is rare. The exact frequency of incontinence in different seizure types is not known.

Micturition in localization related epilepsy (partial seizures) The urinary system is primarily under the control of the autonomic nervous system and, therefore, seizures involving the autonomic nervous system are often associated with urinary symptoms. Autonomic seizures often arise from mesiobasal limbic, frontal, orbital, or opercular

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regions, with likely rapid spread of seizure activity into hypothalamic areas further contributing to autonomic symptoms. Autonomic seizures are more common in the presence of impairment of consciousness, but may also occur with apparently fully preserved awareness and responsiveness.162–164 Symptoms in autonomic seizures include vomiting, pallor, flushing, sweating, piloerection, pupil dilatation, borborygmi, and incontinence. These may occur as simple partial seizures or sometimes as an aura prior to complex partial or secondary generalized seizures, but must be distinguished from secondary effects of other seizure types that invariably cause autonomic signs as a later feature.162 Collectively, autonomic phenomena comprise an important and substantial portion of partial seizure symptoms, representing approximately one-third of all simple partial seizures.163–165

by other auras, which in some can include genital automatisms.172 EEG localization and imaging using high-resolution MRI, supplemented by interictal SPECT studies in four patients and ictal SPECT studies in two patients suggested onset in the right or left temporal lobes, with intracarotid amytal testing confirming that this was the nondominant temporal lobe in all cases.173 Ictal and interictal EEG studies in a subsequent report of six patients with stereotyped ictal urinary urge also found onset in the nondominant, right, temporal lobe.175 In the latter study, temporal lobe resection led to seizure freedom in two cases, confirming the localization to the temporal lobe.175 The authors postulated an area in the nondominant temporal lobe involved in the initiation of micturition.173,175 The recognition of this “ictal urge” in seizure semiology may be of relevance when patients are being considered for epilepsy surgery.

Early onset benign childhood seizures with occipital spikes (Panayiotopoulos syndrome)

Micturition-induced reflex epilepsy

Autonomic symptoms are particularly prominent in the so-called Panayiotopoulos syndrome.166 Cardinal features of this condition include infrequent partial seizures that consist of a combination of autonomic and behavioral disturbances, vomiting, deviation of the eyes, often with impairment of consciousness, which can frequently progress to convulsions. Autonomic disturbances of pallor and sweating, alone or together with behavioral disturbances (mainly irritability), may predominate, particularly in the early stages of the ictus.167–170 Incontinence of urine occurs in 10% of cases, usually when consciousness is impaired even without convulsions; less commonly, fecal incontinence can occur with other autonomic or behavioral features even in nocturnal seizures. Seizures are typically long, often lasting for 5 or more minutes and, in 40% for hours, consistent with partial status epilepticus. The condition is considered benign with an excellent prognosis. About half of all patients only have a single attack, and in the majority of the remainder spontaneous remission occurs within a few years. For this reason, antiepileptic drug treatment is rarely used.

Ictal urinary urge in partial seizures (auras) An ictal desire to void is an infrequent but well-­recognized feature of temporal lobe seizures, with a reported fre­quency of between 0.4% and 8%.163,171–175 Baumgartner et al.173 reviewed video-EEG (electroencephalogram) records of 277 patients with refractory temporal lobe epilepsy and found 6 (2.2%) reported an intense urge to urinate, which they termed “ictal urinary urge.” The urge is usually accompanied

Recently Glass et  al.176 reported a 12-year-old girl with complex partial seizures beginning at age 2. From age 10 she had reflex seizures with every micturition and also with prayer. Seizures occurred 4 to 6 times per day and were refractory to treatment with multiple antiepileptic drugs and the ketogenic diet. Seizure semiology observed during video-EEG monitoring revealed pupil dilatation and staring, followed by loss of body tone and at times deviation of the head and eyes to the left, with occasional rhythmic clonic activity of both arms. Previously, micturition-induced seizures have been reported in a ­ number of other children. Some have had learning difficulties177,178 or structural pathology, such as a calcified granuloma in the right frontal lobe.179 Most recently, Okumura et  al.180 reported an 8-year-old girl with ­micturition-induced seizures and cited two previous cases from the Japanese literature.181,182 EEG recordings have suggested onset of seizures in the central anterior or right frontal lobe in some cases,177,178 or in the deep midline structures with rapid spread to frontal regions in others.176,180 Reports in other children with micturition-induced seizures have failed to demonstrate EEG localization, but semiology has suggested onset in the supplementary sensorimotor region.181–183 Furthermore, in another patient who had reflex seizures induced by micturition and stepping into hot water, onset during videoEEG of immersion-induced attacks suggested the seizures arose in the central midline region.177 In the case reported by Glass et al.,176 ictal SPECT studies revealed activity in the anterior cingulate gyrus and anterolateral right frontal lobe. The regulation of autonomic and endocrine function is one of the number of functions localized to the anterior cingulate gyrus,184 and the cortical control of micturition itself is coordinated from the superomedial portion of the frontal lobe

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(mainly the right) and the anterior aspect of the cingulate gyrus.185 Thus, Glass et  al.176 postulated a region of hyperexcitability in the “affect” component of the anterior cingulate gyrus, with seizures triggered by micturition and emotion in their patient. In the case reported by Okumura et  al.,180 subtraction ictal SPECT studies showed increased perfusion in the mesial frontal region, suggesting onset in the supplementary sensorimotor area of the right frontal lobe.

Urinary symptoms related to antiepileptic drugs Urinary frequency and incontinence has also been reported as an adverse reaction to antiepileptic medication. Incontinence is an unusual side effect of carbamazepine and valproic acid,186 and was reported in a single case during a clinical trial of gabapentin;187 however, details of the urinary disturbance and outcome are not available. Gil-Nagel et  al.188 reported urinary incontinence in 3 of their 394 cases treated with gabapentin at their tertiary referral centre. Gabapentin-related incontinence included isolated urinary incontinence in one case with temporal lobe epilepsy and severe double incontinence in two cases with secondary generalized epilepsy.188 The problem persisted as long as patients were taking the drug and disappeared soon after it was discontinued or the dose was reduced. The three patients had medically refractory seizures and two adults had signs of generalized or multifocal neurologic dysfunction, including mental retardation and hemiplegia. Incontinence did not appear to be related to seizure activity in any patient and video-EEG recordings in one patient corroborated this. Unfortunately, urodynamic assessment was not undertaken in any of the cases and, therefore, the physiologic mechanism for the incontinence is unclear. However, the authors postulated that, because gabapentin is distributed in most organs and tissues, it could act at one or more sites involving not only the brain and spinal cord but also the gastrointestinal and urinary tracts. Gabapentin enhances the action of glutamate dehydrogenase and is a weak inhibitor of γ-aminobutyric acid (GABA) transaminase and may therefore modulate glutamate and GABA. Both these neurotransmitters are involved in the regulation of micturition in the CNS. Thus, incontinence could be related to the effect of gabapentin in the cortex, interfering with the inhibition that the frontal lobe exerts on the pontine micturition center. It is possible that preexisting damage to the cerebral cortex acts as a substrate for the development of gabapentin-induced incontinence. The novel antiepileptic drug retigabine, an activator of KCNQ2/3 potassium channels, has been shown to cause urinary hesitancy and retention in a number of patients, leading to recommendations for its use with caution in patients at risk of urinary retention.189,190 This adverse

effect seems consistent with the documented pharmacological effects of retigabine on smooth muscle in preclinical studies.191

Treatment of bladder symptoms in epilepsy Treatment of incontinence related to epilepsy primarily involves optimization of antiepileptic drug treatment or other therapies to minimize the frequency and severity of seizures. However, Harari and Malone-Lee192 reported beneficial effects of oxybutynin in one patient with epilepsy. The 30-year-old was invariably incontinent during seizures and also at night on occasions. On the assumption that incontinence was due to hyperreflexic detrusor contractions during seizures, the authors prescribed oxybutynin at a dose of 5 mg twice daily. On this dose he remained continent despite further seizures. From the earlier discussion it can be seen that incontinence in seizures has many potential mechanisms. In this case, detrusor hyperreflexia may have been present, however, oxybutynin may not be as effective if other mechanisms are operating, particularly if incontinence is a feature of autonomic seizures themselves.

References 2129. Roijen LE, Postema K, Limbeek VJ, Kuppevelt VH. Development of bladder control in children and adolescents with cerebral palsy. Dev Med Child Neurol 2001; 43: 103–7. 2130. Reid CJ, Borzyskowski M. Lower urinary tract dysfunction in cerebral palsy. Arch Dis Child 1993; 68: 739–42. 2131. Mayo ME. Lower urinary tract dysfunction in cerebral palsy. J Urol 1992; 147: 419–20. 2132. Decter RM, Bauer SB, Khoshbin S et al. Urodynamic assessment of children with cerebral palsy. J Urol 1987; 138: 1110–2. 2133. McNeal DM, Hawtrey CE, Wolraich ML, Mapel JR. Symptomatic neurogenic bladder in a cerebral-palsied population. Dev Med Child Neurol 1983; 25: 612–6. 2134. Karaman MI, Kaya C, Caskurlu T, Guney S, Ergenekon E. Urodynamic findings in children with cerebral palsy. Int J Urol 2005; 12: 717–20. 2135. Mayo ME. Lower urinary tract dysfunction in cerebral palsy. J Urol 1992; 147: 419–20. 2136. Murphy KP, Boutin SA, Ide KR. Cerebral palsy, neurogenic bladder, and outcomes of lifetime care. Dev Med Child Neurol 2012; 54: 945–50. 2137. Drigo P, Seren F, Artibani W, Laverda AM, Battistella PA, Zacchello G. Neurogenic vesico-urethral dysfunction in children with cerebral palsy. Ital J Neurol Sci 1988; 9: 151–4. 2138. Brodak PP, Scherz HC, Packer MG, Kaplan GW. Is urinary tract screening necessary for patients with cerebral palsy? J Urol 1994; 152: 1586–7. 2139. Moulin F, Quintart A, Sauvestre C, Mensah K, Bergeret M, Raymond J. [Nosocomial urinary tract infections: Retrospective study in a pediatric hospital]. Arch Pediatr 1998; 5(Suppl 3): 274S–8S. 2140. Kroll P, Martynski M, Jankowski A. [Staghorn calculi of the kidney and ureter as a urologic complication in a child with cerebral palsy]. Wiad Lek1998; 51(Suppl 3): 98–101.

Cerebral palsy, cerebellar ataxia, AIDS, phacomatosis, neuromuscular disorders, and epilepsy 2141. Connolly B, Fitzgerald RJ, Guiney EJ. Has vesicostomy a role in the neuropathic bladder? Z Kinderchir 1988; 43(Suppl 2): 17–8. 2142. Honda N, Yamada Y, Nanaura H, Fukatsu H, Nonomura H, Hatano Y. Mesonephric adenocarcinoma of the urinary bladder: A case report. Hinyokika Kiyo 2000; 46: 27–31. 2143. Tan PK, Edmond P. Longterm indwelling urethral catheterization for neuropathic bladders—an audit. J R Coll Surg Edinb 1994; 39: 307–9. 2144. Abbott R, Johann-Murphy M, Shiminski-Maher T et  al. Selective dorsal rhizotomy: Outcome and complications in treating spastic cerebral palsy. Neurosurgery 1993; 33: 851–7; discussion 857. 2145. Houle AM, Vernet O, Jednak R, Pippi Salle JL, Farmer JP. Bladder function before and after selective dorsal rhizotomy in children with cerebral palsy. J Urol 1998; 160: 1088–91. 2146. Sweetser PM, Badell A, Schneider S, Badlani GH. Effects of sacral dorsal rhizotomy on bladder function in patients with spastic cerebral palsy. Neurourol Urodyn 1995; 14: 57–64. 2147. Leach GE, Farsaii A, Kark P, Raz S. Urodynamic manifestations of cerebellar ataxia. J Urol 1982; 128: 348–50. 2148. Chami I, Miladi N, Ben Hamida M, Zmerli S. [Continence disorders in hereditary spinocerebellar degeneration. Comparison of clinical and urodynamic findings in 55 cases]. Acta Neurol Belg 1984; 84: 194–203. 2149. Vezina JG, Bouchard JP, Bouchard R. Urodynamic evaluation of patients with hereditary ataxias. Can J Neurol Sci 1982; 9: 127–9. 2150. Schols L, Amoiridis G, Epplen JT, Langkafel M, Przuntek H, Riess O. Relations between genotype and phenotype in German patients with the Machado-Joseph disease mutation. J Neurol Neurosurg Psychiatry 1996; 61: 466–70. 2151. Watanabe M, Abe K, Aoki M et al. Analysis of CAG trinucleotide expansion associated with Machado-Joseph disease. J Neurol Sci 1996; 136: 101–7. 2152. Yeh TH, Lu CS, Chou YH et al. Autonomic dysfunction in MachadoJoseph disease. Arch Neurol 2005; 62: 630–6. 2153. Schmitz-Hubsch T, Coudert M, Bauer P et al. Spinocerebellar ataxia types 1, 2, 3, and 6: Disease severity and nonataxia symptoms. Neurology 2008; 71: 982–9. 2154. Lee WY, Jin DK, Oh MR et al. Frequency analysis and clinical characterization of spinocerebellar ataxia types 1, 2, 3, 6, and 7 in Korean patients. Arch Neurol 2003; 60: 858–63. 2155. Sakakibara R, Uchiyama T, Arai K, Yamanishi T, Hattori T. Lower urinary tract dysfunction in Machado-Joseph disease: A study of 11 clinical-urodynamic observations. J Neurol Sci 2004; 218: 67–72. 2156. Sakakibara R, Hattori T, Uchiyama T, Yamanishi T. Videourodynamic and sphincter motor unit potential analyses in Parkinson’s disease and multiple system atrophy. J Neurol Neurosurg Psychiatry 2001; 71: 600–6. 2157. Kanai K, Sakakibara R, Uchiyama T et al. Sporadic case of spinocerebellar ataxia type 17: Treatment observations for managing urinary and psychotic symptoms. Mov Disord 2007; 22: 441–3. 2158. Sakakibara R, Kishi M, Ogawa E et al. Dentatorubral pallidoluysian atrophy presenting with urinary retention. Mov Disord 2010; 25: 1996–7. 2159. Takeda S, Takahashi H, Ikuta F. [Dentatorubropallidoluysian atrophy (DRPLA): Comparative pathological study on clinical groups classified into juvenile, early adult and late adult types]. No To Shinkei 1992; 44: 111–6. 2160. Synofzik M, Soehn AS, Gburek-Augustat J et al. Autosomal recessive spastic ataxia of Charlevoix Saguenay (ARSACS): Expanding the genetic, clinical and imaging spectrum. Orphanet J Rare Dis 2013; 8: 41. 2161. Sakakibara R, Hattori T, Uchiyama T, Yamanishi T. Micturitional disturbance in a patient with neurosarcoidosis. Neurourol Urodyn 2000; 19: 273–7. 2162. Carod-Artal FJ, del Negro MC, Vargas AP, Rizzo I. [Cerebellar syndrome and peripheral neuropathy as manifestations of infection by  HTLV-1 human T-cell lymphotropic virus]. Rev Neurol 1999; 29: 932–5.

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2163. Nakane S, Motomura M, Shirabe S, Nakamura T, Yoshimura T. [A case of superficial siderosis of the central nervous system—findings of the neuro-otological tests and evoked potentials]. No To Shinkei 1999; 51: 155–9. 2164. Fujiki N, Oikawa O, Matsumoto A, Tashiro K. [A case of HTLV-I associated myelopathy presenting with cerebellar signs as initial and principal manifestations]. Rinsho Shinkeigaku 1999; 39: 852–5. 2165. Sakakibara R, Hattori T, Yasuda K, Yamanishi T, Tojo M, Mori M. Micturitional disturbance in Wernicke’s encephalopathy. Neurourol Urodyn 1997; 16: 111–5. 2166. Gyrtrup HJ, Kristiansen VB, Zachariae CO, Krogsgaard K, Colstrup H, Jensen KM. Voiding problems in patients with HIV infection and AIDS. Scand J Urol Nephrol 1995; 29: 295–298. 2167. Menendez V, Valls J, Espuna M, Perez A, Barranco MA, Carretero P. Neurogenic bladder in patients with acquired immunodeficiency syndrome. Neurourol Urodyn 1995; 14: 253–7. 2168. Zeman A, Donaghy M. Acute infection with human immunodeficiency virus presenting with neurogenic urinary retention. Genitourin Med 1991; 67: 345–7. 2169. Hermieu JF, Delmas V, Boccon-Gibod L. Micturition disturbances and human immunodeficiency virus infection. J Urol 1996; 156: 157–9. 2170. Thurnher MM, Post MJ, Jinkins JR. MRI of infections and neoplasms of the spine and spinal cord in 55 patients with AIDS. Neuroradiology 2000; 42: 551–63. 2171. Rocha PN, Rehem AP, Santana JF et al. The cause of urinary symptoms among Human T Lymphotropic Virus Type I (HLTV-I) infected patients: A cross sectional study. BMC Infect Dis 2007; 7: 15. 2172. Baraister M. Neurocutaneous disorders. In: Baraister M, ed. The Genetics of Neurological Disorders, 3rd edn. Oxford, United Kingdom: Oxford University Press, 1997: 85–101. 2173. Dahan D, Fenichel GM, El-Said R. Neurocutaneous syndromes. Adolesc Med 2002; 13: 495–509. 2174. Evans DGR. Neurofibromatosis 2. In: Ferner RE, Huson SM, Evans DGR, eds. Neurofibromatoses in Clinical Practice. London, United Kingdom: Springer-Verlag, 2011: 46–71. 2175. Ferner RE. Neurofibromatosis 1. In: Ferner RE, Huson SM, Evans DGR, eds. Neurofibromatoses in Clinical Practice. London, United Kingdom: Springer-Verlag, 2011: 1–43. 2176. Huson SM. The neurofibromatoses: Differential diagnosis and rare subtypes. In: Ferner RE, Huson SM, Evans DGR, eds. Neurofibromatoses in Clinical Practice. London, United Kingdom: Springer-Verlag, 2011: 71–122. 2177. Viskochil D, Buchberg AM, Xu G et al. Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell 1990; 62: 187–92. 2178. Wallace MR, Andersen LB, Fountain JW et al. A chromosome jump crosses a translocation breakpoint in the von Recklinghausen neurofibromatosis region. Genes Chromosomes Cancer 1990; 2: 271–7. 2179. Rouleau GA, Merel P, Lutchman M et al. Alteration in a new gene encoding a putative membrane-organizing protein causes neurofibromatosis type 2. Nature 1993; 363: 515–21. 2180. Smith MJ, Wallace AJ, Bowers NL et  al. Frequency of SMARCB1 mutations in familial and sporadic schwannomatosis. Neurogenetics 2012; 13: 141–5. 2181. MacCollin M, Chiocca EA, Evans DG et al. Diagnostic criteria for schwannomatosis. Neurology 2005; 64: 1838–45. 2182. Hintsa A, Lindell O, Heikkila P. Neurofibromatosis of the bladder. Scand J Urol Nephrol 1996; 30: 497–9. 2183. Hulse CA. Neurofibromatosis: Bladder involvement with malignant degeneration. J Urol 1990; 144: 742–3. 2184. Nyholm HC. [Neurofibromatosis with bladder localization]. Ugeskr Laeger 1980; 142: 2426–7. 2185. Kramer SA, Barrett DM, Utz DC. Neurofibromatosis of the bladder in children. J Urol 1981; 126: 693–4. 2186. Aygun C, Tekin MI, Tarhan C, Ozdemir H, Peskircioglu L, Ozkardes H. Neurofibroma of the bladder wall in von Recklinghausen’s disease. Int J Urol 2001; 8: 249–53.

326

Textbook of the Neurogenic Bladder

2187. Miller WB Jr., Boal DK, Teele R. Neurofibromatosis of the bladder: Sonographic findings. J Clin Ultrasound 1983; 11: 460–2. 2188. Kargi HA, Aktug T, Ozen E, Kilicalp A. A diffuse form of neurofibroma of bladder in a child with von Recklinghausen disease. Turk J Pediatr 1998; 40: 267–71. 2189. Jensen A, Nissen HM. Neurofibromatosis of the bladder. Scand J Urol Nephrol 1976; 10: 157–9. 2190. Torres H, Bennett MJ. Neurofibromatosis of the bladder: Case report and review of the literature. J Urol 1966; 96: 910–2. 2191. Winfield HN, Catalona WJ. An isolated plexiform neurofibroma of the bladder. J Urol1985; 134: 542–3. 2192. Merksz M, Toth J, Kiraly L. Neurofibromatosis of the bladder. Int Urol Nephrol 1985; 17: 53–9. 2193. Gold BM. Neurofibromatosis of the bladder and vagina. Am J Obstet Gynecol 1972; 113: 1055–6. 2194. Dahm P, Manseck A, Flossel C, Saeger HD, Wirth M. Malignant neurofibroma of the urinary bladder. Eur Urol 1995; 27: 261–3. 2195. Rober PE, Smith JB, Sakr W, Pierce JM Jr. Malignant peripheral nerve sheath tumor (malignant schwannoma) of urinary bladder in von Recklinghausen neurofibromatosis. Urology 1991; 38: 473–6. 2196. Borden TA, Shrader DA. Neurofibromatosis of bladder in a child: Unusual cause of enuresis. Urology 1980; 15: 155–8. 2197. Pycha A, Klingler CH, Reiter WJ, Schroth B, Haitel A, Latal D. Von Recklinghausen neurofibromatosis with urinary bladder involvement. Urology 2001; 58: 106. 2198. Carlson DH, Wilkinson RH. Neurofibromatosis of the bladder in children. Radiology 1972; 105: 401–04. 2199. Maneschg C, Rogatsch H, Bartsch G, Stenzl A. Treatment of giant ancient pelvic schwannoma. Tech Urol 2001; 7: 296–8. 2200. Mimata H, Kasagi Y, Ohno H, Nomura Y, Iechika S. Malignant neurofibroma of the urinary bladder. Urol Int 2000; 65: 167–8. 2201. Sharma NS, Lynch MJ. Intrapelvic neurilemmoma presenting with bladder outlet obstruction. Br J Urol 1998; 82: 917. 2202. Salvant JB Jr, Young HF. Giant intrasacral schwannoma: An unusual cause of lumbrosacral radiculopathy. Surg Neurol 1994; 41: 411–3. 2203. Burton EM, Schellhammer PF, Weaver DL, Woolfitt RA. Paraganglioma of urinary bladder in patient with neurofibromatosis. Urology 1986; 27: 550–2. 2204. Reich S, Overberg-Schmidt US, Leenen A, Henze G. Neurofibromatosis 1 associated with embryonal rhabdomyosarcoma of the urinary bladder. Pediatr Hematol Oncol 1999; 16: 263–6. 2205. Dominguez J, Lobato RD, Ramos A, Rivas JJ, Gomez PA, Castro S. Giant intrasacral schwannomas: Report of six cases. Acta Neurochir (Wien) 1997; 139: 954–9; discussion 959–60. 2206. Chakravarti A, Jones MA, Simon J. Neurofibromatosis involving the urinary bladder. Int J Urol 2001; 8: 645–7. 2207. Clark SS, Marlett MM, Prudencio RF, Dasgupta TK. Neurofibromatosis of the bladder in children: Case report and literature review. J Urol 1977; 118: 654–6. 2208. Daneman A, Grattan-Smith P. Neurofibromatosis involving the lower urinary tract in children. A report of three cases and a review of the literature. Pediatr Urol 1976; 4: 161–6. 2209. Cheng L, Scheithauer BW, Leibovich BC, Ramnani DM, Cheville JC, Bostwick DG. Neurofibroma of the urinary bladder. Cancer 1999; 86: 505–13. 2210. Evans DG, Huson SM, Donnai D et  al. A clinical study of type 2 neurofibromatosis. Q J Med 1992; 84: 603–18. 2211. Evans DG, Mason S, Huson SM, Ponder M, Harding AE, Strachan T. Spinal and cutaneous schwannomatosis is a variant form of type 2 neurofibromatosis: A clinical and molecular study. J Neurol Neurosurg Psychiatry 1997; 62: 361–6. 2212. Brownlee RD, Clark AW, Sevick RJ, Myles ST. Symptomatic hamartoma of the spinal cord associated with neurofibromatosis type 1. Case report. J Neurosurg 1998; 88: 1099–103.

2213. Chaparro MJ, Young RF, Smith M, Shen V, Choi BH. Multiple spinal meningiomas: A case of 47 distinct lesions in the absence of neurofibromatosis or identified chromosomal abnormality. Neurosurgery 1993; 32: 298–301; discussion 301–292. 2214. Babjakova L, Jurkovic I, Krajcar R, Kocan P. [Multiple intracranial and intraspinal meningiomas in the neurocristopathy (phacomatosis) type of neurofibromatosis]. Cesk Patol 2000; 36: 150–5. 2215. Kawsar M, Goh BT. Spinal schwannoma as a cause of erectile dysfunction with urinary incontinence and groin and testicular pain. Int J STD AIDS 2002; 13: 584–5. 2216. Honda E, Hayashi T, Goto S et  al. [Two different spinal tumors (meningioma and schwannoma) with von Recklinghausen’s disease in a case]. No Shinkei Geka 1990; 18: 463–8. 2217. Mizuo T, Ando M, Azima J, Ohshima H, Yamauchi A. [Manifestation of mictional disturbance in four cases of von Recklinghausen’s disease]. Hinyokika Kiyo 1987; 33: 125–32. 2218. Caputo LA, Cusimano MD. Schwannoma of the cauda equina. J Manipulative Physiol Ther 1997; 20: 124–9. 2219. Acharya R, Bhalla S, Sehgal AD. Malignant peripheral nerve sheath tumor of the cauda equina. Neurol Sci 2001; 22: 267–70. 2220. Kissel P, Dureurx JB. Cobb syndrome. Cutaneomeningospinal angiomatosis. In: Bruyn GW, Vinken PJ, eds. Handbook of Clinical Neurology. New York, NY: North Holland, 1972: 429–45. 2221. Wakabayashi Y, Isono M, Shimomura T et  al. Neurocutaneous vascular hamartomas mimicking Cobb syndrome. Case report. J Neurosurg 2000; 93: 133–6. 2222. Klippel M, Trenaunay P. Du naevus variquex osteo-hypertropique. Arch Genet Med 1900; 3: 641–72. 2223. Weber FP. Angioma formation in connection with hypertrophy of limbs and hemihypertrophy. Br J Dermatol 1907; 19: 231–5. 2224. Weber FP. Hemiangioectatic hypertrophy of limbs. Congential phlebarteriectasia and so-called congenital varicose veins. Br J Child Dis 1918; 15: 13–7. 2225. Kojima Y, Kuwana N, Sato M, Ikeda Y. Klippel-Trenaunay-Weber syndrome with spinal arteriovenous malformation—case report. Neurol Med Chir (Tokyo) 1989; 29: 235–40. 2226. Furness PD, 3rd, Barqawi AZ, Bisignani G, Decter RM. KlippelTrenaunay syndrome: 2 case reports and a review of genitourinary manifestations. J Urol 2001; 166: 1418–20. 2227. Ben Becher S, Bouaziz A, Harbi MM, Hammou A, Boudhina T. [Protee syndrome associated with renal lithiasis and vesico-ureteral reflux]. Arch Fr Pediatr 1993; 50: 599–601. 2228. Horie Y, Fujita H, Mano S, Kuwajima M, Ogawa K. Regional proteus syndrome: Report of an autopsy case. Pathol Int 1995; 45: 530–5. 2229. Sawamura Y, Abe H, Murai H, Tashiro K, Doi S. [An autopsy case of neurocutaneous melanosis associated with intracerebral malignant melanoma]. No To Shinkei 1987; 39: 789–5. 2230. Berger AR, Swerdlow M, Herskovitz S. Myasthenia gravis presenting as uncontrollable flatus and urinary/fecal incontinence. Muscle Nerve 1996; 19: 113–4. 2231. Christmas TJ, Dixon PJ, Milroy EJ. Detrusor failure in myasthenia gravis. Br J Urol 1990; 65: 422. 2232. Howard JFJ, Donovan MK, Tucker MS. Urinary incontinence in myasthenia gravis: A single fibre electromyographic study. Ann Neurol 1992; 32: 254. 2233. Matsui M, Enoki M, Matsui Y et al. Seronegative myasthenia gravis associated with atonic urinary bladder and accommodative insufficiency. J Neurol Sci 1995; 133: 197–9. 2234. Sandler PM, Avillo C, Kaplan SA. Detrusor areflexia in a patient with myasthenia gravis. Int J Urol 1998; 5: 188–90. 2235. Kaya C, Karaman MI. Case report: A case of bladder dysfunction due to myasthenia gravis. Int Urol Nephrol 2005; 37: 253–5. 2236. Greene LF, Ghosh MK, Howard FM. Transurethral prostatic resection in patients with myasthenia gravis. J Urol 1974;112:226-227. 2237. Wise GJ, Gerstenfeld JN, Brunner N, Grob D. Urinary incontinence following prostatectomy in patients with myasthenia gravis. Br J Urol 1982; 54: 369–71.

Cerebral palsy, cerebellar ataxia, AIDS, phacomatosis, neuromuscular disorders, and epilepsy 2238. Khan Z, Bhola A. Urinary incontinence after transurethral resection of prostate in myasthenia gravis patients. Urology 1989; 34: 168–9. 2239. Newsom-Davis J. Lambert-Eaton myasthenic syndrome. Curr Treat Options Neurol 2001; 3: 127–31. 2240. Sanders DB. The Lambert-Eaton myasthenic syndrome. Adv Neurol 2002; 88: 189–201. 2241. Vincent A, Lang B, Newsom-Davis J. Autoimmunity to the voltagegated calcium channel underlies the Lambert-Eaton myasthenic syndrome, a paraneoplastic disorder. Trends Neurosci 1989; 12: 496–502. 2242. Khurana RK, Koski CL, Mayer RF. Autonomic dysfunction in Lambert-Eaton myasthenic syndrome. J Neurol Sci 1988; 85: 77–86. 2243. O’Suilleabhain P, Low PA, Lennon VA. Autonomic dysfunction in the Lambert-Eaton myasthenic syndrome: Serologic and clinical correlates. Neurology 1998; 50: 88–93. 2244. Waterman SA. Autonomic dysfunction in Lambert-Eaton myasthenic syndrome. Clin Auton Res 2001; 11: 145–54. 2245. Waterman SA, Lang B, Newsom-Davis J. Effect of Lambert-Eaton myasthenic syndrome antibodies on autonomic neurons in the mouse. Ann Neurol 1997; 42: 147–56. 2246. O’Neill JH, Murray NM, Newsom-Davis J. The Lambert-Eaton myasthenic syndrome. A review of 50 cases. Brain 1988; 85: 577–96. 2247. Henriksson KG, Nilsson O, Rosen I, Schiller HH. Clinical, neurophysiological and morphological findings in Eaton Lambert syndrome. Acta Neurol Scand 1977; 56: 117–40. 2248. Satoh K, Motomura M, Suzu H et  al. Neurogenic bladder in Lambert-Eaton myasthenic syndrome and its response to ­ 3,4-­diaminopyridine. J Neurol Sci 2001; 183: 1–4. 2249. Frew R, Lundy PM. A role for Q type Ca2+ channels in neurotransmission in the rat urinary bladder. Br J Pharmacol 1995; 116: 1595–8. 2250. Houzen H, Hattori Y, Kanno M et  al. Functional evaluation of inhibition of autonomic transmitter release by autoantibody from Lambert-Eaton myasthenic syndrome. Ann Neurol 1998; 43: 677–80. 2251. Roses AD, Chang L. Myotonic dystrophy. In: Gilman S, ed. MedLink Neurology. San Diego, CA: MedLink Corporation, 2002. 2252. Harper PS. Smooth muscle in myotonic dystrophy. In: Major Problems in Neurology: Myotonic Dystrophy, 3rd edn, No 37. London, United Kingdom: WB Saunders, 2001: 91–108. 2253. Harvey JC, Sherbourne DH, Siegel CI. Smooth muscle involvement in myotonic dystrophy. Am J Med 1965; 39: 81–90. 2254. Kohn NN, Faires JS, Rodman T. Unusual manifestations due to involvement of involuntary muscle in dystrophia myotonica. N Engl J Med 1964; 271: 1179–83. 2255. Pruzanski W. Myotonic dystrophy. A multisystem disease. Report of 67 cases and a review of the literature. Psychiatr Neurol (Basel) 1965; 149: 302–22. 2256. Bundschu HD, Hauger W, Lang HD. [Myotonic dystrophy (urological features and histochemical findings in muscle) (author’s translation)]. Dtsch Med Wochenschr 1975; 100: 1337–41. 2257. Orndahl G, Kock NG, Sundin T. Smooth muscle activity in myotonic dystrophy. Brain 1973; 96: 857–60. 2258. Bernstein IT, Andersen BB, Andersen JT, Arlien-Oborg P. Bladder function in patients with myotonic dystrophy. Neurol Urody 1992; 11: 219–23. 2259. Sakakibara R, Hattori T, Tojo M, Yamanishi T, Yasuda K, Hirayama K. Micturitional disturbance in myotonic dystrophy. J Auton Nerv Syst 1995; 52: 17–21. 2260. Dickson MJ, Massiah N, Church E. Urinary stress incontinence as the presenting feature of myotonic dystrophy. J Obstet Gynaecol 2012; 32: 102. 2261. Black WC, Ravin A. Studies in dystrophia myotonica: Autopsy observations in five cases. Arch Pathol (Chic) 1947; 44: 176–91. 2262. Pruzanski W, Huvos AG. Smooth muscle involvement in primary muscle disease. I. Myotonic dystrophy. Arch Pathol 1967; 83: 229–33. 2263. Bushby KM. Making sense of the limb-girdle muscular dystrophies. Brain 1999; 122(Pt 8): 1403–20.

327

2264. Bushby K. The limb-girdle muscular dystrophies. Eur J Paediatr Neurol 2001; 5: 213–4. 2265. Bushby K, Norwood F, Straub V. The limb-girdle muscular dystrophies—Diagnostic strategies. Biochim Biophys Acta 2007; 1772: 238–42. 2266. Dixon PJ, Christmas TJ, Chapple CR. Stress incontinence due to pelvic floor muscle involvement in limb-girdle muscular dystrophy. Br J Urol 1990; 65: 653–4. 2267. Kishnani PS, Steiner RD, Bali D et al. Pompe disease diagnosis and management guideline. Genet Med 2006; 8: 267–88. 2268. Chancellor AM, Warlow CP, Webb JN, Lucas MG, Besley GT, Broadhead DM. Acid maltase deficiency presenting with a myopathy and exercise induced urinary incontinence in a 68 year old male. J Neurol Neurosurg Psychiatry 1991; 54: 659–60. 2269. Karpati G, Carpenter S, Eisen A, Aube M, DiMauro S. The adult form of acid maltase (alpha-1,4-glucosidase) deficiency. Ann Neurol 1977; 1: 276–80. 2270. Kretzschmar HA, Wagner H, Hubner G, Danek A, Witt TN, Mehraein P. Aneurysms and vacuolar degeneration of cerebral arteries in late-onset acid maltase deficiency. J Neurol Sci 1990; 98: 169–83. 2271. Hobson-Webb LD, Proia AD, Thurberg BL, Banugaria S, Prater SN, Kishnani PS. Autopsy findings in late-onset Pompe disease: A case report and systematic review of the literature. Mol Genet Metab 2012; 106: 462–9. 2272. Acsadi G. Duchenne muscular dystrophy. In: Gilman S, ed. MedLink Neurology. San Diego, CA: MedLink Corporation, 2002. 2273. Brooke MH. Muscular dystrophies: Duchenne muscular dystrophy. In: Brooke MH, ed. A Clinicians View of Neuromuscular Diseases, 2nd edn. Baltimore, MD: Williams and Wilkins, 1986: 117–54. 2274. Boland BJ, Silbert PL, Groover RV, Wollan PC, Silverstein MD. Skeletal, cardiac, and smooth muscle failure in Duchenne muscular dystrophy. Pediatr Neurol 1996; 14:7–12. 2275. Caress JB, Kothari MJ, Bauer SB, Shefner JM. Urinary dysfunction in Duchenne muscular dystrophy. Muscle Nerve 1996; 19: 819–22. 2276. MacLeod M, Kelly R, Robb SA, Borzyskowski M. Bladder dysfunction in Duchenne muscular dystrophy. Arch Dis Child 2003; 88: 347–9. 2277. van Wijk E, Messelink BJ, Heijnen L, de Groot IJ. Prevalence and psychosocial impact of lower urinary tract symptoms in patients with Duchenne muscular dystrophy. Neuromuscul Disord 2009; 19: 754–8. 2278. Smith MD, Seth JH, Hanna MG, Panicker JN. Detrusor overactivity in Becker muscular dystrophy. Muscle Nerve 2013; 47: 464–5. 2279. Tubbs RS, Oakes WJ. Urinary incontinence in a patient with Duchenne muscular dystrophy and cord in the normal position with fatty filum terminale. Childs Nerv Syst 2004; 20: 717–9. 2280. CoCaTotILA E. Proposal for revised clinical and electro-­ encephalographic classification of epileptic seizures. Epilepsia 1981; 22: 489–501. 2281. Blok BF, Holstege G. The central control of micturition and ­continence: Implications for urology. BJU Int 1999; 83(Suppl 2): 1–6. 2282. Blok BF, Sturms LM, Holstege G. Brain activation during micturition in women. Brain 1998; 121(Pt 11): 2033–42. 2283. Blok BF, Willemsen AT, Holstege G. A PET study on brain control of micturition in humans. Brain 1997; 120(Pt 1): 111–21. 2284. Andrew J, Nathan PW. Lesions on the anterior frontal lobes and disturbances of micturition and defaecation. Brain 1964; 87: ­ 233–62. 2285. Maurice-Williams RS. Micturition symptoms in frontal tumours. J Neurol Neurosurg Psychiatry 1974; 37: 431–6. 2286. Griffiths D. Clinical studies of cerebral and urinary tract function in elderly people with urinary incontinence. Behav Brain Res 1998; 92: 151–5. 2287. Sekido N, Akaza H. Neurogenic bladder may be a side effect of focus resection in an epileptic patient. Int J Urol 1997; 4: 101–3.

328

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2288. Gastaut H, Batini C, Broughton R, Lob H, Roger J. Polygraphic study of enuresis during petit mal seizures. Electroencephalogr Clin Neurophysiol 1964: 616–26. 2289. Gastaut H, Broughton R, Roger J, Tassinari C. Generalized nonconvulsive seizures without local onset. In: Vinken PJ, Bruyn GW, eds. Handbook of Clinical Neurology. New York, NY: 1974: 130–44. 2290. Liporace JD, Sperling MR. Simple autonomic seizures. In: Engel JJ, Pedley TA, eds. Epilepsy: The Comprehensive CD-ROM: Lippincott Williams and Wilkins, 1999. 2291. Gupta AK, Jeavons PM, Hughes RC, Covanis A. Aura in temporal lobe epilepsy: Clinical and electroencephalographic correlation. J Neurol Neurosurg Psychiatry 1983; 46: 1079–83. 2292. Palmini A, Gloor P. The localizing value of auras in partial seizures: A prospective and retrospective study. Neurology 1992; 42: 801–8. 2293. Devinsky O, Kelley K, Porter RJ, Theodore WH. Clinical and electroencephalographic features of simple partial seizures. Neurology 1988; 38: 1347–52. 2294. Panayiotopoulos CP. Autonomic seizures and autonomic status epilepticus specific to childhood. Arch Pediatr Adolesc Med 2002; 156: 945. 2295. Panayiotopoulos CP. Early-onset benign childhood occipital seizure susceptibility syndrome: A syndrome to recognize. Epilepsia 1999; 40: 621–30. 2296. Panayiotopoulos CP. Extraoccipital benign childhood partial seizures with ictal vomiting and excellent prognosis. J Neurol Neurosurg Psychiatry 1999; 66: 82–5. 2297. Panayiotopoulos CP. Benign childhood epileptic syndromes with occipital spikes: New classification proposed by the International League Against Epilepsy. J Child Neurol 2000; 15: 548–52. 2298. Panayiotopoulos CP. Panayiotopoulos syndrome. Lancet 2001; 358: 68–9. 2299. Feindel W, Penfield W. Localization of discharge in temporal lobe automatism. AMA Arch Neurol Psychiatry 1954; 72: 603–30. 2300. Inthaler S, Donati F, Pavlincova E, Vassella F, Staldemann C. Partial complex epileptic seizures with ictal urogenital manifestation in a child. Eur Neurol 1991; 31: 212–5. 2301. Baumgartner C, Groppel G, Leutmezer F et  al. Ictal urinary urge indicates seizure onset in the nondominant temporal lobe. Neurology 2000; 55: 432–4. 2302. O’Donovan C, Burgess R, Luders H. Aura in Temporal Lobe Epilepsy. New York, NY: Churchill Livingstone, 2000. 2303. Loddenkemper T, Foldvary N, Raja S, Neme S, Luders HO. Ictal urinary urge: Further evidence for lateralization to the nondominant hemisphere. Epilepsia 2003; 44: 124–6.

2304. Glass HC, Prieur B, Molnar C, Hamiwka L, Wirrell E. Micturition and emotion-induced reflex epilepsy: Case report and review of the literature. Epilepsia 2006; 47: 2180–2. 2305. Bourgeois BF. A retarded boy with seizures precipitated by stepping into the bath water. Semin Pediatr Neurol 1999; 6: 151–6; discussion 156–7. 2306. Spinnler H, Valli G. [Micturition “reflex” epilepsy. Presentation of a clinical case]. Riv Patol Nerv Ment 1969; 90: 212–20. 2307. Pradhan S, Kalita J. Micturition-induced reflex epilepsy. Neurol Ind 1993; 41: 221–3. 2308. Okumura A, Kondo Y, Tsuji T et al. Micturition induced seizures: Ictal EEG and subtraction ictal SPECT findings. Epilepsy Res 2007; 73: 119–21. 2309. Ikeno T, Morikawa A, Kimura I. A case of epileptic seizure evoked by micturition. Rinsho Nouha 1998; 40: 205–8. 2310. Yamatani M, Murakami M, Konda M et  al. [An 8-year-old girl with micturition-induced epilepsy]. No To Hattatsu 1987; 19: 58–62. 2311. Zivin I, Rowley W. Psychomotor epilepsy with micturition. Arch Intern Med 1964; 113: 8–13. 2312. Devinsky O, Morrell MJ, Vogt BA. Contributions of anterior cingulate cortex to behaviour. Brain 1995; 118(Pt 1): 279–306. 2313. Blok BF. Central pathways controlling micturition and urinary continence. Urology 2002; 59: 13–7. 2314. Physicians’ Desk Reference, 50th edn. Montvale, NJ: Medical Economics, 1996: 2350. 2315. Handforth A, Treiman DM. Efficacy and tolerance of long-term, high-dose gabapentin: Additional observations. Epilepsia 1994; 35: 1032–7. 2316. Gil-Nagel A, Gapany S, Blesi K, Villanueva N, Bergen D. Incontinence during treatment with gabapentin. Neurology 1997; 48: 1467–8. 2317. Brickel N, Gandhi P, VanLandingham K, Hammond J, DeRossett S. The urinary safety profile and secondary renal effects of retigabine (ezogabine): A first-in-class antiepileptic drug that targets KCNQ (K(v)7) potassium channels. Epilepsia 2012; 53: 606–12. 2318. Ciliberto MA, Weisenberg JL, Wong M. Clinical utility, safety, and tolerability of ezogabine (retigabine) in the treatment of epilepsy. Drug Healthc Patient Saf 2012; 4: 81–6. 2319. Rode F, Svalo J, Sheykhzade M, Ronn LC. Functional effects of the KCNQ modulators retigabine and XE991 in the rat urinary bladder. Eur J Pharmacol 2010; 638: 121–7. 2320. Harari D, Malone-Lee JG. Oxybutynin and incontinence during grand mal seizures. Br J Urol 1991; 68: 658.

28 Syringomyelia and lower urinary tract dysfunction Marc Le Fort, Jean-Jacques Labat, and Brigitte Perrouin-Verbe

Introduction Syringomyelia manifests as a liquid cavity in the spinal cord. It may be accompanied by neurologic signs. This type of spinal cord cavity has been known for a long time through autopsies and dissections. The name ­“syringomyelia” was coined by Olivier d’Angers in 1824 (syrinx = flute used by the Greek god Pan), described in 1867 by Bastian and only accepted as a real entity since the years 1950–1960 after Freeman’s studies (1953) and the first report by Barnett and Jousse in 1966. Its evolution is classically slow and can become functionally disabling if untreated. Most syringomyelias occur in a congenital malformative context (primary syringomyelia), with a late clinical expression. A secondary syringomyelia can occur after a spinal cord injury (SCI). The diagnosis is made by magnetic resonance imaging (MRI), but the mechanisms of syringomyelia occurrence are not perfectly understood.

Primary syringomyelia Etiopathogeny Dysraphic theory1 According to this ancient theory, syringomyelia would be due to a closing defect of the neural tube, which normally occurs between the 21st and 28th days of embryonal life. This embryopathy would arise from abnormal constitution of the posterior raphe. Bony anomalies associated with cervico-occipital transition and Chiari malformation would have no physiopathologic link.

comprises a lack or late opening of the roof orifices of the fourth ventricle that links the great cistern with the perimedullary and pericerebral subarachnoid spaces. Thus, a CSF hyperpressure is responsible for downward dilation of the spinal central canal. At birth, this hydromyelia bursts into a zone of lower resistance, the gray posterior commissure. It  generates the syringomyelic cavity that will have a permanent tendency to extend. Prolapse of the cerebellar tonsils, which by itself can hamper CSF circulation, and the cervico-occipital bony abnormalities would be consequences of the hydroencephalomyelia (Arnold–Chiari malformation). Aboulker’s theory 3  This theory insists on the transition effect. Any effort generating veinous hyperpressure creates growth of CSF pressure in the perimedullary spaces. This hyperpressure is normally transmitted upward to the cranious spaces. In the case of cervico-occipital bony abnormalities, CSF passage to the great cistern is held up and the consequent hyperpressure furthers CSF entry into the medullary spaces, about the level of the posterior rootlets. Coalescence of the liquidian lakes forms the syringomyelic cavity.

Clinical signs Physical examination may provide the diagnosis of intramedullary cavity and specify its extension that could even involve the high spinal cord (syringobulbomyelia). Its classic description is ••

Hydrodynamic theories Gardner’s theory 2  In the 1950s, Gardner revolutionized the physiopathologic concepts of syringomyelia, intro­ ducing the notion of a pathogenic role of cerebrospinal fluid (CSF) dynamics. This primitive embryologic disorder

••

A lesional syndrome of the spinal cord, combining a deficiency of the lower motor neuron with dissociative sensory loss: abolished reflexes, amyotrophy, peripheral motor weakness, thermic and pain anesthesia but with relative sparing of light touch and perception A sublesional syndrome of the spinal cord, under the lesion level with central motor weakness and vibratory sensory deficiency

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The clinical signs are not often as typical as the classical description. One symptom can raise suspicions of a spinal cord pathology and should lead to MRI. However, CSF accumulation within the spinal cord does not necessarily result in clinical neurologic deterioration, and the time period between the first sign and the diagnosis is still 6–8 years.1 Xenos et  al.4 mention, in cases of spinal lipomas, a possible role for syringomyelia in accelerating clinical deterioration. The most frequent early functional signs are subjective sensitivity of an upper limb (paresthesiae, pain), walking incapacity, cervical or cephalic pain, vertigo, motor deficiency of a limb, trophic signs (painless burn), and rapidly progressing thoracic scoliosis of adolescence. Electrophysiologic exploration may contribute to the early diagnosis, not so much to affirm a syringomyelia as to suspect a pathology of the spinal cord.5

Radiologic signs Standard radiography There could be indirect signs of an expansive intraspinal process: interpedicle enlargement, pedicle thinning, and spinal scalloping. A cervico-occipital abnormality, an associated bony dysraphism (spina bifida occulta), or kyphoscoliosis should be investigated.

Neuroradiology MRI supplants myelography. Myeloscans can be useful to study lower dysraphisms. MRI6,7 has close to 100% sensitivity and specificity. The signal of a syringomyelic cavity is the same as a CSF signal and is better seen with T2 exploration. A syrinx is tube shaped and extends beyond the SCI site to at least two vertebral levels. The signal is homogeneous and clearly delimits the upper and lower limits of the syringomyelia. The extension is always much more significant than the clinics suppose. The syringomyelic cavity may be multiloculated, and neuroradiology also gives information on tension inside the syrinx. MRI can show the associated abnormalities, neuromeningeal or cerebellar. There seems to be a significant correlation between the location of a segmental cavity in the spinal cord and the type of presenting symptomatology; however, in the case of a holocord cavity, the different types of signs may be evenly distributed.8

Urinary signs Neuro-urologic disorders rarely reveal the development of a syringomyelia but are, on the contrary, regarded as a late symptomatology.9 Nevertheless, they may be present at the time of the diagnosis and should be explored

systematically, clinically, or through urodynamic studies. These urinary symptoms appeared after 5.3 years (ranging from 2 months to 13 years) from the occurrence of neurologic symptoms in a Japanese study.9 Neuro-urologic signs readily coexist with bowel function and lower extremity abnormalities. Lower urinary tract dysfunction and spinal cord lesions may be suspected in patients with anorectal abnormalities: among 30 patients presenting with anorectal abnormalities, Taskinen et al.10 found four syringomyelias on systematic MRIs, with two normal on urodynamic evaluation and two neurogenic detrusor overactivity. The urinary signs are not specific most of the time, as they constitute a part of the sublesional syndrome syringomyelia, with an upper motor neuron bladder due to a suprasacral lesion. Their presentation is close to that of incomplete spinal cord lesions and may mimick urinary tract infection: urgency and eventually urge incontinence, pollakiuria, hesitancy, polyphasic micturition, occasional temporary urination impossibility, and even acute urine retention. Dysuria should also provoke the search for other apparent causes such as prostate hypertrophy. Urodynamic studies argue in favor of such a spinal cord lesion, showing a poorly inhibited and/or dyssynergic bladder: lasting and wave-like high contractions are evocative. Extension of the cavity into the sacral gray matter can give rise to signs of lower motor neuron bladder. Blunted micturition need, impaired perception of urine flow, or a progressively growing functional capacity of the bladder with a lower micturitional frequency can correspond to decreased bladder sensitivity or reflexivity on urodynamic assessment. Acute urinary retention has been described as the first manifestation of syringomyelia and can possibly be triggered by a well-defined factor—the Valsalva maneuver—which would acutely create increased pressure within the intraspinal space and the syrinx,11 or a pharmacologic side-effect of cyproheptadine.12 These neuro-urologic disorders will progress in the same way as the disease. Serious disease forms will then combine with other functional incapacities and loss of autonomy. Sakakibara et  al.,9 studying 11 primary and 3 secondary syringomyelias, tried to find a relationship between micturitional disturbance and neurologic signs. Besides neurogenic detrusor overactivity, common in patients with Babinski’s sign (suprasacral lesion with pyramidal tract involvement), urinary disturbances (detrusor hyperreflexia or voiding difficulty) seem to be linked with other neurologic deficiencies, especially disturbed sleep sensation. Patients are determined to be candidates for treatment on the basis of their clinical status and MRI findings. Surgery of a primary syringomyelia may be complex because of associated malformations. It is difficult to separate symptoms attributed to the syrinx alone, and, when associated with syringomyelia, lipoma excision, resection of an arachnoid cyst,13 and cord untethering can, for instance, lead to a reduction in syrinx size: it is

Syringomyelia and lower urinary tract dysfunction controversial whether syrinx cavities should be allowed to drain by themselves.4 Intraoperative ultrasonography may be helpful in determining the optimal length of the dural opening.13 In patients with Arnold–Chiari malformation and syringomyelia, suboccipital craniotomy seems to give the best chance for syrinx reduction, particulary in children younger than 10 years. Scoliosis correction without prior syrinx decompression carries a high neurologic risk.14 The main goal of surgery is, however, to at least stabilize progression of the symptoms.8 According to Oakes (editorial comment to La Marca et al.8), the smaller a symptomatic syrinx is at the time of initial treatment, the more likely a successful therapeutic intervention will be.

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represents one-quarter of all syringomyelia cases. The incidence of post-traumatic syringomyelia is estimated to be 28.9%.22 Any spinal level can be affected by complete or incomplete lesions. The first clinical signs can occur between 2 months and 36 years.15

Etiopathogeny Pathogenesis theories are still being discussed, but two phases (initial formation and cavity extension) have to be taken into account.

Initial formation of the cavity

Secondary syringomyelia Syringomyelia can occur without any malformations due  to spinal cord pathologies: arachnoiditis, tumors, or overall post-traumatic condition (Figure 28.1). The neurourologic status of SCI patients may change and raise suspicions of cavity occurrence. Post-traumatic syringomyelia is defined as an intramedullary cavity that occurs secondarily to SCI. This etiology

The mechanisms that lead to syrinx occurrence are not unequivocal. One is a vascular mechanism, especially secondary necrosis of a myelomalacic zone and a direct action of lysosomal enzymes on the injured parenchyma. The other mechanism is arachnoiditis, which is responsible not only for ischemia but also for permanent stretching of the injured zone during spinal movements.

Cavity extension This mechanism is a more mechanical one. Williams.16 ­proposed the most compelling theory with a main role for  variations in venous pressures. Any rise in pressure of the abdominal or thoracic cavity is transmitted to the epidural veins, squeezing the spinal cord and pushing the eventual intracystic fluid upwards. It is called the “slosh” effect, an energetic and upward pulsatile movement of fluid, with energy so significant that blockage occurs at the lesion site. These phenomena dissect the spinal cord at the extremities of the cavity where the spinal cord ­parenchyma is more fragile. The downward extension can be explained by another mechanism—slush—a negative pressure g­ radient in relation to the upward movement, making liquid enter the cavity.17,18 The extensions are favored by arachnoiditis, a tethered spinal cord, or persistent compression (Figure 28.2). Treatment of post-traumatic syringomyelia is essential in cases of intractable pain and progression of a motor deficit, but it may also include the management of canal stenosis and arachnoiditis.19

Clinical signs

Figure 28.1 Post-traumatic syringomyelia.

Pain, the main sign, is often associated with paresthesiae and numbness; it is noted in more than one-half of patients: Rossier et al.20 reported pain in 17 out of 30 cases, dysesthesia in 8, and motor deficiency in 7. Cough or pushing efforts may make this pain worse and radiating. The other signs are rarely inaugural and isolated. Most of the time, sensitive signs consist of thermoalgesic dissociation

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Suck

Figure 28.2 According to Williams’ theory, secondary extension from the initial necrosis zone is a consequence of increased epidural venous pressure at the origin of intrachordal fluid movements due to thoracic and/or abdominal pressure increase. “Slush” leads to rostral extension and breaks down the zones of structural weakness; “suck” is the consequence of a pressure gradient at the origin of the caudal extension and filling of the cavity. These two phenomena are increased in the case of blockage in the subarachnoid space, notably in the case of arachnoiditis after a traumatic spinal cord injury. (Reproduced with permission from Macmillan Publishers Ltd. Paraplegia, Williams, B, Posttraumatic syringomyelia, an update, 28(5), 296–313, June 1990, copyright 1990.)

with preservation of tactile sensitivity and proprioception. Preservation of normal sensitivity between the injury level and the upper sensory signs is often found.21 Rossier et al.20 described an ascending sensory level in 28/30 patients; this ascending sensory level is generally unilateral. Increased motor weakness above the level of the lesion and loss of reflexes are early signs that can also be found.19

Radiologic signs The diagnosis is also made by MRI, which can disclose the upper and lower levels, a multiloculated cavity, and intracystic turbulences. The signal criteria of syringomyelia are the same. Cross-sections transversely localize the cavity in the spinal cord. Perrouin-Verbe et al.22 reported a mean extension of 3.5 segments in asymptomatic patients and 10 segments in symptomatic cases. The persistent bony compression has also been assessed in the genesis of posttraumatic syringomyelia.19,23

Urinary signs The urinary signs are not specific for post-traumatic syringomyelia, but their occurrence in an SCI patient must make them suspect. Dysuria may worsen due to increased detrusor–sphincter dyssynergia or decreased bladder reflectivity; reflex voiding may disappear. Fading of reflex erections, difficult ejaculation, or deterioration of autonomic dysreflexia can also constitute an alert. These signs of lower motor neuron bladder lead to MRI, in a way investigating the downward extension of the syringomyelic cavity. Possible lesion evolution imposes neuro-urologic followup in SCI patients. Clinical analysis must include determination of the level and flaccid or spastic character of the lesion, particularly in the sacral area. The mode of voiding and its eventual changes have to be assessed. Follow-up must be regular during the first 2 years and then it should become annual with clinical, urodynamic, and morphologic studies. Less frequent follow-up can be discussed in case there is no significant risk factor. The quality of the initial treatment of a SCI is the first step in the prevention of a syrinx whose treatment, besides techniques of drainage, must also take into account the spinal realignment.19 The most suited surgical technique combines spinal laminectomy, a drainage of the cavity, an arachnoid liberation, and a dural plasty enlargement.22 Jaksche reported improved conditions in 70% of cases with a significant effect on the reduction of pain and improvement of motor deficit if recent.24 It is also recommended to mobilize early in postoperative patients to prevent further adhesions.25 Preventive treatment should limit closed glottis efforts after SCI (micturition by abdominal pushing, weightlifting, walk with large orthotics, vaginal delivery in the case of SCI women with a syringomyelia …).22 Laparoscopic or robot-assisted surgery, as well as an extracorporeal lithotripsy, should be avoided in the presence of a post-­ traumatic syringomyelia.26

Conclusion Primary or secondary syringomyelia consists of an evolutive spinal cord syndrome that can lead to lower urinary tract dysfunction. MRI can easily confirm the diagnosis if it has previously been suspected by systematic clinical examination or directed by functional symptoms. Most of the urinary signs are not specific. Primary syringomyelias correspond to an upper motor neuron bladder (suprasacral lesion), and in the secondary forms, modification of the voiding mode may be due to extension of the cavity into the sacral level. Treatment indications have not yet been perfectly determined, but surgery is decided on the basis of the patient’s clinical status and MRI findings.

Syringomyelia and lower urinary tract dysfunction

References 2321. Sichez JP, Capelle L. Syringomyélie. Editions techniques. EMC Neurologie, 17077A10, 4–1997. 2322. Gardner WJ, Angel J. The mechanism of syringomyelia and its surgical correction. Clin Neurosurg 1959; 6: 131–40. 2323. Aboulker J. La syringomyélie et les liquides intra-rachidiens. Neurochirurgie (Paris) 1979; 25(Suppl 1): 9–22. 2324. Xenos C, Sgouros S, Walsh R, Hockley A. Spinal lipomas in children. Pediatr Neurosurg 2000; 32: 295–307. 2325. Anderson NE, Frith RW, Synek VM. Somatosensory evoked potentials in syringomyelia. J Neurol Neurosurg Psychiatry 1986; 49: 1407–10. 2326. Wilberger JE, Maroon JC, Prostko ER et  al. Magnetic resonance imaging and intraoperative neurosonography in syringomyelia. Neurosurg 1987; 20: 599–606. 2327. Aubin ML, Baleriaux D, Cosnard G et al. IRM dans les syringomyélies d’origine congénitale, infectieuse, traumatique ou idiopathique. A propos de 142 cas. J Neuroradiol (Paris) 1987; 14: 313–36. 2328. La Marca F, Herman M, Grant JA, MacLone DG. Presentation and management of hydromyelia in children with Chiari type II malformation. Pediatr Neurosurg 1997; 26: 57–67. 2329. Sakakibara R, Hattori T, Yasuda K, Yamanishi T. Micturitional disturbance in syringomyelia. J Neurol Sci 1996; 143: 100–6. 2330. Taskinen S, Valanne L, Rintala R. The effect of spinal cord abnormalities on the function of the lower urinary tract in patients with anorectal abnormalities. J Urol 2002; 168: 1147–9. 2331. Amoiridis G, Meves S, Schöls L, Przuntek H. Reversible urinary retention as the main symptom in the first manifestation of a syringomyelia. J Neurol Neurosurg Psychiatry 1996; 61: 407–8. 2332. Houang M, Leroy B, Forin V et al. Rétention aiguë d’urines: Un mode de révélation rare d’une syringomyélie cervicodorsale à l’occasion de la prise de cyproheptadine. Arch Pédiatrie (Paris) 1994; 1: 260–3. 2333. Holly LT, Batzdorf U. Syringomyelia associated with intradural arachnoid cysts. J Neurosurg Spine 2006; 5: 111–6.

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2334. Ozerdemoglu RA, Transfeldt EE, Denis F. Value of treating primary causes of syrinx in scoliosis associated with syringomyelia. Spine 2003; 28(8): 806–14. 2335. Umbach I, Heilporn A. Post spinal-cord injury syringomyelia. Review. Paraplegia 1991; 29: 219–21. 2336. Williams B. Post-traumatic syringomyelia, an update. Paraplegia, June 1990; 28(5): 296–313. 2337. MacLean DR, Miller JDR, Allen PBR, Ezzedin SA. Post traumatic syringomyelia. J Neurosurg 1973; 39: 485–92. 2338. Ball MJ, Dayan AD. Pathogenesis of syringomyelia. Lancet 1972; 2: 799–800. 2339. Perrouin-Verbe B, Lenne-Aurier K, Robert R et al. Post-traumatic syringomyelia and post-traumatic spinal canal stenosis: A direct relationship: Review of 75 patients with a spinal cord injury. Spinal Cord 1998; 36: 137–43. 2340. Rossier AB, Foo D, Shillito J, Dyro FM. Post traumatic cervical syringomyelia: Incidence, clinical presentation, electrological studies, syrinx protein and results of conservative and operative treatment. Brain 1985; 108: 439–61. 2341. Vernon JD, Silver JR, Ohry A. Post traumatic syringomyelia. Paraplegia 1982; 20: 339–64. 2342. Perrouin-Verbe B, Robert R, Le Fort M et  al. Syringomyélie posttraumatique. Neurochirurgie (Paris) 1999; 45(Suppl 1): 58–66. 2343. Schurch B, Wichmann W, Rossier AB. Post-traumatic syringomyelia (cystic myelopathy): A prospective study of 449 patients with spinal cord injury. J Neurol Neurosurg Psychiatry 1996; 60: 61–7. 2344. Jaksche H, Schaan M, Schulz J, Bosczcyk B. Post-traumatic syringomyelia a serious complication in tetra- and paraplegic patients. Acta Neurochir Suppl 2005; 93: 165–7. 2345. Lee TT, Almeda GJ, Camilo E, Green BA. Surgical treatment of posttraumatic myelopathy associated with syringomyelia. Spine 2001; 26(24 Suppl): S119–27. 2346. Caremel R, Hamel O, Gerardin E et al. Post-traumatic syringomyelia: What should know the urologist? Prog Urol 2013; 23(1): 8–14.

Part IVV Evaluation of neurogenic bladder dysfunction

29 Clinical evaluation: History and physical examination Chasta Bacsu and Gary E. Lemack

Introduction A thorough history and physical examination are the cornerstones of the initial evaluation of patients with neurological diseases, who are suffering from lower urinary tract symptoms (LUTS). Although more exact and specific means are often necessary to pinpoint the nature of bladder dysfunction in such patients, a directed, thorough history and physical examination are essential to determine which patients require more costly and invasive testing, and which can be followed with alternative strategies. Video-urodynamic testing has allowed for more precise characterization of bladder dysfunction in patients with neurological disorders, but failing to know what questions to ask, and what signs to observe can lead to erroneous diagnoses, and inappropriate testing. The focus of this chapter is on obtaining a neuro-urological history and performing a focused physical examination, to help determine what further investigations, if any, are necessary on subsequent visits.

History Nature of neurologic disease In most situations, patients will present to the urologist with an established neurologic diagnosis. In patients with progressive conditions, it is useful to establish the onset of symptoms (often very different than the timing of diagnosis) as well as recent changes in symptom severity, as this information may clearly influence treatment recommendations. Even patients with a presumably “stable” neurologic condition (i.e., spinal cord injury [SCI], myelomeningocele) may have had recent symptomatic deterioration (for example, secondary to syrinx or tethered cord), and therefore any acute changes in sensory or motor

function should be directly questioned. Although stage of a neurological disease may not always correlate with LUTS severity,1 in some cases, stage of disease may give an indication of the likelihood of the progression of symptoms.2 Therefore, if possible, it is useful to document the stages of neurological disease at the time of referral based on the assessment of a neurologist or physiatrist. Staging systems for multiple sclerosis (MS), Parkinson’s disease (PD), and SCI are shown in Table 29.1. Being up to date and familiar with commonly used classification systems of neurologic disease may help the clinician communicate with the patient and referring physician, and better understand the extent of disease. Although these staging systems can be helpful to categorize the severity of neurologic disease, there is not always a clear correlation between disease severity and LUTS. For example, Expanded Disability Symptom Score (EDSS) status in MS patients does not always correlate with urodynamic (UD) findings, so that even in patients with fairly stable MS, bladder dysfunction may be present.1 In patients with more acute events, such as cerebrovascular accident, knowledge about the stroke location and the recovery since the event can be useful, as stroke location can impact on prognosis.3 It is also quite clear from several prospective population-based studies that poststroke persistent incontinence is an ominous sign. Along with intermittent claudication, previous transient ischemic attacks, and prestroke disability, the finding of urinary incontinence after stroke has been shown to be predictive of death within 5 years.4 Patients with a history of lower extremity weakness, numbness, or paresthesia, should be specifically questioned regarding history of intervertebral disc prolapse and/or recent treatments. Those with a history of sciatictype pain or cauda equina syndrome (i.e., low back pain, perineal paresthesia, lower extremity weakness, and diminution of sexual function) should be imaged to document

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Table 29.1  Staging systems for neurologic disease Disease

Staging system

Range

Spinal cord injury (SCI)

American Spinal Cord Injury Association (ASIA) Standard Neurological Classification of SCI

A: Complete B: Incomplete (sensory preserved) C: Incomplete (motor preserved below level, >1/2 of key muscles have active movement with full range of motion when gravity is eliminated) D: Incomplete (motor preserved below level ≥1/2 of key muscles have active movement, full range motion against gravity and may provide resistance) E: Normal

Multiple sclerosis (MS)

Extended Disability Status Scale (EDSS)

0: Normal neurologic exam 1–4.5: Fully ambulatory and varying other neurological deficits 5–9.5: Impaired ambulation and progressive other neurological deficits 10: Death due to MS

Parkinson’s disease (PD)

Hoehn and Yahr Scale

I: Unilateral disease II: Bilateral disease III: Postural instability (mild) IV: Postural instability (marked) V: No independent ambulation (end stage)

possible lumbar disc prolapse that can result in LUT dysfunction in up to 16% of patients. Patients with cervical disc herniation appear to be at even greater risk for both upper and LUT disorders and should certainly be monitored periodically with UD studies and upper tract imaging.5 Patients with SCI should be queried as to the level and completeness of their injury. Their ASIA classification status should be documented (Figure 29.1). The presence of hardware due to surgery at the time of their SCI for spine stabilization should be verified. The nature of bladder and bowel management up until the time of referral should be carefully documented. If major reconstructive surgery is ultimately contemplated, the need for simultaneous bowel surgery (i.e., colostomy, antegrade continence enema procedure) should be considered based on this thorough assessment of baseline genitourinary and gastrointestinal function. Other medical conditions can have a tremendous impact on LUTS. Patients should be specifically questioned for the presence or history of diabetes mellitus, tabes ­dorsalis,  herpes zoster, HIV, or extensive alcohol use. All of these conditions can result in peripheral neuropathies, which may cause significant detrusor dysfunction. Anogenital herpes (simplex) can also result in LUT dysfunction or frank retention typically due in part to severe urethral pain associated with vesicular eruptions.

Surgical history should be elicited. Patients with a history of extensive pelvic surgery (i.e., radical hysterectomy, abdominoperineal resection, and radical prostatectomy) as well as pelvic radiation may suffer from LUT dysfunction secondary to peripheral nerve damage. In addition, direct sphincteric damage may occur during surgery resulting in urinary incontinence. Although in certain instances these processes may cause progressive vesicosphincteric disorders, there is also evidence to suggest that nerve function may recover for a period following these insults (especially up to 6 months).6 Although robotic approaches to pelvic surgery have advanced treatment overall, the impact of robotic approaches on the risk of sphincteric damage during pelvic procedures has not yet been well established.7 Current medical treatments should also be documented. Medications with properties that can affect the bladder outlet (typically with either alpha agonist or antagonist properties) or detrusor contractility (typically those with anticholinergic properties) should be recorded, along with narcotic and skeletal muscle relaxant use. Many commonly prescribed medications have anticholinergic properties (Table 29.2), even as their clinical utility may not be based on this attribute, and therefore carefully documenting all medications used may help in avoiding adverse events related to the addition of a new agent. Many patients may also be taking narcotics for chronic pain relief that clearly

The most caudal segment with normal function

(25)

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SENSORY MOTOR

(50) R L SINGLE NEUROLOGICAL LEVEL

(MAXIMUM) (56)

TOTALS {

C2 C3 C4 C5 C6 C7 C8 T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 L2 L3 L4 L5 S1 S2 S3 S4-5

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LIGHT TOUCH

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C8

Dorsum

C6

LIGHT TOUCH SCORE

PIN PRICK SCORE

ASIA IMPAIRMENT SCALE (AIS)

S1

ZONE OF PARTIAL PRESERVATION

L5

L3

L3

L4

L2

L2

L5

L1

L1

L4

T12

T10 T11

T9

T8

T5 T6 T7

T4

C3

C4

(In complete injuries only)

S1

T2

C3

T2

S1

C6

C6

C3

R

C4

L

Key Sensory Points

Dorsum

Palm

T1

C5

SENSORY MOTOR Most caudal level with any innervation

(max: 112)

(max: 112)

C5

T1

Palm

C6

(DAP) Deep anal pressure (yes/no)

L 2

L 2 L 3

S3

NT = not testable

0 = absent 1 = altered 2 = normal

KEY SENSORY POINTS

COMPLETE OR INCOMPLETE?

(56)

L

SENSORY

Incomplete = any sensory or motor function in S4-S5

(56)

R

PIN PRICK

C2

C2

Example of the ASIA International Standards for Neurological Classification of Spinal Cord Injury scoring sheet. A representation of dermatome levels is shown on the right side of the figure. (Courtesy of ASIA.)

Figure 29.1

(50)

Hip flexors Knee extensors Ankle dorsiflexors Long toe extensors Ankle plantar flexors

(25)

=

Elbow flexors Wrist extensors Elbow extensors Finger flexors (distal phalanx of middle finger) Finger abductors (little finger)

KEY MUSCLES (scoring on reverse side)

(VAC) Voluntary anal contraction (Yes/No)

NEUROLOGICAL LEVEL

(25)

+

(25)

+

L

MOTOR

INTERNATIONAL STANDARDS FOR NEUROLOGICAL CLASSIFICATION OF SPINAL CORD INJURY

Date/Time of Exam

C8 7 C

LOWER LIMB TOTAL (MAXIMUM)

L2 L3 L4 L5 S1

Comments:

UPPER LIMB TOTAL (MAXIMUM)

C5 C6 C7 C8 T1

R

AMERICAN SPINAL INJURY ASSOCIATION

Examiner Name

C7

Patient Name

Clinical evaluation: History and physical examination 339

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Table 29.2  Commonly prescribed medications with anticholinergic properties Anticholinergics Atropine (Atropisol ophthlamic)

Scopolamine (Scopace)

Glycopyrrolate (Robinul)

Benztropine (Cogentin)

Trihexyphenidyl (Artane)

Biperdin (Akinetin)

Oxybutynin (Ditropan)

Tolterodine (Detrol)

Darifenacin (Enablex)

Fesoteridine (Toviaz)

Solifenacin (Vesicare)

Ipratropium bromide (Atrovent)

a

Antihistamines Chlorpheniramine (Chlortrimeton and others) Hydroxyzine (Atarax, Vistaril) Diphenhydramine (Nytol, Sominex and others) Meclizine (Anitvert, Bonine, Dramamine) Promethazine (Phernergan) Antispasmodics Dicyclomine (Bentyl)

Propantheline (Pro-Banthine)

Hyoscyamine (Anaspaz, Cystospaz, Levsin) Antidepressants Amitryptyline (Elavil)

Clomipramine (Anafranil)

Desipramine (Norpramine)

Imipramine (Tofranil)

Nortriptyline (Pamelor)

Duloxetine (Cymbalta)

Paroxetine (Paxil) Antipsychotics Chlorpromazine (Thorazine)

Clozapine (Clozaril)

Thioridazine (Mellaril)

Quetiapine (Seroquel)

Olanzapine (Zyprexa) Mydriatics Cyclopentolate (Ocu-Pentolate ophthlamic) Tropicamide (Ocu-Tropic ophthalmic) Cardiovascular agents Furosemide (Lasix)

Digoxin (Lanoxin)

Nifedipine (Adalat, Procardia) Antiulcer agents Cimetidine (Tagamet) a

Ranitidine (Zantac)

Oxybutinin also has antispasmodic properties.

can impact bladder and bowel function. Use of antibiotic prophylaxis, immunosuppressive agents, diuretics, and anticoagulants also deserve special attention.

Nature of lower urinary tract symptoms Duration of symptoms Determining if LUTS pre-date the neurological disorder is often difficult, although will help to clarify the etiology in

many situations. In some patients, such as those with SCI, date of symptom onset will be quite clear, though often, as is the case in patients with cerebrovascular accidents, the presence of preexisting symptoms may be difficult to discern. In slowly progressive diseases, such as MS, a clear date of onset is often impossible to establish, though a general assessment of the time course over which the symptoms worsened is essential. Patients with PD belong to a demographic that typically has preexisting LUTS, and therefore sorting out which symptoms are neurologically based and which may be due to bladder outlet obstruction, for example, is difficult to distinguish even with the addition of UD studies.

Clinical evaluation: History and physical examination

Prior and current urologic management Patients will often come referred with a diagnosis of recurrent  urinary tract infections, but precisely docu­ menting the offending organism and its sensitivities is essential to ­discovering its source. Failure to clear an ongoing i­ nfection (persistence) and repeated bouts of new infections imply different etiologies. Clearly, the method of bladder management will affect the susceptibility to infection, and the use of indwelling or intermittent ­catheterization should be documented. In addition, the duration of each catheter use before change, and cleaning technique used (for those using clean rather than sterile intermittent catheterization) should be recorded, as well as a careful reassessment of catheterization technique. In general, sterile c­atheterization is recommended for patients reliant on intermittent catheterization when feasible. Medical personnel familiar with intermittent ­catheterization should instruct patients in their initial attempts and observe them as they attempt their first catheterizations. Inquiry of prior investigations and results should also be discussed particularly if diagnosis is unknown or patient has recently transferred care. A history of previous bladder, prostate, or upper tract surgery must be carefully detailed, and operative notes of complex reconstruction reviewed. History of renal or bladder ­calculi may be overlooked if not directly questioned.

Current urinary symptoms Although LUTS should be carefully assessed at the time of initial presentation, there is no doubt that the interpretation of urinary symptoms may be quite different (and masked) in patients with neurological disease. Therefore, the reliability of LUTS questionnaires in most neurological disorders has not been effectively established. Still, sensate patients should be questioned for the presence or progression of urinary urgency, frequency, and nocturia, in addition to other symptoms typically associated with disorders of bladder filling. Often, a 2- or 3-day voiding diary can be of tremendous help in establishing micturition frequency and voided volumes.8,9 Fluid intake and bladder irritants, such as caffeine, acidic/spicy food, and alcohol can exacerbate urinary urgency and frequency. In general, greater than 8 voids per day is considered abnormal, though, clearly, this finding may have many causes. Urinary frequency may represent detrusor overactivity, impaired bladder capacity, excessive urine production (polyuria), impaired bladder emptying, urinary infection, stone disease, inflammatory bladder conditions, as well as many other possible etiologies. LUTS typically associated with the voiding such as urinary hesitancy, straining, loss of stream and interrupted urine flow is also important to establish. A staccato type of voiding pattern (choppy, interrupted pattern) can be a warning sign indicating detrusor sphincter dyssynergia, and may prompt a more thorough evaluation including

341

video-urodynamic testing. Excessive straining is nonspecific and could represent detrusor failure or bladder outlet obstruction, and therefore also may prompt UD testing in patients with known neurologic disease. However, as noted earlier, patients with neurogenic bladder conditions may have elevated postvoid residuals (PVRs) without severe LUTS, so a high index of suspicion is required in their evaluation. in addition, it is generally recommended that a baseline noninvasive assessment of PVR be carried out in patients with known neurological conditions to help determine if more invasive testing is mandated.10 UD testing may indeed be a very important part of the baseline assessment of patients with a variety of neurogenic bladder conditions, though noninvasive PVR assessment may often be helpful to determine if repeat testing or another intervention is required. Urinary incontinence, when present, should be characterized fully. Stress incontinence, occurring with increases in intra-abdominal pressure, and most frequently associated with physical activity, coughing, straining, and change in position should be assessed for severity, approximate time of onset, and degree of progression. During history taking, incontinence may be assessed by pad usage (nonspecific) and questionnaire response although questionnaire response may not be a reliable indicator of severity of stress-related leakage.11–13 Several validated questionnaires are available in men14 and women,15 though few were specifically designed for use in patients with neurogenic bladder conditions.16,17 QUALIVEEN® is a validated questionnaire for urinary symptoms related to quality life for MS and SCI and may be more sensitive to change in symptoms that more general questionnaires such as the SF36® and more applicable to those who perform IC as opposed to those who do not.17–19 SCI patients with lower thoracic or lumbar lesions appear to be at greatest risk for stress incontinence due to intrinsic sphincteric insufficiency, and may note leakage on transfer. Urge incontinence, which may be due to detrusor overactivity, loss of compliance or heightened bladder sensation rather than urethral hypermobility or intrinsic sphincteric weakness alone as is the case with stress leakage, may be best assessed by a voiding diary, pad usage and questionnaire response such as Overactive Bladder Questionnaire (OAB-Q).1 In sensate patients, typical symptoms include the sudden, uncontrollable urge to urinate, nighttime leakage episodes, and sometimes, leakage during intercourse. This is the most common pattern among patients with MS, cerebrovascular accident, and PD, among whom the UD finding of neurogenic detrusor overactivity is often noted. Patients with overflow incontinence may present with constant dribbling, recurrent urinary infections, or renal insufficiency due to the presence of significantly elevated PVRs. In most instances, overflow incontinence is due to an underactive/acontractile detrusor or severe bladder

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Textbook of the Neurogenic Bladder

outlet obstruction. Patients in the spinal shock phase of SCI will typically present with this pattern (due to an acontractile detrusor), which will often persist in those with lower lumbar and sacral cord injuries. Patients with continuous incontinence, which may be due to ureteral ectopy, fistula formation, bladder neck erosion (from longterm Foley catheter use), or occasionally a scarred, fixed urethra from multiple prior procedures, will report constant urinary drainage including at night while supine, often with very infrequent voids due to the lack of urine accumulation in the bladder. Autonomic dysreflexia (AD) can pose a significant risk to patients with SCI above T6, and these patients should be questioned regarding its occurrence. Signs and symptoms of AD can include headache, hypertension, flushing, sweating, bradycardia, and seizures. Left untreated, AD can be fatal. Frequency of AD and provoking factors such as a full bladder or severe constipation may identify areas of care that need further attention. The development of new onset urinary symptoms in a neurogenic patient who has been followed for some time may reflect a new process, and repeat evaluation should be considered. For example, an SCI patient with stable LUT function who suddenly develops worsening incontinence may need to have repeated spinal cord imaging in addition to UD studies, while a patient with slowly improving urinary urgency following a stroke often can be safely followed with non-invasive monitoring. Similarly, neurogenic patients who develop verified recurrent urinary tract infections after a period of stability should be reimaged and consideration given for repeat UD testing, in addition to cystoscopy to evaluate for intravesical sources of infection. In addition, the needs for repeat UD testing may be based on worrisome initial findings. Patients with altered bladder compliance, for example, may be recommended to have repeated bladder testing even in the absence of any worsening symptoms.

Non-genitourinary review of systems Gastrointestinal history An assessment of bowel function is imperative, as often bowel and bladder dysfunction parallel one another in patients with neurologic conditions. In patients with SCI, the nature of bowel program should be established (i.e., digital stimulation and suppository use). The presence of fecal incontinence, tenesmus, chronic constipation, or obstipation should also be recorded. Patients with chronic constipation due to poor bowel contractility may develop significant large bowel distension, which may have ramifications if one is considering bladder reconstruction.

Cross-sectional imaging may be helpful prior to such surgical intervention.

Sexual history Obtaining a thorough sexual history is important, as sexual dysfunction is extremely common among men and women with neurologic conditions.21,22 Women may report lack of desire (loss of libido), difficulty achieving orgasm, or inability to have intercourse secondary to vaginal pain or dryness, or due to enhanced vaginal sensitivity (hyperasthesia), particularly in the case of MS.23 In women with SCI, disorders of arousal and orgasm appear to be the most prevalent conditions.24 Men may report erectile dysfunction often secondary to altered penile sensation. Ejaculatory disturbances due to these changes in sensation (leading to either premature or delayed ejaculation), or bladder neck dysfunction (retrograde ejaculation) are also common. Patients with sympathetic outflow interruption, such as those with complete spinal cord lesions will often experience anejaculation. In such instances, vibratory simulation to the penis or electrical stimulation applied transrectally can often result in successful ejaculation.

Social history A psychosocial history can be especially helpful in c­ aring for the neurogenic patient. Many patients with neurological diseases may be unable to work or be dependent on ­ caregivers for their basic activities of daily living. Accessibility to care, toileting, and supplies may be limited by financial constraints or other social factors. Despite heterogeneity between studies, a systematic review assessing health-related quality of life (HRQoL) and economic impact of urinary incontinence in neurogenic bladder demonstrated lower HRQoL and higher economic burden compared to patients with idiopathic urge incontinence or those with the same neurological disease but without incontinence.25 Behaviors such as cigarette smoking, binge drinking, psychotropic prescription medication use, and being homebound were found to be predictive of increased mortality in SCI.26 Depression or poor self-esteem may result from the underlying neurologic pathology, lack of independence, urinary incontinence, or other factors. Finally, the extent to which a patient with neurological disease has health support systems at home to contend with issues related to bladder dysfunction is vital to assess. This will provide the framework for appropriate treatment modalities to consider. Multidisciplinary involvement with social workers may be especially beneficial for those who are having difficulty coping to improve overall health and compliance with treatment and follow-up regimens.

Clinical evaluation: History and physical examination

Physical examination Neurological assessment A brief neurologic examination is essential when first evaluating patients with presumed neurovesical dysfunction. Mental status should be assessed, as significant cognitive dysfunction and memory disturbances have been independently associated with LUTS and incontinence. An appreciation of past and present intellectual capacity may also provide insight into the progression of LUT disorders, as well as guide the degree of complexity of treatment strategies offered. Both motor strength and sensory level should be determined, as distribution of motor and sensory disturbances can often predict LUT dysfunction.27 There should also be a thorough evaluation of both cutaneous and motor reflexes at the time of the initial encounter (Table 29.3). The bulbocavernosus reflex, which is elicited by gently squeezing the glans penis in men or gentle compression of the clitoris against the pubis in women and simultaneously feeling for an anal sphincter contraction (by placing a finger in the rectum), assesses the integrity of the S2–S4 reflex arc. The anal reflex, which assesses integrity of S2–S5 can be checked by applying a pinprick to the mucocutaneous junction of the anus and evaluating for anal sphincter contraction. The cremasteric reflex may be somewhat less reliable, but assesses sensory dermatomes supplied by L1–L2.

343

Muscle motor reflexes should also be routinely evaluated. The most common of these are the biceps reflex (assesses C5–C6), patellar reflex (L2–L4), and Achilles (ankle) reflex (L5–S2). Evidence of an upper motor neuron injury would include spasticity of the involved skeletal muscle, heightened response to reflex testing, and an upgoing toe on gentle stroking of the plantar surface of the foot (positive Babinski).

General issues Mode of ambulation, and recent progression of ambulatory disturbances, should be assessed at the initial visit. Clearly, the degree of physical independence of the patient, particularly as it relates to the ability to transfer oneself to the toilet often affects the degree of urge-related leakage episodes. in addition, certain patients who are nonambulatory may have great difficulty with self-urethral catheterization. Should that be the case, an abdominal catheterizable stoma may be a more reasonable option in the appropriately selected patient wishing to become more functionally independent. Hand function in patients with cervical SCI, and particularly the ability to grasp firmly between the thumb and index or middle finger must be evaluated in patients who may require intermittent catheterization following treatment. A pencil-and-paper test, where various tasks such as ease in clasping a pencil in different positions and folding

Table 29.3  Reflexes for neurourologic examination Reflex

Nerves

Normal response

Bulbocavernosal reflex

S2–S4

Gently squeezing the glans penis in males or performing gentle compression of clitoris in females to assess for anal sphincter contraction

Anal reflex

S2–S5

Pinpricking mucocutaneous junction of anus to assess for anal sphincter contraction

Cremasteric reflex

L1–L2

Stroking the inner thigh in males to cause contraction of the cremasteric muscle and elevation of the ipsilateral testis

Biceps reflex

C5–C6

Striking the biceps tendon to assess for contraction of the biceps muscles

Patellar reflex

L2–L4

Striking the patellar tendon to assess for leg extension

Achilles reflex

L5–S2

Tapping the Achilles tendon for dorsiflexion of the foot

Babinski reflex

Upper motor neuron

Stroking the lateral edge of the plantar surface of the foot should result in curving toes down and foot eversion in absence of upper motor neuron disease

Source:  Palleschi G, Pastore AL, Stocchi F, et al. Clin Neuropharmacol 2006; 29: 220-229.

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Textbook of the Neurogenic Bladder

and tearing a piece of paper are assessed, has been proposed as a predictive tool to assess an individual’s ability to be able to perform self-catheterization.28 It is not mandatory that patients have use of both hands prior to such an intervention, as single-unit catheter/collection systems are readily available. Examination of the back is easy to perform but can provide clues regarding previous surgery and pathology, which may have been missed during the history. Costovertebral angle tenderness should be assessed particularly in patients with history of UTIs and pyelonephritis but may not be reliable depending on the level of their neurologic disease. One should assess for midline skin dimples, which may be a sign of occult spinal dysraphism. In addition to assessing for scoliosis or abnormal spinal configuration, attention should similarly be paid to the presence of leg contractures as both can make operative patient positioning more challenging due to increased concern for pressure points and possibility of difficult access to the abdomen or pelvis. An evaluation of the skin, particularly in the gluteal region should be carried out, as localized skin and subcutaneous infections as well as more severe skin breakdown are not uncommon among patients with restricted mobility. Such issues will need to be addressed before major reconstructive procedures are considered. In some cases, severe skin breakdown, decubiti, and osteomyelitis related to chronic neurogenic incontinence may be the rationale to consider urinary diversion, and thus, these conditions need to be carefully evaluated. Some patients may also have intrathecal pumps in place and their location, as well as that of their tubing should be assessed prior to surgical endeavors.

Figure 29.2 Traumatic hypospadias on ventral surface of penis resulting from long-term indwelling catheter.

Pelvic examination Pelvic examination should be carried out to assess for vaginal estrogenization (noting a loss of lubrication, rugation, and blanching of the mucosal surface), and pelvic prolapse. One should also observe for urine loss (either spontaneous or induced by Valsalva or cough). An assessment of the urethra is essential in both men and women, particularly those with chronic indwelling catheters, as traumatic hypospadias in men (Figure 29.2) and bladder neck erosion (Figure 29.3) in women may require surgical repair or even closure for severe cases of erosion. A careful examination of sensation of the genitalia may provide insight into the nature of sexual dysfunction, as both hypo- and hyperasthesia has been described among patients with neurologic conditions. A rectal examination should assess for sphincter tone and stool impaction, as chronic constipation often aggravates voiding dysfunction. In men, the prostate should be examined for areas of tenderness or fluctuance since prostatitis and prostatic abscesses are not

Figure 29.3 Bladder neck erosion in female patient with multiple sclerosis from long-term indwelling catheter use.

uncommon among men with severe neurovesical dysfunction, p ­articularly those with chronic indwelling catheters.

Conclusion The initial urologic assessment with thorough history and comprehensive, yet focused, physical examination in individuals with neurovesical dysfunction is necessary to identify if further investigations are warranted.

Clinical evaluation: History and physical examination As neurological disease can be quite variable in presentation and extent, not all patients with neurological conditions and coexisting bladder dysfunction merit the same initial diagnostic evaluation nor the same frequency of follow-up studies. Overinvestigating patients without a clinical question or symptom directing the test is not cost–effective, could result in patient anxiety, distress, discomfort, or serious complications such as urosepsis. Information obtained during history and physical examination including treatment goals and degree of bother provide the framework for ongoing decision making and are essential in establishing patient compliance.

References 2347. Jolijn KJ, Hoogervorst ELJ, Uitdehaag BMJ et al. Relation between objective and subjective measures of bladder dysfunction in multiple sclerosis. Neurol 2004; 63: 1716–8. 2348. Lemack GE, Dewey RB, Roehrborn CG et al. Questionnaire-based assessment of bladder dysfunction in patients with mild to moderate Parkinson’s disease. Urology 2000; 56: 250–4. 2349. Khan Z, Starer P, Yang YC et al. Analysis of voiding disorders in  patients with cerebrovascular accidents. Urology 1990; 32: 265–70. 2350. Kolminsky-Rabas PL, Hilz MJ, Neunderfer B et al. Impact of urinary incontinence after stroke: Results from a prospective population-based stroke register. Neururol Urodyn 2003; 22: ­ 322–6. 2351. Dong D, Xu Z, Shi B et al. Urodynamic study in the neurogenic bladder dysfunction caused by intervertebral disk herniation. Neurourol Urodyn 2006; 25: 446–50. 2352. Hubert J, Hauri K, Leuener M et al. Evidence of trigonal denervation and reinnervation after radical retropubic prostatectomy. J Urol 2001; 165: 111–3. 2353. Froehner M, Koch R, Leilke S et al. Urinary tract-related quality of life after radical prostatectomy: Open versus robotic-assisted laparoscopic approach. Urol Int 2013; 90(1): 36–40. 2354. Wyman JF, Choi SC, Harkins SW et al. The urinary diary in evaluation of incontinent women: A test-retest analysis. Obstet Gynecol 1988; 71: 812–7. 2355. Groutz A, Blaivas JG, Chaikin DC et al. Noninvasive outcome measures of urinary incontinence and lower urinary tract symptoms: A multicenter study of micturition diary and pad tests. J Urol 2000; 164: 698–701. 2356. Winters JC, Dmochowski RR, Goldman HB et al. Adult urodynamics: AUA/SUFU guideline. J Urol 2012; 188 (6 Suppl): 2464–82, doi: 10.1016/j.juro.2012.09.081. 2357. Lemack GE, Zimmern PE. Predictability of urodynamic findings based on the Urogenital Distress Inventory questionnaire. Urology 1999; 54: 461–6.

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2358. Harvey MA, Kristjansson B, Griffith D et al. The Incontinence Impact Questionnaire and the Urogenital Distress Inventory: A revisit of their validity in women without a urodynamic diagnosis. Am J Obstet Gynecol 2001; 185: 25–31. 2359. Caruso DJ, Kanagarajah P, Cohen BL et al. What is the p ­ redictive value  of urodynamics to reproduce clinical findings of urinary frequency, urge urinary incontinence, and/or stress urinary ­ ­incontinence? Int Urogynecol J. 2010; 21(10): 1205–9. 2360. Barry MJ, Fowler FJ Jr, O’Leary MP et al. The American Urological Association symptom index for benign prostatic hyperplasia. J Urol 1992; 148: 1549–57. 2361. Uebersax JS, Wyman FF, Shumaker SA et al. Short forms to assess life quality and symptom distress for urinary incontinence in women: The incontinence impact questionnaire and urogenital distress inventory. Neurourol Urodyn 1995; 14: 131–9. 2362. Sakakibara R, Shinotoh H, Uchiyama T et al. Questionnaire-based assessment of pelvic organ dysfunction in Parkinson’s disease. Auton Neurosci 2001; 92: 76–85. 2363. Cuidin A, Franco A, Diaconu MG et al. Quality of life of multiple sclerosis patients: Translation and validation of the Spanish version of Qualiveen. Neurourol Urodyn 2012; 31: 17–20. 2364. Castel-Lacanal E, Game X, De Boissezon X et al. Impact of intermittent catheterization on the quality of life of multiple sclerosis patients. World J Urol2013; doi: 10.1007/s00345-012-1017-8. 2365. Bonniaud V, Bryant D, Parratte B et al. Development and validation of the short form of a urinary quality of life questionnaire: SF-Qualiveen. J Urol 2008; 180: 2592–8. 2366. Palleschi G, Pastore AL, Stocchi F et al. Correlation between the Overactive Bladder questionnaire (OAB-q) and urodynamic data of Parkinson disease patients affected by neurogenic detrusor overactivity during antimuscarinic treatment. Clin Neuropharmacol 2006; 29: 220–9. 2367. Lundberg PO, Hutler B. Female sexual dysfunction in multiple sclerosis: A review. Sex Dis 1996; 14: 65–72. 2368. Aisen ML, Sanders AS. Sexual dysfunction in neurologic disease: Mechanisms of disease and counseling approaches. AUA Update Series 1998: 17: 274–9. 2369. Fletcher SG, Castro-Borrero W, Remington G et al. Sexual dysfunction in patients with multiple sclerosis: A multidisciplinary approach to evaluation and management. Nat Clin Pract Urol 2009; 6: 96–107. 2370. Forsythe E, Horsewell JE. Sexual rehabilitation of women with a spinal cord injury. Spinal Cord 2006; 44: 234–41. 2371. Tapia CI, Khalaf K, Berenson K et al. Health-related quality of life and economic impact of urinary incontinence due to detrusor overactivity associated with a neurologic condition: A systematic review. Health Qual Life Outcomes 2013; 11: 13, doi: 10.1186/1477-7525-11-13. 2372. Krause JS, Sanders LL. Risk of mortality and life expectancy after spinal cord injury: The role of health behaviors and participation. Top Spinal Cord Inj Rehabil 2010; 16(2): 53–6, doi: 10.1319/sci1602-53. 2373. Betts CD, D’ Mellow MT, Fowler CJ. Urinary symptoms and the neurological features of bladder dysfunction in multiple sclerosis. J Neurol Neurosurg Psychiatry1993; 56(3): 245–50. 2374. Amarenco G, Guinet A, Jousse M et al. Pencil and paper test: A new tool to predict the ability of neurological patients to practice clean intermittent self-catheterization. J Urol 2011; 185: 678–82.

30 The voiding diary Matthew Young and Eric S. Rovner

Introduction The International Continence Society describes lower urinary tract symptoms (LUTS) as the subjective indicator of a disease or change in condition as perceived by the patient, caregiver, or partner that may lead him/ her to seek care from healthcare professionals.1 These symptoms, however, are usually qualitative and cannot be reliably used to make a definitive diagnosis and care plan. Various clinical tools are available ranging from simple to complex, including a thorough history, physical examination, symptom questionnaires, voiding diaries, pad tests, uroflowmetry, postvoid residual measurements, and urodynamics. The voiding diary is a simple, noninvasive method to objectively quantify a patient’s usual voiding behavior. Its utility as a diagnostic tool is not limited to initial quantification of symptoms, but can be used to follow the effectiveness of treatments and is considered to be a foundation in the initial management of the neurogenic patient.2 It is notable that there exists very little normative data for diary parameters specifically in the neurogenic population. Furthermore, although it is widely used and advocated as a diagnostic, management, and outcomes assessment tool, there is only sparse literature supporting its use in such a manner. Nevertheless it is well accepted in this population and its utility is underscored by its use as a primary or secondary outcome parameter by most regulatory bodies in the evaluation of therapies for urinary incontinence.3 This chapter will review the utility of the voiding diary in the non-neurogenic as well as the neurogenic population where appropriate.

Definitions The 2009 Fourth International Consultation on Incontin­ ence (ICI) describes three types of diaries ranging from simple to more complex:

1. Micturition time chart: Includes only frequency of voiding and incontinence episodes (diurnal and nocturnal) 2. Frequency–volume chart: Includes the frequency of voids along with the voided volumes 3. Bladder diary: Includes frequency of voiding, incontinence episodes (diurnal and nocturnal), voided volumes, and type and quantity of volume intake (Figure 30.1) Although there was no consensus at the Fourth ICI on the type of diary to be used, it was highly suggested that the length of evaluation of LUTS should be at least 24 hours.4

Diary characteristics As voiding symptoms are inherently a perceived measure qualitatively described by patients, there is no consensus to “normal” parameters found on voiding diaries in the neurogenic and non-neurogenic populations. Indeed, all the parameters recorded on a diary are strongly influenced not only by the intrinsic function and anatomy of the lower urinary tract but also importantly by a number of factors outside the lower urinary tract and pelvis including fluid intake, ambient environmental temperature, type of fluid consumed, physical activity and availability, and convenience of toileting facilities as well as other factors. Fitzgerald and Brubaker5 studied the voiding patterns of 137 asymptomatic women using a 24-hour voiding diary and found high variability in this population in the number of voids, individual voided volumes, and total voided volumes. Likewise, Latini et al. performed a similar study on 284 asymptomatic men in an attempt to define an abnormal value for urinary frequency. This study, too, found a large range in asymptomatic men in fluid intake, urine volume, and frequency. In fact, by setting a threshold of 8 to define urinary frequency, more than 1/3 of

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Textbook of the Neurogenic Bladder Time of day

7 AM 8 AM 9 AM 10 AM 11 AM 12 PM 1 PM 2 PM 3 PM 4 PM 5 PM 6 PM 7 PM 8 PM 9 PM 10 PM 11 PM 12 AM 1 AM 2 AM 3 AM 4 AM 5 AM 6 AM Total for 24 hours

Amount of urine voided (oz or mL)

Amount of fluid (drinks) intake (oz or mL)

Type of fluid consumed (water, coffee, soda, beer, etc.)

10 oz 16 oz/12 oz

Cranberry juice Coffee/Ginger Ale

600 mL

4 oz

Water

8 oz

Water

16 oz 12 oz 4 oz

Lemonade Ginger Ale Water

4 oz

Water

400 mL

200 mL

600 mL 16 oz

Leakage of urine (incontinence) at any time prior to voiding? (yes or no)

Yes

Yes

Yes

Yes

Yes Yes

No No

Yes

Yes

No

No

Lemonade

200 mL

2000 mL

Urgency or pain before voiding? (yes or no)

102 oz

Please indicate the time that you went to bed: Please indicate the time that you woke up:

10 PM 6 AM

Figure 30.1 Twenty-four-hour voiding diary sample.

their asymptomatic males would have been defined as abnormal.6 These studies illustrate the importance of the subjective perception of bother and stress for patients in conjunction with objective data found using a noninvasive voiding diary when defining and treating LUTS. There are several lengths of voiding diaries that can be used in the evaluation of LUTS. Studies have used diaries ranging from 1 to 7 days, with the most common diaries used being the 1 and 3 day diaries. Regulatory bodies often recommend a 3–7 day diary, whereas for clinical use, generally a 1–3 day diary is used. As mentioned previously, the fourth ICI strongly recommends using at least a 1-day diary, whether it is a bladder diary or a frequency volume chart, to accurately evaluate urinary incontinence and LUTS. Important features for a 24-hour voiding diary (Figure 30.1) include recording the time of day when he/ she awakes as well as when he/she goes to sleep at night so as to get an accurate differentiation between diurnal and nocturnal voids. It is important to specifically define bedtime as the time at which the patient lays down to sleep with the intention of sleeping for night and wake up as

the time the patient awakens from sleep (not necessarily gets out of bed) with the intention of staying awake for the reminder of the day. These simple but important definitions can skew the accuracy of a diary in patient populations such as those working night shifts. Other important features of a 24-hour voiding diary include fluid intake, type of fluid, number of voids, urgency associated with voids, voided volumes, and incontinent episodes. Similarly, a 72-hour voiding diary contains these parameters, but is continued for a 72-hour consecutive period. Multiple tests have shown that the test–retest reliability increases as the duration of the voiding diary increases. Groutz reviewed 109 patients undergoing 24-, 48-, and 72-hour voiding diaries, assessing the test–retest reliability of strictly the number of incontinence episodes and total number of voids. It was found that for a 24-hour voiding diary, the number of incontinence episodes was reliable, but the number of voiding episodes was only marginally reliable. For the 48-hour diary, the number of incontinence and voiding episodes were reliable, but as the diary was increased to 72 hours, these parameters became highly reliable. Importantly, the

The voiding diary study found that as the duration of the study was inversely related to patient compliance, the 72-hour voiding diary is having the worst compliance.7 It is generally agreed that the accuracy of the information obtained in the diary is proportional to the length of the diary; however, patient compliance with completion of the diary is inversely related to the length of the diary in days. Brown further showed that a 7-day diary is highly reliable when recording episodes of urgency, urge incontinence, and micturitions. Within a subgroup analysis it was found there was no significant difference in the reliability of a 3- or 4-day voiding diary when compared to the 7-day diary. This study concluded that advantages of a 3-day diary could include increased patient compliance as well as decreased heterogeneity among recorded days as the diary did not span both weekends and weekdays.8 As with any instrument, the voiding diary is not a perfect tool for the diagnosis of lower tract symptoms. The diary does not account for postvoid residuals or bladder pressure (both storage and voiding), which can be critically important especially in association with the risk of upper tract deterioration in the neurogenic population. Another important limitation of the voiding diary is that patients may modify their behavior once assigned to complete a voiding diary, in essence nullifying the validity of the test.

Catheterization diary In the neurogenic population, especially those with spinal lesions and peripheral nerve lesions, bladder emptying failure is common. Such patients are often managed with intermittent urethral catheterization, with or without voiding between catheterizations. Catheterization diaries are used in these patients in the same manner as the voiding diary in the non-neurogenic population. Parameters recorded on the catheterization diary include time and volume of urine obtained at catheterization, as well as the same values obtained for any voids between catheterizations. In neurogenic populations with preserved sensation, urgency episodes may also be recorded. As noted below, comparison of the catheterized volumes to the volumes obtained during pressure flow urodynamics, especially in patients with impaired bladder compliance, may be very useful in assessing prognosis and directing therapy.

Utility of the voiding diary Diagnostic An extensive history and physical examination are critical tools in the evaluation of incontinence and LUTS. However, the bladder has been termed an “unreliable witness” and as such patient recall is often inaccurate when discussing individual symptoms.9 It has been estimated that over half of patients will overestimate daytime

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urinary frequency when comparing subjective symptoms to objective findings on voiding diaries.10 Voiding diaries are most helpful and reliable in measuring urgency, urge incontinence, and frequency.8 Unfortunately, to date, no information on the reliability of the voiding diary in neurogenic incontinence has been published.4

Prognostic Although there are some deficiencies in the quality and quantity of data that can be obtained using a voiding diary, some very important prognostic information can be gathered from this test. Studies have suggested that maximum voided volumes correlate well with cystometric capacity, especially effective capacity in non-­neurogenic males.11 In the neurogenic population, a catheterized or voiding diary is essential. If a catheterization diary suggests that a patient does not reach volumes where measured urodynamic compliance become dangerous, then the prognosis for renal function is probably good. On the contrary, in patients with decreased bladder compliance, the filling pressures may exceed a safe range during urinary storage. This is particularly troubling in patients with compromised sensory function, which is not an uncommon scenario in the neurogenic population. These individuals may have an impaired ability to sense elevated pressures and such pressures are potentially detrimental to the upper urinary tract if left untreated. Catheterization diaries interpreted in the context of the filling pressures on cystometry permit an assessment of ambient intravesical pressure at the volumes seen at the time of catheterization. In those circumstances where catheterization volumes exceed the volume at which filling pressures become unsafe on the cystometrogram, appropriate alterations in management of the lower urinary tract should be initiated.

Therapeutic Behavioral interventions have proven to be effective in the treatment of conditions such as overactive bladder and urge urinary incontinence. A voiding diary can be an excellent tool in helping to identify dietary bladder irritants, abnormal volume intake, or abnormal voiding intervals. In turn, these symptoms can be successfully treated using simple behavior modifications.12 Finally, voiding diaries not only assist clinicians in the assessment of LUTS but also permit the assessment of the effectiveness of treatments such as behavioral therapy, oral medications, sacral nerve stimulation, or botulinum toxin A injection. Clinically, a baseline diary as compared to a subsequent voiding diary following initiation of therapy is often helpful in quantifying the success of therapy. For example, following pharmacological intervention for urinary incontinence voiding diary parameters such as urgency, frequency, and incontinence episodes would be expected to decrease while voided volume per void would

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be expected to increase. As noted previously, such a use of diaries has been also been promoted by regulatory authorities as a primary or secondary outcome measure during the approval process in the both the non-neurogenic and neurogenic patient populations.3

References 2375. Abrams A, Cardozo L, Fall M et al. The standardization of terminology in lower urinary tract function: Report from the standardization sub-committee of the International Continence Society. Urology 2003; 61: 37–49. 2376. Panicker JN, de Sèze M, Fowler CJ. Neurogenic lower urinary tract dysfunction. Handb Clin Neurol 2013; 110: 209–20. 2377. U.S. Food and Drug Administration. Guidance for Industry and FDA Staff—Clinical Investigations of Devices Indicated for the Treatment of Urinary Incontinence. March 8, 2011. http://www.fda.gov /­medicaldevices/deviceregulationandguidance/­guidancedocuments /ucm070852.htm#5m. 2378. Abrams P, Cardozo L, Khoury S et al. Incontinence. Paris, France: Health Publications, 2009. 2379. Fitzgerald MP, Brubaker L. Variability of 24-hour voiding diary variables among asymptomatic women. J Urol 2003; 169: 207–9.

2380. Latinin JM, Mueller E, Lux MM et al. Voiding frequency in a sample of asymptomatic American men. J Urol 2004; 172(3): 980–4. 2381. Groutz A, Blaivas JG, Chaikin DC et al. Noninvasive outcome measures of urinary incontinence and lower urinary tract symptoms: A multicenter study of micturition diary and pad tests. J Urol 2000; 164: 698–701. 2382. Brown JS, McNaughton KS, Wyman JF et al. Measurement characteristics of a voiding diary for use by men and women with overactive bladder. Urology 2003; 61: 802–9. 2383. Turner-Warwick R, Whiteside CG, Worth PH et al. A urodynamic view of the clinical problems associated with bladder neck dysfunction and its treatment by endoscopic incision and trans-trigonal posterior prostatectomy. Br J Urol 1973; 45: 44–59. 2384. Stav K, Dwyer PL, Rosamilia A. Women overestimate daytime urinary frequency: The importance of the bladder diary. Journal Urol 2009; 181(5): 2176–80. 2385. van Vernrooij GE, Eckhardt MD, Gisolf KW et al. Data from frequency-volume charts versus filling cystometric estimated ­ capacities and prevalence of instability in men with lower urinary tract symptoms suggestive of benign prostatic hyperplasia. Neurol Urodynam 2002; 21(2): 106–111. 2386. Wyman JF, Burgio KL, Newman DK. Practical aspects of lifestyle modifications and behavioral interventions in the treatment of overactive bladder and urgency urinary incontinence. Int J Clin Pract 2009; 63(8): 1177–91.

31 The pad-weighing test Matthew Young and Eric S. Rovner

Introduction Urinary incontinence (UI), regardless of etiology, is a common condition that can cause significant social ­distress to both men and women. Subjective measurements of ­incontinence can be obtained using a thorough history, obtaining a voiding diary, or through patient recall questionnaires. The pad test is a noninvasive, inexpensive tool to acquire objective data vital in confirming the diagnosis of incontinence, assessing its severity, and aiding in the treatment pathway needed. Pad tests may be used as a diagnostic and outcomes tool in both neurogenic and n ­ on-neurogenic patients. Currently, it is used both clinically as well as an outcomes assessment measure by ­regulatory authorities in the evaluation and approval process for UI interventions.1 As there is little data on the utility of pad tests specifically in the neurogenic population, this chapter will emphasize its use in the non-neurogenic population.

Definition The 4th International Consultation on Incontinence (ICI) defines a pad test as a diagnostic method to detect and quantify urine loss based on weight gain of absorbent pads during a test period under standardized conditions.2 Pad tests can be divided into two groups: quantitative and qualitative. Quantitative pad are used to measure the amount of urine leakage during a set period after executing either a standardized set of activities or a normal daily routine. These tests can range from short-time pad tests done in the office to home-based pad tests, which are typically longer in duration. In contrast, qualitative pad tests typically are used to detect the presence of UI when the diagnosis is in doubt or requires objective confirmation. Such tests use a colored dye, either administered directly into the bladder or given orally or parentally, which stains the urine a predetermined color allowing the examination of the pad to assess for the presence of urine leakage. These tests are often

helpful in diagnosing fistulas from the urinary tract to the vagina but may lack the ability to quantify the amount or volume of incontinence if used in the short term.

Quantitative pad test Regardless of the duration of the test, a pad test is performed by weighing pads after a set period or activity to determine the total amount of urine leakage. It is essential (especially in the home-based testing) that the patient brings a dry pad to account for its contribution to the total weight. Leakage is calculated as follows: Total leakage = Total weight of pad(s) – (Weight of one dry pad × Number of pads used) Defining continence is difficult, as it is not a universally well-understood term among patients. For example, some patients may feel that using 0–1 pads per day is continent, while others may feel that a single drop of fluid of any kind justifies the label of incontinence. Pads may be used by patients for many reasons other than collecting UI, including menstrual flow, vaginal discharge, “sanitary” reasons, or “just in case.” Several studies have been conducted to try to determine a “normal” value of urine leakage during a 24-hour period. Ryhammer et al.3 reported a mean pad test result of 3.1 g in postmenopausal continent women while Lose reported approximately 4 g in a similar study on continent women ranging from 34- to 69-years of age.4 Other investigators have published normal pad test weights ranging from 0 to 15g, highlighting the importance of social and hygienic distress in defining and treating incontinence. The definition of an abnormal pad test according to the proceedings of the 4th ICI is >1 g weight gain on a structured 1-hour pad test, and >1.3 g weight gain on a 24-hour pad test.2 Pad tests are not 100% sensitive or specific to UI. False positives can arise in situations of excessive vaginal secretions or menstrual flow, especially in younger women. In addition, the sensitivity of individual scales may affect pad weight resulting with respect to false negative results.

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Office- and home-based pad testing As mentioned earlier, there are multiple versions of the pad test based on length of time as well as activity. The variability, in general, can be divided into office-based or home-based pad tests.

first reported a very weak correlation coefficient of .68 in a test–retest study of the 1-hour pad test, showing wide variation in at least 50% of the patients.9 Later, the test was refined by starting with a standardized bladder volume (50% of the cystometric bladder volume) and was found to be much more reliable (r = .97).10 The most valuable use of the 1-hour pad test seems to be in monitoring changes after surgical or medical intervention.11–13

Office-based pad test

Home-based pad test

Office-based pad tests can range from 15 minutes to 2 hours and are advantageous in that they are often easy, quick, and can provide immediate information. Disadvantages are that they are performed under standardized conditions and do not necessarily capture a patient’s normal daily activity.5 Short pad tests can differ somewhat, but typically involve emptying a patient’s bladder by catheterization, followed by the instillation of a specified amount of fluid. The patient is then asked to perform a number of exercises for a specified length of time (usually less than 1 hour) meant to mimic normal daily activity. The pads are then weighed for evidence of any urine leakage.2 The validity of this test is somewhat controversial, as some groups have published results showing no correlation between short pad tests and the degree of continence6 while others have shown it to be more sensitive for stress UI as compared to a 1-hour pad test.5 Likewise, the reproducibility of this short test ranges from low to high. The 1-hour pad test is a variation on the short pad test, but is done for a longer duration and is more standardized. As with the short pad test, the 1-hour pad test is meant to simulate home incontinence by standardizing activities done in the office.7 This test was first made uniform by Abrams in 1988 and is performed as follows:

Home-based pad tests were developed to most closely resemble a patient’s daily activity and therefore more closely capture his or her true severity of incontinence. The most common adaptation of this test is the 24-hour pad test, but both 12- and 48-hour tests can be implemented if warranted. Twenty-four-hour pad tests are performed by asking the patient to wear a pad(s) while performing normal daily activities for a full day, including sleep. These pads are then brought to the office, along with a dry pad of the same type, which are weighed and total leakage is calculated as described earlier. It is strongly recommended that patients perform a voiding diary along with this test to help correlate activities, urge, and volume intake with incontinence episodes. Lose et al. found a high correlation between a 24-hour pad test and the history of stress incontinence.4 Various studies have shown high test–retest reliability with correlation coefficients ranging from .82 to .9 in populations that included stress UI and severe lower urinary tract symptoms.4,14 Matharu et al.15 examined 341 women reporting lower urinary tract symptoms and compared the reported pad test leakage with urodynamic findings. This study suggested a higher volume of leakage in those patients with urodynamic confirmed diagnoses of stress or mixed UI when compared to those with detrusor overactivity. Given the reliability of the 24-hour pad test when compared to office-based pad tests, it is often considered the gold standard for quantification of UI.

1. Test starts without the patient voiding. 2. Patient puts on the first pad, and the hour time is started. 3. Patient drinks 500 cc of sodium-free liquid within 15 minutes, then rests. 4. In the following 30 minutes, patient walks, including climbing up and down at least 1 flight of stairs. 5. During the remaining time, the patient must stand from a sitting position 10 times, cough 10 times, run in place for 1 minute, bend over to pick up an object from the floor 5 times, and wash his/her hands in running water for 1 minute. 6. Pads are collected and weighed. 7. Patient urinates and this volume is recorded.8 As with other office-based pad tests, the reported reproducibility of this test ranges from high to low. Lose et al.

Diagnosis of urinary incontinence The ability of the pad test to differentiate diagnostically between different types of UI (i.e., stress vs. urge) is controversial. It was previously thought that higher volumes of UI were indicative of urge urinary incontinence (UUI) over stress urinary incontinence. While it may be true the there is a trend toward higher volumes of UI in UUI, there have been no studies to prove such a correlation. In fact, most research in UI has moved away from the pad test as a diagnostic tool and toward its use as a connection between patient perception and reality.

The pad-weighing test

Pyridium pad test The pyridium pad test is a qualitative counterpart to the quantitative pad test. It is performed by asking a patient to take phenazopyridine hydrochloride (pyridium), a medication that turns the urine orange. The patient then wears a pad for the next 24 hours while performing ­normal daily activities. This test is considered positive if there is any orange staining seen on the pad(s). Wall et al. showed 100% sensitivity in symptomatic patients with stress urinary incontinence when using the pyridium pad test. However, the group found a 52% false-positive rate in healthy, asymptomatic continent women. They concluded that the addition of pyridium to a standard pad weighing test was not useful, and may in fact be ­misleading.16 Important causes of a false-positive pyridium pad test are postvoid dribbling and vaginal voiding. Patients undergoing this test should be counseled to lean forward on the commode following the completion of a void and thoroughly wash the vaginal introitus before applying a pad test to avoid a false-positive test.

4th ICI recommendations 1. The pad test is an optional investigative tool in routine evaluation of UI. 2. Pad test is a useful outcome measure in clinical trials and research studies. 3. A 20-minute to 1-hour ward test with fixed bladder volume (pad weight gain ≥ 1 g = positive test). 4. A 24-hour home-based pad test during daily activity (pad weight gain ≥ 1.3 g/24 h = positive test).2

References 2387. U.S. Food and Drug Administration. Guidance for Industry and FDA Staff—Clinical Investigations of Devices Indicated for the Treatment of Urinary Incontinence. March 8, 2011. http:// www.fda.gov/­m edicaldevices/deviceregulationandguidance /­guidancedocuments/ucm070852.htm#5m. 2388. Abrams P, Cardozo L, Khoury S et al. Incontinence, 4th ed. Health Publications Ltd, 2009,

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2389. Ryhammer AM, Laurberg S, Djurhuus JC et al. No relationship between subjective assessment of urinary incontinence and pad test weight gain in a random population sample of menopausal women. J Urol 1998; 159(3): 800–3. 2390. Lose G, Jorgensen L, Thunedborg P. 24-h home pad weighing test versus 1-hour ward test in the assessment of mild stress incontinence. Acta Obstet Gynecol Scand 1989; 68(3): 211–5. 2391. Wu W, Sheu B, Lin H. Comparison of 20-minute pad test versus 1-hour pad test in women with stress urinary incontinence. Urology 2006; 68: 764–8. 2392. Kinn AC, Larsson B. Pad test with fixed bladder volume in urinary stress incontinence. Acta Obstet Gynecol Scand 1987; 66(4): 369–71. 2393. Ryhammer AM, Djurhuus JC, Laurberg S. Pad testing in incontinent women: A review. Int Urogynecol J 1999; 10: 111–5. 2394. Abrams P, Blaivas JG, Stanton SL. The standardization of terminology of lower urinary tract function. The International Continence Society Committee on Standardization of Terminology. Scan J Urol Nephrol 1988; 114(Suppl): 5–19. 2395. Lose G, Gammelgaard J, Jorgensen TJ. The 1-hour pad-weighing test: Reproducibility and the correlation between the test result, the start volume in the bladder, and the diuresis. Neurology and Urodynamics 1986; 5(1): 17–21. 2396. Lose G, Rosenkilde P, Gammelgaard J et al. Pad-weighing test performed with standardized bladder volume. Urology 1988; 32(1): 78–80. 2397. Floratos DL, Sonke GS, Rapidou CA et al. Biofeedback vs. verbal feedback as learning tools for pelvic muscle exercises in the early management of urinary incontinence after radical prostatectomy. BJU Int 2002; 89(7): 714–9. 2398. Ward KL, Hilton P. A prospective multicenter randomized trial of tension-free vaginal tape and colposuspension for primary urodynamic stress incontinence: Two-year follow-up. Am J Obstet Gynecol 2004; 190(2): 324–31. 2399. Bladwell AL, Yoong W, Moore KH. Criterion validity, test-retest reliability and sensitivity to change of the St George Urinary Incontinence Score. BJU Int 2004; 93(3): 331–5. 2400. Versi E, Orrego G, Hardy E et al. Evaluation of the home pad test in the investigation of female urinary incontinence. Br J Obstet Gynaecol 1996; 103(2): 162–7. 2401. Matharu GS, Assassa RP, Williams KS et al. Objective Assessment of Urinary Incontinence in women: Comparison of the one-hour and 24-hour pad tests. Eur Urol 2004; 45: 208–12. 2402. Wall LL, Wang K, Robson I et al. The pyridium pad test for diagnosing urinary incontinence. A comparative study of asymptomatic and incontinent women. J Reprod Med 1990; 35(7): 682–4.

32 Endoscopic evaluation of neurogenic bladder Romain Caremel, Saad Aldousari, and Jacques Corcos

Introduction Urethrocystoscopy is not useful in the initial evaluation of neurogenic bladder, but becomes very instrumental in the assessment of lower urinary tract complications. Urethrocystoscopy cannot, by any means, give information on lower urinary tract function. For example, external sphincter contractions and relaxation observed during voluntary movement do not reflect the real functional value of this complex unit. Another classic example is the examination of endoscopic aspects of the bladder neck, which cannot replace functional studies for the evaluation of its opening and closing. Urethrocystoscopy helps in the appraisal of urethral and bladder anatomic anomalies, most of the time secondary to complications such as urethral strictures, trabeculations, bladder stones, and diverticula. The aim of this chapter is to review these different aspects with some illustrations.

Figure 32.1 Rigid cystoscope.

Equipment Different companies offer different types and sizes of  extremely well-designed, rigid urethrocystoscopes (Figure  32.1), some with fixed lens (12°–70°), others with exchangeable lens (0°, 30°, 70°, 120°). The choice of lens depends on the segment of urinary tract that we want to study: 0° or 30° for the urethra and 70° or 120° for the bladder in general. Since sensitivity is often not a problem in neurogenic bladder patients, rigid urethrocystoscopes are often preferred. They give a much better optical field than flexible cystoscopes (Figure 32.2) and allow various manipulations through a bigger working channel (irrigation, washing, small-stone extraction, etc.). Flexible cystoscopes are extremely useful in men with preserved sensitivity, and the test is usually painless. In our experience, we do not use any local anesthetic, but only lubricating jelly. Others prefer to inject 2% Xylocaine (lidocaine) jelly transurethrally 2–4 minutes before the procedure. One of the biggest advantages

Figure 32.2 Flexible cystoscope.

of these cystoscopes is the possibility of introducing them in a supine as well as in a sitting position. Because of their deflection abilities, they allow a retrograde view of the bladder neck as well as the complete exploration of diverticulae, whatever the position.

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Technique Most of the time, the patient is installed in the lithotomy position, but, as mentioned earlier, a supine or a sitting position can be used with a flexible cystoscope. After the usual disinfection of the genitalia with a nonalcoholic solution, draping creates a sterile field around the genitalia. Once the patient is informed of the beginning of the examination, the cystoscope, lubricated with sterile jelly, is very gently introduced into the meatus. A global view of the urethra permits the confirmation of penile urethra integrity in men. The cystoscope is then pushed forward into the membranous urethra, making the external sphincter visible. This concentric muscle closes the urethra, and can usually be passed by gentle pressure on the cystoscope. The prostatic urethra is then observed, and the anatomy of the prostate is then noted, mainly the size of the lateral lobes and the presence or absence of a median lobe. Once into the bladder, the technique is slightly different, depending on the type of cystoscope. With a rigid cystoscope, we normally use a 70° or 120° lens. The instrument will have only in–out and rotating motions, allowing a complete view of the bladder without bending the unit, which may cause unnecessary pain and discomfort. With a flexible cystoscope, the same in–out motion is applied, but the rotation motion is replaced by deflections of the instrument’s tip, which gives a complete view of the bladder wall. Observation of the ureteral orifices, urine efflux from these orifices, and exploration of bladder diverticulae may be necessary. Washings, biopsies, and so on are performed at that time if indicated. Once the test is completed, the instrument is gently withdrawn after emptying the bladder (when using a rigid instrument). Drinking up to 6–8 glasses of water per day for 3 days is usually recommended and the patient is discharged. No antibiotics are required unless the patient has an artificial heart valve or it is considered necessary by the physician.

Figure 32.3 Urethral stricture.

Figure 32.4 Urethral stricture.

Urethrocystoscopic findings Urethral abnormalities Urethral strictures Indwelling catheters, multiple endoscopic manipulations, intermittent catheterizations, and neurogenic trophicity changes lead to frequent urethral strictures and false passages (Figures 32.3 and 32.4). For instance, in Goteborg, Sweden, a study was carried out to identify complications of clean intermittent catheterization in males and young boys with neurogenic bladder dysfunction. Major urethral lesions were seen on cystoscopy, and included urethral stricture, false passages, and meatal stenosis.1

Bladder neck cystoscopic evaluation The degree of opening of the neurogenic bladder neck cannot be adequately evaluated by cystoscopy. False results can be induced by irrigation flow. These changes are dynamic and not anatomic. They should be evaluated by videourodynamic or simple voiding cystogram. In fact, a voiding cystourethrography (VCUG) might provide a tremendous amount of information useful in identifying multiple complications such as trabeculations, sacculations, diverticulae, vesicoureteric reflux, and postvoid residual, as well as the bladder’s ability to empty.2 However, after bladder neck incision or resection to decrease bladder neck resistance, bladder neck strictures can be easily seen by cystoscopy, but, here again, their real impact on bladder function can be assessed only by voiding cystogram.

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Endoscopic evaluation of urethral stents Some specialized centers no longer perform incisional sphincterotomies, preferring endoluminal stents instead (i.e., Urolume—AMS). The techniques and results with these stents are detailed in Chapter 49. It is usually easy to introduce a flexible cystoscope through these stents, which “disappear” completely after a few months as the device is epithelialized through and in between its pores: 90%–100% of epithelialization of the stent has been demonstrated in 47.1% of cases 3 months after insertion, and in 87.7% of cases 12 months after insertion. Mild epithelial hyperplasia can occur (34%–44.4%) after stent insertion and may look like an obstructed urethra. Much less frequently, these strictures are severe (3.1%), requiring urethrotomy and sometimes insertion of a second stent at the same level as the first.3 Occasionally, however, and even several years later, part of the stent may remain visible, but usually does not cause any problem. Calcifications of the stents are rare. No stone formation has been reported.3 A study was carried out by Denys and colleagues,4 to evaluate another type of urethral stent, the Ultraflex, for detrusor sphincter dyssynergia. In that study, endoscopic evaluation proved to be very valuable. The mean follow-up of 39 patients was 1.73 ± 1.11 years. No stone encrustation or stenosis of stent extremities was observed. Nonobstructive granulation tissue was identified in 6.8%. The mean percentage of epithelialization of the stent was 90.8% ± 19.7%. No migration of the stent into the bladder was seen in that study, however, minimal displacement of the stent compared to the initial position was observed in 21.7% of cases.

Figure 32.5 Normal bladder mucosa.

Structural bladder anomalies The well-balanced bladder of a patient compliant with therapy looks normal (Figure 32.5) most of the time. However, it may show significant changes because of patient noncompliance with intermittent catheterization, medication, and so on, or because these treatments may have no effect.

Bladder wall abnormalities Often associated with chronic infections but also often not related to any obvious disease, cystitis glandularis (Figure 32.6) and cystitis follicularis (Figure 32.7) can be found during systematic cystoscopic evaluation.

Bladder wall trabeculations There is no consensus in the literature regarding the significance of bladder wall trabeculations (Figures 32.8 through 32.11). O’Donnell5 suggested that they could be related to high bladder pressure.3 To Brocklehurst,6 McGuire,7 Shah,8 and O’Reilly 9 they are secondary to an

Figure 32.6 Cystitis glandularis.

infravesical obstruction. More authors believe that trabeculations reflect bladder overactivity and uninhibited contractions. Schick and Tessier10 studied the correlation between the endoscopic aspects of bladder walls and urodynamic parameters in 220 women. They concluded that there is a close correlation between trabeculation grade and the percentage of unstable bladders (Figure 32.12).

Ureteral orifices High bladder pressure, recurrent infections, and changes in bladder wall thickness may provoke alterations in the shape of the ureteral orifices. In some cases, they can look wide open. Their appearance cannot preclude the efficacy

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Figure 32.7 Cystitis follicularis.

Figure 32.10 Trabeculation grade 3.

Figure 32.8 Trabeculation grade 1.

Figure 32.11 Trabeculation grade 4.

of the intramural ureteral valve mechanism and the presence of reflux. Reflux can be diagnosed only by cystogram with a contrast agent or a radioisotope fluid. Ureterocele can be of variable size (Figure 32.13).

Tumors, stones, and foreign bodies Bladder stones Figure 32.9 Trabeculation grade 2.

Usually secondary to infections, bladder stones are very frequent findings in neurogenic patients. They must be suspected in cases of recurrent Proteus mirabilis infections,

Endoscopic evaluation of neurogenic bladder 100

Stable bladder Unstable bladder

80 % Patients

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60 40 20 0

Grade 0

Grade I

Grade II Grade III Trabeculation

Grade IV

Figure 32.12 Correlation between the trabeculation grade and percentage of unstable bladders.

Figure 32.14 Bladder stone.

Figure 32.13 Ureterocele.

increased spasticity or incontinence, elimination of small calcified fragments, and so on. They are easy to diagnose by cystoscopy, and sometimes can be crushed for removal in the same setup. Their aspects are extremely variable, from small, round, single, or multiple stones to huge “egglike” stones (Figures 32.14 and 32.15).

Bladder tumors Patients with chronic indwelling catheters must undergo annual cystoscopic evaluation. Usually, this routine starts after 5 years of continuous indwelling catheterization. Cystoscopy remains the only way (with cytology) to detect suspicious lesions such as bladder carcinoma. Usually, these lesions start at the level of the trigone, where the catheter and the balloon lie down. In these patients, there is almost always a small reddish area, which is difficult to differentiate from an early carcinoma (Figure 32.16). Biopsy of these lesions

Figure 32.15 Bladder stone.

is a simple way of reassuring the physician and patient. Bladder tumors can be located anywhere in the bladder and have d ­ ifferent aspects, but most frequently papillary (Figure  32.17). Much less frequent are urethral tumors (Figure 32.18).

Foreign bodies Foreign bodies are rare. Not infrequently, hairs can be found in patients with intermittent catheterization. Sometimes, they start to be calcified, and always have to be removed. Even less frequently are iatrogenic foreign bodies. Pieces of Foley catheter balloons or sutures from urologic or nonurologic procedures are eroded into the bladder (Figures 32.19 and 32.20).

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Special considerations Suprapubic tubes Patients with urinary drainage from a suprapubic catheter deserve special mention based on the additional clinical scenarios and technical aspects associated with evaluation of the lower urinary tract. Indications for cystourethroscopy

Figure 32.16

include regular inspection for bladder stones and surveillance for bladder tumors in patients with suprapubic catheters for more than 5–10 years. Endoscopy may be performed per urethra (when patent) or through the suprapubic tract. Navigation and visualization of the suprapubic tract is usually straightforward in patients with normal body habitus and a mature urinary tract. Conversely, immature urinary tracts or those traversing a large mobile pannus may be difficult to follow. When these situations occur, it is helpful to place a wire through the suprapubic tract into the urinary bladder to guide the endoscope during inspection. The wire can be backloaded into the working channel to further guide the endoscope. Rigid cystoscopes may fit into large mature-urinary tracts and are advantageous when ancillary procedures are indicated, but they may be difficult to maneuver in long urinary tracts, and orientation in the bladder can be challenging. Flexible cystoscopes offer

Figure 32.18

Mucosal catheter reaction.

Urethral papillary tumor.

Figure 32.17

Figure 32.19

Bladder papillary tumor (partially calcified).

Stitch eroding the bladder wall.

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(e.g.,  a  flexible ureteroscope), but if ancillary procedures are indicated, percutaneous access should be used. Similarly, percutaneous access for interventions other than simple diagnostic procedures in orthotopic neobladders may avoid the risk of bladder neck contracture or sphincteric damage. In both types of diversions, orientation and visualization can be impaired by mucus and debris, bowel peristalsis, mucosal folding, and tortuous afferent limbs. Steps to overcome these difficulties include thorough irrigation and use of fluoroscopy with intravesical administration of a contrast agent to identify the os of the afferent limb and guide endoscope advancement. When present, afferent limbs are best visualized with flexible endoscopes because they are best suited to navigate limb folding, kinking, and tortuosity.

Figure 32.20 Calcified stitch into the bladder.

improved maneuverability and may fit into smaller urinary tracts. Identification of the ureteral orifices may be challenging owing to edema related to the indwelling catheter or to the angle of vision through the tract.

Continent urinary diversions Continent urinary diversion is a common urinary reconstructive technique used after cystectomy. Diversions can be categorized as cutaneous continent diversions or orthotopic diversions. In cutaneous continent urinary diversions, detubularized bowel is arranged to create a urinary reservoir with a catheterizable limb anastomosed to the umbilicus or another site on the abdominal wall that provides access for drainage. In orthotopic diversions, the urinary reservoir is anastomosed to the urethra, allowing for volitional voiding. Detailed understanding of the diversion construction is crucial before any endoscopic intervention. Key elements include the type and location of the ureteroenteric anastomosis, the presence or absence of an afferent limb, and the continence mechanism used. Many neobladders have an afferent limb extending from the reservoir to which the ureters are anastomosed. In orthotopic neobladders, the continence mechanism is the external urinary sphincter. Typical continence mechanisms in cutaneous catheterizable diversions include the tunneled appendix (Mitrofanoff), the tapered/­imbricated terminal ileum and ileocecal valve, and the intussuscepted nipple valve. The Mitrofanoff and tapered/imbricated ileal continence mechanisms are fragile, and aggressive manipulation can lead to stomal stenosis and/or loss of urinary continence. In these cases, simple visualization and reservoir filling through the catheterizable channel may be performed with small-caliber flexible endoscopes

Conclusion Urethrocystoscopy may be part of the regular evaluation of neurogenic bladders. It often allows us to understand the patient’s worsening LUT function. Until now, and for most of the changes and abnormalities found by cystoscopy, no other test can replace it with the same accuracy and reliability.

References 2403. Lindehall B, Abrahamsson K, Hjalmas K et al. Complications of clean intermittent catheterization in boys and young males with neurogenic bladder dysfunction. J Urol 2004; 172: 1686–8. 2404. Palmer LS. Pediatric urologic imaging. Urol Clin N Am 2006; 33: 409–23. 2405. Rivas DA, Chancelor MB. Sphincterotomy and sphincter stent prosthesis. In: Corcus J, Schick E, eds. The Urinary Sphincter. New York, NY: Marcel Dekker, 2001: 565–82. 2406. Denys P, Thiry-Escudie I, Ayoub N et al. Urethral stent for the treatment of detrusor-sphincter dyssynergia: Evaluation of the clinical, urodynamic, endoscopic, and radiological efficacy after more than 1 year. J Urol 2004; 172: 605–7. 2407. O’Donnell P. Water endoscopy. In: Rax S, ed. Female Urology. Philadelphia, PA: WB Saunders, 1983: 51–60. 2408. Brocklehurst JC. The genitourinary system. In: Brocklehurst JC, ed. Textbook of Geriatric Medicine and Gerontology. New York, NY: Churchill Livingstone, 1978: 306–25. 2409. McGuire EJ. Normal function of lower urinary tract and its relation to neurophysiology. In: Libertino IA, ed. Clinical Evaluation and Treatments of Neurogenic Vesical Dysfunction. International Perspectives in Urology. Baltimore, MD: Williams & Wilkins, 1984: 1–15. 2410. Shah PJR. Clinical presentation and differential diagnosis. In: Fitzpatrick JM, Krane RJ, eds. The Prostate. Edinburgh: Churchill Livingstone, 1989: 91–102. 2411. O’Reilly PH. The effect of prostatic obstruction on the upper urinary tract. In: Fitzpatrick JM, Krane RJ, eds. The Prostate. Edinburgh: Churchill Livingstone, 1989: 111–18. 2412. Schick E, Tessier J. Trabeculation de la paroi vesicale chez la femme: Que signifie-t-elle? Presented at the 18th Annual Congress of the Association des Urologues du Quebec, Montreal, November 1993.

33 Imaging techniques in the evaluation of neurogenic bladder dysfunction John T. Stoffel

Introduction Radiologic imaging is an important tool for evaluating neurogenic bladder patients. Techniques such as ultrasound and fluoroscopy have been used for decades to assess bladder and renal anatomy. More advanced techniques now provide insight into relationships between voiding dysfunction and central nervous system injuries. Despite the frequency of use, there are few published imaging guidelines for neurogenic bladder patients (Table 33.1). Given this lack of standardization, practitioners caring for neurogenic bladder patients need to have a basic understanding of how imaging can be used to assess renal physiology, ureteral anatomy, and bladder function. In this chapter, we will review how ultrasound, fluoroscopy, nuclear medicine, and other advanced imaging techniques can be used to answer questions important to the physiology and anatomy of neurogenic bladder patients.

Ultrasound Hydronephrosis Many neurogenic bladder patients have potential to develop hydronephrosis through vesicoureteral reflux or poorly compliant bladder physiology. Ultrasound gray scale sonography (B Mode) is commonly used for detecting collecting system dilation. Ultrasound images are generated by exposing the ultrasound transducer–embedded crystals to alternating electrical current. The crystals contract and expand to create a mechanical longitudinal wave, usually ranging from 3.5–12 MHz in frequency. The wave compresses tissues and it reflects back to the transducer. These signals are then converted to an electronic display. Large body habitus or poor interface with the transducer can significantly reduce image quality.

Gray-scale ultrasound gives two-dimensional (2D) information about renal size, cortical thickness, and collecting system dilation. Healthy adult kidneys commonly measure between 9 and 12 cm in length and have a cortical thickness measurement greater than 1.5 cm.8 Ultrasound findings such as cortical echogenicity are associated with various renal parenchymal diseases, which may impact renal function.9 In the literature, hydronephrosis lacks a standardized definition and is qualitatively described as being mild, moderate, or severe. Severe hydronephrosis has characteristic ultrasound findings, including collecting system dilation, which extends into the renal parenchyma. Long-standing hydronephrosis is also associated with cortical loss (Figure 33.1). It can be challenging, however, for practitioners to differentiate between mild and moderate hydronephrosis, particularly when parapelvic cysts are present (Figure 33.2). To address this difficulty, there have been some attempts to standardize hydronephrosis reporting. The Society of Fetal Medicine has described a subjective grading scale of 0–4 for measuring fetal hydronephrosis. However, Keays reported that inter-rater agreement for staff individuals using this system was high for grade 0, moderate for grades 1, 2, and 4, and only slight for grade 3.10 This variability likely limits widespread adoption of the scale for adults. More objective measurements for hydronephrosis have also been proposed, including the Hydronephrosis Index (HI) = 100 × (Total area of the kidney minus area of dilated pelvis and calices)/(Total area). In the HI scale, a normal kidney would have HI = 100% and progressive hydronephrosis would be represented through lower percentages.11 Currently, HI grading scales have not been validated in the adult neurogenic bladder population. Although gray-scale ultrasound can identify hydronephrosis, it cannot determine if the process is acute or chronic. Doppler ultrasound can be used to gauge the impact of hydronephrosis on renal function by measuring blood flow and resistance in the intrarenal arterial

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Table 33.1  Current radiologic imaging recommendations for neurogenic bladder conditions Pathology

Recommended imaging

Frequency

Spinal cord injury

Renal ultrasound, urodynamics

3–6 months after injury, 6–12 months, then yearly1,2

Multiple sclerosis

MRI spine, renal ultrasound

Unknown: as needed to every 8 years3,4

Spinal bifida

Renal ultrasound

Baseline evaluation then yearly to every 3 years5,6

Parkinson’s disease

No recommendations

No recommendations

Transverse myelitis

Renal ultrasound

Baseline evaluation then yearly7

Voiding dysfunction neurogenic bladder

Videourodynamics

Variable

Figure 33.1 Ultrasound from patient with obstructed ileal loop. Note thin renal cortex and intrarenal collecting system dilation. These findings are typical of long-standing hydronephrosis.

waveforms. In principle, an acute obstruction will decrease arterial perfusion differently than a chronic process. This resistive index (RI) of renal blood flow is defined as [peak systolic velocity—end diastolic velocity]/peak systolic velocity. Work performed by Platt at the University of Michigan found that kidneys with RI > 0.70 had hydronephrosis from an obstructive nephropathy where as those 0.70 as a reasonable suggestion of an acute obstructive process causing hydronephrosis.13 However, RI values do not correlate with hydronephrosis severity.14 Furthermore, approximately 50% patients with partial ureteral obstruction in one study were also found to have normal RI.15 Given these limitations, RI is an untested modality for assessing hydronephrosis in neurogenic ­bladder patients with low bladder compliance or vesicoureteral reflux (VUR).

Bladder wall thickness

Figure 33.2 Ultrasound from patient with chronic reflux. Parapelvic cyst confounds image, making it difficult to determine if hydronephrosis is mild or moderate.

Studies have attempted to associate the bladder wall ­thickness on ultrasound with clinical outcomes in selected ­neurogenic bladder patients. Moderate correlation between thickness and upper tract status was found in spina bifida of children16 and spinal cord injury patients.17 Findings have been more mixed when examining bladder wall thickness and urinary symptoms. Silva examined 47 cerebral palsy patients and found no significant differences in bladder wall thickness between continent and i­ ncontinent c­ hildren (2.46 vs. 2.19 mm).18 In contrast, Uzun noted diabetic women with thicker bladder walls or had increased urinary symptoms compared to those with less thick walls.19 The clinical usefulness of bladder wall thickness measurements is likely limited because ultrasound ­ ­techniques for assessing bladder wall thickness have not been ­standardized. For example, different thicknesses are measured if detrusor wall thickness is used instead of entire bladder wall (Figure 33.4). The International Continence Society issued a report in 2010, which attempted to address

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Figure 33.3 Doppler ultrasound demonstrating intrarenal arterial waveforms. Mild to moderate hydronephrosis was noted on gray scale ­ultrasound in a spinal cord injury patient with a neurogenic bladder. Resistive index was less than 0.6 in both patients, indicating no acute obstruction. Nuclear medicine scan confirmed hydronephrosis was not from obstruction.

(a)

(b)

Figure 33.4 Bladder wall thickness. (a) Magnified ultrasound of bladder wall. Blue crosses represent adventitial and mucosal borders, defined by hyperechoic white lines. Red crosses represent detrusor, defined by hypoechoic space. (b) Measurements of bladder wall thickness using detrusor wall (DWT) or complete bladder wall (BWT) borders. (Modified from Oelke, M, Neurourol Urodyn, 29(4), 634–9, 2010.)

these concerns.20 ICS recommendations for bladder wall measurements included •• •• ••

Using high-frequency ultrasound probes greater than 7.5 MHz to improve resolution. Using digital ultrasound machines so images can be enlarged. Any part of the bladder can be measured as dome, anterior, posterior, and lateral walls have the same thickness.

•• ••

Bladder wall thickness may vary considerably with volume until 50% of maximum capacity is reached. Bladder wall thickness and detrusor wall thickness can be reproduced through anatomic landmarks.

With better standardization of techniques and definitions, ultrasound measurement of bladder wall thickness may become a more important diagnostic tool in the future.

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Safety Ultrasound is a very safe modality because it does not expose the patient or practitioner to ionizing radiation. But ultrasound can, in theory, cause cavitation of microbubbles within an acoustic field. If enough cavitation occurs, tissue loss can occur through thermal and mechanical changes. Consequently, ultrasound outputs are measured through thermal and mechanical indexes as safety requirement. Thermal index estimates temperature rises when ultrasound travels through soft tissues. Mechanical index estimates the risk of tissue cavitation during evaluation.21 Although, cavitation rarely occurs during diagnostic ultrasound settings, practitioners should be aware of how ultrasound outputs are measured and take precautions to use ultrasound equipment within the recommended parameters.

Fluoroscopy: Videourodynamic studies The 2012, American Urological Association Urodynamic guidelines state that fluoroscopy at the time of urodynamics can be helpful when studying neurogenic bladder conditions.22 Specifically, these guidelines note that fluoroscopy adds •• •• ••

Anatomic imaging correlation during pressure flow studies Improved diagnosis of VUR, bladder diverticulum, and bladder neck abnormalities More precise localization of obstruction in the bladder and urethra

An international consensus panel on neurogenic lower urinary tract dysfunction similarly recommend using videourodynamics.23 In addition to identifying uncommon conditions such as pelvic lipomatosis (Figure 33.5), we have found video­ urodynamics to be particularly helpful for assessing detrusor external sphincter dyssynergia and low bladder compliance.

Detrusor sphincter dyssynergia Detrusor sphincter dyssynergia (DSD) is a condition defined by incomplete relaxation of urethral sphincters during a detrusor contraction. In urodynamic studies performed without fluoroscopy, DSD is diagnosed through urethral pressure changes and electromyography (EMG) findings. Regarding urethral pressure changes in DSD, Sakakibara studied 44 patients with neurogenic bladder voiding dysfunction and found a 6.4-cm H2O mean reduction in urethral voiding pressures for men with DSD, compared to a 39-cm H2O reduction in those

Figure 33.5 Cystogram of patient with pelvic lipomatosis. Note “bottleshaped” extrinsic bladder compression from pelvic mass.

without.24 Although urethral pressure profiles are an intriguing tool for investigating the severity of DSD, the methodology used to assess urethral pressure changes is not standardized. Consequently, there are no universally accepted ranges for grading DSD findings. Currently, the International Continence Society considers urethral pressure measurements to be investigational. DSD is more commonly diagnosed during urodynamics through characteristic EMG findings, specifically involuntary sphincter activity during detrusor contractions. EMG tracings of DSD can show increasing muscle activity (Type 1), intermittent activity (Type 2), or fixed continuous activity (Type 3) during voiding.25 However, DSD can be sometimes challenging to detect on EMG tracings because of low-quality tracings from an altered body habitus. EMG tracings acquired through pads may also be less accurate than those from needle electrodes for a similar reason. Given the limitations of urethral pressure measurements and EMG tracings, fluoroscopy is recommended as helpful an adjunct for identifying DSD in neurogenic patients. DSD on fluoroscopy is diagnosed by noting a closed bladder neck during bladder filling, followed by dilation of the proximal urethra during voiding (Figure 33.6). Interestingly, fluoroscopy findings do not always correlate with EMG findings and De et al. noted that some patients with known DSD had disparate findings between voiding cystourethrogram (VCUG) and EMG.26 Although the fluoroscopy findings can be dramatic, false positive results can occur if the patient voluntarily guards during voiding or if confounding urethral strictures are present. Kuo also reported that 20% of neurologically normal men studied for lower urinary tract symptoms demonstrated poor sphincter relaxation during voiding.27 Consequently, clinical correlation must be used when observing proximal urethral dilation during videourodynamics before diagnosing DSD.

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Pves 1 191* Pabd 4 58* Pdet 5 165* Pura 1 237*

Dilated proximal urethra

EMG 110

Increased EMG

107* Uroflow

12* Voided volume

203* Volume

0000600B_12

302*

(b)

(a)

Figure 33.6 Detrusor sphincter dyssynergia (DSD). (a) Characteristic fluoroscopic image of DSD, notable for involuntary dilated proximal urethra during bladder contraction. (b) CMG/EMG tracings from same patient demonstrating increased EMG activity during voiding.

Low bladder compliance Urodynamics is frequently performed on neurogenic bladder patients to study bladder compliance. Low bladder compliance is usually defined less than 20 cm H2O/cc on cystometrogram and patients with low bladder compliance have an increased risk over time for hydronephrosis and urinary tract infections. However, bladder compliance measurements during urodynamics assume that the bladder approximates a spherical shape during filling and that pressure equalizes within the bladder proper. If the detrusor pressure bleeds off into the upper tracts through VUR or into an expanding bladder diverticulum during filling (Figure 33.7), the true bladder compliance will be underestimated (Figure 33.8). CMG tracings may also be incorrect if the urodynamic catheter is inadvertently placed into a dilated ureteral orifice or inside a bladder diverticulum. There are little data on how frequently these anatomic abnormalities are actually found during neurogenic ­bladder videourodynamic studies, compared to studies performed for symptoms of obstruction or incontinence. The author examined data in his practice from 251 consecutive videourodynamic studies and found patients with a bladder compliance less than 20 cm had four times greater odds of having bladder diverticulum and/or VUR on cystogram. Patients with a neurogenic bladder diagnosis also had statistically significantly more diverticula/

Figure 33.7 Neurogenic bladder patient with low bladder compliance and findings of thick bladder wall, diverticulum, and vesicoureteral reflux.

VUR than patients studied for bladder outlet obstruction or non-neurogenic incontinence (personal communication). In a different series, Caramella et al. examined videourodynamic studies from multiple sclerosis patients

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Pves 40 224* Pabd 35 211*

Pressure rise attenuated

Pdet 8 30* Pura 26 159* EMG 15 365* Pump Vol 81 89* Volume 21 37* Flow 0 3*

(a)

(b)

Figure 33.8 Upper tract urine storage. (a) Urine refluxes into upper tracts at low volumes. (b) Bladder compliance is artificially low because of upper tract urine storage.

and concluded that fluoroscopy was useful for tracking bladder morphology, diverticulum, and VUR in patients because these findings changed over time.28 These observations suggest that fluoroscopy is an important visual confirmation during neurogenic bladder urodynamic testing that cystometrogram compliance measurements are correct in this vulnerable population.

Safety Exposure to ionizing radiation during fluoroscopy has potential to cause considerable morbidity for both patients and practitioners. Prolonged exposure to fluoroscopy can result in skin erythema, permanent epilation, skin necrosis, and cataracts.29 Long-term radiation exposure may also increase the risk of developing malignancies. Consequently, it is critically important for practitioners to understand how radiation exposures are measured. Currently, four metrics are used to estimate radiation dose exposure for patients during fluoroscopy:30,31 1. Peak skin dose: This is the highest radiation dose delivered to a person’s skin, including scatter radiation. There are no real-time measurements for displaying this during a study. 2. Reference dose: This is the energy emitted from the source to a theoretical point near the patient. It is a proxy measurement for total dose delivered to the skin as this number cannot be directly

measured. The majority of C-Arm units used during ­v ideourodynamics provide this value. 3. Dose area product: Total x-ray energy leaving the tube. Frequently used in European studies, this number best correlates with overall cancer risk. 4. Fluoroscopy time: Time exposed to fluoroscopy. This number does not accurately reflect dose. Some interventional radiology societies caution that this number should not be used in assessing patient safety. The U.S. Nuclear Regulatory Commission Guidelines (10 CFR 20.1003) recommend that practitioners should follow the ALARA (As low as reasonably achievable) principle to minimize exposures to ionizing radiation. They also recommend that the occupational annual radiation dose limits do not exceed 15 rems for eyes and 50 rems for whole body or extremities. 32 To minimize radiation exposure, basic fluoroscopy safety recommendations include •• •• •• ••

Keep tube current as low as possible by keeping tube potential as high as possible. Keep image intensifier as close to patient as possible. Keep x-ray tube maximum distance from patient. Position x-ray tube under patient if beam is horizontally positioned.

There is growing interest in examining radiation exposure during videourodynamic studies. Giarenis et al.

Imaging techniques in the evaluation of neurogenic bladder dysfunction studied radiation exposure in 345 women undergoing videourodynamics to determine mean radiation dosing during testing. In this study, the effective delivered dose was 0.34 mSv and the mean fluoroscopic time was 63.15  seconds. They concluded that radiation exposure during videourodynamics was minimal.33 Likewise, Arbique et  al. examined the safety of videourodynamic studies in 118 non-neurogenic women and found a 99.997% chance that no radiation detriment to the patient occurred from the study.34 Urodynamic techniques have been examined to identify when the largest radiation exposure occur ­during the study. Guild et al. examined 88 videourodynamic examinations and found that 60% of radiation exposure occurred during lateral imaging of the voiding phase. The group found that no more than three lateral views, taken from the middle voiding phase, were usually sufficient for a complete evaluation.35 However, despite these reassuring studies, there are few recommendations regarding radiation exposure during videourodynamics for adult neurogenic bladder patients. Lee et al. have described a quality improvement protocol where fluoroscopy was limited to 4–5 images taken at preselected time points. Through this protocol, the authors were able to reduce mean patient/study radiation exposure from 41 seconds to 12 seconds without changing diagnostic accuracy.36 Although only 20%–25% of patients studied in this protocol had a neurogenic bladder diagnosis, the data suggests that ALARA principles can be applied to neurogenic bladder videourodynamics without loss of study quality.

Nuclear medicine/ physiologic imaging Nuclear medicine studies are performed by injecting radiopharmaceutical compounds that will concentrate in targeted tissues or organs. Gamma cameras measure uptake of radiation emitted from these isotopes and organspecific physiology can be inferred from a time-dependent projection of these emissions. The most common urologic application for nuclear medicine is radioisotope renography for evaluating renal function and/or obstruction. Nuclear medicine studies can also be combined with computed tomography (CT) (SPECT) and MRI (fMRI) images to provide practitioners with both physiologic and anatomic information about a pathologic process. Nardos examined 20 women with fMRI during bladder filling and found 7 brain regions37 that were tightly integrated during normal urine storage. Likewise, Tadic et al. demonstrated that there is greater neurologic brain activity in the supplemental motor area and posterior cingulate gyrus in elderly women with detrusor overactivity compared to unaffected elderly women.38 Advanced nuclear medicine testing has also been used to identify brain regions associated with increased incontinence in patients with

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degenerative neurologic conditions such as Parkinson’s disease (PD). Sakakibara studied 7 PD patients with bothersome urinary symptoms and found an association on SPECT between urinary dysfunction and degeneration of the nigrostriatal dopaminergic cells.39 In a different study, Winge et al. also used SPECT imaging to show that urinary symptoms in PD patients correlated with degree of caudate nucleus degeneration.40 Although these findings are encouraging, more research is needed before nuclear medicine can provide disease-specific “road maps” of affected brain regions in the larger neurogenic bladder patient population.

Computed tomography With advances in CT techniques such as multichannel detectors and 3D reconstruction capabilities, high-quality images can be gathered during a single held breath with little motion artifact. This improved anatomic definition has expanded the use of this modality beyond evaluations of hematuria, urinary tract calculi, and urologic malignancies. For example, CT can now be used to identify the morphology and anatomy of reconstructed bladders. Stenzl et al. published their experience with 3D CT technique in 50 orthotopic bladder substitutions. In this cohort, they were able to effectively demonstrate the location of ureteral and urethral anastomosis in the 3D images.41 These reconstructed images can yield very helpful anatomic information, particularly during planning for reoperative surgery. At the author’s institution, 3D CT has particularly helpful in identifying ileal loop anatomy (Figure 33.9), ureteral strictures, and the viability of previous enterocystoplasty reconstructions.

Figure 33.9 3D reconstruction of ileal loop. Note duplicated left ureteral system and orientation of loop in pelvis.

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As with nuclear medicine studies, CT can also be combined with urodynamics to better understand physiology and anatomy. Crivellaro et al. investigated relationships between anatomic findings and urinary storage in orthotopic bladder substitutions by correlating 3D CT images with concomitant urodynamics. They found that the distance from the left femoral head correlated with neobladder postvoid residual and inversely correlated with the maximal flow. They also noted that the farther the center of the neobladder from the right femoral head, the higher the risk of incontinence.42 Findings from this study suggest that CT may yield some additional anatomic information not obtained through fluoroscopy during videourodynamics.

Conclusion Radiologic imaging remains an important part of the care for neurogenic bladder patients. Imaging can be used to obtain simple descriptions of anatomy, physiologic assessments of organ function, and 3D modeling of reconstructed tissues. Practical applications will likely increase as the technology continues to develop.

References 2413. Abrams P, Agarwal M, Drake M et al. A proposed guideline for the urological management of patients with spinal cord injury. BJU Int 2008; 101(8): 989–94. 2414. Sahai A, Cortes E, Seth J et al. Neurogenic detrusor overactivity in patients with spinal cord injury: Evaluation and management. Curr Urol Rep 2011; 12(6): 404–12. 2415. Lemack GE, Hawker K, Frohman E. Incidence of upper tract abnormalities in patients with neurovesical dysfunction secondary to multiple sclerosis: Analysis of risk factors at initial urologic evaluation. Urology 2005; 65(5): 854–7. 2416. Stoffel JT. Contemporary management of the neurogenic bladder for multiple sclerosis patients. Urol Clin North Am 2010; 37(4): 547–57. 2417. Mourtzinos A, Stoffel JT. Management goals for the spina bifida neurogenic bladder: A review from infancy to adulthood. Urol Clin North Am 2010; 37(4): 527–35. 2418. Elliott SP, Villar R, Duncan B. Bacteriuria management and urological evaluation of patients with spina bifida and neurogenic bladder: A multicenter survey. J Urol 2005; 173(1): 217–20. 2419. Tanaka ST, Stone AR, Kurzrock EA. Transverse myelitis in children: Long-term urological outcomes. J Urol 2006; 175(5): 1865–8; discussion 8. 2420. Emamian SA, Nielsen MB, Pedersen JF, Ytte L. Kidney dimensions at sonography: Correlation with age, sex, and habitus in 665 adult volunteers. Am J Roentgenol 1993; 160(1): 83–6. 2421. Khati NJ, Hill MC, Kimmel PL. The role of ultrasound in renal ­insufficiency: The essentials. Ultrasound Q 2005; 21(4): 227–44. 2422. Keays MA, Guerra LA, Mihill J et al. Reliability assessment of Society for Fetal Urology ultrasound grading system for hydronephrosis. J Urol 2008; 180(4 Suppl): 1680–2; discussion 2–3. 2423. Shapiro SR, Wahl EF, Silberstein MJ, Steinhardt G. Hydronephrosis index: A new method to track patients with hydronephrosis quantitatively. Urology 2008; 72(3): 536–8; discussion 8–9. 2424. Platt JF, Rubin JM, Ellis JH. Distinction between obstructive and nonobstructive pyelocaliectasis with duplex Doppler sonography. Am J Roentgenol 1989; 153(5): 997–1000.

2425. Shokeir AA, Abdulmaaboud M, Farage Y, Mutabagani H. Resistive index in renal colic: The effect of nonsteroidal anti-inflammatory drugs. BJU Int 1999; 84(3): 249–51. 2426. Rud O, Moersler J, Peter J et al. Prospective evaluation of interobserver variability of the hydronephrosis index and the renal resistive index as sonographic examination methods for the evaluation of acute hydronephrosis. BJU Int 2012; 110(8 Pt B): E350–6. 2427. Chen JH, Pu YS, Liu SP, Chiu TY. Renal hemodynamics in patients with obstructive uropathy evaluated by duplex Doppler sonography. J Urol 1993; 150(1): 18–21. 2428. Tanaka H, Matsuda M, Moriya K et al. Ultrasonographic measurement of bladder wall thickness as a risk factor for upper urinary tract deterioration in children with myelodysplasia. J Urol 2008; 180(1): 312–6; discussion 6. 2429. Pannek J, Bartel P, Gocking K, Frotzler A. Clinical usefulness of ultrasound assessment of detrusor wall thickness in patients with neurogenic lower urinary tract dysfunction due to spinal cord injury: urodynamics made easy? World J Urol 2013; 31(3): 659–64. 2430. Silva JA, Gonsalves Mde C, Saverio AP et al. Lower urinary tract dysfunction and ultrasound assessment of bladder wall thickness in children with cerebral palsy. Urology 2010; 76(4): 942–5. 2431. Uzun H, Ogullar S, Sahin SB et al. Increased bladder wall thickness in diabetic and nondiabetic women with overactive bladder. Int Neurourol J 2013; 17(2): 67–72. 2432. Oelke M. International Consultation on Incontinence-Research Society (ICI-RS) report on non-invasive urodynamics: The need of standardization of ultrasound bladder and detrusor wall thickness measurements to quantify bladder wall hypertrophy. Neurourol Urodyn 2010; 29(4): 634–9. 2433. Dalecki D. Mechanical bioeffects of ultrasound. Annu Rev Biomed Eng 2004; 6: 229–48. 2434. Winters JC, Dmochowski RR, Goldman HB et al. Urodynamic studies in adults: AUA/SUFU guideline. J Urol 2012; 188(6 Suppl): 2464–72. 2435. Rosier PF, Hosker GL, Szabo L et al. Executive Summary: The International Consultation on Incontinence 2008—Committee on: “Dynamic Testing”; for urinary or fecal incontinence. Part 3: Anorectal physiology studies. Neurourol Urodyn 2010; 29(1): 153–8. 2436. Sakakibara R, Hattori T, Uchiyama T, Yamanishi T. Videourodynamic and sphincter motor unit potential analyses in Parkinson’s disease and multiple system atrophy. J Neurol Neurosurg Psychiatry 2001; 71(5): 600–6. 2437. Bacsu CD, Chan L, Tse V. Diagnosing detrusor sphincter d ­ yssynergia in the neurological patient. BJU Int 2012; 109(3 Suppl): 31–4. 2438. De EJ, Patel CY, Tharian B et al. Diagnostic discordance of electromyography (EMG) versus voiding cystourethrogram (VCUG) for detrusor-external sphincter dyssynergy (DESD). Neurourol Urodyn 2005; 24(7): 616–21. 2439. Kuo HC, Tsai TC. Assessment of prostatic obstruction and bladder function by urodynamic pressure flow study. Taiwan Yi Xue Hui Za Zhi 1987; 86(10): 1084–92. 2440. Caramella D, Donatelli G, Armillotta N et al. Videourodynamics in patients with neurogenic bladder due to multiple sclerosis: Our experience. Radiol Med 2011; 116(3): 432–43. 2441. Valentin J. Avoidance of radiation injuries from medical interventional procedures. Ann ICRP 2000; 30(2): 7–67. 2442. Fletcher DW, Miller DL, Balter S, Taylor MA. Comparison of four techniques to estimate radiation dose to skin during angiographic and interventional radiology procedures. J Vasc Interv Radiol 2002; 13(4): 391–7. 2443. Miller DL, Vano E, Bartal G et al. Occupational radiation protection in interventional radiology: A joint guideline of the Cardiovascular and Interventional Radiology Society of Europe and the Society of Interventional Radiology. Cardiovasc Intervent Radiol 2010; 33(2): 230–9. 2444. Mauer A. Status and plans for implementation of NRC regulatory authority for certain naturally occurring and accelerator-produced radioactive material. J Nucl Med Technol 2007; 35(2): 112–3.

Imaging techniques in the evaluation of neurogenic bladder dysfunction 2445. Giarenis I, Phillips J, Mastoroudes H et al. Radiation exposure during videourodynamics in women. Int Urogynecol J 2013; 24(9): 1547–51. 2446. Arbique GM, Gilleran JP, Guild JB et al. Radiation exposure during standing voiding cystourethrography in women. Urology 2006; 67(2): 269–74. 2447. Guild J, Takacs E, Kircher S, Arbique G, Zimmern PE. The number of voiding radiographs during cystourethrography in women with stress incontinence or prolapse can be reduced to enhance safety without compromising study interpretation. Neurourol Urodyn 2009; 28(5): 385–9. 2448. Lee CL, Wunderle K, Vasavada SP, Goldman HB. Reduction of radiation during fluoroscopic urodynamics: Analysis of quality assurance protocol limiting fluoroscopic images during fluoroscopic urodynamic studies. Urology 2011; 78(3): 540–3. 2449. Nardos R, Gregory WT, Krisky C et al. Examining mechanisms of brain control of bladder function with resting state functional connectivity MRI. Neurourol Urodyn 2014; 33(5): 493–501.

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2450. Tadic SD, Griffiths D, Schaefer W et al. Brain activity underlying impaired continence control in older women with overactive bladder. Neurourol Urodyn 2012; 31(5): 652–8. 2451. Sakakibara R, Shinotoh H, Uchiyama T et al. SPECT i­maging of  the dopamine transporter with [(123)I]-beta-CIT reveals marked decline of nigrostriatal dopaminergic function in Parkinson’s disease with urinary dysfunction. J Neurol Sci 2001; 187(1–2): 55–9. 2452. Winge K, Friberg L, Werdelin L, Nielsen KK, Stimpel H. Relationship between nigrostriatal dopaminergic degeneration, urinary symptoms, and bladder control in Parkinson’s disease. Eur J Neurol 2005; 12(11): 842–50. 2453. Stenzl A, Frank R, Eder R et al. 3-Dimensional computerized tomography and virtual reality endoscopy of the reconstructed lower urinary tract. J Urol 1998; 159(3): 741–6. 2454. Crivellaro S, Mami E, Wald C et al. Correlation between urodynamic function and 3D cat scan anatomy in neobladders: Does it exist? Neurourol Urodyn 2009; 28(3): 236–40.

34 Evaluation of neurogenic lower urinary tract dysfunction: Basic urodynamics Benjamin M. Brucker, Christopher E. Kelly, and Victor W. Nitti

Classification of neurogenic voiding dysfunction The primary objectives of evaluating patients suspected of having neurogenic lower urinary tract dysfunction (NLUTD) are •• ••

To determine if the upper urinary tract is at risk for damage and ultimate renal failure To understand the process(s) resulting in signs or symptoms of dysfunction

Ultimately, this evaluation should allow for prevention of upper tract deterioration and implementation of treatment(s) to relieve bothersome symptoms. Wein’s “Functional Classification” of NULTD1 provides a simple, eloquent framework to conceptualize the ­underlying  pathology that affects patient with neurologic conditions. It also allows for systematic interpretation of the NLUTD evaluation (i.e., urodynamics), and very practically guides the choice of treatments. The Functional Classifi­cation system is based on the simple concept that the LUT has two basic functions: storage of adequate volume of urine at low pressures, and voluntary and complete evacuation of urine from the bladder. For normal storage and emptying to occur there must be proper and coordinated ­functioning of the bladder and bladder outlet (bladder neck, urethra, ­external sphincter). Hence, NLUTD can be classified under the following rubrics: “failure to store” (storage abnormality), “failure to empty” (emptying abnormality), or a c­ ombination of both. Each type of failure may result from bladder dysfunction, bladder o ­ utlet dysfunction,  or a combined ­dysfunction (Table 34.1). Using this basic concept, examples of ­urodynamic findings seen in neurological ­disease are shown. It is important to emphasize that symptoms do not always indicate the magnitude to which the disease is

affecting the urinary tract, especially in neurologic disorders. Serious urinary tract damage can result in the absence of symptoms. It is also vital to realize that patients with neurologic disease are at risk for developing the same urologic and gynecologic problems as those of the same age without neurologic disease.2 Just because a women had a cerebral vascular accident does not prevent her from having stress urinary incontinence. And finally, the clinician should remember that neurological lesions may be “complete” or “incomplete.” Hence, urologic manifestations of neurologic disease may not always be predictable. A complete neurourologic evaluation of patients with neurogenic voiding dysfunction is therefore recommended.3 This chapter discusses the evaluation of patients with NLUTD by urodynamics. Prior to this discussion, a working knowledge of the neurophysiology of micturition is essential. In addition, the effect of particular neurological diseases on lower urinary tract function can be helpful in understanding the context of this chapter. Those topics are covered in Parts II and III of this book.

Assessment of the patients with neurogenic lower urinary tract dysfunction History and physical examination Prior to any supplementary diagnostic testing, a complete detailed history and physical examination are required. Specific question should be asked about past medical and surgical history; current medication; present functional status and social situation; bladder, bowel, and sexual functions; and impact on quality of life. In addition, a neurologic history should be obtained. It is important to

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Table 34.1  Functional classification of voiding disorders with examples of dysfunction

Failure to store • Bladder dysfunction

Neurogenic DO, impaired compliance

• Bladder outlet dysfunction

Neurogenic intrinsic sphincter deficiency

• Combined dysfunction of bladder and bladder outlet

(see above)

Failure to empty • Bladder dysfunction

Detrusor underactivity, acontractile detrusor

• Bladder outlet dysfunction

DESD, DISD

• Combined dysfunction of bladder and bladder outlet

(see above)

DO, detrusor overactivity; DESD, detrusor-external sphincter dyssynergia; DISD, detrusor-internal sphincter dyssynergia.

understand how the neurological disease affects the person’s daily activities and other social functions. Some diseases are chronic and stable, and others are more rapidly progressing. This initial evaluation should try to understand the trajectory of the underlying process. If the neurologic lesion(s) or process is unclear (or in some cases undiagnosed) a complete neurological evaluation may be needed. Although there is no consensus, after initial evaluation, we recommend that patients are followed annually to assess significant changes in lower urinary tract symptoms (LUTS) or neurological status unless more frequent follow-up is needed based on other risk factors or clinical scenarios.4 Significant changes to health status may warrant reevaluation. A standard and complete urological examination should be performed on all patients with suspected NLUTD. A good general neurologic examination should assess sensation, strength, dexterity, and mobility. Acknowledging patients’ specific disabilities help in planning further investigation and treatments. Specific and comprehensive evaluation of the sacral nerve (S2–S4) reflex arc is needed as part of this evaluation. A digital rectal examination (and pelvic examination in women) will establish rectal (and pelvic floor) tone and control. The bulbocavernosus reflex and perianal sensation should also be assessed. Finally, lower extremity spasticity along with patellar and ankle reflexes should be evaluated.

Laboratory studies On the basis of a panel consensus, the highest level of recommendation (A) was given to basic serum chemistry and urinalysis.3 This allows establishment of baseline renal function and detection of any other abnormalities. Urinalysis and urine culture, when appropriate, are essential in patients with an increased risk for developing urinary tract infections. A bladder diary (and related assessments such as frequency/volume chart or logs of catheterized volumes) is another potentially useful tool that gives more objective

information about fluid consumption and characteristics of urine output over a 24-hour period.5,6 This information can be diagnostic and also allow for tracking of treatment progress. It is also useful for patients requiring catheterization to ultimately ensure appropriate time intervals between catheterizations. This semiobjective qualification of patients’ LUT status and other behavior/dietary habits is considered highly advisable, and the information is extremely useful in some cases.7

Noninvasive urodynamic assessment According to the recently published American Urological Association/Society of Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction (AUA/SUFU) Urodynamic Guideline, a postvoid residual (PVR) is considered a standard (grade B evidence). EAU guidelines terminology considers this a mandatory part of the assessment during initial urologic evaluation of patients with neurologic conditions.3,8 PVR testing is easily performed, and though it does not determine the underlying dysfunction, it can provide an initial assessment of the patient’s ablility to empty the urinary bladder. It may also be useful for periodic monitoring of patients with NLUTD. Noninvasive uroflowmetry is another tool that can be used as a screening test for voiding dysfunction. This may help select the NLUTD patients that require more sophisticated urodynamic studies. It provides objective information about voiding but is nonspecific and does not allow for assessment of bladder compliance. Bladder compliance is a critical component of the evaluation of some neurogenic patients (i.e., spinal cord injury).

Other tools to evaluate Since the upper urinary tract in patients with a neurogenic bladder can be adversely affected by secondary reflux, ascending infection, hydronephrosis or stones, a

Evaluation of neurogenic lower urinary tract dysfunction baseline upper urinary tract study is also recommended. Vesicoureteral reflux (VUR) can be assessed by either ­videourodynamics or a voiding cystourethrogram. A renal ultrasound is a good noninvasive test to assess the kidneys for stones or hydronephrosis. In some cases, intravenous pyeloureterogram, CT scan, retrograde studies, or nuclear renogram may be needed. Bladder ultrasound provides an excellent modality to rule out bladder stones, which are reported in over 30% of patients with indwelling catheters.9 Finally, cystourethroscopy deserves mention. In addition to detecting sources of recurrent infection, stones, or strictures, it can be used to ensure there are no suspicious urothelial changes that require further investigation with biopsy or excision. It is important to remember that in patients with neurogenic bladders and indwelling catheters there may be up to a 2%–10% lifetime risk of developing squamous cell carcinoma of the bladder or other possibly premalignant lesions.10–12 Details on appropriate surveillance interval are beyond the scope of this chapter.

Pressure flow urodynamics for evaluation of neurogenic bladder Pressure flow urodynamics (also known as multichannel urodynamics) evaluation is the mainstay of evaluation in patients with NULTD. Urodynamics have a role because the presenting symptoms do not always correlate with the type or extent of the disease or injury, the severity of symptoms and physical examination findings do not correlate well with prognosis or risk of deterioration to the upper tracts, and in spinal cord injury the level of injury is not always predictive of urodynamic findings.13,14 Therefore, the goals of urodynamic testing in patients with neurological disease are •• •• ••

To provide documentation of the effect of neurological disease on the LUT To correlate patient symptoms with urodynamic events To assess for the presence of urologic risk factors associated with urologic complications (detrusor striated sphincter dyssynergia, poor bladder compliance, sustained high-pressure detrusor contractions, and VUR)

The urodynamic evaluation consists of several components including uroflowmetry, cystometrogram (CMG), abdominal pressure monitoring, electromyography (EMG), and voiding pressure-flow studies. Simultaneous fluoroscopic imaging of the entire urinary tract during urodynamics (also known as videourodynamics or VUD) is extremely useful in cases of known or suspected neurogenic voiding dysfunction. In these complicated cases,

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urodynamic studies may need to be repeated several times to fulfill the above objectives.

Cystometrogram The filling CMG is used to mimic the bladder’s filling and storage of urine while the pressure–volume relationship within the bladder is recorded. This is now recommended (based on grade C evidence) as part of the initial urological evaluation of patients with relevant neurological conditions with or without symptoms and used as a part of ongoing follow-up when appropriate.8 The bladder should be emptied before filling, and filling should ideally commence with body-temperature fluid at a physiological filling rate (less than predicted maximum body weight in kilogram divided by 4 expressed as mL/min) to minimize provocation maneuvers of the bladder (those that may provoke detrusor overactivity). Practically, it is best to fill the bladder at a rate of 30 mL/min or less. Bladder compliance also seems more reproducible using slower fill rates. Important bladder filling urodynamic observations with respect to neurologic disease are bladder sensation, capacity, the presence of involuntary detrusor contractions (detrusor overactivity), and ­storage pressures. When involuntary detrusor contractions are seen in the setting of a relevant n ­ eurologic condition, this is referred to as neurogenic detrusor overactivity according to the International Continence Society (ICS) (replaced the term detrusor hyperreflexia) (see Figure 34.1).15 However, involuntary detrusor contractions are not always reflective of the primary ­neurologic disease, but can reflect other pathologies such as increased outlet resistance. The intensity, ­frequency, and timing of the overactivity should be noted. There are several very important points regarding involuntary contractions: 1. The clinician must be absolutely sure that the contraction is indeed involuntary. Sometimes a patient may become confused during the study and actually void as soon as he feels the desire. 2. It is extremely important to determine whether or not a patient’s symptoms are reproduced during the involuntary contraction. However, in cases of neurologic disease, involuntary detrusor contractions (IDCs) can occur without symptoms and should not be discounted. 3. The volume at which contractions occur and the pressure of the contractions should be recorded. 4. It is often worthwhile to repeat the CMG at a slower filling rate if the patient experiences uncharacteristic symptoms (e.g., incontinence or spasms) or detrusor overactivity. 5. If the patient experiences incontinence during an involuntary contraction (urge incontinence), this should be noted. Sometimes the involuntary contraction will bring on involuntary voiding to completion (precipitant micturition).16

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Textbook of the Neurogenic Bladder 100 Pves

cmH2O 0 100 Pabd

cmH2O 0 100 Pdet

cmH2O 0

Figure 34.1 Filling phase of a urodynamic study in a 68-year-old woman with urge incontinence after cerebrovascular accident. Note the involuntary detrusor contractions (arrows). There is a rise in total bladder pressure (P ves) and detrusor pressure (Pdet), but no change in abdominal pressure (Pabd).

Storage parameters: Compliance and leak point pressures Compliance is defined as the change of volume for a change in detrusor pressure and is calculated by dividing the ­volume change (Δ V) by the change in detrusor pressure (Δ pdet) during that change in bladder volume. According to the ICS this calculation should be carried out at the following points: •• ••

The detrusor pressure at the start of bladder filling and the corresponding bladder volume (usually zero) The detrusor pressure (and corresponding bladder volume) at cystometric capacity or immediately before the start of any detrusor contraction that causes significant leakage (and therefore causes the bladder volume to decrease, affecting compliance calculation)

Both points are measured excluding any detrusor contraction. The second point can be more difficult to define in neurogenic patients with phasic detrusor overactivity that results in significant leakage of urine. This may require repeated filling cycles to ensure an adequate bladder volume is achieved (i.e., one that recreates a typical bladder volume in the everyday setting).

Compliance is expressed in milliliters per centimeter H2O. Impaired compliance is common in neurogenic voiding dysfunction and is potentially hazardous. The degree of impaired compliance in neurogenic voiding dysfunction is often dependent on outlet resistance. However, poor compliance can also occur with chronically catheterized bladders. Impaired compliance leads to high bladder storage pressures. (See Figure 34.2) The calculated value of compliance is probably less important than the actual bladder pressure during filling. This is because the calculated compliance value can change, depending on the volume over which it is calculated and normal compliance is difficult to establish. Toppercer and Tetreault17 evaluated a group of normal asymptomatic women and women with stress incontinence and found mean compliance to be 55.71 ± 27.37. If two standard deviations are used, normal would be between 1 and 110 mL/cmH2O. When compliance is calculated as a single point on the pressure–volume curve it becomes a “static” property. Gilmour et al. point out that this oversimplifies the concept of compliance and may lead to potentially erroneous conclusions.18 One must remember that compliance is dependent on filling rate during a urodynamic study; overly rapid filling rates may produce erroneously lower compliance values. Finally, neurogenic detrusor overactivity can mimic impaired compliance; two methods of

Evaluation of neurogenic lower urinary tract dysfunction

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100 Pves

cmH2O 0 100 Pabd

cmH2O 0 100 Pdet

cmH2O 0

Figure 34.2 Impaired compliance in a 35-year-old male with a T8 spinal cord injury. Note that there is an initial rise in both total vesical p ­ ressure (P ves) and abdominal pressure (Pabd), but the P ves and, thus, the detrusor pressure (Pdet) continue to rise to pressures exceeding 40 cmH2O.

differentiating these two entities are (1) stopping the infusion rate and, if necessary, (2) having the patient perform a sustained Kegel maneuver to suppress a possible involuntary contraction (see Figure 34.3). Storage pressures are critical in neurogenic patients. Storage pressures greater than 40 cm H2O was shown by McGuire in myelodysplastic patients to result in risk of upper tract changes.19 Though this 40 cm H2O is often used as a cut point of concern because of risk for upper urinary tract damage (i.e., renal failure), the actual “danger level” is likely lower. One of the roles of simultaneous fluoroscopy in neurogenic patients is the ability to assess for VUR. In cases of VUR, the bladder storage pressure or compliance may seem safe, but this is secondary to a reduction of bladder pressure secondary to a “pop off valve” phenomenon into the upper tracts. It is true that this may lower the bladder pressure, but in essence this is the very thing we are trying to prevent. When this is seen the volume and pressure that VUR is seen should be noted as well as the grade of VUR. During the filling portion of the urodynamics, continence status should also be assessed. Assessment of effective storage is important because patients with neurogenic bladders often have issues pertaining to urinary incontinence. Urinary leakage (a storage problem) can be secondary to a bladder dysfunction (detrusor overactivity

or impaired compliance) and/or bladder outlet dysfunction (i.e., intrinsic sphincter deficiency). The detrusor leak point pressure (DLPP) (also sometimes referred to as the bladder leak point pressure bladder) measures the lowest detrusor pressure required to cause urinary incontinence in the absence of increased abdominal pressure. According to the ICS, this should also be measured in the absence of a detrusor contraction.15 This leak point pressure should not be confused with the abdominal leak point pressure (ALPP), which is defined by the ICS as the intravesical pressure at which urine leakage occurs due to the increased abdominal pressure in the absence of a detrusor contraction. The DLPP is a direct reflection of the amount of resistance provided by the bladder outlet (bladder neck, urethra, pelvic floor, and external sphincter). Given this relationship, the higher the bladder outlet resistance (e.g., closed fixed external sphincter), the higher the DLPP. High storage pressures and high DLPP are potentially dangerous to upper urinary tracts (see Figure 34.3). Knowledge of the DLPP is useful because it allows the clinician to determine the volume at which detrusor pressure reaches dangerous levels. However, this value does not indicate the amount of time that the urinary tract is exposed to the elevated pressure, or if excessive pressure is experienced during involuntary contractions (assuming no leakage), which may also have a roll in management options.

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Urinary leakage secondary to sphincteric (and or bladder neck) dysfunction can be measured by ALPP (also known as Valsalva leak point pressure).15 The ALPP is an indirect measure of the ability of the urethra to resist changes in abdominal pressure as an expulsive force.20 Clinically, it is used to determine the presence of stress

urinary incontinence and the degree of sphincter incompetence (see Figure 34.4). Normally, there is no physiologic abdominal pressure that should cause incontinence and therefore there is no “normal ALPP.” Unlike the DLPP, an elevated ALPP does not indicate potential danger to the kidneys.

43

3

40

57

100

4

0 100

53

0 100

Pves

0

cmH2O Pabd cmH2O Pdet cmH2O

Figure 34.3 Involuntary detrusor contractions occurring in the face of impaired compliance in a teenage girl with myelomeningocele. The left arrow indicates where detrusor pressure equals and then exceeds 40 cmH2O. The right arrow indicates where leakage occurs—at a bladder leak point pressure of 53 cmH2O. P ves, total vesical pressure; Pdet, detrusor pressure; Pabd, abdominal pressure.

0

50

109

0 150

108

0 100

Flow

mL/s Pves

0 100

cmH2O Pabd

cmH2O Pdet

cmH2O 0

Figure 34.4 Urodynamic tracing of a female patient with stress incontinence. Tracing shows progressive Valsalva maneuvers until leakage occurs (arrow) at an abdominal pressure of 109 cmH2O, which is the abdominal leak point pressure (ALPP). Note that there is no rise in detrusor pressure. P ves, total vesical pressure; Pdet, detrusor pressure; Pabd, abdominal pressure.

Evaluation of neurogenic lower urinary tract dysfunction

Voiding phase As important as filling and storage is, the voiding or emptying phase, known as micturition is equally important. Prior to urodynamic assessment, one must determine how the patient voids. If voiding is voluntary, the strength and duration of the detrusor contraction is assessed. Detrusor contractility may be impaired in particular types of neurologic disease, particularly with lower motor neuron lesions. Besides detrusor contraction, outlet resistance can be measured while voiding. Although the most common cause of outlet resistance in neurogenic voiding dysfunction is detrusor-external sphincter dyssynergia (DESD), bladder outlet obstruction can occur anywhere distal to the bladder. Several nomograms and formulas exist to categorize pressure–flow relationships in terms of nonobstructed, obstructed, or equivocal.21–25 It is important to note that interpretation of bladder outlet obstruction during urodynamics should be performed at the point at which the patient was given a command to void. If the patient has an involuntary bladder contraction and empties the bladder prematurely, this pressure–flow relationship should not be misinterpreted as being equivalent to normal physiological voiding. It is now part of the AUA/SUFU urodynamic guidelines that a clinician “should” perform EMG in combination with cystometrogram (with or without pressure flow studies) with relevant neurologic diseases at risk for neurogenic bladder or in patients with other neurologic diseases and elevated PVR or urinary symptoms.8 EMG during urodynamics permits the urologist to evaluate the striated sphincter function during micturition. Often, surface patch electrodes are used, but surface EMG is prone to artifacts (in neurogenic and non-neurogenic patients).26 Needle electrodes permit more accurate recordings but are more cumbersome and not practical in most settings. Normally, voluntary voiding is preceded by a complete relaxation of the striated sphincter. DESD refers to “a detrusor contraction

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concurrent with an involuntary contraction of the ­u rethral and/or p ­ eriurethral striated muscle.” 15 DESD results in a functional obstruction, which may impair emptying, ­u ltimately leading to high storage pressures. True DESD is often seen in patients with lesions between the brain stem and sacral spinal cord (see Table 34.2 and Figure 34.5).

Videourodynamics Videourodynamics, or simultaneous fluoroscopic monitoring of the urinary tract during urodynamics, is the most comprehensive and accurate way of assessing NULTD.27 During the evaluation of filling and storage, videourodynamics allows for the determination of VUR and the pressure at which this occurs. Moreover, assessment of the DLPP or ALPP is facilitated as fluoroscopy is often more sensitive than direct observation in determining urinary leakage. Videourodynamics also permits the radiographic evaluation of the internal urethral sphincter or bladder neck during storage and helps determine the level of continence. Some neurologic lesions may result in an open bladder neck at rest where other lesions do not affect the bladder neck function, but without fluoroscopy this cannot be easily determined. Other anatomic abnormalities such as bladder and urethral diverticulae and fistula can be seen. During the voiding phase, fluoroscopy permits an accurate determination of the site of obstruction when highpressure/low flow states exist. Videourodynamics also provides an excellent way to evaluate sphincter behavior during voiding, especially in cases where EMG tracing is imperfect or equivocal. Videourodynamics is the best test to determine the presence of detrusor-internal sphincter dyssynergia (DISD) by the lack of opening of the bladder neck on fluoroscopy during a detrusor contraction. Using fluoroscopy with EMG can help make the diagnosis of DISD and DESD28 (see Figure 34.6).

Table 34.2  Basic urodynamic finding based on level of lesion or area affected by neurological disease13 Lesion location Above the brain stem

Common to see detrusor overactivity. Depends on (1) lesion nature—destructive or irritative and (2) area affected—normally inhibitory or stimulatory. Rare to see DESD (if ever)

Between brain stem and sacral cord

Often see detrusor overactivity ± DESD. Can see DISD (sympathetic, smooth muscle) if complete transection and above T6

Sacral cord and distal

Often detrusor areflexia. Not always sphincter function—normal or may keep residual resting tone: decrease and/or nonrelaxing (i.e., not under control)

Source:  Adapted from Wein, AJ, Voiding Dysfunction in Neurologic Injury and Disease, 2012.

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Textbook of the Neurogenic Bladder IDC

IDC

Void 50

8

128

Flow

mL/s 0 600 Volume

27

97

??

36

37

4

5

0 cmH2O 100 P abd

75

32

93

0 cmH2O 100 P det

??

554 66

0 cmH2O 600 EMG 0

0 100

mL Pves

–600

Figure 34.5 Urodynamic tracing of an 18-year-old woman with frequency, urgency, and urge incontinence, who was diagnosed with a tethered cord. Note the involuntary detrusor contraction (IDC, arrow) associated with high-volume urine loss as registered in the flow meter. There is increased sphincter activity, as demonstrated by increased electromyograph (EMG) activity consistent with detrusor-external sphincter dyssynergia. On the second fill there is again an IDC, but this time the patient is instructed to void (double void). Note that there is increased EMG activity throughout the IC and “voluntary void.” Detrusor pressures with IDCs are quite high because of the resistance of the contracting striated sphincter. P ves, total vesical pressure; Pdet, detrusor pressure; Pabd, abdominal pressure.

100

0 100

0 100

0 600

Pves cmH2O Pabd cmH2O Pdet cmH2O EMG

0 –600

None

Figure 34.6 Detrusor-external sphincter dyssynergia (DESD) and detrusor-internal sphincter dyssynergia (DISD) in a 35-year-old male with a high cervical spinal cord injury. There are two IDCs with associated increased electromyograph (EMG) activity consistent with DESD. However, the fluoroscopic picture taken at the time of the second IDC shows an incompletely opened bladder neck consistent with DISD. This patient underwent a striated sphincterotomy as well as a bladder neck incision to facilitate emptying and lower pressures. P ves, total vesical pressure; Pdet, detrusor pressure; Pabd, abdominal pressure.

Evaluation of neurogenic lower urinary tract dysfunction

Conclusion In patients with known neurological disease, careful urodynamic evaluation may be necessary to gauge any deleterious effect on the urinary tract, to determine the etiology of LUTS and to screen for any urologic risk factors. Often times, urodynamics are needed on the asymptomatic patient because the effects of the disease on the urinary tract can be “silent.” In these patients, management is often dictated by urodynamic findings. Patients without a history of neurological disease, whose urological evaluation is suspicious for NLUTD, should be evaluated for occult neurologic disease.

References 2496. Wein AJ. Classification of neurogenic voiding dysfunction. J Urol 1981; 125(5): 605–9. 2497. Nitti VW. Evaluation of the female with neurogenic voiding ­dysfunction. Int Urogynecol J Pelvic Floor Dysfunct 1999; 10: 119–29. 2498. Pannek J, Blok B, Castro-Diaz D et al. Neurogenic Lower Urinary Tract Dysfunction. 2013. 2499. Shenot PJ, Moy ML. Current Bladder Dysfunction Reports, Volume 6, Number 2 - SpringerLink. Curr Bladder Dysfunct Rep, 2011. 2500. Stöhrer M, Goepel M, Kondo A et al. The standardization of terminology in neurogenic lower urinary tract dysfunction: With suggestions for diagnostic procedures. International Continence Society Standardization Committee. Neurourol Urodyn 1999; 18: 139–158. 2501. de SÈZE M, Ruffion A, Denys P et al. The neurogenic bladder in multiple sclerosis: Review of the literature and proposal of management guidelines. Mult Scler 2007; 13: 915–28. 2502. Pannek J, Einig E-M and Einig W. Clinical management of bladder dysfunction caused by sexual abuse. Urol Int 2009; 82: 420–5. 2503. Winters JC, Dmochowski RR, Goldman HB et al. Urodynamic studies in adults: AUA/SUFU Guideline. J Urol 2012; 188: 2464–72. Available at: http://www.sciencedirect.com.ezproxy.med.nyu.edu /science?_ob=MiamiImageURL&_cid=273470&_user=30681& _pii=S0022534712049610&_check=y&_origin=article&_zone =toolbar&_coverDate=2012-Dec-31&view=c&originContent Family=serial&wchp=dGLzVlS-zSkzV&md5=cec64fae253a783188 8e2afb1c232da3&pid=1-s2.0-S0022534712049610-main.pdf. 2504. BUNTS RC. Management of urological complication in 1000 paraplegics. JURO 1958; 79: 733–1. 2505. Delnay KM, Stonehill WH, Goldman H et al. Bladder histological changes associated with chronic indwelling urinary catheter. J Urol 1999; 161: 1106–9.

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2506. Kaufman JM, Fam B, Jacobs SC et al. Bladder cancer and squamous metaplasia in spinal cord injury patients. JURO 1977; 118: 967–71. 2507. Jacobs SC, Kaufman JM: Complications of permanent bladder ­catheter drainage in spinal cord injury patients. JURO 1978; 119: 740–1. 2508. Wein AJ. Voiding Dysfunction in Neurologic Injury and Disease. 2012. PowerPoint presentation. 2509. Weld KJ, Dmochowski RR. Association of level of injury and bladder behavior in patients with post-traumatic spinal cord injury. Urology 2000; 55: 490–4. 2510. Abrams P, Cardozo L, Fall M et al. The standardisation of terminology in lower urinary tract function: Report from the standardisation sub-committee of the International Continence Society. Urology 2003; 61: 37–49. 2511. Nitti VW. Cystometry and abdominal pressure monitoring. In: Nitti VW, ed. Practical Urodynamics. Philadelphia, PA: W B Saunders, 1998: 38–51. 2512. Toppercer A, Tetreault JP. Compliance of the bladder: An attempt to establish normal values. Urology 1979; 14: 204–5. 2513. Gilmour RF, Churchill BM, Steckler RE et al. A new technique for dynamic analysis of bladder compliance. JURO 1993; 150: 1200–3. 2514. Ej M, JR W, TA B et al. Prognostic value of urodynamic testing in myelodysplastic patients. JURO 1981; 126: 205–9. 2515. McGuire EJ, Cespedes RD, O’Connell HE. Leak-point pressures. Urologic Clinics of North America 1996; 23: 253–62. 2516. Abrams PH, Griffiths DJ. The assessment of prostatic obstruction from urodynamic measurements and from residual urine. Br J Urol 1979; 51: 129–34. 2517. Schäfer W. Principles and clinical application of advanced urodynamic analysis of voiding function. Urol Clin North Am 1990; 17: 553–66. 2518. Abrams P. Bladder outlet obstruction index, bladder contractility index and bladder voiding efficiency: Three simple indices to define bladder voiding function. BJU Int 1999; 84: 14–15. 2519. Blaivas JG, Groutz A. Bladder outlet obstruction nomogram for women with lower urinary tract symptomatology. Neurourol Urodyn 2000; 19: 553–64. 2520. Lemack GE, Zimmern PE. Pressure flow analysis may aid in identifying women with outflow obstruction. J Urol 2000; 163: 1823–8. 2521. Brucker BM, Fong E, Shah S et al. Urodynamic differences between dysfunctional voiding and primary bladder neck obstruction in women. Urology 2012; 80: 55–60. 2522. Blaivas JG. Videourodynamics studies. In: Nitti VW, ed. Practical Urodynamics. Philadelphia, PA: W B Saunders, 1998: 78–93. 2523. Watanabe T and Chancellor M: Neurogenic Voiding Dysfunction. In: Nitti VW, ed. Practical Urodynamics. Philadelphia, PA: W B Saunders, 1998; 142–55.

35 Advanced urodynamics: Toward clinical useful neuroimaging in urology Bertil F.M. Blok

Abstract Urodynamic parameters do not correlate very precisely with urological symptoms of the lower urinary tract. Possibly, the combination of urodynamics with dynamic imaging of the brain can improve this correlation with the symptoms, which may influence the diagnostic process of functional urology. After a brief summary of the physiology of the micturition cycle, this chapter will discuss the present state of clinical research on dynamic imaging in urology and what is necessary to give fMRI an essential biomarker role in the diagnostic decision process before treatment. Finally, expectations about future developments are expressed.

Introduction The urodynamic investigation is the preferred method to study the function of the lower urinary tract. This diagnostic tool is supposed to reflect bladder and pelvic floor symptoms according to good urodynamic practices as published by the International Continence Society.1 However, practice shows that there is only weak correlation between symptoms, such as the feeling of strong urge and urge incontinence, and urodynamic findings. Furthermore, there is great variability in the urodynamic results between different patients or even in consecutive recordings in the same individual. The possible causes of this variability have been extensively described by Derek Griffiths in the earlier version of this chapter.2 Usually, the lower urinary tract is seen as a mechanical system with rather fixed parameters and the variation in urodynamics is seen as annoying artifacts. This view may be popular in clinical urology partly because it fits perfectly with the organ-based view of most of the urologists. Griffiths argued that the lower urinary tract should not be viewed without taking into account

its afferent and efferent neural control system. It has been shown, for example, that in patients with an intact neuraxis, the amplitude of detrusor overactivity diminishes in each repeated urodynamic study by almost 50% from the first to the third study.3 In contrast, in patients with a complete spinal cord injury, this variability with repetition is absent. The source of the variability is not known but it must be of supraspinal origin, presumably from cortical or subcortical areas. These forebrain structures might be also responsible for the well-known 50%–60% beneficial placebo effect observed in many randomized drug trials in patients with overactive bladder.4,5 This chapter discusses the areas known to be involved in the normal control of micturition and continence, provides insight in recent clinical dynamic imaging studies in urology, and presents possible ways to establish a diagnostic role for dynamic imaging in the evaluation of bladder dysfunction.

Basic control mechanism of the lower urinary tract Normally, the main role of the urinary bladder is to store and expel urine. Only few times a day it expels urine under appropriate and safe circumstances, i.e., when a toilet is reached and starts only with the pants down. The urinary bladder has the ability to hold an increasing amount of urine without a significant increase in pressure, up to a certain volume. The bladder neck and the urethra remain closed during the filling or storage phase to maintain continence. A sensation of fullness gradually develops, as bladder filling progresses and an appropriate place to empty the bladder will be looked for. The initiation of voiding is an involuntary phenomenon that starts with the relaxation of the striated external urinary sphincter and the pelvic floor, followed by a contraction of the detrusor

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muscle with an increase in the intravesical pressure and opening of the bladder neck and the urethra. The increased pressure is sustained until the bladder is empty. Voiding cannot be started voluntarily when an individual does not feel safe even though he or she wants to start micturition.6 The extreme form of this condition is called paruresis or shy bladder syndrome and is thought to affect about 15% of the healthy young people.7 The three micturition cycle phases—(1) feeling safe during premicturition to initiate voiding, (2) relaxation of the external urethral sphincter, and (3) contraction of detrusor muscle—are controlled by separated specific central pathways, i.e., forebrain and midbrain pathway to the so-called pontine micturition center (PMC), PMC excitatory pathway to inhibitory sacral interneurons and PMC excitatory pathway to sacral bladder motor neurons, respectively. Most of the time urine is stored in the relaxed bladder and the external urethral sphincter is contracted involuntarily continuously by another central pathway, i.e., the pathway from the socalled pontine continence center (PCC) to the motor neurons of the external urethral sphincter. Apparently, there are three levels of the central nervous system involved in the control of continence and micturition: the caudal spinal cord, the caudal brainstem including the pons, and the forebrain. The innervation of the lower urinary tract ­originates from  three sacral spinal nuclei. The sacral segments S2 through S4 contain the preganglionic parasympathetic bladder motor neurons. Activation of these neurons induces, via the postganglionic motor neurons, a contraction of the smooth detrusor muscle in the bladder wall, so that bladder emptying can take place. The efferent nerves involved travel within the pelvic nerve. Situated in the sacral segments S1 through S3 is Onuf’s nucleus after Onufrowitz, which contains the somatic motor neurons of the pelvic floor. The efferent fibers of this nucleus travel within the pudendal nerve and innervate the external urethral sphincter, where they control its contraction. This striated sphincter is partly under conscious control, but the tonic contraction necessary for urinary continence is under involuntary control from the PCC.9 Remarkably, afferents terminating on motor neurons of the Onuf’s nucleus differ considerably from those terminating on adjoining motor neurons of the back and hindlimb musculature10 and resemble supraspinal limbic afferents to the motor neurons of the diaphragm and of the striated part of the oesophagus. Preganglionic sympathetic motor neurons in the thoracolumbar segments T10 to L2 are involved in relaxation of the detrusor muscle and, consequently, in the compliance or elasticity of the bladder, denoting that intravesical pressure will only marginally increase if the bladder expands. It has been shown in cat that the sympathetic system inhibits actively bladder contraction when the bladder is filled at 60% or more of its maximal capacity.11 The sympathetic nerve fibers travel within the hypogastric nerve.

Afferent nerve fibers from the urinary bladder and urethra travel within the pelvic and pudendal nerves, respectively. They originate from muscle structures and the suburothelium. A significant role as a sensory organ has recently been attributed to the urothelium, the inner lining of the lower urinary tract. It has been recognized that the urothelium influences bladder function and not only acts as a barrier between bladder contents and bladder tissue.12 Two types of afferent nerves have been identified: myelinated Aδ and unmyelinated C fibers. The Aδ fibers respond to normal bladder distention and play a role during normal micturition. The C fibers are normally inactive. They become activated during a local pathologic state such as a bladder infection or as a consequence of a neurologic disease such as a spinal cord injury. They may then mediate pathologic voiding reflexes. Bladder filling activates Aδ afferents, which leads to contraction of smooth muscles in the bladder neck and proximal urethra and to relaxation of the detrusor muscle. Also, the tone of the striated urethral sphincter increases. The initiation of micturition is thought to be dependent by excitatory signals from the hypothalamus, and the periaqueductal gray (PAG) to the PMC. It has been suggested that afferent information from the filled bladder is relayed to cortical areas, including the cingulate gyrus and the insula. These latter parts of the brain makes sensations accessible to conscious awareness in the cerebral cortex, which in turn makes decisions on the initiation of micturition (via the prefrontal cortex) and monitors and controls the micturition process.6 When the individual feels safe, the PMC is activated and micturition starts involuntarily. The PMC sends long descending excitatory fibers to inhibitory interneurons in the sacral intermediomedial cell column, which in turn inhibit the motor neurons of the external urethral sphincter in Onuf’s nucleus (Figure 35.1).13 This inhibition results in a relaxation of the sphincter and opening of the urethra.14 At the same time, the PMC sends excitatory fibers to the preganglionic parasympathetic motor neurons of the detrusor muscle in the intermediolateral cell column, which results in a relatively slow contraction of the smooth muscle of the urinary bladder.

Clinical studies Most of the dynamic imaging studies in urology are on group analysis in healthy individuals.6,15–22 Common activations during urine storage and micturition were observed in the PMC, PAG, hypothalamus, insula, anterior cingulate, and orbito- and prefrontal cortex. Furthermore, several studies have been published on group analysis of dynamic imaging of the brain in patients with urologic symptoms like urge and urge incontinence who did not receive treatment.23–25 It was shown by Griffiths et al.24 that

Advanced urodynamics

IC

Pontine micturition center

GABA-ergic neurons

(+)

(+)

Bladder motor neurons

S2

Bladder sphincter motor neurons

(–)

Bladder (+)

(+)

Bladder sphincter

Figure 35.1 Schematic representation of the descending pathways from the pontine micturition center to inhibitory GABA-ergic interneurons to indirectly relax the urethral sphincter and to preganglionic bladder motor neurons to contract the bladder muscle.

385

the anterior cingulate gyrus appears to be more active in urge urinary incontinent patients. This cingulate activation was interpreted as a sign of abnormal sensation of urgency in the face of fear of leakage. The authors concluded that the pattern of brain activity was more a reaction to poor bladder control than a cause of it. Only a few studies are available on dynamic imaging in patients with functional bladder symptoms receiving treatment. Two of those were on sacral neuromodulation (SNM): one in patients with urge incontinence26 and the other in patients with urinary retention.27 The first study put forward that sacral neuromodulation for urgency may alter cortical sensory areas of the brain. Positron emission tomography (PET) was used to evaluate regional cerebral blood flow in patients with acute and chronic SNM.26 One of the main findings was that SNM appeared to modulate cortical and subcortical areas important not only for the sensation of bladder filling and the timing of micturition but also for general alertness and attention (Figure 35.2). Another finding was that the effect of SNM shifted in time from areas involved in sensorimotor learning (primary and supplementary sensorimotor cortex) toward areas involved in more reflex-like and unconscious behavior (midbrain and midline thalamus). This implies that the brain undergoes neuroplasticity during periods of longterm beneficial SNM. Activation of afferent pathways by SNM may result in modulation of cortical and subcortical brain structures important for alertness and awareness, which in turn inhibit reflex detrusor contractions, thereby restoring urinary continence. The effect of SNM on the whole body system including the lower urinary tract can be compared to the effect of a tactile or painful stimulus. The individual is aware of the stimulus even before he knows the exact location. In that circumstance, it is not allowed to lose excrements, overactive bladder contractions are inhibited, and the brain prepares the body to react. There exist only very few studies on dynamic imaging and systemic drug treatments. This is surprising because many of these treatments, such as antimuscarinics, antiandrogens, and alpha adrenergic blockers, may have direct and indirect effects on the central nervous system

CG OFG OFG

Figure 35.2 Areas significantly modulated in patients with chronic beneficial sacral neuromodulation for urge urinary incontinence. CG, cingulate gyrus; OFG, orbitofrontal gyrus.

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and could be studied by dynamic imaging. Functional magnetic resonance imaging (fMRI) activation has been used to study patients with urinary frequency before and after treatment with tolterodine or placebo.28 The authors observed differences in the parietal cortex and cerebellum, but these results are difficult to interpret as there was no control group without urinary frequency. Unfortunately, none of the mentioned published studies could present reproducible activations in individual healthy volunteers or patients as the resolution of the imaging techniques was not high enough. At present, the available publications are helpful in explaining certain mechanisms of the normal physiology and pathophysiology in urologic patients. However, these studies are far from useful in the decision process of subscribing the appropriate treatment to patients with functional bladder problems.

Could dynamic imaging have a role in clinical urology? It can be assumed that a patient with a functional bladder problem would be helped most with a system approach. This would imply that the visited care giver would have knowledge of, and access to, diagnostic tools that provide insight into the function at all levels of the individual urinary control system: urethra, bladder muscle and urothelium, afferent nerves, spinal cord, brain, efferent nerves, and ganglion cells. On the basis of the patient history, a decision could be made for the choice of the most appropriate and cost–effective diagnostic tool, which could vary from cystoscopy, urodynamics to fMRI. In the early days of dynamic imaging of the brain and bladder connection, the technique of choice was the PET scanner. The PET provided great insight in basic mechanisms and could be used for patients with implanted devices, which were not MRI-safe. However, it is very unlikely that PET will have a prominent role in the future diagnostic process of the individual patient with bladder problems due to the relatively poor individual resolution, the necessity of a nearby cyclotron, the high costs, and the potential damaging isotopes. It is much more likely that fMRI will play a role in the decision model for treatment of functional bladder problems. Until recently, this was unimaginable because fMRI could be done only with 1.5 or 3 Tesla magnets. This has been changed with the introduction of 7 Tesla magnets. For example, a recent study on finger movements showed that fMRI can give significant and reproducible differences in relevant cerebral blood flow in one subject.29 This development could prelude the use of fMRI in individual urologic patients, but several criteria for optimal use have to be fulfilled before clinical application. Potential criteria to be considered are, for instance, the following: the individual fMRI results are reproducible by different research groups, there

are significant inter- and intra-individual differences in patients with or without urge incontinence, there are significant intra-individual differences before and after treatment, there is low or absent inter-observer variability, it has high specificity and high sensitivity for a specific functional bladder dysfunction, it is cost–effective, it changes potential medical practice and, consequently, will have widespread use in the urological community, and it can be easily incorporated in a decision algorithm. Only with fulfillment of such basic criteria could the “advanced” urodynamics offer similar diagnostic advantages for functional urology as has molecular biology for the diagnostics of prostate cancer.

Acknowledgment I am thankful to Derek Griffiths for his kind advice on the manuscript.

References 2524. Abrams P, Cardozo L, Fall M et al. The standardisation of terminology of lower urinary tract function: report from the standardisation sub-committee of the International Continence Society. Neurourol Urodyn 2002; 21: 167–178. 2525. Griffiths DJ. Advanced urodynamics. In: Corcos J, Schick E, eds. Textbook of the Neurogenic Bladder, 2nd ed. London: Informa UK Ltd., 2008; 464–74. 2526. Ockrim J, Laniado ME, Khoubehi B et al. Variability of detrusor overactivity on repeated filling cystometry in men with urge symptoms: Comparison with spinal injury patients. BJU Int 2005; 95: 587–90. 2527. Chapple C, van Kerrebroeck P, Tubaro A et al. Clinical efficacy, safety, and tolerability of once-daily fesoterodine in subjects with overactive bladder. Eur Urol 2007; 52: 1204–12. 2528. Herschorn S, Barkin J, Castro-Diaz D et al. A phase III, randomized, double-blind, parallel-group, placebo-controlled, multicentre study to assess the efficacy and safety of the β₃ adrenoceptor agonist, mirabegron, in patients with symptoms of overactive bladder. Urology 2013; 82: 313–20. 2529. Blok BFM, Willemsen ATM, Holstege G. A PET study on brain control of micturition in humans. Brain 1997; 120; 111–21. 2530. Williams GW, Degenhart ET. Paruresis: A survey of a disorder of micturition. J Gen Psychol 1954; 51: 19–29. 2531. Blok BFM. Central pathways controlling micturition and urinary continence. Urology 2002; 59: 13-7. 2532. Holstege G, Griffiths D, de Wall H, Dalm E. Anatomical and physiological observations on supraspinal control of bladder and urethral sphincter muscles in the cat. J Comp Neurol 1986; 250: 449–61. 2533. Holstege G, Tan J. Supraspinal control of motoneurons innervating the striated muscles of the pelvic floor including urethral and anal sphincters in the cat. Brain 1987; 110: 1323–44. 2534. Vaughan CW, Satchell PM. Role of the sympathetic innervation in the feline continence process under natural filling conditions. J Neurophysiol 1992; 68: 100–8. 2535. Birder LA, Ruggieri M, Takeda M et al. How does the urothelium affect bladder function in health and disease? ICI-RS 2011. Neurourol Urodyn 2012; 31: 293–9. 2536. Blok BFM, De Weerd H, Holstege G. The pontine micturition center projects to sacral cord GABA immunoreactive neurons in the cat. Neurosci Lett 1997; 233: 109–12.

Advanced urodynamics 2537. Blok BFM, van Maarseveen, JTPW, Holstege G. Electrical stimulation of the sacral dorsal gray commissure evokes relaxation of the external urethral sphincter in the cat. Neurosci Lett 1998; 249: 68–70. 2538. Blok BFM, Sturms LM, Holstege G. Brain activation during micturition in women. Brain 1998; 121: 2033–42. 2539. Nour S, Svarer C, Kristensen JK, Paulson OB, Law I. Cerebral activation during micturition in normal men. Brain 2000; 123: 781–9. 2540. Athwal BS, Berkley KJ, Hussain I et al. Brain responses to changes in bladder volume and urge to void in healthy men. Brain 2001; 124: 369–77. 2541. Matsuura S, Kakizaki H, Mitsui T, Shiga T, Tamaki N, Koyanagi T. Human brain region response to distention or cold stimulation of the bladder: A positron emission tomography study. J Urol 2002; 168: 2035–9. 2542. Kuhtz-Buschbeck JP, van der Horst C, Pott C et al. Cortical representation of the urge to void: A functional magnetic resonance imaging study. J Urol 2005; 174: 1477–81. 2543. Mehnert U, Boy S, Svensson J. Brain activation in response to bladder filling and simultaneous stimulation of the dorsal clitoral nerve: An fMRI study in healthy women. Neuroimage 2008; 41: 682–9. 2544. Krhut J, Tintera J, Holy P, Zachoval R, Zvara P. A preliminary report on the use of functional magnetic resonance imaging with simultaneous urodynamics to record brain activity during micturition. J Urol 2012; 188:474–9.

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2545. Tadic SD, Tannenbaum C, Resnick NM, Griffiths D. Brain responses to bladder filling in older women without urgency incontinence. Neurourol Urodyn 2013; 32: 435–40. 2546. Griffiths D, Derbyshire S, Stenger A, Resnick N. Brain control in normal and overactive bladder. J Urol 2005; 174:1862–7. 2547. Griffiths D, Tadic SD, Schaefer W, Resnick NM. Cerebral control of the bladder in normal and urge-incontinent women. Neuroimage 2007; 37: 1–7. 2548. Tadic SD, Griffiths D, Schaefer W, Resnick NM. Abnormal connections in the supraspinal bladder control network in women with urge urinary incontinence. Neuroimage 2008; 39: 1647–53. 2549. Blok BFM, Groen J, Bosch JLHR, Veltman DJ, Lammerstma AA. Different brain effects during chronic and acute sacral neuromodulation in urge incontinent patients with implanted neurostimulators. BJU Int 2006; 98: 1238–43. 2550. Dasgupta R, Critchley HD, Dolan RJ, Fowler CJ. Changes in brain activity following sacral neuromodulation for urinary retention. J Urol 2005; 174: 2268–72. 2551. Pontari MA, Mohamed FB, Lebovitch S. Central nervous system findings on functional magnetic resonance imaging in patients before and after treatment with anticholinergic medication. J Urol 2010; 183: 1899–905. 2552. Besle J, Sanchez-Panchuelo R, Bowtell R et al. Event-related fMRI at 7T reveals overlapping cortical representations for adjacent fingertips in SI of individual subjects. Hum Brain Mapp 2013; 35(5): 2027–43.

36 Normal urodynamic parameters in children Diego Barrieras and Orchidée Djahangirian

Introduction Urodynamic evaluation yields invaluable information about lower urinary tract function in infants and children. First developed in adults, it has been adopted in children, using the same terminology. The equipment used is similar to that used in adults, with appropriate catheter sizes according to age. It is best performed by professionals specialized in pediatric care, as the results must not reflect apprehension. Patience and playfulness help distract the child’s attention from the surrounding  environment and alleviate the pressure of performance. A child with suspected lower urinary tract ­dysfunction deserves a detailed history including previous urinary tract infection or surgery, trauma, and neurologic disease. Voiding pattern including incontinence, urgency, frequency, urinary stream, and bowel habits should be noted. Recording a voiding diary gives objective data that can be followed-up. Physical examination should include abdominal, genitalia, lumbo-sacral spine, and a brief neurological examination. Upper urinary tract imaging by ultrasonography helps detect those patients more likely to have a pathology on urodynamic studies.1 The less invasive uroflowmetry should be performed as an initial investigation of lower urinary tract dysfunction in children. It has been popularized as a study of lower urinary tract obstruction, mainly for benign prostatic hyperplasia.2,3 Although its use in children dates back to the 1950s,4 it became a widespread tool in the 1980s.5–7 Williot et al.8 have coupled measurement of uroflowmetry to postvoid residual volume assessment using biplanar ultrasound. They stated that the combination of dynamic flow analysis and accurate bladder residual volume assessment have proven to be a simple yet comprehensive appraisal of the physiology of the lower urinary tract. These studies have advantages that make them almost ideal for the pediatric population (Table 36.1).

Table 36.1  U  roflowmetry: Advantages and disadvantages Advantages

Disadvantages

Simple to perform

Not etiologic

Simple equipment

Less reproducible than in adults

Non-invasive

Need to be toilet trained

Physiologic Can be repeated Low cost

Indications for uroflowmetry Uroflowmetry can be used in any patient with suspected lower urinary tract dysfunction. Although it is not a highly specific diagnostic tool,9 it has semiological value and is a good screening tool. The studies can also be used as a follow-up tool to assess results of surgical treatment such as hypospadias repair or posterior urethral valve surgery. It is also very useful in following medical treatment, as in bladder retraining for dysfunctional voiding and nonneurogenic neurogenic bladder.10,11 It is important to know that uroflowmetry in children is not as reproducible as in adults.9,10 Therefore, the trend analysis of multiple studies has more value. Current indications for performing uroflowmetry are listed in Table 36.2. Figure 36.1 shows the different parameters of uroflowmetry.

Technical aspects and pitfalls To obtain optimal results from uroflowmetry, voiding condition must be as close to normal as possible. This is true in adults and even more important in children.6,7 Children under the age of 6 are usually less motivated, less patient, more apprehensive, and have limited

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Table 36.2  Indications for uroflowmetry evaluation •• Urgency, frequency syndrome •• Urinary tract infection •• Incontinence (except isolated night time incontinence) •• Dysfunctional voiding syndrome •• Non-neurogenic neurogenic bladder (Hinman/Allen syndrome) •• Vesicoureteral reflux before and after surgical correction •• Neurogenic bladder •• Infravesical obstruction (posterior urethral valves, urethral, or meatal stenosis) •• Follow-up in hypospadias surgery and other urethral reconstruction •• Biofeedback method for bladder retraining

mL/s Max flow Avg flow s Time to max flow Flow time

Figure 36.1 Different parameters of uroflowmetry.

understanding.7 The postvoid residual volume can be determined by ultrasound using a model that considers the bladder to be a rectangular box. This equipment is readily available and cost-effective. Using a sagittal and a transverse view, two measures of bladder size are taken, and a volume generated. This technique is simple, noninvasive, accurate, and reproducible.8 It should be noted that it has a slight tendency to overestimate the residual volume when compared to urethral catheterization.9 Finally, like any ultrasonic technique, it is operator dependent, but this technique is easy to learn for those involved in urodynamic testing.

Interpretation of uroflowmetry The availability of nomograms for analysis of uroflow data have been helpful in providing relative data for size and weight while recognizing that the absolute interpretation can be misleading.11–14 However, there are general principles that guide the interpretation of uroflowmetry in

children. As in adults, the results obtained are an integration of detrusor contractility and urethral resistance.6 We believe that the shape of the flow curve is the most important feature, followed by maximal flow rate. The shape of the normal flow curve is a bell-shaped curve (Figure 36.2a) in more than 90% of normal children, even with voided volume less than 100 mL.6,11,12 With low or high voided volume, the shape of the curve can have a more plateau appearance. There are three frequently encountered shapes. The staccato shape (Figure 36.2b) is indicative of either abnormal sphincter relaxation in dysfunctional voiding of non-neurogenic neurogenic bladder, or unsustained bladder contraction and abdominal straining. Children with dysfunctional voiding often benefit from bladder retraining, in which case uroflowmetry can act as biofeedback. A plateau-shaped (Figure 36.2c) curve may be normal but can indicate infravesical obstruction, especially if associated with a low maximal and average flow rate. In such a case, depending on history and physical examination, further diagnostic tests may be indicated, such as a voiding cystogram to diagnose posterior urethral valves. Also of note, following hypospadias surgery, a plateau-shaped curve with low maximal and average flow rate is expected, but a physician should watch the trend on subsequent studies.15 A tower-shaped curve (Figure 36.2d) is usually associated with high maximal flow rate and is believed to reflect dysfunctional voiding. It is more frequently encountered in girls and is often referred to as “supervoiders.” One has to be critical when looking at these results. Artifacts, mostly caused by misdirection of the stream, will change the shape of the curve and thus the numbers generated.6 The maximal and average flow rates closely correlate with voided volume, which is dependent on age and size of the child. Again, the nomograms are helpful as references. From a practical standpoint, the maximal flow rate has more value than the average flow rate and has a linear relationship with the voided volume. The maximal flow rate should equal the square root of the voided volume.7 For example, with a voided volume of 100 mL, the maximal expected flow rate should be 10 mL/sec. Most often, when these values are low, they are associated with a plateaushaped curve (Figure 36.2).

Uroflowmetry and electromyography recordings There is no absolute truth when analyzing postvoid ­residual volume in children, particularly in view of their fear and anxiety. We believe, however, that a normal flow rate coupled with complete emptying (0 mL) excludes the likelihood of serious underlying abnormalities.3,8,14 On the contrary, defining what is a clinically significant residual volume is ­difficult in children and its value as a single m ­ easure of urologic abnormality is poor. An isolated ­postvoided ­residual

Normal urodynamic parameters in children

Normal

391

Staccato

(b)

(a)

Tower

Plateau

(c)

(d)

Figure 36.2 (a) Normal and (b–d) abnormal flowmetry patterns in children.

volume measure without symptoms may merely reflect the child’s apprehension. Thus, we routinely use simultaneous EMG recordings with perineal patch electrodes as a means to discriminate normal children from patients with abnormal voiding pattern16 (Figure 36.3). Treatment and further evaluation are then tailored according to the findings. If a child with no anatomical anomalies presents with high residual volume or dyssynergia on cutaneous EMG recording, we would proceed with bladder and bowel management. If the latter should fail, despite added bladder-oriented pharmacotherapy, we would proceed with complete urodynamic studies. If a child presents anatomical abnormalities and an abnormal EMG-uroflowmetry, then we would proceed directly toward a full urodynamic evaluation. In summary, the non-invasive nature of EMG-coupled uroflowmetry and postvoided residual assessment by ultrasound make them ideal as a screening and follow-up tool in children. Their relative simplicity and ease of use add to their wide application. The results of these studies are not highly specific, but when interpreted in light of the history, physical findings, and other tests, they aid in establishing a diagnosis, elaborating a treatment plan and following the results of treatment during bladder retraining and posthypospadias surgery.

Complete urodynamic studies Some children require more extensive urodynamic studies, which includes a cystometrogram to determine ­bladder capacity, contractility, compliance, voiding, and

Dyssynergia

Figure 36.3 Dyssynergia.

continence.1 Indications include abnormal curve pattern associated with detrusor-sphincter dyssynergia (DSD) on cutaneous EMG, abnormal flow rate with daytime urinary incontinence, and chronic or recurrent bacteriuria that is refractory to bladder and bowel management. Clear indications for complete urodynamics as the initial test exist in patients with suspected infravesical obstruction such as posterior urethral valves, suspected neurogenic bladder dysfunction, and failed management of vesicoureteral reflux. Only few studies have looked at normal urodynamics in children. Sillen17 evaluated bladder function in healthy neonates and infants using free voiding studies with a 4-hour voiding observation and subsequent urodynamic studies. Thirty percent of the cases presented an

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interrupted voiding pattern, which seems to be an immature phenomenon, as it is seen in 60% of preterm neonates, and disappears completely before the age of toilet training. They theorized that a physiological DSD explains the frequent postvoid residual observed.18,19 Along with the small caliber of the urethra, this can explain the high voiding pressure levels. There were also signs of bladder hyperactivity, as patients exhibited premature voiding contractions after only a few milliliters of filling with leakage of urine. The normal neonate micturition is thus characterized by small, frequent voids of varying volume. Their findings challenge the concept that neonates display simply a voiding reflex and that regulation of micturition involves higher neuronal pathways. Another study from Sweden evaluated urodynamics in normal infants and children.7 One of the most important statements of the study is that a tense and apprehensive child will not produce reliable urodynamic data. Studies should be done in an appropriate setting with an experienced urodynamicist. Lorenzo et al. showed that outcomes were similar whether the patient was placed in a supine or sitting position.20 Their study showed that inhibition of the detrusor improves in the first 5 years of life. Better bladder proprioception allows for better control of micturition. To this, we must add the concept of improvement of physiological DSD as suggested by the study of Sillen.17

Bladder capacity Hjamlas observed that most urodynamic variables are age dependent.7 Several formulae have been proposed in the literature (see Table 36.3). The most urodynamically sound formula, however, was described by Houle et al.,21 as they evaluated 69 normal children, measuring total bladder capacity (mL), full resting pressures (cmH2O), and the volumes (mL) and percentage of the total bladder capacity stored at detrusor pressures less than 10, 20, 30, and 35 cmH2O. According to their results, minimal acceptable total bladder capacity for age can be estimated by 16(age) + 70 in mL, which was derived using criteria for safe storage characteristics of the bladder in children.

Bladder compliance Normal compliance in children has been established somewhat arbitrarily. The minimally acceptable value for bladder compliance during bladder filling has been arbitrarily set at 10 mL/cmH2O.21 Others have further stratified compliance as being poor at 10 mL/cmH2O23

Voiding pressures

Infant male: median 100 cmH2O17 Infant female: median 70 cmH2O17 1–3 yrs old child male: 70 cmH2O7 1–3 yrs old child female: 60 cmH2O27 7 years and older: similar to adult

Postvoid residual

Infant: 1 void/4 hour complete, median PVR 4–5 mL

(limited reliability)

up to 2 yrs old: 4–5 mL17 3 yrs old and up: 0 mL

Normal urodynamic parameters in children the expected bladder capacity per minute. Compliance should be evaluated at regular intervals during cystometric recording (25%–50%–75%) and not only at final capacity, since loss in compliance occurring early in the filling phase is more detrimental to the upper urinary tract.23 Uninhibited contractions are recorded as any apreciable detrusor contraction, especially if it causes urine leakage or urgency. Since this chapter deals with normal urodynamics in children, detrusor leak point pressure or abdominal leak point pressure will not be discussed here.

Voiding pressures Hjalmas described intravesical pressures to be lower in girls than in boys, lower in infants than in older children, but independant of age.7 However, it is mentioned that bladder pressure recordings represent the most common source of error in children and emphasizes that examination be performed in relaxed environment. Standards are listed in Table 36.3.

Postvoid residual It is known that infants do not empty their bladder at each void, but seem to empty completely their bladder at least once during a 4-hour observation period.17 Residual urine during this period is minimal (4–5 mL) up to age 2. Residual urine should be 0 mL as of 3 years of age.24 Caution should be taken in interpretation of postvoid residual as it may be falsified by the child’s anxiety. A summary of normal urodynamic values in children is presented in Table 36.3.

References 2553. Drzewiecki B, Bauer S. Urodynamic testing in children: Indications, technique, interpretation and significance. J Urol 2011; 186: 1190–7. 2554. Gleason DM, Lattimer JK. The pressure flow study: A method for measuring bladder neck resistance. J Urol 1962; 827: 844. 2555. Abrams PH, Griffits DJ. The assessment of prostatic obstruction from urodynamics measurements and from residual urine. Br J Urol 1979; 51: 129. 2556. Scott RJ, McIlhaney JS. The voiding rates in normal children. J Urol 1959; 82: 224. 2557. Churchill BM, Gilmour RF, Williot P. Urodynamics. Pediatr Clin North Am 1987; 34(5): 1133–57.

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2558. Jorgensen JB, Jensen KM. Uroflowmetry. Urol Clin North Am 1996; 23(2): 237–42. 2559. Hjalmas K. Urodynamics in normal infants and children. Scand J Urol Nephrol Suppl 1988; 114: 20–7. 2560. Williot P, McLorie GA, Gilmour RF, Churchill BM. Accuracy of bladder volume determinations in children using a suprapubic ultrasonic bi-planar technique. J Urol 1989; 141(4): 900–2. 2561. Meunier P, Mollard P, Nemoz-Behncke C, Genet JP. [Urodynamic exploration in functional micturition disorders in children]. Arch Pediatr 1995; 2(5): 483–91. 2562. Ewalt DH, Bauer SB. Pediatric neurourology. Urol Clin North Am 1996; 23(3): 501–9. 2563. Segura CG. Urine flow in children: A study of flow chart parameters based on 1361 uroflowmetry tests. J Urol 1997; 157: 1426. 2564. Jensen KM, Nielsen KK, Jensen H, Pedersen OS, Krarup T. Urinary flow studies in normal kindergarten- and school children. Scand J Urol Nephrol 1983; 17(1): 11–21. 2565. Gaum LD, Wese FX, Liu TP, Wong AK, Hardy BE, Churchill BM. Age related flow rate nomograms in a normal pediatric population. Acta Urol Belg 1989; 57(2): 457–66. 2566. Wese FX, Gaum LD, Liu TP, Wong AK, Hardy BE, Churchill BM. Body surface related flow rate nomograms in a normal pediatric population. Acta Urol Belg 1989; 57(2): 467–74. 2567. Jayanthi VR, McLorie GA, Khoury AE, Churchill BM. Functional characteristics of the reconstructed neourethra after island flap urethroplasty. J Urol 1995; 153(5): 1657–9. 2568. Hoebeke P, Bower W, Combs A et al. Diagnostic evaluation of children with daytime incontinence. J Urol 2010; 183: 699. 2569. Sillen U. Bladder function in healthy neonates and its development during infancy. J Urol 2001; 166(6): 2376–81. 2570. Roberts DS, Rendell B. Postmicturition residual bladder volumes in healthy babies. Arch Dis Child 1989; 64(6): 825–8. 2571. Sillen U, Solsnes E, Hellstrom AL, Sandberg K. The voiding pattern of healthy preterm neonates. J Urol 2000; 163(1): 278–81. 2572. Lorenzo AJ, Wallis MC, Cook A et al. What is the variability in urodynamic parameters with position change in children? Analysis of a prospectively enrolled cohort. J Urol 2007; 178: 2567. 2573. Houle AM, Gilmour RF, Churchill BM, Gaumond M, Bissonnette B. What volume can a child normally store in the bladder at a safe pressure? J Urol 1993; 149(3): 561–4. 2574. Horowitz M, Combs AJ, Shapiro E. Urodynamics in Pediatric Urology. In: Nitty VW, ed. Practical Urodynamics. Philadelphia, PA: W B Saunders, 1998. 2575. Gilmour RF, Churchill BM, Steckler RE, Houle AM, Khoury AE, McLorie GA. A new technique for dynamic analysis of bladder compliance. J Urol 1993; 150(4): 1200–3. 2576. Jansson UB, Hanson M, Hanson E, Hellstrom AL, Sillen U. Voiding pattern in healthy children 0 to 3 years old: A longitudinal study. J Urol 2000; 164(6): 2050–4. 2577. Koff SA. Estimating bladder capacity in children. Urology 1983; 21(3): 248. 2578. Kaefer M, Zurakowski D, Bauer SB et al. Estimating normal bladder capacity in children. J Urol 1997;158(6):2261–4. 2579. Wen JG, Tong EC. Cystometry in infant and children with no apparent voiding symptoms. Br J Urol 1998; 81: 468.

37 Urodynamics in infants and children Kate Abrahamsson, Gundela Holmdahl, and Ulla Sillén

Introduction Urodynamics in infants and children is basically the same procedure as in adults and shares the same techniques and objectives. There is, however, one fundamental difference: the patient is a child. Essentially, this means two things. First, a child harbors intuitive fear for any unknown procedure but is, at the same time, largely unresponsive to rational argumentation about the nature of and the need for the examination. Second, the child is a growing individual, increasing in weight 20-fold from infancy to puberty. This means that for children there exists no single set of “normal” urodynamic variables but rather a continuum of each variable, depending on and correlating to the age and the body size of the individual. This chapter will concentrate on those two aspects: first, on how to prepare, inform, reassure, encourage, and comfort the child before and during the urodynamic examination; second, how to report the expected range of “normal” values for urodynamic variables from infancy to adolescence.

Historical notes on urodynamics in infants and children It is hard to understand why bladder function in children did not receive any attention from medical scientists until the mid-twentieth century. Before that time, it seems to have been understood, that almost all children had bladders that worked well, regarding both storage and evacuation of urine. If a functional disturbance such as incontinence was indeed noted, traditional wisdom suggested that it was due to psychological problems within the child and/or the family. In contrast, we are now aware that non-neurogenic bladder/sphincter dysfunction in children is caused by delayed maturation (most often genetically determined) of the central nervous system (CNS) bladder control. Psychological problems in an incontinent

child could be a consequence of the bladder dysfunction, not the other way round. Since 1959, the first urodynamic studies on normal and pathological bladder function in infants and children came into print.1–9 A rapidly increasing number of studies followed, once it became clear that at age 7 years as many as 10% of children have non-neurogenic disturbance of bladder/sphincter function. Knowledge surfaced that bladder dysfunction plays a major role not only for urinary incontinence but also, even more importantly, for the creation and persistence of vesicoureteral reflux (VUR) and urinary tract infection (UTI), with the accompanying risk for deterioration of renal function.10 Children with neurogenic bladder dysfunction (NBD) due to myelodysplasia and other disorders of the CNS were exposed to the same risk to an even larger degree. Surprisingly, however, this fact did not become obvious until the late 1960s, when it was finally understood that the UTIs and the frequent progress of bacterial resistance during antibiotic therapy in myelomeningocele children was caused by inadequate bladder emptying, leaving postvoid residual behind. Regular and low-pressure bladder evacuation with the aid of clean intermittent catheterization (CIC), introduced by Jack Lapides in 1972, led to a dramatic reduction in the rate and severity of UTIs in this patient group and even resulted in disappearance of reflux in many patients.11

Development of bladder function The normal development of lower urinary tract function from infancy to adolescence has to be reviewed before describing the urodynamic procedures and techniques used in children and what results to expect. This is necessary to understand the dynamic nature of the urodynamic variables in the growing individual. Bladder function during infancy has previously been regarded as automatic, with voiding induced by a constant volume in the bladder12 and without cerebral influence.

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During the last decade, it has been shown convincingly that the brain is already involved in the voiding reflex from birth. This is best illustrated by the finding that in the majority of cases newborn babies wake up or show signs of arousal before voiding.13,14 This means that the reflex pathway connection to the cerebral cortex is anatomically already developed in this age group; however, voiding is neither conscious nor voluntary – the infant is only disturbed by the signal. Both maturation and probably training are needed for the voidings to be conscious and voluntary. Neonates and infants void at varying bladder volumes and this is contrary to the belief that the voiding reflex is a simple spinal reflex elicited by a constant bladder volume. This has been shown in free voiding studies of both preterm15 and full-term infants13 in whom bladder volume initiating voiding varies from 30% to 100% of functional bladder capacity. The reason for this variation is unknown, but the bladder volume initiating micturition is higher after a period of sleep. The infant’s voiding is also characterized by a physiological form of detrusor-sphincter dyscoordination, which has been shown in free voiding studies as interrupted voidings and increase in postvoid residual urine (Figure 37.1).16 This phenomenon has also been observed in urodynamic studies as an intermittent increase in the electromyographic (EMG) activity of the pelvic floor during voiding, concomitant with fluctuations in voiding Full-term neonate Void./Res. Vol/Urine Bladder volume at voiding 8 10 (mL – %)

9

10

11

12

20 30 40 50 00 10 20 30 40 50 00 10 20 30 40 50 00 10 20 30 40 50 00

24 19

30

21 6

6

Preterm infant (32w) Bladder volume at voiding (mL – %)

45 100% 25 4

4

8

35%

10 5

3 2

13 56% 7 35%

15 6

8 3

23 100% 9 39%

36 80%

16

2

18 40%

15

0

15 33%

17

0

17 38%

EMG 100 Pdet 0 100 Pves 0

Premature voiding

Voiding

Figure 37.2 Cystometric recording in a nonrefluxing newborn sibling of a child with vesicoureteral reflux (VUR). Note the premature voiding contraction after infusion of 5 mL with leakage of urine. Voiding after a total filling of 30 mL of saline shows an increase of electromyographic (EMG) activity of the pelvic floor and concomitant fluctuation in detrusor voiding pressure.

detrusor pressure (Figure 37.2).14,17 A longitudinal study of free voids from birth to age 3 years in healthy children revealed that the suggested dyscoordination disappears successively, and is not seen after potty-training age.13 Another important observation in the study by Jansson et al.13 is the increase in postvoid residual urine during the first couple of years. The reason for the incomplete emptying in infancy is probably the physiological form of dyscoordination discussed earlier, with interruption of the urine stream before the bladder is empty. However, with the acquisition of continence the residual volume decreased in this group of healthy children, and the ability to empty the bladder was complete at the age of 3. In the longitudinal study of free voidings by Jansson et  al.,13 it was also observed that bladder capacity was almost  unchanged during the first 2 years of life but showed a  steep  increase at the time the child gets dry (see Figure 37.6). A similar accelerated increase in b ­ ladder capacity, which is age related, has also been noted in other studies.12,18 This increased bladder capacity has been ­considered as a prerequisite for both day and nighttime continence. Conversely, continence during night has been considered to be obtained only after achievement of day dryness.19,20 The reason for this increase in bladder ­capacity has previously only been discussed in terms of general maturation.

Figure 37.1

Acquisition of bladder control

Four-hour voiding observation in a full-term neonate and a preterm infant (gestation age 32 weeks) showing varying bladder volumes initiating voiding (the sum of voided volume and residual urine). The volumes vary between 33% and 100% of the highest volume in the bladder (= the bladder capacity) during the observation. Note the interrupted voiding seen once in the full-term and twice in the preterm infant.

Development of bladder control was earlier supposed to begin at 1 year of age and often to be fully developed by age 4.5 years. It was described by Muellner as “a maturation which could not be influenced by training.” Another factor that was considered important was the doubling of bladder capacity between 2 and 4.5 years of age.12,21 These

Urodynamics in infants and children statements about maturation, combined with the improvement in the quality of disposable napkins, have contributed to a more liberal view about what age potty training should be started. In fact, during the last decades, potty training has been regarded as unnecessary due to the belief that physical maturation should dictate when a child becomes dry. It is quite clear from other areas, however, that training can accelerate maturation. Potty training was instituted early before the era of disposable napkins. Some authors have reported bladder control much earlier than nowdays,19,20 whereas others have not been able to show such a connection.22 In published data from Vietnam, it was shown that it is possible to start potty training with good outcomes very early in life.23,24 When daily potty training was achieved, the children were able to empty their bladders completely already at the age of 9 months.24 If bladder control only means to void on the potty when the child is put there by the parent regularly or when the child indicates a need to void, it can be obtained early. The degree of maturation needed for such basic training is probably already present during the first year of life.25 The goal of potty training, to obtain full social bladder control, cannot be achieved solely with the early potty training discussed earlier. The prerequisites for success are influenced both by physical maturation and the child’s interest in this task as well as by support from adults, routines, and parental expectations. Most children may stay dry in their usual milieu around the age of 2. However, the child has to reach at least 3.5–4 years of age to become mature enough to be able to cope with every aspect of their own toileting (including taking off and on clothes, flushing the toilet, closing the door, etc.). The markedly improved emptying after potty training, discussed earlier, is very interesting, since it is something that can be used in the treatment of incomplete emptying in this age group, through institution of potty training earlier than what is common.

Indications for urodynamics in children The indications for urodynamics in infants and children are the same as for adults: namely, suspicion of neurogenic, non-neurogenic bladder dysfunction, or structural outflow obstruction. Thus, they include neurogenic bladder, gross VUR (particularly in infants), recurrent UTIs, uroflow/ residual measurement suggesting infravesical obstruction, and urinary incontinence that has been refractory to conventional treatment (urotherapy and drugs). Neurogenic bladder dysfunction, whether suspected or established, is the most important of these indications. It should be said upfront that cystometry in a patient with neurogenic bladder has to be repeated regularly during the patient’s lifetime. In a child, cystometry should be

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performed at least once yearly because neurogenic bladder in the child is a dynamic disorder that is prone to change and then most often deterioration. The common cause is tethering of the spinal cord, which occurs in 75% of myelomeningoceles and in 100% of lipomyelomeningoceles.26

Age-related aspects Investigation must be adapted to the child’s needs! It is important that a child is well prepared for a urodynamic investigation. Children are irrational, sensitive, and skeptical toward all kinds of medical technology. Thus, their need for information, patience, and loving care cannot be emphasized too much. The stress felt by a tense child during a urodynamic examination may very well generate results suggesting bladder dysfunction (overactive bladder and/or sphincter) even if that same child in a safe and relaxed mood would have shown completely normal urodynamic findings. Ideally, the child should be prepared for what will be coming being shown around the laboratory the day before the examination and given a summary in everyday language of what is going to happen (Figure 37.3). Many of these children already have unpleasant memories of catheterization, so this topic has to be touched upon with great care. During the examination, the child is handled in a relaxed and patient way. Even young children should be handled with respect for their personal integrity. As much as possible, the procedure should be performed “as in play.” A video with popular cartoons has been a great asset in our laboratory and has helped children to overlook frightening equipment in the room (Figure 37.4). However, nothing can substitute for an experienced nurse or laboratory assistant who loves to take care of children.27,28

Sedation Exceptionally, when a child expresses outspoken anxiety for the procedure, in particular the catheterization, sedation with midazolam may be an option.29 We have no experience with using midazolam in urodynamic studies but have used the drug for several years when performing voiding cystourethrography (VCUG).30 In these studies, the drug does not seem to affect bladder/sphincter function. Midazolam for sedation of a child going through an urodynamic investigation may be a good option in the future once placebocontrolled, randomized studies have been performed.

Age Infants below 1 year of age pose very few problems during urodynamic investigation. They are simply too young

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Textbook of the Neurogenic Bladder Children with neurogenic bladder generally accept the urodynamic investigation without many problems. A majority of these children are treated with CIC and it is easier for them to accept and for the staff to perform the procedure than is the case for children with intact lower urinary tract sensation.

Urodynamic methodology Noninvasive urodynamics Uroflow Measurement of the urinary flow rate, including assessment of the shape of the flow curve, is a very useful investigative tool in children with non-neurogenic bladder/sphincter dysfunction but has a limited value in neurogenic bladder patients. A child with a neurogenic bladder disturbance is seldom able to perform a formal micturition.

Postvoid residual urine (assessed with ultrasound)

Figure 37.3 Child familiarizing herself with the urodynamic laboratory while receiving information from the laboratory assistant the day before the actual investigation.

This procedure is mandatory and should be repeated frequently in all children with neurogenic bladder. In infants and small children, who are not treated with CIC, the 4-hour voiding observation is used to investigate emptying ability.16 The child uses a napkin during the test and voids are indicated by a gossip strip or a light signal. Voided volume is measured by weighing the napkin after each void, and postvoid residual urine is checked by ultrasonography. Since postvoid residual urine varies also in healthy babies with complete emptying only occasionally, the investigation has to include a 4-hour period and not only isolated voids. Postvoid residual urine should also be checked in patients on CIC to make sure that the catheterization is performed in a correct and efficient way. Some children tend to withdraw the catheter too early. Others may get a dislocation of the bladder when growing up, necessitating a change of body position during CIC to achieve complete emptying. Another reason for an extra check of postvoid residual urine is suspicion of bad compliance by the patient on CIC regimen and anticholinergic treatment, especially in puberty.

Figure 37.4 Cystometry is not necessarily a distressful experience, especially when an interesting video is running.

to be afraid of the procedure. The most problematic age group is children aged 2–4 years who are old enough to feel scared but too young to understand the reasons for the examination.

Pad test To estimate and follow urinary leakage between voids or catheterizations during daily activity, the pad test is the most appropriate investigation, including hourly change of pads that are weighed to get the leakage volume. When combined with a 3-hour-interval change of pads at home, the most reliable results will be produced.31 The leakage

Urodynamics in infants and children volume and frequency are important parameters to follow at least once a year, since changes can indicate tethering. It is also important as an indicator of the efficacy of treatment with anticholinergic medication.

Pelvic floor electromyography using cutaneous electrodes EMG for registration of pelvic floor activity during cystometry will sometimes detect neuromuscular activity even in patients with neurogenic bladder, but it will be difficult or impossible to find out from which portion of the pelvic floor muscles the signals emanate.

Invasive urodynamics: Traditional cystometry Invasive urodynamics is synonymous with cystometry (with the possible addition of EMG using needle electrodes).

Frequently asked questions (FAQs) regarding cystometric techniques At which points of time should infants and children with neurogenic bladder dysfunction be examined with cystometry? The literature provides strong evidence that CIC in congenital NBD should be started as soon as possible in infancy,32,33 because there is an obvious risk of deterioration of bladder function already in infancy as well as later in childhood.34,35 Frequent and regular follow-up of bladder function (cystometry at least once a year) is mandatory.36 Fluid-filled or transducer tip catheters for pressure measurement? For obvious reasons, transducer tip catheters must be used for natural fill (ambulatory) cystometry. When traditional cystometry is performed in the laboratory, a fluid-filled pressure measurement system still is the standard. Transurethral or suprapubic catheters? Doublelumen transurethral catheters are ideal for infants and children with neurogenic bladder. Most of these patients have limited or absent urethral sensation. Moreover, the possible obstruction caused by the transurethral catheter is of minor importance in this patient group, since it is seldom possible to perform a formal pressureflow measurement. What filling rate should be used? The rate at which fluid is instilled in the bladder influences bladder wall dynamics, thus capacity, intravesical pressure, and compliance.37 High filling rates create an artificial situation, with continuous pressure rise.

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Therefore, filling rates have to be standardized and not allowed to exceed physiological filling rates during maximal diuresis. The recommended rate is 1/20 (5%) of the patient’s expected bladder capacity per minute, because in a healthy individual the bladder will be filled to capacity in 20 min during maximal diuresis. The patient’s expected bladder capacity can be assessed from a diary in which the parents note the CIC volumes for a couple of days. The largest volume should be chosen excluding the first morning voids. Alternatively (particularly in severe incontinence with small CIC volumes), the expected bladder capacity in children 3 years of age and above can be calculated from the simple rule-of-thumb equation:  xpected bladder capacity (mL) = 30 + (age in E years × 30)27,38 A 3-year-old would be expected to have a bladder capacity around 120 mL, so a filling rate of 6 mL/min should be used. An alternative rule of thumb is that 1% of the body weight approximately predicts a child’s bladder capacity. When to stop filling in a patient unable to feel a desire to void? This is the common situation in patients with NBD. The infusion should be finished when any of the following occurs: •• •• •• •• •• ••

Strong urgency Micturition Feeling of discomfort High basic detrusor pressure (>40 cmH2O) Large infused volume (>150% of the expected bladder capacity unless the CIC diary has shown larger volumes at CIC) Rate of urinary leakage ≥ rate of infusion

How many filling cycles are needed? In non-­ neurogenic cases, two. Even if the child seems to be at ease during the examination, the first filling is experienced by the child as more stressful than the following ones. Detrusor and/or sphincter overactivity is therefore more commonly seen during the first filling. The second filling will already reflect the urodynamic status of the bladder in a more reliable way. Additional fillings do not need to be done because they produce similar findings to the second one.9 However, in children with neurogenic bladder a single filling may be sufficient because lower urinary tract sensation is impaired and psychological mechanisms hardly influence bladder/sphincter function. When is the bladder cooling test (formerly Bors ice water test) indicated in the urodynamic investigation of infants and children with established or suspected NBD? In every case, as a general rule.

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It has been shown that neurologically normal infants and children exhibit a positive bladder cooling test (BCT) during the first 4 years of life, whereas the test is negative in children older than 6 years.39 In infants and children with NBD, a negative BCT before age 4 demonstrates a lesion of the sacral reflex arch, whereas a positive BCT in children older than 6 years indicates a lesion of inhibiting suprasacral spinal pathways.40 The BCT is performed after finishing the traditional cystometry. The reactivity of the detrusor is first checked with body-warm saline infused rapidly in an amount corresponding to one-third of the cystometric bladder capacity. If this infusion does not elicit any significant detrusor contraction, the bladder is emptied and the same amount (one-third of bladder capacity) of cold (4°C–8°C) saline is infused rapidly. A positive test is defined as a detrusor contraction within 1  minute with detrusor pressure >30 cmH2O. How to measure leak point pressure – and what is its value? The ideal way of measuring leak point pressure (LPP) is to note the detrusor pressure at the moment when leakage of urine is observed, during cystometry. This means that the laboratory assistant would have to monitor the patient’s genital area continuously, which is seldom possible. Instead, the flowmeter is often used to indicate leakage; but it is then important to make adjustments for the time delay between pressure registration and the flowmeter deflection, in particular, when leakage occurs in connection with a phasic detrusor contraction. It is assumed that LPP >40 cmH2O in children with NBD suggests an increased risk for development of renal damage. This assumption makes sense, because maintained intravesical pressure above 30–40 cmH2O is certainly associated with an increased incidence of VUR and upper tract dilatation.41 Thus, an assessment of LPP should be routinely included in the urodynamic evaluation of a child with NBD. What is the role of electromyography in the urodynamic evaluation of children with neurogenic bladder dysfunction? “Quantitative” EMG using perineal surface electrodes (Ag/AgCl) will not always produce clinically valuable information in this patient group. How should intra-abdominal pressure be measured? The intrarectal pressure is easily accessible with a catheter passed through the anus (or an enterostoma) and is used as standard for assessing perivesical pressure. The rectal catheter should be opened and continuously and slowly (3 mL/h) perfused with saline to prevent blocking by feces. It is important to check pressure transmission by

asking the patient to strain or cough or by applying pressure on the suprapubic area. Be aware that the rectal catheter will sometimes transmit pressure peaks generated by spontaneous rectal contractions, something that may result in falsenegative detrusor pressure readings. Thus, detrusor pressure calculated as intravesical minus intrarectal pressure is not always a reliable urodynamic variable.

Invasive urodynamics: Videocystometry Performing cystometry and fluoroscopic monitoring of the bladder and urethra at the same time no doubt increases the diagnostic accuracy of the urodynamic procedure, e.g., by allowing determination of bladder pressure at the moment when VUR occurs. The combined examination is also of value in patients with high-grade VUR where a common problem is to decide how much of the infused volume corresponds to bladder capacity and how much is stored in the refluxing systems. It can thus be said that some clinical questions will not be possible to answer without concurrent use of cystometry and x-ray. Therefore, videocystometry has become a standard urodynamic procedure for children with NBD (and other diagnoses) in many centers. However, videocystometry has its disadvantages. The most important of these is that videocystometry makes the examination even more complex by introducing additional machinery face-to-face to the child. Even well-prepared and cooperative children may have difficulties in adapting to a highly sophisticated procedure. As the child patient needs significant modification of the cystometric techniques compared to the adult, it can be questioned whether increasing the level of investigative sophistication is the right way to go.

Invasive urodynamics: Natural fill (ambulatory) cystometry Natural fill cystometry differs from traditional laboratory cystometry by (1) allowing the patient to be mobile, i.e., not restricting him to the laboratory chair, and (2) using the patient’s own diuresis as the filling medium of the bladder. In both adults and children significant differences have been found between values obtained by artificial and natural filling urodynamics, respectively. Especially, steeper pressure rise and larger voided volumes were observed during and after artificial filling, whereas voiding pressures were found to be higher after natural filling. The natural fill cystometry also seems to be more sensitive in detecting detrusor instability than the traditional, artificial filling method.42 The lower incidence of detrusor

Urodynamics in infants and children instability and the greater voided volumes found on traditional cystometry probably reflect an inhibition of detrusor function because of the relatively fast artificial filling. In neurogenic bladders in adults, high increases in pressure was registered during artificial filling, interpreted as low compliance of the bladder wall, that was not reproduced during natural fill cystometry but rather replaced by phasic detrusor activity.43 It cannot be excluded that ‘low compliance neurogenic bladder’ might sometimes turn out to be an investigational artifact due to the unphysiological high rate of artificial bladder filling. In children, results obtained by conventional cystometry and natural fill cystometry have shown the same differences as in adults regarding both non-neurogenic44,45 and neurogenic bladder dysfunction.46–49 In the studies comparing conventional cystometry with natural fill during a couple of bladder cycles or during 24 hours in infants and children with neurogenic bladder, the natural fill was more sensitive identifying detrusor activity and showed less steep pressure rise on filling. In one study, the authors compared bladder behavior during day and night in children with neurogenic vesical dysfunction and found a good correlation between bladder behavior during awakeness and sleep, thus recommending overnight urodynamics as it is well tolerable and less embarrassing for a child.46 As natural fill urodynamics very likely causes less psychological trauma, especially important for the pediatric patient, it is no doubt that it delivers a more authentic reflection of true bladder physiology. However, data on natural fill cystometry in children with neurogenic bladder are still sparse, and, before replacing traditional with natural fill urodynamics, additional studies are needed. In particular, it will be necessary to find out how decreased distensibility of the bladder wall is presenting itself in the natural fill studies. Increase of basal detrusor pressure above 20–30 cmH2O is seldom seen during natural fill but has been interpreted as an important sign of poor compliance when seen in traditional cystometry and found to be associated with dilatation of the upper tracts and deterioration of renal function. Since the rapid rise of basal detrusor pressure may be looked upon as a significant finding, it is still too early to appoint natural fill urodynamics to be the future golden standard in the investigation of neurogenic bladders in children, even if the possibility remains that natural fill may lead to reassessment of the urodynamic neurogenic pathophysiology.

Evaluation of urodynamic results What are we looking for? As in adult urodynamics, the four Cs are •• ••

Capacity (of the bladder reservoir) Contractility (of the detrusor and sphincter)

•• ••

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Compliance (of the bladder wall) Continence And, in addition

•• ••

Lower urinary tract sensation Evacuation (as reflected by absence or presence of postvoid residual).

Normal urodynamic variables in infants and children In infants and children, normal values differ widely from the adult ones; and that, in growing individuals, variables such as bladder capacity vary according to the age and size of the child.

Bladder capacity Increase of bladder capacity is not linear to age or weight during the first years of life. There are two periods when the increase is accelerated. The first is during the first months of life. In free voiding studies of preterm infants in gestation week 32, median bladder capacity was 12 mL15 (Figure 37.5), and in similar studies of full-term, babies 3 months of age median capacity was 52 mL13 (Figure 37.6). The capacity is almost unchanged at 1 and 2 years of age (67 and 68 mL, respectively). At 3 years of age, on the other hand, the median capacity is 123 mL, meaning a doubling during the third year of life (see Figure 37.6).13 The first step in increase of bladder capacity is thus around birth and is a fourfold increase, which should be compared with the increase in body weight, which is only threefold. The second step is at the age of toilet training, when gaining control over voidings. The main stimulant for this second increase in bladder capacity can be suggested to be due to the fact that the child starts to get dry at night, which means higher overnight bladder volumes. Indications for such a connection are the finding that high overnight bladder volumes have been suggested to be one factor responsible for development of high bladder capacity in patients with VUR50 and also in boys with posterior urethral valves.46 Overnight bladder volume has also been shown to be the determinant for functional bladder capacity in healthy children after potty training.51 The relationship between free voiding and cystometric capacity changes during the first years of life. In the neonatal period, cystometric capacity17 is lower as compared to free voiding capacity13 (see Figure 37.5), whereas after the infant year the opposite is seen. This can be partly attributed to the fact that older children postpone voiding at cystometry due to fear of voiding with a catheter in the bladder and of the unfamiliar situation of the assessment. This fear cannot be expected in the neonatal child

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140 Bladder capacity (mL)

120

Preterm infants

Full-term infants

100 80 60 40 20 0 –4

–2

0

2

4

6

Age (months) Free voiding

Crystometric

Figure 37.5 Age versus bladder capacity as measured in free voiding studies in both preterm15 and full-term13 infants, and at cystometry in full-term infants.17

350

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6

9

12

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Figure 37.6 Bladder capacity versus age in a longitudinal study of free voidings in infants and children aged 0–3 years, investigated every 3rd month. The lines indicate the 5th, 50th, and 95th percentiles.13

and voiding is thus not postponed for this reason. Another possible explanation for the low cystometric capacity in the neonatal period might be the overactivity suggested by Bachelard et al., shown as an ease to induce detrusor contractions prematurely in catheter investigations.17 Even if development of bladder capacity during the first years of life is not linear, we suggest that a linear formula is used for calculation of expected bladder capacity for age as a simple rule of thumb. We have chosen to use Expected bladder capacity (mL) = 30 + (Age in years × 30)38 since this linear increase in capacity is very similar to the nonlinear increase in capacity as described by Jansson et al.13 investigating children longitudinally from birth to 3 years of age in free voiding studies (see Figure 37.6).

According to the International Continence Society (ICS), the term “functional bladder capacity”’ should no longer be used because of difficulties of definition, and it should be replaced with “voided volume.” Children void widely different volumes during the same day, sometimes when they feel a desire to void but quite often because their mothers tell them to go to the toilet.51 The common way to decide a child’s bladder capacity is to keep a voiding diary (frequency–volume chart) for 2 days and select the largest voiding volume, excluding the first morning voidings that rather represent nocturnal bladder capacity. For children on CIC, the same method is used to define the child’s approximate b ­ ladder volume. Measured capacity less than 65% of the calculated value is believed to denote a bladder that is small for age, whereas a measured volume that is more than 150% of the calculated value may denote a bladder that is large for age.27,38

Detrusor contractility Storage phase  It has been shown during recent years that  instability is rarely seen in infants,14,17 which is contrary to the earlier concept of instability as a normal phenomenon in this age group.9 The lack of unstable contractions during filling has been shown in natural fill cystometry,14 which is an investigation that is sensitive when it comes to identification of instability. This lack of instability during filling has also been observed in standard cystometric investigations of healthy infants, including a study of siblings of children with reflux.17 In infants with bladder dysfunction, on the other hand, instability during filling is common, such as those with posterior urethral valves46 and neurogenic bladder.34 Therefore, instability can probably be used to diagnose bladder ­dysfunction in this age group just like in older children. During the first months of life, on the other hand, there seems to be another form of overactivity, which was observed in 20% of the children as an isolated detrusor contraction after only a few milliliters of filling at cystometry and, with leakage of urine, looked at as a premature voiding contraction.17 Bladder capacity in these age groups urodynamically registered was also low,17 and was much lower than that seen after free voidings.13 These findings, taken together, indicate that the voiding reflex can easily be elicited in this age group, in the cystometric investigations, by a catheter in the bladder and infusion of saline (see Figure 37.2). This overactivity vanishes after a few months and, simultaneously, bladder capacity increases. The phenomenon does not seem to have anything to do with instability, as instability is seldom seen in infants,14,17 but can rather be looked upon as an immature behavior of the detrusor muscle.52,53 Voiding phase  Voiding detrusor pressure is probably higher during early infancy compared to that seen in older children. Bachelard et al.17 and Wen and Tong54 investigated

Urodynamics in infants and children infants considered to have normal lower urinary tract with conventional cystometry using a urethral catheter. The pressure levels registered in these studies were very different; median 127 vs. mean 75 cmH2O. One explanation of the different results may be the age of the infants studied, which was median 1 month and 6 months, respectively. Yeung et al. also found high voiding pressure levels in small infants.44 However, it should be noted that they used natural fill cystometry, which gives higher pressure levels than standard cystometry. Female infants have significantly lower pressures at voiding compared with males and only slightly higher than those of older girls (Table 37.1). This difference in voiding detrusor pressure between males and females could be attributed to the difference in anatomy, with the long narrow urethra in male infants allowing higher outflow resistance and inducing higher voiding pressure. Thus, the standards for voiding pressure in healthy infants are imprecise and can be a median of more than 100 cmH2O in males and 60–70 cmH2O in females (see Table 37.1). In children 1–3 years of age, median voiding pressures have been reported to be 70 cmH2O in males9 and 60 in females.54 High voiding pressure in infants is correlated with low bladder capacity. This further explains the abovedescribed differences in voiding pressure levels in the studies by Wen and Tong54 and Bachelard et al.17 In the latter study, the infants were younger and thus had lower capacity. Any discernible peak in the detrusor pressure recording during the filling phase is a pathological finding, but to avoid recording artifacts it may be prudent to allow only for peaks with a duration of >10 seconds and amplitude of >10 cmH2O. In neurogenic bladder urodynamics, one should keep in mind that traditional cystometry seems to suppress phasic detrusor activity and exaggerate the rise of basic pressure (giving the impression of low compliance) compared with natural fill cystometry.43,48 Variables to register  Variables to register comprise the following: ••

Number of phasic contractions and their duration and amplitude together with the infused volume when they occurred. Note subjective reaction, if any.

Table 37.1  Voiding detrusor pressure in infants Mean voiding detrusor pressure (cmH2O) References

Males

Females

117

75

Bachelard et al.

127

72

Wen and Tong54

75

60

Yeung et al.44 17

•• •• ••

403

Basic detrusor pressure at start and end of filling (excluding a possible sharp terminal rise of pressure). Avoid including phasic contractions. Detrusor pressure at start of significant leakage (LPP) and the infused volume when leakage occurred. Absence or presence of a coordinated detrusor micturition contraction. In the case of a micturition contraction, any detrusor pressure above 100 cmH2O is to be regarded as pathological in children, denoting outflow obstruction or detrusor overactivity, or both. In infant boys, higher values may be normal.

Bladder cooling test  Variables to register are as follows: •• ••

Outcome: positive (detrusor contraction >30 cmH2O) or negative (≤30 cmH2O) Maximal detrusor pressure, registered in cmH2O

Sphincter contractility In children with neurogenic bladders, EMG registration will not always produce any information about urethral sphincter activity. When the EMG recording seems unreliable, indirect evidence will have to do. LPP > 40 cmH2O denotes either neurogenic sphincter overactivity or a sphincter with intact innervation. Likewise, the finding of intravesical pressures well above 40 cmH2O without any detectable leakage of urine suggests detrusor/sphincter dyssynergia or, alternatively, a normal sphincter contracting to prevent leakage (guarding reflex).

Compliance of the bladder wall The concept of compliance characterizes the distensibility of the bladder wall during the reservoir phase. A ­subnormal compliance value denotes increase of bladder wall stiffness due to change of wall structure or a tonic detrusor contraction and is a risk factor for development of upper tract damage. Compliance is expressed as the volume (mL) that the bladder can accommodate with a resulting pressure increase of 1 cmH 2O. It is calculated from a middle segment of the detrusor pressure registration up to 30  cmH 2O, avoiding phasic contractions. A “normal” value for compliance in adults has not been validated, but it is generally felt that it should be more than 20 mL/cmH 2O, e.g., that basic pressure increase up to an adult bladder volume of 400 mL should be 20 cmH2O or less from empty to full bladder. But we will encounter problems trying to apply this value of compliance to the wide range of bladder volumes in children. For example, a child with a bladder capacity of 100 mL (which would be normal in a 3-year-old child), and a 20-cmH 2O pressure increase from empty to full bladder will give a compliance value of 5 mL/cmH 2O, a value which would be clearly pathological in an adult. An adjustment must be

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done to make values c­ omparable between children and adults. It has been suggested that the lowest acceptable value of compliance in a child should be 1/20 (5%) of the child’s normal capacity per cmH 2O, a c­ alculation that would be compatible with the lowest limit of “normal” compliance, 20 mL/cmH 2O, in adults. Then, a compliance of 5 mL/cmH 2O at a ­bladder  capacity of 100 mL would be within the normal range. Safe capacity. Instead of calculating compliance to characterize the reservoir properties of the bladder wall, we use the concept of “safe capacity” at our institution. The bladder volumes at 20 cmH2O and 30 cmH2O base line detrusor pressure are registered. The 20-cmH2O value stands for a truly safe and the 30-cmH2O a borderline value for compliance at reservoir capacity.

Continence Cystometry of a child is not only a laboratory investigation but also allows for a careful and prolonged clinical observation of the child. In addition to the urodynamic results produced by cystometry, this observation provides important information regarding the child’s reactions to bladder filling and, not least, in which situations and at which bladder volumes leakage of urine can be noted.

Lower urinary tract sensation From age 4 onwards, it is possible to extend the clinical observation during cystometry by asking the child whether he feels the catheter being introduced and if he experiences any sensation from the bladder during filling. Some degree of urethral sensation is seldom present in children with neurogenic bladder, whereas bladder sensation is most often absent or very weak. Discomfort or pain at end filling when the bladder has become filled to capacity is probably elicited from functional sensory nerve endings in the peritoneum partly covering the bladder. When the child signals discomfort (in small children seldom verbally, but rather by being anxious, crying, or moving restlessly), infusion should be discontinued. The cystometry protocol should include the soft data obtained regarding sensation.

Bladder evacuation at free voidings Infants do not empty the bladder at every voiding,13,15,16,55,56 but, characteristically one voiding during 4 hours is complete, according to results from the 4-hour observations. This is seen both in preterm infants (gestation week 32)15 and neonates, and during the first years of life.13 The residual urine during 4 hours is more or less constant from the neonatal period until just before the age of 2 years; median

4–5 mL.13,15,16 During the third year, when gaining control over voidings, on the other hand, the emptying of the bladder becomes complete, so that the median residual urine is 0 mL.13 In healthy children above 3–4 years of age, the bladder empties completely at each voiding. Five milliliters in postvoid residual may be accepted due to the unavoidable time delay from the end of voiding until the bladder can be examined with ultrasound; 5–20 mL is borderline and is an indication for repeating the ultrasound. In schoolgirls treated for bacteriuria, recurrence was significantly more common in those with postvoid residual urine greater than 5 mL.57 In children with NBD, assessing postvoid residual urine by aspiring through the bladder catheter may not always yield reliable results due to the common dislocation of the base of the neurogenic bladder, so a check with ultrasound is strongly recommended. Ultrasound to determine residual urine should also be performed frequently on all children on CIC for the same reason.

Conclusions The free voiding pattern in the neonatal period is characterized by small, frequent voidings (one voiding per hour) with volumes that vary intra-individually and leave residual urine most of the time. The incomplete emptying is suggested to be due to a physiological form of dyscoordination. Toward potty-training age the emptying improves, and, at that time (third year), the bladder capacity also doubles. Voiding during quiet sleep is rarely seen, even in the neonatal infant, meaning that the child shows signs of arousal at voiding. Bladder instability is rarely seen in urodynamic studies of young infants, although premature voiding contractions are seen in the neonatal period, with leakage of urine after only a few milliliters of filling. This latter increased reactivity of the detrusor muscle is also suggested to be responsible for the cystometric small bladder capacity in this age group and the high voiding pressure levels. When estimating compliance of the bladder wall in children, expected bladder capacity for age must be taken in account. It may be advantageous to use the concept of “safe capacity” instead.

Classification of neurogenic bladder dysfunction in infants and children A classification of neurogenic bladder in spina bifida children was suggested by van Gool. 58 As can be seen in Table 37.2, a simple but clinically useful classification

Urodynamics in infants and children can be created from the urodynamic data. Detrusor and sphincter are classified as underactive or overactive, so the neurogenic dysfunction can be categorized in four main groups. Two of these display underactive sphincter with incontinence as the major clinical problem, and the two others have overactive sphincter with outflow obstruction and deficient bladder emptying as their main clinical characteristics. It should be added, however, that about 5% of children with myelomeningocele display normal bladder function at cystometry, in particular those who have their spinal cord anomaly in a high position (cervical, thoracic, or high thoracolumbar) (Figure 37.7).

Table 37.2  F  our patterns of bladder-sphincter dysfunction in children with myelomenigocele53 Detrusor Sphincter

Underactive

Overactive Clinical correlate

Underactive

35

10

Incontinence

Overactive

13

42

Outflow obstruction

mL/s Qura

cmH 2O Pdet

cmH 2O Pabd(2)

cmH 2O Pves(1)

mL V in V mic

405

Examples of common urodynamic patterns in neurogenic bladder dysfunction in children A dangerous urodynamic pattern, threatening the integrity of the kidneys, is dyssynergia between detrusor and sphincter. The micturition detrusor contraction is counteracted by sphincter contractions, leading to poor evacuation of the bladder, as seen in a 4-year-old boy with lumbosacral myelomeningocele (Figure 37.8). Also ominous for the renal health is the pattern with low compliant bladder wall and overactive sphincter (Figure 37.9). The child attempts, without much success, to empty the bladder by forceful contractions of the abdominal muscles. As in the previous case, a regular, carefully performed CIC program is essential to avoid UTIs, reflux, and renal damage in this 4-year-old boy with lumbosacral myelomeningocele. The pattern is often not as clear-cut as in the two previous cases. In the next example, the detrusor is overactive and there is borderline compliance (Figure 37.10). The sphincter may also be somewhat overactive, as judged from the EMG; but, on the other hand, there are several small micturitions and a larger one at the end of the registration. This patient, with lumbosacral

25 20 15 10 5 0 100 80 60 40 20 0 100 80 60 40 20 0 100 80 60 40 20 0 500 400 300 200 100 0

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Figure 37.7 Normal cystometry in a 4-year-old boy with high thoracolumbar myelomeningocele.

0:21

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EMG1 mL/s Qura

cmH 2O P det

cmH2O Pabd(2) cmH2O Pves(1) mL V in V mic

Compliance

50 25

uV

0 25 50 25 20 15 10 5 0 100 80 60 40 20 0 100 80 60 40 20 0 100 80 60 40 20 0 500 400 300 200 100 0

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MMS

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Figure 37.8 Normal compliance, discrete detrusor overactivity, and micturition contraction forcefully counteracted by sphincter contraction, thus pronounced dyssynergia, in a 4-year-old boy with lumbosacral myelomeningocele.

mV

1 0

EMG1

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Compliance

First sensation (242 mL) First desire (317 mL)

1 25 20 15 10 5 0

cmH2O 100 80 60 Pdet 40 20 0 cmH2O 100 80 60 Pabd 40 20 0 cmH2O 100 80 60 40 Pves(1) 20 0 mL

500

Figure 37.9 Low bladder wall compliance and poor effect of straining, suggesting sphincter overactivity, in a 4-year-old boy with lumbosacral myelomeningocele.

Urodynamics in infants and children mV

1 0

EMG1

0 0

407

1 mL/s

10 8 6 Qura 4 2 0 cmH 2O 100 80 60 P det 40 20 0 cmH 2O 100 80 60 P abd 40 20 0 cmH 2O 100 80 60 P ves (1) 40 20 0 200 mL

Figure 37.10 Detrusor overactivity and borderline bladder wall compliance in a 9-month-old boy with lumbosacral myelomeningocele. Electromyography (EMG) indicates an overactive pelvic floor, but there are frequent mini-micturitions and a larger one at the end of the registration (START MIKT).

Detr. P. Before 100

Infused volume 100 mL

1 Detr. P. After 100

Figure 37.11 Infused volume 190 mL

1

myelomeningocele, is only 9 months old, so there may remain an element of physiological immaturity in the urodynamic pattern. The final example, a 5-year-old girl with lumbosacral myelomeningocele (Figure 37.11), depicts the beneficial effect on detrusor overactivity that is often attained with the use of detrusor-relaxing drugs (in this case, oxybutynin 5 mg twice daily is administered intravesically). As can be seen, both phasic and tonic (compliance!) detrusor contractility normalizes.

Intravesical oxybutynin may efficiently inhibit detrusor overactivity in a 5-year-old girl with lumbosacral myelomeningocele. Detrusor pressure and compliance become normal and capacity nearly doubles after intravesical instillation of 5 mg of oxybutynin.

References 2580. Scott R Jr, McIlhaney JS. The voiding rates in normal male children. J Urol 1959; 82: 244. 2581. Zatz LM. Combined physiologic and radiologic studies of bladder function in female children with recurrent urinary tract infections. Invest Urol 1965; 3: 278. 2582. Whitaker J, Johnston GS. Estimation of urinary outflow resistance in children: Simultaneous measurement of bladder pressure, flow rate and exit pressure. Invest Urol 1969; 7: 127. 2583. Palm L, Nielsen OH. Evaluation of bladder function in children. J Pediatr Surg 1967; 2: 529.

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2584. Starfield B. Functional bladder capacity in enuretic and nonenuretic children. J Pediatr 1967; 70: 777. 2585. Gierup HJW. Micturition studies in infants and children. Intravesical pressure, urinary flow and urethral resistance in boys without infravesical obstruction. Scand J Urol Nephrol 1970; 3: 217. 2586. Kroigaard N. The lower urinary tract in infancy and childhood. Micturition cinematography with simultaneous pressure-flow measurement. Acta Radiol suppl 1970; 300: 3–175. 2587. O’Donnell B, O’Connor TP. Bladder function in infants and children. Br J Urol 1971; 43: 25. 2588. Hjalmas K. Micturition in infants and children with normal lower urinary tract. A urodynamic study. Scand J Urol Nephrol 1976; (suppl 37): 9–17. 2589. Gool JD van, Kuijter RH, Donckerwolcke RA et al. Bladdersphincter dysfunction, urinary infection and vesico-ureteral reflux with special reference to cognitive bladder training. Contrib Nephrol 1985; 39: 190. 2590. Lindehall B, Claesson I, Hjalmas K, Jodal U. Effect of clean intermittent catheterisation on radiological appearance of the upper urinary tract in children with myelomeningocele. Br J Urol 1991; 67: 415–9. 2591. Muellner SR. Development of urinary control in children. JAMA 1960; 172: 1256–60. 2592. Jansson UB, Hanson M, Hanson E et al. Voiding pattern in healthy children 0 to 3 years old: A longitudinal study. J Urol 2000; 164: 2050–4. 2593. Yeung C, Godley M, Ho C et al. Some new insights into bladder function in infancy. Br J Urol 1995; 76: 235–40. 2594. Sillén U, Sölsnes E, Hellström A-L, Sandberg K. The voiding pattern of healthy preterm neonates. J Urol 2000; 163: 278. 2595. Holmdahl G, Hanson E, Hanson M et al. Four-hour voiding observation in healthy infants. J Urol 1996; 156: 1809–12. 2596. Bachelard M, Sillén U, Hansson S et al. Urodynamic pattern in asymptomatic infants: Siblings of children with vesicoureteral reflux. J Urol 1999; 162: 1733. 2597. Zerin M, Chen E, Ritchey M, Bloom D. Bladder capacity as measured at voiding cystourethrography in children: Relationship to toilet training and frequency of micturition. J Urol 1993; 187: 803. 2598. Bakker E, Wyndaele JJ. Change in the toilet-training of children during the last 60 years: The cause of an increase in lower urinary tract dysfunction? BJU Int 2000; 86: 248. 2599. Brazelton TB. A child-oriented approach to toilet training. Pediatrics 1962; 29: 121. 2600. Klackenberg G. A prospective longitudinal study of children. Data on psychic health and development up to 8 years of age. Acta Paediatr Scand Suppl 1971; 224: 1–239. 2601. Largo R, Molinari L, von Siebenthal K, Wolfensberge U. Does a profound change in toilet-training affect development of bowel and bladder control? Dev Med Child Neurol 1996; 38: 1106–16. 2602. Duong TH, Jansson UB, Holmdahl G et al. Development of bladder control in the first year of life in children who are potty trained early. J Pediatr Urol 2010; 6(5): 501–5. 2603. Duong TH, Jansson UB, Holmdahl G et al. Urinary bladder control during the first 3 years of life in healthy children in Vietnam-A comparison study with Swedish children. J Pediatr Urol. 2013; 9(6 Pt A): 700–6. doi:pii: S1477-5131(13)00119-8. 10.1016/j. jpurol.2013.04.022. 2604. Marten W, deVries MD, deVries PNP. Cultural relativity of toilet training readiness: A perspective from East Africa. Pediatrics 1977; 60:170–7. 2605. Shurtleff DB. 44 years’ experience with management of myelomeningocele: Presidential address, Society for Research into Hydrocephalus and Spina Bifida. Eur J Pediatr Surg 2000; 10(suppl 1): 5–8. 2606. Hjälmås K. Urodynamics in normal infants and children. Scand J Urol Nephrol 1988; (suppl 114): 20–7. 2607. Swithinbank L, O’Brien M, Frank D et al. The role of paediatric urodynamics revisited. Neurourol Urodyn 2002; 21: 439–40.

2608. Bozkurt P, Kilic N, Kaya G et al. The effects of intranasal midazolam on urodynamic studies in children. Br J Urol 1996; 78: 282–6. 2609. Stokland E, Andreasson S, Jacobsson B, Jodal U, Ljung B. Sedation with midazolam for voiding cystourethrography in children: A randomized double-blind study. Pediatr Radiol 2003; 33(4): 247–9. 2610. Hellström AL, Andersen K, Hjälmås K, Jodal U. Pad test in children with incontinence. Scand J Urol Nephrol 1986; 20: 47–50. 2611. Tanikaze S, Sugita Y. [Cystometric examination for neurogenic bladder of neonates and infants]. Hinyokika Kiyo 1991; 37:1403–5. 2612. Agarwal SK, McLorie GA, Grewal D et al. Urodynamic correlates or resolution of reflux in meningomyelocele patients. J Urol 1997; 158: 580–2. 2613. Sillén U, Hanson E, Hermansson G et al. Development of the urodynamic pattern in infants with myelomeningocele. Br J Urol 1996; 78: 596–601. 2614. Bauer SB. The argument for early assessment and treatment of infants with spina bifida. Dialog Pediatr Urol 2000; 23(11): 2–3. 2615. Tarcan T, Bauer S, Olmedo E et al. Long-term follow up of newborns with myelodysplasia and normal urodynamic findings: Is follow up necessary? J Urol 2001; 165: 564–7. 2616. Klevmark B. Natural pressure-volume curves and conventional cystometry. Scand J Urol Nephrol 1999; (suppl 201): 1–4. 2617. Nevéus T, von Gontard A, Hoebeke P et al. The standardization of terminology of lower urinary tract function in children and adolescents: Report from the Standardisation Committee of the International Children’s Continence Society. J Urol. 2006; 176(1): 314–24. 2618. Geirsson G, Lindstrom S, Fall M et al. Positive bladder cooling test in neurologically normal young children. J Urol 1994; 151: 446–8. 2619. Gladh G, Lindstrom S. Outcome of the bladder cooling test in children with neurogenic bladder dysfunction. J Urol 1999; 161: 254–8. 2620. Flood HD, Ritchey ML, Bloom DA et al. Outcome of reflux in children with myelodysplasia managed by bladder pressure monitoring. J Urol 1994; 152: 1574–7. 2621. Robertson A, Griffiths C, Ramsden P, Neal D. Bladder function in healthy volunteers: Ambulatory monitoring and conventional urodynamic studies. Br J Urol 1994; 73: 242–9. 2622. Webb RJ, Griffiths CJ, Ramsden PD, Neal DE. Ambulatory monitoring of bladder pressure in low compliance neurogenic bladder dysfunction. J Urol 1992; 148: 1477–81. 2623. Yeung C, Godley M, Duffy P, Ransley P. Natural filling cystometry in infants and children. Br J Urol 1995; 75: 531–7. 2624. Holmdahl G, Sillén U, Bertilsson M et al. Natural filling cystometry in small boys with posterior urethral valves: Unstable bladders become stable during sleep. J Urol 1997; 158: 1017–21. 2625. Samuel M, Boddy SA, Wang K. What happens to the bladder at night? Overnight urodynamic monitoring in children with neurogenic vesical dysfunction. J Urol. 2001; 165(6 Pt 2): 2335–40. 2626. De Gennaro M, Capitanucci ML, Silveri M et al. Continuous (6 hour) urodynamic monitoring in children with neuropathic bladder. Eur J Pediatr Surg 1996; 6(suppl 1): 21–4. 2627. Zermann DH, Lindner H, Huschke T, Schubert J. Diagnostic value of natural fill cystometry in neurogenic bladder in children. Eur Urol 1997; 32: 223–8. 2628. Jorgensen B, Olsen LH, Jorgensen TM. Natural fill urodynamics and conventional cystometrogram in infants with neurogenic bladder. J Urol. 2009; 181(4): 1862–7; discussion 1867–8. 2629. Sillén U, Hellström A-L, Sölsnes E, Jansson U-B. Control of voidings means better emptying of the bladder in children with congenital dilating VUR. BJU Int 2000; 85(suppl 4): 13. 2630. Mattsson SH. Voiding frequency, volumes and intervals in healthy school children. Scand J Urol Nephrol 1994; 28: 1–11. 2631. Sugaya K, de Groat WC. Influence of temperature on activity of the isolated whole bladder preparation of neonatal and adult rats. Am J Physiol Regul Integr Comp Physiol 2000; 278: 238. 2632. Zderic SA, Sillén U, Liu G-H et al. Developmental aspects of bladder contractile function: Evidence for an intracellular calcium pool. J Urol 1993; 150: 623.

Urodynamics in infants and children 2633. Wen JG, Tong EC. Cystometry in infants and children with no apparent voiding symptoms. Br J Urol 1998; 81: 468. 2634. Roberts DS, Rendell B. Postmicturition residual bladder volumes in healthy babies. Arch Dis Child 1989; 64: 825–8. 2635. Gladh G, Persson D, Mattsson S, Lindstrom S. Voiding patterns in healthy newborns. Neurourol Urodyn 2000; 19: 177–84.

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2636. Lindberg U, Bjure J, Haugstvedt S, Jodal U. Asymptomatic bacteriuria in schoolgirls. III. Relation between residual urine volume and recurrence. Acta Paediatr Scand 1975; 64: 437–40. 2637. Van Gool J. Spina bifida and neurogenic bladder dysfunction: A  urodynamic study. Thesis. Utrecht: Uitgeverij Impress, 1986:154.

38 Normal urodynamic parameters in adults Romain Caremel and Jacques Corcos

Introduction Urodynamic studies play an important role in the evaluation and diagnosis of lower urinary tract dysfunction. Evaluation can be undertaken in a noninvasive manner, with a voiding diary, a pad test, and free flow rate or in an invasive manner by cystometry, pressure flow assessment, and urethral pressure profiling. The normality of urodynamic parameters in a healthy population is found in ranges rather than in precise values. As some tests are invasive, most published data are derived from patients and not from healthy volunteers. Furthermore, urodynamic investigations may be considered as nonphysiologic tests because of the introduction of several artificial factors, such as urethral catheterization, a filling rate that is different from the usual physiologic rate, and the immobile position of patients during evaluation.1,2 With the help of clinical data and abnormal pathologic values, it is, however, possible to define some “normality” for most of the different parameters measured by urodynamics, and, therefore, to establish reference values for clinicians.

Pad test The pad test is a diagnostic tool that assesses the degree of incontinence in patients in a semi-objective manner. Pad weight gain in nonmenstruating women can be attributed mainly to urine but also to perspiration and vaginal discharges.

The short-term pad test The short-term pad test is a standardized, objective way of assessing incontinence, lasting 15 minutes to 2 hours and including a standardized, provocative evaluation. It is often used in office practice because of its convenient nature. As described by Abrams et al., the test requires the intake of a fixed amount of fluid. The pad is weighed before

and after the 1-hour period in the office. Specific activities are performed in this time frame, such as walking, standing, coughing, running, and bending forward.3 There are conflicting data concerning the correlation between severity of incontinence and increase in pad weight.4–6

In women After 1 hour, any increment in pad weight of more than 1 g is considered incontinence. Hourly pad weight increases in continent women vary from 0 to 2.1 g/h, averaging .26 g/h. With the 1-hour ICS (International Continence Society) pad test, the upper limit (99% confidence limit [CL]) has been found to be 1.4 g/h.7 Employing the test in 50 healthy women with self-reported normal urinary control, Sutherst et al.4 determined that pad weight gain after 1 hour was less than 1 g, with a mean of .26 g. They stated that pad weight gains of more than 1 g/h should be regarded as abnormal and warrant further investigation. Versi et al.8 discerned a mean pad weight gain of .39 g/h with an upper 99% CL of 1.4 g in 90 asymptomatic females. Test–retest repeatability in healthy controls was not analyzed, but different studies have examined correlation coefficients between the results in women undergoing the same test twice. They found coefficients ranging from .68 to .97. The data varied if the test was performed with a standardized volume in the bladder.9,10

In men We could not identify any publication giving normal values for men.

The long-term pad test The long-term pad test requires patients to wear pads for 24 or 48 hours during regular everyday activities and in their usual surroundings. Patients are instructed to record

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the frequency and amount of fluid intake as well as the episodes of micturition and incontinence. At the end of the test, the pad is weighed. Urinary continence varies in women, but is generally accepted to be 8 g or less on the 24-hour pad test11–13 or a weight gain of 2 g or less on any one pad in a 24-hour pad test.6,14 Many studies have assessed weight gain in self-reported continent women in the 24-hour pad test. Median vaginal fluid loss could be as high as 2.6–7.0 g, with an upper CL of 5.5–8.0 g in 24 hours12,15 or 14 g over 48 hours.13 Karantanis et al.16 observed a median pad weight gain of .3 g/24 h (upper 95% CL of .4 g) in 134 participants (120 continent females and 14 continent males) with a mean age of 48 years. There was not any significant difference between premenopausal and postmenopausal women. Results obtained from males were two times lower than those obtained from women (n = 21) (.5 vs. .25 g), indicating that vaginal secretions account for half of the weight gain.16 In summary, the short-term pad test in continent subjects gives mean values ranging from 0 to .4 g, whereas the long-term pad test averages between 2.5 and 7.0 g/24  h. Incontinence is diagnosed if pad weight is more than 1 g/h on the short-term pad test and more than 8 g/24 h on the long-term pad test. Nevertheless, any pad test has to be based on a detailed bladder diary. The patient’s history, bladder diary, and pad test usually fit into each other, as they provide useful information about amount and time of leakage.

Voiding diary To objectively measure subjective complaints of lower urinary tract symptoms, patients are asked to complete a voiding diary. The most commonly used is the frequency– volume chart, which provides maximum information to physicians. It records the number and timing of incontinence and micturition episodes along with the amount of urine voided.17

In women These parameters have been studied in normal, healthy ­subjects without any urinary symptoms. Most investigations have dealt with women. Kassis and Schick evaluated a group of 33 asymptomatic women who volunteered to complete a frequency–volume chart over 7 days.18 Daytime frequency was about 6 times (5.63 ± 1.26), and mean total voided ­volume (VV) per 24 hours was 1473 (±386) mL. Mean VV was 237 (±67) mL during the day, and 379 (±132) mL ­during the night. Voiding frequency at night was .08 (±.16) with a night/day diuresis ratio of .81 (±.30).18 Huang et al. analyzed the 3-day voiding diary of 68 healthy Taiwanese women. Their total daily voiding frequency was 7.34 (±1.63) times with a night-time voiding frequency of .25 (±.31), the 24-hour VV was 1634 (±652) mL, and the night-time to whole day urine volume ratio was .24. Mean VV for each void was 225 (±81) mL.19 Boedker et al. reported comparable findings in a subset of 123 women with regard to voiding ­frequency (5.7), total daily VV (1350 mL), and mean VV (380 mL).20 Fitzgerald and Brubaker presented results from an interesting study looking at the variability of 24-hour voiding diary parameters among 137 asymptomatic women. Subjects voided a median of 8 times per 24 hours in the first diary, and 7 times in the second diary. Total 24-hour voided urine volume was 1580 mL in the first and 1485 mL in the second diary. Also, mean VV was 195 mL in the first and 197 mL in the second diary.21 A larger investigation by Van Haarst et al. recruited 1152 asymptomatic subjects aged over 20 years to complete a 24-hour ­frequency–volume chart.22 They observed a 24-hour frequency decline in women of older decades, ranging from 6.9 in the third decade to 8.2 in the sixth decade. The frequency of nocturia increased with age, from .7 in the third decade to 1.4 in women aged more than 70 years. Mean VV decreased from 274 to 240 mL, and 24-hour VV was 1762 mL.22 In summary, normal voiding frequency varies between 5 and 8 times per 24 hours with total urine volume between 1350 and 1800 mL. Mean VV ranges approximately between 200 and 350 mL (Table 38.1).

Table 38.1  Voiding diary of healthy volunteers as reported in the literature

No. of volunteers Mean age

Pauwels et al.32

De Wachter and Wyndaele72

Kassis and Schick73

Pfisterer et al.74

Normal range

32 women

15 women

33 women

24 women

—

49

21

40

50.2

—

Daytime frequency

6.45

7.24 ± 2.27

5.63 ± 1.26

5.7

6–7

No. of nocturia

.07

.07 ± 2.25

.08 ± .16

.2

0–1

Mean VV during day (mL)

289 ± 278

231 ± 128

237 ± 67

1045

200–250

Mean VV during night (mL)

450 ± 189

300 ± 50

379 ± 132

438

300–400

Mean VV in 24 hours (mL)

1962

—

—

1442

1400–1800

Normal urodynamic parameters in adults

In men In the previously cited study by Boedker et al., the same parameters were examined in 102 healthy men aged between 14 and 69 years.20 The median frequency of micturition was 5.6, total VV was 1450 mL, and median bladder capacity was 400 mL. Two hundred and eighty-four asymptomatic males participated in an investigation by Latini et al., where they were asked to complete the IPSS (International Prostate Symptom Score) and a 24-hour voiding diary.23 Subjects voided a median of 7 times in 24 hours, with a total urine volume of 1650 mL; mean VV was 237 mL.23 Van Haarst et al. determined that there was a linear rise with age in 24-hour voiding frequency and nocturia in men, ranging, respectively, from 6.0 and .5 in men in the third decade to 8.5 and 1.6 in men aged over 70  years. Mean VV decreased from 313 to 209 mL, and mean 24-hour VV was 1718 mL.22 To summarize, men void at a frequency between 5 and 7 times per day with a mean volume per void of between 200 and 350 mL. The average 24-hour VV ranges approximately between 1450 and 1700 mL. For more details on voiding diaries, see Chapter 34.

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uroflowmetry. The Qmax was 25, 32, and 23 mL/s, respectively. VV was 225, 335, and 264 mL, respectively. Postvoid residual volume (PVR) in all groups was below 20 mL. In an interesting study, Unsal and Cimentepe26 assessed differences in flowmetry in various positions among 72 healthy male and female volunteers. In the 36 women of this group (mean age 32 years), Qmax values were 28.09 (±.66) and 27.98 (±.59) mL/s in the sitting and crouching position, respectively. Qave was 18.26 (±.36) and 17.31 (±.35) mL/s in the sitting and crouching position, respectively. Mean VV and PVR values were 331.8 (±13.28)  mL and 11.82 (±.99) mL in the sitting position, and 326.9 (±12.87) mL and 12.79 (±1.07) mL in the crouching position, respectively. A group of 140 healthy Thai subjects was divided into two subgroups according to age (18–30 years and 50–60 years).27 Women had a higher Qmax (32.5 ± 10.0 vs. 27.8 ± 8.0 mL/s) and Qave (23.5 ± 8.1 vs. 19.8 ± 5.8 mL/s) than men. PVR was less than 50 mL in all subjects. In summary, Qave in women ranges from 17 to 24 mL/s, and Qmax ranges from 23 to 33 mL/s, depending on age. Regardless of age, PVR should not exceed 50 mL in asymptomatic women.

Flowmetry and postvoid residual volume Flowmetry is the test that evaluates several parameters that vary considerably with gender and age, such as maximal flow rate (Qmax), average flow rate (Qave), and VV (Figure 38.1 and Table 38.2).

In women Haylen et al. constructed the Liverpool nomograms based on the maximum and average flow rates of nor­mal volunteers.24 Their study included 331 males (average age 49 years) and 249 women (average age 32 years). In women, age and parity did not influence flow rates. Different parameters were reported by Pfisterer et al.25 in a group of 24 pre-, peri-, and postmenopausal, healthy female volunteers who underwent

Flow rate (mL/s)

Maximum flow rate Voided volume

Time to maximum flow Flow time Time (seconds)

Figure 38.1 The normal shape of the flow rate curve with frequently measured parameters. (Reproduced from Huang Y-H, Lin ATL, Chen K-K, Chang LS. Urol Int 2007; 77(4): 322–6. With permission.)

Table 38.2  Normal range of uroflowmetry parameters Wyndaele2

VV (mL)

Male

Female

Jensen et al.75 n = 13 males Mean age 61 years

Pfisterer et al.74 n = 24 women Mean age 50 years

210

264

337.7

337.5

Qmax (mL/s)

24.4

30.5

Qave (mL/s)

13.6

21.5

Flow time (seconds)

26

26

25

Residual urine (mL)

19

19

20

15.7

26

7.8 20

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In men

Cystometry during the filling phase During the filling phase, abdominal and bladder pressures are recorded via rectal and urethral catheters, respectively, whereas detrusor pressure is calculated by subtracting abdominal pressure from bladder pressure. Baseline abdominal and bladder pressures are 5–20 cmH2O in the supine position, 15–40 cmH2O in the sitting position, and 30–50 cmH2O in the standing position.32 Detrusor pressure in an empty bladder varies between 0 and 10 cmH2O in 90% of cases. Normal abdominal pressure is 37 ± 7 cmH2O during filling and 35 ± 9 cmH2O during voiding. Normal detrusor pressure during bladder filling should be less than 25 cmH2O.33 Several parameters are recorded during the filling phase, including bladder sensation, compliance, detrusor function, maximum cystometric bladder capacity, and urethral sphincter activity (Figure 38.2 and Table 38.3).

Voiding phase

Filling/storage phase

Pressure

We completed a study of uroflowmetry parameters in 31  male, asymptomatic, middle-aged urologists.28 Qmax and Qave were, respectively, 20.5 mL/s (SD = 3.9) and 14.3 mL/s (SD = 3.0). VV was 331.9 mL (SD = 94.8) with a voiding time of 32.7 seconds (SD = 15.5). Unsal and Cimentepe assessed uroflowmetry parameters in 36 young males (mean age 30 years). Qmax and Qave, respectively, varied between 23.28 and 24.29 mL/s, and between 15.56 and 15.81 mL/s. Mean VV and PVR values ranged between 297.5 and 309.9 mL, and between 12.92 and 14.02 mL, respectively.26 Schmidt et al. undertook ambulatory urodynamic and P/Q measurements of 39 asymptomatic male volunteers (mean age 25.8 years).29 The men were divided into two groups according to water consumption: group 1 with a water consumption of 30 mL/kg daily, and group 2 with a water consumption of 60 mL/kg daily. There were no significant differences between the two groups in Qmax (24.4 ± 1.3 to 25.2  ± 1.8 mL/s) or VV (286 ± 20 to 329 ± 15 mL). Haylen et  al. demonstrated that men showed a decline of 1.0 to 1.6 mL/s/10 years in maximum urine flow rate and a decrease of .6 to 1.0 mL/s/10 years in average urine flow rate.24 Tong evaluated uroflowmetry in a group of 20 males aged over 60 years and recorded values of Qmax between 24.2 and 27.1 mL/s and of Qave between 14.9 and 17.2 mL/s. 30 VV varied between 338 and 532 mL. Jorgensen et al. reported, in a group of asymptomatic men, that median Qmax decreased from 18.5 mL/s at age 50 years to 6.5 mL/s at age 80 years. 31 To summarize, Qave in men ranges between 14.3 and 17.2 mL/s, and Qmax ranges between 20.5 and 27.1 mL/s. The latter values seem to decrease with age. VV varies between 250 and 550 mL, and PVR is less than 15 mL.

I

II

III

IV

Volume

Figure 38.2 The normal cystometrogram curve has four phases: (I) an initial pressure rise to achieve resting bladder pressure; (II) the tonus limb, which reflects the viscoelastic properties of the bladder wall; (III) bladder wall structures achieving maximal elongation and pressure rise caused by additional filling (this phase should not be encountered during cystometry); and (IV) the voiding phase, representing bladder contractility. (Reproduced from Huang Y-H, Lin ATL, Chen K-K, Chang LS. Urol Int 2007; 77(4): 322–6. With permission.)

Sensation Wyndaele studied bladder sensations in 38 normal volunteers by cystometry.34 He described three patterns of normal bladder sensation: the first sensation was bladder filling, the first desire, and then the strong desire to void. The latter sensation was equivalent to cystometric bladder capacity. The first sensation occurred at 40% (253 mL) of bladder capacity, whereas the first desire occurred at 60% (326 mL) of bladder capacity, which was about 563 mL. Furthermore, he reported that the volumes in all three types of sensation were smaller in women. Also, bladder sensation could be assessed by measurement of the electrical sensory threshold (EST). Normal EST should be less than 15 mA.35

Compliance Normal values of bladder compliance have not been well defined. In patients with neurogenic bladder, values of 13–40 mL/cm H2O have been associated with a high risk of upper urinary tract complications.36 Accordingly, normal bladder compliance values vary between 30 and 100 mL/cmH2O. The values are higher for women than for men.2,3,37 Bladder compliance is considered to be compromised if it is below 30 mL/cm H2O.38 Harris et al.39 studied 270 neurologically intact women and reported that normal bladder compliance was >40 mL/cm H2O. Wyndaele2 conducted a urodynamic study of 30 volunteers (20 male and 10 female volunteers), and found that compliance was

Normal urodynamic parameters in adults

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Table 38.3  Normal reported cystometric parameters during filling in both males and females Parameter

Wyndaele2,31

Pfisterer et al.74

Normal range

38 24 253 326 563

24 50.2 107 188 372

— — 100–250 200–330 350–560

56.1 70.9 Stable — 552 453

— 119 — — — 580

— ≥50 Stable 450–550 — —

No. of volunteers Mean age First sensation (mL) First desire to void (mL) Strong desire to void (mL) Bladder compliance (mL/cmH2O) Men Women Detrusor activity MCC (mL) Men Women MCC, maximum cystometric capacity.

higher in female than in male volunteers, with normality exceeding 100 mL/cmH2O. The ICS40 recommends two standard points for measuring bladder compliance: detrusor pressure at empty bladder and at maximum bladder capacity or immediately before the start of any detrusor contraction that causes significant leakage. Both points are measured excluding any detrusor contraction. Wahl et al.41,42 developed another method for measuring bladder compliance that they claimed was more accurate and practical, especially in children. They standardized bladder compliance according to a complex mathematical formula.

Detrusor stability during filling During bladder filling, the absence of involuntary detrusor contractions is considered to be normal and is defined as a stable detrusor.2,35 Uninhibited detrusor contractions occurred in 10%–18% of asymptomatic volunteers, but should be evaluated further because they may indicate an underlying pathology.33,43

Maximum cystometric capacity Normal cystometric bladder capacity can vary widely, but is normally between 300 and 550 mL, with higher values in men than in women.2

Leak-point pressure Detrusor leak-point pressure Leak-point pressure (LPP) is the value where bladder pressure leakage occurs. The rise in bladder pressure can be

secondary to a rise in detrusor pressure that is related to detrusor overactivity or impaired compliance. The value assessed is, therefore, referred to as detrusor leakpoint pressure (DLPP). This value is of great importance because detrusor pressure at leakage reflects the resistance the urethra can offer to the bladder mainly by the action of the striated sphincter. A high DLPP is of clinical relevance as it can jeopardize upper urinary tract function. McGuire et al. followed the clinical urodynamic progress of 42 myelodysplastic children and found that those with a DLPP of 40 cmH2O or more developed upper tract damage if not treated.44 Patients with normal detrusor compliance and without overactivity or outlet resistance will not experience a rise in detrusor pressure to dangerous levels. Detrusor pressure will rise at the initiation of voiding and decrease thereafter when the sphincter relaxes and the bladder empties. Therefore, abnormal detrusor pressure values will be seen in patients suffering from neurogenic bladder dysfunction (e.g., detrusor-sphincter dyssynergia, or DSD), but also in patients with infravesical obstruction.45

Abdominal leak-point pressure Increased abdominal pressure can also be elicited by a rise in abdominal pressure (with the Valsalva maneuver or during coughing). Abdominal leak-point pressure (ALPP) measures the ability of the urethra to resist abdominal pressure as an expulsive force, in the absence of detrusor contraction. This test assesses the severity of stress urinary incontinence (SUI) and may be useful in detecting intrinsic sphincter deficiency (ISD). In normal individuals, no abdominal pressure increase should cause incontinence. Therefore, there is no “normal ALPP.” However, studies have tried to determine a cut-off between patients with

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or without ISD. Using videourodynamics, McGuire et al. determined that 80% of women with Valsalva leak-point pressure (VLPP) below 60 cmH22O had type III SUI.46 They also demonstrated that VLPP values higher than 90 cmH2O can rule out ISD. In fact, in women suffering from SUI without genital prolapse, a high ALPP of 100 cmH2O or more is usually associated with urethral hypermobility. Those with values between 60 and 100 cmH2O have features of both ISD and hypermobility.45

Pressure-flow in men A pressure-flow (P/Q) study simultaneously measures detrusor pressure and flow rate during voiding. P/Q assessment is considered to be the gold standard for quantifying and grading bladder outlet obstruction (BOO) and detrusor contractility.47–52 P/Q data can be plotted on pressure-flow nomograms to classify patients as being either obstructed or not obstructed, and, at the same time, to grade the severity of obstruction. Different types of nomograms have been developed. The most commonly used ones in clinical practice are the Abrams–Griffiths (AG) nomogram, the Schafer nomogram, the urethral resistance factor (URA), and the ICS nomogram.49 These nomograms have a good prognostic

Abdominal pressure (cmH2O)

Intravesical pressure (cmH2O)

Detrusor pressure (cmH2O)

Abdominal premicturition pressure

Abdominal opening pressure

Abdominal pressure at maximum flow

Intravesical opening pressure

Intravesical pressure at maximum flow

Intravesical premicturition pressure

Detrusor premicturition pressure

Maximum intravesical pressure Detrusor opening pressure Maximum detrusor pressure

value in predicting the outcome after prostatectomy. 53–55 During P/Q assessment, several parameters are recorded, including opening detrusor pressure (Pdet.open), maximum detrusor pressure (Pdet.max), detrusor pressure at maximum flow (Pdet.Q ), minimum detrusor pressure during voiding (Pdet.min.void), Qmax, VV, and PVR (Figure 38.3). In normal patients, P/Q shows low pressure generating high flow, which indicates that there is no obstruction and that detrusor function is normal.56 Normal Pdet.max in men ranges between 47 and 58 cmH 2O.29 Walker et al. analyzed P/Q data on 24 asymptomatic volunteers with a mean age of 62.5 years. 57 They found that 14 of the volunteers (58%) fell in the nonobstructed zone according to the ICS nomogram and had grade 0–1 for the Schafer nomogram, correlating with an absence of obstruction. The AG number was −11 ± 11.7 (Qmax 23 ± 5.3 mL/s and PVR 14.5 ± 17 mL). Schmidt et al. undertook ambulatory urodynamic and P/Q measurements of 39 asymptomatic male volunteers (mean age 25.8 years) divided into two groups according to water consumption regimens per day: 30 mL/kg/day in group 1 and 60 mL/kg/day in group 2. They observed that Pdet.max occurred before the onset of urine flow. Furthermore, both detrusor pressure and detrusor contractility increased with augmented water consumption max

Maximum abdominal pressure

Intravesical contraction pressure at maximum flow

Detrusor pressure at maximum flow

Detrusor contraction pressure at maximum flow

Figure 38.3

Flow rate (mL/s)

Maximum flow

Opening time

Pressure-flow study diagram labeled with frequently measured parameters and recommended ­terminology. (Reproduced from Huang Y-H, Lin ATL, Chen K-K, Chang LS. Urol Int 2007; 77(4): 322–6. With permission.)

Normal urodynamic parameters in adults

417

Table 38.4  Normal reported P/Q parameters in men Wyndaele2

Schmidt et al.26 (group 1)

Walker et al.48

Normal range

Pdet.open (cmH2O)

—

51.2 ± 3.2

43.7 ± 17

40–50

Pdet.min.void (cmH2O)

—

—

32.5 ± 23

30

Pdet.max (cmH2O)

—

58.9 ± 4.5

—

60

Pdet.Qmax

47.9

47.8 ± 2.2

49.4 ± 26

50

Maximum contractility

—

15.4 ± 1.4

—

15

Qmax (mL/s)

16.6

24.4 ± 1.4

17.9 ± 17

16–25

VV (mL)

541.3

286 ± 20

254 ± 121

250–550

PVR (mL)

19.7

—

15.1 ± 21

15–20

BOOI

—

—

17 ± 35

≤17

LinPURR

—

—

—

Grade 0–I

URA

—

—

—

≤20

BCI

—

—

—

100–150

Pdet.open, opening detrusor pressure; Pdet.min.void, minimal voiding detrusor pressure; Pdet.max, maximum detrusor pressure during voiding; Pdet.Q max (cmH 2 O) , detrusor pressure at maximum flow; Qmax, maximum flow rate; PVR, postvoid residual urine; BOOI, bladder contractility index; LinPURR, linear passive urethral resistance relation; URA, urethral resistance factor; BCI, bladder contractility index.

and urine production.29 Wyndaele attempted to define what can be considered as normal parameters by urodynamic study in 38 healthy adult volunteers (28 men and 10 women) with a mean age of 24 years. Free flow rate, water cystometry, and P/Q assessment were undertaken for all of them. Micturition bladder pressure was higher in men than in women, reflecting higher outflow resistance in men, but detrusor pressure was not statistically different between the sexes. Flow time was significantly longer and maximum flow rate was significantly lower during P/Q evaluation than during free flow rate measurement in both sexes. There was no residual urine at all in majority of volunteers, but 6 men and 3 women had less than 50 mL residual2 (Table 38.4).

The AG nomogram The AG nomogram was described by Abrams and Griffiths in 1979. It can be calculated from two parameters generating P/Q data: Pdet.Q and Qmax. Both are plotted on a graph, which separates patients into three categories: obstructed, equivocal, and unobstructed.47–49 The ICS recommended this type of nomogram to diagnose BOO in older men.58 Lim and Abrams introduced the AG number, now known as the bladder outlet obstruction index (BOOI), which can be calculated by the following equation: AG number = Pdet.Q − (2xQ max ). According to the BOOI, the ICS nomogram can be divided into three zones. A BOOI greater than 40 indicates obstruction, between 20 and 40 is within an equivocal zone, and below 20 rules out obstruction. The latter category suggests that patients are

potentially normal or that their symptoms are secondary to detrusor hypocontractility49 (Figure 38.4).

Linear passive urethral resistance relation On Schafer’s P/Q diagram, BOO can be classified into seven categories: 0–I = normal or no obstruction, II = mild, III–IV = moderate, and V–VI = severe obstruction. Furthermore, the zone where Pdet⋅Q falls can characterize detrusor muscle strength. Linear passive urethral resistance relation (linPURR) was introduced later on by Schafer in 1990 by manually drawing a straight line between the minimal urethral opening pressure (Pmuo) and Pdet⋅Q . According to the linPURR nomogram, men with Pmuo less than 20 cmH2O and Pdet⋅Q more than 20 cmH2O have normal detrusor function and no obstruction.51,59 The upper normal limit for voiding detrusor pressure is 33 cmH2O (51) (Figure 38.5). max

max

max

max

max

Urethral resistance factor The urethral resistance factor (URA) can be calculated from any simultaneous pressure and flow values during voiding. It should remain constant throughout voiding regardless of the values used for calculation. Patients with URA greater than 29 cmH2O are classified as obstructed, those with URA between 21 and 29 cmH2O are equivocal, and those with URA below 21 cmH2O are unobstructed or normal.60–62

Textbook of the Neurogenic Bladder

(90)

Obstructed

(70) Equivocal 40 20

25

Qmax (mL/s)

Provisional International Continence Society nomogram for analysis of voiding divides patients into three classes according to the bladder outlet obstruction index (BOOI) = (Pdet.Qmax − 2Qmax ). (Reproduced from Huang Y-H, Lin ATL, Chen K-K, Chang LS. Urol Int 2007; 77(4): 322–6. With permission.) 25 N−

0

20

Urine Flow

Strong

100

Normal

Weak

N+

I

II

III

IV

ST

W+

15

V

W−

10

0

0

25

30

Qmax (mL/s)

Figure 38.4

0

150

Unobstructed

0

5

pdetQmax (cmH2O)

Pdet Qmax (cmH2O)

418

Figure 38.6 Bladder contractility nomogram divides patients into three categories according to the bladder contractility index (Pdet.Qmax + 5Qmax ). (Reproduced from Huang Y-H, Lin ATL, Chen K-K, Chang LS. Urol Int 2007; 77(4): 322–6. With permission.)

(Figure 38.7). This nomogram is a combination of the ICS nomogram and the bladder contractility nomogram, classifying patients into 9 zones and 6 groups according to the BOOI and the BCI. Patients in zones 1 and 2 are considered normal.49

VI

VW

Pressure-flow in women 0

10 20 30 40 50 60 70 80 90 100 110 120 130 140 150

pdet

Figure 38.5 Schafer nomogram. The plot indicates that the patient has a grade III severity of obstruction and that the patient has normal detrusor contractility. (Reproduced from Huang Y-H, Lin ATL, Chen K-K, Chang LS. Urol Int 2007; 77(4): 322–6. With permission.)

Detrusor contractility Detrusor contractility is derived from parameters such as the maximal pressure and amplitude slope during ­isovolumetric detrusor contraction as well as the duration of contraction. Detrusor contractility increases with the severity of outlet obstruction. 38 Schafer’s nomogram obtains the bladder contractility index (BCI) with the following formula: BCI = Pdet Q + 5Q max . If the BCI is more than 150, the detrusor is considered strong, between 100 and 150 is normal, and below 100 is weak. Detrusor contractility can also be assessed by the l­inPURR nomogram51 (Figure  38.6). Furthermore, it can be evaluated by estimating bladder voiding efficiency (BVE) according to the formula: BVE = (VV/ total capacity)100; 75% and above is considered to be normal.49 The BOOI and the BCI can also be calculated from the composite nomogram suggested by Abrams 49 max.

Blaivas and Groutz studied 50 women with BOO (mean age 65 years) and 20 normal controls (mean age 67 years) by videourodynamic assessment.63 The pressure-flow (P/Q) parameters recorded in the control group were free Qmax 24.4 ± 8.8 mL/s, Qmaz 13.3 ± 6.3 mL/s, Pdet.Q 17.9 ± 7.5 cmH 2O, Pdet.max 22.2 ± 9.2 cmH 2O, VV 312 ± 131 mL, and PVR 103 ± 100 mL. These authors described a nomogram, which can be used to diagnose BOO in women (Figure 38.8). Two parameters are needed to ­construct this nomogram: free Qmax and Pdet.max . Free Qmax was preferred to Qmax during P/Q because Pdet.Q and Qmax cannot be evaluated if the patient does not void during the test. The Blaivas nomogram consists of four zones that classify patients into four categories: zone 0 (normal or no obstruction), zone 1 (mild obstruction), zone 2 (moderate obstruction), and zone 3 (severe obstruction).63 Defreitas et al. investigated 169 females with BOO and 20 asymptomatic volunteers by P/Q assessment.64 They reported normal Qmax and Pdet.Q as 16 mL/s and 24 cmH 2O, respectively, in the asymptomatic group. The cut-off ­values to detect BOO for Pdet.Q and Qmax were 25 cmH 2O and 12 mL/s, respectively, with sensitivity, specificity, and accuracy of 68%. 55 Chassagne et al. obtained similar results earlier on. Qmax cmH2 O are reasonable P/Q parameters to diagnose female BOO.65 Brostrom et al. undertook a cystometry and P/Q study in 30 normal female volunteers

max

max

max

max

max

Normal urodynamic parameters in adults

Pdet Qmax (cmH2O)

150 7 100

8 4 9

5 2

3

20 0

1

6

40

0

25

30

Qmax (mL/s)

Figure 38.7 The composite nomogram allows categorization of patients into nine zones and therefore six groups according to the bladder outlet obstruction index and the bladder contractility index. (Reproduced from Huang Y-H, Lin ATL, Chen K-K, Chang LS. Urol Int 2007; 77(4): 322–6. With permission.) 160

Pdet.max (cmH2O)

140

Severe obstruction (3)

120 100 80

Moderate obstruction (2)

60 Mild obstruction (1)

40 20 0

No obstruction (0) 0

10

20 30 Free Qmax (mL/s)

40

50

Figure 38.8 Bladder outlet obstruction nomogram for women. (Reproduced from Jensen KM, Jorgensen JB, Mogensen P., Scand J Urol Nephrol Suppl 114, 72–7, 1988. With permission.)

with a mean age of 52 years.66 Two sets of measurements were recorded in all. They found that, between two repeated measurements, there was a statistically significant increase in first desire to void (171 mL and 205 mL) and normal desire to void (284 mL and 351 mL) with a decrease in bladder opening pressure, whereas no change was noted in maximum cystometric capacity (572 mL and 570 mL). Other parameters are listed in Table 38.5.

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(voiding UPP). Urethral pressure rises in “normal” healthy individuals with increasing bladder volume. This is the socalled “guarding reflex.” It also rises in the erect position. However, continuous recording of maximal urethral pressure (MUP) has shown variations and oscillations between 10 and 25 cmH2O.17 Maximum urethral closure pressure (MUCP) above 20 cmH2O is considered hypotonic, whereas MUCP values above 75 cmH2O for women and 90 cmH2O for men are deemed hypertonic. Sorensen et al.67 analyzed urethral pressure variations in 10 healthy fertile female volunteers (mean age 32 years) and 12 healthy postmenopausal volunteers (mean age 58.7 years). In the fertile group, they observed that mean maximum urethral pressure (mMUP) and mean maximum urethral closure pressure (mMUCP) had median values of 66.5 and 60 cmH2O, respectively. Postmenopausal women had significantly lower mMUP and mMUCP: 55.5 and 43.5 cmH2O, respectively. Van Geelen et al. studied 27 nulliparous healthy women between the ages of 19 and 35 years and found mMUP of 98 ± 17 cmH2O in the supine position, with mean urethral closure pressure of 84 ± 18 cmH2O.68 Pfisterer et al. examined bladder function parameters in pre-, peri, and postmenopausal continent women, discerning mMUCP values of 94, 74, and 42 cmH2O and functional urethral lengths of 3.3, 3.3, and 3.5 cm, respectively.25 Stress UPP measures the rise in intra-abdominal pressure transmitted to the proximal urethra. In normal women without urethral hypermobility, the increase in intravesical pressure and proximal urethral pressure should be similar. If this is not the case, different pathologies may be postulated. The pressure transmission ratio is a different parameter, recording the increment of urethral pressure with stress as a percentage of intravesical pressure elevation. In normal women, this value should exceed 100.69 One article70 reviewed a small series of patients to define normal MUP ranges in men. Mean MUP was 75 cmH2O for men under 64 years and 71 cmH2O for men over 64  years. A lower cut-off value of 20 cmH2O for MUCP in men and an upper value of 90 cmH2O can be adopted based on experts’ opinion.71 In postprostatectomy incontinence, a close association exists between sphincter damage and MUCP reduction.70

Urethral pressure profile

Kinesiologic EMG of the pelvic floor and sphincter

The urethral pressure profile (UPP) is a urodynamic test that quantifies the occlusive pressure generated by active and passive structures of the urethra, and allows the evaluation of urethral competence. UPP can be measured when the bladder is empty (resting UPP), during coughing or straining (stress UPP), or during the voiding phase

Kinesiologic measurements are recorded during urodynamic study to assess the integrity of perineal muscle innervation. They can be taken with the application of electrodes. The most commonly used are surface and concentric needle electrodes. Concentric needle electrodes offer a more precise technique, but surface electrodes

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Table 38.5  Normal reported P/Q parameters in women Brostrom et al.57

Blaivas and Groutz54

Pfisterer et al.74

Defreitas et al.55

Chassagne et al.56

Normal range

No. of patients

30

50

24

20

124

—

Mean age

52

64.4

50.2

—

—

—

Qmax(mL/s)

25

13.3

22

12

15

12–25

Qave (mL/s)

12

—

—

—

—

12

TQ (seconds)

67

—

—

—

—

60–70

Pdet.open (cmH2O)

22

—

—

—

—

22

Pdet⋅Qmax

30

17.9

27

24

20

18–30

Pdet.max (cmH2O)

46

22.2

44

—

—

22–46

264

—

—

250–650

VV (mL)

651

312

Qmax, maximum flow rate; Qave, average flow rate; TQ, flow time; Pdet.open, opening detrusor pressure; Pdet⋅Qmax (cmH 2 O), detrusor pressure at maximum flow; Pdet.max, maximum detrusor pressure during voiding.

are more convenient and comfortable for patients, all the while providing an excellent signal source for EMG if placed appropriately after proper skin preparation.72 At the beginning of cystometry and during bladder filling, baseline EMG activity of the external urethral sphincter (EUS) has a low frequency and amplitude if the patient is completely relaxed in the supine position. When the bulbocavernosus reflex test is done by squeezing the glans of the penis or clitoris, EMG activity at the EUS level is increased, indicating that the sacral reflex arc is intact. Furthermore, when intra-abdominal pressure rises during coughing, sneezing, or straining, the EUS contracts and EMG activity is amplified. This condition should be differentiated from DSD by asking the patient to not hold urine. Normally, EMG activity from the EUS at rest is low. It intensifies as fluid volume in the bladder grows, during bladder filling, due to EUS contraction. It is known as the guarding reflex, as already mentioned in relation to UPP.  During voiding, EMG activity disappears completely for a few seconds before detrusor contraction starts. Once the bladder is empty, EMG activity resumes.72–74

Concentric needle EMG of the pelvic floor and sphincter muscle

Neurourologic tests in clinical practice

Single-fiber EMG (SFEMG) records the action potential of a single muscle fiber. In normal muscles, SFEMG quantifies potentials from 1–3 single muscle fibers belonging to the same motor unit. It is a useful test to diagnose lower motor neuron lesions and non-neurogenic urinary retention.76

Electrophysiologic tests are complementary imaging studies of sacral dysfunction. They explore the urogenital region and are useful in evaluating incontinence, erectile dysfunction, and anorectal dysfunction. They give significant information when a lower motor neuron lesion is present.75 Action potentials generated during sphincter activity can be recorded with specialized needle electrodes inserted in the muscle (Table 38.6).76

Concentric needle EMG (CNEMG) is the method of choice to evaluate muscle innervation because a wider range of information from several striated muscles can be assessed.75 EMG of the external anal sphincter (EAS) is the most ­practical test to study the lower sacral nerves.76–78 CNEMG of the pelvic floor and EAS muscle allows the quantitative analysis of motor unit potentials (MUPs) and qualitative assessment of interference patterns (IPs).75 MUP measurement includes amplitude, duration, area, number of phases and turns, rise time, duration of negative peaks, and mean frequency of firing.79 IP investigation comprises the number of turn/s, amplitude/turn, percent activity, number of short segments, and envelope vs. percent activity.80 During relaxation, MUP activity is low, and IP values are equal to zero. During contraction, both activities are increased.80 There is no significant effect of gender and age on MUP/IP.80

Single-fiber EMG

Sacral reflexes The aim of this test is to assess the sacral reflex arc. Electrical, mechanical, or magnetic stimulation can be applied to the penis or clitoris to elicit sacral reflexes.76,81,82

Normal urodynamic parameters in adults

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Table 38.6  Normative data for sacral reflex measurement in men as reported in the literature Number

Muscle examined

Mean ± SD

Author

Single electrical stimulation Reflex latency (ms)

EUS 14

• Needle

33 ± 3.9

Vodusek et al.81

19

• Surface

27.9 ± 5.4

Desai et al.82

BC 60

• Needle

32.3 ± 3.9

Vodusek et al.81

12

• Surface

30.7 ± 4.2

Perretti et al.83

EAS

Sensory threshold (mA)

14

• Needle

35.3 ± 4.6

Vodusek et al.81

19

• Surface

28.1 ± 5.7

Desai et al.82

49

Penilo-cavernosus reflex

29.88 ± 5.65

Podnar80

40

Penilo-cavernosus reflex

7.8 ± 2.73

Podnar80

42

Penilo-cavernosus

28.16 ± 5.8

Podnar80

22

bulbocavernosus muscle

left: 31.6 ± 4.5

Amarenco et al.70

18

EUS

Mechanical stimulation Reflex latency (ms)

right: 31.6 ± 3.8 39.1 ± 4

Dykstra et al.84

Source: Podnar S, Mrkaic M, Vodusek DB. Neurourol Urodyn, 21(6), 540–5, 2002. EUS, external urethral sphincter; BC, bulbocavernosus muscle; EAS, external anal sphincter.

Such studies are useful to detect damage to myelin and axons within the peripheral sacral reflex arc.76 For more details on electrophysiologic evaluation, see Chapter 39.

Summary Urodynamic tests are useful tools to evaluate lower urinary tract dysfunction. They are gold-standard tests for the diagnosis of BOO and urinary incontinence. Urodynamic evaluation is a good predictor of outcome after therapeutic interventions. Urodynamic normality in healthy populations is not well known and illustrates a wide variety of data and patterns. Several important parameters, such as age, sex, and body mass index, affect urodynamic values, rendering it more challenging to define precise, normal values derived from tests performed on patients. Mathematic models and simulation may help in the future to generate more data on normality, but additional studies on healthy volunteers must be encouraged before then to gather more information.

Acknowledgment The authors thank Dr. Erik Schick for his help and advice in writing this chapter.

References 2638. Robertson AS, Griffiths CJ, Ramsden PD, Neal DE. Bladder function in healthy volunteers: Ambulatory monitoring and conventional urodynamic studies. Br J Urol 1994; 73(3): 242–9. 2639. Wyndaele JJ. Normality in urodynamics studied in healthy adults. J Urol 1999; 161(3): 899–902. 2640. Abrams P, Blaivas JG, Stanton SL, Andersen JT. The standardisation of terminology of lower urinary tract function. The International Continence Society Committee on Standardisation of Terminology. Scand J Urol Nephrol 1988; 114(Suppl): 5–19. 2641. Sutherst J, Brown M, Shawer M. Assessing the severity of urinary incontinence in women by weighing perineal pads. Lancet 1981; 1: 1128–30. 2642. Dylewski DA, Jamison MG, Borawski KM et al. A statistical comparison of pad numbers versus pad weights in the quantification of urinary incontinence. Neurourol Urodyn 2007; 26: 3–7. 2643. Ryhammer AM, Laurberg S, Djurhuus JC, Hermann AP. No relationship between subjective assessment of urinary incontinence and pad test weight gain in a random population sample of menopausal women. J Urol 1998; 159: 800–3. 2644. Chapple C, MacDiarmid S, Patel A (eds). Urodynamics Made Easy. Spain: Churchill Livingstone Elsevier, 2009. 2645. Versi E, Cardozo LD. Perineal pad weighing versus videographic analysis in genuine stress incontinence. Br J Obstet Gynaecol 1986; 93: 364–6. 2646. Jorgensen L, Lose G, Andersen JT. One-hour pad-weighing test for objective assessment of female urinary incontinence. Obstet Gynecol 1987; 69: 39–42. 2647. Klarskov P, Hald T. Reproducibility and reliability of urinary inconti­nence assessment with a 60 min test. Scand J Urol Nephrol 1984; 18: 293–8.

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2648. Groutz A, Blaivas JG, Rosenthal JE. A simplified urinary incontinence score for the evaluation of treatment outcomes. Neurourol Urodyn 2000; 19: 127–35. 2649. Lose G, Jorgensen L, Thunedborg P. 24-hour home pad weighing test versus 1-hour ward test in the assessment of mild stress incontinence. Acta Obstet Gynecol Scand 1989; 68: 211–5. 2650. Versi E, Orrego G, Hardy E et al. Evaluation of the home pad test in the investigation of female urinary incontinence. Br J Obstet Gynaecol 1996; 103: 162–7. 2651. Griffiths DJ, McCracken PN, Harrison GM, Gormley EA, Moore KN. Urge incontinence and impaired detrusor contractility in the elderly. Neurourol Urodyn 2002; 21: 126–31. 2652. Mouritsen L, Berild G, Hertz J. Comparison of different methods for quantification of urinary leakage in incontinent women. Neurourol Urodyn 1989; 8: 579–87. 2653. Karantanis E, O’Sullivan R, Moore KH. The 24-hour pad test in continent women and men: normal values and cyclical alterations. BJOG 2003; 110: 567–71. 2654. Jolivet-Tremblay M, Schink E. The voiding diary. In: Corcos J,  Schick E, eds. The Urinary Sphincter. New York, NY: Marcel Dekker, 2001: 262. 2655. Kassis A, Schick E. Frequency–volume chart pattern in a healthy female population. Br J Urol 1993; 72: 708–10. 2656. Huang Y-H, Lin ATL, Chen K-K, Chang LS. Voiding pattern of healthy Taiwanese women. Urol Int 2007; 77(4): 322–6. 2657. Boedker A, Lendorf A, H-Nielsen A, Glahn B. Micturition pattern assessed by the frequency/volume chart in a healthy population of men and women. Neurourol Urodyn 1989; 8: 421–2. 2658. Fitzgerald MP, Brubaker L. Variability of 24-hour voiding diary variables among asymptomatic women. J Urol 2003; 169: 207–9. 2659. Van Haarst EP, Heldeweg EA, Newling DW, Schlatmann TJ. The 24-h frequency–volume chart in adults reporting no voiding complaints: Defining reference values and analysing variables. BJU Int 2004; 93: 1257–61. 2660. Latini JM, Mueller E, Lux MM, Fitzgerald MP, Kreder KJ. Voiding frequency in a sample of asymptomatic American men. J Urol 2004; 172: 980–4. 2661. Haylen BT, Ashby D, Sutherst J, Frazer MI, West CR. Maximum and average urine flow rates in normal male and female populations: The Liverpool nomograms. Br J Urol 1989; 64: 30–8. 2662. Pfisterer MH, Griffiths DJ, Rosenberg L, Schaefer W, Resnick NM. Parameters of bladder function in pre-, peri- and postmenopausal continent women without detrusor overactivity. Neurourol Urodyn 2007; 26: 356–61. 2663. Unsal A, Cimentepe E. Voiding position does not affect uroflowmetric parameters and post-void residual urine volume in healthy volunteers. Scand J Urol Nephrol 2004; 38(6): 469–71. 2664. Suebnukanwattana T, Lohsiriwat S, Chaikomin R, Tantiwongse A, Soontrapa S. Uroflowmetry in normal Thai subjects. J Med Assoc Thailand 2003; 86(4): 353–60. 2665. Cohen DH, Steinberg JR, Rossignol M, Heaton J, Corcos J. Normal variation and influence of stress, caffeine intake and sexual activity on uroflowmetry parameters of a middle-aged asymptomatic cohort of volunteer male urologists. Neurourol Urodyn 2002; 21(5): 491–4. 2666. Schmidt F, Shin P, Jorgensen TM, Djurhuus JC, Constantinou CE. Urodynamic patterns of normal male micturition: Influence of water consumption on urine production and detrusor function. J Urol 2002; 168(4 Pt 1): 1458–63. 2667. Tong YC. The effect of psychological motivation on volumes voided during uroflowmetry in healthy aged male volunteers. Neurourol Urodyn 2006; 25(1): 8–12. 2668. Jorgensen JB, Jensen KM, Bille-Brahe NE, Morgensen P. Uroflowmetry in asymptomatic elderly males. Br J Urol 1986; 58(4): 390–5. 2669. Schafer W, Abrams P, Liao L et al. Good urodynamic practices: Uroflowmetry, filling cystometry, and pressure–flow studies. Neurourol Urodyn 2002; 21(3): 261–74.

2670. Abrams PH, Dunn M, George N. Urodynamic findings in chronic retention of urine and their relevance to results of surgery. Br Med J 1978; 2(6147): 1258–60. 2671. Wyndaele JJ. The normal pattern of perception of bladder filling during cystometry studied in 38 young healthy volunteers. J Urol 1998; 160(2): 479–81. 2672. Pauwels E, De WS, Wyndaele JJ. Normality of bladder filling studied in symptom-free middle-aged women. J Urol2004; 171(4): 1567–70. 2673. Blaivas JG, Chancellor M, Weiss J, Verhaaren M (eds). Atlas of Urodynamics. Oxford, United Kingdom: Blackwell, Milton, 2007. 2674. Bates P, Bradley WE, Glen E et al. The standardization of terminology of lower urinary tract function. Eur Urol 1976; 2: 274–6. 2675. Sullivan MP, Yalla SV. Detrusor contractility and compliance characteristics in adult male patients with obstructive and nonobstructive voiding dysfunction. J Urol 1996; 155: 1995–2000. 2676. Harris RL, Cundiff GW, Theofrastous JP, Bump RC. Bladder ­compliance in neurologically intact women. Neurourol Urodyn 1996; 15: 483–8. 2677. Abrams P, Cardozo L, Fall M et al. The standardisation of terminology of lower urinary tract function: Report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002; 21: 167–78. 2678. Wahl EF, Lerman SE, Lahdes-Vasama TT, Churchill BM. Measurement of bladder compliance can be standardized by a dimensionless number: Clinical perspective. BJU Int 2004; 94:898–900. 2679. Wahl EF, Lerman SE, Lahdes-Vasama TT, Churchill BM. Measurement of bladder compliance can be standardized by a dimensionless number: Theoretical perspective. BJU Int 2004; 94: 895–7. 2680. Ouslander J, Leach G, Abelson S et al. Simple versus multichannel cystometry in the evaluation of bladder function in an incontinent geriatric population. J Urol 1988; 140(6): 1482–6. 2681. McGuire EJ, Woodside JR, Borden TA, Weiss RM. Prognostic value of urodynamic testing in myelodysplastic patients. J Urol 1981; 126: 205–9. 2682. McGuire EJ, Cespedes RD, O’Connell HE. Leak-point pressures. Urol Clin North Am 1996; 23(2): 253–62. 2683. McGuire EJ, Fitzpatrick CC, Wan J et al. Clinical assessment of urethral sphincter function. J Urol 1993; 150: 1452–4. 2684. Lim CS, Abrams P. The Abrams-Griffiths nomogram. World J Urol 1995; 13(1): 34–9. 2685. Abrams P, Torrens M. Urine flow studies. Urol Clin North Am 1979; 6(1): 71–9. 2686. Abrams P. Bladder outlet obstruction index, bladder contractility index and bladder voiding efficiency: Three simple indices to define bladder voiding function. BJU Int 1999; 84(1): 14–5. 2687. Griffiths DJ. Pressure–flow studies of micturition. Urol Clin North Am 1996; 23(2): 279–97. 2688. Schafer W. Analysis of bladder-outlet function with the linearized passive urethral resistance relation, linPURR, and a disease-specific approach for grading obstruction: From complex to simple. World J Urol 1995; 13(1): 47–58. 2689. Eri LM, Wessel N, Tysland O, Berge V. Comparative study of pressure–flow parameters. Neurourol Urodyn 2002; 21(3): 186–93. 2690. Bruskewitz R, Jensen KM, Iversen P, Madsen PO. The relevance of minimum urethral resistance in prostatism. J Urol 1983; 129(4): 769–71. 2691. Jensen KM, Jorgensen JB, Mogensen P. Urodynamics in prostatism. II. Prognostic value of pressure–flow study combined with stopflow test. Scand J Urol Nephrol Suppl 1988; 114: 72–7. 2692. Javle P, Jenkins SA, Machin DG, Parsons KF. Grading of benign prostatic obstruction can predict the outcome of transurethral prostatectomy. J Urol 1998; 160(5): 1713–7. 2693. Gotoh M, Yoshikawa Y, Kondo AS et al. Prognostic value of pressure–flow study in surgical treatment of benign prostatic ­ obstruction. World J Urol 1999; 17(5): 274–8.

Normal urodynamic parameters in adults 2694. Walker RM, Romano G, Davies AH et al. Pressure flow study data in a group of asymptomatic male control patients 45 years old or older. J Urol 2001; 165(2): 683–7. 2695. Griffiths D, Hofner K, van MR et al. Standardization of terminology of lower urinary tract function: Pressure–flow studies of voiding, urethral resistance, and urethral obstruction. International Continence Society Subcommittee on Standardization of Terminology of Pressure–Flow Studies. Neurourol Urodyn 1997; 16(1): 1–18. 2696. Schafer W. Principles and clinical application of advanced urodynamic analysis of voiding function. Urol Clin North Am 1990; 17(3): 553–66. 2697. Eckhardt MD, van Venrooij GE, Boon TA. Urethral resistance factor (URA) versus Schafer’s obstruction grade and Abrams–Griffiths (AG) number in the diagnosis of obstructive benign prostatic hyperplasia. Neurourol Urodyn 2001; 20(2): 175–85. 2698. Rollema HJ, van MR. Improved indication and followup in transurethral resection of the prostate using the computer program CLIM: A prospective study. J Urol 1992; 148(1): 111–5. 2699. Van MR, Kranse M. Analysis of pressure-flow data in terms of computer-derived urethral resistance parameters. World J Urol ­ 1995; 13(1): 40–6. 2700. Blaivas JG, Groutz A. Bladder outlet obstruction nomogram for women with lower urinary tract symptomatology. Neurourol Urodyn 2000; 19(5): 553–64. 2701. Defreitas GA, Zimmern PE, Lemack GE, Shariat SF. Refining diagnosis of anatomic female bladder outlet obstruction: Comparison of pressure–flow study parameters in clinically obstructed women with those of normal controls. Urology 2004; 64(4): 675–9. 2702. Chassagne S, Bernier PA, Haab F et al. Proposed cutoff values to define bladder outlet obstruction in women. Urology 1998; 51(3): 408–11. 2703. Brostrom S, Jennum P, Lose G. Short-term reproducibility of cystometry and pressure-flow micturition studies in healthy women. Neurourol Urodyn 2002; 21(5): 457–60. 2704. Sorensen S, Waechter PB, Constantinou CE et al. Urethral pressure and pressure variations in healthy fertile and postmenopausal women with reference to the female sex hormones. J Urol 1991; 146: 1434–40. 2705. Van Geelen JM, Doesburg WH, Thomas CMG, Martin CB. Urodynamic studies in the normal menstrual cycle: The

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relationship between hormonal changes during the menstrual cycle and the u ­ rethral pressure profile. Am J Obstet Gynecol 1981; 141(4): 384–92. 2706. Steele GS, Sullivan MP, Yalla SV. Urethral pressure profilometry: Vesicourethral pressure measurements under resting and voiding conditions. In: Nitti VW, ed. Practical Urodynamics. Philadelphia, PA: WB Sanders, 1998: 108–30. 2707. Abrams P. Urodynamics, 3rd edn. London, United Kingdom: Springer-Verlag, 2006: 349. 2708. Wein A, Kavoussi L, Novick A, Partin A, Peters C (eds). CampbellWalsh Urology, 10th edn. Philadelphia, PA: WB Saunders, 2011: 4320. 2709. O’Donnell P, Beck C, Doyle R, Eubanks C. Surface electrodes in perineal electromyography. Urology 1988; 32(4): 375–9. 2710. Blaivas JG, Sinha HP, Zayed AA, Labib KB. Detrusor-external sphincter dyssynergia: A detailed electromyographic study. J Urol 1981; 125(4): 545–8. 2711. Blaivas JG, Sinha HP, Zayed AA, Labib KB. Detrusor-external sphincter dyssynergia. J Urol 1981; 125(4): 542–4. 2712. Podnar S, Vodusek DB. Protocol for clinical neurophysiologic ­examination of the pelvic floor. Neurourol Urodyn 2001; 20(6): 669–82. 2713. Podnar S. Neurophysiology of the neurogenic lower urinary tract disorders. Clin Neurophysiol2007; 118(7): 1423–37. 2714. Podnar S, Rodi Z, Lukanovic A, Trsinar B, Vodusek DB. Standardization of anal sphincter EMG: Technique of needle examination. Muscle Nerve 1999; 22(3): 400–3. 2715. Podnar S. Electrodiagnosis of the anorectum: A review of techniques and clinical applications. Tech Coloproctol 2003; 7(2): 71–6. 2716. Podnar S, Vodusek DB. Protocol for clinical neurophysiologic ­examination of the pelvic floor. Neurourol Urodyn 2001; 20(6): 669–82. 2717. Podnar S, Mrkaic M, Vodusek DB. Standardization of anal sphincter electromyography: Quantification of continuous activity during relaxation. Neurourol Urodyn 2002; 21(6): 540–5. 2718. Amarenco G, Ismael SS, Bayle B, Kerdraon J. Dissociation between electrical and mechanical bulbocavernosus reflexes. Neurourol Urodyn 2003; 22(7): 676–80. 2719. Podnar S, Vodusek DB, Trsinar B, Rodi Z. A method of uroneurophysiological investigation in children. Electroencephalogr Clin Neurophysiol 1997; 104(5): 389–92.

39 Electrophysiological evaluation: Basic principles and clinical applications John P. Lavelle

Introduction Clinical electrophysiological techniques are regularly used in the assessment of neurological conditions to assess nerve and muscle function. The purpose of this chapter is to describe the types and clinical use of electrophysiological testing for evaluation of neurogenic bladder. The primary functions of the urinary bladder are to accommodate and store urine at low pressures, and to allow voiding in a controlled, coordinated, socially acceptable manner. A neurogenic bladder is a condition where the nerves or neural pathways controlling or regulating bladder function are dysfunctional. This may be due to neurological or muscular disease, trauma, or metabolic disorders. Research uses of electrophysiology of the pelvic floor are discussed elsewhere.

Anatomical considerations The detailed anatomy relevant to neurogenic bladder is discussed elsewhere in this book. The structures studied by electrophysiological methods are the external urethral sphincter (US), contained in the deep perineal pouch; the external anal sphincter (EAS) complex, which has several components: superficial, deep, and corrigator cutis ani; the bulbocavernosus muscle that surrounds the urethra; and the sensory branches of the pudendal nerve, which are the dorsal penile nerves and the perineal sensory branches. The basis of neurophysiological testing is the standard monosynaptic model of the reflex arc schematically shown in Figure 39.1. The US is found anterior to the ischial tuberosity deep to the urogenital membrane within the deep perineal pouch. The EAS is found posterior to the perineal body, in the anal triangle, located to the posterior aspect of a line drawn through the ischial tuberosity. These bony and soft-tissue landmarks can easily be found with the patient

either in lithotomy position or in the left lateral position during the setup of multichannel cystometry measurement or electromyography (EMG) session. Sensory innervation starting in the dorsal penile nerves brings sensation from the glans to the spinal cord via the pudendal nerve. Sensation from the “saddle” region of the perineum is carried to the spinal cord by the perineal branches of the pudendal nerve. Sensory receptors are the most peripheral part of the somatic and autonomic sensory neurons. Mechanical or chemical stimuli are converted into electrical activity and nerve action potentials by sensory receptors. These signals then traverse the peripheral axon within pelvic nerves through the sacral plexus to the sacral segments of the spinal cord. The central part of the peripheral nerve axon branches, with segmental branches conveying sensory information to the brain, and other parts of the spinal cord. These processes enable completion of the neural pathways that normally voluntarily or by reflex activity control the pelvic viscera by many interneuronal systems.1 Alpha motor neurons to the US arise in Onuf’s nucleus in the anterior horn of the sacral S2–S4 segments in the human.2 The endplate of the neuron is ­distributed to several muscle fibers in the sphincter. This unit of nerve body, axon, and group of innervated muscle fibers is called a motor unit (MU). Autonomic fibers are distributed to the lower urinary tract through the parasympathetic system arising from the interomediolateral bodies of the S2–S4 sacral segments. The fibers are carried via the pelvic and pudendal nerves. The sympathetic fibers are carried via branches of the lesser and least splanchnic nerves through the superior hypogastric plexus, hypogastric nerves and pelvic plexus to the bladder, urethra, and other urogenital organs. These fibers may have sensory (for bladder pain) and

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Textbook of the Neurogenic Bladder α Motor neuron MSA Conus medullaris lesions Spinal dysraphism +– + Sacral plexus

Cauda equina

Pudendal nerve

External anal sphincter muscle

Figure 39.1 Schematic drawing of the sacral reflex arc. The afferent sensory nerves enter the root posteriorly and the efferent (motor) root leaves anteriorly. There are several interneurons within the grey matter of the spinal cord, which may be α motor neuron. These provide facilitatory and inhibitory suprasegmental influences to the sacral reflexes. MSA, multiple system atrophy. (From Corcos, J, and Schnick, E, Textbook of the Neurogenic Bladder. Informa Healthcare UK, London, United Kingdom, 2008.)

motor (to assist accommodation) functions. Sympathetic fibers also are carried with the pudendal nerve arising from the sympathetic chains and its segmental branches. The pathways and physiological interactions between the somatic and autonomic nervous systems in the pelvis are complex and not fully elucidated. For reviews, see Yoshimura’s and Crags’ works.3–5

General principles of electrophysiological testing Electrical activity, the passage of current, or movement of electrical charge occurs across many biological membranes. The passage of this charge is detectable with many different devices; however, the signals received by many of the earlier detection devices were relatively crude, and the signals were difficult to interpret. Gradually, over the last 100–150 years, as these phenomena have been studied, the use of mathematical transforms, and filters to these signals has allowed the development of modern electrophysiology, which first came into regular clinical practice in the early 1960s. Nerves and muscle display movement of electrical charge, both across their cell membranes and along their cell membranes, known as depolarization. This allows for the transmission of a neural signal along the neural axon. The signal then transmits from neuronal end plate to the muscle, and depending on the signal transmitted, excite or

inhibit the muscle contraction. The muscular contraction also relies on transmission of electrical signal throughout its length to facilitate the muscle contraction. Detection of these electrical signals and changes therein form the basis of electrophysiological testing. Electrophysiological testing may determine the conduction velocity of neural impulses, the electrical activity within muscles or neurons, but not the strength of the muscular contractions. In clinical studies, single muscle intracellular or neuronal intracellular measurements are not possible as in a physiology laboratory. Clinical electrophysiological measurements are made from the extracellular space, from the skin surface close to the muscle group of interest, or by placing a small electrode in the muscle to pick up signals from several muscle fibers simultaneously. The principles of detection of signals from muscles follow the laws of volume conduction as the electrical signal has to be picked up a distance from its origin and be transmitted through a volume of tissue to the detector.6 Detection of signals from some structures may not be possible in the clinical setting, and the detection of function of these structures is made by stimulation of the structure and seen a resultant reflex or action of that stimulus. The use of stimulation to elicit a muscular response is called a compound action potential. Surface electrode placement is noninvasive and comfortable for the patient, but is subject to interference from muscle activity outside the muscles of interest. Needle electrode, whether it be bare wire or concentric needle or single fiber needle electrodes, provide better signal from the muscle to be studied, but may be more uncomfortable to the patient. Electrophysiological testing should be performed to provide results that may alter a patient’s treatment, or provide information about the progress of a patient’s disease or likely outcome (Figure 39.2). Therefore, a patient with an already established neurogenic bladder, from a confirmed neurological disorder, may not benefit from electrophysiological testing of the pelvic floor or sphincter mechanisms. Electrophysiological testing may benefit a patient where neurological disease is suspected, and confirmed with the testing, or the results point toward the correct neurological diagnosis. The electrophysiological study timing is also important, due to time-dependent changes that alter neuromuscular function. An example: following spinal cord injury, there is a period of spinal shock, where all the physiological reflexes are suppressed below the level of injury, and then recover over time. Another example is where there maybe time-dependent and/or progressive changes such as those with diabetic neuropathy. Electrophysiological studies are generally not “standardized” and thus rely on the individual performing the test to modify and report the testing based on the information required by the clinical or diagnostic question. Although there have been calls for standardization of the testing, it is important to remember that comparison of

Electrophysiological evaluation

It is imputed that if the segmental reflex arcs are physiologically functional, the innervation of the bladder is also intact and functionally normal.

Cerebral cortex

MEP

SEP

Reflex

Motor pathway

Sensory pathway

Spinal cord

Muscle

427

Receptor

Figure 39.2 Components of the somatic sensory and motor systems. Arrows on the motor (left) side indicate different stimulation sites of the motor cortex, spinal roots and peripheral nerves. Small circles on the sensory (right side) indicate different sensory recording sites (below up) from the peripheral nerve, spinal roots/cord and somatosensory cortex. The recording (Sensory nerve action potential – SNAP) from the sensory nerves to the cortex may be reversed, where the cortex is stimulated and the response seen in the peripheral nerve. CNEMG and SFEMG are used to evaluate the lower motor neuron and muscle, whereas kinesiologic EMG evaluates the integrity of upper motor neuron and neurocontrol reflex arcs. (Original from Vodusek, D.B., Urol Clin North Am 23(3), 427–46, 1996; modified from Corcos, J, and Schnick, E, Textbook of the Neurogenic Bladder. Informa Healthcare UK, London, United Kingdom, 2008.)

tests from different practitioners or institutions may not be comparable unless all the testing parameters are known and allowances can be made in the comparison. There are four types of clinical electrophysiological testing (Figure 39.2): 1. Motor evoked potentials (MEP) for motor activity. 2. Sensory evoked potentials (SEP) for sensation assessment. 3. Assessment of reflexes. The BCR is of primary interest. 4. Autonomic Nervous System Assessment. The actual mechanisms of bladder sensation are currently not yet fully defined. The interactions between the bladder and sphincter are well studied in many animal models. Clinically, the reflex arcs between the urinary bladder and the spinal cord are not actually examined, but the nerves from the same sacral segments are examined.

Electrophysiological testing: General material Two patterns of abnormality are found in the neurogenic bladder. First, those neurological changes are related to central nervous system (CNS) or upper motor neuron (UMN) lesions where the bladder exhibits hyperreflexia. Second, when the neurological lesion affects the anterior horn cell, axon, or segmental sensory nerve, it causes a lower motor neuron (LMN) lesion with a hypotonic or flaccid bladder. Coordination of voiding is managed by the pontine micturition center. Disruptions of the sensory or motor pathways to and from the pontine micturition center may lead to detrusor-sphincter dyssynergia (DSD). In children, neonatal bladder control managed through the sacral micturition center, which is then suppressed as the myelination of the long spinal cord tracts, develops with age. In spina bifida children, DSD may be seen when the child is older. The neurological lesions do not always predict the findings on neurophysiological testing, thus the expected findings as outlined above are not always present.7 Electrophysiological tests can be understood as an extension of the clinical neurological examination. The tests are seldom useful in patients with a completely normal neurological examination and are helpful only in patients in whom specific neurological lesions are suspected.8 In general, neurophysiological tests may be used to elucidate those findings summarized in Table 39.1. Some of these properties are relevant when applied to the striated muscle of the pelvic floor. Other physiological tests used in evaluation of bladder disorders (measurement of postvoid residual [PVR], uroflow, cystometry, etc.) are different in that they test function and, as a consequence, can be regarded as complementary to sacral electrophysiological testing. Similarly, neurophysiological tests are complementary to imaging studies (ultrasound, computer tomography [CT] magnetic resonance imaging [MRI], etc.) of the lower urinary tract. The limitations of neurophysiological tests have been outlined earlier.

Electrophysiological testing: Clinical assessment Electrophysiological testing is seldom useful in patients with a completely normal neurological examination, therefore should only be used in patients in whom a neurological condition is suspected. These questions and the appropriate testing are outlined in Table 39.1.

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Table 39.1  Unique information provided by electrophysiological tests Information

Structure

Method

Finding

Neuronal Integrity preserved

Lower motor neuron

CNEMG

Absent spontaneous denervation activity, continuous MUP firing during relaxation

Lower and upper motor neuron

CNEMG

Dense IP on voluntary activation

Sacral reflex arc

CNEMG sacral reflex

Dense IP on reflex activation by touch. Brisk responses of normal latency

Somatosensory pathways

Pudendal SEP

Normal shape and latency of responses

Root versus plexus/nerve

CNEMG

Paravertebral denervation activity in neighboring myotomes

SNAP

Normal (penile) SNAP with impaired (penile) skin sensation

Complete vs. partial

CNEMG

Profuse spontaneous denervation activity absent MUP’s

Severe vs. moderate

Sacral reflex

Response non-elicitable

Conduction block vs. axonotmeisis

CNEMG

Absent/Sparse spontaneous denervation activity

Axonotmeisis vs. neurotmesis

CNEMG

Appearance of nascent MUPs after complete muscle denervation

Localization of neuronal lesions

Severity of neuronal lesions

Type of neuronal lesion

Source: Corcos, J, and Schnick, E, Textbook of the Neurogenic Bladder. Informa Healthcare UK, London, United Kingdom, 2008. CNEMG, concentric needle electromyography; IP, interference pattern; MUP, motor unit potential; SEP, somatosensory evoked potential; SNAP, sensory nerve action potential. 

To determine what testing should be performed, the neurological question has to be carefully defined. A careful clinical history with emphasis on urinary, sexual, and bowel symptoms should be obtained. A general and a urogenital-focused physical examination should be performed. The focused neurourological examination should include examination of the lower limbs for sensory and motor changes, perineal sensory testing, digital rectal examination to include anal tone, the anal wink reflex (both sides), anal sensation, ability to squeeze and relax the sphincter, and the bulbocaveranosus reflex (BCR).9 Supplemental information may be obtained from measurement of uroflow, PVRs, and imaging as needed. The imaging may be renal/bladder ultrasound, abdominal CT or MRI imaging if required. Judicious use of irradiation is advised during the testing as recent studies on overall patient irradiation dose suggest potential increased cancer and other risks.10 An MRI of the spine may be indicated if there is symptomatic or examination evidence of neurological deficits. Indicators of potential neurological lesions include patients complaining of incomplete bladder emptying, or maintaining a chronic high PVR, difficulty initiating voiding, or patients with abnormalities in sensation or motor function in the perineum or lower limbs,11 and difficulty with bowel and sexual function.11 Many of the neurological conditions are discussed in other chapters of this book.

Low back pain with radiation to a leg(s) associated with numbness or tingling in the saddle region may be caused by the cauda equina syndrome. In older patients, questions about slow movements, difficulty starting or stopping movements, tremor, or autonomic dysfunction by orthostatic hypotension, etc. may reveal extrapyramidal disorders such as Parkinson disease. Neurological symptoms or signs that are separated by anatomical location and time may suggest demyelinating diseases of the CNS such as multiple sclerosis. Dysuria may be a symptom of DSD.

Useful diagnostic tests for pelvic floor disorders Kinesiologic EMG The aim of the kinesiologic EMG is to assess patterns of individual muscle activity during various maneuvers, such as the pelvic floor muscle activity patterns during bladder filling and voiding. In “neurological EMG,” the stimulated muscle is analyzed in a static condition. In this chapter, only kinesiologic EMG is considered. To get a generalized EMG signal, with no intention to analyze the motor unit potentials (MUPs), surface, intramuscular, or bare wire electrodes may be used. The signal will be sampled from a single site, and can be recorded on basic recording devices. This can be used for EMG of the US during cystometry to help determine if there is DSD.

Electrophysiological evaluation

Except for the diagnosis of DSD, especially during cystometry, the diagnostic value of kinesiologic EMG is yet to be established. Voluntary and reflex activation of the pelvic floor muscles is indirect proof of the integrity of the neural pathways. The integrity of the pathways may be individually evaluated with concentric needle EMG.

Concentric needle EMG The aim of concentric needle EMG (CNEMG) is to differentiate abnormal from normally innervated striated muscle. These changes occur due to disease of the muscle fibers and or changes in their innervation. The EAS is the most practical muscle complex for CNEMG testing of the sacral segments, because of easy subcutaneous access, and sufficient muscle bulk.23 The EAS muscle is divided into observation of insertion activity, spontaneous denervation activity, quantitative assessment of MUPs (see Figure 39.3 for measurement parameters schematic) and qualitative assessment of the interference pattern (IP). The number of continuously active MUPs during relaxation14 can be observed as MUP recruitment by reflex or voluntary activation.24 In normal muscle, needle movement elicits a short burst of insertion activity, due to mechanical stimulation of excitable membranes. Absence of insertion activity with an appropriately placed needle electrode usually means complete muscle denervation,25 such as that found in approximately 10% of patients with most severe cauda equina lesions.23

Amplitude

It is assumed that the pelvic floor acts as a single unit in a coordinated manner. There are few studies examining the different parts of the pelvic floor. Peri- and intraurethral sphincter EMG’s have been shown to have different characteristics in normal women.12 Normal findings of the EMG during filling demonstrate increased pelvic floor activity or increased US recruitment during filling, which probably represents increasing recruitment of the sphincter to maintain continence. Increases in EMG activity may also be seen during voluntary sphincteric or pelvic floor contractions, such as during coughing or voluntary squeezes, such as during Kegel exercises. This activity forms the basis for biofeedback training to help with overactive bladder by reflex inhibition of the bladder with pelvic floor contractions. Voluntary contraction of the US, EAS, and pubococcygeus can only be sustained for about 1 minute.13 Reflex increases in EMG activity, associated with sphincter contraction, may be seen during coughing, deep breathing, and other activities. Continuous basal activity of the sphincters is seen at rest, and is also maintained during sleep. This activity is not present in all sites of the levator ani13 or the deeper parts of the EAS musculature.14 During normal voiding, the EMG activity of the sphincter mechanism demonstrates coordination between the sphincter and bladder, by quieting considerably before the detrusor contraction occurs. The sphincteric EMG activity reestablishes on completion of voiding. The pubococcygeus also relaxes during voiding.13 Coordinated behavior is frequently lost in abnormal conditions, and has been shown in the urethral, EAS and the levator ani.15,16 The pubococcygeus, affected by disease, may lose its pattern of activation and coordination between both sides.17 Loss of coordination in the US is called detrusor-sphincter dyssynergia or DSD.18,19 Three types have been described,20 one where the sphincter fails to relax, one where there is a crescendo/decrescendo effect with bladder contraction, and the third as an intermittent contraction–relaxation pattern during voiding, with an intermittent flow during the quiet parts of the EMG. The diagnosis of DSD may not be easy or a foregone conclusion, as about 40% disagreement has been found between simultaneous EMG activity and voiding cystourethrography.19 Uncoordinated sphincteric findings have to be differentiated from voluntary contractions occurring in poorly compliant, or uncooperative patients. Sphincteric discoordination may also be found with learned abnormal behaviors such as the Hinman syndrome or “non-neurogenic neurogenic bladder” that can be encountered in men21 and some women22 presenting with dysfunctional voiding. As with any EMG study, artifact is an important confounder, such as with other muscular activity being picked up by surface EMG electrodes. There are also questions about whether the entire muscle is represented by the measured signal.

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10 ms

50 µV

Duration

Figure 39.3 Schematic diagram of MUP parameters. Amplitude is the ­voltage difference (μV) between the most positive and most negative points of the MUP trace. The MUP duration is the time (ms) between the first deflection and the point when the MUP waveform finally returns to baseline. The number of MUP phases (small circles) is defined by the number of MUP areas alternatively below and above the baseline and can be counted as the “number of baseline crossings plus one.” Turns (arrows) are defined as changes in direction of the MUP trace that are larger than the specified amplitude (e.g., 50 μV) but not crossing the baseline. MUP area measures the integrated surface of the MUP waveform (shaded). (From Corcos, J, and Schnick, E, Textbook of the Neurogenic Bladder. Informa Healthcare UK, London, United Kingdom, 2008.)

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Acute complete denervation, immediately causes cessation of all electrical and MU activity, except insertion activity. After 10–20 days, insertion activity becomes more prominent and prolonged, and abnormal spontaneous activity appears with short biphasic spikes known as fibrillation potentials and biphasic potentials with prominent positive deflections and biphasic potentials with prominent positive deflections or positive sharp waves (Figure 39.4). This type of activity is referred to as “spontaneous denervation activity,” and originates from denervated single muscle fibers. Partially denervated muscle causes some MUPs to remain and mingle eventually with spontaneous denervation activity. As the MUP in sphincter muscles are also short and mostly bi or triphasic, like fibrillation potentials.26 Considerable EMG experience is required to differentiate acute from partial denervation.

1

In this situation, examination of the bulbocavernosus muscle is useful because in contrast to sphincter muscles, in lacks ongoing activity of low-threshold MU during relaxation (Figure 39.4).24 In longstanding partially denervated muscles, particular abnormal activity called simple or complex “repetitive discharges” (CRD) appear caused by repetitive firing of groups of potentials. This activity may be provoked by needle movement, muscle contractions, etc., or may occur spontaneously. This activity may sometimes be found in USs of patients without any other evidence of neuromuscular disease, and indeed without lower urinary tract problems although in such cases CRD are not prominent.27 A type of repetitive discharge activity called decelerating bursts (DB) and complex repetitive discharges has been found in the external US muscles of some young women. This activity may be so abundant as to possibly cause involuntary muscle contraction and urinary retention.28 2

2

10 ms 10 μV (a)

10 ms 500 μV (b)

Figure 39.4 Findings of CNEMG in a 36-year-old man 2 (part a) and 9 months (part b) after surgical cauda equina decompression due to central herniation of L4-5 intervertebral disk. The patient had long-term atonic bladder, severe constipation, and erectile dysfunction. Part (a) shows distinct spontaneous denervation activity with biphasic potentials with prominent positive deflections (1), and short biphasic spikes (fibrillation potentials [2]). No motor unit potentials (MUPs) could be recruited either reflexly or voluntarily suggesting complete muscular denervation. Part (b) MUPs sampled from the external anal sphincter, the readings fall within the mean of a normative population. This shows good muscular reinnervation following complete denervation (as shown in part (a)). This is a combination of neuropraxia (block of neuronal transmission) and axonotmesis (degeneration of the nerve fibers with preserved nerve root continuity) as opposed to neurotmesis (nerve roots severance) as a mechanism of the cauda equina injury. (The MUP data is reads duration = 7.3 ms (Z = +0.7), mean area was 808 μVms (Z = +4.2) and mean number of turns = 4.3 (Z = +1.5)). (From Corcos, J, and Schnick, E, Textbook of the Neurogenic Bladder. Informa Healthcare UK, London, United Kingdom, 2008.)

Electrophysiological evaluation In contrast to limb muscles, where electrical silence is present on relaxation in sphincter muscles, some MUPs are continuously firing.14 Additional sphincter MUPs can be activated reflexly or voluntarily, and it has been shown that there are two MUP populations with different characteristics of reflexly or voluntarily activated high-threshold MUPs, which are larger than continuously active lowthreshold MUPs.29 Consequently, to increase accuracy of MUP analysis for a template-based multi-MUP analysis; standardization of activity level during sampling at which 3–5 MUPs are sampled on a single muscle site is recommended.29 In partially denervated sphincter muscle, there is a loss of MUs. To quantify this exactly, use of multi-MUP analysis was proposed.14 By this approach, the number of remaining MUs after partial denervation can be estimated. Furthermore, using this technique the segmental and suprasegmental inputs as well as the excitation level of the motor neurons within the anterior spinal horns, can be assessed. This approach was found particularly useful in patients with idiopathic fecal incontinence,30 but has not been studied in patients with neurogenic bladders. With direct reinnervation after complete denervation, nascent MUPs appear first of being short-duration, lowamplitude, bi- and triphasic potentials, soon becoming polyphasic, serrated and of prolonged duration. Changes due to collateral reinnervation are reflected by prolongation of the waveform of the MUPs (Figure 39.5), which may have small, late components (i.e., satellites). In newly formed axon sprout endplates, neuromuscular transmission is insecure, resulting in MUP instability (“jitter” and blocking of individual components).31 Over a period of time, provided there is no further denervation, the reinnervating axonal sprouts increase in diameter so that activation of all parts of the reinnervated MU becomes nearly synchronous, which increases the amplitude and reduces the duration of the MUPs (Figure 39.5). This phenomenon may be different in sphincter muscles in ongoing degenerative disorders such as MSA, where long-duration MUPs seem to remain a prominent feature of MUs.32 A less-­pronounced increase in MUP amplitude on reinnervation in sphincter muscles might also be due to a less-efficient fusion of individual muscle fiber potentials in muscles with short spike components of MUPs (also in facial muscles).33 Technical aspects of CNEMG  The concentric needle electrode consists of a central insulated platinum wire that is inserted through a steel cannula. This type of electrode records activity from muscle tissue up to 2.5 mm from the electrode tip.34 For the CNEMG examination, a standard EMG system, which has the facility for quantitative template-based MUP analysis with multi-MUP, is ideal.35 The commonly used amplifier filter setting for CNEMG is 5–10 Hz. This

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must be identical to those set when the reference template values were complied and needs to be checked if MUP parameters are to be measured. To examine the EAS muscle complex, the needle is inserted about 1 cm from the anal orifice to a depth of 3–6 mm at a sharp angle to the skin.25 Both right and left side of the EAS should almost always be examined by needle insertions into the middle of the anterior and posterior halves.36 The needle is angled backward and forward in a systematic manner through two insertion sites on each side.24 The muscle insertion activity is recorded at a gain of 50 uV per division, which is also used to record spontaneous denervation activity (sweep speed 5–10 ms/division, which is also used to record spontaneous denervation activity (sweep speed 5–10 ms/division). Several techniques are available to systematically examine the individual MUPs, including sophisticated templateoperated CNEMG techniques on advanced systems. These perform multi-MUP analyses.37,38 The fastest and easiest quantitative MUP analysis technique is multi-MUP analysis. It can be applied at continuous activity during sphincter muscle relaxation and at slight to moderate levels of activation.39 The needle must be located so that a “crisp” sounding pattern of EMG activity can be heard over the loudspeaker indicating that the needle electrode is near to muscle fibers. Then, during an appropriate level of EMG activity, the operator starts the analysis and the computer takes the previous 4.8-second signal period. From that signal, MUPs are automatically extracted, quantified, and sorted into up to 6 MUP classes; representative consecutive discharges of a particular MUP are then averaged and presented (Figure 39.4).37,39 Duration cursors are set automatically using a computer algorithm. However, after acquisition, the operator has to edit the MUPs; the MUPs with an unsteady baseline (unclear beginning or end) need to be recognized and deleted. The multi-MUP technique has difficulties with highly unstable or polyphasic MUPs, due to sampling error, or recognition error, where the MUP is cut in two or the program has an averaging problem.40 Using multi-MUP analysis sampling of 20 MUPs (standard number in limb muscles) from each side of the EAS muscle present no problem in healthy controls and most patients (Figures 21.3 and 39.4).39 Normative data obtained from the EAS muscle complex by standardized EMG technique have been published.39 Analysis made from the same taped EMG signal using reference data for mean values and outliers (Figure 39.5) revealed similar sensitivity of different MUP analyses for detecting neuropathic changes in the EAS muscle complex of patients with chronic cauda equina lesions.41 A number of MUP parameters are used in the diagnosis of neuromuscular disease (Figure 39.5). MUP amplitude and duration were measured and the number of phases counted.42 However, a study performed in the EAS muscle

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2

1

1

20 ms 500 μV (a)

2

1

10 ms 500 μV (b)

Figure 39.5 Findings of EAS CNEMG of a 36-year-old male with a 2 month history of conus medullaris myelitis. The patient had several episodes of urinary and fecal incontinence, impaired sensation of bladder and rectal fullness, and erectile dysfunction. Part (a) shows extremely polyphasic MUPs with increased duration and late potential (arrows), MUP instability, by changes in the MUP pattern (1 vs. 2). Not shown were findings of no spontaneous denervation activity, or no ‘low threshold MUPs’ continuously firing during relaxation was present, but reflex recruitment was present, but severely reduced. These findings are consistent with subacute partial denervation of the muscle. Part (b) demonstrates MUP sampling for multi-MUP analysis. Only 8 MUPs were required to find 3 with duration, area and number of turn values above the upper outlier limit. To diagnose muscle pathologically changed only 3 out of 20 or less MUPs need to meet the outlier criteria, though all 20 are needed to diagnose neuropathic muscle. MUPs 1 and 2 are the same for parts (a) and (b), but their pattern has been altered by the analysis in (b). (From Corcos, J, and Schnick, E, Textbook of the Neurogenic Bladder. Informa Healthcare UK, London, United Kingdom, 2008.)

revealed that probably only the parameters of area, duration, and the number of turns are needed in MUP analysis.43 Other MUP parameters (amplitude, the number of phases, duration of the negative peak, thickness, and size index) appear to be noncontributory and their use might reduce the specificity of MUP analysis.43 In addition to continuous firing of low-threshold MUPs in sphincters, additional high-threshold MUPs29 are recruited voluntarily and reflexly (Figure 39.5) by such maneuvers, the number of recruitable MUs is estimated. Normally MUPs should intermingle to produce a sense IP on the oscilloscope screen when muscle is contracted well, and during a strong cough. The IP can be assessed using a number of automatic quantitative analyses, the turn/amplitude analysis being the most popular.44,45 However, quantitative IP analysis was shown to be only half as sensitive as MUP analysis techniques in distinguishing between normal and neuropathic muscles. Nevertheless, with the needle electrode in focus, qualitative assessment of IP during voluntary or reflex muscle contraction by coughing is recommended. In summary, template-based multi-MUP analysis is as sensitive as the traditional MUP analysis techniques

(fast, 5–10 minute per muscle), easy to apply,39 less prone to personal bias, and is clinically useful.7 The use of EAS muscle complex is facilitated by available common normative data, which are unaffected by age, gender,35 number and characteristics of vaginal deliveries,46 or mild chronic constipation.47 Criteria for possible, probable, and definite neuropathic changes in the EAS muscle have been proposed.48 All these make multi-MUP analysis, the technique of choice for quantitative analysis of the EAS reinnervation. Research into newer methods of performing CNEMG analysis, as well as research into the muscular function and neurotransmission, will likely make the use of CNEMG easier to interpret and use in a standardized manner.

Single-fiber electromyography The aim of single-fiber electromyography (SFEMG) testing is similar to CNEMG – to differentiate normal from abnormal striated muscle. An SFEMG needle will record only 1–3 single muscle fibers from the same MU because of its anatomical ­arrangement. The contribution of each muscle fiber appears as a short biphasic positive–negative action potential.

Electrophysiological evaluation The SFEMG parameter that reflects MU morphology is the “fiber density,” which is designated as the mean number of muscle fibers per individual MU per detection site. Data recordings from 20 different intramuscular detection sites are necessary for adequate sampling.31 The normal fiber density for the EAS is below 2.0.49 The fiber density is increased in collaterally reinervated muscle. The  technique is useful in anal sphincter evaluation with correlation of the fiber density findings to incontinence. An SFEMG electrode can record small changes in MUs due to reinnervation but is less suitable to detect denervation changes. The SFEMG electrode is best able to record MUP instability or “jitter.” This instability is not routinely assessed in pelvic floor muscles. Technical aspects of SFEMG  The SFEMG electrode has similar external proportions to a concentric needle electrode but instead of having the recording surface at the tine, a fine insulated platinum or silver wire embedded in epoxy resin is exposed through an aperture on the side 1–5 mm behind the tip. The platinum wire forms the recording surface that has a diameter of 25 μm. It will pick up activity from within a hemispherical volume of 0.3 mm in diameter.34 Concentric needle electrode have an uptake area of 2.5 mm diameter, which is much larger than that of the SFEMG. When recording with an SFEMG needle, the amplifier filters are set so that low-frequency activity is eliminated (500 Hz–10 KHz).

SFEMG vs. CNEMG Quantified CNEMG provides the same information as SFEMG’s fiber density50 on muscle reinnervation changes. CNEMG additionally (1) reveals spontaneous denervation activity, (2) allows for wider exploration of muscles after severe partial denervation, where fibrosed areas of muscle are silent to EMG, (3) may be extended over several myotomes in the same diagnostic session, (4) may be used to evaluate evoked direct and reflex muscle responses, and (5) is generally available in most clinical EMG laboratories. SFEMG has not been shown to be advantageous in the clinical evaluation of neurogenic bladder.

Sacral reflexes The aim of electrophysiologic testing of sacral reflexes is to assess integrity of the sacral (S2–S4) spinal reflex arc and to evaluate excitation levels of sacral spinal cord motor neurons. In the lower sacral segments, there are two commonly clinically elicited reflexes, the anal and the penilo/ clitoral–bulbocavernosus9 often known as the bulbocavernosus reflex (BCR). The afferent and efferent limbs of both reflexes are in the pudendal nerve and are centrally integrated at the S2–S4 cord levels.

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Electrophysiological correlates of these and other sacral reflexes have been described, and a uniform two-part nomenclature system has been proposed.9 Measurements of reflex responses and evoked potentials, including sympathetic skin responses (SSRs), relate to both conduction in peripheral and central neural pathways, and to synaptic transmission within networks of CNS interneurons. Therefore, conduction may be influenced by factors that are not apparent from a simplified anatomic model (Figure 39.1). For example, changes in the threshold amplitude and latency of sacral reflex occur as a consequence of changes in the physiological state of the bladder, and differ in pathologic conditions (i.e., suprasacral spinal cord lesions).51 Electrical,52 mechanical,53 or magnetic stimulation54 may be used. Although the latter two modalities have only been applied to the penis and clitoris, electrical stimulation can be applied at various sites to the dorsal penile/ clitoral nerve perianally using a catheter-mounted ring electrode at the bladder neck/proximal urethra.9,55,56 In clinical practice, electrical and mechanical stimulation of the penis or clitoris is usually used (Figure 39.6). The sacral reflex evoked on the dorsal penile or clitoral nerve stimulation was shown to be a complex response, comprising two components (Figures 39.6 and 39.7). The first component has a latency of about 33 ms. It is stable, does not habituate, and based on the variability of single motor neuron latency reflex discharges, and is thought to be an oligosynaptic reflex.1 The second component has a similar latency to the sacral reflexes evoked by stimulation perianally or from the proximal urethra.9 The variability of single motor neuron reflex response within this component is much larger, as is typical for a polysynaptic reflex.1 The second component is not always demonstrable as a discrete response. Double electrical stimuli may be used to facilitate the reflex response if both components cannot be elicited uses single electrical pulses.57 Sacral reflex responses recorded with needle or wire electrodes can be analyzed separately for each side of the EAS or each bulbocavernosus muscle (Figure 39.7). Using unilateral dorsal penile nerve blocks, the existence of two unilateral sacral reflex arcs has been demonstrated.58 Thus, by detection from the left and right bulbocavernosus (­probably also the EAS) muscles, separate testing of both sacral reflex arcs can be performed. Sensitivity of the test can be increased also by the use of the inter-side latency difference (normative limits in case of simultaneous bilateral detection; 20 years) with SPC (8 years) and external appliance (Texas catheter) (>20 years). Results demonstrated a statistically significant increase in caliectasis and a decrease in renal function in the SPC group compared to others. Although the incidence of hydronephrosis was higher in the Foley catheterization group, the incidence of de novo reflux was higher in the SPC group, mainly grade I. Interestingly, only six patients were managed with long-term anticholinergic medication, and of the six patients four did not d ­ emonstrate deteriorating renal function. In the current climate of standard, effective anticholinergic pharmacotherapy, it is difficult to determine the modern-day applicability of these results. Sheriff et al.29 recommended catheter clamping and anticholinergics for this purpose. McGuire and colleagues30 reported a poorer outcome in women with an indwelling urethral catheter (UC) (both transurethral and SPC) than in those on CIC after 2–12 years. They demonstrated a 54% rate of change in pyelography in the indwelling group opposed to none in the CIC group.

Risk of primary bladder neoplasia An important concern with indwelling catheterization, whether transurethral or suprapubic, is the long-term risk of squamous cell bladder neoplasia (squamous cell carcinoma [SCC]). The reported incidence of SCC associated with chronic indwelling urinary catheters is 2.3%–10%.31,32 Although precise long-term consequences of SPC have yet to be completely elucidated, there appears to be an 8% risk of SCC after 25 years of catheterization.33 The pathogenesis of this condition has been described as being secondary to chronic urothelial irritation and inflammation leading to metaplasia and neoplasia. Inherent in bladder management strategies consisting of indwelling catheters is the necessity for lifelong surveillance cystoscopy and upper tract imaging.

Recent analysis and publications Despite earlier evidence indicating a poor success rate with SPC, recent studies highlighting SPC as the primary modality have demonstrated otherwise. Talbot et al.34 were the first to report a relatively benign course for spinal cord–injured patients managed with indwelling catheters (SPC and urethral). Barnes et al.35 described 40 SPC-managed neurogenic bladders with 66-month follow-up data. Poor compliance with CIC, poor dexterity, as well as the desire to be independent of care attendants were the most common indications for SPC placement. Results demonstrated that catheter-related complications were relatively common, with a 38% rate of catheter blockage, 23% rate of recurrent urinary tract infections (UTIs), and 13% rate of catheter misplacement. Nevertheless, the authors point to high patient satisfaction as a strong point in their analysis. Continued urethral leakage, particularly in those with lower spinal lesions, was the factor most associated with poor overall satisfaction. Additionally, in a subgroup of patients managed by SPC catheters for longer than 24 months, no deterioration of renal function was identified aside from two patients who were not adequately medicated with anticholinergic therapy and who did not adhere to their regimen of intermittent catheter clamping. Furthermore, the authors demonstrated that daily clamping of the catheter to preserve bladder function led to maintenance of capacity, absence of new reflux, as well as a trend to lower overall mean detrusor pressure. Further evidence by Nomura et al.36 surfaced when they looked at 118 patients with neurogenic bladders managed by an SPC. The indications for SPC in this patient population were similar to those in other series: failure of CIC in 53%, severe urethral damage in 35%, worsening of the original disease in 13%, as well as various other individual indications. Their results demonstrated frequent bladder complications, with a 25% rate of bladder calculus and 10% persistent urethral leak. By using the Kaplan–Meir technique, the estimated stone-free rates at 5 and 10 years were 77% and 64%, respectively. A modest rate of cystitis was observed, with no flare-ups documented secondary to the SPC procedure. Deterioration of renal function was observed in 5/118 patients, although the authors state that the upper tract stone burden for these 5 particular patients was significant, and was likely the primary factor responsible for their decline in renal function. Further subgroup analysis involved urine pH analysis in the patients who formed bladder calculus, denoting a statistically higher urinary pH value in stone formers compared to stone-free patients. Furthermore, the average urinary pH of the 118 patients was 7.24, and dividing cases into those with lower and higher values than 7.24 revealed predicted stone-free rates of 92% (>7.24) and 71% (100  μm), which reduces the risk of particle migration. This product is non-allergenic, causes minimal inflammatory reaction, and has not been shown to migrate. Upon implantation, the elastomer is encapsulated in fibrin and remains as a bulking agent, while the carrier gel is absorbed and excreted unmetabolized through the kidneys. The fibrous capsule remains stable after formation, which is thought to prevent any subsequent movement or migration.5 A systematic review of Macroplastique treatment for SUI showed a success rate between 46% and 88%.2 Ghoneim et al. in a large,

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prospective, randomized trial evaluated the long-term safety and effectiveness of Macroplastique compared to collagenbased urethral bulking agent Contigen®. The authors found Macroplastique injection was statistically more effective than Contigen® for SUI due to intrinsic sphincter deficiency with a 12.1% cure rate difference at 12-month follow up.6 In a separate study, Maher et al. compared pubovaginal sling with Macroplastique in a prospective, randomized controlled trial. With a median follow-up of 12 month, the authors found no statistical significant difference in subjective success rate and satisfaction rate with no or occasional (less than once a week) SUI episodes.7 To objectively assess dur­ability and outcome to aid in the decision to offer a repeat injection, Poon et al. have employed three-dimensional (3D) ultrasound of the urethra to monitor Contigen® retained volume after injection as well as configuration in the urethral wall.8 Similarly, Hedge et al. have used 3D endovaginal ultrasound to identify sonographic para­meters associated with successful outcomes following injection of Macroplastique®. The authors found that proximal location and circumferential periurethral dis­ tribution of Macroplastique® are individually associated with successful outcomes postinjection.9 Coaptite  Coaptite® is a bulking agent composed of smo­oth calcium hydroxylapatite bioceramic microspheres (diameter range: 75–125 μm) suspended in an aqueous gel carrier.10 The material is identical to normal constituents found in bone and teeth; therefore, it is non-antigenic, nonimmunogenic, and nontoxic. Experimental studies have demonstrated excellent biocompatibility.11 The most current literature suggests that Coaptite® provides a greater (but not statistically significant) improvement in symptoms compared with collagen. Mayer et al. noted that treatment was well tolerated and with no systemic adverse events after injection.10 Coaptite® can be easily injected using a standard cystoscopic equipment available

in most urology offices. The material does not require refrigeration or pre-procedural skin testing. Another potential advantage of Coaptite® is that plain radiographs or ultrasound can be utilized for identification purposes, thus facilitating accurate localization and placement of the material.12 Most literature to date has shown that the inflammatory response associated with Coaptite® is minimal. However, Palma et al. reported a case of urethral prolapse following injection therapy with Coaptite®.13

Transurethral technique A 21–24F cystoscope with a 5F working element and a 25–30 degree lens is introduced in the urethral lumen with a needle delivery system (often 20-gauge) placed through the working port of the cystoscope. After priming the needle with the injecting material, the submucosal space is punctured at 3 or 9 o’clock. The bulking material is slowly injected until a sufficient bleb is raised (Figure  49.1a) The process is repeated on the opposite side or anywhere else necessary to achieve good coaptation of the lumen (Figure  49.1b) Care should be taken to avoid more than one puncture at any single injection site to minimize extrusion. The cystoscope should not be advanced past the injection sites, because this can result in compression or extrusion of the material and loss of the mucosal bleb.

Indications and patient selection The role of injectable agents in the treatment of urinary incontinence in the neurogenic bladder population remains hard to define. The ideal candidate for urethral collagen injection should have a stable, compliant, good capacity bladder with no urethral hypermobility and intrinsic sphincter deficiency typically diagnosed as low Final appearance with good coaptation of urethral lumen

Injected right side

(a)

Injection left side

 

(b)

Figure 49.1 (a and b) Injection of MACROPLASTIQUE in a 45-year-old women with stable multiple sclerosis, a well-supported urethra, no voiding abnormalities on urodynamic testing, and moderate SUI secondary to ISD (VLPP at 75 cm H2O). Injection should be at the mid-urethra in the submucosal plane.

Surgery to improve bladder outlet function Valsalva Leak Point Pressure (VLPP).14,15 Many investigators believe that detrusor overactivity or decreased compliance should be treated with anticholinergics and/ or augmentation cystoplasty before attempting to treat an incompetent outlet with bulking agents.14,16 Perez et al, however, in their series of 32 patients with neurogenic bladder, found that the presence of detrusor overactivity and decreased compliance did not adversely affect the clinical outcome of the bulking agent procedure.17

Conclusion The use of bulking agents to treat incontinence has several advantages including minimal invasiveness, ease to learn, and low morbidity. Furthermore, treatment with injectable substances does not jeopardize the performance and efficacy of other anti-incontinence procedures later on. The liabilities of this technology stem from a relative lack of durability and lower effectiveness when compared to other, albeit more invasive, treatment modalities. This disadvantage often leads to repeat injections, which can elevate the cost of a procedure already known to be expensive.

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Bladder neck slings and wraps Introduction The fascial sling and the artificial urethral sphincter (AUS) are the two most commonly employed surgical treatments for patients with urinary incontinence secondary to neurogenic outlet incompetence. The issue of how much tension to place on the fascial sling is not as problematic in the neurogenic bladder population as it is in patients with SUI, since retention in a patient with neurogenic bladder who already performs clean intermittent catheterization (CIC) is usually a treatment goal rather than a complication. Furthermore, the incidence of tension-induced erosion is low when autologous fascia is utilized as the sling material. Unfortunately, long-term experience with the bladder neck sling in the neurogenic bladder population is seldom reported, with most case series documenting mean followup times of less than 4 years. It is thus unknown whether or not the fascial sling in young women with myelomeningocele may be disrupted by pregnancy and/or childbirth.25

Indications and patient selection

Adjustable continence therapy

The Adjustable Continence Therapy (ACT® or ProACT™) System (Uromedica, Plymouth, Minnesota) is a novel device used for the treatment of recurrent female SUI and postprostatectomy SUI in men.18–20 It is used exclusively in Europe as the device is awaiting FDA approval in the United States. The ACT® device is an inflatable silicone balloon with a titanium port connected by a tubing. Two devices are implanted, one on each side of the urethra near the bladder neck to provide compression at the bladder neck, thus enhancing urethral coaptation. The most common intraoperative and postoperative complications using the ACT® device reported in the current literature are erosion in 2.5%–7.5% of cases, urinary retention in 1.2%–6.3%, migration in 3.8%–5.6%, perforation in 2.5%– 18%, therapy failure in 2.5% and urinary tract infections in 1.9%–5%.21–23 The ACT® device has a unique advantage of being easily adjusted in the office with a needle injection to optimize continence. The evidence for its use in the neurogenic bladder patients is scant as the device is relatively new. Mehnert et al. evaluated the long-term safety and efficacy of ACT® in male and female patients with neurogenic SUI. They found 54.5% of the patients indicated more than 50% improvement of SUI symptoms after 48 months, of whom 38.9% indicated complete continence.24 The ACT® System offers an alternative treatment option for neurogenic bladder patients, especially those in need of additional continence support after previous SUI surgery or those who are not willing, nor suitable or ready yet for more invasive surgery. More studies in this unique patient population are required with long-term follow-up.

The ideal candidate for this procedure is a female patient with bladder outlet incompetence, preserved urethral length, and a well-managed bladder on CIC. Whether or not to perform an enterocystoplasty in addition to a procedure to occlude the bladder outlet is a complex decision based on preoperative urodynamic and radiographic assessments. Supporting the bladder neck with a sling may be enough to abolish leakage if the preoperative urodynamic assessment, performed with some form of bladder outlet occlusion, shows a stable bladder with sufficient capacity and normal compliance.26 Whether or not to perform both procedures together, or to do one before the other, is somewhat controversial. In general, a cystogram showing a wide-open bladder neck and a VLPP less than 30 cm H2O are indications of severe intrinsic sphincter deficiency, for which a procedure to improve bladder outlet competence is recommended.

Results and complications The literature on bladder neck slings to treat neurogenic urinary incontinence consists largely of case series, made up of pediatric or a mixture of pediatric and adult patients (Table 49.1). Most investigators report overall continence rates greater than 70%, with women faring better (85%) than men (69%) in some studies.27–30 Kurzrock et al. suggested that this discrepancy in sling effectiveness between genders may be because the presence of the prostate makes it more difficult to close and elevate the proximal urethra.30 The most recent study by Athanasopoulos et al.31 evaluating the efficacy of an autologous fascia rectus sling

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Table 49.1  Results of fascial slings and wraps in patients with neurogenic bladder outlet incompetence

Study

Year and patient population

Number and type of patients

Mean follow-up (months)

Fontaine et al.27

1997, adult F

21: 9 MMC, 8 SCI, 3 SA, 1 sacral lipoma

Mingin et al.32

2002, pediatric and adult M and F

Rutman et al.33

Athanasopoulos et al.31

Surgical technique

Results

Other surgical procedures

28.6, range 6–60

RF sling done transabdominally, sutured to Cooper’s

85.7% dry day and night, 95.2% dry day only

All had concomitant bladder augmentation

37: 14 M, 23 F 36 neurogenic, 1 traumatic

48, range 6–120

Distally based rectus/ pyramidalis myofascial flap wrapped around BN and sewn to contralateral RF

92% (34) dry 2 M failures, 1 F failure

33 concomitant augmentations, 9 mitrofanoft stomas, 5 reimplantations

2005, adult F

Neurologic/ congenital diseases, multiple prior antiincontinence procedures

12 months, range 6-37

Soft polypropylene mesh wrap secured to anterior abdominal wall

20% failures, 80% improved or cured

91% concomitant urethrolysis, 20% concomitant prolapse repair

2012, Adult F

Mean age 37 years (range: 10–67) 21 MMC, 12 SCI

48 months

RF sling done

75.75% (25) totally dry, 5 15.15% (5) had markedly improved but still required one pad per day

14 concomitant augmentation cystoplasty and 3 myectomy

MMC, myelomeningocele; SCI, spinal cord injury; SA, sacral agenesis; M, male; F, female; RF, rectus fascia; BN, bladder neck; SUI, stress urinary incontinence.

in treating SUI in female patients with neuropathic bladder showed that fascial sling is a highly effective technique. The authors retrospectively reviewed 33 female patients with neuropathic bladder treated over a 3-year period for SUI by implantation of an autologous fascia rectus sling. At a mean follow-up time of 52 months, 30 patients were satisfied with the outcome of the operation (90.9%). Twentyfive patients (75.8%) were totally dry, while 5 (15.1%) were markedly improved but still required one pad per day. The complication rate was 15.2% (5/33), including sling erosion, vesicovaginal fistula, and urethral stenosis occurring in one patient each and requiring re-operation.31 Complications specific to the rectus fascia sling were relatively rare and included sling breakdown resulting in postoperative leakage as a result of fascial breakage or suture pullout, and urethral erosion.34 The urethra may become angulated, resulting in difficulty with catheterization or retraction of the meatus inside the vaginal introitus.28 Care needs to be taken when passing a cystoscope via the urethra post-sling insertion. Bladder perforation may

occur in patients with augmented bladders and bladder neck slings who are not compliant with CIC, or in whom catheterization has become difficult.35,36 Other reported complications were incisional hernia, de-novo DO, retroperitoneal hematoma, and bladder neck contracture when the outlet was tapered along with sling insertion.28,29

Conclusion The rectus fascia bladder neck sling has been shown to be a versatile and valuable addition to the armamentarium of the reconstructive surgeon. Despite its lower rate of success in males with neurogenic incontinence, the lack of requirement for foreign materials and relative ease of implantation make it an attractive option for treatment of the incompetent reservoir outlet in a wide variety of neurogenic female patients. The long-term durability of the bladder neck sling, however, is still unknown. This is an important consideration, particularly for young adults, in whom the procedure may have to last decades.

Surgery to improve bladder outlet function

Artificial urinary sphincters Introduction Ever since the first published clinical report in 1973 by Scott, the AUS has been used extensively to treat sphincteric incontinence.37 High rates of efficacy and patient satisfaction, but also substantial revision rates secondary to mechanical failure as well as problems with infection and erosion resulting in sphincter removal have been reported. Despite its availability since the 1970s, concerns have also been raised regarding silicone shedding, since the longterm sequelae of silicone migration is unknown.38 There have been relatively few large series of AUS use in neurogenic patients, and there are no controlled trials comparing its efficacy to that of fascial slings or bladder neck reconstruction (Figure 49.2).

Indications and patient selection All patients in whom an AUS is being considered should undergo preoperative urodynamic testing to document the severity and mechanism of incontinence and to assess bladder and voiding functions. As for the fascial sling, the ideal candidate for an AUS should have a stable bladder with good compliance and capacity as well as a good emptying. Elevated detrusor pressures can lead to upper tract deterioration once the outlet is occluded by the sphincter cuff. Many authors advocate an AUS as primary treatment for patients who void with weak or absent detrusor contraction as those are the most likely to end up in lifelong retention should a fascial sling be performed.39 Patients, however, should be informed that CIC may have to be performed in the future, particularly if they receive a bladder augmentation or, in men, if prostatic growth later in life produces outlet obstruction. The AUS has also been employed as secondary treatment for patients who have failed other forms of bladder outlet surgery. Aliabadi and Gonzalez described 15 patients who had

(a)

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failed multiple urethral and bladder neck surgeries and were salvaged with an AUS, resulting in an overall continence rate of 73%.40

Results and complications In patients with neurogenic sphincteric incontinence, the AUS has been reported to result in continence rates from 59% to 92%, revision rates of 27% to 57%, and removal rates of 19% to 41% (Table 49.2).39,41–43 Perioperative and immediate postoperative complications include bladder neck, urethral and rectal perforations, UTIs, wound infections, and scrotal hematomas.42,44 Chartier-Kastler et al. evaluated the results and morbidity of the periprostatic insertion of an AUS in adult male patients with a neurogenic bladder.45 In this retrospective study of 51 patients, the authors reported 74% had perfect or moderate continence with a working AUS at 10-year follow-up. The percentage of patients lost to follow up was 29.4%. Perfect continence was defined as a period of dryness of at least 4 hour between two intermittent catheterizations or spontaneous micturitions, whereas moderate incontinence meant nocturnal leakage or the need to wear protection once during the day or for stress leakage. In women, the procedure is less frequently performed due to technical challenges (Figure 49.3), including retropubic dissection of the whole urethra from the vaginal wall and proper sizing (Figure 49.4). Costa et al. have reported on long-term results and mechanical survival of the AUS in 344 patients with mean follow up of 9.6 years. They found a continence rate, defined as fully continent with no leakage, of 85.6% with mean device mechanical survival time of 14.7 years. They identified previous incontinence surgeries, presence of neurogenic bladder, and simultaneous augmentation enterocystoplasty as risk factors for AUS survival.46 AUS infection, one of the most dreaded complications, results in sphincter removal, and accounted for 4%–5% rate in most series.50 The presence of an infection is often detected by skin erythema, induration at the pump or

(b)

Figure 49.2 (a) Artificial urinary sphincter has been sized loosely and (b) placed around the proximal urethra.

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Table 49.2  R  esults of artificial urinary sphincter insertion for the treatment of incontinence in patients with neurogenic bladder Patient population

Type and location of sphincter

Mean follow-up time

Study

Year

Results

Complications

Spiess et al.47

2002

Pediatric, 30 males with MMC

All AMS 800

6.5 years

63% dry, 20%, slightly wet

Only 8.3% lasted >100 months, mean lifetime 4.9 years

Pereira et al.48

2006

Adolescents: 35, 13 F, 22 M, MM 27, SA 4, 4 other

All AMS 800, BN, 13 also had augment

5.5 years (range 4–11)

91.4% dry

8.6% BN erosions, 20% mechanical failure, 7 with worsened bladder function

Bersch et al.49

2008

37 M + 14 F 37 SCI, 8 MMC, 2 others

Modified AMS 800 Peri-bladder neck

7.9 years (5–14.5)

90.2%

8%(4) infection 27% (14) mechanical failure

Chartier et al.45

2011

Average age 35 years (18–58 years) MM16, SCI 35

All AMS 800. Junction between the bladder neck and the anterior face of the prostate.

83 months (6–208 months)

74% had perfect or moderate continence

Complications noted in 19% (10/51), within 30 days after surgery: urinary infection (8), acute urinary retention (3), transient intracranial hypertension (1 myelomeningocele patient), and failure to perform IC (1)

MMC, myelomeningocele; SA, sacral agenesis; SCI, spinal cord injury; BN, bladder neck; BU, bulbar urethra; UTI, urinary tract infection.

Plane of dissection between urethra and vaginal wall

Figure 49.3 Transvaginal view of urethra and anterior vaginal wall to show dissection plane between the vagina and urethra/bladder neck.

reservoir site, erosion of the cuff through the urethra, or erosion of the pump through the scrotal or labial skin. Microorganisms recovered from infected AUS include Staphylococcus epidermidis, β-streptococcus, Bacteroides fragilis, Escherichia coli, Pseudomonas, and diphtheroid species.51,52 The infection rate does not appear to increase in patients who catheterize compared to those who void spontaneously or who empty their bladders using the Credé maneuver.52 AUS erosion rates range from 6% to 31% in contemporary neurogenic bladder series and are the major cause of sphincter removal. Erosion can occur secondary to infection, ischemia from high cuff pressure, devascularization from prior surgery or radiation, and/ or traumatic catheterization.42,51 Factors that increase the likelihood of erosion include prior bladder neck surgery, placement of the cuff around the bulbar urethra in children, and placement of the cuff around the bowel used to create a neobladder.47,53 Patients who receive an AUS must undergo long-term urologic follow-up with urodynamic bladder monitoring and serial upper tract imaging to detect the onset of upper tract deterioration. High intravesical pressure requires the institution of anticholinergic medications, or, if this fails, augmentation cystoplasty. Hydronephrosis or reflux is usually refractory to medical management and indicates a need for cystoplasty, or urinary diversion. The proportion

Surgery to improve bladder outlet function

(a)

537

(b)

(d)

(c)

Figure 49.4 Transvaginal bladder neck closure. (a) Creation of anterior vaginal wall flap. Destroyed urethra is circumscribed. (b) Bladder neck is mobilized and urethral remnant excised. First tension-free layer of bladder neck closure. (c) Transversal second layer closure to protect against a secondary vesicovaginal fistula. (d) Placement of Martius flap tunneled beneath labia minora. (From Sam D Graham and James F Glenn (eds). Glenn’s Urologic Surgery, 5th ed. Philadelphia, PA: Lippincott Williams & Wilkins: 1998. Chapter 49, Figures 49.1, 49.2, 49.3, 49.4. Reproduced with permission.)

of AUS recipients with neurogenic bladder who ultimately require augmentation cystoplasty ranged from 4% to 42%.42,43,53

Conclusions When it was first marketed in the early 1970s, the AUS represented a major advancement in the treatment of patients with severe incontinence secondary to intrinsic sphincteric deficiency. The device has undergone many design modifications since its first inception, all of which have served to increase its efficacy and lower its complication rate. Erosion and infection rates are low in well-selected patients. The possibility of requiring repeat surgery for mechanical failure is high, as is the cost of these revisions, but the AUS will, no doubt, continue to be utilized in the treatment of neurogenic urinary incontinence.

Bladder neck closure Bladder neck closure is considered a last-resort procedure. It is indicated in patients with outlet incompetence who have failed multiple anti-incontinence procedures, those who are poor surgical candidates and cannot tolerate lengthy, complex reconstructive procedures, and in patients with a destroyed urethra that cannot be rebuilt.54 Closure of the bladder neck can be combined with a catheterizable cutaneous stoma or a chronic indwelling suprapubic tube depending on the constitutional and functional status of the patient. Bladder neck closure can be performed via the transabdominal or transvaginal route (Figure 49.4). In the transabdominal approach, a transverse suprapubic incision or vertical midline incision is made and the bladder neck is mobilized. In males, the bladder is transected just cranial

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to the prostate after ligating the superficial dorsal venous complex and dissecting the neurovascular bundles away. The prostate is usually left intact to preserve fertility and antegrade ejaculation. In cases of urethral stricture or prostatorectal fistula, which compromise drainage of prostatic secretions and act as a nidus of infection, the prostate is removed to avoid abscess formation. In females, the bladder is transected at the vesicourethral junction once the deep dorsal vein has been ligated. Intravenous indigo carmine or ureteric catheters are used to help identify the ureteric orifices. The bladder is mobilized posteriorly to the level of the ureteric orifices. A sponge stick in the vagina can aid in identifying the correct plane of dissection. Once the posterior and inferior aspects of the bladder have been mobilized out of its dependent position in the pelvis, the bladder neck opening is closed ventrally in two layers: mucosa and muscle with serosa. A suprapubic tube is placed and brought out through a separate stab incision before closing the bladder neck completely, and if the bladder closure is to be combined with a continent catheterizable stoma it is constructed and attached to the bladder at this stage. The urethral stump is closed dorsally in two layers and an omental flap is mobilized and placed between the closed urethral stump and the bladder neck closure to prevent fistula formation. A drain is usually left in the space of Retzius. Postoperatively, anticholinergics are administered to prevent bladder spasms. The transvaginal approach is typically employed in females with urethral destruction secondary to chronic indwelling Foley catheter drainage who are to be managed with bladder neck closure and suprapubic tube placement. The patient is placed in the dorsal lithotomy position and a suprapubic tube is placed using a Lowsley retractor. This technique is employed to circumvent the difficulty inherent in distending a small contracted bladder with an incompetent outlet. The patient is placed in the Trendelenburg position to displace the bowels cephalad, and the curved Lowsley retractor is inserted into the urethra and pointed toward the anterior abdominal wall 1–2 cm above the pubic symphysis. A small fascial incision is made over the tip of the retractor, which is pushed out through the skin incision. The tip of a large-bore Foley catheter is grasped in its jaws and pulled back into the bladder. Intravesical placement of the catheter can be confirmed by irrigation of the tube or cystoscopic inspection. An incision circumscribing the urethral opening is extended into an inverted U incision on the anterior vaginal wall. The endopelvic fascia is pierced on either side of the bladder neck to free it up completely from the pubic bone, and the pubourethral ligaments are transected. Intravenous indigo carmine is given to visualize the ureteric orifices. The scarred urethra, if present, is excised and the bladder neck closed in two layers: first in the vertical, and then in the horizontal direction. The second suture line should contain tissue from the bladder neck to the anterior wall located behind the symphysis to transfer the closed bladder neck

to the retropubic space and remove it from a dependent position. The integrity of the closure is checked by filling the bladder through the suprapubic tube. A Martius flap is interposed between the bladder neck and anterior vaginal wall to help prevent vesicovaginal fistula formation, and the vaginal wall flap is closed over the Martius flap as a third layer. A vaginal pack containing antibiotic solution is left in for 24 hours and anticholinergics are administered to prevent bladder spasms. In female, spinal cord injury patients who have been managed with a chronic indwelling Foley catheter, bladder neck closure, and suprapubic tube insertion can improve quality of life by eliminating leakage of urine alongside the Foley catheter and chronic skin breakdown, and also facilitate return to sexual activity by eliminating the urethral catheter.55,56 The disadvantages of bladder neck closure are its irreversibility; its abolishment of the pop-off “leakage” valve, which necessitates long-term monitoring of the upper tracts to prevent occult renal deterioration57 and its unpredictable effects on potency and ejaculation when performed in young males.58 There is also a persistent risk of infection secondary to the indwelling catheter presence when this modality is selected. Bladder neck closure is highly effective in treating incontinence secondary to an incompetent bladder outlet. Continence rates of 75%–100% have been reported in the literature, with mean follow-up times ranging from 1.5 to 3 years.54,59,60 In a retrospective study, Hou et al. reported 19 female neurogenic bladder patients that underwent bladder neck closure with an overall dry rate in 90% of the patients.61 The main technical complication was bladder neck fistulization with continued leakage of urine, which has been reported to occur in 6%–25% of cases.55,56,62 Rovner et al. presented a modified transvaginal bladder neck closure technique using a posterior urethral flap to minimize the potential risk of ureteral injury and fistula formation.63 The rate of fistulization was low in their series, which adhered to the following tenets: mobilization of the bladder from its dependent position in the pelvis, closure of the bladder neck and urethral stump in multiple layers without tension, and interposition of omentum or a labial fat pad between the bladder neck and vaginal closure. No adverse effect on potency or ejaculation was noted by Hoebeke et al., who performed the procedure in nine young males.

Surgical treatment of the hyperactive bladder outlet Introduction For several years, it has been recognized that detrusor external sphincter dyssynergia (DESD), a common condition in patients with suprasacral spinal cord lesions,

Surgery to improve bladder outlet function is associated with elevated intravesical pressures, which can result in substantial morbidity and mortality. DESD is defined as a detrusor contraction concurrent with an involuntary contraction of the urethral and/or periurethral striated muscle during voiding. During urodynamic assessment, DESD is denoted by an increase in electromyographic activity of the sphincter or pelvic muscles associated with an involuntary detrusor contraction. On voiding cystourethrogram or videourodynamic assessment, dilation of the bladder neck due to a contracted external sphincter is observed during bladder emptying.64 The condition leads to a complication rate in excess of 50%, resulting in urosepsis, hydronephrosis, nephrolithiasis, and vesicoureteric reflux, all of which can terminate in renal insufficiency and, eventually, dialysis.65,66 DESD is also associated with autonomic dysreflexia, particularly in patients with injuries above the T5 spinal cord level. Since its description by Emmett et al. in 1948, sphincterotomy has been recommended to treat DESD in a subset of spinal cord injured males who are at risk for renal damage.67 By incising the external sphincter to render it incompetent, one can transform intermittent incontinence into continuous incontinence, which can be managed with a condom catheter drainage device. Sphincterotomy is irreversible and has been associated with intraoperative bleeding and erectile dysfunction. A reduction in long-term efficacy has also been observed, which may require repeat external sphincter or bladder neck incision.68 Long-term use of a condom catheter can lead to skin ulceration, urethrocutaneous fistula, and penile retraction.69 Among the latest developments, botulinum toxin A (BTX-A) has been tried to treat DESD, and its role in the current management of the neurogenic bladder patient will be reviewed at the end of this section.

Indications and patient selection Sphincterotomy is employed in the treatment of DESD in male spinal cord injured patients with DO refractory to anticholinergics and CIC, or in those unable or unwilling to carry out this conservative treatment. Sphincterotomy with condom catheter drainage is preferable to a chronic indwelling Foley catheter, which is still often used as the management of last resort in quadriplegic patients who do not have the manual dexterity or caregiver support to perform CIC or change a condom catheter. Chronic indwelling catheters are associated with recurrent urosepsis, bladder calculi, and squamous cell carcinoma in this patient population.70

Results and complications of sphincterotomy Incising the external sphincter results in statistically significant decreases in maximum detrusor pressure,

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postvoid residual, and the occurrence of autonomic dysreflexia. Bladder capacity is usually maintained. Complications include bleeding, clot retention, urosepsis, erectile dysfunction, and sphincterotomy failure secondary to urethral scarring. Making the incision anteriorly at 12 or 11 o’clock, rather than posterolaterally, has lowered the likelihood of damage to the urethral blood supply and cavernous body innervation, resulting in decreased rates of clot retention and erectile dysfunction compared with older series.71,72 The need for repeat sphincterotomy secondary to scarring and stenosis of the external sphincter is usually evident within 12 months of having the procedure, but can occur years later.71 Repeat sphincterotomy rates range from 9%, when the laser is employed, to 31%, with the use of conventional electrocautery.73 Other complications said to be decreased with laser sphincterotomy compared to electrocautery are severe bleeding and erectile dysfunction. In the absence of a prospective randomized trial, there is no conclusive proof of the superiority of laser over electrocautery. The postvoid residual often persists after incising the external  sphincter, but many authors do not consider this finding an indication of treatment failure unless the patient develops recurrent UTIs due to urinary stasis. Treatment failure despite a technically perfect sphincterotomy occurs in 10%–50% of men treated for DESD. Reasons for failure include problems fitting the condom catheter as well as detrusor areflexia, which can result in poor bladder emptying despite an incompetent bladder outlet.71,74 Pan et al. reported long-term outcome data of 81 months in 84 spinal cord injury patients after sphincterotomy, with a second procedure needed in 30/84. External sphincterotomy protects the upper renal tracts and provides extended periods of satisfactory bladder emptying. However, it may require revisions and should potentially be regarded as a staged intervention.75 Urethral stents have also been employed as an alternative to sphincterotomy in patients with DESD. Most of the experience with external sphincter stenting has been with the Urolume prosthesis (American Medical Systems, Minnetonka, Minnesota), a nonmagnetic superalloy woven into a mesh cylinder that is inserted endoscopically across the external sphincter to hold it open. Other urethral stents that have been used to circumvent DESD include the Ultraflex (Boston Scientific Corp., Boston, Massachusetts), which is made of a single elastalloy wire, and the Memokath (Engineers and Doctors A/S, Homback, Denmark), a coil made of thermosensitive titanium/nickel alloy. Sphincteric stenting has several advantages over sphincterotomy. It is an easier and quicker procedure that is associated with shorter hospital stay and cost.64,76 Unlike sphincterotomy, stent insertion is potentially reversible, a characteristic that appeals to spinal cord injured patients still hoping for a cure. Furthermore, sphincteric stents are not associated with diminished erectile ability or significant blood loss.64,77 Despite these advantages, insertion of

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a stent across the external sphincter raises some legitimate concerns. The stent is a foreign body placed in contact with urine, resulting in encrustations. Long-term complications that have been found to occur with the Urolume include epithelial hyperplasia, stent encrustation, stent migration, urethral obstruction, secondary bladder neck obstruction, and difficult stent removal.78,79 The Memokath device is associated with a high rate of migration, recurrent UTIs, and calcification, making it more suitable for the shortterm treatment of DESD.74,80

Botulinum toxin A injection into the external urethral sphincter The following technique was described by Smith et al.81 One hundred to 200 U of BTX-A is mixed with 4 mL of saline just before injection. The vial should not be shaken. A rigid cystoscope and a standard cystoscopic collagen injection needle are used to inject BTX-A deeply into the external sphincter at the 3, 6, 9, and 12-o’clock positions in equal aliquots. These injections should be directed deeper than bulking agent injections to target the nerve terminals innervating the skeletal muscle.

Results and complications of Botulinum toxin A for the external sphincter Smith et al. reported that out of the 68 patients with either  MS or spinal cord injury undergoing this procedure,  32 had follow-up of at least 6 months. The mean postvoid residual urine volume decreased from 250 to 88  mL after the procedure, and maximal voiding pressures decreased as well. Retention requiring catheterization decreased by 80%, and patients experienced decreased urinary tract infection rates. Four percent of patients noted either worsening or new-onset SUI.81 Phelan et al. performed a prospective study on 21 patients, with follow-up ranging from 3 to 16 months. Following urethral injection of Botox, voiding pressures decreased an average of 38%. Sixty-seven percent of patients reported improvement in voiding pattern. No complications or side effects were noted.82 In another study, Schurch treated 24 patients with spinal cord injuries and DESD with Botulinum Toxin A injection.83 Significant improvement in DESD was noted in 88%, with decreased postvoid residuals in most. The effects lasted 3–9 months, with no adverse events reported. Since the muscle relaxing properties of the toxin are time and dose related, repeated injections are expected. Kuo evaluated patient satisfaction after treatment with urethral sphincter botulinum toxin A injection in patients with spinal cord

lesions and DESD.84 and reported an overall satisfactory result in 60.6% of patients. Urodynamic parameters showed significant improvement in voiding detrusor pressure, maximum flow, and postvoid residual volume. Easier voiding and reduced PVR needing CIC were the major reasons for satisfaction, whereas increase in incontinence grade was the major reason for dissatisfaction.84

Conclusion In summary, treatment of the male neurogenic bladder patient with refractory DESD continues to be challenging. Sphincterotomy will undoubtedly continue to be considered in the management of these difficult cases. Botulinum toxin A injection is being performed in the external sphincter with mixed results and shorter duration compared to the effect within the bladder (3–4 months compared to 7–9 months). Side effects such as incontinence and detrusor overactivity have contributed to the low patient satisfaction rate and quality of life improvement.84 Long-term studies are needed to determine if this technique will become a durable option in the treatment of DESD.

Conclusions The surgeon endeavoring to treat a patient with urinary incontinence secondary to neuropathic bladder outlet incompetence has a number of surgical options at his disposal. Injectable agents are often employed in female patients with mild degrees of incontinence, patients who leak small amounts post-bladder neck sling or reconstruction, and patients who are not operative candidates or who are reluctant to undergo open surgery. The sling and AUS are commonly used when a more durable, longterm solution for incontinence is required. Because slings may be more successful in females than in males, some surgeons prefer to use slings as their first-line treatment in females and AUS as their primary treatment in males with neurogenic sphincteric incompetence. The fascial sling may be preferable to the AUS in patients who do not wish to have a foreign body implanted or who, because of their comorbidities or surgical history, are at high risk for cuff erosion or infection of the device. The role of ACT is expanding but is limited by the lack of FDA approval so far. Bladder neck closure is a suitable option for select patients who have failed multiple surgical attempts to increase outlet resistance or who have poor functional and constitutional status. Sphincterotomy has been shown to be effective for DESD. Choice of treatment option is often guided by the irreversibility of sphincterotomy compared to botulinum toxin A injection, but this most recent modality requires lifelong retreatments.

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References 3392. Murless, BC. The injection treatment of stress incontinence. J Obstet Gynaecol 1938; 45: 67–73. 3393. ter Meulen PH, Berghmans LC, van Kerrebroeck PE. Systematic review: Efficacy of silicone microimplants (Macroplastique) therapy for stress urinary incontinence in adult women. Eur Urol 2003; 44(5): 573–82. 3394. Davis NF, Kheradmand F, Creagh T. Injectable biomaterials for the treatment of stress urinary incontinence: Their potential and pitfalls as urethral bulking agents. Int Urogynecol J 2013; 24(6): 913–9. 3395. ter Meulen PH, Berghmans LC, Nieman FH, van Kerrebroeck PE. Effects of Macroplastique Implantation System for stress urinary incontinence and urethral hypermobility in women. Int Urogynecol J Pelvic Floor Dysfunct 2009; 20(2): 177–83. 3396. Tamanini JT, D’Ancona CA, Tadini V, Netto NR Jr. Macroplastique implantation system for the treatment of female stress urinary incontinence. J Urol 2003; 169(6): 2229–33. 3397. Ghoniem G, Corcos J, Comiter C, Bernhard P, Westney OL, Herschorn S. Cross-linked polydimethylsiloxane injection for female stress urinary incontinence: Results of a multicenter, randomized, controlled, single-blind study. J Urol 2009; 181(1): 204–10. 3398. Maher CF, O’Reilly BA, Dwyer PL et al. Pubovaginal sling versus transurethral Macroplastique for stress urinary incontinence and intrinsic sphincter deficiency: A prospective randomised controlled trial. BJOG 2005; 112(6): 797–801. 3399. Poon CI, Zimmern PE, Wilson TS, Defreitas GA, Foreman MR. Three-dimensional ultrasonography to assess long-term durability of periurethral collagen in women with stress urinary incontinence due to intrinsic sphincter deficiency. Urology 2005; 65(1): 60–4. 3400. Hegde A, Smith AL, Aguilar VC, Davila GW. Three-dimensional endovaginal ultrasound examination following injection of Macroplastique for stress urinary incontinence: Outcomes based on location and periurethral distribution of the bulking agent. Int Urogynecol J 2013; 24(7): 1151–9. 3401. Mayer RD, Dmochowski RR, Appell RA et al. Multicenter prospective randomized 52-week trial of calcium hydroxylapatite versus bovine dermal collagen for treatment of stress urinary incontinence. Urology 2007; 69(5): 876–80. 3402. Pettis GY, Kaban LB, Glowacki J. Tissue response to composite ceramic hydroxyapatite/demineralized bone implants. J Oral Maxillofac Surg 1990; 48(10): 1068–74. 3403. Dmochowski RR, Appell RA. Injectable agents in the treatment of stress urinary incontinence in women: Where are we now? Urology 2000; 56(6 Suppl 1): 32–40. 3404. Palma PC, Riccetto CL, Martins MH et al. Massive prolapse of the urethral mucosa following periurethral injection of calcium hydroxylapatite for stress urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct 2006; 17(6): 670–1. 3405. Leonard MP, Decter A, Mix LW, Johnson HW, Coleman GU. Treatment of urinary incontinence in children by endoscopically directed bladder neck injection of collagen. J Urol 1996; 156(2 Pt 2): 637–40; discussion 40–1. 3406. Chernoff A, Horowitz M, Combs A et al. Periurethral collagen injection for the treatment of urinary incontinence in children. J Urol 1997; 157(6): 2303–5. 3407. Kassouf W, Capolicchio G, Berardinucci G, Corcos J. Collagen injection for treatment of urinary incontinence in children. J Urol 2001; 165(5): 1666–8. 3408. Perez LM, Smith EA, Parrott TS et al. Submucosal bladder neck injection of bovine dermal collagen for stress urinary incontinence in the pediatric population. J Urol 1996; 156(2 Pt 2): 633–6. 3409. Gatti L, Moroni A, Cristinelli L et al. Reimpianto del sistema ProACT in caso di fallimento precoce nella cura dell’incontinenza urinaria dopo prostatectomia radicale. [ProACT (Adjustable

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Continence Therapy) implants in case of failure of other techniques for urinary incontinence]. Urologia 2012; 79 Suppl 19: e46–9. PubMed PMID: 23371272. 3410. Aboseif SR, Sassani P, Franke EI et al. Treatment of moderate to severe female stress urinary incontinence with the adjustable continence therapy (ACT) device after failed surgical repair. World J Urol 2011; 29(2): 249–53. 3411. Garcia Matres MJ, Cansino Alcaide JR, Monasterio S, et al. Balones parauretrales (Pro-ACT) en la incontinencia urinaria postqururgica del cancer de prostata. [Paraurethral adjustable continence therapy device (Pro-ACT) in the treatment of urinary incontinence after prostatic surgery]. Archivos espanoles de urologia 2009; 62(10): 871–81. PubMed PMID: 20068264. 3412. Hubner WA, Schlarp OM. Adjustable continence therapy (ProACT): Evolution of the surgical technique and comparison of the original 50 patients with the most recent 50 patients at a single centre. Eur Urol 2007; 52(3): 680–6. 3413. Gregori A, Romano AL, Scieri F et al. Transrectal ultrasoundguided implantation of Adjustable Continence Therapy (ProACT): Surgical technique and clinical results after a mean follow-up of 2 years. Eur Urol 2010; 57(3): 430–6. 3414. Gilling PJ, Bell DF, Wilson LC et al. An adjustable continence therapy device for treating incontinence after prostatectomy: A minimum 2-year follow-up. BJU Int 2008; 102(10): 1426–30; discussion 30–1. 3415. Mehnert U, Bastien L, Denys P et al. Treatment of neurogenic stress urinary incontinence using an adjustable continence device: 4-year followup. J Urol 2012; 188(6): 2274–80. 3416. Elder JS. Periurethral and puboprostatic sling repair for incontinence in patients with myelodysplasia. J Urol 1990; 144(2 Pt 2): 434–7; discussion 43–4. 3417. Kreder KJ, Webster GD. Management of the bladder outlet in patients requiring enterocystoplasty. J Urol 1992; 147(1): 38–41. 3418. Fontaine E, Bendaya S, Desert JF et al. Combined modified rectus fascial sling and augmentation ileocystoplasty for neurogenic incontinence in women. J Urol 1997; 157(1): 109–12. 3419. Walker RD 3rd, Flack CE, Hawkins-Lee B et al. Rectus fascial wrap: Early results of a modification of the rectus fascial sling. J Urol 1995; 154(2 Pt 2): 771–4. 3420. Herschorn S, Radomski SB. Fascial slings and bladder neck tapering in the treatment of male neurogenic incontinence. J Urol 1992; 147(4): 1073–5. 3421. Kurzrock EA, Lowe P, Hardy BE. Bladder wall pedicle wraparound sling for neurogenic urinary incontinence in children. J Urol.1996; 155(1): 305–8. 3422. Athanasopoulos A, Gyftopoulos K, McGuire EJ. Treating stress urinary incontinence in female patients with neuropathic bladder: The value of the autologous fascia rectus sling. Int Urol Nephro 2012; 44(5): 1363–7. 3423. Mingin GC, Youngren K, Stock JA, Hanna MK. The rectus myofascial wrap in the management of urethral sphincter incompetence. BJU Int 2002; 90(6): 550–3. 3424. Rutman MP, Deng DY, Shah SM, Raz S, Rodriguez LV. Spiral sling salvage anti-incontinence surgery in female patients with a nonfunctional urethra: Technique and initial results. J Urol 2006; 175(5): 1794–8; discussion 8–9. 3425. Decter RM. Use of the fascial sling for neurogenic incontinence: Lessons learned. J urol 1993; 150(2 Pt 2): 683–6. 3426. Barthold JS, Rodriguez E, Freedman AL, Fleming PA, Gonzalez R. Results of the rectus fascial sling and wrap procedures for the treatment of neurogenic sphincteric incontinence. J Urol 1999; 161(1): 272–4. 3427. Austin PF, Westney OL, Leng WW, McGuire EJ, Ritchey ML. Advantages of rectus fascial slings for urinary incontinence in children with neuropathic bladders. J Urol 2001; 165(6 Pt 2): 2369–71; discussion 2371–2.

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3428. Scott FB, Bradley WE, Timm GW. Treatment of urinary incontinence by implantable prosthetic sphincter. Urology 1973; 1(3): 252–9. 3429. Reinberg Y, Manivel JC, Gonzalez R. Silicone shedding from artificial urinary sphincter in children. J Urol 1993; 150(2 Pt 2): 694–6. 3430. Kryger JV, Leverson G, Gonzalez R. Long-term results of artificial urinary sphincters in children are independent of age at implantation. J Urol 2001; 165(6 Pt 2): 2377–9. 3431. Aliabadi H, Gonzalez R. Success of the artificial urinary sphincter after failed surgery for incontinence. J Urol 1990; 143(5): 987–90. 3432. Levesque PE, Bauer SB, Atala A et al. Ten-year experience with the artificial urinary sphincter in children. J Urol 1996; 156(2 Pt 2): 625–8. 3433. Simeoni J, Guys JM, Mollard P et al. Artificial urinary sphincter implantation for neurogenic bladder: A multi-institutional study in 107 children. BJU 1996; 78(2): 287–93. 3434. Gonzalez R, Merino FG, Vaughn M. Long-term results of the artificial urinary sphincter in male patients with neurogenic bladder. J Urol 1995; 154(2 Pt 2): 769–70. 3435. Singh G, Thomas DG. Artificial urinary sphincter in patients with neurogenic bladder dysfunction. BJU. 1996; 77(2): 252–5. 3436. Chartier Kastler E, Genevois S, Game X et al. Treatment of neurogenic male urinary incontinence related to intrinsic sphincter insufficiency with an artificial urinary sphincter: A French retrospective multicentre study. BJU Int 2011; 107(3): 426–32. 3437. Costa P, Poinas G, Ben Naoum K et al. Long-term results of artificial urinary sphincter for women with type III stress urinary incontinence. Eur Urol 2013; 63(4): 753–8. 3438. Spiess PE, Capolicchio JP, Kiruluta G et al. Is an artificial sphincter the best choice for incontinent boys with Spina Bifida? Review of our long term experience with the AS-800 artificial sphincter. Can J Urol 2002; 9(2): 1486–91. 3439. Periera PL, Ariba IS, Urrutia M, Romero RL, Monroe EJ. Artificial urinary sphincter: 11-year experience in adolescents with congenital neuropathic bladder. Eur Urol 2006; 50: 1096–101. 3440. Bersch U, Gocking K, Pannek J. The artificial urinary sphincter in patients with spinal cord lesion: Description of a modified technique and clinical results. Eur Urol 2009; 55(3): 687–93. 3441. Hajivassiliou CA. The development and evolution of artificial urethral sphincters. J Med Eng Technol 1998; 22(4): 154–9. 3442. Holmes NM, Kogan BA, Baskin LS. Placement of artificial urinary sphincter in children and simultaneous gastrocystoplasty. J Urol 2001; 165(6 Pt 2): 2366–8. 3443. Light JK, Lapin S, Vohra S. Combined use of bowel and the artificial urinary sphincter in reconstruction of the lower urinary tract: Infectious complications. J Urol 1995; 153(2): 331–3. 3444. Castera R, Podesta ML, Ruarte A, Herrera M, Medel R. 10-Year experience with artificial urinary sphincter in children and adolescents. J Urol 2001; 165(6 Pt 2): 2373–6. 3445. Zimmern PE, Hadley HR, Leach GE, Raz S. Transvaginal closure of the bladder neck and placement of a suprapubic catheter for destroyed urethra after long-term indwelling catheterization. J Urol 1985; 134(3): 554–7. 3446. Syme RR. Bladder neck closure for neurogenic incontinence. Aust N Z J Surg 1981; 51(2): 197–200. 3447. Chancellor MB, Erhard MJ, Kiilholma PJ, Karasick S, Rivas DA. Functional urethral closure with pubovaginal sling for destroyed female urethra after long-term urethral catheterization. Urology 1994; 43(4): 499–505. 3448. Das S, Amar AD. Abdominal transposition of the female urethra. J Urol 1986; 135(2): 373–5. 3449. Hoebeke P, De Kuyper P, Goeminne H, Van Laecke E, Everaert K. Bladder neck closure for treating pediatric incontinence. Eur Urol 2000; 38(4): 453–6.

3450. Jayanthi VR, Churchill BM, McLorie GA, Khoury AE. Concomitant bladder neck closure and Mitrofanoff diversion for the management of intractable urinary incontinence. J Urol 1995; 154(2 Pt 2): 886–8. 3451. Hensle TW, Kirsch AJ, Kennedy WA 2nd, Reiley EA. Bladder neck closure in association with continent urinary diversion. J Urol 1995; 154(2 Pt 2): 883–5. 3452. Hou J, Zimmern P, Lemack G. Bladder neck closure in women: Lessons learned from a tertiary neurogenic bladder clinic. Neurourol Urodyn 2013; 32(2): 181. 3453. Reid R, Schneider K, Fruchtman B. Closure of the bladder neck in patients undergoing continent vesicostomy for urinary incontinence. J Urol 1978; 120(1): 40–2. 3454. Rovner ES, Goudelocke CM, Gilchrist A, Lebed B. Transvaginal bladder neck closure with posterior urethral flap for devastated urethra. Urology 2011; 78(1): 208–12. 3455. Chancellor MB, Gajewski J, Ackman CF et al. Long-term followup of the North American multicenter UroLume trial for the treatment of external detrusor-sphincter dyssynergia. J Urol 1999; 161(5): 1545–50. 3456. Kaplan SA, Chancellor MB, Blaivas JG. Bladder and sphincter behavior in patients with spinal cord lesions. J Urol 1991; 146(1): 113–7. 3457. McGuire EJ, Brady S. Detrusor-sphincter dyssynergia. J Urol 1979; 121(6): 774–7. 3458. Emmett JL, Daut RV, Dunn JH. Role of the external urethral sphincter in the normal bladder. J Urol 1948; 59(3): 439–54. 3459. Noll F, Sauerwein D, Stohrer M. Transurethral sphincterotomy in quadriplegic patients: Long-term-follow-up. Neurourol Urodyn 1995; 14(4): 351–8. 3460. Fontaine E, Hajri M, Rhein F et al. Reappraisal of endoscopic sphincterotomy for post-traumatic neurogenic bladder: A prospective study. J Urol 1996; 155(1): 277–80. 3461. Watanabe T, Rivas DA, Smith R, Staas WE Jr, Chancellor MB. The effect of urinary tract reconstruction on neurologically impaired women previously treated with an indwelling urethral catheter. J Urol 1996; 156(6): 1926–8. 3462. Vapnek JM, Couillard DR, Stone AR. Is sphincterotomy the best management of the spinal cord injured bladder? J Urol 1994; 151(4): 961–4. 3463. Rivas DA, Chancellor MB, Staas WE Jr, Gomella LG. Contact neodymium: Yttrium-aluminum-garnet laser ablation of the external sphincter in spinal cord injured men with detrusor sphincter dyssynergia. Urology 1995; 45(6): 1028–31. 3464. Perkash I. Contact laser sphincterotomy: Further experience and longer follow-up. Spinal cord 1996; 34(4): 227–33. 3465. Low AI, McRae PJ. Use of the Memokath for detrusor-sphincter dyssynergia after spinal cord injury: A cautionary tale. Spinal cord 1998; 36(1): 39–44. 3466. Pan D, Troy A, Rogerson J et al. Long-term outcomes of external sphincterotomy in a spinal injured population. J Urol 2009; 181(2): 705–9. 3467. Rivas DA, Chancellor MB, Bagley D. Prospective comparison of external sphincter prosthesis placement and external sphincterotomy in men with spinal cord injury. J Endourol 1994; 8(2): 89–93. 3468. Chancellor MB, Rivas DA, Linsenmeyer T et al. Multicenter trial in North America of UroLume urinary sphincter prosthesis. J Urol 1994; 152(3): 924–30. 3469. Wilson TS, Lemack GE, Dmochowski RR. UroLume stents: Lessons learned. J Urol 2002; 167(6): 2477–80. 3470. McFarlane IP, Foley SJ, Shah PJ. Long-term outcome of permanent urethral stents in the treatment of detrusor-sphincter dyssynergia. BJU 1996; 78(5): 729–32. 3471. Shaw PJ, Milroy EJ, Timoney AG, el Din A, Mitchell N. Permanent external striated sphincter stents in patients with spinal injuries. BJU 1990; 66(3): 297–302.

Surgery to improve bladder outlet function 3472. Smith CP, Nishiguchi J, O’Leary M, Yoshimura N, Chancellor MB. Single-institution experience in 110 patients with botulinum toxin A injection into bladder or urethra. Urology 2005; 65(1): 37–41. 3473. Phelan MW, Franks M, Somogyi GT et al. Botulinum toxin urethral sphincter injection to restore bladder emptying in men and women with voiding dysfunction. J Urol 2001; 165(4): 1107–10.

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3474. Schurch B, Hauri D, Rodic B et al. Botulinum-A toxin as a treatment of detrusor-sphincter dyssynergia: A prospective study in 24 spinal cord injury patients. J Urol 1996; 155(3): 1023–9. 3475. Kuo HC. Satisfaction with urethral injection of botulinum toxin A for detrusor sphincter dyssynergia in patients with spinal cord lesion. Neurourol Urodyn 2008; 27(8): 793–6.

50 Urinary diversion Sender Herschorn and Greg G. Bailly

Introduction The goals of urologic management of neurogenic bladder dysfunction are to achieve and maintain low-pressure urinary storage and voiding, with preservation of the upper urinary tract and achievement of urinary continence. Long-term management has been facilitated by the widespread acceptance of clean self-intermittent catheterization (CIC).1 The introduction of new medications over the past 15 years has also contributed to management. The vast  majority of patients with neurogenic bladder dysfunction can be managed without resorting to urinary diversion. However, there are patients who are unwilling or unable to perform self-catheterization or to be intermittently catheterized. There are others who despite appropriate management are unable to maintain low-pressure urinary storage and voiding and/or continence. It is these patients who may benefit from lower urinary tract reconstruction and urinary diversion rather than resort to indwelling Foley catheters. Patients with neurogenic bladder dysfunction are followed regularly with clinical evaluation, laboratory testing with serum creatinine and urine cultures, upper tract imaging (usually ultrasound), and if necessary, urodynamic studies. The storage and voiding problems are usually addressed with a combination of CIC and various mediations. Males with spinal cord injuries are frequently managed with condom drainage with or without CIC. However, outlet-relaxing procedures, such as transurethral sphincterotomy2 or Urolume stent,3,4 are occasionally needed in suprasacral cord injury patients with high detrusor pressures and sphincter dyssynergia. Neurogenic bladders in women may be harder to manage. Urethral CIC may be difficult for wheelchair-bound women and incontinence between CICs may also be more difficult to contain. The aim of long-term follow-up of patients with neurogenic bladder disease is to prevent any changes that may lead to upper tract compromise. The complications of

high intravesical pressures are well described and include upper tract dilatation, reflux, stones, pyelonephritis, and renal failure.2,5 In addition, the patients may present with clinical symptoms. Changes in overall health can often be the first sign that the bladder may not be functioning satisfactorily. Worsening of incontinence, recurrent urinary tract infections, autonomic dysreflexia, suprapubic or back pain, as well as changes in the neurologic status of some patients, often indicate an alteration in lower urinary tract. These important clues can direct the urologist toward the appropriate investigations. An outline of management of neurogenic bladder in relation to urinary diversion is shown in Figure 50.1. Urinary diversion, although once frequently employed in the past for the treatment of neurogenic bladder dysfunction, is now only required in special circumstances. The commonly accepted indications include hydronephrosis that may be accompanied by progressive renal deterioration secondary to ureteral obstruction from a thick-walled bladder or intractable ureterovesical reflux, recurrent episodes of urosepsis, and persistent storage or emptying failure when CIC is impossible.6 If, in the opinion of the urologist, the upper tract deterioration and/or storage problem cannot be managed with bladder augmentation surgery alone then urinary diversion may be indicated. Another reason for diversion is when urethral CIC is not feasible. Unmanageable incontinence, while not life-­t hreatening, may lead to skin breakdown, persistent infection, social isolation, and negative psychological impact on patients. When procedures such as bulking agents, slings, artificial sphincters, and augmentation cystoplasty are unsuccessful or contraindicated, and/or urethral CIC is not possible, urinary diversion may be considered. Often the diversion is as an alternative to an indwelling catheter. Although there have been no randomized prospective long-term trials, patients with indwelling catheters have more mobidity, such as infectious complications, calculi, and radiographic abnormalities, than those managed with CIC.7,8 Although

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Textbook of the Neurogenic Bladder Neurogenic bladder • Failure to store • Failure to empty

Conservative management • Intermittent catheterization • Anticholinergic, β3 agonist medication, intradetrusor

Regular evaluation • History and physical • Upper tract imaging • Cystoscopy • Urodynamics • Creatinine

Failure of medical management • Hydronephrosis • Deterioration of renal function • Unacceptable incontinence • Inability to catheterize per urethra

Able to selfcatheterize

Continent diversion A. Continent catheterizable pouch 1. Indiana pouch 2. Kock pouch 3. T pouch 4. Others

• Unable to catheterize • Frail • Creatinine > 1.8 mg/dL or CrCl < 40 mL/min Noncontinent diversion A. Conduit 1. Ileal conduit 2. Colon conduit B. Ileovesicostomy

B. Catheterizable continent stoma with or without augmentation cystoplasty 1. Mitrofanoff 2. Hemi-Kock

a long-term Foley catheter may be convenient, safe, and effective for some patients, urinary diversion may be a reasonable option. The various types of diversions will be discussed in this chapter.

Choosing the most appropriate urinary diversion Patient considerations The selection of urinary diversion procedure is largely based on the surgeon’s opinion and experience, as well as his or her understanding of each individual patient’s medical condition. Several important patient characteristics are considered when choosing an appropriate form of diversion

Figure 50.1 Surgical management of patients with neurogenic bladders requiring urinary diversion.

(Figure 50.1). Although continent urinary diversion is considered appropriate in selected patients, these procedures are technically more challenging and are associated with higher short-term and long-term complication rates than those operations that employ an incontinent technique.9 The patient’s ability to perform self-­catheterization must be evaluated as it significantly impacts on whether to construct a noncontinent or continent form of urinary diversion. Patients who cannot adequately perform selfcatheterization through an abdominal stoma because of underlying and/or progressive neurologic disease or poor manual dexterity are not well suited for continent diversion. Those patients with multiple sclerosis, quadriplegia, and frail, or cognitively impaired persons who require the care of members of the family or support workers, may be poor candidates for any kind of continent diversion,

Urinary diversion especially if the caregiver is unwilling or unable to perform the intermittent catheterization. If manual dexterity is sufficient for catheterization, other medical conditions may exclude a patient from undergoing a continent diversion. Elderly, debilitated patients with other significant medical comorbidities are generally not good candidates for continent diversion. In addition to poor outcomes, these patients have higher perioperative risks. Although surgical techniques have improved over the past two decades, continent diversions often take longer to perform and have increased potential for complications compared to noncontinent diversion, and therefore proper patient selection is paramount to successful outcome. Renal insufficiency is a relative contraindication to continent forms of diversion.10–12 Continent diversion allows longer exposure time of urine to mucosa, subsequently increasing the risk of developing electrolyte disturbances, particularly in the patient with renal insufficiency. As a general rule, patients with a preoperative creatinine of greater than 1.8 mg/dL should undergo a noncontinent form of diversion.11 A patient with borderline renal function should have a creatinine clearance calculated. A minimal creatinine clearance of 40 mL/min should be documented before the patient is deemed an appropriate candidate for a continent diversion.13 Hepatic function must also be evaluated. Significant hepatic dysfunction increases the risk of developing hyperammonemia if the liver is unable to adequately process the ammonium chloride that may be produced by bacterial growth in the retained urine of a pouch.10 Once the patient has been assessed and more information is available on the risk factors, it is important that the surgeon work with the patient and family/­caregivers, without needlessly forcing the patient into one decision or the other. The patient’s mental status may reflect the willingness and motivation to comply with self-care and follow-up. Speaking to other patients with various forms of diversions often helps the patient to better realize the expectations of surgery. The Internet may also provide valuable information on different forms of diversion. The surgeon should inform the patient of the potential risks and benefits of each type of diversion. Clearly, the surgeon’s experience and evidence-based knowledge is crucial in protecting the patient from inappropriate or unrealistic expectations. Ultimately the decision is made on an individual basis by the patient with physician, family, and caregiver input.

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ulcerative colitis, diverticulitis, intraperitoneal malignancy, or prior bowel resection. The patient should be seen by the enterostomal therapist to have appropriate marking of the stoma site. The spot should be marked carefully with ink and then the skin etched when the patient is anesthetized.

Bowel preparation Preoperative mechanical bowel preparation is an issue of controversy. In the colorectal surgery literature, it does not lower the rate of postoperative complications (wound infection, intraperitoneal abscess, or anastomotic leak)14,15 and some patients have reported adverse events from it.16–18 There are two pediatric studies that have reported no increase in complications after augmentation cystoplasty (AC) following no preoperative mechanical bowel preparation.19,20 However, there are no prospective randomized trials, so caution should be exercised especially in patients with ventriculoperitoneal shunts that may be exposed to fecal contamination intraoperatively.21 Even though there is no consensus among the studies with the duration, the dosage, and the type of bowel preparation to use, we agree with the most recent CDC guidelines (published in 1999)22 and still routinely prescribe mechanical bowel preparation and clear fluids diet the day prior to the intervention. The type of preparation varies from center to center, but usually includes either fleet phospho-soda, polyethylene glycol electrolyte (PEG) solution (GoLYTELY or NuLYTELY, Braintree Laboratories, Braintree, Massachusetts), or magnesium citrate. PEG requires administration of large volumes (~4 L) of fluid but is extremely safe in most cases because there is virtually no net absorption of ions or water in the gut. When compared with PEG, phospho-soda has been shown to be better tolerated and equally effective as judged by the surgeon, with similar wound infection rates.23 Patients appear to prefer phospho-soda to PEG, as well.24,25 It is, however, absolutely contraindicated in patients with renal insufficiency, symptomatic congestive heart failure, or liver failure with ascites.26 Most clinical studies also exclude patients with a creatinine greater than 2 mg/dL.23,24 A combination of sodium picosulfate and magnesium oxide, and citric acid (PICO-SALAX®, Ferring Pharmaceuticals, Canada). The active components are sodium picosulfate, a stimulant cathartic, and magnesium citrate, an osmotic laxative. It has been compared to other preparations and has been found to be as effective27 but in some cases more tolerable.28

General principles of surgery Preoperative preparation

Antibiotic coverage

Extensive history and physical examination is required to ascertain any risk factors that may affect bowel segment selection. These include previous surgery, regional enteritis,

Preoperative antibiotic coverage for elective bowel surgery continues to be an issue of controversy. Similar to our understanding of the benefits of a mechanical preparation

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for urinary diversion, urologists tend to use prophylactic antibiotics based on information extrapolated from colorectal surgery. Even so, the literature is not clear on what to give and how to give it, and no clear consistent recommendations exist. In an extensive review of the use of antibiotic and mechanical preparations in urologic diversion surgery, Ferguson recommended 1 g of oral-based neomycin and 1 g of metronidazole at 5 and 11 pm the night before surgery.26 The use of antibiotics administered intravenously within  an hour before making the skin incision is less controversial. The periprocedural systemic administration of an antimicrobial agent to reduce infectious risks in contaminated urology surgery29 is an evidence-based supported concept but the literature is not clear about the optimal therapeutic regimen (type of medication, dosage, and route of administration). Available practice guidelines recommend a combination of either second- or third-­ generation cephalosporin with an aminoglycoside and metronidazole, with special caution for patients with prosthetic devices such as ventriculoperitoneal shunts or orthopedic hardware.22,29 Additional doses may be required during the surgery based on the half-life of the antibiotic, or if blood loss exceeds 1 L. The benefit of continued prophylactic antibiotics during the postoperative period is unproven. The CDC recommends that prophylactic antibiotics should not be continued more than 24 hours.30 The disadvantages of antibiotic use includes postoperative increase in the incidence of diarrhea; pseudomembranous colitis; and with prolonged use, the potential for malabsorption of protein, carbohydrate, and fat.31

Surgical principles Intestinal anastomosis Because urinary diversion is dependent on reconstructing various segments of bowel, it is important to u ­ nderstand certain basic principles of intestinal surgery. Much of the morbidity and mortality associated with urinary ­diversion in the immediate postoperative period relates to intestinal complications.32 The fundamental principles of ­intestinal anastomoses include adequate ­mobilization, maintenance of blood supply, apposition of serosa to ­ serosa of the two bowel segments, and creation of a watertight and ­tensionless anastomotic line. Various methods of performing the enteroenterostomy are well described.31 Sutures or staples can be used, both having similar complication rates.31

Ureterointestinal anastomoses Different types of ureterointestinal anastomoses have been used in urinary diversion surgery, but all should follow basic surgical principles. Only as much ureter should

be mobilized as necessary to result in a tensionless anastomosis. Periadventitial tissue should remain to ensure adequate blood supply. The anastomosis with the intestine should be performed with fine (4-0 or 5-0), delayed absorbable sutures, with the creation of a watertight mucosa-to-mucosa apposition. At our center, we attempt to retroperitonealize the anastomoses. The issue of antirefluxing ureteric anastomoses is ­controversial. Some experimental literature indicates a benefit, yet the results of clinical studies of colonic conduits with antirefluxing anastomoses are equivocal. Deterioration of the upper tracts for ileal and colon conduits has been reported in 10%–60% of the patients.33 In one series, 49% of the upper tracts showed changes after conduit diversion, 16% of which had a blood urea nitrogen increase of 10 mg/dL or more.34 However, deterioration of the upper tracts is usually a consequence of either infection or stones, or less commonly obstruction at the ureteral intestinal anastomosis.33 In a prospective randomized comparison of ileal and colonic conduits into which one ureter was implanted with and the other without the antireflux technique, renal scarring was more prominent on the refluxing side.35 However, split renal function test data for separate glomerular filtration rate (GFR)s showed no difference after 10 years.35 These findings do not support the use of nonrefluxing ureterointestinal anastomoses for conduits. The final decision often rests with the surgeon’s preference. At our center, we use refluxing anastomoses (Bricker or Wallace technique) for ileal conduits (Figures 50.2 and 50.3). The ureterointestinal anastomoses of continent reservoirs are usually nonrefluxing.36 Dependent upon which continent reservoir is chosen, the nonrefluxing mechanism can be constructed from intussuscepted bowel segments made by forming a flap valve in the intestinal wall, by tunnel implantation of the ureters, or by providing a long proximal loop.36 The type of urinary diversion usually dictates which method of ureterointestinal anastomoses is chosen.

Stoma For many patients, the stoma is a very important aspect of the surgery. Much of the success of a stoma can be dependent on appropriate selection of the stomal site. A noncontinent stomal site should accommodate a collection device that does not leak, while maintaining patient comfort when wearing clothes. It should meet these requirements in the standing, sitting, and supine positions (Figure 50.4). Although commonly located in the right lower quadrant, the stoma may be positioned in other locations if body habitus creates a problem as is sometimes seen in patients with neurogenic bladders. Patients in wheelchairs, especially those with quadriplegia may require stomas above the umbilicus to facilitate access for application of the

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(a)

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(b)

(a)

(c)

(d)

Figure 50.3 (b)

Figure 50.2 Bricker ureterointestinal anastomosis. (a) A full thickness serosa and mucosal plug is removed from the bowel. Interrupted 5-0 delayed absorbable suture approximates the ureter to the full thickness of the bowel mucosa and serosa. (b) A supportive suture layer can be added from the adventitia of the ureter to the serosa of the bowel. (From McDougal, WS, Campbell’s Urology, WB Saunders, Philadelphia, PA, 2002, p. 3766.)

Wallace ureterointestinal anastomosis. (a) Both ureters are spatulated and are laid adjacent to each other. (b) The apex of one ureter is sutured to the apex of the other ureter. The medial walls of both ureters are then sutured together with interrupted or running 5-0 delayed absorbable suture. The lateral walls are then sutured to the bowel. (c) A Y-type variant of above. (d) The head-to-tail variant. (From McDougal, WS, Campbell’s Urology, WB Saunders, Philadelphia, PA, 2002, p. 3766.)

appliance. A commonly used stoma for an incontinent conduit is the nipple, or sometimes called the rosebud, described by Brooke in 195437 (Figure 50.5). It is usually created as the last step in the conduit construction. The catheterizing stoma for continent diversions is often placed in the lower quadrant of the abdomen through the rectus bulge and below the bikini line, or at the umbilicus. The umbilicus is the preferred location for someone in a wheelchair because of easier access, and occasionally it is placed even higher than the umbilicus due to body habitus.

Diversions Noncontinent urinary diversion The first attempt at using isolated segment of bowel for urinary diversion was reported in 1908 by Verhoogen,38 who described a technique to divert urine into an isolated segment of ileum and ascending colon. Construction

Figure 50.4 The stoma site is selected and marked on the surface of the abdomen where the skin is not rolled into folds while the patient is either sitting or standing. (From Hinman, F, Jr, Atlas of Urologic Surgery, WB Saunders, Philadelphia, PA, 1998, p. 647.)

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(a)

(b)

Figure 50.5 (a,b) Rosebud stoma. Five to six cm of intestine is brought through the abdominal wall. The open bowel is sutured to the skin with four quadrant sutures of 3-0 delayed absorbable sutures that pass through the skin edge, then catch the adventitia of the bowel well below the level of the skin, and finally go through the mucosal edge, thus everting the stoma. Additional sutures are placed through the skin and bowel edge between the quadrant sutures to close the gap. (From McDougal, WS, Campbell’s Urology, WB Saunders, Philadelphia, PA, 2002, p. 3760.)

of the ileal loop conduit was first reported by Seiffert in 1935.39 His procedure, however, lacked effective means to collect and store urine. It was not until Bricker reported his technique that the ileal conduit became an acceptable method of urinary diversion.40 This generally refers to the ileal conduit, although various forms of conduits can be constructed from colon or jejunum. An alternative form of noncontinent diversion to the conduit is an ileovesicostomy.

Conduits Ileal conduit Background Since 1950, the Bricker ileal conduit has been the standard for noncontinent urinary diversion.40 Still today, the ileal conduit remains the most popular form of urinary diversion.41 It is the most straightforward to construct of the diversionary procedures, with overall fewer complications than its rival continent diversions.41 It is the most appropriate urinary diversion in elderly, debilitated patients, and in those who lack the hand–eye coordination or manual dexterity for self-catheterization, or the motivation to care for a continent pouch.

Technique Little has changed since Bricker described the technique of ileal conduit in 1950.40 Blood supply is based on the superior mesenteric artery (SMA). The jejunal and ileal branches of the SMA anastomose to form arcades of vessels, which can be easily transilluminated through the

Figure 50.6 The ileal conduit at completion. (From Hinman, F, Jr, Atlas of Urologic Surgery, WB Saunders, Philadelphia, PA, 1998, p. 654.)

mesentery during the operation for preservation of the blood supply to the conduit. A lower vertical midline incision is made from the symphysis pubis to the umbilicus or beyond. The ureters are identified and transected approximately 3 or 4 cm above the bladder. The left ureter is brought under the sigmoid colon through the sigmoid mesentery to the right side, taking care to avoid damage to both the sigmoid and the ureteral blood supply. The ileum is inspected to ensure healthy disease-free tissue. About 15–20 cm from the ileocecal valve, a 15–20 cm segment of ileum is selected, a length that will extend from the sacral promontory to the abdominal wall without tension. Two windows are constructed in the mesentery with care taken to keep the base of the mesentery as wide as possible to prevent ischemia of the segment. The distal window usually measures 10–15 cm, and the proximal window can be much shorter at 3–5 cm. The bowel is transected, and the disconnected ileal segment is placed inferior to the remaining bowel segments. The bowel is reanastomosed using staplers or a standard two-layer closure. The mesenteric trap is closed. The ureteroileal anastomoses are performed either separately as with the Bricker technique or cojoined as in the Wallace technique, at the proximal end of the loop. The final step is the creation of the stoma (Figure 50.6).

Colon conduit Background A colon conduit may be chosen when there are functional or anatomical factors that preclude the use of ileum. It has a larger diameter than ileum and can usually be easily mobilized into any portion of the abdomen or pelvis. The three types of colon conduits are transverse, sigmoid, and ileocecal, each having specific indications with advantages and disadvantages. The transverse colon is used

Urinary diversion when one wants to be sure that the segment of conduit employed has not been irradiated in individuals who have received extensive pelvic irradiation. It is also an excellent segment when an intestinal pyelostomy needs to be performed. The sigmoid conduit is a good choice in patients undergoing a pelvic exenteration who will have a colostomy. An ileocecal conduit has the advantage of providing a long segment of ileum when long segments of ureter need replacement as well as the advantage of providing colon for the stoma. Because of its large lumen, stomal stenosis is rare. It may also be used in situations in which free reflux of urine from the conduit to the upper tracts is thought to be undesirable. Contraindications to the use of transverse, sigmoid, and ileocecal conduits include the presence of inflammatory large bowel disease and severe chronic diarrhea.

Ileal vesicostomy The concept of ileal vesicostomy arose from the successful management of pediatric neurogenic bladders by the creation of a vesicostomy. It is an alternative to an ileal conduit in some patients. It avoids the complications of ureterointestinal anastomosis, while maintaining the native ureteral antireflux mechanism. The addition of a small segment of ileum from the bladder to the abdominal wall acts to maintain low pressure in the bladder. The ileal segment is often referred to as a chimney, the distal end of which is brought up to the abdominal wall and a rosebud stoma fashioned. It is important to use as short a segment of ileum as possible and to avoid a circular anastomosis between the ileum and the bladder. Redundancy of bowel may inhibit urinary flow and lead to electrolyte disturbances.42 Theoretically, this results in a low-pressure reservoir that, if indicated at a later date, can be converted back to normal anatomy.

and exits through the stoma. An ileovesicostomy cystogram is performed 3 weeks postoperatively to ensure adequate healing of the suture line, and if there is no leak, the catheter is removed.42

Continent urinary diversion Background Continent urinary diversion includes any reservoir subserved by a catheterizable efferent mechanism other than the native urethra and bladder neck.43 Continent urinary diversion is used in patients with malignancy who require cystectomy and/or urinary diversion. It may also be used for patients with other bladder diseases who requires urinary diversion and wish to remain continent, and ­ who are deemed to be good candidates based on factors described earlier. The surgeon must consider the patient’s motivation, adaptability, coping skills, and overall dexterity before embarking on a more complex continent diversion. If possible, we generally try to preserve the bladder, thus maintaining the ureteral antireflux mechanism while adding to the capacity of the reservoir. When this cannot be achieved due to significant bladder disease, a continent catheterizable pouch may be a better option. The following

Technique With the patient in the supine position, a lower midline incision is usually adequate. A 10- to 15-cm ileal segment is isolated, depending on what length is required to bridge the gap between the abdominal wall and the bladder dome, leaving approximately 20 cm of terminal ileum and the ileocecal valve intact. The bowel reanastomosis is performed as described earlier. The bladder is mobilized from the pelvic wall by dividing its lateral attachments, and the bladder dome is generously opened transversely. The proximal ileal segment is spatulated approximately 4–6 cm along its antimesenteric border, and anastomosed to the open bladder with 2-0 absorbable suture. The distal tabularized segment is brought out to the abdominal wall at a predetermined site and a stoma is created as in the ileal conduit (Figure 50.7). A Foley catheter is left indwelling

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Figure 50.7 The ileovesicostomy. (From Hinman, F, Jr, Atlas of Urologic Surgery, WB Saunders, Philadelphia, PA, 1998, p. 641.)

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section will review the continent supravesical reservoir and the continent bladder stoma.

nipple destabilization and stomal stenosis and will not be discussed.

Continent supravesical reservoir Continence mechanisms

Types of continent supravesical reservoirs

Although various forms of continent diversions were attempted in the past, it was not until Kock, in 1982, reported the construction of an ileal reservoir for use in urinary diversion that renewed interest in continent diversion was generated.44 Its use in the neurogenic bladder population requires careful evaluation of physical and mental capabilities to ensure proper patient selection. Continent catheterizable pouches are much more surgically complex than conduits. Perhaps, the single most demanding technical aspect of a catheterizable pouch is the construction of the continence mechanism, of which four general techniques have been described.31 The first technique is sometimes performed for right colon pouches, and involves using the appendix or a pseudoappendiceal tube fashioned from ileum or right colon.11 The second type of continence mechanism used in right colon pouches is the tapered or imbricated, or both, terminal ileum and ileocecal valve. This involves imbrication or plication of the ileocecal valve region along with tapering of the more proximal ileum in the fashion of a neourethra.45–48 This technique has been criticized by some because of the loss of the ileocecal valve and the potential consequence of more frequent bowel movements in some patients. The third type of continence mechanism uses an intussuscepted nipple valve, or more recently, the flap valve. The creation of the nipple valve is very technically demanding, and is associated with the highest complication and reoperation rate.45 A significant learning curve is required, and thus this technique is not meant for the surgeon who performs the occasional continent pouch. Many modifications have been made to the original Kock pouch description, because of the disappointment in long-term stability of the nipple valve in some patients. Despite the modifications, nipple valve failure can be observed in 10%–15% of cases despite the most experienced surgeons.45 Failure may result from eversion and effacement of the intussusception and ischemic atrophy requiring a new nipple be constructed. As well, stone formation on eroded or exposed staples can present a problem. A group from the University of Southern California has developed a different procedure, the T-pouch, which uses a nonstapled procedure to create a double-thickness valve, which results in both a continence and antireflux mechanism.49,50 The fourth procedure involves the construction of a hydraulic valve as in the Benchekroun nipple.51 This procedure has been largely abandoned because of

Indiana pouch The Indiana pouch was first reported by Rowland et al.46 at the University of Indiana in 1985, and has since become one of the most popular forms of continent urinary diversion. It uses the right colon as a reservoir while using reinforcement of the ileocecal valve for continence and tunneled taenial ureteral reimplantation for antireflux (Figure 50.8). The remaining ileal limb acts as the neourethra, which can be tapered and brought out through the abdominal wall as a stoma (Figure 50.9). Minor variations of the Indiana Pouch exist, including the Florida pouch47 and the University of Miami pouch.48

Kock pouch (continent ileal reservoir) Unlike the Indiana pouch, the Kock pouch maintains the ileocecal valve and uses only small bowel to create a lowpressure reservoir.44 Continence of urine and prevention of reflux to the upper tracts are achieved by constructing nipple valves (Figure 50.10). It has been criticized for being technically difficult and is associated with a high complication rate. As such, it has been abandoned by many urologists. However, the Kock limb (nipple valve) remains an important procedure as a means for constructing a continent catheterizable stoma, such as with the hemi-Kock augmentation cystoplasty. Other types of pouches that are used less frequently include the Mainz pouch, the UCLA pouch, the T-pouch, and the Penn pouch, none of which will be discussed here.

Continent bladder stoma At our center, we aim to preserve the patient’s native bladder if possible, thereby performing an augmentation cystoplasty and incorporating a continent bladder stoma. Preserving the bladder and avoiding the ureterointestinal anastomoses should lead to fewer complications. It is desirable for the patient to be able to visualize the opening so that the catheter tip may be directed easily and unimpeded. Two popular methods of achieving a continent catheterizable bladder stoma include the Mitrofanoff procedure or the hemi-Kock (nipple valve) with or without formal augmentation cystoplasty. Urethral continence may be addressed simultaneously if necessary depending on its severity. This usually involves a pubourethral sling,

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(a)

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Figure 50.8 Indiana pouch. (a) A 25- to 30-cm segment of cecum, ascending colon, and hepatic flexure, in addition to 8- to 10-cm terminal ileum, is selected. The ascending colon is split down the antimesenteric border to within 2 cm of the caudal tip. (b) Perform an ileocolostomy using a suture technique or by a stapled method. Insert the ureters by a submucosal technique. (c) Place a Malecot catheter through the wall of the lowest part of the complex, in a position to allow direct exit through the abdominal wall. Close the U-shaped defect by folding the distal portion of the colon into the proximal end and suture it in place with a running 3-0 absorbable suture. Add a serosal Lembert stitch with occasional lock stitches. Leave the ileum to form the cutaneous conduit with tapering, as shown in Figure 50.9. (From Hinman, F, Jr, Atlas of Urologic Surgery, WB Saunders, Philadelphia, PA, 1998, p. 698.)

bladder neck plasty or closure, or insertion of an artificial urinary sphincter.52

Mitrofanoff principle In 1980, Mitrofanoff described a continence mechanism using the appendix or ureter to create a flap valve, and at the same time a neourethral conduit to the bladder.53,54 The appendix is mobilized on its mesenteric stalk and implanted on the bladder dome (Figures 50.11 through 50.13). The proximal lumen is tunneled as an antireflux mechanism. As the reservoir fills, the rise in intravesical pressure is transmitted through the epithelium and to the implanted conduit, coapting its lumen. This mucosal tunneling technique is very important to achieving continence. The appendix has many advantages over other methods for creating a continent catheterizable stoma.55 The intraluminal pressure can rise nearly threefold that of the reservoir itself.56 Perhaps, the most important aspect of the flap-valve mechanism is the tunnel length to lumen ratio. Urodynamic evaluation has shown that a minimal tunnel length of 2 cm is required to achieve continence.57 The Mitrofanoff principle can be used on native bladder,

enterocystoplasty, or in a continent urinary reservoir. Because it is so reliable in preventing incontinence, it may place the patient at risk for upper tract deterioration or spontaneous rupture of the bladder or reservoir if regular catheterization is not performed. The appendix is particularly well suited for children because it is relatively longer and the abdominal wall is thinner. It also circumvents many of the secondary complications associated with using the ileocecal valve or other bowel segments. One possible disadvantage is with occurrence of bladder stones, simple endoscopic cystolitholapaxy may not be possible because of the narrow lumen. Other procedures such as percutaneous cystoscopy, laparoscopic, or open surgery may be required.

Hemi-Kock augmentation enterocystoplasty As an alternative to the Mitrofanoff procedure, patients may undergo a hemi-Kock ileocystoplasty with continent stoma permitting abdominal catheterization into the bladder. At our center, we have performed this procedure on various patients including those who are wheelchair dependent when urethral catheterization

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(b)

(a)

Figure 50.9

(c)

is difficult or impossible due to physical disability, and those who are unable to perform intermittent urethral catheterization or had a urethra that could not be rehabilitated as trauma or surgery. 58 This procedure can be performed in conjunction with an incontinence procedure, including closure of the bladder neck in select cases. Using a low midline incision, the bladder is accessed and in the case of an augmentation, the bladder is bivalved (clam) in the anteroposterior direction in the midline from the bladder neck to 1 cm above the trigone. The ileal segment is measured from a point 25–30 cm proximal to the ileocecal valve. The next 15 cm proximal to this segment are for the nipple valve and the efferent limb. Up to another 45 cm is isolated on a mesenteric pedicle if an augmentation is performed. The nipple valve is constructed in the usual fashion with three lines of TA55 staples, with one line fashioning the nipple to the segment. If no augmentation is performed, the bowel segment with the nipple is approximated to the bowel incision, and the third TA55 staple line fastens the nipple directly to the bladder wall. The catheterizing limb is brought out through a hiatus in the lower abdominal wall, usually on the right side, although other sites, including the umbilicus, can be used (Figure 50.14).

Tapering of ileal cutaneous conduit for Indiana pouch. (a) Apply apposing Lembert sutures on each side of the terminal ileum. Excess ileum can also be tapered (b) by suturing or (c) by a stapling technique. (From Benson, MC, Olsson, CA, Campbell’s Urology, WB Saunders, Philadelphia, PA, 2002, p. 3821.)

In a review of 47 patients who had construction of a hemi-Kock nipple valve as a catheterizable bladder stoma, Herschorn reported that 36 were dry or had mild leakage, and 44 (94%) patients considered their surgery to be successful compared with their preoperative management at a mean follow-up of 56 months.59 Six patients required valve revision and/or stomal hernia surgery within the first 2 years. Because the technique was modified by tapering the limb, there was a significant improvement in revision rate. Kreder has also reported success with using the hemi-Kock as a means of catheterizable bladder stoma.60

Complications of urinary diversion The complications associated with urinary diversion can be categorized as technical, surgical, metabolic, and neuromechanical. Surgical complications are related to the reconstruction of the bowel and diversionary unit. Metabolic complications are the result of how the reabsorption of solutes is altered by the contact of urine with bowel. The neuromechanical aspects involve the configuration of the reconstructed urinary reservoir and conduits and how this impacts on storage of urine.

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Urinary diversion

Surgical complications The complications associated with intestinal urinary diversion are displayed in Table 50.1. Postoperative surgical complications can also be classified as early or late. Nurmi reported on 144 patients with ileal conduits and found that the most common early postoperative complication was wound infection, followed by ureteroileal leakage, intestinal obstruction, intestinal fistulas, and acute pyelonephritis. Long-term complications were related to the delayed sequelae of intestinal surgery: stomal stenosis; ureteroileal stenosis; elongation; subsequent failure of the loop to propel urine adequately; and deterioration of the upper urinary tract.61

The complications that can occur with ureterointestinal anastomosis include leakage, stenosis, reflux in those anastomoses that were performed to prevent reflux, and pyelonephritis. Urine leakage usually presents within the first 7–10 days postoperatively with an incidence of 3%–9%.62,63 The use of soft ureteral stents reduces this incidence. Most leaks, fortunately resolve with time and proper drainage, but they have been associated with periureteral fibrosis and scarring leading to stricture formation.64 The incidence of ureteric stenosis is approximately 1%–14%.64 Stricture formation can occur at any time in the life of the patient, hence the importance of following patients with regular (every 1–2 years) upper tract imaging. Strictures can anywhere along the ureter, as well as at

Table 50.1  Complications of urinary intestinal diversion Complications

Type of diversion

Bowel obstruction

Ureteral intestinal obstruction

Patients (complications/N)

Incidence (%)

Ileal conduit

124/1289

10

Colon conduit

9/230

5

Gastric conduit

2/21

10

Continent diversion

2/250

4

Ileal conduit

90/1142

8

Antireflux colon conduit

25/122

20

Colon conduit

8/92

9

Continent diversion

16/461

4

Ileal conduit

23/886

3

Colon conduit

6/130

5

Continent diversion

104/629

Ileum colon

5/123

Ileal conduit

196/806

24

Colon conduit

45/227

20

Continent diversion

28/310

9

Ileal conduit

70/964

7

Antireflux colon conduit

5/94

5

Pouch calculi

Continent diversion

42/317

13

Acidosis requiring treatment

Ileal conduit

46/296

16

Antireflux colon conduit

5/94

5

Gastric conduit

0/21

0

Ileum

21/263

8

Colon or colon-ileum

17/63

27

Ileal conduit

132/1142

12

Antireflux colon conduit

13/96

13

Continent diversion

15/296

5

Ileal conduit

146/808

18

Antireflux colon conduit

15/103

15

Urine leak

Stomal stenosis or hernia

Renal calculi

17 4

Continent diversion

Pyelonephritis

Renal deterioration

Source: Dahl, D.M., McDougal, W.S., Campbell-Walsh Urology, WB Saunders, Philadelphia, PA, 2012, pp. 2411–49.

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Textbook of the Neurogenic Bladder Figure 50.10

(a)

(b)

(d)

(c)

(e)

the site of anastomosis. A common location is on the left ureter where it crosses over the aorta and beneath the inferior mesenteric artery. When a stricture is detected, it is often treated first by endourologic or percutaneous means using balloon dilation or incision. Although these methods offer less morbidity to the patient, the long-term success rate is lower than open exploration (90% vs. 50%).65,66 Stomal complications are the single most common problem encountered in the postoperative period after urinary diversion.64 Early complications include bowel necrosis, bleeding, dermatitis, parastomal hernia, prolapse, obstruction, stomal retraction, and stomal stenosis. The incidence of stomal stenosis has been reported on average 20%–24% in patients with ileal conduits and 10%–20% in those with colon conduits.31 Today, stomal stenosis has improved with proper stomal care and better fitting appliances.

Construction of a nipple valve for the Kock pouch. (a) A 15-cm s­ egment of terminal ileum is isolated and opened along its antimesenteric wall. The proximal 10 cm serves as the continent intussusception and the distal 5–10 cm as the patch. The size of the patch varies according to the size of the excised segment. (b) A Babcock clamp is advanced into the terminal ileum, the full thickness of the intussuscipiens is grasped, and it is prolapsed into the pouch. (c) Three rows of 4.8-mm staples are applied to the intussuscepted nipple valve using the TA-55 stapler. (d) A small buttonhole is made in the back wall of the ileal plate to allow the anvil of the TA-55 stapler to be passed through and advanced into the nipple valve. A fourth row of staples is applied. The figure shows two valve mechanisms. In this instance, there would be only one. (e) The anvil of the stapler can be directed between the two leaves of the intussuscipiens and the fourth row of staples applied in this manner. The figure shows two valve mechanisms. In this instance, there would be only one. ((a): From Ghoneim, MA et al. J. Urol. 138, 1150–1154, 1987. (b)–(e): From Hinman, F, Jr, Atlas of Urologic Surgery, WB Saunders, Philadelphia, PA, 1998, pp. 688–9; Benson, MC, Olsson, CA, Campbell’s Urology, WB Saunders, Philadelphia, PA, 2002, p. 3808.)

Metabolic complications Metabolic alterations are dependent on many variables including the segment of bowel used, the surface area of the bowel, the amount of time the urine is exposed to the bowel, the concentration of the solutes in the urine, the  renal function, and the pH. When stomach is used, the patient may develop a hypochloremic, hypokalemic metabolic acidosis. In patients with normal renal function, this is usually not clinically significant. Jejunal diversions are rarely chosen because of their metabolic complications. They can cause hyponatremia, hypochloremia, hyperkalemia, and metabolic acidosis, leading to lethargy, nausea, vomiting, dehydration, weakness, and hyperthermia. This syndrome is more profound if proximal jejunum is used. Ileum and colon urinary diversion

Urinary diversion

(a)



557

(b)

Figure 50.11 Mitrofanoff (Appendicovesicostomy). (a) Stay sutures are placed at the base of the a­ ppendix, and the wall of the cecum is incised circumferentially to take a small cuff of cecum with the appendix. The ­appendiceal mesentery is separated a short distance from that of the cecum, p ­ reserving all of the appendicieal blood supply. The cecal defect is closed. The appendix is ­extraperitonealized behind the ileocecal junction. For umbilical placement of the stoma, it is not necessary to extraperitonealize the appendix. (b) For a short appendix or an obese patient, the appendix can be made longer by incorporating some of the cecal wall. (From Hinman, F, Jr, Atlas of Urologic Surgery, WB Saunders, Philadelphia, PA, 1998, p. 709.)

(a)



(b)

Figure 50.12 (a,b) Through a cystotomy, a submucosal tunnel is made in the posterolateral wall of the bladder, beginning well above the right ureteral orifice. The appendix tip is implanted. A bladder augmentation is usually done next. (From Hinman, F, Jr, Atlas of Urologic Surgery, WB Saunders, Philadelphia, PA, 1998, p. 710. )

may result in similar abnormalities: hyperchloremic metabolic acidosis. Abnormalities are worse in those with continent diversions than conduits, but unless renal

function is impaired, their clinical significance is low. Symptoms can include easy fatigability, anorexia, weight loss, polydipsia, and lethargy. Regardless of the type of

558

Textbook of the Neurogenic Bladder

Figure 50.13 The appendiceal base is passed through an opening in the abdominal wall muscles large enough to accommodate a finger. The appendiceal opening is sutured to the skin (sometimes at the umbilicus). The bladder should be hitched to the anterior abdominal wall, and a catheter left in the appendix. (From Hinman, F, Jr, Atlas of Urologic Surgery, WB Saunders, Philadelphia, PA, 1998, p. 710.)

Figure 50.14 Hemi-Kock augmentation cystoplasty. (From Hinman, F, Jr, Atlas of Urologic Surgery, WB Saunders, Philadelphia, PA, 1998, p. 732.)

diversion, patients require regular screening of their electrolytes.33 Magnesium deficiency, drug intoxication, and abnormalities in ammonia metabolism are uncommon, but may lead to alteration of the sensorium. Each should be identified and treated accordingly. Drugs more likely to be

problems are those that are absorbed by the gastrointestinal tract and excreted unchanged by the kidneys. This has been reported for phenytoin.67 Methotrexate toxicity has been documented in a patient with an ileal conduit.68 The problems with chemotherapeutic agents, in particular the antimetabolites, are relatively rare, but caution should be given to those with continent diversions receiving chemotherapy. In this case, it is recommended that a pouch be drained during the time the toxic drugs are being administered. Osteomalacia may occur in patients with urinary diversion secondary to a combination of persistent acidosis, vitamin D resistance, and excessive calcium loss by the kidney.33 The degree to which each of these factors contributes to the syndrome varies from patient to patient. With this syndrome comes lethargy, joint pain, especially on the weight-bearing joints, and proximal myopathy. Serum calcium may be low or normal, and the alkaline phosphatase is usually elevated. Treatment involves correcting the acidosis and providing dietary supplements of calcium, and rarely vitamin D supplements. Bacteriuria, bacteremia, and sepsis occur with greater frequency when patients have intestinal diversions, especially in those with conduits. About three quarters of those with conduits have bacteriuria at any time, yet many of them are asymptomatic and do not require treatment for their colonization. The main indication to treat asymptomatic bacteriuria is the presence of cultures dominant for Proteus or Pseudomonas. It has been suggested that these organisms may contribute to upper tract damage.31 The majority of patients with catheterizable pouches will have chronic bacteriuria. Most urologists do not suggest treating asymptomatic bacteriuria.69 Patients are usually well protected from pyelonephritis from their nonrefluxing ureterointestinal anastomosis. With a symptomatic pouch infection or pyelonephritis, antibiotic treatment should be administered. True pouch infections may require long courses of antibiotics, and if frequently recurrent, we occasionally employ regular pouch instillation with antibiotics. A condition known as pouchitis is manifested by pain in the region of the pouch along with increased pouch contractility.31 The patient may experience sudden explosive discharge of urine from the continent stoma in this setting. This type of scenario usually responds to longer courses of antibiotics. Because of the devastating consequences, these patients and caregivers must be well informed regarding urinary retention. It may occur from simply not catheterizing the stoma or occasionally when the stoma, particularly those with a nipple valve, obstructs or does not allow entry of a catheter. This is considered a true emergency and the patient is instructed to seek attention by an experienced medical personnel. It is recommended that various sizes and types of catheters are used including the coude tip catheter. Sometimes, flexible cystoscopy is necessary.

Urinary diversion When significant manipulation of the stoma/pouch is required, we recommend leaving a catheter in for about 3 days due to edema. There is substantial evidence that urinary intestinal diversion has a negative impact on growth and development.70 These effects are most prominent in children who have diversions performed prior to puberty. Most stones formed in intestinal urinary diversions are composed of calcium, magnesium, and ammonium phosphate. Patients with hyperchloremic metabolic acidosis, preexisting pyelonephritis, and urinary tract infection with urea-splitting organisms are at the greatest risk of developing stones.71 The major cause of calculus formation in conduits and pouches is the presence of a foreign body, such as staples or nonabsorbable sutures. The exact risk of developing cancer in a segment of bowel that has been incorporated into the urinary tract is unknown. After bladder augmentation for benign disease, there have been 14 cases of malignancy reported in the literature.72 In a series of 2000 patients with a maximum follow-up of 22 years, only one case of malignancy was reported.73

Neuromechanical complications Perforation of a cutaneous continent diversion or augmentation cystoplasty with catheterizable stoma ­ occurs infrequently. In the former, the incidence of ­perforation/rupture is in the range of 1%–2%.74 In a survey of 1700 patients in Scandinavia, 20 episodes of perforation occurred in 18 patients.75 Rupture may occur from reservoir catheterization, endoscopic examination, a fall, or spontaneously. The signs and symptoms may be vague, especially in patients with neurological disease who may not sense fullness. This possible complication should be kept in mind when these patients present with pain, and consideration should be given to perform enterocystography or CT scan.

Quality of life In addition to maintaining low-pressure urinary storage and protecting the upper tracts, urinary diversion in the patient with a neurogenic bladder aims to improve the patient’s QoL (Quality of Life). Often this translates into providing a reliable state of urinary continence that positively impacts on the patients’ lives. QoL issues in neurogenic bladder patients who have undergone urinary diversion are poorly described in the literature. Much of what we know is extrapolated from the cancer population, which, in many ways, is an entirely different patient population. Several studies have recently shown an improved QoL in the neurogenic bladder population undergoing continent urinary diversion.76,77 Whether one procedure is better than another, is very much based on what factors were considered

559

when choosing which type of diversion. Newer or more ­complicated methods do not always result in a ­better QoL in these  patients.78 In a prospective study, perceived global satisfaction was found to be high with both ­conduit  and continent cutaneous diversion; it was also noted that most patients would choose the same procedure again.79 The most important aspect of the decision-­ making process is to try to tailor the medical needs and wishes of the individual patient. If this can be achieved, the discussion regarding which method offers the best QoL is superfluous. Another important issue regarding continent versus noncontinent forms of diversion is the effect on the body image and sexuality of the patient. From the reports in the literature, the creation of a continent stoma results in an improved body image, a better QoL, and even a better sex life when compared to the patients’ prior management.80,81

References 3476. Barkin M, Dolfin D, Herschorn S, Bharatwal N, Comisarow R. The urologic care of the spinal cord injury patient. J Urol 1983; 129(2): 335–9. 3477. Madersbacher H, Scott FB. Twelve o’clock sphincterotomy: Tech­ nique, indications, results. (Abbreviated report). Urol Int 1975; 30(1): 75–6. 3478. Chancellor MB, Gajewski J, Ackman CF et al. Long-term follow-up of the North American multicenter UroLume trial for the treatment of external detrusor-sphincter dyssynergia. J Urol 1999; 161(5): 1545–50. 3479. Abdul-Rahman A, Ismail S, Hamid R, Shah J. A 20-year follow-up of the mesh wallstent in the treatment of detrusor external sphincter dyssynergia in patients with spinal cord injury. BJU Int 2010; 106(10): 1510–3. 3480. Rivas DA, Karasick S, Chancellor MB. Cutaneous ileocystostomy (a bladder chimney) for the treatment of severe neurogenic vesical dysfunction. Paraplegia 1995; 33(9): 530–5. 3481. Wein A, Dmochowski R. Neuromuscular dysfunction of the lower urinary tract. In: Wein A, Kavoussi LR, Novick AC, Partin AW, Peters CA, eds. Campbell-Walsh Urology, 10th edn, Vol 3. Philadelphia, PA: Elseveir, WB Saunders, 2012: 1909–46. 3482. Weld KJ, Dmochowski RR. Association of level of injury and bladder behavior in patients with post-traumatic spinal cord injury. Urology 2000; 55(4): 490–4. 3483. Jamil F, Williamson M, Ahmed YS, Harrison SC. Natural-fill urodynamics in chronically catheterized patients with spinal-cord injury. BJU Int 1999; 83(4): 396–9. 3484. McKiernan JM, DeCastro GJ, Benson MC. Cutaneous continent diversion. In: Wein A, Kavoussi LR, Novick AC, Partin AW, Peters CA, eds. Campbell-Walsh Urology, Vol 3. Philadelphia, PA: Elseveir, WB Saunders, 2012: 2450–78. 3485. Mills RD, Studer UE. Metabolic consequences of continent urinary diversion. J Urol 1999; 161(4): 1057–66. 3486. Benson MC, Olsson CA. Continent urinary diversion. Urol Clin North Am 1999; 26(1): 125–47, ix. 3487. Kristjansson A, Mansson W. Renal function in the setting of urinary diversion. World J Urol 2004; 22(3): 172–7. 3488. Kristjansson A, Davidsson T, Mansson W. Metabolic alterations at different levels of renal function following continent urinary diversion through colonic segments. J Urol 1997; 157(6): 2099–103. 3489. Bucher P, Mermillod B, Gervaz P, Morel P. Mechanical bowel preparation for elective colorectal surgery: A meta-analysis. Arch Surg 2004; 139(12): 1359–64, discussion 1365.

560

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3490. Slim K, Vicaut E, Launay-Savary MV, Contant C, Chipponi J. Updated systematic review and meta-analysis of randomized clinical trials on the role of mechanical bowel preparation before colorectal surgery. Ann Surg 2009; 249(2): 203–9. 3491. Belsey J, Epstein O, Heresbach D. Systematic review: Adverse event reports for oral sodium phosphate and polyethylene glycol. Aliment Pharmacol Ther 2009; 29(1): 15–28. 3492. Franga DL, Harris JA. Polyethylene glycol-induced pancreatitis. Gastrointest Endosc 2000; 52(6): 789–91. 3493. Adverse Drug Reactions Advisory Committee. Electrolyte disturbances with oral phosphate bowel preparations. Aust Advers Drug React Bull 1997; 16: 2. 3494. Gundeti MS, Godbole PP, Wilcox DT. Is bowel preparation required before cystoplasty in children? J Urol 2006; 176(4 Pt 1): 1574–6, discussion 1576–7. 3495. Victor D, Burek C, Corbetta JP et  al. Augmentation cystoplasty in children without preoperative mechanical bowel preparation. J Pediatr Urol 2012; 8(2): 201–4. 3496. Canning DA. Re: Augmentation cystoplasty in children without preoperative mechanical bowel preparation. J Urol 2012; 188(6): 2368–9. 3497. Mangram AJ, Horan TC, Pearson ML, Silver LC, Jarvis WR. Guideline for prevention of surgical site infection, 1999. Centers for Disease Control and Prevention (CDC) Hospital Infection Control Practices Advisory Committee. Am J Infect Control 1999; 27(2): 97–132, quiz 133–4, discussion 196. 3498. Oliveira L, Wexner SD, Daniel N et al. Mechanical bowel preparation for elective colorectal surgery. A prospective, randomized, surgeon-blinded trial comparing sodium phosphate and polyethylene glycol-based oral lavage solutions. Dis Colon Rectum 1997; 40(5): 585–91. 3499. Thomson A, Naidoo P, Crotty B. Bowel preparation for colonoscopy: A randomized prospective trail comparing sodium phosphate and polyethylene glycol in a predominantly elderly population. J Gastroenterol Hepatol 1996; 11(2): 103–7. 3500. Heymann TD, Chopra K, Nunn E et al. Bowel preparation at home: Prospective study of adverse effects in elderly people. BMJ 1996; 313(7059): 727–8. 3501. Ferguson KH, McNeil JJ, Morey AF. Mechanical and antibiotic bowel preparation for urinary diversion surgery. J Urol 2002; 167(6): 2352–6. 3502. Lai AK, Kwok PC, Man SW, Lau RS, Chan SC. A blinded clinical trial comparing conventional cleansing enema, Pico-salax and Golytely for barium enema bowel preparation. Clin Radiol 1996; 51(8): 566–9. 3503. Hookey LC, Vanner SJ. Pico-salax plus two-day bisacodyl is superior to pico-salax alone or oral sodium phosphate for colon cleansing before colonoscopy. Am J Gastroenterol 2009; 104(3): 703–9. 3504. Wolf JS, Bennett CJ, Dmochowski RR et  al. Best practice policy statement on urologic surgery antimicrobial prophylaxis. J Urol 2008; 179(4): 1379–90. 3505. Rowe-Jones DC, Peel AL, Kingston RD et al. Single dose cefotaxime plus metronidazole versus three dose cefuroxime plus metronidazole as prophylaxis against wound infection in colorectal surgery: Multicentre prospective randomised study. BMJ 1990; 300(6716): 18–22. 3506. Dahl DM, McDougal W. Use of intestinal segments in urinary diversion. In: Wein A, Kavoussi LR, Novick AC, Partin AW, Peters CA, eds. Campbell-Walsh Urology, 10th edn, Vol 3. Philadelphia, PA: Elseveir, WB Saunders, 2012: 2411–49. 3507. Mansson W, Colleen S, Stigsson L. Four methods of uretero-intestinal anastomosis in urinary conduit diversion. A comparative study of early and late complications and the influence of radiotherapy. Scand J Urol Nephrol 1979; 13(2): 191–9.

3508. Dahl DM, McDougal WS. Use of intestinal segments in urinary diversion. In: Wein AJ, Kavoussi LR, Novick AC, eds. CampbellWalsh Urology, 9th edn. Philadelphia, PA: WB Saunders, 2007: 2534–78. 3509. Schwarz GR, Jeffs RD. Ileal conduit urinary diversion in children: Computer analysis of followup from 2 to 16 years. J Urol 1975; 114(2): 285–8. 3510. Kristjansson A, Bajc M, Wallin L, Willner J, Mansson W. Renal function up to 16 years after conduit (refluxing or anti-reflux anastomosis) or continent urinary diversion. 2. Renal scarring and location of bacteriuria. Br J Urol 1995; 76(5): 546–50. 3511. Hinman F, Jr. Atlas of Urologic Surgery. Philadelphia, PA: WB Saunders, 1998: 682. 3512. Brooke BN. Ulcerative Colitis and Its Surgical Management. Edinburgh, United Kingdom: Churchill Livingstone, 1954: 92. 3513. Verhoogen J. Neostomie urétéro-caecale. Formation d’une nouvelle poche vésicale et d’un nouvel urètre. Assoc Fr Urol 1908; 12: 362–5. 3514. Seiffert L. Die “Darm-Siphonblase.” Arch Klin Chir 1935; 183: 569–74. 3515. Bricker EM. Bladder substitution after pelvic evisceration. Surg Clin North Am 1950; 30(5): 1511–21. 3516. Williams O, Vereb MJ, Libertino JA. Noncontinent urinary diversion. Urol Clin North Am 1997; 24(4): 735–44. 3517. Atan A, Konety BR, Nangia A, Chancellor MB. Advantages and risks of ileovesicostomy for the management of neuropathic bladder. Urology 1999; 54(4): 636–40. 3518. Kaefer M, Retik AB. The Mitrofanoff principle in continent urinary reconstruction. Urol Clin North Am 1997; 24(4): 795–811. 3519. Kock NG, Nilson AE, Nilsson LO, Norlen LJ, Philipson BM. Urinary diversion via a continent ileal reservoir: Clinical results in 12 patients. J Urol 1982; 128(3): 469–75. 3520. Benson MC, Olsson CA. Cutaneous continent urinary diversion. In: Walsh PC, Retik AB, Vaughan EDJ, Wein AJ, eds. Campbell’s Urology. Philadelphia, PA: WB Saunders, 2002: 3789–834. 3521. Rowland RG, Mitchell ME, Bihrle R. The cecoileal continent urinary reservoir. World J Urol 1985; 3: 185–90. 3522. Lockhart JL. Remodeled right colon: An alternative urinary reservoir. J Urol 1987; 138(4): 730–4. 3523. Bejany DE, Politano VA. Stapled and nonstapled tapered distal ileum for construction of a continent colonic urinary reservoir. J Urol 1988; 140(3): 491–4. 3524. Stein JP, Lieskovsky G, Ginsberg DA, Bochner BH, Skinner DG. The T pouch: An orthotopic ileal neobladder incorporating a serosal lined ileal antireflux technique. J Urol 1998; 159(6): 1836–42. 3525. Stein JP, Skinner DG. The craft of urologic surgery: The T pouch. Urol Clin North Am 2003; 30(3): 647–61, xi. 3526. Benchekroun A. Hydraulic valve for continence and antireflux. A 17-year experience of 210 cases. Scand J Urol Nephrol Suppl 1992; 142: 66–70. 3527. Leng WW, McGuire EJ. Reconstructive surgery for urinary incontinence. Urol Clin North Am 1999; 26(1): 61–80, viii. 3528. Mitrofanoff P. [Trans-appendicular continent cystostomy in the management of the neurogenic bladder]. Chir Pediatr 1980; 21(4): 297–305. 3529. Keating MA, Rink RC, Adams MC. Appendicovesicostomy: A useful adjunct to continent reconstruction of the bladder. J Urol 1993; 149(5): 1091–4. 3530. Hinman F, Jr. Functional classification of conduits for continent diversion. J Urol 1990; 144(1): 27–30. 3531. Malone RR, D’Cruz VT, Worth PHL, Woodhouse RJ. Why are continent diversions continent? J Urol 1989; 141: 303A. 3532. Watson HS, Bauer SB, Peters CA et  al. Comparative urodynamics of appendiceal and ureteral Mitrofanoff conduits in children. J Urol 1995; 154(2 Pt 2): 878–82. 3533. Herschorn S, Thijssen AJ, Radomski SB. Experience with the hemiKock ileocystoplasty with a continent abdominal stoma. J Urol 1993; 149(5): 998–1001.

Urinary diversion 3534. Herschorn S. Durability of the hemi-Kock continent bladder stoma. J Urol 2001; 165(5 Suppl): 88. 3535. Kreder K, Das AK, Webster GD. The hemi-Kock ileocystoplasty: A versatile procedure in reconstructive urology. J Urol 1992; 147(5): 1248–51. 3536. Nurmi M, Puntala P, Alanen A. Evaluation of 144 cases of ileal conduits in adults. Eur Urol 1988; 15(1–2): 89–93. 3537. Beckley S, Wajsman Z, Pontes JE, Murphy G. Transverse colon ­conduit: A method of urinary diversion after pelvic irradiation. J Urol 1982; 128(3): 464–8. 3538. Loening SA, Navarre RJ, Narayana AS, Culp DA. Transverse colon conduit urinary diversion. J Urol 1982; 127(1): 37–9. 3539. McDougal WS. Use of intestinal segments and urinary diversion. In: Walsh PC, Retik AB, Vaughan EDJ, Wein AJ, eds. Camp­bell’s Urology, 8th edn. Philadelphia, PA: WB Saunders, 2002: 3745–88. 3540. Kramolowsky EV, Clayman RV, Weyman PJ. Endourological management of ureteroileal anastomotic strictures: Is it effective? J Urol 1987; 137(3): 390–4. 3541. Kramolowsky EV, Clayman RV, Weyman PJ. Management of ureterointestinal anastomotic strictures: Comparison of open surgical and endourological repair. J Urol 1988; 139(6): 1195–8. 3542. Savarirayan F, Dixey GM. Syncope following ureterosigmoidostomy. J Urol 1969; 101(6): 844–5. 3543. Bowyer GW, Davies TW. Methotrexate toxicity associated with an ileal conduit. Br J Urol 1987; 60(6): 592. 3544. Skinner DG, Lieskovsky G, Skinner EC, Boyd SD. Urinary diversion. Curr Probl Surg 1987; 24(7): 399–471. 3545. Koch MO, McDougal WS, Hall MC et  al. Long-term metabolic effects of urinary diversion: A comparison of myelomeningocele patients managed by clean intermittent catheterization and urinary diversion. J Urol 1992; 147(5): 1343–7. 3546. Dretler SP. The pathogenesis of urinary tract calculi occurring after ileal conduit diversion. I. Clinical study. II. Conduit study. 3. Prevention. J Urol 1973; 109(2): 204–9. 3547. Treiger BF, Marshall FF. Carcinogenesis and the use of intestinal segments in the urinary tract. Urol Clin North Am 1991; 18(4): 737–42. 3548. Rowland RG, Regan JS. The risk of secondary malignancies in urinary reservoirs. In: Hohenfellner R, Wammack R, eds. Continent Urinary Diversion. London, United Kingdom: Churchill Livingstone, 1992: 299–308. 3549. Studer UE, Stenzl A, Mansson W, Mills R. Bladder replacement and urinary diversion. Eur Urol 2000; 38(6): 790–800. 3550. Mansson W, Bakke A, Bergman B et  al. Perforation of continent urinary reservoirs. Scandinavian experience. Scand J Urol Nephrol 1997; 31(6): 529–32. 3551. Zommick JN, Simoneau AR, Skinner DG, Ginsberg DA. Continent lower urinary tract reconstruction in the cervical spinal cord injured population. J Urol 2003; 169(6): 2184–7. 3552. Pazooki D, Edlund C, Karlsson AK et al. Continent cutaneous urinary diversion in patients with spinal cord injury. Spinal Cord 2006; 44(1): 19–23. 3553. Mansson A, Mansson W. When the bladder is gone: Quality of life following different types of urinary diversion. World J Urol 1999; 17(4): 211–8.

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3554. Hardt J, Petrak F, Filipas D, Egle UT. Adaptation to life after surgical removal of the bladder-an application of graphical Markov models for analysing longitudinal data. Stat Med 2004; 23(4): 649–66. 3555. Moreno JG, Chancellor MB, Karasick S et  al. Improved quality of life and sexuality with continent urinary diversion in quadriplegic women with umbilical stoma. Arch Phys Med Rehabil 1995; 76(8): 758–62. 3556. Watanabe T, Rivas DA, Smith R, Staas WE Jr, Chancellor MB. The effect of urinary tract reconstruction on neurologically impaired women previously treated with an indwelling urethral catheter. J Urol 1996; 156(6): 1926–8. 3557. Adams MC, Mitchell ME, Rink RC. Gastrocystoplasty: An alternative solution to the problem of urological reconstruction in the severely compromised patient. J Urol 1988; 140(5 Pt 2): 1152–6. 3558. Althausen AF, Hagen-Cook K, Hendren WH 3rd. Non-refluxing colon conduit: Experience with 70 cases. J Urol 1978; 120(1): 35–9. 3559. Boyd SD, Schiff WM, Skinner DG et al. Prospective study of metabolic abnormalities in patient with continent Kock pouch urinary diversion. Urology 1989; 33(2): 85–8. 3560. Castro JE, Ram MD. Electrolyte imbalance following ileal urinary diversion. Br J Urol 1970; 42(1): 29–32. 3561. Elder DD, Moisey CU, Rees RW. A long-term follow-up of the colonic conduit operation in children. Br J Urol 1979; 51(6): 462–5. 3562. Flanigan RC, Kursh ED, Persky L. Thirteen year experience with ileal loop diversion in children with myelodysplasia. Am J Surg 1975; 130(5): 535–8. 3563. Hagen-Cook K, Althausen AF. Early observations on 31 adults with non-refluxing colon conduits. J Urol 1979; 121(1): 13–16. 3564. Jaffe BM, Bricker EM, Butcher HR Jr. Surgical complications of ileal segment urinary diversion. Ann Surg 1968; 167(3): 367–76. 3565. Malek RS, Burke EC, Deweerd JH. Ileal conduit urinary diversion in children. J Urol 1971; 105(6): 892–900. 3566. Middleton AW Jr, Hendren WH. Ileal conduits in children at the Massachusetts general hospital from 1955 to 1970. J Urol 1976; 115(5): 591–5. 3567. Pitts WR Jr, Muecke EC. A 20-year experience with ileal conduits: The fate of the kidneys. J Urol 1979; 122(2): 154–7. 3568. Richie JP. Intestinal loop urinary diversion in children. J Urol 1974; 111(5): 687–9. 3569. Schmidt JD, Hawtrey CE, Flocks RH, Culp DA. Complications, results and problems of ileal conduit diversions. J Urol 1973; 109(2): 210–6. 3570. Shapiro SR, Lebowitz R, Colodny AH. Fate of 90 children with ileal conduit urinary diversion a decade later: Analysis of complications, pyelography, renal function and bacteriology. J Urol 1975; 114(2): 289–95. 3571. Smith ED. Follow-up studies on 150 ileal conduits in children. J Pediatr Surg 1972; 7(1): 1–10. 3572. Sullivan JW, Grabstald H, Whitmore WF Jr. Complications of ureteroileal conduit with radical cystectomy: Review of 336 cases. J Urol 1980; 124(6): 797–801. 3573. Ghoneim MA, Kock NG, Lycke G, el-Din AB. An appliance-free, sphincter-controlled bladder substitute: The urethral Kock pouch. J Urol 1987; 138(5): 1150–4.

51 The trans-appendicular continent cystostomy technique (Mitrofanoff principle) Bernard Boillot, Jacques Corcos, and Paul Mitrofanoff

Introduction

Technique

Since its brief description by Mitrofanoff in 1980, in a French pediatric journal,1 trans-appendicular continent cystostomy has become the most frequently used operation in patients of all ages. Surprisingly, the technique has not been formally described, although it is often mentioned in technical reference books and numerous articles.2–9 Only Mitrofanoff’s second publication in 200210 gave more technical details, but it was mainly oriented toward pediatrics (congenital malformations and neurologic bladders). Initially described as an intervention “reserved” for pediatric neurogenic bladders, this procedure has seen its indications broadened to complex cases: serious malformations of the lower urinary tract in infants and acquired urinary retention of neurologic, traumatic, or iatrogenic origin in adults. Advances in urodynamics have redefined its indications of bladder augmentation, which are now more frequent; in all these cases, the question of whether to perform a concomitant trans-appendicular cystostomy should be raised. Thus, more than 30 years after its initial description, the Mitrofanoff technique remains topical, and we think it is important to provide technical information on an operation whose success depends on respecting both its broad principles and procedural details. After having reviewed the literature, we realized that numerous modifications and variations of the initial technique have been proposed, some of which represent significant changes of the original procedure.8,11–15 We are describing the original technique that we still follow today in our daily practice, irrespective of patient age and pathology. We will detail some technical points, to simplify this demanding procedure as much as possible. Recently, laparoscopic and robotically assisted procedures have also been described, but the principle is unchanged.16

The cystostomy implantation site is chosen before the intervention, appreciating that when umbilical implantation is not possible or inappropriate (girls, young women), the right iliac site can be targeted. If the cystostomy is in the right iliac site, we tend to prefer to realize a VR flap or a VQZ flap:16–19 the length of the flap is drawn at the exact size of the subcutaneous fat thickness. So the skin will achieve the tube in the extra abdominal part, and the appendix can be short.

Approach Figure 51.1 illustrates the median infra- and periumbilical laparotomy. To undertake umbilical cystostomy implantation, a cutaneous incision must be made at more than 10 mm from the left external edge of the umbilicus. However, the white line incision must remain medial until the umbilicus is relieved of its ligament attachments. The umbilical depression, freed of all its subcutaneous attachments, must be perfectly mobile. We resect the bottom so that a 20F catheter can pass through easily. It is extremely important to avoid traumatizing the umbilical skin, to limit the risk of stomal stenosis. The abdominal cavity is explored and, if present, the ventriculoperitoneal diversion catheter is displaced to the level of the upper abdomen.

Appendix preparation Creating a skin channel until the abdominal muscles enables to use a short appendix, i.e., 4–4.5 cm. This length has always been sufficient in our experience, but many prefer a longer tube. Above all, it allows

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(a)

Figure 51.1 Median sub- and periumbilical laparotomy.

us to divide the appendix into two tubes (appendicular ­bipartition), as well as to achieve the Malone procedure.16 After palpation of the appendix, we dissect the mesoappendix by freeing it from the internal side of the cecum, with 4-0 absorbable ligatures (Figure 51.2a). We progress until we make it mobile without traction up to the cystostomy opening. If necessary, the cecum and right colon are mobilized medially. The ascending colon is then clamped to allow sectioning of the appendix tip and measurement of its lumen: it should admit a 14F catheter. If not, it should be recut higher until 14F catheter passage is possible. The ceco–appendicular junction is sectioned with a cold blade and a cecal collar of 1 cm maximum diameter, which will disclose the appendix’s vascularization, and facilitate stomal suturing. The cecal stump is closed by running suture with an absorbable monobrin 4-0 suture, without burying it. It may be that the appendix is too short; in this case, we eventually perform an enlargement procedure with a cecal tube modeled after a 14F catheter (Figure 51.2b). However, the vasculature of that enlargement has to be evaluated meticulously to prevent tubal stricture. If the appendix is not usable, a tube can be tailored according to Monti’s technique and shortened if needed.20 One will have to implant it as an appendix. At the level of the appendicular tip resection, the mucosa is attached to the appendix wall by four stitches with a rapidly absorbable 5-0 suture (Figure 51.3a). The last 2 cm of the appendix tip must be freed from the mesoappendix by bipolar cautery of the appendix; this distal part will be implanted in the bladder (Figure 51.3b and c). At the end of the preparation stage, the tube must have the following characteristics: • Sufficient mobility to link the bladder with the umbilicus or right iliac fossa • A rectilinear aspect • A regular caliber equal to at least 14F

(b)

Figure 51.2 (a) The appendix tip is resected for insertion of a 14F catheter. The appendix is then mobilized with selective ligatures of the mesoappendix vessels, and a cecal collar is sectioned. (b) If the appendix is too short, and if the mesoappendix is favorable, we perform a cecoplasty to enlarge the appendix 4–8 cm.

• A well-vascularized cecal mucosa collar for the cutaneous side of the stoma • A well-vascularized tip despite sectioning of the mesoappendix over its last 2 cm (Figure 51.3c) The tube is then cleaned well with saline solution, ­intubated with a 14F catheter, and wrapped in damp compresses, making sure that the pedicle is not twisted. If we choose subperitoneal passage (possible only if the stoma is in the right iliac fossa, but not necessarily), we can create slight peritoneal scarification through which the appendix and mesoappendix are exteriorized.

Preparation of the bowel for eventual bladder augmentation and/or cecostomy The intestinal segment chosen for bladder enlargement is isolated, prepared, and wrapped in damp compresses for the time being. It is now that a continent Malone type cecostomy is performed, if planned.

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(a)

(b)

3 cm (c)

Figure 51.3 (a) After resection of the appendix tip, the mucosa is fixed to the appendix wall by four stitches of rapidly absorbable 5-0 sutures. (b) At the end of preparation, the appendix conduit must be freed from the mesoappendix up to 2 cm to allow its implantation in the bladder. (c) An operative view of the same step.

*

Cystostomy The bladder is filled with saline, and then opened. The type of bladder incision must allow a long enough bladder flap to be fixed to the posterior side of the anterior abdominal wall 2 cm below the level chosen for the cystostomy implant (taking its oblique trajectory into account). This is a key point. Indeed, the bladder fixation on the abdominal wall will make the cystostomy short, rectilinear and “easy to catheterize.” This flap will be the implantation site of the cystostomy tube. The bladder incision line will depend on bladder size and choices for mobilizing the right lateral side. Generally, the cystostomy is created with a very full bladder through a median line if the bladder is large (Figure 51.4a); if the bladder is small a V- or Y-shaped incision with a posterior upper angle in then recommended (Figure 51.4b). This will create a large anterior flap (Figure 51.5). Three traction sutures, facilitating easy access to both sides of the flap, are positioned at least 15 mm from the appendix opening in the bladder. If the bladder is supple and large, it is, of course, possible to avoid the flap procedure, but, here again, placement of the three sutures framing the ­appendix opening in the bladder will simplify all ­subsequent m ­ anipulations. In any case, the vesical peritoneum is removed on what will be sutured on the abdominal wall.

(a)

*

(b)

Figure 51.4 (a) If the bladder is large, it is opened along the median line, and the implantation zone is marked off with three absorbable Monobrin 2-0 sutures. (b) If the bladder is small, an inverted Yor V-shaped incision is made in such a way that a long anterior tip reaches the area chosen for the continent stoma.

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2 cm

(a)

Figure 51.5 Interest of creating an anterior bladder flap (a) with an inverted V-shaped incision: creation of submucosal channel becomes easy, appendix (b) will have a straight implantation, and starting bladder augmentation (c) is easier to perform.

Appendix implantation in the bladder This procedure should have been qualified as “anti-reflux,” instead of “continent.” Rules of the ureterovesical surgery have therefore to be applied. In fact, the appendicular tube is implanted into the bladder by an anti-reflux technique similar to the Glenn– Anderson type of ureterovesical reimplantation.21 The bladder tip (or the right side of the bladder in the case of a large bladder) is presented by the three triangulation sutures oriented toward four, six, and twelve o’clock (Figure 51.6a). The suture needles are retained. This triangulation will allow good disposition of the mesoappendix at that level. The opening for bladder penetration is made with an electrical knife and should admit a 20F catheter. In the case of a bladder flap, it must be situated at least 15 mm from the sides of the tip to allow parietal anchorage without risk, and easy bladder closure. The part of the appendix without the mesoappendix is brought down into the bladder. A broad submucosal trajectory is created with scissors over at least 2 cm toward the bladder base (Figure 51.6b). The tube is placed in this trajectory and fixed to the bladder by five absorbable 4-0 suture stitches, of which the two that are the most external firmly hold the bladder musculature. From here onward, the trajectory must be rectilinear, oriented toward the bladder neck, and easy to catheterize. The mesoappendix must be placed harmoniously between the bladder and the abdominal wall. We must sometimes shorten the appendix to ensure that the whole tube is perfectly rectilinear and that there is no misalignment of its trajectory. Generally, the cecal part can be easily shortened, but if the disposition of the appendix vessels requires it, we may then have to undo the bladder implantation and shorten the tip. When we are certain of its good positioning, the appendix is lightly fixed to the external side of the bladder to ensure the stability of its length along the anti-reflux trajectory (Figure 51.6c). See Tables 51.1 and 51.2.

(b)

(c)

Figure 51.6 (a) The distal part of the appendix, relieved of its mesoappendix up to 2 cm, is passed through the opening situated 1 cm from the tip. (b) The appendix is positioned in the bladder submucosa for a length of at least 2 cm. (c) The appendix is lightly fixed to the bladder exterior by three stitches with absorbable 3-0 sutures.

“Parietalization” of the bladder and cutaneous suture The bladder segment where the appendix is implanted must be firmly fixed to the abdominal wall by three to five stitches with a slowly absorbable 2-0 suture. A 14F catheter serves as a suture guide for bladder fitting and fixation (Figure  51.7a). In cases of umbilical stomas, this is the time when the fitting becomes a bit more difficult, as the autostatic retractor must be loosened. Umbilico–appendicular attachment is accomplished by six to eight stitches with absorbable PDF (monofilament) 5-0 sutures, after placement of a Foley 14F catheter. The congruence of the two diameters must be perfect; if not, a spatulation must be made either on the umbilical skin or on the appendix. Then, the three triangulation suture stitches of the bladder flap are firmly fixed to the anterior abdominal wall (Figure 51.7b). The positioning of these “parietalization” points determines whether the cystostomy trajectory is rectilinear, and whether the mesoappendix is harmoniously placed. Slight downward

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Table 51.1  Patient selection

Table 51.2  Broad principles of cystostomy performance

Patient capable of personal control

Give preference to an appendix that is usable

Good knowledge of self-catheterization via the urethra

Keep the appendix for the bladder

Bladder can be emptied via two continence orifices

“Parietalize” the bladder and fix it to the anterior abdominal wall

Implant in the bladder (and not in an intestinal patch)

Early and long-term treatment Associated Malone cecostomy

Follow a rectilinear and downward trajectory to the bladder neck

Commitment of the surgeon to treat possible residual incontinence

Give preference to the umbilicus, except in women who could be pregnant

(a)

(b)

(c)

Figure 51.7 (a) The bladder and appendix are brought toward the opening under slight tension. (b) The three sutures for presentation of the bladder are fixed to the abdominal wall. The 14F catheter, which is calibrated to the suture scars, serves as a guide to assemble the a­ ppendix– bladder. (c) The three stitches are tightened and then knotted for perfect positioning of the appendix and the mesoappendix.

traction of the bladder will help in aligning the appendix (Figure 51.7c). Several important steps have to be followed:

Globally, this implantation site is easier to target than the umbilical option.

••

Bladder drainage and closure

•• ••

The appendix must cross the median line 1–3 cm below the previous umbilicus. No excess appendicular length must be allowed. The route being median first, we are obliged to lightly push the tube to the right side of the incision, to fix the bladder well, and also to be able to continue the operation (bladder augmentation) with a loosened retractor.

If the site chosen for the stoma is the right iliac fossa, according to patient habitus and desire, the cutaneous V-shaped incision will be slightly oblique in case of very thin patient. In the case of obesity, the flap will be adapted to the abdomen shape: in our experience, one can fix any situation with VRF flaps and VQZ flaps whose size is adapted to obesity. The bladder is fixed to the abdominal wall in the same way, and the appendix is attached to the skin by separate stitches with 5-0 absorbable sutures.

The final part of the operation consists of closing the bladder on itself or on an intestinal segment for bladder enlargement. In general, we prefer not to install a urethral catheter, as a Malécot 24F transvesicoparietal catheter will keep the bladder empty. A Jackson–Pratt type drain is installed in the perivesical space. Any mesenteric windows or other causes of secondary ileus must be meticulously controlled at this stage.

Parietal closure This part of the operation is difficult in the case of an umbilical cystostomy, since the median line must be closed with slowly absorbable, interrupted 1 PDF sutures. We ensure that neither the appendix nor the mesoappendix is too tight.

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Table 51.3  Specific problems and solutions during implantation Appendix part

Specific problems

Prevention and solutions

External part

Stenosis

1. Large interrupted suture with a big cecal collar 2. Interposition of a cutaneous flap in an appendicular refend

Middle part

Mesoappendix constriction

Always inspect the mesoappendix and color of the appendix •• At bladder fixation points •• During closure of the median incision

Terminal part

Nonrectilinear trajectory (kink) because of excessive length

Reposition the parietal mooring, shorten the appendix

Submucosal trajectory is too short (incontinence)

Re-do the assembly

Postoperative care Second-generation cephalosporin is administered for antibio-prophylaxis at the beginning of the operation, and continued if the intervention lasts more than 4 hours. Systemic antibiotherapy is not provided postoperatively. The bladder is kept empty for 2 weeks with a transparietal cystostomy catheter at least equal to 20F. A closed 14F catheter is left in place in the cystostomy. As in any reconstructive surgery, a complete stop of tobacco is required, to preserve the appendix vascularization. At the first follow-up visit, 3 weeks after surgery, the surgeon removes the 14F catheter and verifies the ease of catheter passage into the bladder through the Mitrofanoff and its downward orientation toward the bladder neck (see Table 51.3).

Discussion Numerous studies and publications have been devoted to the Mitrofanoff technique of watertight cystostomy, which is considered more as “a principle,”1,3,10 but very few have given details of its implementation. The technique that we have described here is the fruit of experience of the initial author and of our centers that learned from him.22 We consider that the original technique, by its coherence, reduces the risk of complications. On a purely technical point, we would insist on implantation of the tube in the fixed portion of the bladder, as described earlier under “Appendix implantation in the bladder” and “‘Parietalization’ of the bladder and cutaneous suture.” This technical aspect is probably the most frequently altered by other surgeons.2–9,23 Appendix implantation into the mobile part of the bladder (bladder dome, lateral face, or an intestinal segment) is often suggested. Respect of this relatively difficult technical detail may, in our view, prevent major complications, such as stomal retraction and difficult catheterization. We think that tube implantation on a mobile wall carries the inconvenience of having a variable axis dependent on bladder filling, with the possibly increased risk of going down a wrong route.

When the cystostomy is parietalized in front and toward the bladder neck, the urethra is, as a matter of fact, in the axis of the cystostomy. This fixed position makes catheterizations and eventual endoscopic manipulations easier. Another important technical point is the stomal implantation site. It is chosen according to criteria, which will not be discussed here in detail. These criteria are particular: patient anatomy and scars, the personal wishes of patients, possible future pregnancies, the risk of renal transplantation, and the potential concomitant creation of a continent Malone cecostomy. This decision, well known in pediatric centers, is rarely proposed in adults, although its impact on quality of life is very significant.22,24,25 We are increasingly inclined to propose umbilical implantation, except in patients likely to be pregnant. It is theoretically contraindicated in such cases because of the surgical risk of vesicostomy injury during cesarean section performed by obstetricians not aware of its technical details. Several case reports and a few articles have dealt with the issue of delivery and bladder reconstruction.20,26–28 Vaginal delivery has been shown to be possible, but no long-term follow-up has evaluated the effects on continence and prolapse. In our practice, we encourage cesarean section, considering that a neurogenic pelvic musculature may not respond to delivery trauma as well as a normal pelvis. Furthermore, experience has taught us that in “medializing” the urinary assembly, renal transplantation can be undertaken with an acceptable level of difficulty. The notable inconvenience of umbilical implantation relates to positioning of the stoma at the center of the abdominal incision. Space given by the incision is limited for bladder augmentation, making the procedure more difficult and a bit longer. Another frequent inconvenience encountered is the difficulty with repeated abdominal laparotomies: in our experience, in such rare cases, the problem is resolved with a catheter in the appendicular tube, filling the bladder to the maximum, making a longer incision upward in the abdomen, and moving the aponevrotic incision a few centimeters left of the appendicostomy. These inconveniences do not appear to obviate the advantages of the technique, particularly in terms of continence. Complications are not very frequent when

The trans-appendicular continent cystostomy technique (Mitrofanoff principle) the technique is meticulously done. Incontinence through the stomal opening rarely occurs with a scrupulously performed technique (parietalization and minimum submucosal trajectory of at least 2 cm). When it does occur, endoscopic treatment of incontinence under cystoscopic guidance appears to be rarely effective.29 Based on very limited experience with only one case, we believe, however, that endoscopic treatment inspired by the anti-reflux procedure, via the urethral route, can be effective and less invasive than a reoperation. Similarly, residual incontinence through the urethra can also be improved by endoscopic treatment, by a fascial sling procedure in females, or a mesh sling procedure in males. In general, we prefer to implant a sling at the time of abdominal surgery, but in the absence of any history of stress urinary incontinence, we may decide, with the patient, to wait and see the results of bladder augmentation on continence and go with the sling only afterward, if needed. Experience with such a technique in our hands and in the literature is extremely limited.30,31 Stomal stricture may occur, even with a perfectly performed technique. It seems to be related to poor vascularization of the base of the implanted appendix and/or to traction on the stoma secondary to a too short appendix or a mobile “montage.” Nevertheless, if dilations are needed, the known direction and fixed submucosal trajectory make them simpler.

Conclusions The trans-appendicular continent cystostomy technique that we have described here has proven advantages: easier catheterization, optimal continence, and the facility of possible surgical changes, which remain frequent. The choice of doing everything to implant the appendix in the bladder (and not in an intestinal patch), as well as its solid parietalization in regard to the stoma so that the trajectory is toward the bladder neck, appears to be indispensable in the success of this therapeutic option. In our experience, however, the intervention will satisfy the patient only if his/her motivation is strong, if quasi-perfect urinary continence remains the common goal of the patient and the surgical team, and if anorectal incontinence is treated efficiently to eliminate the need for diapers.

References 3574. Mitrofanoff P. Cystostomie continente transappendiculaire dans le traitement des vessie neurologiques. [Trans-appendicular continent cystostomy in the management of the neurogenic bladder.] Chir Pediatr 1980; 21: 297–305. [In French] 3575. Woodhouse CRJ, Malone PR, Cumming J, Reilly TM. The Mitrofanoff principle for continent urinary diversion. Br J Urol 1989; 63: 53–7.

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3576. Duckett JW, Snyder HM 3rd. Use of the Mitrofanoff principle in urinary reconstruction. Urol Clin North Am 1986; 13(2): 271–4. 3577. Mitchell ME, Rink RC. Pediatric urinary diversion and undiversion. Pediatr Clin North Am 1987; 34: 1319–32. 3578. Skinner EC, Xie HW. Urinary undiversion using the Mitrofanoff technique. In: Douglas Whitehead E, ed. Atlas of Surgical Techniques in Urology. Philadelphia, PA: Lippincott-Raven, 1997; 118–22. 3579. Turner-Warwick R, Chapple CR. The Mitrofanoff appendix-­conduit procedure. Functional Reconstruction of the Urinary Tract and Gynaeco-Urology. London, United Kingdom: Blackwell Science, 2002: 733–5. 3580. Hinman F. Appendicovesicostomy. In: Hinman F Jr, ed. Atlas of Pediatric Urologic Surgery. Philadelphia, PA: WB Saunders, 1994: 421–5. 3581. Harris CF, Cooper CS, Hutcheson JC, Snyder HM 3rd. Appendicovesicostomy: The Mitrofanoff procedure – a 15-year perspective. J Urol 2000; 163(6): 1922–6. 3582. Cendron M, Gearhart JP. The Mitrofanoff principle. Technique and application in continent urinary diversion. Urol Clin North Am 1991; 18(4): 615–21. 3583. Mitrofanoff P, Liard A. Continent diversions, bladder reconstruction and substitution. In: Gearhart JP, Rink RC, Mouriquand PDE, eds. Pediatric Urology. Philadelphia, PA: WB Saunders, 2002: 947–55. 3584. Hsu TH, Shortliffe LD. Laparoscopic Mitrofanoff appendicovesicostomy. Urology 2004; 64(4): 802–4. 3585. Clark T, Pope JC 4th, Adams C, Wells N, Brock JW 3rd. Factors that influence outcomes of the Mitrofanoff and Malone antegrade continence enema reconstructive procedures in children. J Urol 2002; 168(4 Pt 1): 1537–40. 3586. Cain MP, Casale AJ, King SJ, Rink RC. Appendicovesicostomy and newer alternatives for the Mitrofanoff procedure: Results in the last 100 patients at Riley Children’s Hospital. J Urol 1999; 162(5): 1749–52. 3587. Bruce RG, McRoberts JW. Cecoappendicovesicostomy: conduitlengthening technique for use in continent urinary reconstruction. Urology 1998; 52(4): 702–4. 3588. Cromie WJ, Barada JH, Weingarten JL. Cecal tubularization: Lengthening technique for creation of catheterizable conduit. Urology 1991; 37(1): 41–2. 3589. Farrugia M-K, Malone PS. Educational article: The Mitrofanoff procedure (Review) J Pediatr Urol 2010; 6(4): 330–7. 3590. Franc-Guimond J, González R. Simplified technique to create a concealed catheterizable stoma: The VR flap. J Urol 2006; 175(3): 1088–91. 3591. Ransley PG. The VQZ plasty for catheterizable stomas. In: Frank JD, Gearhart JP, Snyder HM, eds. Operative Pediatric Urology. London, United Kingdom: Churchill-Livingstone, 2002: 109. 3592. Itesako T, Nara K, Matsui F, Matsumoto F, Shimada K. Clinical experience of the VQZ plasty for catheterizable urinary stomas. J Pediatr Urol 2011; 7(4): 433–7. 3593. Liard A, Seguier-Lipszyc E, Mathiot A, Mitrofanoff P. The Mitrofanoff procedure: 20 years later. J Urol 2001; 165(6 Pt 2): 2394–8. 3594. Kaefer M, Retik AB. The Mitrofanoff principle in continent urinary reconstruction. Urol Clin North Am 1997; 24(4): 795–811. 3595. Liard A, Bocquet I, Bachy B, Mitrofanoff P. Enquête sur la satisfaction after orthotopic continent urinary diversion. Surg Gynecol des patients porteurs d’une caecostomie continente de Malone. [Survey on satisfaction of patients with Malone continent cecostomy.] Prog Urol 2002; 12(6): 1256–60. [In French] 3596. Perez M, Lemelle JL, Barthelme H, Marquand D, Schmitt M. Bowel management with antegrade colonic enema using a Malone or a Monti conduit – clinical results. Eur J Pediatr Surg 2001; 11(5): 315–18. 3597. Fenn N, Barrington JW, Stephenson TP. Clam enterocystoplasty and pregnancy. Br J Urol 1995; 75: 85–6.

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3598. Kennedy WA 2nd, Hensle TW, Reiley EA, Fox HE, Haus T. Pregnancy after orthotopic continent urinary diversion. Surg Gynecol Obstet 1993; 177(4): 405–9. 3599. Mundy AR. Continent urinary reconstruction and reproductive function. Scand J Urol Nephrol Suppl 1992; 142: 129. 3600. Glenn JF, Anderson EE. Distal tunnel ureteral reimplantations. J Urol 1967; 97: 623–6. 3601. Schilling A, Krawczak G, Friesen A, Kruse H. Pregnancy in a patient with an ileal substitute bladder followed by severe destabilization of the pelvic support. J Urol 1996; 55(4): 1389–90.

3602. Godbole P, Bryant R, MacKinnon AE, Roberts JP. Endourethral injection of bulking agents for urinary incontinence in children. BJU Int 2003; 91(6): 536–9. 3603. Austin PF, Westney OL, Leng WW, McGuire EJ, Ritchey ML. Advantages of rectus fascial slings for urinary incontinence in children with neuropathic bladders. J Urol 2001; 165(6 Pt 2): 2369–71; discussion 2371–2. 3604. Hamid R, Khastgir J, Arya M, Patel HR, Shah PJ. Experience of tensionfree vaginal tape for the treatment of stress incontinence in females with neuropathic bladders. Spinal Cord 2003; 41(2): 118–21.

52 Tissue engineering and cell therapies for neurogenic bladder augmentation and urinary continence restoration René Yiou

Introduction Research in the field of cell-based therapy and tissue engineering for functional urologic disorders has advanced considerably over the past decade, allowing several recent clinical trials. Here, we review these new technologies applied to neuro-urologic disorders, namely bladder tissue engineering for neurogenic bladder and cell therapy for urethral rhabdosphincter insufficiency.

Part 1: Bladder replacement for patients with neurogenic bladder Hypertonic low-compliant bladder responsible for urinary incontinence or reflux in the upper urinary tract can develop during the course of several neurological disorders.1,2 Bladder augmentation performed to treat neurogenic bladder traditionally involves the use of intestinal segments, which can lead to complications such as urolithiasis, adhesion formation, increased intestinal mucus secretion, and metabolic disturbances.3 Therefore, investigators have evaluated a number of other methods for increasing the size of the bladder. Many tissues have been used to create free grafts, including the skin, omentum, dura, and peritoneum. However, the results were unsatisfactory, mainly due to mechanical failure. In recent years, attention has turned to tissue engineering as an alternative to free tissue grafts for bladder augmentation.4–12 Promising results were obtained in various animal models of cystectomy. Acellular matrices or scaffolds made of various materials have been tested, either alone or after seeding with viable cells. The most sophisticated

tissue engineering approach involves harvesting autologous cells from the diseased organ, e­ xpanding these cells in vitro, and seeding them onto a matrix, which is then implanted into the donor organ (Figure  52.1). Several artifices can be used to promote ­vascularization of the construct, allowing the cells to grow in the shape of the scaffold. Eventually, the artificial scaffold breaks down, leaving a functionally normal organ. The main factors known to influence the organ regeneration process are the biomaterial, which should replicate the effects of the extracellular matrix (ECM); the source of the cells that are seeded onto the biomaterial; and the environmental conditions during regeneration, which influence the development of the blood vessel and nerve supply to the construct.

Biomaterials The biomaterial used to produce the scaffold acts as a substitute for the ECM, providing anchorage for the seeded cells, guiding their growth into the appropriate tissue architecture, and storing and releasing growth factors that are crucial to growth and repair. The main ECM components are fibrous proteins and glycosaminoglycans (GAGs), which are produced by resident cells. GAGs are carbohydrate polymers that attach to ECM proteins, forming proteoglycans. Proteoglycans have a negative charge that attracts water molecules, ensuring adequate hydration of the ECM and resident cells. ECM proteoglycans include heparan sulfate, chondroitin sulfate, and keratan sulfate. Heparan sulfate regulates a wide range of biological activities, including developmental processes and angiogenesis. Chondroitin sulfate contributes to the tensile strength of the cartilage, tendons, ligaments, and aortic walls. In addition to proteoglycans, the ECM contains hyaluronic acid,

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Figure 52.1 Bladder augmentation after cystectomy

collagens, fibronectin, elastin, and laminin. Hyaluronic acid absorbs water, causing the tissue to swell and therefore to resist compression. Hyaluronic acid acts as an environmental cue that regulates cell behavior during embryonic development, healing processes, inflammation, and tumor development. Collagens, the most abundant glycoprotein in the ECM, form fibrillar proteins that serve as struts to resident cells. They can be divided into several families based on their structure: fibrillar collagen is composed of collagens types I, II, III, V, and XI; fibril-associated collagen with interrupted triple helices (FACIT) is composed of types IX, XII, and XIV; short-chain collagen is composed of types VIII and X; basement membrane collagen is type IV; and other collagens include types VI, VII, and XIII. Fibronectin connects cells to collagen fibers, allowing the cells to move through the ECM. Elastins, which are produced by fibroblasts and smooth muscle cells, confer elasticity, allowing the tissue to stretch and subsequently to recover its previous shape. Laminins are proteins found in the basal lamina, where they form networks of web-like structures that resist tensile forces related to the adhesion of cells, most notably muscle cells. Integrins are cell-­ surface proteins that bind cells to ECM components such as fibronectin and laminin, as well as to integrin proteins on the surface of other cells. The ideal biomaterial for tissue engineering should be biocompatible, promote cellular interactions, and enhance tissue development; thus, replicating the functions of the normal ECM. The biomaterial should degrade slowly after implantation while undergoing colonization by host cells, so that it is eventually replaced by ECM components produced by the seeded or ingrowing cells. Biomaterials that have been evaluated for engineering genitourinary tissues include naturally derived materials, such as collagen and alginate; decellularized tissue matrix such as bladder

Matrix seeded with cells

Design of bladder tissue engineering protocols. PGA, polyglycolic acid; SIS, small intestinal submucosa.

submucosa and small intestinal submucosa (SIS); and synthetic polymers such as polyglycolic acid (PGA), polylactic acid (PLA), and polylactic-coglycolic acid (PLGA). The degradation products of PGA, PLA, and PLGA are nontoxic and slowly eliminated from the body in the form of carbon dioxide and water. Because these polymers are thermoplastics, they can easily be formed into a three-dimensional scaffold with a desired microstructure, gross shape, and dimension by various techniques. SIS is a xenogenic, nonimmunogenic, acellular, biodegradable, collagen-rich membrane derived from the submucosal layer of the porcine small intestine. SIS has been shown to promote bladder regeneration in vivo8,10,11 and to support three-dimensional growth of human bladder cells in vitro.5 After implantation in the bladder, SIS is resorbed within 8–12 weeks and replaced by bundles of organized smooth muscle cells.13 The results differ, however, according to the bowel segment and to the age of the donor animal, with optimal results possibly being obtained with distal ileum from sows older than 3 years.11 In early experiments, unseeded SIS was used to replace bladder tissue. Strips of rat bladder regenerated from SIS were capable of contracting in organ-bath studies; in addition, histology established the presence of muscarinic, purinergic, and beta-­adrenergic receptors, indicating sprouting of host nerves toward the scaffold.8 In dogs, unseeded SIS promoted bladder regeneration with mucosal, smooth muscle, and serosal layers.10 Overall, experiments with SIS yielded promising results, although studies in dogs raised concern about possible stone formation, calcification, and graft shrinkage.4 Bladder augmentation with unseeded biomaterial relies on the ingrowth of smooth muscle and urothelial cells from the surrounding residual bladder tissue. It has been shown that urothelial cells that have shown considerable

Tissue engineering and cell therapies for neurogenic bladder augmentation regenerative potential in vivo,14 can colonize the inner surface of the scaffold, whereas smooth muscle cells cannot if replacement of large bladder segments is required.7,15 The lack of colonization by smooth muscle cells results in collagen deposition on the scaffold, eventually leading to scaffold shrinkage. These data suggesting a need for seeding the scaffold were confirmed by Oberpenning et al.,15 who compared seeded and unseeded PGA scaffolds used in dogs for bladder replacement after subtotal cystectomy. The seeded scaffolds were obtained by culturing autologous urothelial and smooth muscle cells from bladder biopsies and seeding them onto bladder-shaped PGA scaffolds. Identical scaffolds were used unseeded in the other group of dogs. After 11 months, the neo-bladders obtained using seeded PGA were histologically normal and had identical urodynamic parameters to those measured before cystectomy. In contrast, compared to pre-cystectomy values, bladder capacity was 46% in the group treated with unseeded PGA and 22% in the cystectomy-only control group. Overall, most attempts with unseeded synthetic materials failed due to urinary stone formation and fibroblast deposition, which led eventually to bladder shrinkage. Therefore, seeding of the biomaterials with urothelial and smooth muscle cells before implantation is likely the best option.

Cells for bladder tissue engineering Bladder smooth muscle cells An area of concern is the quality of the smooth muscle cells harvested from the neurogenic bladder for in vitro ­expansion and seeding of the biomaterial. It is unclear whether cells from diseased bladders can produce functionally normal tissue. Cultured smooth muscle cells from neurogenic bladders showed abnormal phenotypic features and gene expression profiles.16,17 They grew more quickly, contracted less frequently, and adhered less well than smooth muscle cells from normal bladder.16 Abnormal expression profiles were noted for up to 18 genes, including genes for fibroblast growth factor and integrin signaling.17 In another study, however, muscles engineered from normal and diseased bladders exhibited similar phenotypes.18 In this study, human smooth muscle cells from functionally normal bladders, exstrophic bladders, and neurogenic bladders were grown, expanded, and seeded onto polymer scaffolds, which were then implanted into athymic mice. The engineered bladders were removed subsequently for evaluation of their contractile response to various stimuli in organ-bath studies. Contractility to electrical and chemical stimulation was the same r­ egardless of the origin of the cells. Therefore, it can be assumed that, although smooth muscle cells from neurogenic bladders may exhibit phenotypic differences compared to those from normal bladders, they remain capable of generating a normally functioning

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bladder in vivo. One possible explanation is that the regenerated muscle originates in a small subset of the seeded smooth muscle cells characterized by stem cell capabilities, which are unaffected by the neurological disorder. Possible harmful effects of the cell-culturing process constitute another focus of concern when producing smooth muscle cells for bladder engineering. In recent investigations of muscle precursor cell (myoblast) therapy for striated muscle diseases, the culture conditions and enzymatic digestion severely reduced the myogenic potential of the cells after transplantation, although vitality and function seemed normal in vitro.18–24 Whether prolonged culturing of smooth muscle cells results in similar deleterious effects remains unknown. Controversy continues to surround the relative merits of using large numbers of fully differentiated smooth muscle cells expanded by culturing, or smaller numbers of smooth muscle cell progenitors capable of proliferating and differentiating in vivo. A similar debate exists in the field of myoblast therapy for striated muscle diseases, as discussed later in this chapter.

Bone marrow mononuclear cells Bone marrow mononuclear cells obtained by Ficoll–Paque density gradient separation of bone marrow aspirate constitute another source of smooth muscle cells for tissue engineering. The bone marrow mononuclear cell population contains several types of multipotent stem cells capable of differentiating into smooth muscle cells, including hematopoietic stem cells and mesenchymal stem cells. Studies comparing bone marrow cells and bladder smooth muscle cells for bladder tissue engineering in dogs showed similar contractile responses to calcium ionophore.4 Bone marrow cells differentiated into contractile cells expressing alpha-smooth muscle actin but not desmin or myosin. In the future, other cell sources might be investigated. The same stem cell source might be suitable for obtaining both urothelial cells and smooth muscle cells. Adult multipotent stem cells have been isolated from the skin25 and from fat tissue.4 Embryonic stem cells and amniotic stem cells constitute additional promising sources of cells for bladder tissue engineering.26

Vascularization and innervation of engineered bladder Vascularization and innervation of the implanted scaffold are critical to successful tissue engineering. Tissue thicker than .8 mm can survive only if ingrowing blood vessels supply sufficient oxygen and nutrients to all the cells in the tissue.27,28 Several methods for promoting neoangiogenesis have been investigated, including omental wrap,12 incorporation of vascular growth factor into the scaffold,29 seeding

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of endothelial progenitor cells, and prevascularization of the scaffold.4 The development of new vascular beds from endothelial cells present within tissues is enhanced by several angiogenic factors, such as vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor. Local, controlled delivery of these factors via incorporation into the scaffold of plasmids carrying the relevant genes may enhance blood vessel formation in the engineered tissue.29 Injecting autologous endothelial progenitor cells constitutes another approach. The endothelial progenitor cells and mesenchymal stem cells found in bone marrow have proangiogenic properties that may hold promise for treating ischemic diseases.30 In experimental and clinical studies, when these cells were transplanted into ischemic or infarcted foci of the myocardium, they were incorporated into sites of new vessel growth, and regional blood flow was improved. These cells might therefore enhance the development of an adequate vascular bed within engineered bladders. Schultheiss et  al. described an original technique for increasing the vascular supply of decellularized porcine SIS seeded with smooth muscle cells and urothelial cells.9 The arteriovenous pedicles were preserved during SIS preparation, then injected with endothelial progenitor cells. The pedicles were then clamped for 24 hours, and the reseeded matrix was cultured under specific conditions designed to promote vessel development and re-­endothelialization. After 3 weeks of cultivation, the larger vessels, as well as the intramural scaffold capillary network, were repopulated with cell monolayers expressing endothelium-­ specific markers. When the scaffold was implanted into the SIS-donor animal, the arterial and venous pedicles were anastomosed to the corresponding iliac vessels. After implantation, vascular perfusion remained intact, with no thrombus formation. In contrast, implanted scaffolds that were not previously seeded with endothelial progenitor

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cells exhibited stagnant blood flow and thrombosis within 30 minutes. This promising approach deserves further investigation.

Clinical reports of bladder augmentation using tissue engineering In 2006, Atala and colleagues reported the first clinical trial of tissue-engineered bladders in seven patients who had myelomeningocele with poorly compliant bladders and frequent urinary leakage as often as every 30 minutes despite maximal pharmacotherapy.12 For the scaffolds, collagen matrix derived from decellularized bladder submucosa was used in the first four patients and a composite of collagen and PGA in the next three patients. The scaffolds were seeded with autologous smooth muscle and urothelial cells. A bladder biopsy of 1–2 cm2 was obtained from the bladder dome through a small suprapubic incision. Smooth muscle cells and urothelial cells were cultured separately for 7 weeks. Then, the smooth muscle cells were seeded on the outer surface and the urothelial cells on the inner surface of the scaffold. The scaffold was covered with omentum in four patients (including the three patients with composite scaffolds) (Figure 52.2). Compared to preoperative values, mean maximum bladder capacity decreased by 30% in the three patients treated with collagen scaffolds and no omental wrap. A 1.22-fold increase (from 438 mL to a mean of 535 mL) was noted in the patient treated with collagen and omental wrap, suggesting a major role of the omentum in the development of an adequate vascular bed in the neo-bladder. In the three patients treated with the composite scaffold and omental wrap, mean maximum bladder capacity increased

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Figure 52.2 (a) Scaffold seeded with cells and (b) engineered bladder ­anastamosed to native bladder with running 4-0 polyglycolic sutures. (c) Implant covered with fibrin glue and omentum. (Reprinted from The Lancet, 367, Atala A, Bauer SB, Soker S, Yoo JJ, and Retik AB, Tissue-engineered autologous bladders for patients needing cystoplasty, 1241–1246, Copyright 2006, with permission from Elsevier.)

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Figure 52.3 (a) Preoperative and (b) 10-month postoperative cystograms and urodynamic findings in patient with a collagen-PGA scaffold-­engineered bladder. Note irregular bladder on cystogram, abnormal bladder pressures on urodynamic study preoperatively, and improved findings postoperatively. (Reprinted from The Lancet, 367, Atala A, Bauer SB, Soker S, Yoo JJ, and Retik AB, Tissue-engineered autologous bladders for patients needing cystoplasty, 1241–1246, Copyright 2006, with permission from Elsevier.)

1.58-fold (Figure 52.3) and the maximum mean dry intervals during the day increased from 3.0 to 7.0 hours. This pioneering study shows that tissue engineering can be used to generate bladders for patients who require cystoplasty. The beneficial effects of omental wrap emphasize the crucial role played by the vascular supply in the development of the seeded scaffold. Several questions remain open, such as the long-term fate of cultivated cells and the risk of premature senescence. In addition, recurrence of the urinary symptoms is theoretically possible, since the underlying neurological disease remains present.

Part 2: Cell therapy for urethral rhabdosphincter insufficiency Urinary incontinence due to intrinsic urethral sphincter insufficiency develops in many central or peripheral neurological disorders affecting the nerves that supply the urethral rhabdosphincter. In patients with severe i­ncontinence, the treatment of reference remains the implantation of an artificial urinary sphincter.31–35 Alternatively, a compressive device36–39 can be implanted or a bulking agent injected.40 Biologic or synthetic bulking agents investigated over the last decades include collagen, polytetrafluoroethylene paste (Teflon), silicone microparticules, carbon beads, polyacrylamide hydrogel, adipocytes, and chondrocytes.31,37,41,42 These agents may increase resistance to urine flow, augment urethral mucosa, and improve coaptation and intrinsic sphincter function. However, overall results have been disappointing,40 because of particle migration or rapid resorption. Cell therapy holds promise for restoring urethral tonicity and sphincter function in patients with urinary sphincter insufficiency since it represents the first therapeutic option aimed at repairing the cellular damages at

the origin of urinary incontinence. Several types of precursor or stem cells have been tested to improve the tone exerted by the smooth or striated components of the urethral musculature; these are mainly stem cells derived from bone marrow,43–45 adipose tissue,4,46 or skeletal muscle. At present, urethral injection of striated muscle precursor cells (MPCs) remains the most extensively studied cell therapy approach to urinary incontinence.47–52 In rodents, improved contractility of the urethral rhabdosphincter was noted after the injection of autologous MPCs.47,49 Results of several clinical trials conducted with MPCs are now available.48,51–56 Here, we provide an overview of MPC-based cell therapy for skeletal muscle diseases and we discuss the biological basis for MPC transfer into the urethra to treat urinary incontinence. Then, we expose the new sources of stem cells including bone marrow and adipose-derived stem cells that showed promise in this indication.

Origin and function of skeletal muscle precursor cells (MPCs) The cells involved in regenerating adult skeletal muscle are believed to closely resemble the cells involved in myogenesis. During embryogenesis, the somites give rise to successive waves of myoblasts, which colonize the limbs within the first 18 days after conception. These myoblasts fuse into primary myotubes, which eventually mature into myofibers. A subset of myoblasts sequestered in a quiescent state between the basal lamina and the sarcolemma, known as satellite cells, ensures muscle repair in adulthood. Satellite cells constitute the main population of MPCs. In the event of muscle injury, the satellite cells proliferate and differentiate into secondary myoblasts, which fuse into new myotubes or repair the parental m ­ yofibers (Figure 52.4).

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(a)

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Figure 52.4 Description of satellite cells (main muscle precursor cells) and of the myogenic process using the single myofiber implant technique. (a) Longitudinal and (b) transversal cross section of a skeletal muscle biopsy showing organization of myofibers parallel to each other. Figure (b) shows nuclei stained with DAPI (blue). Nuclei of satellite cells (arrows) are detected by immunostaining with anti-Pax7 (red). The extracellular matrix is immunostained with anti-laminine (green). Only one satellite cell can be observed on this cross section. Resident satellite cells can fully reconstitute the myofiber mass lost after a muscle injury, although they initially contribute less than 1% of all myonuclei. Scale bar for figures (a) and (b) = 100 µm. (c–f) One myofiber has been isolated by gentle trituration of a muscle biopsy, placed in a petri dish and immunostained with desmin (red) to detect satellite cells. All nuclei are counterstained with DAPI (blue). One satellite cell can be detected (arrow). (f) Superposition of (d) and (e). (g, h) 24 hours after plating, satellite cells (desmin, red) detach and proliferate around the parental myofiber. (i) after 2 weeks in culture, the satellite cells have fused to form new myofibers (immunostaining with anti-alpha-actinine-2, green). Scale bar for figures (c –i) = 20 µm.

Tissue engineering and cell therapies for neurogenic bladder augmentation Importantly, resident satellite cells can fully reconstitute the myofiber mass lost after a muscle injury, although they initially contribute less than 1% of all myonuclei.57 The considerable myogenic potential of MPCs was recently emphasized by Collins et  al.,20 who found that as few as seven satellite cells could generated more than 100 new myofibers, each of which contained thousands of myonuclei. Importantly, all satellite cells are not at the same stage of commitment in the myogenic lineage.58 Therefore, the potential for producing myofibers may vary considerably. Most satellite cells express the early myogenic marker Myf5. A small subset of Myf5-negative satellite cells, may serve as stem cells that renew the satellite cell compartment. This subset of so-called muscle stem cells was found in mice to express markers (sca-1) common to other stem cell types, such as hematopoietic stem cells.59,60 Muscle stem cells have also been found in the connective tissue surrounding each myofiber, in association with capillaries, and it is believed that they may originate from the bone marrow.61,62

Muscle precursor cell transfer for neuromuscular disorders Pioneering work done in the 1980s showed that MPCs transferred from normal muscle into genetically deficient muscle fused with the host myofibers, thereby supplying them with the missing gene.63 These studies suggested that MPC injections might hold promise for treating many genetic muscular diseases, mainly Duchenne muscular dystrophy,64 as well as heart disease.65 However, clinical trials involving injection of a myoblast suspension into genetically deficient muscle consistently produced disappointing results22,64,66,67. Many factors contributed to the failure of this approach, including immune reactivity against allogeneic myoblasts, poor survival of cells exposed to ischemia, and limited cell migration requiring multiple injection sites for each muscle.19,22,60,64,67,68 This approach has been nearly abandoned as a tool for treating genetic muscle diseases, the group of conditions for which it was initially designed. Researchers have shifted their focus to the use of autologous MPCs for treating localized muscle abnormalities. Intrinsic rhabdosphincter insufficiency is among the most promising candidates for treatment with MPC injection. The main challenge faced by autologous MPC transfer resides in the high sensitivity of these cells to ischemia, which may impair their survival after implantation. Several solutions to this problem have been investigated. Beauchamps et al. showed that the majority of MPCs died after injection into muscle, despite in vitro evidence of vitality, and that the tiny minority that survived exhibited stem cell characteristics.19 These findings were confirmed by several other groups, prompting ­researchers to investigate new preparation methods that select MPC exhibiting

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the stem cell phenotype.59,60 However, no clinical studies of such selected MPCs are available. Other groups investigated the impact of the cell preparation process on myoblast survival.18,20–24 The few animal studies comparing injections of myoblasts with or without prior culturing consistently showed deleterious effects of culture conditions. Enzymatic disaggregation of muscle biopsies was a major cause of MPC death following implantation. For instance, 150 MPCs obtained by gentle physical means were several thousand times more efficient in producing new myofibers than 104 MPCs dissociated by enzyme digestion.20 MPC exposure to culture conditions may also contribute to loss of myogenic potential.23 Montarras et al. found that culturing before transplantation markedly reduced the regenerative efficiency of MPCs so that culture expansion seemed to constitute an “empty” process yielding the same amount of muscle as the number of cells from which the culture was initiated.18 Thus, there is evidence that the myogenic potential of injected MPCs can be impaired by the cell preparation process, most notably the enzyme digestion step, and by cell culture conditions. It remained to be determined whether injecting small numbers of cells without previous cultivation is more effective than ­injecting large numbers of MPCs previously expanded in vitro.

Challenges faced by using muscle precursor cells to treat intrinsic urethral rhabdosphincter insufficiency We reviewed the data obtained by several groups, including ours, about the biology of MPC transfer into the urethra for the treatment of intrinsic rhabdosphincter insufficiency. In addition to MPC survival after implantation into the sphincter, important issues have been addressed through animal experimentations, including the following: •• •• •• ••

The paracrine and neurotrophic effects of MPC injection The effects of MPC injection on urethral muscle tone The quantity and type of MPCs (stem cell-like vs. mature) required to improve sphincter function The appropriate site of injection

Paracrine and neurotrophic effects of MPC injections Whether the host tissue can innervate MPC-derived myotubes is of special concern when seeking to treat intrinsic sphincter insufficiency, since this condition is often associated with chronic muscle denervation.69 Several groups

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found that activated MPCs and the myofiber regeneration process promoted motor neuron sprouting.49,70,71 For instance, following experimental muscle denervation via afferent nerve transection, myofibers and the surrounding ECM released potent neurotrophic factors, such as neuroleukin, insulin-like growth factor, and neural cell adhesion molecules, which can stimulate the sprouting of nearby nerve endings, ultimately leading to myofiber reinnervation.71 These cytokines and growth factors represent the main mechanism for self-repair of the neuromuscular junction. Consequently, the injection of MPCs or myofibers with attached satellite cells may improve neurogenic intrinsic sphincter insufficiency by activating the sprouting of urethral nerves through a paracrine effect. We used a rat model of electrocautery-induced sphincter injury to show that the injection of autologous MPCs obtained by the myofiber explant technique led to the development of innervated and functional myotubes in the damaged area (i.e., on the side of the sphincter). Interestingly, we found that this injury irreversibly destroyed not only sphincter myofibers with their satellite cells, but also their nerve supply, resulting in the development of dense fibrosis. The regenerated myotubes were connected to newly formed nerve endings after 1 month, strongly suggesting that the myogenic process induced by MPC injection exerted neurotrophic effects resulting in the sprouting of residual nerves. A neurotrophic effect of MPC injection was demonstrated subsequently by Cannon et al. in a model of neurogenic sphincter insufficiency induced by sciatic nerve transection.47 We recently described a new method of MPC transfer into the urethra, in which myofibers and their attached satellite cells, without prior tissue processing, were implanted near the bladder neck at distance from the rhabdosphincter.72 The satellite cells underwent activation and fusion, replacing the parent myofibers, which degenerated rapidly after implantation. A large number of myotubes exerting tonic contraction developed. Importantly, these myotubes had cholinergic receptors connected to nerve endings after 1 month, showing connection with urethral nerves. Thus, it can be assumed that the myogenic process allows self-innervation of the new muscle in an ectopic position through a potent paracrine and neurotrophic effect on the environment.

Can MPC transplantation increase urethral muscle tone? Another important issue is whether myotubes derived from transplanted MPCs improve urethral muscle tone. In  humans, the urethral rhabdosphincter is a unique muscle that participates in urinary continence by developing tonic contractions, thereby maintaining a resting urethral tone. Classically, this activity is mediated by type

I myofibers, which are slow-twitch, tonic, aerobic fibers that can sustain long periods of contraction.69,73 Type II myofibers, in contrast, are fast-twitch, chiefly anaerobic fibers that develop strong contractions but fatigue rapidly. Therefore, it was important to determine whether the phenotype of myotubes derived from transplanted MPCs is consistent with sphincter-like muscle activity. The development of models in large animals was required to investigate this point, since the small sphincter of rodents precludes intraurethral pressure measurements and chiefly contains type II myofibers.74 In several large animal model,72,75,76 it was found that MPC injection improved intraurethral basal pressure, however, it remains to be determined whether this effect is mediated by a bulking effect and/or a genuine de novo muscular tonic activity. An original porcine model developed by Zini et  al.77 consists in recording urethral pressure before and after curare injection. The pig sphincter contains 52% of type I myofibers exhibiting tonic contractions. Curare specifically blocks the neuromuscular junctions of striated muscle, its effect on smooth muscle being minimal. Therefore, the comparison of urethral pressure profiles before and after curare injection provides an evaluation of the tonic contraction of functional, innervated, striated muscle. In this model, the myotubes developed after implantation of myofibers with their satellite cells exhibited tonic contractions under neural control. These preliminary results suggest that MPCs exhibit plasticity, which allows them to adapt to their new function. Environmental factors, most notably interaction of MPCs with urethral nerves, may be critical to the terminal differentiation of the myotubes, as previously observed in cross-innervation studies of striated muscles.78

How many and what type of MPCs (stem cell-like vs. mature) are required to improve sphincter function? Most of the MPCs die shortly after implantation.19 The current method of reference for delivering MPCs to diseased muscle involves isolating cells from a muscle biopsy by enzymatic digestion then expanding the cell population by cultivation. The low yield of this method has been demonstrated in the mdx mouse, the animal model for Duchenne muscular dystrophy: fewer than 3% of the injected cells survived and participated in myofiber formation.19 The small subset of surviving cells, which eventually generates new muscle tissue, exhibits several features of hematopoietic stem cells.19,59 This fact suggested two methods for increasing the number of surviving MPCs, namely selection and amplification of so-called muscle stem cells, and increasing the number of injected MPCs under the assumption that the injected stem cell population would increase commensurately.

Tissue engineering and cell therapies for neurogenic bladder augmentation Improved sphincter function has been reported after the injection of muscle-derived stem cells obtained by the preplating technique in a model of sciatic nerve transection.47 However, we found that muscle-derived stem cells obtained using another method (presence of the MDR receptor59) survived after injection but failed to form myotubes in an irreversibly injured sphincter characterized by complete myofiber destruction. When the stem cells were mixed with differentiated MPCs before injection, myotubes developed, whereas mature MPCs deprived of their stem cell subpopulation failed to survive after injection. Taken together, these results suggest that environmental cues and/or interactions between mature and stem celllike MPCs are crucial to myotube development in vivo. The effect of increasing the number of injected MPCs was evaluated in a porcine model under the working hypothesis that increasing the number of injected MPCs would increase the number of surviving MPCs.79 Although the number of animals was too small (n = 5) to detect a plateau effect, which was previously reported with MPCs, a dose-dependent increase in urethral closure pressure was noted with the best results obtained with 7.8 × 107 cells (myoblasts). We recently suggested a new approach to improving MPC survival after injection, based on the hypothesis that the MPC preparation process may cause alterations responsible for cell death after injection.72 We developed a method in which myofibers and satellite cells are isolated then immediately implanted into the urethra. The number of injected MPCs was several thousand times smaller than with previously reported techniques. Nevertheless, a large amount of myotubes developed. Thus, attention to cell quality rather than quantity may be in order.

Where should the MPCs be injected? In most studies that investigated MPC injections,48,51,54,55 the rhabdosphincter was targeted using echography or EMG to deliver the cells. The assumed fate of MPC injected in this setting is to reinforce deficient sphincter myofibers, mainly by fusing with them, thus generating hypertrophy. However, the rhabdosphincter, which has a mean thickness of 3 mm,80 is difficult to localize precisely. Moreover, it remains to be demonstrated that the injecting needle does not cause further injuries to the rhabdosphincter. The injection of MPCs at the vicinity of the rhabdosphincter could be another option avoiding localization issues. It has been shown that MPCs injected in the smooth muscle part of the urethra may also develop and differentiate into new myofibers generating a distinct tonic muscular activity.72 As a consequence, para-­sphincteric MPC injection may participate to overall urethral ­ tonicity improvement. In addition, the mechanisms of action of MPCs injections are multiple, and a potent paracrine effect (mainly neurotrophic and angiogenic) has been shown.47,49,72 The delivery of trophic factors in the urethra

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outside the rhabdosphincter may be of interest in neurogenic incontinence to promote nerve sprouting. Comparative studies are required to determine the most efficient method of cell injection in the urethra.

Results of clinical trials using MPCs Several clinical trials have been conducted with different methods of MPC preparation. Strasser et al. reported the first randomized clinical trial of cell therapy for urinary incontinence.53 Sixty-three women with urinary stress incontinence were randomly allocated to treatment with transurethral ultrasonography-guided injections of autologous MPCs into the urethral sphincter and of injection of fibroblasts in collagen into the submucosa to treat atrophy (n = 42) or to endoscopic collagen injections (n = 21). After 12 months, 38 of the 42 women given cell therapy were completely continent, compared to only 2 of the 21 controls. Ultrasonographic measurements showed increase in thickness and contractility of the sphincter in the cell therapy group. However, this clinical trial has been invalidated due to ethical issues. Sebe et al.51 conducted a prospective study on 12 women presenting severe stress urinary incontinence (SUI) with fixed urethra, after previous failed surgical management. Patients underwent intrasphincteric injections of autologous MPCs isolated from a biopsy of deltoid muscle. Three of 12 patients were dry at 12 months, seven other patients were improved on pad test, and two patients were slightly worsened by the procedure. Quality of life was improved in half of patients. Interestingly, in this study, the MPC injection did not modify intraurethral pressure, suggesting that the effect of cell therapy was not the result of improvement of sphincter contraction, but rather a paracrine effect on the urethra. We assessed the safety of periurethral myofiber ­implantation in 10 patients (5 men after radical prostatectomy and 5 women) with severe urinary incontinence due to intrinsic sphincter deficiency. 56 The objective was to assess the myogenic process resulting from direct implantation of myofiber with their satellite cells— the main MPCs—without cell culture expansion. The maximum urethral closure pressure and concomitant periurethral electromyographic activity were recorded before surgery and 1 and 3 months after surgery. Continence was assessed using the 24-hour pad test and self-completed questionnaires for 12 months. No serious side effect was detected. Continence improved significantly during the 12-month follow-up in 4/5 women, including 2 who recovered normal continence. In the women, maximum urethral closure pressure (MUCP) increased twofold and de novo EMG periurethral activity was recorded. In the men, MUCP and EMG recordings showed similar improvements but the effect on

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continence was moderate. The small number of patients enrolled could affect theses results, however, this is the first report of a one-step procedure for transferring autologous MPCs via myofiber implantation that showed improvement of periurethral muscular activity. Car et al.55 reported a 1-year follow-up on eight women in which SUI was treated with MPC injections. The MPCs were considered as muscle-derived stem cell obtained from a muscle biopsy and expanded in culture after selection according to the pre-plating technique. Mean and median follow-up in this group was 16.5 and 17 months (range 3–24 months). Improvement in SUI was seen in five of eight women, with one achieving total continence. Onset of improvement was between 3 and 8 months after injection. Evaluation of sphincter function was not reported in this study; therefore, the mechanism of action of the therapy cannot be determined. Gerullis et  al.54 reported the results of transurethral injections of autologous muscle-derived cells into the urinary sphincter in 222 male patients with SUI after prostate surgery. The transplanted cells were characterized after culture using different markers of myogenic differentiation. Overall, 120 patients responded to therapy of whom 26 patients (12%) were continent, and 94 patients (42%) showed improvement. In 102 (46%) patients, the therapy was ineffective. Clinical improvement was observed on average 4.7 months after transplantation and continued in all improved patients. The authors conclude that transurethral injection of muscle-derived cells into the damaged urethral sphincter of male patients is a safe procedure and improve continence. Overall, initial clinical results are encouraging in the setting of intrinsic sphincter deficiency in women and in the men after radical prostatectomy. No clinical trials are available in the context of neurogenic incontinence. However, basic science and research in animal models suggest that the neurotrophic effects mediated by MPC injection may find application in neurogenic incontinence. The most appropriate procedure of cell preparation and transfer into the urethra remains to be determined.

Other promising sources of stem cells to treat urinary incontinence Bone marrow and adipose tissue contain mesenchymal stem cells that where investigated in several animal models of sphincter damage4,44–46,81–87 and clinical cases of patients treated with such cells have been reported.88,89 The rationale behind the use of mesenchymal stem cells for urinary incontinence resides in (1) their capacity to transdifferenciate into muscle cells, (2) their antiapoptotic effects, (3) the releasing of angiogenic and neurotrophic

growth factors, (4) their ability to recruit local stem cells to participate to the regeneration process, and (5) their ability to fuse with preexisting cells. Mesenchymal stem cells may be harvested from adipose tissue after enzymatic digestion or from bone marrow by simple centrifugation in a Ficoll gradient. Cell culture is required to select mesenchymal stem cells but protocols of cell injection avoiding this step are now available. In the absence of culture selection, the population of cells obtained is more heterogeneous and also contains endothelial progenitors or endothelial cells that may also have a therapeutic implication.

References 3605. Kiddoo DA, Carr MC, Dulczak S, Canning DA. Initial management of complex urological disorders: Bladder exstrophy. Urol Clin North Am 2004; 31: 417. 3606. Snodgrass WT, Adams R. Initial urologic management of myelomeningocele. Urol Clin North Am 2004; 31: 427. 3607. McDougal WS. Metabolic complications of urinary intestinal diversion. J Urol 1992; 147: 1199. 3608. Jack GS, Almeida FG, Zhang R et al. Processed lipoaspirate cells for tissue engineering of the lower urinary tract: Implications for the treatment of stress urinary incontinence and bladder reconstruction. J Urol 2005; 174: 2041. 3609. Zhang Y, Kropp BP, Moore P et al. Coculture of bladder urothelial and smooth muscle cells on small intestinal submucosa: Potential applications for tissue engineering technology. J Urol 2000; 164: 928. 3610. Zhang Y, Kropp BP, Lin HK, Cowan R, Cheng EY. Bladder regeneration with cell-seeded small intestinal submucosa. Tissue Eng 2004; 10: 181. 3611. Yoo JJ, Meng J, Oberpenning F, Atala A. Bladder augmentation using allogenic bladder submucosa seeded with cells. Urology 1998; 51: 221. 3612. Vaught JD, Kropp BP, Sawyer BD et  al. Detrusor regeneration in the rat using porcine small intestinal submucosal grafts: Functional innervation and receptor expression. J Urol 1996; 155: 374. 3613. Schultheiss D, Gabouev AI, Cebotari S et al. Biological vascularized matrix for bladder tissue engineering: Matrix preparation, reseeding technique and short-term implantation in a porcine model. J Urol 2005; 173: 276. 3614. Kropp BP, Rippy MK, Badylak SF et al. Regenerative urinary bladder augmentation using small intestinal submucosa: Urodynamic and histopathologic assessment in long-term canine bladder augmentations. J Urol 1996; 155: 2098. 3615. Kropp BP, Cheng EY, Lin HK, Zhang Y. Reliable and reproducible bladder regeneration using unseeded distal small intestinal submucosa. J Urol 2004; 172: 1710. 3616. Atala A, Bauer SB, Soker S, Yoo JJ, Retik AB. Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet 2006; 367: 1241. 3617. Badylak SF, Kropp B, McPherson T, Liang H, Snyder PW. Small intestinal submucosa: A rapidly resorbed bioscaffold for augmentation cystoplasty in a dog model. Tissue Eng 1998; 4: 379. 3618. de Boer WI, Rebel JM, Vermey M, de Jong AA, van der Kwast TH. Characterization of distinct functions for growth factors in murine transitional epithelial cells in primary organotypic culture. Exp Cell Res 1994; 214: 510. 3619. Oberpenning F, Meng J, Yoo JJ, Atala A. De novo reconstitution of a functional mammalian urinary bladder by tissue engineering. Nat Biotechnol 1999; 17: 149. 3620. Lin HK, Cowan R, Moore P et al. Characterization of neuropathic bladder smooth muscle cells in culture. J Urol 2004; 171: 1348.

Tissue engineering and cell therapies for neurogenic bladder augmentation 3621. Dozmorov MG, Kropp BP, Hurst RE, Cheng EY, Lin HK. Differentially expressed gene networks in cultured smooth muscle cells from normal and neuropathic bladder. J Smooth Muscle Res 2007; 43: 55. 3622. Montarras D, Morgan J, Collins C et al. Direct isolation of satellite cells for skeletal muscle regeneration. Science 2005; 309: 2064. 3623. Beauchamp JR, Morgan JE, Pagel CN, Patridge TA. Dynamics of myoblast transplantation reveal a discrete minority of precursors with stem cell-like properties as the myogenic source. J Cell Biol 1999; 144: 1113. 3624. Collins CA, Olsen I, Zammit PS et al. Stem cell function, self-renewal, and behavioral heterogeneity of cells from the adult muscle satellite cell niche. Cell 2005; 122: 289. 3625. Fan Y, Beilharz MW, Grounds MD. A potential alternative strategy for myoblast transfer therapy: The use of sliced muscle grafts. Cell Transplant 1996; 5: 421. 3626. Fan Y, Maley M, Beilharz M, Grounds M. Rapid death of injected myoblasts in myoblast transfer therapy. Muscle Nerve 1996; 19: 853. 3627. Smythe GM, Grounds MD. Exposure to tissue culture conditions can adversely affect myoblast behavior in vivo in whole muscle grafts: Implications for myoblast transfer therapy. Cell Transplant 2000; 9: 379. 3628. Smythe GM, Hodgetts SI, Grounds MD. Problems and solutions in myoblast transfer therapy. J Cell Mol Med 2001; 5: 33. 3629. Bartsch G, Yoo JJ, De Coppi P et  al. Propagation, expansion, and multilineage differentiation of human somatic stem cells from dermal progenitors. Stem Cells Dev 2005; 14: 337. 3630. De Coppi P, Bartsch G Jr, Siddiqui MM et  al. Isolation of amniotic stem cell lines with potential for therapy. Nat Biotechnol 2007; 25: 100. 3631. Walles T, Herden T, Haverich A, Mertsching H. Influence of scaffold thickness and scaffold composition on bioartificial graft survival. Biomaterials 2003; 24: 1233. 3632. Nomi M, Atala A, Coppi PD, Soker S. Principals of neovascularization for tissue engineering. Mol Aspects Med 2002; 23: 463. 3633. Shea LD, Smiley E, Bonadio J, Mooney DJ. DNA delivery from polymer matrices for tissue engineering. Nat Biotechnol 1999; 17: 551. 3634. Kinnaird T, Stabile E, Epstein SE, Fuchs S. Current perspectives in therapeutic myocardial angiogenesis. J Interv Cardiol 2003; 16: 289. 3635. Haab F, Zimmern PE, Leach GE. Female stress urinary incontinence due to intrinsic sphincteric deficiency: Recognition and management. J Urol 1996; 156: 3. 3636. Thuroff JW, Abrams P, Andersson KE et al. [EAU guidelines on urinary incontinence]. Actas Urol Esp 2011; 35: 373. 3637. Mottet N, Boyer C, Chartier-Kastler E et  al. Artificial urinary sphincter AMS 800 for urinary incontinence after radical prostatectomy: The French experience. Urol Int 1998; 60(Suppl 2): 25. 3638. Costa P, Poinas G, Ben Naoum K et al. Long-term results of artificial urinary sphincter for women with type III stress urinary incontinence. Eur Urol 2013; 63: 753. 3639. Abrams P, Andersson KE, Birder L et al. Fourth international consultation on incontinence recommendations of the international scientific committee: Evaluation and treatment of urinary incontinence, pelvic organ prolapse, and fecal incontinence. Neurourol Urodyn 2010; 29: 213. 3640. Hubner WA, Gallistl H, Rutkowski M, Huber ER. Adjustable bulbourethral male sling: Experience after 101 cases of moderate-tosevere male stress urinary incontinence. BJU Int 2011; 107: 777. 3641. Hubner WA, Schlarp OM. Treatment of incontinence after prostatectomy using a new minimally invasive device: Adjustable continence therapy. BJU Int 2005; 96: 587. 3642. Kjaer L, Fode M, Norgaard N, Sonksen J, Nordling J. Adjustable continence balloons: Clinical results of a new minimally invasive treatment for male urinary incontinence. Scand J Urol Nephrol 2012; 46: 196. 3643. Lebret T, Cour F, Benchetrit J et al. Treatment of postprostatectomy stress urinary incontinence using a minimally invasive adjustable continence balloon device, ProACT: Results of a preliminary, multicenter, pilot study. Urology 2008; 71: 256.

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3644. Keegan PE, Atiemo K, Cody J, McClinton S, Pickard R. Periurethral injection therapy for urinary incontinence in women. Cochrane Database Syst Rev 2007; CD003881. 3645. Haab F, Zimmern PE, Leach GE. Urinary stress incontinence due to intrinsic sphincteric deficiency: Experience with fat and collagen periurethral injections. J Urol 1997; 157: 1283. 3646. Wilson TS, Lemack GE, Zimmern PE. Management of intrinsic sphincteric deficiency in women. J Urol 2003; 169: 1662. 3647. Adamiak A, Rechberger T. [Potential application of stem cells in urogynecology]. Endokrynol Pol 2005; 56: 994. 3648. Stangel-Wojcikiewicz K, Majka M, Basta A et  al. Adult stem cells therapy for urine incontinence in women. Ginekol Pol 2010; 81: 378. 3649. Smaldone MC, Chen ML, Chancellor MB. Stem cell therapy for urethral sphincter regeneration. Minerva Urol Nefrol 2009; 61: 27. 3650. Zhao W, Zhang C, Jin C et al. Periurethral injection of autologous adipose-derived stem cells with controlled-release nerve growth factor for the treatment of stress urinary incontinence in a rat model. Eur Urol 2011; 59: 155. 3651. Cannon TW, Lee JY, Somogyi G et al. Improved sphincter contractility after allogenic muscle-derived progenitor cell injection into the denervated rat urethra. Urology 2003; 62: 958. 3652. Strasser H, Marksteiner R, Margreiter E et al. [Stem cell therapy for urinary incontinence]. Urologe A 2004; 43: 1237. 3653. Yiou R, Yoo JJ, Atala A. Restoration of functional motor units in a rat model of sphincter injury by muscle precursor cell autografts. Transplantation 2003; 76: 1053. 3654. Peyromaure M, Sebe P, Praud C et  al. Fate of implanted syngenic muscle precursor cells in striated urethral sphincter of female rats: Perspectives for treatment of urinary incontinence. Urology 2004; 64: 1037. 3655. Sebe P, Doucet C, Cornu JN et  al. Intrasphincteric injections of autologous muscular cells in women with refractory stress ­urinary incontinence: A prospective study. Int Urogynecol J 2011; 22: 183. 3656. Cornu JN, Doucet C, Sebe P et al. [Prospective evaluation of intrasphincteric injections of autologous muscular cells in patients with stress urinary incontinence following radical prostatectomy]. Prog Urol 2011; 21: 859. 3657. Strasser H, Marksteiner R, Margreiter E et al. Autologous myoblasts and fibroblasts versus collagen for treatment of stress urinary incontinence in women: A randomised controlled trial. Lancet 2007; 369: 2179. 3658. Gerullis H, Eimer C, Georgas E et al. Muscle-derived cells for treatment of iatrogenic sphincter damage and urinary incontinence in men. ScientificWorldJournal 2012; 2012: 898535. 3659. Carr LK, Steele D, Steele S et  al. 1-year follow-up of autologous muscle-derived stem cell injection pilot study to treat stress urinary incontinence. Int Urogynecol J Pelvic Floor Dysfunct 2008; 19: 881. 3660. Yiou R, Hogrel JY, Loche CM et al. Periurethral skeletal myofibre implantation in patients with urinary incontinence and intrinsic sphincter deficiency: A phase I clinical trial. BJU Int 2013; 111: 1105. 3661. Zammit PS, Heslop L, Hudon V et al. Kinetics of myoblast proliferation show that resident satellite cells are competent to fully regenerate skeletal muscle fibers. Exp Cell Res 2002; 281: 39. 3662. Beauchamp JR, Heslop L, Yu DS et al. Expression of CD34 and Myf5 defines the majority of quiescent adult skeletal muscle satellite cells. J Cell Biol 2000; 151: 1221. 3663. Gussoni E, Soneoka Y, Strickland CD et al. Dystrophin expression in the mdx mouse restored by stem cell transplantation. Nature 1999; 401: 390. 3664. Qu-Petersen Z, Deasy B, Jankowski R et al. Identification of a novel population of muscle stem cells in mice: Potential for muscle regeneration. J Cell Biol 2002; 157: 851. 3665. Tavian M, Zheng B, Oberlin E et al. The vascular wall as a source of stem cells. Ann N Y Acad Sci 2005; 1044: 41.

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3666. Dreyfus PA, Chretien F, Chazaud B et al. Adult bone marrow-derived stem cells in muscle connective tissue and satellite cell niches. Am J Pathol 2004; 164: 773. 3667. Partridge TA, Morgan JE, Coulton GR, Hoffman EP, Kunkel LM. Conversion of mdx myofibres from dystrophin-negative to -positive by injection of normal myoblasts. Nature 1989; 337: 176. 3668. Mendell JR, Kissel JT, Amato AA et  al. Myoblast transfer in the treatment of Duchenne’s muscular dystrophy. N Engl J Med 1995; 333: 832. 3669. Menasche P, Hagege AA, Scorsin M et al. Myoblast transplantation for heart failure. Lancet 2001; 357: 279. 3670. Tremblay JP, Malouin F, Roy R et al. Results of a triple blind clinical study of myoblast transplantations without immunosuppressive treatment in young boys with Duchenne muscular dystrophy. Cell Transplant 1993; 2: 99. 3671. Urish K, Kanda Y, Huard J. Initial failure in myoblast transplantation therapy has led the way toward the isolation of muscle stem cells: Potential for tissue regeneration. Curr Top Dev Biol 2005; 68: 263. 3672. Qu Z, Balkir L, van Deutekom JC et al. Development of approaches to improve cell survival in myoblast transfer therapy. J Cell Biol 1998; 142: 1257. 3673. Hale DS, Benson JT, Brubaker L, Heidkamp MC, Russell B. Histologic analysis of needle biopsy of urethral sphincter from women with normal and stress incontinence with comparison of electromyographic findings. Am J Obstet Gynecol 1999; 180: 342. 3674. van Mier P, Lichtman JW. Regenerating muscle fibers induce directional sprouting from nearby nerve terminals: Studies in living mice. J Neurosci 1994; 14: 5672. 3675. English AW. Cytokines, growth factors and sprouting at the neuromuscular junction. J Neurocytol 2003; 32: 943. 3676. Lecoeur C, Swieb S, Zini L et  al. Intraurethral transfer of satellite cells by myofiber implants results in the formation of innervated myotubes exerting tonic contractions. J Urol 2007; 178: 332. 3677. Gosling JA, Dixon JS, Critchley HO, Thomson SA. A comparative study of the human external sphincter and periurethral levator ani muscles. Br J Urol 1981; 53: 35. 3678. Yiou R, Delmas V, Carmeliet P et  al. The pathophysiology of pelvic floor disorders: Evidence from a histomorphologic study of the perineum and a mouse model of rectal prolapse. J Anat 2001; 199: 599. 3679. Badra S, Andersson KE, Dean A, Mourad S, Williams JK. Long-term structural and functional effects of autologous muscle precursor cell therapy in a nonhuman primate model of urinary sphincter deficiency. J Urol 2013; 190: 1938.

3680. Eberli D, Aboushwareb T, Soker S, Yoo JJ, Atala A. Muscle precursor cells for the restoration of irreversibly damaged sphincter function. Cell Transplant 2012; 21: 2089. 3681. Zini L, Lecoeur C, Swieb S et al. The striated urethral sphincter of the pig shows morphological and functional characteristics essential for the evaluation of treatments for sphincter insufficiency. J Urol 2006; 176: 2729. 3682. Bacou F, Rouanet P, Barjot C et al. Expression of myosin isoforms in denervated, cross-reinnervated, and electrically stimulated rabbit muscles. Eur J Biochem 1996; 236: 539. 3683. Mitterberger M, Pinggera GM, Marksteiner R et al. Functional and histological changes after myoblast injections in the porcine rhabdosphincter. Eur Urol 2007; 52: 1736. 3684. Morgan DM, Umek W, Guire K et al. Urethral sphincter morphology and function with and without stress incontinence. J Urol 2009; 182: 203. 3685. Zou XH, Zhi YL, Chen X et  al. Mesenchymal stem cell seeded knitted silk sling for the treatment of stress urinary incontinence. Biomaterials 2010; 31: 4872. 3686. Smaldone MC, Chancellor MB. Muscle derived stem cell therapy for stress urinary incontinence. World J Urol 2008; 26: 327. 3687. Lin CS, Lue TF. Stem cell therapy for stress urinary incontinence: A critical review. Stem Cells Dev 2012; 21: 834. 3688. Kinebuchi Y, Aizawa N, Imamura T et al. Autologous bone-marrowderived mesenchymal stem cell transplantation into injured rat urethral sphincter. Int J Urol 2010; 17: 359. 3689. Furuta A, Jankowski RJ, Pruchnic R, Yoshimura N, Chancellor MB. The promise of stem cell therapy to restore urethral sphincter function. Curr Urol Rep 2007; 8: 373. 3690. Furuta A, Carr LK, Yoshimura N, Chancellor MB. Advances in the understanding of sress urinary incontinence and the promise of stem-cell therapy. Rev Urol 2007; 9: 106. 3691. Corcos J, Loutochin O, Campeau L et al. Bone marrow mesenchymal stromal cell therapy for external urethral sphincter restoration in a rat model of stress urinary incontinence. Neurourol Urodyn 2011; 30: 447. 3692. Yamamoto T, Gotoh M, Kato M et al. Periurethral injection of autologous adipose-derived regenerative cells for the treatment of male stress urinary incontinence: Report of three initial cases. Int J Urol 2012; 19: 652. 3693. Gotoh M, Yamamoto T, Kato M et al. Regenerative treatment of male stress urinary incontinence by periurethral injection of autologous adipose-derived regenerative cells: 1-year outcomes in 11 patients. Int J Urol 2014; 21: 294.

53 Restoration of complete bladder function by neurostimulation Michael Craggs and Sarah Knight

Introduction During the past 30 years, two key developments using implantable neuroprostheses have had a significant impact on treating and managing patients with a neurogenic bladder. The first of these was the Brindley sacral anterior root stimulator,1 used principally for bladder ­emptying. The second was the sacral nerve stimulator developed by Tanagho2 and Schmidt3 for neuromodulating  a variety of bladder dysfunctions, including the ­overactive bladder and urinary retention. It is timely to consider how these two techniques, among others, may in the future  be c­ ombined using emerging technologies to restore more complete control of the dysfunctional ­bladder  in people with a suprasacral spinal cord injury (SCI). In a­ddition, new developments and technologies may help overcome some of the obstacles encountered when using the ­presently available devices in this patient population. Suprasacral lesions to the spinal cord nearly always lead to serious disruption of lower urinary tract function: development of aberrant bladder and sphincter reflexes, loss of voluntary control of bladder and sphincter, and lack of s­ensation of bladder fullness.4 As a consequence, bladder emptying is impaired and reflex incontinence can occur. Reflex incontinence is primarily caused by neurogenic detrusor overactivity (NDO), an aberrant reflex that emerges after a period of spinal shock ­following SCI (Figure 53.1). It is often associated with dyssynergic contractions of the striated sphincter muscle of the urethra, preventing efficient emptying of the bladder and potentially causing dangerously high pressures which can impair renal function. Inefficient emptying and high detrusor pressures can lead to increased urinary tract infections and subsequent renal failure if not correctly managed. Medical treatment is usually by a combination of drugs for suppressing NDO and intermittent catheterization for

emptying the bladder. However, the antimuscarinic drugs used to treat incontinence often have debilitating side effects such as constipation, dry mouth, and visual disturbance. More recently, intradetrusor botulinum toxin injections have proven to be popular; however, the longterm effects of repeated injections are still unknown, and some patients have experienced temporary systemic weakness, which leaves them unwilling to repeat injections. Emptying the bladder can also be very troublesome, especially in women for whom no reliable collection devices exist (other than indwelling catheters and bags or ungainly pads). Intermittent and indwelling catheters can both introduce bladder infections, with the latter also precipitating stone formation. Other more radical approaches such as surgery for augmenting the bladder, sphincterotomies, cutting the sacral roots to suppress NDO may all have irreversible destructive effects that could preclude the use of future developments, including more novel implantable neurostimulating devices. This chapter briefly reviews some of the future possibilities for combining existing and emerging science and technologies to develop an implantable neuroprosthesis capable of restoring complete control of the bladder and sphincters in SCI.5,6 The following areas of development will be addressed: •• •• •• •• ••

Sacral anterior root stimulation (SARS) for emptying the paralyzed bladder Sacral nerve stimulation for suppressing NDO Conditional neuromodulation for automatic control of reflex incontinence The extradural sacral posterior and anterior root stimulator implant (SPARSI) Differential motor and sensory stimulation of sacral roots through a new sacral posterior and anterior intrathecal root stimulator implant (SPAIRS)

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+ + Detrusor hyperreflexia

Detrusor pressure

Pelvic nerves

Pudendal nerves

Urine flow Intraurethral pressure Sphincter EMG

Sphincter dyssynergia

(a)

•• •• ••

(b)

Selective stimulation of sacral roots to prevent d ­ etrusor– sphincter dyssynergia, high-frequency ­blockade, and stimulation of pudendal nerves for bladder excitation Laparoscopic approach to implantation Prospects for complete restoration of bladder control by neuroprosthesis

Sacral anterior root stimulation for emptying the paralyzed bladder In the 1970s, Brindley7 developed an implantable device to empty the bladder and control the sphincters. The prosthesis uses SARS (Finetech–Brindley SARS; Finetech Medical Limited, Welwyn Garden City, United Kingdom) to activate bladder motor pathways and to produce clinically effective voiding (Figure 53.2). For reflex incontinence and sphincter dyssynergia to be overcome in these patients, the sacral sensory nerve roots from S2 to S4 have to be cut (sacral deafferentation or posterior rhizotomy).8 The device  consists of electrodes, which can be placed intrathecally or extradurally (the deafferentation is usually ­performed intradurally as it is easier to separate the nerves at this level). Cables are tunneled subcutaneously to a receiver block, which is placed on the chest wall. The device is ­activated through radio frequency coupling using a transmitter block aligned over the receiver. An external control box is programmed by the clinician to activate the efferent pathways to the bladder. As the sacral anterior roots S2–S4 innervate both the bladder and sphincters, an implant-induced dyssynergia is produced. This is overcome by using the differential properties of smooth and striated muscles of the bladder and sphincters. By using short bursts of stimulation, poststimulus voiding occurs in gaps between stimulation, although not physiological this gives extremely efficient voiding with low residuals. The sacral anterior root stimulator can also be used to aid bowel evacuation and produce implant-driven erections

(c)

The neurogenic bladder in suprasacral spinal cord injury. (a) Aberrant pelvic reflexes causing neuro­ genic detrusor overactivity and ­detrusor–sphincter ­dyssynergia. (b) Traces show­ ing the high bladder pres­ sure generated, dyssynergia of the sphincter, associated electromyography (EMG), and urine leakage during video­ urodynamics. (c) X-ray image shows the bladder and sphinc­ ter at the exact time of the dyssynergia.

in males. The same nerves that innervate the bladder also innervate the lower part of the colon and the rectum. This stimulation can facilitate movement of stool into the rectum as well as evacuating the rectum in approximately 50% of patients. Even if some degree of manual evacuation is still required, the whole process of bowel emptying has been shown to be decreased to a significant degree by the use of the stimulator. The Finetech–Brindley device has been used success­ fully in many countries throughout the world.9 The implant, when combined with sacral deafferentation, has been shown to be very effective in increasing bladder volume, promoting complete bladder emptying and reducing infection and significantly improving the quality of life for many patients10 (Figure 53.3). However, no implant can be designed to be completely guaranteed against technical failure. The body is a hostile environment to implanted materials, and patients do not always comply with recommendations of how best to protect an implant. The Finetech–Brindley SARS is extremely well tolerated in the body and has an exceptional life ­expectancy. Indeed, some patients are still successfully using a device which was implanted over 30 years ago. Technical failures will undoubtedly occur and ­therefore implants must be designed to enable repair to ensure patients continue to receive benefit. Brindley11 reported on the technical failures of his first 500 implants and found a mean time to failure of 19.6 years which is exceptionally good in terms of implanted devices. The main failures were of cables, receiver blocks, and at the region where the cables enter the intrathecal space. Cable failures are relatively easy to repair as are receiver blocks. The difficulties arise when cable failures occur very close to electrodes. In the case of an intrathecal implant failing near the electrodes, it is possible to replace the device with an extradural implant, especially if a sacral deafferentation has already been performed. If the failure appears to be at the extradural electrode site but not in the appropriate nerves, then it may be possible to access these intact

S2–S5 Sacral posterior roots cut bilaterally

1

Pdet Bladder pressure

2

585

Pura Sphincter pressure

Restoration of complete bladder function by neurostimulation

Electrical stimulation of the S2–S4 sacral anterior roots

Q Flow rate

Bladder

Sphincter muscles

3

(a)

Stimulation 25 pps, 200 µs pulse width, 5 seconds on 6 seconds off

(b)

(c)

Figure 53.2 Sacral anterior root stimulation (SARS) with sacral deafferentation for bladder control. (a) The Finetech–Brindley SARS implantable stimulator uses bilaterally placed intrathecal or extradural electrodes on the S2–S4 sacral roots to activate the preganglionic para­ sympathetic pathway to produce efficient bladder emptying. A rhizotomy of the corresponding posterior roots (sensory) prevents neurogenic detrusor overactivity, dyssynergia of the sphincter, and incontinence. (b) Anatomic configuration of the Finetech–Brindley implant: (1) electrodes, (2) transmitter and receiver coil, and (3) external control box. (c) Bursts of stimulation activate simultaneously the striated sphincter muscle and the detrusor smooth muscle. During the intervals between the bursts, the sphincter relaxes rapidly to leave a low urethral resistance while the detrusor is still contracting slowly to a higher pressure so as to enable very efficient voiding. 100 90

% Voiding efficiency

80

Figure 53.3

70 60 50 40 30 20 10 0

1

2

3

4

5

6

7

8

9

No. of patients Before implant

After implant

nerves from the anterior side of the sacrum as they exit through the foramina using a recently described laparoscopic technique.12–14 Possover described a laparoscopic technique to access the pelvic autonomic plexus via a transperitoneal approach This technique has been used successfully in patients who have already undergone a sacral deafferentation but require a revision to the existing intrathecal or extradural electrodes to regain use of a Finetech–Brindley bladder stimulator. The laparoscopic approach enables new extradural electrodes to be placed on the mixed nerve roots in the pelvic plexus without having to revisit the original surgical site which may be difficult due to scarring.

10

11

12

13

Data graphed from information in Cardozo et al. to show the significant benefit of using a Brindley SARS implant to improve voiding efficiency in a group of 13 patients. Voiding efficiency (%) = Vv/(Vv + Vr) x 100 (where Vv = voided volume and Vr = residual bladder volume). Reflex voiding before implantation gave an efficiency of 31% (±32) across this group of patients, whereas with their SARS the efficiency was greater than 96% (±4) giving a very signifi­ cant improvement (p < .001). (Adapted from Cardozo L, Krishnan KR, Polkey CE et al. Paraplegia 1984; 22: 201–209.)

Although the Finetech–Brindley has excellent longevity and outcomes in terms of bladder and bowel management, the need for sacral deafferentation, with the consequent loss of reflex erections, reflex ejaculation, bowel problems, and potential pelvic floor weakness, can deter many very suitable young male patients from accepting the device. Furthermore, the hope by some patients of a “cure” for SCI in the near future using neural regeneration and repair techniques is a further obstacle to acceptance. Patients who have already suffered accidental damage to their spinal cord are understandably reluctant to accept deliberate cutting of their sacral afferent roots. Realistically, a cure for restoring autonomic functions controlling bladder and

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bowel may take many years to perfect; meanwhile, management has to try to give the patient the best quality of life while maintaining organ viability. With good medical management of the neurogenic bladder in SCI, most patients can now expect a near normal life span and SARS can definitely help many patients, but clearly it would be much more acceptable if it did not involve further destruction of potentially useful reflexes. There may be an alternative solution to sacral deafferentation, which involves stimulation of these afferent pathways rather than cutting them to suppress reflex incontinence.

Sacral nerve stimulation for suppressing neurogenic detrusor overactivity During the 1980s Tanagho and Schmidt15 developed the use of electrical stimulation of sacral nerves to treat a variety of lower urinary tract problems, including those of the neurogenic bladder. Subsequently, a neuroprosthesis was developed (Interstim, Medtronic Inc, Minneapolis, MN) which comprised an implanted pulse generator attached to a multipole electrode surgically inserted into the S3 sacral foramina for stimulating the mixed sacral nerves.16 Such stimulation, commonly known as neuromodulation, has also been successfully used to increase bladder capacity in patients with SCI.17 Studies using noninvasive multipulse magnetic stimulation over the sacrum to stimulate the mixed extradural sacral roots (S2–S4) have demonstrated that the increase in bladder capacity is brought about by suppression of NDO in patients with SCI.118 The mechanism of this “neuromodulatory” action has yet to be determined in man, but one theory based on experimental work in animals19 suggests that neuromodulation involves inhibitory action by pudendal afferent (sensory) nerve stimulation on pelvic nerve motor pathways to the bladder through spinal cord circuits.20 Pudendal afferents course through S2–S4 posterior (sensory) roots to the spinal cord. Evidence in support of this theory was obtained by electrically stimulating purely afferent pathways at the level of the dorsal penile21,22 (or dorsal clitoral) nerves in patients. Dorsal penile nerve (DPN) stimulation through surface electrode in patients with SCI produces a profound and repeatable suppression of provoked NDO when applied either continuously (preemptively) or conditionally (i.e., when bladder pressure just begins to increase) (Figure 53.4).23,24 Furthermore, in addition to suppressing NDO, DPN stimulation can produce significant increases in bladder volume, as demonstrated in serial cystometrograms.25 These effects depend essentially on stimulation and diminish when stimulation is switched off. Interestingly, intermittent stimulation also appears to produce good results, although the ideal interval between bursts has yet to be determined, balancing the

need to suppress every NDO contraction reliably against preserving the battery life of the stimulator.26 In a pilot study, the same benefit has been shown using a Finetech– Brindley implantable device to stimulate extradural or intradural sacral roots but without deafferentation.27 In a small group of patients with a suprasacral SCI, electrodes were placed bilaterally on either mixed extradural (S2– S4) sacral roots or separated anterior and posterior sacral nerve roots (S3) intrathecally. Each patient was assessed preoperatively with DPN stimulation, as described above, to demonstrate the efficacy of neuromodulation. Preliminary results indicated that patients were able to achieve both good suppression of NDO and clinically useful increases in bladder volume (Figure 53.5).

Conditional neuromodulation for automatic control of reflex incontinence In the implant studies described above, it was also demonstrated that conditional stimulation, applied only at the onset of NDO, was at least as good as continuous stimulation in increasing bladder capacity and was sometimes better. Bladder contractions were sensed by measuring intravesical pressure with a standard catheter and the pudendal afferents stimulated either at the level of the DPN or sacral roots to inhibit bladder contractions (Figure 53.6).25,27 Interestingly, a similar approach has recently been used to suppress NDO in patients with multiple sclerosis.28 A conditional system that detects the onset of NDO contractions and then suppresses them has a number of theoretical advantages. Although continuous neuromodulation is an effective and simple way to increase bladder capacity in people with SCI, in many situations it may not be ideal, not least because of the effects of reflex habituation. Furthermore, the need for constant current delivery could shorten both battery and electrode life in a completely implanted system, and continuous stimulation of the sacral afferents may have undesirable long-term reflex effects on the anal and urethral sphincter, perhaps exacerbating any residual dyssynergia. Hence, a device that could stimulate the sacral nerves for neuromodulation only when necessary might have considerable benefits and would have the added advantage that it could provide feedback about bladder fullness to the patient. That is, stimulation pulses associated with the conditional neuromodulation could also be applied to sensate parts of the body to warn of NDO contractions at maximum bladder capacity. What sort of reliable detection system for conditional neuromodulation could be incorporated into an implant? Brindley was the first to suggest that it might be possible to monitor bladder pressure by implant and use the

Restoration of complete bladder function by neurostimulation

Bladder pressure cmH2O

140

587

Continuous stimulation

0

Bladder pressure cmH2O

140 Conditional stimulation

0

(b)

200 Mean % change bladder capacity

Electrical stimulation of pudendal afferent pathways at the dorsal penile nerves

100

0 (a)

Neuromodulation

Serial cystometrograms (c)

Figure 53.4 Controlling neurogenic detrusor overactivity by noninvasive neuromodulation through pudendal afferent pathways. (a) By stimulat­ ing the dorsal penile (or clitoral) nerves with electrical impulses between 10 and 20 per second and above twice the threshold for the pudendal anal reflex, it is possible to profoundly suppress neurogenic detrusor overactivity. (b) The upper trace shows the effect of continuous stimulation of the dorsal penile nerves on the bladder pressure rise associated with a neurogenic detrusor overactive contraction provoked at the middle arrow. Control contractions provoked at the other arrows can be seen before and after the stimula­ tion. The lower trace shows the effect of applying neuromodulation conditionally (that is only when the overactivity just appears) in response to provocation at the middle arrow. Again, this response is flanked by control provocations. (c) Repeated cystometrograms with continuous neuromodulation (shaded area), demonstrating significant increases in bladder volume when compared to control fills. Following stimulation, the bladder takes some time to restore to its smaller capacity, probably as a result of stretching the bladder wall during the period of neuromodulation.

information to control electrical stimulation of the pudendal nerves to inhibit NDO contractions. Subsequently, an implanted applanation tonometer was developed which could be sutured onto the bladder wall to record pressure. However, tests to assess its long-term performance in experimental animals were not very successful, as the device eroded or became dislodged from the bladder.29 Further obstacles, such as infection and encrustation, preclude the immediate development and implementation of such vesicle devices. Recently it has been shown in experimental animals that it is possible to detect very small electroneurographic signals at fractional microvolt levels, using sophisticated recording techniques, from the afferents in the mixed

sacral nerve roots during NDO-like bladder contractions.30 The recorded signals could then be used to trigger stimulation of the pudendal or sacral posterior nerves to inhibit conditionally in a closed loop feedback system (Figure 53.7). Some preliminary work in patients with SCI during implantation of sacral anterior root stimulators indicated that detecting bladder contractions from the sacral sensory nerves may also be possible.31–33 However, although an implanted conditional neuromodulation device may be feasible in people with SCI, it is likely to be considerably more complex than present devices tried in animals and will have to be very reliable. Implantable microcircuits for detecting minute neural signals in humans which could

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Electrical stimulation of pudendal afferent pathways at the sacral posterior roots

Bladder pressure cm H2O

100 EFV = 110 mL 0 Leak 100 End fill volume (EFV) = 380 mL

0

Leak

Continuous stimulation

750

750

500

500

250

250

0 (a)

Bladder capacity (mL) with neuromodulation

Bladder capacity (mL) control no neuromodulation

(b)

0 (c)

Figure 53.5 Controlling neurogenic detrusor overactivity and increasing bladder capacity by neuromodulation through sacral posterior root stimulation. (a) A Finetech–Brindley implanted stimulator (without sacral deafferentation) is used to apply neuromodulation bilat­ erally through the S3–S4 sacral roots using semipermanent coil fixed to the skin over the implanted receiver (inset photograph). (b) Continuous stimulation at about 15 pulses per second (240 µs pulse width) with a current level set to suppress neurogenic detrusor overactivity significantly increased bladder capacity over control tests (EFV = end fill volume). (c) The graph shows box and whisker results from a group of 11 patients with spinal cord injury tested using continuous neuromodulation through the dorsal penile nerves (DPN) compared with the effect of applying neuromodulation through the posterior roots in four patients (solid lines with symbols) from this same group with a sacral posterior and anterior root stimulator implant implant. It can be seen that bladder capacity is markedly increased with stimulation of the roots and compares favorably with the significant group result using DPN stimulation. DPN stimulation may be a good predictor for success with a sacral nerve stimulator.

be used to activate conditional neuromodulation are now being developed for this purpose.34 Whether NDO is to be controlled by automatic conditional stimulation or simply by continuous neuromodulation, the interesting possibility now exists for combining the benefits of bladder emptying with control of reflex incontinence in one implantable sacral roots stimulator.

The sacral posterior and anterior root stimulator This new concept was developed using a single implant (Finetech–Brindley) to combine bladder emptying through SARS with posterior sacral roots stimulation to abolish NDO contractions.35 If successful, the major advantage of SPARSI would be the restoration of b ­ ladder function w ­ ithout the need for sacral deafferentation. In

one  study, five patients with a suprasacral spinal injury were implanted with a standard bilateral extradural Finetech–Brindley device (Figure 53.8), but without sacral deafferentation, to test the concept of SPARSI. These patients were part of the neuromodulation study described above.27 A significant finding in this study, reported first in 2001,36 demonstrated that the benefits of neuromodulation by a SPARSI implant at home were comparable to the effects of oxybutynin in improving functional bladder capacity in the same patient (Figure 53.9). Furthermore, the improvement also compared favorably with the benefits of sacral deafferentation. Another interesting finding, which agrees with other studies of sacral neuromodulation for the overactive bladder (e.g., using the Medtronic Interstim), showed that the effects do not necessarily diminish appreciably with time, but that when stimulation is stopped symptoms such as incontinence return.

Restoration of complete bladder function by neurostimulation

Electrical stimulation of pudendal afferent pathways at the sacral posterior roots

100

EFV = 220 mL

cmH2O

Bladder pressure

+

0

Leak

Bladder Pressure

EFV = 400 mL

Bladder pressure rise detected by catheter at start of hyperreflexia used to activate stimulation conditionally

100 cmH2O

–

589

Leak 0 2 minutes

(b)

(a)

Figure 53.6 Using bladder pressure to automatically control neurogenic detrusor overactivity with conditional neuromodulation. (a) By measuring bladder pressure with a catheter it is possible to detect exactly when an overactive contraction begins and this can be used to activate stimulation of the sacral posterior roots to suppress the contraction automatically. The cystometrograms in this figure were obtained from a patient with an incomplete upper thoracic spinal lesion, but similar results have also been shown in patients with complete lesions. (b) The upper trace shows a cystometrogram without stimulation and a relatively low bladder capacity. The lower trace shows that when a pressure rise is detected, the applied stimulation immediately reduces the pressure, and by automatically repeating this suppression on successive contractions a much larger bladder capacity can be achieved. A point is reached at this new maximum capacity when suppression is no longer possible. EFV = end fill volume.

Hyperreflexialike bladder contractions recorded as neural activity in sacral roots

Signal processing, threshold detection and trigger circuitry

(a)

(b)

Electrical stimulation of sacral roots to suppress hyperreflexia (c)

Figure 53.7 Sacral nerve activity as feedback con­ trol for conditional neuromodulation. (a) A ­miniature electrical signal (15,000 IU of preformed vitamin A per day from food and supplements to the prevalence among the babies whose mothers consumed 5000 IU or less per day was 3.5. Cigarette smoking during pregnancy is a causative factor for the occurrence of cleft lip or cleft palate, congenital heart defects, decrease in birth weight, placental abruption, sudden infant death syndrome, and Down syndrome.32–35 Although none of these reports suggested a direct linkage between cigarette smoking and NTDs, women with MTHFR 677TT who smoked were identified to have significantly lower serum folate levels,36 and this indirectly suggests that smoking is detrimental to both the mother and her unborn child. Alcohol consumption during pregnancy is significantly  associated with low birth weight, cleft lip/palate, and fetal alcohol syndrome, but its relation to NTDs is yet uncertain.

Prevention of neural tube defects Prepregnancy counseling is of prime importance for women who had an affected pregnancy or have a family history of NTDs. Periconceptional consumption of folic acid supplementation is strongly recommended for the women.

623

Gene screening tests are not necessary before pregnancy Van der Put et  al.37 from the Netherlands analyzed the distribution of the C677T mutation in the MTHFR gene and showed in 1995 that an increased frequency of the homozygous genotype (TT) among mothers of a patient with SB is a risk factor for having a child with SB. If this were the case among Japanese women, it would be recommendable for all childbearing women to undergo genetic screening tests before a pregnancy. Recently, we clarified the association of C677T mutation of MTHFR and SB development in the Japanese population.38 Genotype distribution of C677T mutation was assessed in 115 mothers who gave birth to an affected infant, which were compared with that of 4517 control individuals.39 The prevalence of the homozygous genotype (TT) among SB mothers was not significantly different from that among the controls (odds ratio = 0.65; 95% CI = 0.31–1.25; p =.182) as shown in the first row of Table 55.2, suggesting that MTHFR 677TT genotype in Japanese women is not associated with SB development in newborns. It is of interest to note that the association between the groups have internationally been reported from 15 countries (Brazil, Canada, India, Indonesia, Ireland, Japan, Korea, Mexico, Poland, South Africa, Spain, the Netherlands, Turkey, United Kingdom, and the United States) and that we identified the similar outcome in 14 countries but not in the Netherlands. In conclusion, it is not necessary for Japanese women to undergo genetic screening C677T mutation of the MTHFR gene as a predictive marker for SB prior to pregnancy because the TT genotype is not a risk factor for having an affected infant.

Risk factors for spina bifida in Japanese women Various risk factors have been reported as described in the previous section. Since no studies have been attempted to identify risk factors for the occurrence of SB in infants born to Japanese women, we recently conducted a case– control study.40 A total of 360 case mothers who gave birth to SB-affected offspring and 2333 control mothers who gave birth to offspring without SB between 2001 to 2012 were subjects of our study. Information on the lifestyles, vitamin use, medical and family history, infertilities and diabetes mellitus, and anthropometric factors of the women and their offspring was collected and analyzed with multiple logistic regression models. Of 15 variables, 4 were significantly associated with an increased risk of having newborns afflicted with SB, namely no intake of folic acid supplements, SB patients being present in relatives, intakes of AEDs without taking folic acid, and birth weight of infants ≤500 g (Table 55.3). Surprisingly, the majority

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Table 55.2  Th  e prevalence of the C677T mutation in the MTHFR gene among spina bifida mothers and control mothers, which was reported from 15 countries. Actual data of five countries are shown here Genotype, n (%) Countries (authors year)

p-value

Subjects (n)

CC

CT

TT

SB mothers (115)

47 (40.9%)

56 (48.7%)

12 (10.4%)

Controls (4517)

1763 (39%)

2060 (45.6%)

694 (15.4%)

SB mothers (131)

67 (51.1%)

55 (42%)

9 (6.9%)

Control mothers (126)

70 (55.6%)

54(42.9%)

2 (1.6%)

The Netherlands (Van der Put et al. 1995)

SB mothers (70) Controls (207)

32 (46%) 111 (54%)

27 39%) 86 (42%)

11 (16%) 10 (5%)

United Kingdom (Papapetrou et al. 1996)

SB mothers (36)

16 (44.5%)

15 (41.7%)

5 (13.9%)

Controls (199)

81 (40.7%)

94 (47.2%)

24 (12.1%)

United States (Speer et al. 1997)

SB mothers (65)

25 (38.5%)

31 (47.7%)

9 (13.8%)

Control mothers (65)

30 (46.2%)

29 (44.6%)

6 (9.2%)

Japan (present study) Brazil (Perez et al. 2003)

0.347 0.109 0.012 0.571 0.571

MTHFR, 5, 10-Methylenetetrahydrofolate reductase.

Table 55.3  F  our risk factors of 15 variables were significantly associated with the occurrence of spina bifida among Japanese women: A case–control study Multiple regression analysis (stepwise method)

Cases

Controls

(n = 360)

(n = 2333)

35

538

No intakes of FA supplements

325

1795

No SB patients in relatives

356

2326

4

7

Intakes of FA supplements

SB patients in relatives Intake of no AED or AED with FA Intakes of AED without FA

356

Crude OR

1

Birth weight >2500 g

265

2140

Birth weight ≤2500 g

95

193

p-value

95% CI

OR

Referent 2.78

3.73

100 cmH2O).

has been implicated in the pathogenesis of the prostatitis syndrome. On videourodynamic studies, many patients with prostatitis show incomplete funneling of the bladder neck as well as vesicourethral dyssynergic patterns. This high-pressure, dysfunctional voiding may increase intraprostatic ductal reflux in susceptible individuals (Figures 62.4 and 62.5). Alternatively, this dyssynergic voiding may lead to an autonomic overstimulation of the perineal–pelvic neural system with subsequent development of a chronic neuropathic pain state.24 The most common cause of prostatitis is the Enterobacteriaceae family of gram-negative bacteria, commonly strains of Escherichia coli, identified in 65% to 80% infections. Pseudomonas aeruginosa, Serratia species, Klebsiella species, and Enterobacter aerogenes are identified in a further 10% to 15%.25 Bacterial prostatitis in NBD is generally chronic and asymptomatic. The most important clue in the diagnosis is a history of documented recurrent UTIs. Between 25% and 43% patients diagnosed with chronic bacterial prostatitis were reported to have had a history of recurrent UTIs.26 Urinalysis is usually free of pus cells. Segmented lower urinary tract cultures should be done to localize the infection in the prostate.27 Treatment is composed mainly of antibiotics that have good diffusion power into the prostatic tissues, such as trimethoprim and fluoroquinolones. Other agents such as alpha-blockers and anti-inflammatory drugs may also be used.1

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Figure 62.5 Cystoscopy of the same patient showing closed bladder neck with bladder filling (left side, black arrow). On bladder contraction, the bladder neck opens (right side, black arrow) but the external sphincter contracts at the same time (right side, blue arrow) leaving only the prostatic urethra opened.

Upper urinary tract infection (pyelonephritis) There are two main risk factors contributing to the occurrence of pyelonephritis among NBD patients. First, recurrent lower urinary tract infections may interfere with the anti-reflux mechanism, causing reflux of infected urine to the kidney. Second, functional infravesical obstruction, such as detrusor–sphincteric dyssynergia (DSD), leads to stasis of urine and high intravesical pressure, both creating a risk of reflux of an already infected urine.21 In a study on a group of patients with detrusor– external sphincteric dyssynergia (DESD), Chancellor and Rivas found that over 50% of men with DESD will develop significant complications, such as VUR, upper tract deterioration, urolithiasis, urosepsis, and ureterovesical obstruction.28 As sensation is often absent in neurologic patients, the main clinical symptom of acute pyelonephritis is fever up to 40°C. Urinalysis shows pyuria, bacteriuria, and microscopic hematuria. Blood tests may show a polymorphonuclear leukocytosis, increased erythrocyte sedimentation rate, elevated C-reactive protein levels, and elevated creatinine levels if renal impairment developed. Acute pyelonephritis in NBD patients is considered a complicated infection and requires hospitalization. At first, the patient should be adequately hydrated, blood culture and urine culture should be done three times, and double intravenous antibiotics (ampicillin–gentamicin) should be started until the results of cultures appear. On day 3, appropriate oral antibiotic should be started, and the duration of therapy should be 14 days.29 If symptoms persist beyond 72 hours, however, the possibility of perinephric or intrarenal abscesses, urinary tract abnormalities, or obstruction should be considered and radiologic investigation with ultrasonography or

computed tomography (CT) should be performed. Urine and blood cultures should be repeated at appropriate intervals, and antimicrobial therapy should be adjusted, if necessary, on the basis of susceptibility testing.30

Lithiasis Incidence Urolithiasis is a well-documented problem in patients with neurogenic voiding dysfunction. It is estimated that 10%– 20% of patients with SCI will have struvite stones within 10 years of injury; of these, 7% will have renal stones.31,32 The incidence of renal calculi in myelomeningocele patients may be greater.33 Once a kidney stone develops, there is a 34% chance of a second stone developing within the next 5 years.34

Risk factors The main risk factors for stone development are recurrent UTIs, especially due to urea-splitting organisms, infravesical obstruction producing stasis, indwelling catheters, VUR, hypercalciuria resulting from immobilization, demineralization of bone, and high specific gravity of urine.35 The patient’s age and injury characteristics have an important role in determining the type of urinary stone formed. In a longitudinal cohort study, Chen et al.36 found that the risk factors for bladder stone were younger age, neurologically complete lesion, and indwelling catheterization. In a case–control study, DeVivo et al. noted that patients who developed renal stones were more likely to be older, have had neurologically complete quadriplegia, and have had a history of bladder stone.37,38

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Stone composition For the last few decades, most studies have reported that patients with NBD exclusively develop struvite stones composed of magnesium ammonium phosphate. This was attributed to UTI with urea-splitting organisms that render the urine pH >7.24.39,40 Recent studies, however, reported that many patients with NBD harboring calculi have been found to have metabolic stones. Matlaga et al.41 found that out of 32 patients with NBD who harbored urinary stones, 20 patients (62.5%) had metabolic stones, while the remaining 12 (37.5%) had infection stones. They related this observation to the advances in urologic care of patients with NBD, including accurate urodynamic evaluation of the detrusor and sphincteric function and greater use of CIC and bladder augmentation. These led to a significant decrease in the incidence of UTI among patients with NBD and subsequently a fall in the incidence of struvite stones among those patients.42,43 The importance of this observation is that once a metabolically derived stone is identified, the patient should be offered further metabolic evaluation and medical and dietary therapy.44

Diagnosis Patients with renal stones usually have nonspecific symptoms including feeling unwell, abdominal discomfort, increased spasms, and autonomic dysreflexia. These vague symptoms can alert a well-informed physician, so the need for radiologic examination by plain kidney, ureter, and bladder (KUB), ultrasonography, CT, and intravenous pyelography (IVP) becomes essential for diagnosis.45 Patients with bladder stones usually suffer from irritative symptoms, hematuria, and recurrent UTI. Again, radiologic examination is essential. Bladder stones usually start as small pieces of thin struvite calculi formed around the balloon of the Foley’s catheter. These calculi may grow but retain the typical eggshell shape that appears in cystoscopy (Figure 62.6). Small struvite stones with a low calcium content can easily be missed on x-ray and are often incidentally discovered during cystoscopy.46

Treatment Successful treatment of renal stones depends on complete elimination of the calculus, eradication of infection, and removal of the obstruction. Selection of the best method of treatment should be individualized and adapted to every patient.47 Management of upper urinary tract stones in SCI is complex regarding surgical technique, postoperative care, and recurrence rates. In paraplegic and quadriplegic patients, typical extracorporeal shock wave lithotripsy

Figure 62.6 Cystoscopy of a 22-year-old male patient with a history of chronic indwelling catheter. Multiple typical eggshell-shaped stones could be seen, which were formed around the balloon of the Foley’s catheter.

(ESWL) alone is not recommended because of the difficulty in eliminating the stone fragments.48 Furthermore, ESWL may predispose to the development of autonomic dysreflexia. Stow et al. reported 9 out of 52 patients with NBD (17.3%), who developed autonomic dysreflexia after ESWL.49 If ESWL is considered in these patients, it is better to be done without adding the risk of general anesthesia but with careful monitoring to avoid development of hypertension. Prophylaxis can also be done by giving 10–20 mg of nifedipine sublingually 15–20 minutes before the procedure.50 The other drawback of ESWL is that it may exacerbate posttraumatic syringomyelia, presumably by reverberating the fluid within the intramedullary cavity, producing further damage to the spinal cord.51 The recommended technique for treatment is percutaneous nephrolithotripsy (PCNL). It is considered the “gold standard,” specially for stone size above 2 cm. In rare cases, patients may require surgery to remove the stones. Nephrectomy should be performed when the kidney is nonfunctioning, or if there is pyonephrosis (Figure 62.7). Ureteric stones can be managed through ureteroscopic fragmentation and extraction. Access can be limited by lower limb contractures. However, if the stone is big enough and remains blocked in the middle third of the ureter, surgery or laparoscopic removal should be considered. Treatment of bladder stones is straightforward, because of easy access to the bladder both endoscopically and surgically. The stone can be fragmented endoscopically by mechanical forceps, holmium laser, ultrasonics,

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can stabilize the urinary pH at a value of 5.5, so reducing urinary saturation and crystallization of phosphates and carbonates.54 Other examples of urinary acidifiers are 3–4 g daily of L-methionine and 3–4 g daily of ammonium chloride.55,56

Neoplasm Incidence and types It is estimated that patients with NBD are 16–28 times more susceptible to develop bladder cancer than the normal population.57 Recent studies reported a bladder cancer incidence of 0.1%–2.4%. SCI patients tend to present with bladder cancer at earlier age and more advanced stage, on average of 18–24 years after onset of SCI.58 The most common histologic type occurring in these patients is squamous cell carcinoma.59 Bejany et al.60 found that 81% bladder cancer patients in SCI units harbored squamous cell carcinoma, while the other 19% had either transitional cell or mixed tumor.

Figure 62.7 A surgical specimen from a 31-year-old patient who underwent nephrectomy for a nonfunctioning kidney harboring a staghorn stone.

pneumatics, or electrohydraulic lithotripsy. Small fragments can then be washed out from the bladder by the Ellik evacuator. Careful monitoring of blood pressure, however, is important because of the fear of development of autonomic dysreflexia, which is also reported after cystolithotripsy in NBD patients.52 Open surgery is indicated only when bladder capacity is small or the size of the stone is so big that endoscopic litholapaxy would be extremely difficult. Impacted urethral stones are rare and occur mainly with obstruction or urethral diverticulum.53 Endoscopic treatment is by visual urethrotomy, pushing the stone into the bladder and fragmenting it. Surgery is performed in cases of a stone in a diverticulum, where diverticulectomy is used for stone removal.

Prevention Successful prevention of urinary stones in NBD patients depends on regular positioning of the paralyzed patients, high fluid intake, early mobilization, proper treatment of UTI, and prevention of subsequent infection. One of the most effective methods in prevention of struvite stone formation is the use of urinary acidifiers; these agents will decrease the urinary pH, preventing precipitation of phosphate stones and subsequently struvite stone formation. One of the most commonly used urinary acidifiers is methenamine mandelate at a dose of 4–5 g/day. It

Risk factors The most important risk factor for the development of ­bladder carcinoma is irritation of the bladder mucosa. These include chronic bladder infection, prolonged indwelling catheterization, and bladder stone disease. Other risk factors include smoking, increased time of urine contact with urothelium, and altered immunological function. This is why squamous cell carcinoma is the most common type of malignancy among these patients.61 Vaidyanathan et al. hypothesized that certain histologic changes are seen more frequently in SCI patients with long-term indwelling catheters. These changes include papillary or polypoid cystitis, widespread cystitis glandularis, moderate to severe acute and chronic inflammatory changes in bladder mucosa, follicular cystitis, squamous metaplasia, and urothelial dysplasia.62

Screening The screening of NBD patients with chronic indwelling catheterization is controversial. Some advocate the use of screening cystoscopy, arguing that this will detect malignant lesions in an earlier stage.63 Others believe that cystoscopy with or without biopsy does not fulfill the necessary criteria for screening of bladder cancer in NBD patients.64,65 Screening cytology may be of benefit. Stonehill et al. studied patients with indwelling catheters for more than 5 years. Positive cytology had a sensitivity of 71% and a specificity of 97%. On the basis of these observations, they

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Figure 62.8 CT scan of augmented bladder in SCI patient with bladder and augment stones. The augmentation scarred down and formed an ­hour-glass appearance with poor drainage into native bladder. Patient presented 7 years after augmentation with sepsis, retention, and renal failure. (Provided through the courtesy of Dr. G. Ghoniem.)

recommended yearly cytology in all patients with chronic indwelling catheters, followed by biopsy if it was positive.66 This review of the literature suggests that NBD patients with longstanding indwelling catheterization (certainly after 10 years post trauma) should undergo yearly urine cytology. If it is doubtful or positive, cystoscopy and cold cup biopsy should be performed randomly, if no suspicious lesion was found. A history of bladder stone and chronic UTI should be considered as significant risk factors for the development of bladder cancer in these patients. New onset of gross hematuria should be investigated in the same way as in the neurologically normal population.

References 4575. Achaeffer AJ. Infections of the urinary tract. In: Walsh PC, Retik AB, Vaughan ED, Wein AJ, eds. Campbell’s Urology, 8th ed. Philadelphia, PA: WB Saunders, 2002: 515–7. 4576. Menon EB, Tan ES. Pyuria: Index of infection in patients with spinal cord injuries. Br J Urol 1992; 69: 144–6. 4577. Stover SL, Lioyd LK, Waites KB, Jackson AB. Urinary tract infection in spinal cord injury. Arch Phys Med Rehab 1989; 70: 47–54. 4578. Waites KB, Canupp CK, Devivo MJ. Epidemiology and risk factors for urinary tract infection following spinal cord injury. Arch Phys Med Rehab 1993; 74: 691. 4579. Beraldo PSS, Neves EGC, Alves CMF et al. Pyrexia in hospitalized spinal cord injury patients. Paraplegia 1993; 31: 186. 4580. Ward TT, Jones SR. Genitourinary tract infections. In: Reese RE, Betts RF, eds. A Logical Approach to Infectious Diseases, 3rd ed. Boston, Germany: Little, Brown and Company, 1991: 357–89. 4581. Horton JA 3rd, Kirshblum SC, Lisenmeyer TA, Johnston M, Rustagi A. Does refrigeration of urine alter culture results in hospitalized patients with neurogenic bladder? J Spinal Cord Med 1998; 21: 342–7.

4582. Gilmore DS, Schick DJ, Young MN, Montgomerie JZ. Effect of external urinary collection system on colonization and urinary tract infections with Pseudomonas and Klebsiella in men with spinal cord injury. J Am Paraplegia Soc 1992; 15: 155. 4583. Lapides J, Diokno AC, Silber SJ et al. Clean intermittent self-­ catheterization in the treatment of urinary tract disease. J Urol 1972; 107(3): 458–16. 4584. Tambyah PA, Maki DG. Catheter-associated urinary tract infection is rarely symptomatic: A prospective study of 1,497 catheterized patients. Arch Intern Med 2000; 160: 678. 4585. Cardenas DD, Hooton TM. Urinary tract infection in persons with spinal cord injury. Arch Phys Med Rehab 1995; 76: 272. 4586. National Institute on Disability and Rehabilitation Research Consensus Statement. The prevention and management of urinary tract infections among people with spinal cord injury. SCI Nurs 1993; 10: 49–61. 4587. Babayan RK. Urinary calculi and endourology. In: Siroky MB, Krane RJ, eds. Manual of Urology. Boston, Germany: Little, Brown and company, 1990; 123–31. 4588. Silverman DE, Stamey TA. Management of infection stones: The Stanford experience. Medicine (Baltimore) 1983; 62: 44–51. 4589. Edwards LE, Lock R, Powell C, Jones P. Post-catheterization urethral strictures: A clinical and experimental study. Br J Urol 1983; 55: 53. 4590. Nickel JC, Olson ME, Costerton JW. In vivo coefficient of kinetic friction: Study of urinary catheter biocompatibility. Urology 1987; 14: 501. 4591. Gabriel MM, Mayo MS, May LL et al. In vitro evaluation of the efficacy of a silver-coated catheter. Curr Microbiol 1996; 33: 1. 4592. Hockstra D. Hyaluronan-modified surfaces for medical devices. Med Device Diagn Ind 1999; 48–56. 4593. Liedberg H, Lundeberg T. Silver alloy-coated catheters reduce catheterassociated bacteriuria. Br J Urol 1990; 65: 379. 4594. Hooton TM, Bradley SF, Cardenas DD et al. Diagnosis, prevention, and treatment of catheter associated urinary tract infection in adults: 2009 International Clinical Guidelines from the Infectious Disease Society of America. Clin Infect Dis 2010; 50(5): 625–63. 4595. Buczynski AZ: Urological complications in paraplegic and quadriplegic patients. New Med 1999; 89: 13–15.

Complications related to neurogenic bladder dysfunction I 4596. Berger RE, Kessler D, Holmes KK. The etiology and manifestations of epididymitis in young men: Correlations with sexual orientation. J Infect Dis 1987; 155: 1341. 4597. McNaughton-Collins M, Stafford RS, O’Leary MP, Barry MJ. How common is prostatitis? A national survey of physician visits. J Urol 1998; 159: 1224–8. 4598. Kaplan SA, Te AE, Jacobs BZ. Urodynamic evidence of vesical neck obstruction in men with misdiagnosed chronic nonbacterial prostatitis and the therapeutic role of endoscopic incision of the bladder neck. J Urol 1994; 152: 2063–5. 4599. Weidner W, Schiefer HG, Krauss H et al. Chronic prostatitis: A thorough search for etiologically involved microorganisms in 461 patients. Infection 1991; 19: 119–25. 4600. Weidner W, Ludwig M. Diagnostic management of chronic prostatitis. In: Weidner W, Madsen PO, Schiefer HG, eds. Prostatitis – Etiopathology, Diagnosis and Therapy. Berlin, Germany: SpringerVerlag, 1994: 158–74. 4601. Stamey TA, Meares EMJ, Winningham DG. Chronic bacterial prostatitis and the diffusion of drugs into prostatic fluid. J Urol 1970; 103: 187–94. 4602. Chancellor MB, Rivas DA. Current management of detrusorsphincter dyssynergia. In: McGuire E, ed. Advances in Urology. Mosby, CV: St Louis, 1995: 291–324. 4603. Talan DA, Stamm WE, Hooton TM et al. Comparison of ciprofloxacin (7 days) and trimethoprim-sulfamethoxazole (14 days) for acute uncomplicated pyelonephritis in women. JAMA 2000; 12: 1583. 4604. Soulen MC, Fishman EK, Goldman SM et al. Bacterial renal infection: Role of CT. Radiology 1989; 171: 703. 4605. Chen Y, DeVivo MJ, Roseman JM. Current trend and risk factors for kidney stones in persons with spinal cord injury: A longitudinal study. Spinal Cord 2000; 38: 346–53. 4606. Takasaki E, Suzuki T, Honda M et al. Chemical compositions of 300 lower urinary tract calculi and associated disorders in the urinary tract. Urol Int 1995; 54: 89–94. 4607. Nimkin K, Lebowitz RL, Share JC, Teele RL. Urolithiasis in a children’s hospital from 1985 to 1990. Urol Radiol 1992; 14: 193–7. 4608. Chen Y, DeVivo MJ, Stover SL, Lioyd LK. Recurrent kidney stone: A 25 year follow up study in persons with spinal cord injury. Urology 2002; 60: 228–32. 4609. Ost MC, Lee BR. Urolithiasis in patients with spinal cord injuries: Risk factors, management, and outcomes. Curr Opin Urol 2006; 16(2): 93–109. 4610. Chen Y, DeVivo MJ, Lioyd LK. Bladder stone incidence in persons with spinal cord injury: Determinants and trends, 1973–1996. Urology 2001; 58: 665–70. 4611. Devivo MJ, Fine PR. Predicting renal calculus occurrence in spinal cord injury patients. Arch Phys Med Rehab 1986; 67: 722–5. 4612. Hyeon KU, Jung TY, Lee JK, Park WH, Shim HB. Risk factors for urinary stone formation in men with spinal cord injury: A 17-year follow up study. BJU Int 2006; 97: 790–3. 4613. Burr RG. Urinary calculi composition in patients with spinal cord lesions. Arch Phys Med Rehab 1978; 59: 84–9. 4614. Nikakhter B, Vaziri ND, Khonsary F, Gordon S, Mirahmadi MD. Urolithiasis in patients with spinal cord injury. Paraplegia 1981; 19: 363–9. 4615. Matlaga BR, Kim SC, Watkins SL et al. Changing composition of renal calculi in patients with neurogenic bladder. J Urol 2006; 175(5): 1716–9. 4616. Donnellan SM, Bolton DM. The impact of contemporary bladder management techniques on struvite calculi associated with spinal cord injury. BJU Int 1999; 84: 280–7. 4617. vanGool JD, deJong TP, Boemers TM. Effect of intermittent catheterization on urinary tract infection and incontinence in children with spina bifida. Monatsschr Kinderheilkd 1991; 193: 592–9. 4618. Mardis HK, Parks JH, Muller G, Ganzel K, Coe FL. Outcome of metabolic evaluation and medical treatment for calcium nephrolithiasis in a private urological practice. J Urol 2004; 171: 85–93.

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4619. Vaidyanathan S, Singh G, Soni BM et al. Silent hydronephrosis/pyonephrosis due to upper urinary tract calculi in spinal cord injury patients. Spinal Cord 2000; 38: 331–8. 4620. Park YI, Linsenmeyer TA. A method to minimize indwelling catheter calcification and bladder stones in individuals with spinal cord injury. J Spinal Cord Med 2001; 24: 105–8. 4621. Robert M, Bennani A, Ohanna F et al. The management of upper urinary tract calculi by piezoelectric extracorporeal shock wave lithotripsy in spinal cord injury patients. Paraplegia 1995; 33: 132–5. 4622. Niedrach WL, Davis RS, Tonetti FW, Cockett AT. Extracorporeal shock-wave lithotripsy in patients with spinal cord dysfunction. Urology 1991, 38: 152–6. 4623. Stow DF, Bernstein JS, Madson KE, McDonald DJ, Ebert TJ. Autonomic hyperreflexia in spinal cord injured patients during extracorporeal shock wave lithotripsy. Anath Analg 1989; 68: 788–91. 4624. Sugiama T, Fugelso P, Avon M. Extracorporeal shock wave lithotripsy in neurologically impaired patients. Semin Urol 1992; 10: 109–11. 4625. DiLorenzo N, Maleci A, Williams BM. Severe exacerbation of posttraumatic syringomyelia after lithotripsy: Case report. Paraplegia 1994; 32: 694–6. 4626. Vespasiani G, Pesce F, Finazzi AE et al. Endoscopic ballistic lithotripsy in the treatment of bladder calculi in patients with neurogenic voiding dysfunction. Endourology 1996; 10: 551–4. 4627. Vaidyanathan S, Singh G, Sett P, Soni BM. Complication of penile sheath drainage in a spinal cord injury patient: Calculus impacting in the urethra proximal to the rim of a condom. Spinal Cord 2001; 39: 240–1. 4628. Jeantet A, Thea A, Fernando U et al. Infectious nephrolithiasis: Results of treatment with methenamine mandelate. Contrib Nephrol 1987; 58: 233–5. 4629. Jarrar K, Boedeker RH, Weidner W. Struvite stones: Long term follow up under metaphylaxis. Ann Urol 1996; 30(3): 112–17. 4630. Wall I, Tieselius HG. Long term acidification of urine in patients treated for infected renal stones. Urol Int 1990; 45(4): 336–41. 4631. Hess MJ, Zhan Eh, Foo DK, Yalla SV. Bladder cancer in patients with spinal cord injury. J Spinal Cord Med 2003; 26(4): 335–8. 4632. Welk B, McIntyre A, Teasell R, Potter P, Loh E. Bladder cancer in individuals with spinal cord injuries. Spinal Cord 2013; 51: 516–21. PMID: 23608811. 4633. van Velzen D, Kirshnan KR, Parsons KF et al. Comparative pathology of dome and trigone of urinary bladder mucosa in paraplegics and tetraplegics. Paraplegia 1995; 33: 565–72. 4634. Bejany DE, Lockhart IL, Rhamy RK. Malignant vesical tumors following SCI. J Urol 1987; 138: 1390–2. 4635. Groah SL, Weitzenkamp DA, Lammertse DP et al. Excess risk of bladder cancer in spinal cord injury: Evidence for an association between indwelling catheter use and bladder cancer. Arch Phys Med Rehab 2002; 83: 346–51. 4636. Vaidyanathan S, Mansour P, Soni BM, Singh G, Satt P. The method of bladder drainage in spinal cord injury patients may influence the histological changes in the mucosa of the neuropathic bladder: A hypothesis. BMC Urol 2002; 2: 5–11. 4637. Navon JD, Soliman H, Khonsari F, Ahlering T. Screening cystoscopy and survival of SCI patients with squamous cell carcinoma of the bladder. J Urol 1997; 157: 2109–11. 4638. Yang CC, Clowers TE. Screening cystoscopy in chronically catheterized SCI patients. Spinal Cord 1999; 37: 204–7. 4639. Hamid R, Bycroft J, Arya M, Shah PJ. Screening cystoscopy and  biopsy in patients with neuropathic bladder and chronic suprapubic indwelling catheter: Is it valid? J Urol 2003; 170(2 Pt 1): 425–7. 4640. Stonehill WH, Goldman HB, Dmochowski RR. The use of urine cytology for diagnosing bladder cancer in spinal cord injured patients. J Urol 1997; 157: 2112–14.

63 Complications related to neurogenic bladder dysfunction II: Vesicoureteral reflux and renal insufficiency Claire C. Yang and Brandon M. Haynes

Introduction The function of the bladder and sphincters depends on an intact nervous system. Neurogenic bladder (NGB) dysfunction results from lesions or derangements in the nervous system and can result in a number of bladder problems, such as urinary tract infections (UTIs), urinary incontinence, and retention. Lower urinary tract dysfunction can also affect the upper urinary tract (i.e., the kidneys and ureters), with complications such as vesicoureteral reflux (VUR), hydronephrosis, and loss of renal function. Thus, minimizing the complications of NGB dysfunction—particularly the health- and life-threatening upper tract changes—remains the goal of treatment. Historically, patients with significant NGB dysfunction had poor survival after the development of bladder failure. In the mid-twentieth century, the primary cause of death in patients with spinal cord injury (SCI) was due to UTI and renal failure.1,2 Children born with neural tube defects (e.g., myelomeningocele) and significant NGB dysfunction were similarly affected, and as a result, did not typically live to adulthood.3 However, in the 1960s and 1970s, the medical community recognized that, in large part, renal failure resulted from inadequate bladder management. Improved bladder emptying, along with more widespread antibiotic use, improved both renal function and, ultimately, survival rates in persons with NGB dysfunction. As a result of better NGB management, upper tract sequelae have decreased dramatically in the last 50 years for patients with access to adequate medical care. However, these complications still occur, and healthcare providers of patients with NGB dysfunction must continuously remember the possibility of upper tract deterioration as they treat their patients.

To more fully understand the upper tract complications of NGB, this chapter will discuss the clinical conditions that contribute to upper tract deterioration, the general pathophysiology of renal deterioration and the pathophysiology specific to upper tract deterioration in patients with NGB dysfunction, the incidence of upper tract damage in common neurologic conditions that result in NGB dysfunction, the evaluation and diagnosis of upper tract complications, and options for the surgical treatment of upper tract complications and renal failure in patients with NGB. Other chapters in this textbook discuss the management of NGB dysfunction, so it will not be discussed here beyond brief mentions of treatment principles. Information on the management of primary VUR (congenital, absent NGB dysfunction) can be found in other sources.

Clinical conditions contributing to upper tract deterioration in NGB dysfunction Renal and ureteral injury in NGB dysfunction can result from both acute and chronic conditions. Acute causes include infection and sudden obstruction. Pyelonephritis is a common infection in persons with NGB dysfunction. Acute pyelonephritis stems from ascending bacteriuria, which in NGB dysfunction, commonly arises from bacterial colonization in the lower urinary tract due to catheterization or poor bladder emptying. Acute obstruction of a renal unit is typically caused by nephrolithiasis, which is a risk factor for developing both temporary and permanent renal insufficiency. In patients with NGB dysfunction, stones are frequently composed of struvite (infection

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stone), due to the high urinary pH typical in persons with chronic bacteriuria, although metabolic stones can be present as well.4 In acute nephrolithiasis, the degree of obstruction, duration of obstruction, and presence of bacteriuria all affect the severity of the renal injury and the likelihood of functional recovery. In addition, nephrolithiasis itself (without NGB) is an independent factor for developing renal insufficiency. In an epidemiologic study by Rule et al.,5 residents from Olmsted County with a history of kidney stone (n = 4774) were more likely to develop chronic kidney disease than controls without nephrolithiasis. It is likely that the high incidence of nephrolithiasis in some groups of patients with NGB dysfunction (e.g., reported as 7%–30% in patients with SCI6,7) contributes to the higher risk of renal insufficiency compared to the general population. Chronic infections and obstruction compound the likelihood of upper tract damage. For example, repeated episodes of pyelonephritis or chronic pyelonephritis result in cortical and medullary scarring8 and loss of renal function. (However, repeated episodes of pyelonephritis uncomplicated by obstruction, structural alterations of the urinary tract, or NGB dysfunction does not result in end-stage renal disease.8,9) Compared to chronic infections, chronic obstruction has worse outcomes for patients with NGB dysfunction. On a structural level, repeated episodes of acute obstruction or chronic, untreated obstruction eventually result in permanent nephron loss and a decrease in glomerular filtration rate (GFR). A more insidious—oftentimes silent—etiology for the loss of renal function in NGB dysfunction is the presence of chronically high pressures within the bladder in the absence of acute obstruction. These pressures result from either a poorly compliant bladder or a poorly emptying bladder, both obstructing urine drainage “upstream” from the kidney. In the first case, the fibrotic, noncompliant bladder itself becomes the point of obstruction for ureteral drainage, and hydronephrosis develops. In fact, several studies have shown that urodynamic parameters such as persistent poor compliance and high detrusor pressures predict upper tract decompensation.10–12 Elevated detrusor storage or voiding pressures may also contribute to the development of VUR, which further increases the risk of upper tract deterioration. This was nicely demonstrated in a study of 170 SCI patients with NGB dysfunction, followed for 5 years following injury. These patients were injured in the mid-twentieth century, without the aggressive antibiotic and bladder management currently available. In this series, the incidence of renal dysfunction temporally tracks with the development of VUR.2 In healthy bladders, the valvular function of the ureterovesical junction (UVJ) protects the low-pressure upper urinary tract from urine refluxing from the bladder. When an individual has NGB dysfunction, chronically high detrusor pressures compromise this protective

function and are believed to alter the anatomy of the bladder trigone, distorting the angle of ureteral entry into the trigone and shortening the tunneled portion of the intramural ureter.13 This altered intramural obliquity triggers urinary reflux. With VUR, the low-pressure upper tracts are then exposed to higher pressures and result in a loss of GFR (see below). VUR also facilitates ascending bacteriuria and predisposes the renal unit to struvite stone growth.7

Pathophysiology of renal deterioration Whether due to obstruction or reflux, elevated intrarenal pressures result in decreased renal blood flow and decreased GFR. Factors influencing GFR are expressed in the following equation: GFR = Kf (PGC − P BC − πGC) Kf signifies a glomerular ultrafiltration coefficient related to the surface area and permeability of the capillary membrane. PGC signifies the glomerular capillary pressure, which is influenced by renal plasma flow and the resistances of the afferent and efferent arterioles. The hydraulic pressure driving fluid out of the capillaries is resisted by the hydraulic pressure of fluid in Bowman’s capsule (P BC) and also the increasing oncotic pressure (π) of the proteins remaining at higher concentrations in the late glomerular capillary and efferent arteriolar blood (Figure 63.1). The net pressure determining glomerular filtration is referred to as the ultrafiltration pressure (P UF) and is derived from (PGC − P BC − πGC). As a consequence of obstructed urine flow, elevated pressures within the kidney increase the tubule hydraulic pressure in Bowman’s capsule (P BC) and result in an overall decrease in ultrafiltration pressure and GFR. A healthy bladder remains compliant during the filling phase and empties without excessive detrusor contraction pressures, thus maintaining an environment without resultant high bladder pressures. However, NGB dysfunction can result in poor bladder compliance, high detrusor contraction pressures, and incomplete bladder emptying. In all three conditions, excessively high pressure in the lower urinary tract is generated. Whether the bladder pressure results in the loss of integrity of the UVJ (causing VUR) or compromises efficient ureteral drainage, the elevated pressures are eventually transmitted to the upper tracts. Intrarenal pressure increases, GFR decreases, and ultimately, nephron loss results. The most important goal of managing NGB is to preserve renal function, and this is primarily achieved through treatment aimed at minimizing the generation of elevated pressure in the lower urinary tract.

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Bowman’s capsule

PBC

Glomerular capillary PGC πGC

Figure 63.1 Schematic of the pressures within the nephron, resulting in glomerular filtration. Glomerular filtration rate (GFR) is affected by the glomerular capillary pressure (PGC), the oncotic pressure of the proteins within the glomerular capillary (π), and the hydraulic pressure from the fluid in Bowman’s capsule (PBC). Elevated pressures from the lower urinary tract in neurogenic bladder dysfunction can be transmitted to the kidney, which then increases the pressure within Bowman’s capsule (PBC). The result is a net decrease in GFR. (From http://onlinephysiology.blogspot.com/2010/10/direct-determinants-of-gfr.html, accessed on June 4, 2013.)

Incidence of upper tract damage related to neurogenic bladder dysfunction in patients with neurologic conditions As stated in the introduction, healthy bladder and renal function depend on an intact nervous system. Individuals with neurologic injury or disease resulting in NGB dysfunction, particularly injury or disease affecting the spinal cord, experience higher risks of bladder dysfunction and related renal insufficiency compared to the general population. NGB commonly affects patients with SCI, neural tube defects (e.g., spina bifida), and multiple sclerosis (MS), and results in a variety of manifestations, depending on the condition. For example, in the mid-twentieth century, the most common cause of death for patients with SCI was from complications relating to the genitourinary system, with UTI, and secondary upper tract deterioration responsible for up to 80% of deaths.1 With the increasing availability of antibiotics, the use of anticholinergic medications, and improved catheterization regimens, the incidence of renal insufficiency and failure in patients with SCI and neural tube defects has fallen dramatically since then. However, renal insufficiency and failure still represent late consequences of NGB. This section will explore the incidence of upper tract complications due to NGB dysfunction in different groups of patients with neurologic disease or injury. Most studies on the incidence of upper tract complications do not take into account factors such

as severity and duration of disease, and so subgroup analyses are not available.

Spinal cord injury As noted above, SCI has historically been associated with frequent urologic sequelae. Hydronephrosis, VUR, pyelonephritis, and renal insufficiency in patients with minimally treated NGB were commonplace, with incidence increasing with time from injury.2,14 Compared to historic levels, contemporary incidence of upper tract complications in SCI has dropped significantly. In 2005, Ku et al.15 retrospectively reported on 179 patients with traumatic SCI for a minimum of 10 years to identify the risk of complication of the upper urinary tract in relation to bladder management. In this series, 32.4% of patients developed some degree of renal deterioration. In 2001, Lawrenson et  al.16 used a large, community-based data set, comparing patients with SCI with the general population. Patients with SCI were found to have a fivefold increased risk of renal failure compared with the general population. But overall, genitourinary causes of death (primarily renal failure) in patients with SCI have become significantly less common. In a large database of 29,000 patients with SCI in the United States, genitourinary causes of death ranked 10, behind pneumonia, septicemia, cancer, heart disease, and other etiologies.17 Other parts of the world have also documented the same findings.18 In the past 50 years, it is clear that better urinary tract management has improved the length and quality of life in patients with SCI with

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access to health care, but renal failure and upper tract morbidity related to NGB dysfunction still persists.

Neural tube defects Historically, children born with neural tube defects and significant NGB dysfunction did not typically live to adulthood, often as a result of renal failure.3 Currently, only 60% of children with spina bifida in the United Kingdom reach the age of 21,19 with renal failure still one of the leading causes of death, presumably a sequela of NGB dysfunction. In two U.K. series, renal failure was the most common cause of death (18%), especially in those with sensory levels above T11.20 Singhal and Mathew21 examined an unselected group of adult patients with spina bifida in the United Kingdom, and in their series of 30 patients with identifiable causes of death, 10 died as a result of renal failure. Moreover, the aforementioned Lawrenson study estimated that the risk of renal failure for patients with neural tube defects was eight times than that of the general population.16 Recent studies show that with early evaluation, follow-up examinations, and adequate therapy, a reduction in renal function was noticed in only 1.2%–2.1% of children with spina bifida.22,23 However, the low incidence of renal deterioration may not be maintained as these children transition through puberty and progress through adulthood.19 As demonstrated in patients with SCI, patients with neural tube defects have also benefitted from improved urinary tract management, but upper tract complications of NGB dysfunction are still cause for concern.

Multiple sclerosis Bladder dysfunction, resulting in abnormalities in both ­storage and emptying, affects up to 90% of patients with MS.24  It has long been recognized that detrusor hyperreflexia  and external sphincter dyssnergia are the most common  forms of bladder and sphincter dysfunction.25 Furthermore, the greater the impairment with MS, the greater the risk of urinary tract abnormalities.26 Despite these  findings, renal insufficiency secondary to NGB in patients with MS is not particularly common. A meta-analysis of 14 studies comprising 2076 patients by Koldewijn et al.27 in 1995 found a .34% incidence of hydronephrosis or renal complications. In addition, Lawrenson et al.16 reported no increased risk in persons with MS for the development of renal insufficiency when compared to the general population.

Other conditions manifesting neurogenic bladder dysfunction The incidence and prevalence of upper tract deterioration in persons with NGB due to neurologic conditions other than SCI, neural tube defects, and MS are likely

slightly higher than that of the general population, but very little has been published regarding these epidemiologic data.

Pathophysiology of upper tract deterioration in neurogenic bladder dysfunction Given that the incidence of renal insufficiency differs across conditions, why is upper tract deterioration more likely in some neurologic conditions than others? The physiology behind the higher incidence of upper tract deterioration and renal failure in some neurologic conditions compared to others should be considered in the context of how high pressure in the bladder develops, particularly during filling. Understanding that poor bladder compliance results in elevated pressures and poses greater risks for upper tract deterioration, the neurologic conditions most likely to result in poor bladder compliance are those with significant spinal lesions, such as SCI and neural tube defects. Spinal lesions disrupt neural transmission between the pontine micturition center (PMC) and the motor neurons in the sacral cord that innervate the bladder and sphincters (Figure 63.2). The PMC, located in the midbrain between the cortex and the spinal cord, generates the signal for detrusor contraction, coordinates the activity between bladder and sphincters, and regulates detrusor compliance.28 Thus, significant lesions of the spinal cord below the level of the pons and above the lumbosacral spinal cord—lesions that effectively isolate the peripheral innervation of the bladder and sphincters from the “coordination center”—have the potential to result in incomplete detrusor contractility, lost compliance, and detrusor–sphincter dyssynergia, all of which can contribute to upper tract deterioration. However, not all patients with SCI or neural tube defects develop poorly compliant or high-pressure bladders, since the severity and location of the injury contribute to the development of dysfunction. For example, SCI patients with an “incomplete” injury have less severe NGB dysfunction than those with a “complete” injury, depending on the particular spinal level of the injury. In spina bifida, the degree of neurologic compromise can be highly variable. In addition to the location and the extent of spinal lesions, the integrity of the bladder outlet determines whether a poorly compliant bladder will generate high pressures. In many patients with neural tube defects, the resultant neuropathology results in very low outlet resistance from a denervated, open bladder neck. The lack of outlet resistance then does not allow the generation of overly high detrusor pressures, even with a noncompliant bladder, and the upper tracts are preserved.

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Brain

Central nervous system (brain and spinal cord)

Spinal cord

Bladder

Nerve signals to bladder and sphincter muscles

Urethra Sphincter muscles

Figure 63.2 Schematic depiction of the innervation of the bladder and sphincters. Neurogenic bladder dysfunction can result from disease or injury to the central nervous system or the peripheral nerves (between the end organ and the spinal cord). Significant neurologic lesions occurring between the pontine micturition center in the midbrain (arrowhead) and the lumbosacral cord (where the peripheral nerves to the bladder and sphincters exit) result in the most severe dysfunction and pose the highest risk for upper tract complications. (Accessed from http://kidney .niddk.nih.gov/kudiseases/pubs/nervedisease/.)

The higher incidences of renal failure and other upper tract sequelae from NGB dysfunction in patients with SCI and neural tube defects, compared patients with MS, most likely originate from the more severe spinal disruptions that occur with those conditions. However, severe para- and tetraplegia does develop in MS, and these patients are at risk for upper tract deterioration, particularly men, because the prostate maintains high outlet resistance at the bladder neck. But in women, similar to the situation with some patients with spina bifida, the outlet resistance of the internal and external sphincter is rarely so great as to generate elevated detrusor pressures, even in the presence of detrusor–sphincter dyssynergia or poor compliance; the outlet is usually (but not always)

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incompetent enough that urine leakage occurs before detrimental bladder pressures develop (i.e., the detrusor leak point pressure 40 cm H2O are associated with the risk of renal deterioration.29 Other components of urodynamics—­ ­ uroflowmetry, postvoid residual, and ­pressure flow s­tudies—can identify d ­ ysfunction in bladder emptying. Electromyography ­ measures the function of striated urinary sphincteric muscles during both filling and storage. When evaluating the patient with NGB d ­ ysfunction, one of the primary goals is to identify and prevent high intravesical pressures, and cystometry/urodynamics is often a necessary component in the assessment.

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Figure 63.6 Filling cystometry. (a) Cystometrogram of patient with a normal, compliant bladder. With increasing bladder volumes, there is no appreciable rise in detrusor pressure. (b) Cystometrogram of patient with poorly compliant bladder. With increasing bladder volumes, there is a gradual rise in detrusor pressure. Note that there is no bladder contraction recorded, but end-filling pressure is 55 cm H2O. For both tracings: x axis represents increasing bladder volume to 200 cc; y axis represents detrusor pressure, full scale = 100 cm H2O.

Surgical treatment of upper tract complications due to neurogenic bladder The most important objective in managing NGB dysfunction is preserving renal function. Treatments to maintain healthy intravesical pressures and facilitate urine drainage achieve this objective. Multiple chapters in this textbook cover the treatment of the NGB and thus it will not be repeated here. What follows are surgical treatment options for managing chronic upper tract complications of NGB dysfunction.

Hydronephrosis Impaired urinary drainage from the kidneys due to NGB dysfunction usually results from urinary retention caused by obstruction at the bladder outlet, detrusor acontractility, or obstruction of one or both ureters from stones, stricture, or detrusor thickening from fibrosis or hypercontractility. Treatment of stones and stricture is well defined, as is urinary retention, and treatment of a poorly compliant bladder is described elsewhere in this textbook. If progressive hydronephrosis persists despite standard treatments to address obstruction or poor bladder compliance, bilateral nephrostomy tubes can be considered. However, this is rarely a viable long-term treatment option because of the difficulty in maintaining the tubes, the frequency of tube changes, and the rate of UTI. In some patients, chronic ureteral double J stents may be an option, but they require regular stent exchanges and usually require chronic Foley catheterization to drain the kidneys efficiently. Lower urinary tract reconstruction (e.g., ileal conduit or urinary reservoir with ureteral reimplantation) is an option and requires that the patient

is willing and medically able to tolerate such an operation. To complicate matters, if renal insufficiency is present, a continent reservoir may worsen renal function due to substantial reabsorption of urinary constituents that will place an increased workload on the kidneys.34 Before creating a continent urinary reservoir, the surgeon must consider the current and future neurologic function of the patient and whether the patient will be able to effectively empty the reservoir.

Vesicoureteral reflux Treatment of VUR in patients with NGB differs from the treatment of primary VUR in pediatric patients. In NGB dysfunction, VUR results from either a poorly compliant or a high-pressure bladder, where the elevated pressures have overwhelmed the normal vesicoureteral anatomy. The standard antireflux treatments alone, such as ureteral reimplantation or endoscopically administered bulking agents in the ureteral orifice, will not yield long-term efficacy in the untreated, high-pressure bladder. If treatments to diminish bladder pressure do not resolve the progression of reflux or renal insufficiency, urinary reconstruction (with or without ureteral reimplantation) or supravesical diversion will be necessary, similar to the treatment of hydronephrosis (see the Section “Hydronephrosis”).

Poorly functioning/ nonfunctioning kidney Managing the poorly functioning or nonfunctioning renal unit (degree of function typically determined by nuclear scintigraphy) is dictated by the complications. If the compromised renal unit causes recurrent infections or frequently becomes obstructed with stones, it should

Complications related to neurogenic bladder dysfunction II be surgically removed. But in a patient with significant global renal insufficiency, the decision for nephrectomy is tempered by whether the operation would hasten dialysis dependence.

Renal failure At this writing, the only treatment options for renal failure include dialysis and renal transplantation. Discussion of these options is beyond the scope of this chapter.

Summary In conclusion, NGB dysfunction affects many individuals with compromised nervous systems, particularly persons with SCI and neural tube disorders. Thanks to improvements in bladder management techniques that have evolved over the past five decades, and outcomes have improved for patients with NGB dysfunction that experience resultant VUR and renal insufficiency. However, because of the pathophysiology of both the bladder and the spinal lesions accompanying these conditions, healthcare providers must remain vigilant in evaluating and treating patients with NGB dysfunction to prevent longterm kidney damage.

References 4641. Barber KE, Cross RR Jr. The urinary tract as a cause of death in paraplegia. J Urol 1952; 67(4): 494–502. 4642. Hutch JA, Bunts RC. The present urologic status of the war-time paraplegic. J Urol 1951; 66(2): 218–28. 4643. Doran PA, Guthkelch AN. Studies in spina bifida cystica. I. General survey and reassessment of the problem. J Neurol Neurosurg Psychiatry 1961; 24: 331–45. 4644. Matlaga BR, Kim SC, Watkins SL, Kuo RL, Munch LC, Lingeman JE. Changing composition of renal calculi in patients with neurogenic bladder. J Urol 2006; 175(5): 1716–9; discussion 1719. 4645. Rule AD, Bergstralh EJ, Melton LJ 3rd, Li X, Weaver AL, Lieske JC. Kidney stones and the risk for chronic kidney disease. Clin J Am Soc Nephrol 2009; 4(4): 804–11. 4646. Comarr AE, Kawaichi GK, Bors E. Renal calculosis of patients with traumatic cord lesions. J Urol 1962; 87: 647–56. 4647. Hall MK, Hackler RH, Zampieri TA, Zampieri JB. Renal calculi in spinal cord-injured patient: Association with reflux, bladder stones, and foley catheter drainage. Urology 1989; 34(3): 126–8. 4648. Freedman LR. Natural history of urinary infection in adults. Kidney Int Suppl 1975; 4: S96–100. 4649. Asscher AW, McLachlan MS, Jones RV et al. Screening for asymptomatic urinary-tract infection in schoolgirls. A two-centre feasibility study. Lancet 1973; 2(7819): 1–4. 4650. Styles RA, Ramsden PD, Neal DE. Chronic retention of urine. The relationship between upper tract dilatation and bladder pressure. Br J Urol 1986; 58(6): 647–51.

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4651. Ghoniem GM, Bloom DA, McGuire EJ, Stewart KL. Bladder compliance in meningomyelocele children. J Urol 1989; 141(6): 1404–6. 4652. Ghoniem GM, Roach MB, Lewis VH, Harmon EP. The value of leak pressure and bladder compliance in the urodynamic evaluation of meningomyelocele patients. J Urol 1990; 144(6): 1440–2. 4653. Morales PA. Renal complications of the neurogenic bladder. In: Boyarsky S, ed. The Neurogenic Bladder. Baltimore, MD: Williams and Wilkins Co., 1967. 4654. Bors E. Neurogenic bladder. Urol Surv 1957; 7(3): 177–250. 4655. Ku JH, Choi WJ, Lee KY et al. Complications of the upper urinary tract in patients with spinal cord injury: A long-term follow-up study. Urol Res 2005; 33(6): 435–9. 4656. Lawrenson R, Wyndaele JJ, Vlachonikolis I, Farmer C, Glickman S. Renal failure in patients with neurogenic lower urinary tract dysfunction. Neuroepidemiology 2001; 20(2): 138–43. 4657. National Spinal Cord Injury Statistical Center. The 2012 Annual Statistical Report for the Spinal Cord Injury Model Systems. Table 10: Cause of Death. Birmingham, AL: University of Alabama, 2012: 8. 4658. Soden RJ, Walsh J, Middleton JW, Craven ML, Rutkowski SB, Yeo JD. Causes of death after spinal cord injury. Spinal Cord 2000; 38(10): 604–10. 4659. Woodhouse CR. Myelomeningocele in young adults. BJU Int 2005; 95(2): 223–30. 4660. Hunt G, Lewin W, Gleave J, Gairdner D. Predictive factors in open myelomeningocele with special reference to sensory level. Br Med J 1973; 4(5886): 197–201. 4661. Singhal B, Mathew KM. Factors affecting mortality and morbidity in adult spina bifida. Eur J Pediatr Surg 1999; 9(Suppl 1): 31–2. 4662. Hopps CV, Kropp KA. Preservation of renal function in children with myelomeningocele managed with basic newborn evaluation and close followup. J Urol 2003; 169(1): 305–8. 4663. Dik P, Klijn AJ, van Gool JD, de Jong-de Vos van Steenwijk CC, de Jong TP. Early start to therapy preserves kidney function in spina bifida patients. Eur Urol 2006; 49(5): 908–13. 4664. McGuire EJ, Savastano JA. Urodynamic findings and long-term ­outcome management of patients with multiple sclerosis-induced lower urinary tract dysfunction. J Urol 1984; 132(4): 713–5. 4665. Bradley WE. Urinary bladder dysfunction in multiple sclerosis. Neurology 1978; 28(9 Pt 2): 52–8. 4666. Betts CD, D’Mellow MT, Fowler CJ. Urinary symptoms and the neurological features of bladder dysfunction in multiple sclerosis. J Neurol Neurosurg Psychiatry. 1993; 56(3): 245–50. 4667. Koldewijn EL, Hommes OR, Lemmens WA, Debruyne FM, van  Kerrebroeck PE. Relationship between lower urinary tract abnormalities and disease-related parameters in multiple sclerosis. J Urol 1995; 154(1): 169–73. 4668. Barrington FJF. The effect of lesions of the hind- and mid-brain on micturition in the cat. Quart J Exp Physiol 1925; 15: 81–102. 4669. McGuire EJ, Woodside JR, Borden TA, Weiss RM. Prognostic value of urodynamic testing in myelodysplastic patients. J Urol 1981; 126(2): 205–9. 4670. Compston A, Sadovnick AD. Epidemiology and genetics of multiple sclerosis. Curr Opin Neurol Neurosurg 1992; 5(2): 175–81. 4671. Griffiths D, Tadic SD. Bladder control, urgency, and urge incontinence: Evidence from functional brain imaging. Neurourol Urodyn 2008; 27(6): 466–74. 4672. Meyer TW, Hostetter TH. Uremia. N Engl J Med 2007; 357(13): 1316–25. 4673. Tublin ME, Bude RO, Platt JF. Review. The resistive index in renal Doppler sonography: Where do we stand? AJR Am J Roentgenol 2003; 180(4): 885–92. 4674. Mills RD, Studer UE. Metabolic consequences of continent urinary diversion. J Urol 1999; 161(4): 1057–66.

64 Benign prostatic hyperplasia and lower urinary tract symptoms in men with neurogenic bladder Jeffrey Thavaseelan and Akhlil Hamid

Introduction Diagnosis and management of benign prostatic hyperplasia (BPH) in neurologically impaired patients is challenging for the urologist. The assumption that lower urinary tract symptoms (LUTS) in these patients are invariably due to the underlying neuropathology may result in inadequate treatment of BPH. However, ignoring the underlying neurological condition can exacerbate symptoms and dramatically worsen quality of life. It is therefore crucial to understand the pathophysiology underlying the neurological disease as well as the impairment caused by benign prostatic hyperplasia. In this chapter, we discuss the pathophysiology and the mechanism by which BPH results in outflow symptoms, evaluation of patients, and how specific neurological diseases may influence management and treatment options. It is not in the scope of this chapter to recap on the neurophysiology of the neurogenic bladder as it has been well detailed in other chapters.

Benign prostate hyperplasia Prevalence and pathophysiology BPH is the most common disease that affects man. Histologically, it is found in 10% of men of 40 years of age and in 90% of those 80 years of age. Only 50% of ­histologically positive patients have clinically recognizable BPH based on symptom evaluation, uroflowmetry, transrectal ultrasound, and quality-of-life measures. Nevertheless, only 20% of these patients will require a prostatectomy indicating the prevalence of histological BPH far exceeds that of clinical BPH.1,2 BPH is due to nonmalignant cellular proliferation of both  the epithelial and stromal elements of the prostate. Growth results from proliferation of fibroblasts and

smooth muscle cells as well as epithelial glandular elements primarily in the transition zone of the prostate gland.3,4 It is generally accepted that both an increase in obstructive tissue mass and the dynamic component related to smooth muscle tone results in increased prostatic urethral tension, bladder outflow obstruction, and clinical BPH.5 Anatomical evidence demonstrates that prostatic stroma accounts for 90% of BPH growth, of which 30% is composed of smooth muscle. The pharmacotherapeutic evidence for this is established. 5-alpha-reductase is the enzyme that converts testosterone to active dihydrotestosterone within the prostate, necessary for normal prostate growth. Finasteride is a 5-alpha-reductase inhibitor (5ARI) and has been used to reduce the size of the prostate gland in BPH by up to 30% to 40%. Evidence from large clinical trials investigating the efficacy of 5ARIs have shown a sustained decrease in the incidence of acute urinary retention (AUR) and/or BPH-related surgery in men with BPH and enlarged prostate.6,7 The contractile mechanism of prostatic smooth muscle is modulated by alpha adrenoceptors. The prominent place of selective alpha-1 antagonists such as tamsulosin and alfuzosin in treatment of BPH8 emphasizes the importance of prostatic smooth muscle influences in addition to increased tissue mass in the pathophysiology of BPH. Clinically, this is reflected by the enhanced efficacy of using both an alpha antagonists and a 5ARI to improve symptoms and prevent disease progression.9

Benign prostate hyperplasia and lower urinary tract symptoms: Is there a direct relationship? Traditionally, LUTS are divided between storage (irritative) and voiding (obstructive) symptoms on the basis that the former alludes to bladder dysfunction while the latter

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to outflow obstruction. Although there is some merit to this, focusing on storage versus voiding symptoms cannot definitively predict BPH as the underlying cause. So, does BPH actually cause LUTS and what is the evidence? It has always been assumed that BPH contributes to LUTS as a result of obstruction. There is little doubt that the size of prostate is directly correlated to symptom progression and, more importantly, risk of progression to AUR and surgery.10 However, obstruction only explains voiding symptoms but not storage symptoms. In fact, many men with LUTS and BPH complain of bothersome storage symptoms as much or more than voiding symptoms.11 It is estimated that nearly two-thirds of men presenting with LUTS have a mixture of storage and voiding symptoms.12 Increasingly, this is reflected by a paradigm shift in the treatment of BPH with increased use of antimuscarinic agents. It has been suggested that LUTS in BPH may not only be due to obstruction but also due to changes to the detrusor, which may or may not be related to BPH. In vitro evidence in patients with bladder outlet obstruction suggests that BPH leads to LUTS by causing morphological changes to detrusor structure, function and, consequently, bladder function.13 Furthermore, the correlation between prostate size, symptoms as measured by International Prostate Symptom Score (IPSS), and flow rates in large studies of male LUTS and BPH is not that clear cut.14 Although physical obstruction due to BPH can cause deterioration in urinary flow, the maximum flow rate achievable requires the combination of both effective detrusor function and minimal outlet resistance. Therefore, any impairment of either of these components may lead to reduced urinary flow. It is this combination of factors that likely results in the relatively poor correlation between LUTS as defined by IPSS scores and other measurable parameters such as flow rate and prostate volume. This is reflected by the inability of urodynamic testing to correlate LUTS related to BPH and obstruction. The presence or absence of obstruction does not reliably correlate with either specific symptoms or their overall severity.15

Role of ageing in benign prostate hyperplasia There is evidence that BPH may be part of a spectrum of pathophysiological processes that results in LUTS, erectile dysfunction (ED), and chronic pelvic pain syndrome (CPPS).16 Increasingly, strong associations between ED and LUTS have been demonstrated whereby treatment of one appears to significantly improve the other.17,18 This ­association may be explained by changes that occur due to ageing. It is well established that ageing is associated with increased LUTS.19 It is also notable that the incidence of LUTS increases with age in both men and women, which suggests a non-BPH related cause to the development

of age-related LUTS. In a ­ population-based study of men aged 40–79 years in Olmstead county,  Minnesota, ­moderate to severe symptoms were seen in 13% of men aged 40–49 years and in 28% of men older than 70 years.20 Given that we know the histological p ­ revalence of BPH is much greater, clearly there are a large ­number of men with BPH who do not suffer LUTS. It is not fully understood why ageing is associated with increasing LUTS. It is possible that changes in detrusor morphology, innervation, and partial denervation may be linked to increased detrusor excitability but also reduced contractility resulting in reduced urinary flow and incomplete emptying.16 Interestingly, surgical treatment of outlet obstruction remains a highly effective therapy for LUTS, with very good success rates superior to those of medical therapy in many patients regardless of whether they have proven outflow obstruction or not in association with the LUTS.21 The mechanism for this remains a mystery in the treatment of BPH. One theory proposed by Bushman compares the pathophysiology of BPH to that of c­ ongestive cardiac failure. He proposed that the ageing bladder has many similarities with the ageing heart and therefore, reducing the after load, in this case by performing a transurethral prostatectomy (TURP), results in better bladder function and improved symptoms.16 Clearly then, in the ageing patient, it can be difficult to establish whether BPH is the cause of the clinical presentation or simply an innocent bystander. Therefore, in patients who have LUTS, are older and more likely to have BPH with a neurogenic bladder, the cause of LUTS is a complex clinical problem and hence a diagnosis and therefore treatment becomes less clear cut and at times impossible.

Assessment The assessment of a male presenting with LUTS is well described in several established guidelines.22,23 Figure 64.1 illustrates diagnostic work-up of LUTS in men over the age of 40 years.23 It is important to note that the presence of neurological disease automatically necessitates further evaluation. First, a detailed history is obtained with particular emphasis on delineating the symptoms including the presence or absence of incontinence and also establishing a comparative timeline of the symptoms and the neurological disease. It is important to note LUTS due to neurological diseases may precede the diagnosis and may not be related to BPH. For example, in multiple system atrophy (MSA), LUTS may be the first manifestation, seen significantly before the diagnosis is made.24 Physical examination should include a focused urological assessment with examination of the prostate and neurological system. The latter should include perianal sensation, anal tone, and bulbocavernosus reflex. This is particularly relevant in sacral neurological pathology.

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Figure 64.1 Algorithm showing recommended assessment for patients with BPH. Note that additional tests are necessary for patients with neurological diseases.23 (Reproduced with permission from Oelke, M et al., Guidelines on the Management of Male Lower Urinary Tract Symptoms (LUTS), incl. Benign Prostatic Obstruction (BPO). (Available at http://www.uroweb.org/gls/pdf/12_Male_LUTS_LR.pdf; accessed September 12, 2013.)

Simple tools that further assist in making a diagnosis and treatment decision include a 3-day bladder diary, urinalysis, and assessment of flow rate and residual volume. 22 In the neurologically impaired patient with LUTS, a renal ultrasound and serum creatinine are also recommended.25 The extent to which one proceeds with further detailed evaluation of these patients is dependent on several factors. If any of the above assessments reveals an abnormality, in particular hydronephrosis with or without an elevated creatinine, then we recommend proceeding to urodynamic and possible cystoscopic evaluation. If the initial assessment has no untoward findings and minimally bothersome symptoms, then urodynamics are arguably not indicated. It is however, important to continue with long-term surveillance as some of these patients are at risk of silent upper tract deterioration. We recommend, in such patients, performing a renal ultrasound and serum creatinine on a 6- to 12-monthly basis once symptoms are stable.

In those with significant symptoms and underlying ­neurological disease, further evaluation is required to exclude other causes and, in the older male, BPH. Urodynamics are essential in this situation as is continued close monitoring to avoid upper tract deterioration. Risk factors for renal tract deterioration include detrusor–external sphincter dyssynergia (DESD), poor bladder compliance, urethral obstruction, and increased post-void residual (PVR). 25

Urodynamic testing Urodynamic testing is an essential element in the evaluation of patients with LUTS and neurological disease. Although not readily available to all general urologists, videourodynamics or voiding cystourethrogram (VCUG) are recommended as they may help in the differentiation of prostatic or sphincteric obstruction because of DESD. The use of electromyography (EMG), although ideal, is again not readily available in many centers. Its use is not

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well standardized and interpretation can be influenced by type of electrode (patch or needle), type of needle used, and electrode placement.26 However, when used properly, it is a useful tool for demonstration of DESD. There are primarily five questions that need to be answered when performing urodynamic assessment: 1. 2. 3. 4.

Is there detrusor overactivity (DO) during fill phase? Is there DESD? Is the bladder compliant? Is there obstruction during voiding and if so at which level? 5. What is the contractility of the bladder during voiding?

Details of the abovementioned have been provided in previous chapters and so we will only briefly outline certain aspects of urodynamic assessment. DO may be neurogenic or nonneurogenic as is the case in BPH.27 Between 46% and 66% of men with prostatic obstruction may have concurrent DO.28 In men with BPH and underlying neurological disease, it can be difficult to determine the true cause of DO. The question arises whether the urodynamic characteristics of DO can be used to differentiate between neurogenic and nonneurogenic causes. The definition of DO is well described by the International Continence Society (ICS) but its classification does not discriminate the underlying cause. Several publications have attempted to classify DO characteristics into clinical groups with varied success.29,30 Kageyama et al.30 published a classification of detrusor hyperreflexia and likelihood of persisting problems post TURP.30 They described three patterns: Pattern 1 is continual with sporadic onset and offset of detrusor hyperreflexia (phasic); Pattern 2 is a single episode of DO occurring at a bladder volume of less than 160 mL; and Pattern 3 is a single episode occurring >160 mL. Patterns 1 and 2 are suggestive of underlying neurogenic pathology and as a consequence demonstrate persistent postoperative symptoms, particularly of urgency.30 Despite these attempts, DO characteristics have not reliably been shown to differentiate neurogenic and nonneurogenic causes and in many cases will require an individualized holistic clinical approach. A helpful urodynamic finding to differentiate neurogenic DO and nonneurogenic DO is the additional finding of DESD. DESD is defined by the ICS as a “detrusor contraction concurrent with an involuntary contraction of the urethral and/or periurethral striated muscle.” Occasionally flow can be prevented altogether and can only be diagnosed with urodynamic studies. It only arises in the patient with pathology between the pontine micturition center (PMC) and the sacral micturition center (S2–S4).31 Examples of neurological diseases that may result in DESD include spinal cord injury, multiple sclerosis, spinal dysraphism, and transverse myelitis.26 Blaivas, in the previous edition,

describes three main types of DESD.25 Type I refers to a progressive increase in external urethral sphincter (EUS) activity, which peaks at maximal detrusor pressure. At this point the sphincter suddenly relaxes and unobstructed voiding occurs (Figure 64.2). Type 2 refers to sporadic contractions of the EUS throughout detrusor contraction resulting in intermittent flow (Figure 64.3). Type 3 results in continuous sphincter contraction throughout detrusor contraction resulting in inability to void (Figure 64.4).25,26 Weld and Graney simplified the classification into intermittent or continuous stating that the latter was more likely related to complete spinal cord lesion and higher bladder pressures.32 VCUG may show the classical dilated bladder neck and posterior urethra with narrowing at the external sphincter with voiding as shown in Figure 64.5. The diagnosis of DESD is important in men with LUTS and should be differentiated from bladder outlet obstruction (BOO) secondary to benign prostatic enlargement (BPE) using VCUG with EMG. It must also be remembered that in a patient who does not have spinal cord pathology as described above, a similar discrepancy can be seen between detrusor and sphincter activity but is referred to as dysfunctional voiding. In these patients, there is a voluntary or involuntary attempt to abort micturition. Careful interpretation of EMG in such patients may reveal that EMG activity is reduced just before detrusor contraction (as with normal micturition) and then intermittently increases with the patient contracting and relaxing the sphincter.25 In the absence of DESD, we feel that the diagnosis of LUTS due to BPH requires urodynamic demonstration of

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Figure 64.2 Type 1 detrusor–external sphincter dyssynergia (DESD). Involuntary detrusor contraction is preceded by involuntary sphincter contraction. At the peak of detrusor contraction, the striated sphincter relaxes suddenly and completely (EMG silence) and unobstructed voiding ensues.

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the diagnosis of outflow obstruction based primarily on the Abrams–Griffiths and Schafer nomograms.34 Using this nomogram, men can be divided into three groups according to their Bladder Outlet Obstruction Index (BOOI) (Figure  64.6).34,35 For a more complete assessment it is ideal to add a bladder contractility component (Figure 64.7) The Bladder Contractility Index (BCI) was described by Schafer and can be used to add a contractility component to the ICS nomogram.35 Figure 64.8 shows a composite nomogram with groups ranging from unobstructed and strong contractility to obstructed and weak contractility.35 A point to consider is that many patients with neurogenic DO experience uncontrollable involuntary voids during urodynamic studies. Although there is evidence that the pressure–flow relationship from an involuntary void is still valid,36 ideally, in this situation one should repeat the test to include a voluntary void if possible.

Underlying disease The following discussion concentrates on special circumstances that must be considered in patients with certain underlying diseases.

Parkinson’s disease Q pves pabd pdet

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Figure 64.4 Type 3 DESD. The involuntary detrusor contraction is preceded by the involuntary sphincter contraction. There is a crescendo– decrescendo pattern in EMG activity and voiding is obstructed throughout.

obstruction at the level of the posterior urethra. VCUG is helpful in demonstrating narrowing of the posterior urethra during voiding. Although there are various parameters that can be used to detect obstruction such as detrusor opening pressure, minimum voiding pressure, and maximum detrusor pressure; the most widely used is detrusor pressure at maximum flow (Pdet at Qmax).33 In 1997, the ICS published a nomogram for

Idiopathic Parkinson’s disease (PD) is defined as a movement disorder characterized by loss of dopaminergic neurons in the substantia nigra and the development Lewy bodies; however, there are many non-motor symptoms in PD that suggest involvement of other regions.24,37 LUTS associated with PD is primarily a disorder of ­bladder storage rather than voiding; however, the severity of the symptoms tends to be exacerbated by the immobility, cognitive impairment, and poor manual dexterity that are typically seen in this condition.37 The most common symptoms described are nocturia (77.5%), urgency (36.7%), and increased urinary frequency (32.6%), which reflects DO commonly seen in urodynamic testing.37,38 There may also be voiding symptoms including hesitancy, straining to void, and diminished flow. Historically, this was thought to be due to pseudodyssnergia, where the patient voluntarily contracts their pelvic floor to prevent leakage or sphincter bradykinesia.39 However, it is not as common as previously thought and in the older PD patient, BPH may be the cause of voiding symptoms. Furthermore, there is also evidence to suggest higher resting urethral pressures secondary to levodopa or its metabolites, a common treatment for PD, which leads to increased bladder neck tone via the alpha-1 adrenoreceptor.40 Clearly, urodynamic studies are mandatory in patients with PD to determine treatment. The key question is, if outflow obstruction can be demonstrated and there is

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clinical evidence of an enlarged prostate, is it safe to perform surgery if conservative therapy fails? Roth et al.41 published a series of patients with PD who underwent TURP. Patients were classified using the Hoehn and Yahr

scale42 with the median grade being 2. Of the 23 patients undergoing TURP, 52% were obstructed according to the Abrams–Griffiths nomogram, 22% equivocal, and 26% unclassified as they could not void but did demonstrate

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increase in detrusor pressure. At 3 years, success following TURP was 70%. Of the 10 patients with urge urinary incontinence, 5 resolved, and 3 improved; no patients experienced denova incontinence.41 Thus, surgical treatment of prostatic obstruction in a patient with definite PD seems reasonable. It is notable that previously, a high incidence of incontinence had been reported after TURP in patients with PD.43 However, in this study, it was noted that some of these patients were likely to have had MSA.24 Indeed, accurately distinguishing between PD and MSA is critical before surgical intervention for BPH is considered. The reason for this is outlined in the following section.

Multiple system atrophy MSA is a progressive degenerative neurological disorder, which shares symptoms with PD and is considered

Composite nomogram allowing categorization of patients into nine zones and therefore six groups, according to BOOI and BCI.35 (Reproduced with permission from Abrams, P, BJU Int, 84, 14–15, 1999.)

a form of atypical parkinsonism. Patients may also suffer from variable degrees of cerebellar ataxia and autonomic dysfunction.44 Although sometimes misdiagnosed as PD, its underlying neuropathology is more extensive involving not only the substantia nigra, but other areas such as cerebellar hemisphere, inferior olivary nucleus, locus coeruleus (PMC), intermediolateral cell column, and Onuf ’s nucleus.44 Consistent with the sites of abnormal pathology, urinary symptoms are seen in a significant proportion (>80%) of MSA patients and tend to occur earlier in the disease process than with PD.45 Particular genitourinary findings that are more common to MSA as opposed to PD include increased post-micturition volume (>100 mL), open bladder neck at the start of filling on VCUG, and DESD.40 Most important, however, is the recognition that in MSA there is denervation of the EUS as a consequence of the involvement of Onuf ’s nucleus.40,41 This is best diagnosed using EMG. Clearly therefore, surgical treatment of BPH in MSA patients could result in genuine stress incontinence. If EMG is not available, caution must be taken if considering a TURP in a patient presenting with a diagnosis of PD but who has clinical features that are more extensive such as pyramidal or cerebellar signs, erectile dysfunction, severe postural hypotension, and marked urinary incontinence. In this situation, MSA should be suspected and investigated before proceeding to surgery.46

Stroke Prevalence of urinary incontinence following stroke has been reported to range between 28% and 79%.47 The most common cause of incontinence was traditionally thought to be DO, however urodynamic testing in these patients has shown that DO, acontractility, and also normal bladder function can be evident.47,48 In this cohort, the symptoms

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described as most bothersome by patients include nocturia (53%), urgency (48%), and daytime frequency (40%).49 In addition to the disruption of the micturition neural control, other factors thought to contribute to poststroke voiding symptoms include cognitive and language deficits, concurrent neuropathy, or medication use.50 Interestingly, neither the localization of the stroke nor the laterality has been shown to predict the occurrence of incontinence clinically or in urodynamic testing.51 However, it has been documented that the nature of the stroke (i.e., hemorrhagic or ischemic) may influence the type of voiding dysfunction. Han et al.52 suggested that in ischemic stroke, patients were more likely to have overactivity compared with underactivity, whereas the converse was true for hemorrhagic stroke. As the prevalence of stroke increases with age so does the presence of outflow obstruction. Urodynamic testing is crucial in delineating the bladder dysfunction poststroke and allows the demonstration of prostatic obstruction if present. Lum and Marshall53 published a series of 39 patients who had a history of stroke and underwent endoscopic prostatectomy. The criteria influencing outcome included age of the patient, timing of the operation, site of the stroke, degree of neurological deficit at the time of operation, and indication for the operation. Better outcomes were achieved in patients under the age of 70 and who had their operation more than 1 year after the stroke.53 In addition, patients with left cerebral hemisphere lesions did better than those with right or bilateral lesions.53

Diabetes mellitus It is unclear if patients with diabetes are at risk of a greater incidence of BPH. Some studies have shown that men diagnosed with BPH are more likely to have diabetes than the general population and associated with more severe symptoms.54 In contrast, there is also a suggestion that metabolic factors may increase the rate of prostatic enlargement, thus influencing the development and progression of LUTS.55 Either way, it is likely that the severity of symptoms can be explained by the degree of bladder dysfunction that is found in patients with diabetes. Bladder dysfunction is a common sequela to diabetes and usually secondary to peripheral neuropathy. Symptoms include decreased sensation, increased bladder capacity, DO, urinary incontinence, poor urinary flow rate, and incomplete bladder emptying with high PVRs. The prevalence of urodynamically diagnosed bladder DO varies between 25% and 90% and can either exist with or without impaired detrusor contractility.56 The pathophysiology behind this may not only be due to peripheral neuropathy but also central neuropathy, with up to 76% of diabetic patients with DO having multiple cerebral infarctions on MRI (58). 57 Indeed, urinary incontinence is a greater complication

than neuropathy and nephropathy in diabetes.58 In addition, there are other ways in which diabetes may give rise to LUTS. These include diabetic polyuria, neurogenic dysfunction of detrusor smooth muscle cells, and a greater risk of symptomatic urinary tract infections. Certainly, the modern understanding of diabetic cystopathy is a combination of impaired detrusor contractility leading to incomplete emptying but also elements of DO and increased sensation.59 Therefore, the use of urodynamic testing is absolutely crucial in the management of patients with diabetes and LUTS. In a study by Kaplan et al., of 182 patients, 55% had DO, 23% had impaired detrusor contractility, and 10% had bladder atonia. Significantly, 36% of patients were also found to have bladder outflow obstruction.59 In summary therefore, patients with diabetes may be at greater risk of developing BPH. The pathophysiology of greater significance, however, is likely to be the degree of bladder cystopathy. The presence of DO in diabetic older men may be either due to diabetes or secondary to BPH or both. These may coexist and contribute to the worsening of LUTS. In either case, the management of these patients should be tailored according to severity of symptoms and urodynamic findings. The practical management of diabetic cystopathy should start with a thorough history of symptoms but also a review of medications. Calcium channel blockers, anticholinergics, antidepressants, and antipsychotics can all cause a degree of voiding dysfunction. Vinik et al.60 recommend screening that includes renal function, residual urine, and urodynamic studies in any diabetic patient with recurrent urinary tract infections, pyelonephritis, incontinence, or palpable bladder. In a typical patient with diabetes, urodynamic testing often demonstrates lack of sensation on filling with an occasional moderate increase in detrusor pressure. There is often prolonged voiding with relatively low peak flow and residual urine. Therefore, it is important to recognize that in patients with diabetes, DO and detrusor underactivity may coexist leading to a confusing combination of symptoms of urgency, frequency, and incomplete emptying. Therefore, the management of LUTS in this group of patients should be tailored on an individual basis. Poor glycemic control needs to be addressed as this may increase urine output and therefore incontinence, frequency, and urgency. Bladder retraining should be introduced (e.g., scheduled voiding every 3 to 4 hours) to minimize the impact of reduced bladder sensation. Significant residual urine complicated by renal impairment and UTI should be treated with intermittent self-catheterization. When BPH is thought to contribute to the overall symptoms, it is important that the abovementioned measures are introduced, and TURP performed only in the event failure of less invasive treatments. Alpha blockers and/or 5ARIs should be used in conjunction with other measures when appropriate.

Benign prostatic hyperplasia and lower urinary tract symptoms Bladder outflow surgery can improve symptoms overall in those patients with prostatic obstruction demonstrated by urodynamic testing; however, patients need to be counseled appropriately before commencing surgery.

Multiple sclerosis Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) leading to multiple physical disabilities. MS can present with various urological manifestations. Bladder dysfunction is common in MS, affecting 80%–100% of patients during the course of the disease and has a severe effect on patients’ quality of life.61 Patients with MS can present with abnormalities to the detrusor, EUS, or both, and therefore may have either failure to store or failure to empty or a combination of both. Indeed, 60%–80% of patients show neurogenic DO, which results in a functionally small capacity bladder and may present with urgency, frequency, and urge incontinence. 20% suffer from impaired detrusor contractility and atonic bladder presenting with overflow incontinence, poor flow, and incomplete emptying.62 Furthermore, 25% of patients have a degree of DESD from spinal cord involvement. DESD can lead to incomplete emptying,

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urinary retention, or present with urgency, frequency, and incontinence.63 Less commonly, MS in the sacral cord can produce a hypotonic bladder that empties poorly. These factors often lead to UTIs in MS patients. 64 In addition, in 10% of MS patients, the combination of abnormal lower urinary tract function and infection can lead to complications such as renal failure, hydronephrosis, and bladder and kidney stones. Hence, it is clear that symptoms alone cannot distinguish between the types of neurogenic bladder caused by MS. As MS is primarily a disease that occurs in the younger age group and more so in women, the issue of bladder dysfunction in relation to BPH is rare. In these rare cases, differentiating LUTS associated with BPH from that which is caused by MS becomes a very difficult task. Certainly, urodynamic testing is crucial to delineate the pathophysiological cause but is likely to be more useful in ensuring the absence of DSD as the cause of obstruction. EMG can be useful in this setting (Figure 64.9). It should also be borne in mind that MS is a progressive disease, and  medium/long-term surgical outcomes may be negatively impacted by new onset LUTS secondary to evolving neurology. Therefore, it is our belief that if an older man who is felt to have LUTS secondary to BPH, conservative treatments should be explored thoroughly before proceeding to surgery.

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Figure 64.9 Urodynamic test in MS male with LUTS and BPH. Trace shows high pressure, poor flow but increased EMG activity during void indicative of DESD rather than BPH being the cause of LUTS.

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Conclusion Diagnosis and management of LUTS and BPH in the older man with underlying neurological disease is complex. The potential for an adverse outcome following surgical intervention in these patients with BPH reinforces the importance of a detailed clinical history and knowledge of how neurological conditions present themselves with respect to LUTSs. VCUG with/without EMG is an essential part of the diagnostic process, but it must be recognized that it is not always possible to discriminate between LUTS secondary to BPH and LUTS secondary to neurological disease. As a consequence, in many circumstances conservative treatment is preferable to irreversible surgical intervention.

References 4675. Barry MJ. Epidemiology and natural history of benign prostatic hyperplasia. Urol Clin North Am 1990; 17: 495–507. 4676. Garraway WM, Collins GN, Lee RJ. High prevalence of benign prostatic hypertrophy in the community. Lancet 1991; 338: 469–71. 4677. Bierhoff E, Vogel J, Benz M et al. Stromal nodules in benign prostatic hyperplasia. Eur Urol 1996; 29: 345–54. 4678. Kirby RS. Benign prostatic hyperplasia. In: Whitfield H, Kirby RS, Duckett JW, eds. Textbook of Genitourinary Surgery. Oxford, United Kingdom: Blackwell Science, 1999: 509–31. 4679. Kenny B, Ballard S, Blagg J, Fox D. Pharmacological options in the treatment of benign prostatic hyperplasia. J Med Chem 1997; 40: 1293–315. 4680. Boyle P, Roehrborn C, Harkaway R et al. 5-Alpha reductase inhibition provides superior benefits to alpha blockade by preventing AUR and BPH-related surgery. Eur Urol 2004; 45: 620–6; discussion 6–7. 4681. Roehrborn CG. Meta-analysis of randomized clinical trials of finasteride. Urology 1998; 51: 46–9. 4682. Chapple CR. Medical therapy and quality of life. Eur Urol 1998; 34(Suppl 2): 10–7; discussion 46. 4683. McVary KT, Roehrborn CG, Avins AL et al. Update on AUA guideline on the management of benign prostatic hyperplasia. J Urol 2011; 185: 1793–803. 4684. Roehrborn CG, Bruskewitz R, Nickel GC et al. Urinary retention in patients with BPH treated with finasteride or placebo over 4 years. Characterization of patients and ultimate outcomes. The PLESS Study Group. Eur Urol 2000; 37: 528–36. 4685. Roehrborn CG. Male lower urinary tract symptoms (LUTS) and benign prostatic hyperplasia (BPH). Med Clin North Am 2011; 95: 87–100. 4686. Irwin DE, Milsom I, Hunskaar S et al. Population-based survey of urinary incontinence, overactive bladder, and other lower urinary tract symptoms in five countries: Results of the EPIC study. Eur Urol 2006; 50: 1306–14; discussion 14–5. 4687. Mirone V, Imbimbo C, Longo N, Fusco F. The detrusor muscle: An innocent victim of bladder outlet obstruction. Eur Urol 2007; 51: 57–66. 4688. Ezz el Din K, Kiemeney LA, de Wildt MJ, Debruyne FM, de la Rosette JJ. Correlation between uroflowmetry, prostate volume, postvoid residue, and lower urinary tract symptoms as measured by the International Prostate Symptom Score. Urology 1996; 48: 393–7. 4689. Nitti VW, Kim Y, Combs AJ. Correlation of the AUA symptom index with urodynamics in patients with suspected benign prostatic hyperplasia. Neurourol Urodyn 1994; 13: 521–7; discussion 7–9.

4690. Bushman W. Etiology, epidemiology, and natural history of benign prostatic hyperplasia. Urol Clin North Am 2009; 36: 403–15. 4691. Gacci M, Eardley I, Giuliano F et al. Critical analysis of the relationship between sexual dysfunctions and lower urinary tract symptoms due to benign prostatic hyperplasia. Eur Urol 2011; 60: 809–25. 4692. Rosen RC, Wei JT, Althof SE et al. Association of sexual dysfunction with lower urinary tract symptoms of BPH and BPH medical therapies: Results from the BPH Registry. Urology 2009; 73: 562–6. 4693. Guzzo TJ, Drach GW. Major urologic problems in geriatrics: Assessment and management. Med Clin North Am 2011; 95: 253–64. 4694. Jacobsen SJ, Jacobson DJ, Girman CJ et al. Treatment for benign prostatic hyperplasia among community dwelling men: The Olmsted County study of urinary symptoms and health status. J Urol 1999; 162: 1301–6. 4695. van Venrooij GE, van Melick HH, Boon TA. Comparison of outcomes of transurethral prostate resection in urodynamicallyobstructed versus selected urodynamicallyunobstructed or equivocal men. Urology 2003; 62: 672–6. 4696. American Urological Association. Guidelines on the management of benign prostatic hyperplasia, 2010. Available at: http://www .auanet.org/education/guidelines/benign-prostatic-hyperplasia. cfm; accessed September 12, 2013. 4697. Oelke M, Bachmann A, Descazeaud A et al. Guidelines on the management of male lower urinary tract symptoms (LUTS), incl. benign prostatic obstruction (BPO), 2012. Available at: http://www.uroweb .org/gls/pdf/12_Male_LUTS_LR.pdf; accessed September 12, 2013. 4698. Fowler CJ, Dalton C, Panicker JN. Review of neurologic diseases for the urologist. Urol Clin North Am 2010; 37: 517–26. 4699. Blaivas J. Benign prostatic hyperplasia and lower urinary tract symptoms in men with neurogenic bladder. In: Corcos ES, Schik E, eds. Textbook of Neurogenic Bladder: Adults and Children. Boca Raton, FL: CRC Press, 2008: 860–78. 4700. Bascu C-D, Chan L, Tse V. Diagnosing detrusor sphincter dyssynergia in the neurological patient. BJU Int 2012; 109: 31–4. 4701. Abrams P, Cardozo L, Fall M et al. The standardisation of terminology of lower urinary tract function: Report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002; 21: 167–78. 4702. Blaivas JG, Marks BK, Weiss JP, Panagopoulos G, Somaroo C. Differential diagnosis of overactive bladder in men. J Urol 2009; 182: 2814–7. 4703. Flisser AJ, Walmsley K, Blaivas JG. Urodynamic classification of patients with symptoms of overactive bladder. J Urol 2003; 169: 529–33; discussion 33–4. 4704. Kageyama S, Watanabe T, Kurita Y et al. Can persisting detrusor hyperreflexia be predicted after transurethral prostatectomy for benign prostatic hypertrophy? Neurourol Urodyn 2000; 19: 233–40. 4705. Sadananda P, Vahabi B, Drake MJ. Bladder outlet physiology in the context of lower urinary tract dysfunction. Neurourol Urodyn 2011; 30: 708–13. 4706. Weld KJ, Graney MJ, Dmochowski RR. Clinical significance of detrusor sphincter dyssynergia type in patients with post-traumatic spinal cord injury. Urology 2000; 56: 565–8. 4707. Eri LM, Wessel N, Tysland O, Berge V. Comparative study of pressureflow parameters. Neurourol Urodyn 2002; 21: 186–93. 4708. Griffiths D, Hofner K, van Mastrigt R et al. Standardization of terminology of lower urinary tract function: Pressure-flow ­studies of voiding, urethral resistance, and urethral obstruction. International Continence Society Subcommittee on Standardization of Terminology of Pressure-Flow Studies. Neurourol Urodyn 1997; 16: 1–18. 4709. Abrams P. Bladder outlet obstruction index, bladder contractility index and bladder voiding efficiency: Three simple indices to define bladder voiding function. BJU Int 1999; 84: 14–5. 4710. Dorkin TJ, Leonard AS, Pickard RS. Can bladder outflow obstruction be diagnosed from pressure flow analysis of voiding initiated by involuntary detrusor overactivity? J Urol 2003; 170: 1234–6.

Benign prostatic hyperplasia and lower urinary tract symptoms 4711. Ragab MM, Mohammed ES. Idiopathic Parkinson’s disease patients at the urologic clinic. Neurourol Urodyn 2011; 30: 1258–61. 4712. Vaughan CP, Juncos JL, Trotti LM, Johnson TM 2nd, Bliwise DL. Nocturia and overnight polysomnography in Parkinson’s disease. Neurourol Urodyn 2013; 32: 1080–5. 4713. Galloway NT. Urethral sphincter abnormalities in Parkinsonism. Br J Urol 1983; 55: 691–3. 4714. Sakakibara R, Hattori T, Uchiyama T, Yamanishi T. Videourodynamic and sphincter motor unit potential analyses in Parkinson’s disease and multiple system atrophy. J Neurol Neurosurg Psychiatry 2001; 71: 600–6. 4715. Roth B, Studer UE, Fowler CJ, Kessler TM. Benign prostatic obstruction and Parkinson’s disease—Should transurethral resection of the prostate be avoided? J Urol 2009; 181: 2209–13. 4716. Goetz CG, Poewe W, Rascol O et al. Movement Disorder Society Task Force report on the Hoehn and Yahr staging scale: Status and recommendations. Mov Disord 2004; 19: 1020–8. 4717. Staskin DS, Vardi Y, Siroky MB. Post-prostatectomy continence in the parkinsonian patient: The significance of poor voluntary sphincter control. J Urol 1988; 140: 117–8. 4718. Ahmed Z, Asi YT, Sailer A et al. The neuropathology, pathophysiology and genetics of multiple system atrophy. Neuropathol Appl Neurobiol 2012; 38: 4–24. 4719. Stefanova N, Bucke P, Duerr S, Wenning GK. Multiple system atrophy: An update. Lancet Neurol 2009; 8: 1172–8. 4720. Eardley I, Quinn NP, Fowler CJ et al. The value of urethral sphincter electromyography in the differential diagnosis of parkinsonism. Br J Urol 1989; 64: 360–2. 4721. McKenzie P, Badlani GH. The incidence and etiology of overactive bladder in patients after cerebrovascular accident. Curr Urol Rep 2012; 13: 402–6. 4722. Linsenmeyer TA. Post-CVA voiding dysfunctions: Clinical insights and literature review. Neuro Rehabilitation 2012; 30: 1–7. 4723. Tibaek S, Gard G, Klarskov P et al. Prevalence of lower urinary tract symptoms (LUTS) in stroke patients: A cross-sectional, clinical survey. Neurourol Urodyn 2008; 27: 763–71. 4724. Gelber DA, Good DC, Laven LJ, Verhulst SJ. Causes of urinary incontinence after acute hemispheric stroke. Stroke 1993; 24: ­ 378–82.

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4725. Kim TG, Yoo KH, Jeon SH, Lee HL, Chang SG. Effect of dominant hemispheric stroke on detrusor function in patients with lower urinary tract symptoms. Int J Urol 2010; 17: 656–60. 4726. Han KS, Heo SH, Lee SJ, Jeon SH, Yoo KH. Comparison of urodynamics between ischemic and hemorrhagic stroke patients; can we suggest the category of urinary dysfunction in patients with cerebrovascular accident according to type of stroke? Neurourol Urodyn 2010; 29: 387–90. 4727. Lum SK, Marshall VR. Results of prostatectomy in patients following a cerebrovascular accident. Br J Urol 1982; 54: 186–9. 4728. Michel MC, Mehlburger L, Schumacher H, Bressel HU, Goepel M. Effect of diabetes on lower urinary tract symptoms in patients with benign prostatic hyperplasia. J Urol 2000; 163: 1725–9. 4729. Timms BG, Hofkamp LE. Prostate development and growth in benign prostatic hyperplasia. Differentiation 2011; 82: 173–83. 4730. Kirschner-Hermanns R, Daneshgari F, Vahabi B et al. Does diabetes mellitus-induced bladder remodeling affect lower urinary tract function? ICI-RS 2011. Neurourol Urodyn 2012; 31: 359–64. 4731. Yamaguchi C, Sakakibara R, Uchiyama T et al. Overactive bladder in diabetes: A peripheral or central mechanism? Neurourol Urodyn 2007; 26: 807–13. 4732. Daneshgari F, Liu G, Birder L, Hanna-Mitchell AT, Chacko S. Diabetic bladder dysfunction: Current translational knowledge. J Urol 2009; 182: S18–26. 4733. Kaplan SA, Te AE, Blaivas JG. Urodynamic findings in patients with diabetic cystopathy. J Urol 1995; 153: 342–4. 4734. Vinik AI, Maser RE, Mitchell BD, Freeman R. Diabetic autonomic neuropathy. Diabetes Care 2003; 26: 1553–79. 4735. Nicholas R, Young C, Friede T. Bladder symptoms in multiple sclerosis: A review of pathophysiology and management. Expert Opin Drug Saf 2010; 9: 905–15. 4736. Tubaro A, Puccini F, de Nunzio C et al. The treatment of lower urinary tract symptoms in patients with multiple sclerosis: A systematic review. Curr Urol Rep 2012; 13: 335–42. 4737. Mahfouz W, Corcos J. Management of detrusor external sphincter dyssynergia in neurogenic bladder. Eur J Phys Rehabil Med 2011; 47: 639–50. 4738. Hennessey A, Robertson NP, Swingler R, Compston DA. Urinary, faecal and sexual dysfunction in patients with multiple sclerosis. J Neurol 1999; 246: 1027–32.

Part X Sexual dysfunction in neurologic disorders

65 Pathophysiology of male sexual dysfunction after spinal cord injury Pierre Denys and Clément Chéhensse†

This chapter is dedicated in loving memory to Clément Chéhensse.

Introduction After spinal cord injury (SCI), the impairment of neural command and its consequences on genitosexual organs have been extensively described in humans. Overall, sexual activity and satisfaction decrease1 but sexuality remains a major concern, especially after the first year after injury.2 Moreover, recovery of sexual function is the first priority for paraplegic patients before locomotion, after the acute reha­bilitation phase.3 The majority of traumatic spinal ­cord-injured patients are male and young at the time of injury.4,5 The impact of the neurologic lesion and its physiologic consequences must be balanced by the fact that the quality of  life satisfaction with respect to sexuality after ­spinal cord lesion has a significant correlation with the quality of relationship with a sexual partner, with sexual desire, and with the mental well-being of the subject, but not to preserved sexual abilities.2,6 Moreover, the type and enjoyment of sexual activities engaged substantially change after SCI with, for instance, a decrease in vaginal intercourse.1

Impact of spinal cord injury on sexual behavior Male sexual behavior comprises desire, erection, ejaculation, and orgasm (Chapter 4). About 40% of SCI men report to be dissatisfied with their sexual life.1,2 Sexual behavior is controlled by supraspinal structure and spinal centers.7 Impairment in sexual behavior can be due to lesion of the spinal centers per se (lower thoracic, lumbar, or sacral) and/or by lesion of descending and/or ascending pathways from and to the brain, respectively. The impact of SCI on self-esteem and body image can also have a

deleterious effect on sexual behavior.2 After complete SCI, connections between the autonomic i.e. sympathetic and parasympathetic, and somatic centers and the brain are disrupted. Except for desire and central arousal, the other components of sexual response, i.e., erection, ejaculation, and general physiological events during sexual climax can occur in case of complete spinal cord lesion, independently from any brain control. In able-bodied patients, ejaculation and orgasm occurs concomitantly. In clinical practice, it is well known that SCI patients have specific problems such as dissociation between desire, erection, ejaculation, and orgasm.8,9 As for able-bodied men, SCI men’s sexual concerns, activities, satisfaction, and responsiveness to treatments evolve with age. This should be kept in mind by physicians to adapt sexual counseling and management.10,11

Desire and arousal After injury, desire for sexual activity is reduced and about 20% of SCI men describe their sexual desire to be weak and decreased as compared to prior injury. The ability to become sexually aroused tends to be reduced after SCI. Moreover, areas specified by SCI men to induce sexual arousal when stimulated change as compared to prior injury. Even if genitals remain the most commonly reported area, some men develop new areas of arousal at the level of their lesion but many more above the level of injury, for instance, the head, neck, and torso. This “arousal neuroplasticity” is unsurprisingly more frequently reported by men with complete SCI.1,12–14 Underdiagnosed traumatic brain injuries in SCI patients15 may lead to cognitive, behavioral, and neuroendocrine impairment that might affect sexual behavior.16 Besides traumatic brain injury, total testosterone serum levels can be low after isolated SCI.13,17,18 However, a strict correlation between testosterone level and sexual function has not been evidenced in SCI patients.13,19

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Erection Erection is often impaired after SCI. In response to penile glans and perineal stimulation, reflexogenic erection can occur. It requires at least partial preservation of the sacral parasympathetic centers (segments S2–S4).20 In response to psychogenic stimulation, i.e., thoughts, dreams, visual, auditory or olfactory stimuli, psychogenic erection can occur. It requires the sympathetic centers to be located above the injury (Figure 65.1).20,21 Cerebral outputs to the spinal sympathetic centers for erection (segments T11– L2) relieve the vasoconstrictor tone and thus the sympathetic brake on erection. Usually, psychogenic stimulation induces a soft swelling but not a rigid enough erection to allow intromission.9,20 If the upper limit of lesion is below T12, sparing at least part of the erection spinal sympathetic centers, and the lower limit above S2, mixed, i.e., psychogenic, and reflex erection can occur.20 Overall, before development of phosphodiesterase type 5 inhibitors, erection was reported to occur in 54%–95% and intromission followed by coïtus achieved by 5%–75% of SCI patients.1,22 Erectile potential and response to pharmacological treatments depends on (1) the lesion characteristics, i.e., completeness and craniocaudal extent and (2) the source of stimulation.23 Without medication, erection is reported as not reliable because not lasting long enough and/or being not firm enough by the vast majority of the SCI patients.14

requirement for very high intensity stimulation during PVS in SCI men can be related to dynamic neurologic process and reorganization (neuroplasticity) that might occur after a spinal lesion and to the loss of facilitator inputs of supraspinal origin. These phenomenon are involved in the inability of most SCI patients to reach ejaculation during intercourse and the high level of vibratory stimulation parameters used to obtain ejaculation, which are beyond the intensity required for normal sensation in the ablebodied population. Overall, about 50% of SCI patients can ejaculate in response to PVS.24 As for erection, the ability to ejaculate depends on the lesion characteristics. Secretion, the first phase of emission, is under the control of spinal parasympathetic centers (segments S2–S4). Lesion of the parasympathetic centers impairs reflective erection, secretion, and transmission of the genital stimuli to the spinal cord. The sympathetic centers (segments T12–L2) induce sexual glands and seminal tract smooth muscle cell contraction and bladder neck closure. Lesion of these centers severely impairs ejaculation. In particular, lesion of 2 or 3 spinal segments T12, L1, L2 usually preclude ejaculation occurrence. Once seminal fluid reaches the prostatic urethra, the expulsion phase occurs under the control of the somatic centers. Lesion of the sacral spinal cord impairs, but less severely, ejaculation and if ejaculation occurs, semen expulsion throughout the urethral meatus is not rhythmic forceful but dribbling (Figure 65.2).24,26

Ejaculation

Orgasm

Ejaculation is severely impaired after SCI. Only 12% of complete and 33% of incomplete SCI patients can ejaculate during masturbation or coïtus without the aid of medication or devices.24 Penile vibratory stimulation (PVS) represents the first line of treatment for sperm retrieval.25 The

The impairment of orgasm by SCI is difficult to assess. First because more than 20 definitions of orgasm have been proposed.27 Overall, orgasm tends to be defined as a psychological, transient peak sensation of pleasure with altered state of consciousness, and a physiological

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Figure 65.1 Prototypical type of complete SCIs and related sexual functions are (a) lesion above thoracolumbar and sacral spinal cord: reflex erection +, psychogenic erection −, reflex rhythmic forceful ejaculation +, psychogenic ejaculation −; (b) thoracolumbar and sacral lesion: erection and ejaculation are unlike to occur; (c) thoracolumbar lesion: reflex erection +, psychogenic erection −, reflex and psychogenic ejaculation −; (d) mid and lower lumbar lesion: reflex and psychogenic erection +, psychogenic and reflex ejaculation unlike −; (e) sacral lesion: reflex erection −, psychogenic erection +, reflex ejaculation −, psychogenic ejaculation (emission without involvement of somatic centers, possibly premature) +. UMN, upper motor neuron; LMN, lower motor neuron.

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Figure 65.2 Impact of a complete spinal cord injury (SCI), with lower limit above T12, on ascending and descending projections from/to the spinal centers controlling sexual behavior. Disruption of the brain projections to the autonomic and somatic centers and to the spinal generator of ejaculation (SGE). Disruption of the lumbar spinothalamic pathway to the subparafascicular nucleus (purple). Preservation of the genitospinogenital reflex pathway. Black, afferents; green, orange, red, and purple, efferents; SPN, sacral parasympathetic nucleus; DGC, dorsal grey commissure; IML, inter mediolateralis column; BS, bulbospongiosus; IC, ischiocavernosus.

experience including sexflush; sweating; myotonia; rhythmic pelvic muscle contractions; and increased heart rate, respiration, and blood pressure.28,29 Next, some SCI patients may not recognize some of the physiological events that occur during sexual climax. Finally, contrarily to erection or ejaculation, orgasm monitoring is difficult and require to compile self-reported perceptions and blood pressure, heart and respiratory rates. 30 Following SCI, depending on authors, up to 50% of SCI men can achieve orgasm.1,13 In laboratory conditions, Sipski et al. assessed the ability for SCI men to achieve orgasm through manual stimulation. Orgasm was achieved by 64.4% of SCI patients without and 50% of SCI patients with a lesion of the sacral parasympathetic and somatic centers as compared to 100% of able-bodied men. According to self-reported data, men with incomplete SCI are more likely to experience orgasm (82%) than men with complete SCI (50%). A complete injury of the spinal cord extending to the sacral segments seems to preclude the occurrence of orgasm. Of interest is that SCI patients may experience orgasm without ejaculation or ejaculate without achieving orgasm.31 Overall, one should keep in mind that, if experienced by SCI men, feelings perceived during sexual climax are usually reported as weakened, sometimes unpleasant, and even painful.30,32

Some studies reported cardiovascular, respiratory, muscular, and autonomic events during sexual climax in SCI men to be similar to those in able-bodied men.33,34 SCI patients can experience autonomic dysreflexia (AD) during sexual climax. AD is defined by an increase on systolic blood pressure (SBP) of at least 20 mmHg and is often accompanied by pulsatile headaches, tightness of the chest, hot flushes, goose bump, tachy or bradycardia, sweating, and skeletal muscles spasms.35 AD occurs mainly if the injury is cranial to T6, because in this case, the extensive abdominal circulation is under uninhibited spinal reflexes induced by both noxious and non-noxious stimulation below the level of the lesion.36 Autonomic events occurring during orgasm in able-bodied and some SCI men can be defined as autonomic arousal. The loss of supraspinal inhibition on the autonomic nervous system that maintains the autonomic hyperactivation, in upper thoracic and cervical SCI men, leads to AD.37 Indeed, cardiovascular events associated with sexual climax in able-bodied men satisfy the definition of AD as an SBP increase of 40–60 mmHg can occur associated to signs of autonomic arousal. The main differences with SCI men are the intensity, especially SBP increase, and the duration of autonomic arousal signs with a return to baseline within 2 minutes after ejaculation.28,37,38 To help physicians and SCI

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men to perceive sexual climax, a questionnaire has been developed and validated by Courtois et al. Men with an upper limit of SCI below T6 usually do not experience AD and describe that muscular, including pelvi-perineal, and/ or autonomic and/or cardiovascular events as lacking climactic characteristics in opposition to men with more cranial SCI.30 This tool can efficiently help patients to perceive and integrate the somatic and autonomic events occurring during sexual climax. Although beyond the scope of this review, it is of interest that, in SCI women, sensory information from the genitals and hypogastric area can bypass the spinal cord and reach the brainstem via the vagus nerve to finally be integrated by the encephalon.39 Such an accessory pathway may explain why, even in case of complete SCI, some SCI women report to experience orgasms “as before the injury.”40 Few therapeutic options exist to induce or enhance orgasm after SCI. The first step is to apply appropriate stimulation to induce ejaculation, even if ejaculation and orgasm can be dissociated in SCI men. As specified before, PVS is an efficient and simple tool to elicit ejaculation thus sexual climax. Associated to PVS, midodrine, an α1 agonist prescribed to prevent orthostatic hypotension,41,42 increases ejaculation rate43 and orgasm occurrence.44 Some results about midodrine and orgasm are conflicting30,44 but none of these studies were designed to assess, in a same series of patients, the occurrence and intensity of orgasm during PVS with or without midodrine. However, the studies by Soler et al. and Courtois et al. provide new insights about anorgasmia m ­ anagement in SCI men.

Animal models to study sexual behavior after spinal cord injury Rat is the animal model most extensively used to investigate sexual behavior.45–47 To assess the impact of spinal ascending and/or descending pathways disruption on sexual functions, the location of injury must be above the spinal autonomic centers, and the effect of the lesions must be evaluated at least 15 days after injury.47 Early behavioral studies on rats with transections at the midthoracic level showed an enhanced erectile and depressed ejaculatory reflex.47–49 More recently, Nout  et  al. used telemetric monitoring of corpus spongiosum penis pressure. They reported that the number of full erectile episodes decreased significantly 24 days after T10 standardized lesions, but the level of pressure registered in the bulb increased during erection.50 Johnson and colleagues developed rodent models with chronic midthoracic incomplete SCI to assess the function of descending pathways involved in ejaculation. Spinal ejaculatory

pathways are dependent on bilateral pathways from the brainstem which modulate pudendal motor reflex and pudendal nerve autonomic fiber activities. Sensory input from the dorsal nerve of the penis required to trigger ejaculation is no longer inhibited from the nPGi after unilateral incomplete lesion. This inhibition is important in the organization of rhythmic contractions of the perineal muscles during the expulsion phase of ejaculation. Chronic incomplete unilateral lesion of the descending pathways from the brain to the spinal cord results in new connections of the pudendal reflex inhibitory and pudendal sympathetic activatory pathways across the midline below the lesion, which contributes to poor coordination of the perineal muscles during the contractions that are mandatory for ejaculation.51 After spinal transection, when ejaculation is elicited by electrical52 or pharmacological stimulation, 53 the specific pattern of urogenital smooth and striated muscle cell contractions comparable to the one described in intact animals54,55 occurs involving the vas deferens, seminal vesicles, and prostate during emission, followed by bulbospongiosus muscle during expulsion associated with ischiocavernosus and bulbospongiosus muscle contraction responsible for phasic penile erection.45,53 In female rats, rhythmic contractions of the vaginal, uterine, and anal sphincter muscles are observed. In both sexes, rhythmic firing of the hypogastric, pelvic, and pudendal motor nerves are recorded.56 This pattern of reflex contractions is relatively insensitive to the effects of gonadal hormones.57,58 Because of the similarities of this reflex pattern of contractions in lower mammals to the physiology of sexual climax in humans, it is thought that a similar pattern of neural activity generated and coordinated at the spinal level may occur at sexual climax in men and women with SCIs.59–61

The spinal generator of ejaculation The description of a spinal generator of ejaculation (SGE) has changed the way of thinking about modifications induced by spinal lesions, both in terms of pharmacologic regulation and the impact on the regulation of this paramount sexual function from a fertility ­perspective. A group of lumbar spinothalamic (LSt) neurons p ­ rojects to the ­parvocellular subparafascicular thalamic nucleus.62 Another subset of neurons express gastrin-releasing ­peptide (GRP) (Chapter 4).63 Altogether, these ­neurons form an SGE connected with motor neurons of the ­dorsomedial nucleus and both sympathetic and parasympathetic preganglionic neurons innervating the b ­ulbospongiosus muscle and the prostate, respectively.52,64–66 The impact of spinal lesions on ejaculation and orgasm should be considered in terms of the existence of a putative SGE in the lumbar spinal cord.

Pathophysiology of male sexual dysfunction after spinal cord injury

Evidences for the existence of SGE in man How could normal ejaculation as well as somatic and autonomic events occur during sexual climax despite the loss of supraspinal control? Even though normal ejaculation, i.e., rhythmic forceful ejaculation is often abolished, ejaculation can still occur in response to peripheral stimulation in complete SCI patients. The autonomic and somatic spinal centers that control emission and expulsion can be activated in a coordinated manner without any supraspinal input. This leads to the hypothesis that an SGE might also exist in humans. Some physiologic data support the existence of an SGE in man. In men with upper limit of complete SCI above T12, Sonksen recorded the intraurethral pressures at the level of the internal and external urinary sphincter during PVS or electroejaculation procedures. A specific and reproducible pattern of pressure variations occurred during ejaculation. Moreover, the discontinuation of vibratory or electrical stimulation, once this pattern began, did not prevent the specific series of contractions to occur.61 The historical approach consists of characterizing sexual response to the level and extent of the injury in men and women.67 This provided a lot of information on the respective roles of the spinal segments (i.e., sacral, thoracolumbar) for reflexogenic, psychogenic erection and ejaculation, orgasm, and sexual response in both men and women.9,20,68–70 Ejaculation rate is significantly reduced when the spinal segments controlling ejaculation, i.e., sympathetic (T12–L2) and parasympathetic and somatic (S2–S4) are lesioned.9 Unsurprisingly, the lesion of the somatic centers precludes ejaculation to be rhythmic forceful. Numerous studies highlight the crucial role of the T12–L2 segments in the control of ejaculation insomuch that it has been supposed to be “the ejaculation center.”26,71 Other authors assessed the importance for an intersegmental pathway between L2 and S1 to be uninjured for ejaculation to occur.72–75 More than a pathway to connect autonomic and somatic spinal centers, these segments probably harbors an SGE. In light of the description of an SGE in rat, studies that assessed the occurrence of ejaculation as a function of the status of the spinal segments have been reviewed and meta-analyzed recently. The results strengthen the role of the spinal ejaculation centers at the level of T12–L2 and S2–S4 but also point a key role for the segments L3 to L5 (Figure 65.2). Ejaculation rate dropped sharply when the injury extent to the segments L3 and below. Apart from the limits inherent to the variable methods used to elicit ejaculation and the heterogeneity of the studies, this analysis provides only indirect evidences for the existence of an SGE in man.24 In rodent, within the dorsal horn after SCI, the dendritic arborization of calcitonin gene-related peptide (CGRP)-immunoreactive, small-diameter, primary afferent neurons enlarge significantly,76 and the extent of this

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immunoreactivity correlates with the magnitude of AD.77 This modification of afferent arbors seems to be dependent on nerve growth factor (NGF) action. Furthermore, treatment with high-affinity NGF antibody of trk A-IgG fusion protein delivered intraspinally can limit the development of afferent sprouting and the magnitude of AD.78,79 This strongly suggests an ongoing process after SCI led by neuroplasticity. Sexual stimulation during masturbation, coïtus, or PVS can induce AD even in the absence of ejaculation. In other patients, autonomic AD only occurs at ejaculation.80–82 Complete SCI disrupts the pathways that convey pleasurable sensation to the brain, especially putative LSt neurons axons that could convey orgasm specifically related informations to the thalamus (Figure 65.2). Perception of “autonomic arousal” or AD signs during sexual climax, concurrently with, and possibly induced by, the activation of the SGE might be one of the mechanisms whereby complete SCI men experience orgasm at sexual climax.30

Summary Spinal cord lesions dramatically impair sexual behavior in animals and humans. Sexual behavior after SCI depends on the location and extent of the SCI but also the dynamic process of reorganization within the spinal cord of pathways and centers involved in sexual function. Desire is often decreased after SCI, even in the absence of associated TBI. Erectile dysfunction and efficacy of medical treatments depend on the status of the sympathetic and somatic but mostly the parasympathetic centers. Ejaculation and orgasm are more severely impaired and the functional prognosis depends on the status of the lumbosacral spinal cord and especially the putative location of an SGE in segments L3 to L5. An ongoing process of reorganization occurs after SCI, which can be correlated with difficulty in inducing ejaculation via stimulation of perineal afferents, and with the development of AD after SCI.

References 4739. Alexander CJ, Sipski ML, Findley TW. Sexual activities, desire, and satisfaction in males pre- and post-spinal cord injury. Arch Sex Behav 1993; 22(3): 217–28. 4740. Reitz A, Tobe V, Knapp PA, Schurch B. Impact of spinal cord injury on sexual health and quality of life. Int J Impot Res 2004; 16(2): 167–74. 4741. Anderson KD. Targeting recovery: Priorities of the spinal cordinjured population. J Neurotrauma 2004; 21(10): 1371–83. 4742. Jackson AB, Dijkers M, Devivo MJ, Poczatek RB. A demographic profile of new traumatic spinal cord injuries: Change and stability over 30 years. Arch Phys Med Rehabil 2004; 85(11): 1740–8. 4743. Devivo MJ. Epidemiology of traumatic spinal cord injury: Trends and future implications. Spinal Cord 2012; 50(5): 365–72. 4744. Phelps J, Albo M, Dunn K, Joseph A. Spinal cord injury and sexuality in married or partnered men: Activities, function, needs, and predictors of sexual adjustment. Arch Sex Behav 2001; 30(6): 591–602.

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4745. Sakamoto H. Brain-spinal cord neural circuits controlling male sexual function and behavior. Neurosci Res 2012; 72(2): 103–16. 4746. Everaert K, de Waard WI, Van Hoof T et al. Neuroanatomy and neurophysiology related to sexual dysfunction in male neurogenic patients with lesions to the spinal cord or peripheral nerves. Spinal Cord 2010; 48(3): 182–91. 4747. Grossiord A, Chapelle PA, Lacert P, Pannier S, Durand J. [The affected medullary segment in paraplegics. Relation to sexual function in men (author’s transl)]. Rev Neurol (Paris) 1978. 134(12): 729–40. 4748. Lombardi G, Macchiarella A, Cecconi F, Aito S, Del Popolo G. Sexual life of males over 50 years of age with spinal-cord lesions of at least 20 years. Spinal Cord 2008; 46(10): 679–83. 4749. Larsen E, Hejgaard N. Sexual dysfunction after spinal cord or cauda equina lesions. Paraplegia 1984; 22(2): 66–74. 4750. Cardoso FL, Savall AC, Mendes AK. Self-awareness of the male sexual response after spinal cord injury. Int J Rehabil Res 2009. 32(4): 294–300. 4751. Phelps G, Brown M, Chen J et al. Sexual experience and plasma testosterone levels in male veterans after spinal cord injury. Arch Phys Med Rehabil 1983; 64(2): 47–52. 4752. Anderson KD, Borisoff JF, Johnson RD, Stiens SA, Elliott SL. Long-term effects of spinal cord injury on sexual function in men: Implications for neuroplasticity. Spinal Cord 2007; 45(5): 338–48. 4753. Tolonen A, Turkka J, Salonen O, Ahoniemi E, Alaranta H. Traumatic brain injury is under-diagnosed in patients with spinal cord injury. J Rehabil Med 2007; 39(8): 622–6. 4754. Sander AM, Maestas KL, Pappadis MR et al. Sexual functioning 1  year after traumatic brain injury: Findings from a prospective traumatic brain injury model systems collaborative study. Arch Phys Med Rehabil 2012; 93(8): 1331–7. 4755. Durga A, Sepahpanah F, Regozzi M, Hastings J, Crane DA. Prevalence of testosterone deficiency after spinal cord injury. PM R 2011; 3(10): 929–32. 4756. Safarinejad MR. Level of injury and hormone profiles in spinal cordinjured men. Urology 2001; 58(5): 671–6. 4757. Celik B, Sahin A, Caglar N et al. Sex hormone levels and functional outcomes: A controlled study of patients with spinal cord injury compared with healthy subjects. Am J Phys Med Rehabil 2007; 86(10): 784–90. 4758. Chapelle PA, Durand J, Lacert P. Penile erection following complete spinal cord injury in man. Br J Urol 1980; 52(3): 216–9. 4759. Sipski M, Alexander C, Gómez-Marín O, Spalding J. The effects of spinal cord injury on psychogenic sexual arousal in males. J Urol 2007; 177(1): 247–51. 4760. Biering-Sorensen F, Sonksen J. Penile erection in men with spinal cord or cauda equina lesions. Semin Neurol 1992; 12(2): 98–105. 4761. Courtois FJ, Goulet MC, Charvier KF, Leriche A. Posttraumatic erectile potential of spinal cord injured men: How physiologic recordings supplement subjective reports. Arch Phys Med Rehabil 1999; 80(10): 1268–72. 4762. Chéhensse C, Bahrami S, Denys P et al., The spinal control of ejaculation revisited. A systematic review and meta-analysis of anejaculation in spinal cord injured patients. Hum Reprod Update 2013; 19(5): 507–26. 4763. Brackett NL, Lynne CM, Ibrahim E, Ohl DA, Sønksen J. Treatment of infertility in men with spinal cord injury. Nat Rev Urol 2010; 7(3): 162–72. 4764. Chapelle PA, Colbeau-Justin P, Durand J, Richard F. [Ejaculation problems in traumatic paraplegia]. Sem Hop, 1982; 58(28–29): 1691–7. 4765. Mah K, Binik YM. The nature of human orgasm: A critical review of major trends. Clin Psychol Rev 2001; 21(6): 823–56. 4766. Masters WH, Johnson VE. Human Sexual Response. San Rafael, CA: Ishi Press International, 2010.

4767. Bohlen JG, Held JP, Sanderson MO, Patterson RP. Heart rate, ratepressure product, and oxygen uptake during four sexual activities. Arch Intern Med 1984; 144(9): 1745–8. 4768. Courtois F, Charvier K, Vézina JG et al. Assessing and conceptualizing orgasm after a spinal cord injury. BJU Int 2011; 108(10): 1624–33. 4769. Sipski M, Alexander CJ, Gomez-Marin O. Effects of level and degree of spinal cord injury on male orgasm. Spinal Cord 2006; 44(12): 798–804. 4770. Dahlberg A, Alaranta HT, Kautiainen H, Kotila M. Sexual activity and satisfaction in men with traumatic spinal cord lesion. J Rehabil Med 2007; 39(2): 152–5. 4771. Courtois F, et al. Sexual and climactic responses in men with traumatic spinal cord injury: A model for rehabilitation. Sexologies 2009; 18: 79–82. 4772. Szasz G, Carpenter C. Clinical observations in vibratory stimulation of the penis of men with spinal cord injury. Arch Sex Behav 1989; 18(6): 461–74. 4773. Karlsson AK. Autonomic dysreflexia. Spinal Cord 1999; 37(6): 383–91. 4774. Lindan R et al. Incidence and clinical features of autonomic dysreflexia in patients with spinal cord injury. Paraplegia 1980; 18(5): 285–92. 4775. Courtois F et al. H-reflex and physiologic measures of ejaculation in men with spinal cord injury. Arch Phys Med Rehabil 2004; 85(6): 910–8. 4776. Pollock ML, Schmidt DH. Heart disease and rehabilitation, 3rd ed. Champaign, IL: Human Kinetics 1995, 243–276. 4777. Komisaruk BR, Gerdes CA, Whipple B. ‘Complete’ spinal cord injury does not block perceptual responses to genital self-stimulation in women. Arch Neurol 1997; 54(12): 1513–20. 4778. Sipski ML, Alexander CJ, Rosen R. Sexual arousal and orgasm in women: Effects of spinal cord injury. Ann Neurol 2001; 49(1): 35–44. 4779. Lossnitzer K, Letzel H. [Efficacy of midodrin in orthostatic circulatory disorders. Results of a 2D multicentric field study of 942 patients]. Med Welt 1983; 34(42): 1190–3. 4780. Wright RA, et al. A double-blind, dose-response study of midodrine in neurogenic orthostatic hypotension. Neurology 1998; 51(1): 120–4. 4781. Soler JM et al. Midodrine improves ejaculation in spinal cord injured men. J Urol 2007; 178(5): 2082–6. 4782. Soler JM et al. Midodrine improves orgasm in spinal cord-injured men: The effects of autonomic stimulation. J Sex Med 2008; 5(12): 2935–41. 4783. McKenna KE, Chung SK, McVary KT. A model for the study of sexual function in anesthetized male and female rats. Am J Physiol 1991; 261(5 Pt 2): R1276–85. 4784. Hart BL. Sexual reflexes and mating behavior in the male rat. J Comp Physiol Psychol 1968; 65(3): 453–60. 4785. Sachs BD, GarinelloLD. Spinal pacemaker controlling sexual reflexes in male rats. Brain Res 1979; 171(1): 152–6. 4786. Hart BL, Odell V. Elicitation of ejaculation and penile reflexes in spinal male rats by peripheral electric shock. Physiol Behav 1981; 26(4): 623–6. 4787. Hart BL, Odell V. Effects of intermittent electric shock on penile reflexes of male rats. Behav Neural Biol 1980; 29(3): 394–8. 4788. Nout YS et al. Telemetric monitoring of corpus spongiosum penis pressure in conscious rats for assessment of micturition and sexual function following spinal cord contusion injury. J Neurotrauma 2005; 22(4): 429–41. 4789. Johnson RD. Descending pathways modulating the spinal circuitry for ejaculation: Effects of chronic spinal cord injury. Prog Brain Res 2006; 152: 415–26. 4790. Borgdorff AJ et al. Ejaculation elicited by microstimulation of lumbar spinothalamic neurons. Eur Urol 2008; 54(2): 449–56.

Pathophysiology of male sexual dysfunction after spinal cord injury 4791. Clement P et al. Ejaculation induced by i.c.v. injection of the preferential dopamine D(3) receptor agonist 7-hydroxy-2-(di-N-propylamino)tetralin in anesthetized rats. Neuroscience 2007; 145(2): 605–10. 4792. Beyer C et al. Patterns of motor and seminal vesicle activities during copulation in the male rat. Physiol Behav 1982; 29(3):495–500. 4793. Holmes GM et al. Electromyographic analysis of male rat perineal muscles during copulation and reflexive erections. Physiol Behav 1991; 49(6): 1235–46. 4794. Cai RS, Alexander MS, Marson L. Activation of somatosensory afferents elicit changes in vaginal blood flow and the urethrogenital reflex via autonomic efferents. J Urol 2008; 180(3): 1167–72. 4795. Park JH et al. Androgen- and estrogen-independent regulation of copulatory behavior following castration in male B6D2F1 mice. Horm Behav 2009; 56(2): 254–63. 4796. Holmes GM Sachs BD. Erectile function and bulbospongiosus EMG activity in estrogen-maintained castrated rats vary with behavioral context. Horm Behav 1992; 26(3): 406–19. 4797. Bohlen JG et al. The female orgasm: Pelvic contractions. Arch Sex Behav 1982; 11(5): 367–86. 4798. Bohlen JG, Held JP, Sanderson MO. The male orgasm: Pelvic contractions measured by anal probe. Arch Sex Behav 1980; 9(6): 503–21. 4799. Sonksen J, Ohl DA, Wedemeyer G. Sphincteric events during penile vibratory ejaculation and electroejaculation in men with spinal cord injuries. J Urol 2001; 165(2):426–9. 4800. Ju G et al. Immunohistochemical evidence for a spinothalamic p ­ athway co-containing cholecystokinin- and galanin-like ­immunoreactivities in the rat. Neuroscience 1987; 20(2): 439–56. 4801. Sakamoto H et al. Sexually dimorphic gastrin releasing peptide system in the spinal cord controls male reproductive functions. Nat Neurosci 2008; 11(6): 634–6. 4802. Truitt WA Coolen LM. Identification of a potential ejaculation generator in the spinal cord. Science 2002; 297(5586): 1566–9. 4803. Xu C et al. Identification of lumbar spinal neurons controlling simultaneously the prostate and the bulbospongiosus muscles in the rat. Neuroscience 2006; 138(2): 561–73. 4804. Xu C et al. Galanin and neurokinin-1 receptor immunoreactive [corrected] spinal neurons controlling the prostate and the bulbospongiosus muscle identified by transsynaptic labeling in the rat. Neuroscience 2005; 134(4): 1325–41. 4805. Grossiord A et al. Studies on Motor Metamerisation of the Upper and Lower Limbs. Paraplegia 1963; 1: 81–97.

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4806. Berard EJ. The sexuality of spinal cord injured women: Physiology and pathophysiology. A review. Paraplegia 1989; 27(2): 99–112. 4807. Bors EC. Neurological disturbances of sexual function with special reference to 529 patients with spinal cord injury. Urol Surv 1960; 10: 191–221. 4808. Munro D, Horne HW Jr., Paull DP. The effect of injury to the spinal cord and cauda equina on the sexual potency of men. N Engl J Med 1948; 239(24): 903–11. 4809. Nehra A et al. Vibratory stimulation and rectal probe electroejaculation as therapy for patients with spinal cord injury: Semen parameters and pregnancy rates. J Urol 1996; 155(2): 554–9. 4810. Brindley GS. Reflex ejaculation under vibratory stimulation in paraplegic men. Paraplegia 1981; 19(5): 299–302. 4811. Bird VG et al. Reflexes and somatic responses as predictors of ejaculation by penile vibratory stimulation in men with spinal cord injury. Spinal Cord 2001; 39(10): 514–9. 4812. Sonksen J. Assisted ejaculation and semen characteristics in spinal cord injured males. Scand J Urol Nephrol Suppl 2003; 213(213): 1–31. 4813. Ohl DA, Menge AC, Sonksen J. Penile vibratory stimulation in spinal cord injured men: Optimized vibration parameters and prognostic factors. Arch Phys Med Rehabil 1996; 77(9): 903–5. 4814. Wong ST, Atkinson BA, Weaver LC. Confocal microscopic analysis reveals sprouting of primary afferent fibres in rat dorsal horn after spinal cord injury. Neurosci Lett 2000; 296(2–3): 65–8. 4815. Krenz NR, Weaver LC. Changes in the morphology of sympathetic preganglionic neurons parallel the development of autonomic dysreflexia after spinal cord injury in rats. Neurosci Lett 1998; 243(1–3): 61–4. 4816. Krenz NR et al. Neutralizing intraspinal nerve growth factor blocks autonomic dysreflexia caused by spinal cord injury. J Neurosci 1999; 19(17): 7405–14. 4817. Marsh DR et al. Neutralizing intraspinal nerve growth factor with a trkA-IgG fusion protein blocks the development of autonomic dysreflexia in a clip-compression model of spinal cord injury. 4818. J Neurotrauma 2002; 19(12): 1531–41. 4819. McBride F et al. Tripling of blood pressure by sexual stimulation in a man with spinal cord injury. J R Soc Med 2003; 96(7): 349–50. 4820. Sheel AW et al. Autonomic dysreflexia during sperm retrieval in spinal cord injury: Influence of lesion level and sildenafil citrate. J Appl Physiol 2005; 99(1): 53–8. 4821. Courtois FJ et al. Blood pressure changes during sexual stimulation, ejaculation and midodrine treatment in men with spinal cord injury. BJU Int 2008; 101(3): 331–7.

66 Sexual consequences of multiple sclerosis and other central nervous system disorders Maarten Albersen and Dirk De Ridder

Introduction Neurological diseases such as multiple sclerosis (MS) have a serious impact on the patient’s personal, professional, and social life. Although many physicians often focus on the medical aspects of the disease, patients themselves and their partners are confronted with an uninvited third partner in their relationship. Although sexual problems often have a dramatic negative impact on the psychosocial life and self-esteem of the MS patient, it often remains unacknowledged. Owing to shame and embarrassment on the part of the patient, and unawareness or even neglect of the problem by the physician, they fail to attract medical attention and, as a consequence, the possibility of treatment.1 Furthermore, limiting the investigation and treatment of sexual dysfunction (SD) to the mechanics of sex is not always an answer to the real underlying anxiety. Addressing the psychological needs is at least as important.

Prevalence In the literature, there are many studies on different health-related subjects connected to MS but very few facing sexual issues. Few large-scale epidemiologic studies exist, which address the incidence of SDs in patients suffering from disorders affecting the central nervous system (CNS), among which is MS. Notwithstanding variations in definitions, methodology, and study populations, various smaller reports however substantiate the global presence and extent of SDs in both sexes. A recent survey in women with MS showed an overall prevalence of SD of 82.5%, and 45% reported worsening of their sexual functioning after the onset of the disease.2 In men, only a small number of reports have focused on erectile dysfunction (ED), which is also the most commonly reported sexual complaint in men both with and without MS. Compared to other cofounding diseases such as diabetes or radical

pelvic surgery, ED in MS is generally understudied in spite of its apparent high prevalence. Zorzon et  al3 reported ED, ejaculatory dysfunction, and decreased libido in approximately 63%, 50%, and 40% of male MS patients, respectively. A survey conducted in 38,000 ED patients and 262,000 controls revealed that men with ED were 2.3 times more likely to have been previously diagnosed with MS than controls, even after correcting for various cofounders such income, geographic location, hypertension, diabetes, coronary heart disease, hyperlipidemia, obesity, and alcohol abuse.4

Primary, secondary, and tertiary sexual dysfunction A conceptual subdivision of SD in MS in terms of primary, secondary, and tertiary SD has been developed by Foley et al.5 Although the clinical situation often is far too complex to classify a patient suffering from SD into one category, this division provides structure and may therefore help to identify and clarify certain symptoms, and can be useful in both reporting on SD as well as counseling of the patient. Primary SD describes the situation in which the biological cause of SD in MS can, both in the male and female, in part be directly attributed to MS pathophysiology. In secondary SD, the presence of other than sexual MS symptoms such as fatigue, spasticity, impaired coordination, impaired mobility, muscle weakness, bladder and bowel dysfunction, cognitive dysfunction, and medication side effects cause difficulty in experiencing sexual intercourse or other sexual acts. Tertiary SD describes the sexual issues that involve MS-related changes in the social and psychological context: the role of sexual partner versus caregiver, social isolation, sexual isolation, changing expectations, but also changes in body image, self-esteem, anxiety, and depression.

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Primary sexual dysfunction As illustrated above, the prevalence of SD is high in MS. MS affects people at a young age, when their sexual relationship is still quite young and their family planning is not always completed. In a minority of patients SD even precedes the diagnosis of MS or is present at the time of the diagnosis, indicating that the presence of SD might help to define the diagnosis of MS. Once MS has been diagnosed, nearly 60% of men and 25% of women will have a lessactive sex life as before, whereas 87% of men and 66% of women find sexual issues to be very important. However, less than 10% of patients will discuss sexuality with their physician, which means that an active attitude must be adopted by neurologist, urologist, and rehabilitation specialists to incorporate sexuality in the routine work-up of these patients.

Hypoactive sexual desire Many regions in the brain contribute to the sexual response, ranging from centers in the hindbrain to areas in the cerebral cortex. Researchers have not been able to identify a single area in the CNS that control sexual activity, thus control is distributed throughout multiple areas of the brain and spinal cord and is susceptible to interference with CNS diseases at multiple levels (Table 66.1). In both men and women, an observed reduction in sex drive can be explained by demyelinating lesions of fiber bundles in and adjacent to the hypothalamus (i.e., the fornix, anterior commissure, internal capsule, and optic system).6 A Dutch study revealed that 60% of MS patients had active lesions

Table 66.1  N  euroanatomical sites of sexual functioning and sexual response Libido and orgasm

Brainstem, midbrain, cortex, pudendal nerve

Attention

Reticular system

Affection

Limbic system

Voluntary movement

Motoric cortex

Cognition, emotion

Frontal and temporal cortex

Perception, sensory awareness

Parietal cortex

Reflex erection/lubrification

Sacral innervation S2–S4

Psychogenic erection/ lubrification

Spinal cord Th11–L2

Ejaculation

Spinal cord L1–L3

Detumescence

Sympathetic control

Source: Adapted from Rees PM, Fowler CJ, Maas CP, Sexual function in men and women with neurological disorders, The Lancet 2007; 369(9560): 512–25. With permission.

in these brain areas. These lesions further may impact on endocrine functioning by interfering with the pituitary– hypothalamus axis, which further impacts libido.

Male sexual dysfunction In men, ED is the most prevailing sexual symptom and occurs in approximately 63% of patients. The parasympathetic penile innervation comprises the major excitatory input to the penis responsible for vasodilation of the penile vasculature and erection. Preganglionic fibers originate in the sacral parasympathetic nucleus (SPN). Thus, lower spinal cord lesions can interfere with the parasympathetic innervation of the corpora and thus result in a lack of bioavailable nitric oxide (NO, the main proerectile neurotransmitter) from penile nerve terminals. Besides, hypothalamic lesions can affect the mainly oxytoninergic and dopaminergic neurons in the medial preoptic area (MPOA), thus disturbing erectile pathways in a supraspinal locus. Ejaculation is constituted by two distinct phases, emission and expulsion. Orgasm, a feature perhaps unique in humans, is a cerebral process that occurs, in normal conditions, concomitantly to expulsion of semen.7 The thoracolumbar sympathetic as well as the sacral parasympathetic (specifically the SPN) and somatic (Onuf’s nucleus) spinal ejaculatory nuclei play a pivotal role in ejaculation as they integrate peripheral and cerebral signals and sends coordinated outputs to pelvi-perineal anatomical structures that lead to a normal ejaculatory process to occur.7 It thus follows that MS lesions in the spinal cord can have a profound impact on the normal control of ejaculation, while again, higher supraspinal networks involving the thalamus and hypothalamus may further contribute to ejaculatory disorders in MS. Orgasm can further be diminished in MS by effects of plaque formation on relaying of signals generated by genital sensory nerves. The pudendal nerve also conveys most of the sensory stimuli from the external genitalia and perigenital area to the spinal cord. Pudendal afferent fibers are located in the spinal cord in the dorsal columns, in the medial half of Lissauer’s tract, and in a large terminal field in the dorsal gray commissure in the spinal cord. Implied by the complex innervation and regulation of the male sexual response, it logically follows that men suffering from MS can experience a wide range of sexual symptoms, which are directly related to MS lesions at various levels in these neuronal cascades. The resulting symptoms may include diminished libido; ED; anorgasmia or dysorgasmia; diminished, absent, or unpleasant genital sensations; and reduced force of ejaculation or even anejaculation. Besides a direct profound impact on sexuality and self-perception, these issues may further cause infertility, which is especially important in young MS patients who have not completed their family planning.

Sexual consequences of multiple sclerosis and other central nervous system disorders

Female sexual dysfunction Besides a loss of libido (approximately 58%), MS interferes with other important steps in the female sexuality by direct damage to brain or spinal loci involved in the female sexual response cycle. According to a recent survey, the most common SDs in woman include arousal dysfunction (decreased genital sensation in 47%, decreased lubrication in 48%, and decreased subjective arousal in 45%) and orgasmic dysfunction (40%).2 In a similar fashion as it occurs in males, genital sensory input derived from the pudendal nerves can be hampered at the level of the spinal cord or higher up in the cerebrum. Orgasm in females consists of a pleasant subjective sensation that is often paired by clonic contractions of the perineal striated muscles and rhythmic vaginal and uterine contractions. The so-called “urethrogenital reflex,” which is observed in spinalized rodents, describes the immediate appearance of clonic contractions in the perineum and vagina on manipulation of the urethra. The fact that a spinal reflex arch exists to attain orgasm on genital stimulation also implies that lesions in the sacral spinal cord can interrupt this reflex and combined with diminished genital sensation it is evident that female MS may suffer from diminished orgasm. Besides, unpleasant genital sensations can further hamper the ability to enjoy sexual activity. As well as in females, it has been demonstrated that the MPOA is important in genital arousal in females. Therefore, lesions in this region and in the spinal tracts connecting the MPOA to the nerve fibers supplying the female genital tract can have detrimental effects on genital arousal and result in decreased lubrication and decreased blood flow to the clitoral corpora cavernosa and the vaginal wall. Besides these rather biological issues, female and male sexual experiences are further hampered by psychological impact of both MS and the occurrence of primary SDs, as is discussed below.

Secondary sexual dysfunction Of the secondary factors, fatigue was reported as the most important one (up to 40%), followed by muscle weakness, spasticity, dysesthesia, pain, or concerns about urinary and fecal continence. Fatigue was more frequently reported by women than by men. Several authors have found significant correlations between interfering secondary symptoms and SD (Table  66.2).8–14 Comparison of the studies is difficult since the definition of SD may vary from author to author. Some authors use the presence of one or more symptoms to define SD, whereas others use a validated questionnaire with several subscores for primary, secondary, and tertiary SD.13 All authors agree that gender, fatigue, disease course, cognitive problems, and sphincter and bladder problems

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Table 66.2  S ignificant correlations between sexual dysfunction and secondary influencing factors according to several authors All MS patients

Women

Men

+

++

Age

+

0

+

Age at onset of disease

+

+

+

Duration of disease

?

?

?

Primary of secondary progressive MS

+

+

+

EDSS

+

+

0

Dependency

+

+

0

Sphincter dysfunction

+

+

0

Bladder dysfunction

+

+

0

Bowel dysfunction

0

0

0

Fatigue

+

+

+

Cognition

+

+

0

Gender

MS, multiple sclerosis; EDSS, Expanded Disability Status Scale; +, positive correlation; 0, no correlation; ?, ­conflicting data.

interfere considerably with sexuality. Conflicting data are found on the duration of the disease. Some gender differences may also exist. Men seem to be less bothered by some of these secondary factors than women. However, the number of men was invariably lower than the number of women in all studies, making these findings less robust. The degree of disability might also play a role: in severely disabled women with MS bowel dysfunction was a significant factor, whereas this was not the case in less-disabled women.15 Patients with advanced disease have been less investigated, but even in this group sexuality seems to be of major concern. Specifically for urinary factors, such as lower urinary tract symptoms and incontinence, either or not in the presence of MS, a strong link has been demonstrated with SD in a series of studies by various authors.16–19

Tertiary sexual dysfunction Tertiary aspects of SD are very important to the patient and his or her partner and family. These psychological, emotional, social, and cultural aspects may induce negative changes in self-image and self-esteem, mood, body image as well as depression, anxiety, and sexual aversion. The influence of emotional aspects of MS affects sexuality in correlation with depression and anxiety scores. This influence also correlates with a lower level of education and even unemployment.8–14 Being married is associated with complaining of more symptoms of SD. This may reflect a higher number of coital attempts in stable relationships than in single or divorced patients. The impact of

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MS on the stability of a relationship is substantiated in the fact that marital problems have been noted in 71% of MS patients with SD.20 Besides these, medical treatments of these psychological consequences by antidepressants and anxiolytic agents might interfere with sexual function as well. The prevalence of sexual disorders in women taking antidepressants varies from 22% to 58% with higher rates for selective serotonin reuptake inhibitors and lower rates for bupropion. In most cases, the antidepressant cannot be stopped just for SD and drug holidays are not recommended either because of the risk of withdrawal symptoms and less compliance.21

Practical approach to sexual dysfunction in MS In essence, the first step of treatment of SD in general, but specifically in MS, is identification and recognition of the problem. As patients do not often initiate the discussion themselves, it is the role of the healthcare provider to initiate an open discussion on the subject. Presence of the partner in these discussions helps to assess the impact of SD on the relationship and allows for also addressing the partners’ feelings about the limitations in sexual functioning that are encountered in MS. Recognition of SD can help patients to understand the problem, build healthier relationships, enhance self-esteem, reduce depression, and lead to treatment. It can improve overall quality of life and help to promote patient–healthcare provider relationships. Coping with SDs in MS patients was studied by McCabe and coworkers. In their sample, the coping strategies used by people with MS were certainly not measures that would enhance relationship functioning. Patients tended to withdraw, express negative emotions, or try to sort things out by themselves.20 When these coping strategies are encountered, it can be beneficial to refer patients and their partners to professional counselors, psychiatrists, psychologists, or sex therapists. The multilevel assessment of SD can easily be done in an open interview or by using the validated Multiple Sclerosis Intimacy and Sexuality Questionnaire (MSISQ-15).22 Other specific questionnaires can be used for the assessment of ED or female SD as well. Questionnaires may help to counsel patients about their dysfunction and can be of assistance in evaluation treatment efficacy. The diagnosis of MS, however, does not preclude other e­ tiologies of SDs to be present as well: hypercholesterolemia, diabetes mellitus, cardiovascular disease, etc., must be investigated guided by the clinical need. In man, the minimal investigation should consist of a medical and psychosexual history, which can identify common causes of SD (other than MS) and reversible risk factors (e.g., smoking). The clinical examination should focus on eventual penile deformities (Peyronie’s disease), prostatic disease (men over 50), signs of hypogonadism, and the neurological status. Moreover, a blood pressure

measurement should be performed. Eventually laboratory tests such as a glucose–lipid profile and testosterone measurements can complete the assessment. Specialized test such as nocturnal penile tumescence and rigidity measurements, vascular studies, electrophysiological tests, endocrinology studies and specialized psychodiagnostic testing are not routinely used, but should be reserved for special indications.23 Problems at the secondary and tertiary level must be addressed as well. ED can be difficult to treat as the lack of bioavailable NO in the corpus cavernosum renders patients nonresponsive to oral pharmacotherapy.24 For the treatment of ED, we refer to Chapter 67. In women history taking should focus on several issues: decrease in libido, impaired arousal, orgasmic dysfunction, pain from attempted or completed intercourse, difficulty with vaginal entry (due to fear, avoidance of muscle spasticity), and the awareness of vaginal lubrification. Fatigue as a cause for SD must be asked for specifically, while other secondary and tertiary problems are assessed. Physical examination can be very useful to assess the sensory function, reflexes, and muscle tone of the pelvic region while it also offers gynecological information (vaginal infection, postmenopausal changes, prolapsed, and so on). Additional laboratory testing can be useful if urinary or vaginal infections are suspected. Hormonal testing for estrogen and testosterone levels can be useful in perimenopausal women or in women where estrogen therapy or testosterone therapy is being proposed to treat libido and arousal disorders.25,26 The treatment of female SD needs further study. Sildenafil citrate was proven to have only a marginal effect on vaginal lubrification and not to have an effect on orgasm.11 Treatment of orgasmic disorders in both men and women is disappointing.27 Increasing the sensory stimulation at the genitals by vibratory stimulation can be tried. Besides the treatment of the physical features of SD in MS, strategies to cope with the secondary SD can be developed. For example, changing the time when a couple usually wants to have intercourse from evening to the morning can limit the effect of fatigue considerably. Adequate treatment of urinary and fecal incontinence can reduce the fear of leaking during sexual activities. Finding physical positions to allow painless and comfortable sex can be taught through specific tips, books, or even videos. The development of these coping strategies and the improvement of the communication within the couple can be guided by a counselor or specialized therapist, provided that the physician who detects the primary SD is open to collaboration with other specialists and is able and willing to discuss secondary and tertiary SD. Sexual rehabilitation in MS has not yet been studied properly, but initial reports are encouraging.5,28 It is clear that the treatment of SD in MS must be multimodal, taken into account the impact of the disease on different levels. To achieve this, a team approach will be necessary in many cases.

Sexual consequences of multiple sclerosis and other central nervous system disorders

Sexual dysfunction in other CNS disorders As in MS, other neurological diseases will be accompanied by SD at different levels. Progressive diseases such as Parkinson’s disease and multiple system atrophy (MSA) will yield a different symptomatology than nonprogressive stabilizing disorders such as craniocerebral trauma, spinal cord injury, cauda equina syndrome, etc. The age at which some of these ­diseases occur will also dictate the eventual comorbidities such as diabetes, cardiovascular disease, and cognitive deterioration.

Parkinson’s disease and multiple system atrophy Parkinson’s patients are likely to suffer from SD in 35%–87.5% of cases. Especially in young-onset Parkin­ sonism this might lead to a serious impact on the quality of life.29 The presence of depression (and its treatment) and unemployment are known risk factors. Patients taking dopaminergic drugs can develop compulsive sexual behavior.30 Patients with atypic Parkinsonism might suffer from MSA. In these patients SD usually precedes the n ­eurological symptoms by a few years. Although phosphodiesterase-5 inhibitors can successfully be used in Parkinson’s patients, care should be taken in MSA patients where these drugs might induce severe arterial hypotension.31

Stroke SD after stroke is very common. Often preexisting cardiovascular disease will have caused ED even before the stroke occurred. Interfering factors such as depression, impaired mobility, and the use of antihypertensive drugs must be taken into account. Depending on the site and the extent of the stroke, variable changes in sexual function can be seen. Spontaneous recovery of erectile function has been described, but sexual satisfaction does not seem to be correlated with a successful recovery of other functions.32

Epilepsy Most people with epilepsy maintain normal reproductive and sexual lives. Some women develop problems with libido, arousal, and orgasm. Men with epilepsy are at risk for decreased libido and ED. Increased sex ­hormone–binding globulin levels and lower bioactive testosterone levels, particularly in association with the use of enzyme-inducing antiepileptic drugs, such as phenytoin and carbamazepine are at the base of these problems.33 The experience with

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enzyme-neutral drugs such as gabapentin and lamotrigine is limited. Psychosocial factors, anxiety and stigma associated with epilepsy, can also affect the sexual life of patients with epilepsy.

References 4822. Haensch C-A, Jörg J. Autonomic dysfunction in multiple sclerosis. J Neurol 2006; 253(Suppl): I3–9. 4823. Lew-Starowicz M, Rola R. Prevalence of sexual dysfunctions among women with multiple sclerosis. Sex Disabil 2013; 31(2): 141–53. 4824. Zorzon M, Zivadinov R, Bosco A, Bragadin LM, Moretti R, Bonfigli L et  al. Sexual dysfunction in multiple sclerosis: A case-control study. I. Frequency and comparison of groups. Mult Scler 1999; 5(6): 418–27. 4825. Keller JJ, Liang Y-C, Lin H-C. Association between multiple sclerosis and erectile dysfunction: A nationwide case-control study. J Sex Med 2012; 9(7): 1753–9. 4826. Foley FW, LaRocca NG, Sanders AS, Zemon V. Rehabilitation of intimacy and sexual dysfunction in couples with multiple sclerosis. Mult Scler 2001; 7(6): 417–21. 4827. Huitinga I, De Groot CJ, Van der Valk P, Kamphorst W, Tilders FJ, Swaab DF. Hypothalamic lesions in multiple sclerosis. J Neuropathol Exp Neurol 2001; 60(12): 1208–18. 4828. Giuliano F, Clément P. Physiology of ejaculation: Emphasis on serotonergic control. Eur Urol 2005; 48(3): 408–17. 4829. Demirkiran M, Sarica Y, Uguz S, Yerdelen D, Aslan K. Multiple sclerosis patients with and without sexual dysfunction: Are there any differences? Mult Scler 2006; 12(2): 209–14. 4830. Zivadinov R, Zorzon M, Locatelli L, Stival B, Monti F, Nasuelli D et al. Sexual dysfunction in multiple sclerosis: A MRI, neurophysiological and urodynamic study. J Neurol Sci 2003; 210(1–2): 73–6. 4831. Gruenwald I, Vardi Y, Gartman I, Juven E, Sprecher E, Yarnitsky D et  al. Sexual dysfunction in females with multiple sclerosis: Quantitative sensory testing. Mult Scler 2007; 13(1): 95–105. 4832. Dasgupta R, Wiseman OJ, Kanabar G, Fowler CJ, Mikol DD. Efficacy of sildenafil in the treatment of female sexual dysfunction due to multiple sclerosis. J Urol 2004; 171(3): 1189–93; discussion 1193. 4833. Zorzon M, Zivadinov R, Monti Bragadin L, Moretti R, De Masi R, Nasuelli D et al. Sexual dysfunction in multiple sclerosis: A 2-year follow-up study. J Neurol Sci 2001; 187(1–2): 1–5. 4834. McCabe MP. Exacerbation of symptoms among people with multiple sclerosis: Impact on sexuality and relationships over time. Arch Sex Behav 2004; 33(6): 593–601. 4835. Zivadinov R, Zorzon M, Bosco A, Bragadin LM, Moretti R, Bonfigli L et al. Sexual dysfunction in multiple sclerosis: II. Correlation analysis. Mult Scler 1999; 5(6): 428–31. 4836. Hulter BM, Lundberg PO. Sexual function in women with advanced multiple sclerosis. J Neurol Neurosurg Psychiatr 1995; 59(1): 83–6. 4837. Salonia A, Zanni G, Nappi RE, Briganti A, Dehò F, Fabbri F et al. Sexual dysfunction is common in women with lower urinary tract symptoms and urinary incontinence: Results of a cross-sectional study. Eur Urol 2004; 45(5): 642–8; discussion 648. 4838. Cohen BL, Barboglio P, Gousse A. The impact of lower urinary tract symptoms and urinary incontinence on female sexual dysfunction using a validated instrument. J Sexual Med 2008; 5(6): 1418–23. 4839. Korda JB, Braun M, Engelmann UH. [Sexual dysfunction at urinary incontinence]. Der Urologe Ausg A 2007; 46(9): 1058–65. 4840. Coyne KS, Sexton CC, Thompson C, Kopp ZS, Milsom I, Kaplan SA. The impact of OAB on sexual health in men and women: Results from EpiLUTS. J Sex Med 2011; 8(6): 1603–15. 4841. McCabe MP, McDonald E, Deeks AA, Vowels LM, Cobain MJ. The impact of multiple sclerosis on sexuality and relationships. J Sex Res 1996; 33(3): 241–8.

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4842. Taylor MJ, Rudkin L, Hawton K. Strategies for managing antidepressant-induced sexual dysfunction: Systematic review of randomised controlled trials. J Affect Disord 2005; 88(3): 241–54. 4843. Foley FW, Zemon V, Campagnolo D, Marrie RA, Cutter G, Tyry T et al. The Multiple Sclerosis Intimacy and Sexuality Questionnaire— Re-validation and development of a 15-item version with a large US sample. Mult Scler 2013; 19: 1197–203. 4844. Hatzimouratidis K, Amar E, Eardley I, Giuliano F, Hatzichristou D, Montorsi F et  al. Guidelines on male sexual dysfunction: Erectile dysfunction and premature ejaculation. Eur Urol 2010; 57(5): 804–14. 4845. Albersen M, Shindel AW, Mwamukonda KB, Lue TF. The future is today: Emerging drugs for the treatment of erectile dysfunction. Expert Opin Emerg Drugs 2010; 15(3): 467–80. 4846. Basson R, Wierman ME, van Lankveld J, Brotto L. Summary of the recommendations on sexual dysfunctions in women. J Sex Med 2010; 7(1 Pt 2): 314–26. 4847. Laan E, Both S. Sexual desire and arousal disorders in women. Adv Psychosom Med 2011; 31: 16–34.

4848. Sipski ML, Behnegar A. Neurogenic female sexual dysfunction: A review. Clin Auton Res 2001; 11(5): 279–83. 4849. Christopherson JM, Moore K, Foley FW, Warren KG. A comparison of written materials vs. materials and counselling for women with sexual dysfunction and multiple sclerosis. J Clin Nurs 2006; 15(6): 742–50. 4850. Jacobs H, Vieregge A, Vieregge P. Sexuality in young patients with Parkinson’s disease: A population based comparison with healthy controls. J Neurol Neurosurg Psychiatr 2000; 69(4): 550–2. 4851. Weintraub D, Siderowf AD, Potenza MN, Goveas J, Morales KH, Duda JE et al. Association of dopamine agonist use with impulse control disorders in Parkinson disease. Arch Neurol 2006; 63(7): 969–73. 4852. Hussain IF, Brady CM, Swinn MJ, Mathias CJ, Fowler CJ. Treatment of erectile dysfunction with sildenafil citrate (Viagra) in parkinsonism due to Parkinson’s disease or multiple system atrophy with observations on orthostatic hypotension. J Neurol Neurosurg Psychiatr 2001; 71(3): 371–4. 4853. Rees PM, Fowler CJ, Maas CP. Sexual function in men and women with neurological disorders. Lancet 2007; 369(9560): 512–25. 4854. Luef GJ. Epilepsy and sexuality. Seizure 2008; 17(2): 127–30.

67 Treatment modalities for erectile dysfunction in neurological patients Reinier-Jacques Opsomer

Introduction Sexual dysfunction is no longer a taboo subject, but is now clearly recognized as a potential medical disorder. The term “impotence” has become obsolete not only because of its pejorative connotations but also because of its oversimplification of the complexity of the male sexual function and dysfunctions. Indeed, it makes no distinction between libido, erectile, ejaculatory, and orgasmic disorders.1 This chapter focuses on the therapeutic modalities of erectile dysfunction (ED), a medical problem that affects a large number of men and so deserves the careful attention of both general practitioners and specialists. The first precise figures for the prevalence of ED were compiled by Feldman and coworkers in the Massachusetts Male Aging Study.2 They estimated the prevalence of complete ED to be approximately 5% among 40-to 50-year old men, 10% of those in their 60s, 15% of those in their 70s, and more than 30% of those in their 80s.2 Extensive epidemiological studies have been undertaken all over the world confirming and extending the results of the Boston study. Porst and Sharlip3 summarized these epidemiological studies in a report of the Standards Committee of the International Society for Sexual Medicine in 2006. The therapeutic approach to ED has evolved dramatically over the last two decades thanks to the improvement of our understanding of the physiology of erection and the development of effective drugs that can be taken “on demand” before sexual intercourse. The best results in the treatment of ED have been observed when the problem is viewed from the perspective of the couple with a multidisciplinary approach. ED in the neurological population is a frequent condition sometimes being the first symptom of the underlying disorder leading to the definitive diagnosis (e.g., multiple sclerosis (MS) and multiple system atrophy [MSA]).4 Most neurological patients may benefit from a symptomatic

(pharmacological or nonpharmacological) therapy for ED, adapted to their physical condition, and combined with sexual counseling.

Pathophysiology of erectile function Penile erection is a vascular event controlled by the autonomic and the somatic nervous systems. Neuroendocrine messages from the brain activate the autonomic nuclei in the spinal cord.1 These result in •• •• ••

Dilatation of the cavernosal and helicine arteries, which significantly increases the blood flow to the penis Relaxation of the cavernosal smooth muscle fibers, which opens the vascular lacunar spaces Expansion and filling of the lacunar spaces, which leads to the tumescence and consequently the rigidity of the penis

In the healthy man, sexual stimulation triggers the release of nitric oxide (NO), which is produced by endothelial cells and nonadrenergic noncholinergic nerve terminals. NO stimulates the enzyme guanylate cyclase in the cavernosal smooth muscle fiber leading to the production of cyclic guanosine monophosphate (cGMP), which, in turn, mediates intracellular signal transduction. Consequently, corporeal smooth muscle fibers relax, allowing the opening and filling of the lacunar spaces, leading to penile rigidity5 (Figure 67.1). ED is defined as the persistent inability of a man to achieve and/or to maintain an erection sufficient to enable sexual performance that is satisfactory to both partners. From a “cartesian” point of view, a subdivision of the causes of ED into organic and psychogenic

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etiologies is convenient but simplistic since most patients present with a mixed etiology. Table 67.1 lists the different etiologies of ED of organic origin. Patients with a primary “­mechanical–organic” problem will sooner or later develop performance anxiety. Arterial risk factors such as diabetes mellitus, hypertension, hypercholesterolemia, and smoking contribute to the development of ED. The Cologne study showed that 20% of ED patients suffer from diabetes mellitus, 30% from hypertension, and 30% are current smokers.6 Other factors may also interfere with sexual function such as depression, drugs, obesity, alcohol, and lack of regular exercise.7,8 Patients with an overt neurological pathology often suffer from a sexual dysfunction: in some situations, ED is directly related to the neurological deficit as is the case with traumatic spinal cord disorders, but in others the relationship is unclear or dubious, as is the case with epilepsy and depression.

Cavernous nerves

Endothelial cells

NO

GTP

NO

Guanylate cyclase cGMP

GMP

PDE5

Figure 67.1 Physiology of erection at the level of the cavernosal smooth muscle fiber. Nitric oxide (NO) produced by endothelial cells and nonadrenergic noncholinergic nervous fibers activates the production of cyclic guanosine monophosphate (cGMP). Type-5 phosphodiesterase (PDE5) will convert cGMP into guanosine monophosphate (GMP).

Table 67.1  Etiologies of organic erectile dysfunction •• Vascular −− Arteriogenic −− Venous −− Combined arteriogenic + venous •• Neurogenic •• Endocrine •• Congenital •• Iatrogenic −− Drugs −− Radical surgery for cancer −− Prosthetic surgery for aortic aneurysms

A full history and a thorough physical examination are mandatory to determine the cause of ED. Physical examination consists of an assessment of the external genitalia and the lower extremity pulses and a digital rectal examination of the prostatic gland in patients over 50 years old. Neurological examination includes evaluation of the tonus of the anal sphincter and the voluntary control over the pelvic floor. The genital reflexes (bulbocavernosus reflex and anal reflex) and the lower limb reflexes (Achilles reflex and Babinski’s sign) will be tested. When hormonal evaluation is indicated, the laboratory tests should be performed in the morning (between 7 and 9 am).1,9 Theoretically, the persistence of spontaneous rigid nocturnal and/or morning erections will help to differentiate organic from psychogenic ED: a patient complaining of ED during intercourse but who has spontaneous nocturnal or morning rigid erections may be assumed to be suffering from psychogenic ED. However, the possibility of “false positive” and “false negative” observations has to be kept in mind, especially in neurological patients: for example, most MS patients complain of ED even though they regularly have spontaneous and involuntary rigid nocturnal erections.9,10 Furthermore, patients with a spinal cord injury frequently have spontaneous reflex erections during nursing care but develop short-lasting, nonrigid erections during sexual intercourse. In the general population, the cornerstone of the evaluation of ED is the Duplex Doppler sonogram combined with an intracavernous (IC) injection of a vasoactive agent (prostaglandin E1[PGE1]). The test has not only diagnostic but also therapeutic value as the patient is given an IC injection of a small dose of PGE1, a drug that is regularly proposed as a treatment, after adaptation of the dosage, to achieve a full erection. Duplex Doppler sonogram evaluates the arterial inflow (measurement of the systolic peaks), the venous outflow (measurement of the telediastolic flows), and the resistive indexes of the corpora cavernosa. Classic neurological tests (pudendal somatosensory evoked potentials, motor evoked potentials, ­ electromyogram studies of the pelvic floor, and sacral reflexes) explore the somatic nervous system.10–12 These tests are useful to differentiate Parkinson’s disease from MSA. The integrity of the genitourinary autonomic nervous system will be “approached” by testing the cardiovascular reflexes and by sympathetic skin responses.13 Urodynamic tests (pressure flow studies) may also provide some “indirect” information regarding the autonomic innervation to the genital tract. ED also has to be evaluated from the perspective of the couple. In our institution, a multidisciplinary center (Centre de Pathologie Sexuelle Masculine) including urologists, gynecologists, endocrinologists, sexologists, and psychiatrists was created in 1997. The objective is to assess the different aspects of the sexual function (libido, erection, ejaculation, orgasm) from a multidisciplinary perspective by taking into account the organic,

Treatment modalities for erectile dysfunction in neurological patients the psychological, and the relational aspects of the sexual problem of the subject and his partner.

GTP

749

Guanylate cyclase cGMP

Treatment modalities of ED Patients with an obvious psychogenic or relational problem will be referred to a sexologist (psychiatrist). In most cases, however, ED is mixed or multifactorial in origin, and so the urologist and the sexologist will frequently be consulted. In neurological patients, only symptomatic (nonetiological) therapeutic modalities will be proposed. The medical treatment of ED is stratified into five levels (Table 67.2). It should be emphasized that in sexology, unlike other medical specialties, the treatment is selected by the patient himself, preferably in agreement with his partner after having been informed by the clinician of the different treatment options appropriate for his situation and physical condition. The first level of medical therapy consists of prescribing an oral treatment: type 5 phosphodiesterase inhibitors (PDE5 inhibitors) constitute the first choice. Patients who do not respond to oral pharmacotherapy and those for whom PDE5 inhibitors are contraindicated may be candidates for intraurethral or IC injections of a vasoactive drug, such as PGE1. The efficacy of IC injections is high, but the invasiveness of the procedure is certainly a disadvantage. The fourth-line treatment option is a vacuum device, whereas the fifth modality is a penile prosthesis implanted surgically.

Oral pharmacological agents The concept of taking a pill before engaging in sexual intercourse has been popularized with the development of the first PDE5 inhibitor. The arrival of the “blue pill” (sildenafil citrate) on the market in 1998 launched a revolution in the minds of both doctors and patients Table 67.2  A  lgorithm for the treatment of erectile dysfunction 1. Oral treatment: inhibitors of type 5 phosphodiesterase: −− Sildenafil −− Tadalafil −− Vardenafil 2. Intraurethral injections 3. Intracavernous injections 4. Vacuum devices 5. Penile prostheses: −− Malleable −− Inflatable 6. Sexual counseling

GMP

PDE5

PDE5 inhibitors

Figure 67.2 Mechanism of action of type-5 phosphodiesterase (PDE5) inhibitors. They inhibit the PDE5 enzyme responsible for the degradation of cyclic guanosine monophosphate (cGMP) into guanosine monophosphate (GMP).

alike and was a breakthrough in the treatment of ED. Although sildenafil was being tested in cardiac patients, fortuitously, it was found that it had a positive effect on erection. Twenty years of intensive research on sildenafil led to the recognition of multiple indications for this drug not only for ED but also for premature ejaculation, lower urinary tract symptoms, pulmonary hypertension, and other conditions.14 Two other PDE5 inhibitors have been available since March 2003: tadalafil and vardenafil. PDE5 inhibitors are potent and selective inhibitors of the cGMP-specific PDE5, which is responsible for the degradation of cGMP into guanosine monophosphate in the corpus cavernosum (Figure 67.2). PDE5 inhibitors improve penile rigidity by local control mechanisms but do not act on the central nervous system.

Sildenafil Sildenafil is available in three dosages: 25, 50, and 100 mg. The medication has to be taken 30 minutes before anticipated intercourse. The half-life of the drug ranges from 3 to 5 hours. It should not be taken during a heavy meal, as this may delay the time of onset of efficacy. 5,15 The period of responsiveness is approximately 6–8 hours. Since July 2013, several generic formula of sildenafil are available.

Vardenafil Vardenafil is available in three dosages: 5, 10, and 20 mg. Like sildenafil, its half-life is about 4–5 hours. Interaction with food is minimal. As with sildenafil, the period of responsiveness is approximately 6–8 hours. Vivanza® is a generic formula of vardenafil, proposed by Bayer.

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Tadalafil Tadalafil is available in three dosages: 5, 10, and 20 mg. It has a half-life of 17.5 hours, which clearly distinguishes it from sildenafil and vardenafil. Consequently, the period of responsiveness with tadalafil is significantly longer than with the two other PDE5 inhibitors: it extends to at least 24 hours and in certain cases up to 36 hours.16 It  offers ­ efficacy without planning and thus reduces dependency on a pill. The advantage of the long half-life is that the patient may engage in sexual activity more than once after a single dose. Furthermore, there is no interaction between tadalafil and food intake.15,17 These two characteristics of the drug may be expected to contribute to more spontaneity during sexual activity. On the other hand, the long half-life of tadalafil has to be taken into account in elderly and cardiac patients: indeed, the general practitioner and the intensive care unit specialist should be aware that, in patients with cardiovascular problems, NO donors and nitrates will be contraindicated for a longer period after intake of tadalafil than with the other PDE5 inhibitors. The side effects of the three PDE5 inhibitors are mild and transient. They include flushing, nasal congestion, headache, and visual disturbances (at higher dosages). These medications, as usual, are contraindicated for subjects for whom sexual intercourse is not recommended for cardiac reasons (recent myocardial infarction, unstable angina) and for patients taking nitrates or NO donors. PDE5 inhibitors are effective in approximately 80% of patients, being effective for ED of psychogenic, organic, and/or mixed etiologies. They are usually less effective in peripheral neuropathies such as diabetes mellitus and after radical pelvic surgery for cancer (radical prostatectomy, cystectomy, or rectal surgery). However, after nerve-sparing radical prostatectomy, PDE5 inhibitors are showing some encouraging results. In a large multicenter study undertaken with ED patients after nerve-sparing radical prostatectomy, the best responses were observed in patients who had undergone a bilateral nerve-sparing procedure and in the younger group.15 PDE5 inhibitors have been tested in spinal cord injured patients. The presence of an upper motor neuron lesion was significantly associated with therapeutic success, while lower motor neuron lesions and cauda equina syndrome patients were poor responders.18 Sorensen and Wessells evaluated the effectiveness and safety of PDE5 inhibitors by reviewing 22 papers. They concluded that: “PDE5 inhibitors are efficacious in men with diabetes, spinal cord injury, depression and after nerve-sparing radical prostatectomy, although their efficacy is lower than in otherwise healthy men (strong recommendation, Grade 1A)”.19 Lombardi et al. reviewed 28 articles on PDE5 inhibitors used to treat patients with central neurological disorders. They concluded that PDE5 inhibitors represent first-line

therapy in patients with spinal cord injury. Encouraging results were reported in patients suffering from Parkinson’s disease or MS.20 The following drugs have been tested with some “subjective results”: l-arginine, Gingko biloba extract, and Korean red ginseng.21

Intraurethral (transurethral) therapy The vasoactive drug (Alprostadil) is delivered as a pellet into the urethra by means of a specific polypropylene applicator. The pellet dissolves in the urethra, and the drug is then assumed to reach the corpus cavernosum by diffusion through the tissues. This drug is not available in several countries in Europe. An extensive review of the results in terms of clinical efficacy and safety with ­intraurethral therapy has been presented by Padma-Nathan et al.22 Overall response rates are lower than with IC prostaglandin injections23 and the intraurethral route has not been extensively studied in the neurogenic population.

Intracavernosal injection therapy Erection can be obtained pharmacologically by injecting a vasoactive drug directly into the corpora cavernosa. Several drugs have been tested such as papaverine, phentolamine, phenoxybenzamine, PGE1, and a combination of several components. The compound is injected 5–10  minutes before sexual intercourse, the patient having been instructed by the urologist or his team on how to perform self-injections (Figure 67.3). When the patient is reluctant to inject himself (or unable to do so), the partner may be initiated to the technique. In our department, the patient who is a candidate for IC therapy is first administered a duplex Doppler sonogram with an IC injection of a standard 3 µg dose of PGE1. The test has both a diagnostic (vascular evaluation) and a therapeutic value (clinical responsiveness to the drug). IC injections are recommended for patients who do not respond to oral treatment or who may not benefit from PDE5 inhibitors. The patient is enrolled in an injection training program: increasing dosages of PGE1 are injected in the clinic (once a week): the nurse injects the first two doses, then the patient performs the next injection under supervision. Once he is able to inject himself, the final titration is performed at home. In this way, prolonged erections seldom occur. The patient is allowed to perform one or two injections/week. In the event of a prolonged erection, the patient is instructed to contact the urologist on duty. This happens very rarely. Spinal cord injured patients, especially those with thoracic and cervical lesions, often will respond to

Treatment modalities for erectile dysfunction in neurological patients

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Figure 67.4 Vacuum device Active® distributed in Belgium by Porgès, a division of Coloplast.

Figure 67.3 Intracavernosal injection of a vasoactive drug: principle of the method. The medication has to be injected into the lateral aspect of one of the two corpora cavernosa. Injections will alternatively be performed into the right or the left corpus cavernosum to avoid local fibrosis.

lower doses than what may normally be required in nonneurogenic patients with ED. This should be remembered when titrating to the appropriate dose to minimize risk of prolonged erection.24 In our institution, when a patient is admitted for a prolonged erection, initial treatment consists of a simple puncture of the corpora cavernosa to aspirate a small volume of blood to decompress the corpora. If need be, the corpora cavernosa are irrigated using normal saline and diluted solution of phenylephrine or other similar α-adrenergic agents under careful cardiovascular monitoring especially with patients with a previous history of cardiovascular disease.9,25,26 A surgical procedure (surgical shunt) is rarely requested.

Vacuum constriction devices The vacuum constriction device consists of a cylinder with a vacuum pump and a constrictive tension ring (Figure 67.4). The principle behind the vacuum device is to obtain an erection by inserting the penis into the cylinder and creating a negative pressure in the “chamber.” In this way, blood is aspirated and collected in the penis and then mechanically blocked by the tension ring applied at the base of the penis. The device is recommended in elderly patients for whom pharmacotherapeutic agents are contraindicated.27,28 The constriction ring should be removed within 30 minutes to avoid ischemic tissue ­ damage. The device has to be used with caution in patients presenting with sensory deficits at the level of the penis.23

Penile prostheses Penile prosthetic implants are an adequate alternative for patients who refuse IC injections or a vacuum device and for whom oral drugs are either ineffective or con­ traindicated. Two types of implants are available: malleable and inflatable prostheses (Figures 67.5 and 67.6).28,29 The motivation of the partner has to be taken into account before deciding on the implantation. Montorsi conducted a multicenter study assessing the long-term reliability of three-piece AMS prostheses: at a mean follow-up of 59 months, 92.5% of the patients were still engaging in sexual intercourse with a mean frequency of  1.7 times weekly. Patient and partner satisfaction rates reached 98% and 83%, respectively. 30 Postoperative complications are rare and include mechanical malfunction, corporal crossover, corporal and urethral perforation, infection (in 3%–5% of the patients), erosion of the prosthesis (especially with ­malleable implants), and glans bowing (supersonic transport deformity). Malleable prostheses may also be indicated in incontinent patients to facilitate the a­ pplication and maintenance of a urine-collecting device. 29,31

Discussion Comprehensive studies evaluating the different therapeutic modalities of ED in specific neurological pathologies (diabetes mellitus, MS, and spinal cord injured patients) have been published over the last years.32,33,34 All of these authors concluded that PDE5 inhibitors have revolutionized the treatment of ED by introducing an effective noninvasive approach to the management of this “difficult-to-treat condition” in disabled patients.32 Basu and Ryder,32 in a extensive review paper, evaluated the

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Figure 67.5

Figure 67.6

Two-piece inflatable penile implant (AMS Ambicor). (Courtesy of American Medical Systems, Inc., Minnetonka, MN.)

Three-piece inflatable penile implant (AMS 700 MS Series). (Courtesy of American Medical Systems, Inc., Minnetonka, MN.)

effectiveness of the different treatments of ED in diabetic patients. Ramos and Samso33 detailed the specific aspects of ED in spinal cord injured patients from two rehabilitation centers in Spain. Landtblom34 published a very elegant contribution in 2006 entitled “Treatment of erectile dysfunction in multiple sclerosis”: the author not only reviewed the pharmacological and psychological therapeutic options to be recommended in MS patients but also raised a series of fundamental questions on the ethical and socioeconomic aspects of the “modern” therapeutic approach to sexual dysfunction. ED in MS patients may be multifactorial: it may be related to the neurological dysfunction, to psychological factors, to side effects of medication, or to generalized MS symptoms, such as fatigue and depression, frequently in combination. First-line treatments of ED in MS patients are PDE5 inhibitors and IC injections of PGE1.34 Sexual counseling is recommended for all cases to help the patient and his partner deal with the functional and relational aspects of the sexual problem (Table 67.2). The  efficacy of the treatment will be greatly enhanced when the partner is closely involved in the evaluation of ED and in the selection of the adequate therapy. Sexual counseling is particularly advisable in paraplegic and ­tetraplegic patients: indeed in these patients, the partner is closely involved in the “administration of the therapy” as well as in the “general” care. Sexual assistants are available in some countries to help paraplegic or tetraplegic patients cope with their sexual difficulties. This may raise some ethical considerations. In most countries, ED is considered to be outside the framework of general health care and PDE5 inhibitors are not reimbursed. However, sexuality is one of the basic

needs and should, therefore, be a natural part of health care. Sexuality symptoms are as equally worthy of treatment as any other complaint.34,35

Conclusion ED is no longer a “hidden disorder” but is clearly r­ ecognized as a medical pathology that requires a­dequate diagnosis and investigations. With the d ­ evelopment of effective oral drugs, general practitioners and ­specialists are encouraged to talk openly with their patients about sexual function and dysfunction(s). Oral ­pharmacotherapy is clearly the first-line therapeutic option for most patients. The three PDE5 inhibitors have proven to be effective in patients with moderate or severe erectile dysfunction. Neurological patients may benefit from these therapies provided both the indications and the contraindications have been taken into account.36

References 4855. Kirby RS, Holmes S, Carson C. Erectile dysfunction. In Fast Facts— Indispensable Guides to Clinical Practice. Oxford, United Kingdom: Health Press, 1998. 4856. Feldman HA, Goldstein I, Hatzichristou DG. Impotence and its medical and psychological correlates: Results of the Massachussetts Male Aging Study. J Urol 1994; 150: 54–61. 4857. Porst H, Sharlip ID. History and epidemiology of male sexual dysfunction. In: Porst H, Buvat J, eds. Standard Practice in Sexual Medicine. Oxford, United Kingdom: Blackwell Publishing, 2006: 43–8. 4858. Chandiramani VA, Fowler CJ. Urogenital disorders in Parkinson’s disease and multiple system atrophy. In: Fowler CJ, ed. Neurology of Bladder, Bowel and Sexual Dysfunction. Boston, MA: ButterworthHeineman, 1999: 245–54.

Treatment modalities for erectile dysfunction in neurological patients 4859. Gresser U, Gleitter CH. Erectile dysfunction: Comparison of efficacy and side effects of the PDE-5 inhibitors sildenafil, vardenafil and tadalafil. Review of the literature. Eur J Med Res 2002; 7: 435–46. 4860. Braun M, Wassmer G, Klotz T et al. Epidemiology of erectile dysfunction: Results of the “Cologne Male Survey”. Int J Impot Res 2000; 12: 305–11. 4861. Condra M, Surridge DH, Morales A et  al. Prevalence and significance of tobacco smoking in impotence. Urology 1986; 27: 495–98. 4862. Horrowitz JD, Goble AJ. Drugs and impaired male sexual function. Drugs 1979; 18(3): 206–17. 4863. Carson C, Kirby RS, Goldstein I. Textbook of Erectile Dysfunction. Oxford, United Kingdom: ISIS Medical Media, 1999. 4864. Opsomer RJ. Management of male sexual dysfunction in multiple sclerosis. Sex Disabil 1996; 14: 57–63. 4865. Opsomer RJ. Electrophysiological evaluation of genitourinary nervous pathways. In: Corcos J, Schick E, eds. The Urinary Sphincter. New York, NY: Marcel Dekker, 2001: 423–35. 4866. Ginger VAT, Yang CC. The diagnosis and treatment of patients with neurologic dysfunction of the urinary bladder. In: Low PA, Benarroch EE, eds. Clinical Autonomic Disorders, 3rd edn. Baltimore, MD: Lippincott, Williams & Wilkins, 2008: 637–56. 4867. Opsomer RJ, Boccasena P, Traversa R, Rossini P. Sympathetic skin responses from the limbs and the genitalia: Normative study and contribution to the evaluation of neurourological disorders. Electroencephal clin Neurophysiol 1996; 101: 25–31. 4868. Ghofrani HA, Osterloh IH, Grimminger F. Sildenafil: From angina to erectile dysfunction to pulmonary hypertension and beyond. Nat Rev 2006; 5: 689–702. 4869. Montorsi F, Salonia A, Deho F et al. Pharmacological management of erectile dysfunction. BJU Int 2003; 91(5): 446–54. 4870. Porst H, Padma-Nathan H, Giuliano FR et al. Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: A randomized controlled trial. Urology 2003; 62: 121–6. 4871. Patterson B, Bedding A, Jewell H et  al. The effect of intrinsic and extrinsic factors on the pharmacokinetic properties of tadalafil (IC351). Int J Impot Res 2001; 13(Suppl 4): A120. 4872. Soler JM, Prévinaire JG, Denys P, Chartier-Kastler E. Phosphodiesterase inhibitors in the treatment of erectile dysfunction in spinal cord-injured patients. Spinal Cord 2007; 45: 169–73. 4873. Sorensen MD, Wessels H. Management of erectile dysfunction. In: Dahm PH, Dmochowski R, eds. Evidence-Based Urology. Oxford, United Kingdom: Wiley-Blackwell, BMJI Books, 2010: 134–45. 4874. Lombardi G, Nelli F, Celso M et al. Treating erectile dysfunction and central neurological diseases with oral phosphodiesterase type 5 inhibitors. Review of the literature. J Sex Med 2012; 9: 970–85.

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4875. Choi HK, Seong DH, Rha KH. Clinical efficacy of Korean red ginseng for erectile dysfunction. Int J Impotence Res 1995; 7: 181–6. 4876. Padma-Nathan H, Hellstrom WJ, Kaiser FE et al. Treatment of men with erectile dysfunction with transurethral alprostadil. Medicated Urethral System for Erection (MUSE) Study group. N Engl J Med 1997; 336(1): 1–7. 4877. Hilz MJ. Female and male sexual dysfunction. In: Low PA, Benarroch EE, eds. Clinical Autonomic Disorders, 3rd edn. Baltimore, MD: Lippincott, Williams & Wilkins, 2008: 657–711. 4878. Kirby RS, Carson CC, Webster GD. Impotence: Diagnosis and Management of Male Erectile Dysfunction. Oxford, United Kingdom: Butterworth–Heinemann, 1991. 4879. Vidal J, Curcoll, L, Roig T, Bagunya J. Intracavernous pharmacotherapy for management of erectile dysfunction in multiple sclerosis patients. Rev Neurol 1995; 24(120): 269–71. 4880. Gordon SA, Stage KH, Tansey KE, Lotan Y. Conservative management of priapism in acute spinal cord injury. Urology 2005; 65(6): 1195–7. 4881. Opsomer RJ, Wese FX, Van Cangh PJ. Long-term results with vacuum constriction device. Proceedings of the Eighth World Meeting on Impotence Research. Bologna, Italy: Monduzzi Editore, International Proceedings Division, 1998: 271–4. 4882. Sadeghi-Nejad H, Seftel AD. Vacuum devices and penile implants. In: Seftel AD, ed. Male and Female Sexual Dysfunction. Edinburgh, Scotland: Mosby, 2004: 129–43. 4883. Sohn M, Martin-Morales. Penile prosthetic surgery. In: Porst H, Buvat J, eds. Standard Practice in Sexual Medicine. Oxford, United Kingdom: Blackwell Publishing, 2006: 136–48. 4884. Montorsi F, Rigatti P, Carmignani G et al. AMS three-piece inflatable implants for erectile dysfunction: A long-term multi-institutional study in 200 consecutive patients. Eur Urol 2000; 37: 50–5. 4885. Zermann DH, Kutzenberger J, Sauerwein D, Schubert J, Loeffler U. Penile prosthetic surgery in neurologically impaired patients: Longterm follow-up. J Urol 2006; 175: 1041–4. 4886. Basu A, Ryder REJ. New treatment options for erectile dysfunction in patients with diabetes mellitus. Drugs 2004; 64(23): 2667–88. 4887. Ramos AS, Samso JV. Specific aspects of erectile dysfunction in spinal cord injury. Intern J Impotence Res 2004; 16: S42–5. 4888. Landtblom AM. Treatment of erectile dysfunction in multiple sclerosis. Expert Rev Neurother 2006; 6(6): 931–5. 4889. Maslow AH. Towards a Psychology of Being. New York, NY: Van Nostrand company, 1968. 4890. Corona G, Mondaini N, Ungar A, Razzoli E, Rossi A, Fusco F. Phosphodiesterase type 5 (PDE5) inhibitors in erectile dysfunction: The proper drug for the proper patient. J Sex Med 2011; 8: 3418–32.

68 Fertility issues in men with spinal cord injury Jeanne Perrin, Blandine Courbiere, Vincent Achard, and Catherine Metzler-Guillemain

Introduction Spinal cord injury (SCI) most often affects young men of reproductive age: several millions of men between 16 and 45 years of age face quadriplegia or paraplegia worldwide.1 Only 10% of them can father children without medical assistance; indeed, three main factors may be involved in SCI patients’ infertility: 1. Ejaculatory dysfunction, which was discussed in Chapter 65 2. Erectile dysfunction, which was discussed in Chapters 65 and 67 3. Semen parameters impairment2

Semen parameters are usually impaired in SCI patients Numerous studies demonstrated that more than 90% of SCI patients show altered semen parameters, characterized by asthenospermia, necrospermia, leukocytospermia, but normal sperm concentration.3–7 Ejaculate volume is usually normal, but may be reduced in cases of partially retrograde ejaculation.8 Leukocytospermia is often observed in the absence of an associated infection of urinary tract and/or seminal ducts. Some clinical factors are associated to better semen characteristics: according to Iremashvili et al., semen parameters have higher chances to be normal in two groups of patients: (1) patients obtaining ejaculation by masturbation (which occurs in 1 out of 10 SCI patients9) and (2) patients presenting incomplete lesion of the spinal cord (i.e., American Spinal Injury Association impairment scale grades B, C, and D).10 Nevertheless, when semen can be obtained by ejaculation, the total number of motile sperm in the ejaculate is usually greater than five million; this result generally allows intravaginal insemination or the use of simple assisted reproductive techniques (ARTs) like intrauterine insemination (IUI).11

Pathophysiology of semen parameters impairment Pathophysiology of semen parameters impairment, particularly the acute phase of SCI, is more extensively studied in animal model than in human, due to ethical restrictions and technical feasibility.

Animal data Acute phase after SCI In rat, as soon as acute SCI, hormonal testis environment and blood–testis barrier (BTB) are impaired. It was suggested that SCI damages a neural circuit between hypothalamus and testis, travelling through the cord.11 This neuronal pathway of central origin plays an important role in Leydig cell function for the control of androgen release, independently of the pituitary, and could explain the deterioration of spermatogenesis despite normal luteinizing hormone (LH) levels.11 It was also demonstrated that acute SCI modifies the signal mediating the effects of follicle-stimulating hormone and testosterone on Sertoli cells.12 According to Huang et al.,13 these anomalies could be due to the absence of normal neural impulses on the activities of Sertoli and Leydig cells. Overall, acute SCI modifies hormonal and neural regulation of Sertoli and Leydig cells, which may affect the endocrine and/or paracrine microenvironment within the testis and impair the Sertoli support for normal spermatogenesis. Moreover, SCI rapidly decreases BTB permeability. Dulin et  al.14 suggested that the dysfunction of BTB is due to the decreased expression of occludin, a tight junction protein. At 72 hours postinjury, the disruption of the BTB exposes germ cells to the immune system, enabling systemic autoimmunity to develop. Moreover, an inflammatory response is reported in the testis, indicated by the presence of interleukin (IL)-1β, a proinflammatory cytokine. IL-1β promotes the activation of immune cells,

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which infiltrate the seminiferous tubules; consequently, germ cell undergo sustained apoptosis; and IL-1β could also damage the tight junctions.14 All these events contribute to early s­permatogenesis impairment. A study on SCI dogs showed a significant impairment of sperm motility and spermatogenesis 3 weeks after SCI,15 compared with non-SCI controls. In acute SCI rats, spermatogenesis showed a qualitative and quantitative decrease, compared to non-SCI controls.16 This observation could be explained by the alteration of cyclic adenosine monophosphate signaling in spermatocytes and spermatids, leading to the disruption of germ cell differentiation.17 A precocious dysfunction was also assessed in the seminal vesicles during the acute phase in rat. Five days postinjury, Dashtar and Valojerdi18 assessed an acute inflammation with vasodilatation and infiltration of leukocytes in the epithelium.

Chronic phase after SCI In animal models, during the chronic phase of SCI, autoimmunity and oxidative stress impair semen parameters. In the rat testis, the disruption of BTB remains during the chronic phase of SCI; immune cells still infiltrate the seminiferous tubules 10 months after the SCI and lead to autoimmunity against mature germ cells.14 Interestingly, although a sustained apoptosis was evidenced in the acute phase of SCI, no increase in germ cells apoptosis was shown in the seminiferous tubules of chronic SCI rats.14 Oxidative stress is also involved in semen parameters impairment. Indeed, the treatment of rats with antioxidant vitamin E partially preserved sperm viability during the acute and chronic phases of SCI and induced a better sperm chromatin condensation.19 In rat, sperm motility impairment in minor chronic SCI was shown to be reversible; conversely, in severe chronic SCI, it was shown to persist.13

Human data Acute phase after SCI Few studies have examined the human semen parameters during the acute phase of SCI. Indeed, the resolution of the ejaculatory reflex is required for successful semen retrieval by penile vibratory stimulation (PVS)/electroejaculation (EEJ), and this resolution may require up to 1 year after the SCI.20 Mallidis et al.21 showed in seven acute SCI patients that after the phase of spinal shock, in semen early retrieved by EEJ, sperm motility and viability increase provisionally and then quickly decrease; 16 days after SCI, semen parameters levels are comparable to those of chronic SCI patients.

Chronic phase after SCI Brackett et al.22 showed that in SCI patients, motility and viability of sperm extracted from vas deferens are statistically higher than those observed in sperm from seminal fluid. Motility and viability of SCI patients’ epididymal sperm are also statistically lower than in epididymal sperm of control group (non-SCI men receiving vasectomy). Two studies also demonstrated that the incubation of control sperm (from fertile men or donors) in the seminal fluid of SCI patients induced a major decrease in sperm motility, when the incubation of SCI patients’ sperm in control seminal fluid increased sperm motility.23,24 These results suggested that some testicular/epididymal and seminal factors may account for asthenospermia in chronic SCI patients. In chronic SCI patients, increased scrotal temperature is caused by the continuous sitting position and by a dysregulation of scrotal thermoregulation.25 Thermal stress induces a stress response including hypoxia, oxidative stress, and germ cell apoptosis.26 Oxidative stress could damage testicular microvascularization and hormonal environment.27 Sakkas et  al.28 suggested that a dysregulation of germ cell apoptosis could allow spermatogonia selected for apoptosis to achieve spermatogenesis; consequently, these germ cells could escape the apoptosis process and mature into sperm presenting with increased DNA fragmentation. This rescue mechanism could explain the normal sperm concentration observed in the semen of chronic SCI patients, despite increased germ cell apoptosis. The hormonal characteristics of male SCI patients have been debated. A higher rate of abnormalities in the h ­ ypothalamic–pituitary–testicular axis is described in SCI patients, compared to non-SCI infertile patients and to fertile controls, consistent with an impaired central neurotransmitter activity.29 A statistical decrease of the ratio of testosterone to LH, which reflects the Leydig cells function, is described in SCI patient with abnormal spermatogenesis on testicular histology, compared to SCI patients with normal spermatogenesis.30 Seminal factors are also involved in semen parameters impairment, particularly in the asthenospermy: increased reactive oxygen species (ROS) and inflammatory cytokine concentrations. Chronic SCI patients show high levels of ROS in seminal fluid, which are inversely correlated to sperm motility.31 Increased ROS levels in seminal fluid may be related to a release by activated leukocytes and also to chronic or repeated infections of the seminal tract and accessory glands. Indeed, chronic epididymo-orchitis and prostatitis occur in 28%–38% of SCI patients, influenced by the type of bladder management,32,33 and are responsible for the release of ROS.34 ROS impair the sperm membrane, particularly by damaging unsaturated fatty acids, which

Fertility issues in men with spinal cord injury results in decreased membrane fluidity. ROS also impair sperm mitochondria, which leads to a decreased energy production.35 Increased mitochondrial ROS generation and sperm membrane lipid peroxidation impair sperm motility, leading to a reduced ability to fertilize the oocyte.24 The increased ROS levels in SCI seminal fluid are insufficiently balanced by the antioxidant activity of seminal vesicles. Indeed, a dysfunction of seminal vesicles was suggested by the significant decrease of fructose levels in the seminal fluid of SCI patients.6 Leukocytospermia is also involved in ROS production. The analysis of leukocytes in semen of SCI patients revealed that most of them are T lymphocytes,36 producing a higher level of Th1 than Th2 cytokines. Brackett et  al.37 demonstrated that in chronic SCI patients, the sperm treatment with anticytokine receptor complexes (for cytokines IL-1β, IL-6, and tumor necrosis factor-α) statistically improved sperm motility. The same team recently showed that caspase-1 and apoptosis-associated speck-like protein were elevated in sperm of SCI patients.38 All these data demonstrate that an immunological mechanism participates to sperm motility impairment in SCI patients.31,36,38,39 The high level of platelet-activating factor (PAF) acetylhydrolase observed in the seminal fluid of SCI patients inactivates PAF and contributes to the impairment of sperm motility, capacitation, and fertilization ability.40 Indeed, PAF is an important phospholipid mediator that stimulates sperm motility, improves sperm capacitation and fertilization. As stated for insufficient antioxidant activity, this mechanism could be associated to a dysfunction of seminal vesicles. Another hypothesis to explain semen impairment, particularly necrospermy, in chronic SCI patients was infrequent ejaculation, leading to sperm accumulation in the seminal tract. Sønksen et  al.41 demonstrated in 19 SCI men that weekly ejaculation during 1 year did not improve sperm vitality, which is against this hypothesis.

Sperm DNA quality in SCI In addition to the astheno-necrospermy, chronic SCI patients also show an impaired quality of sperm nuclear content. A higher sperm DNA fragmentation than in nonSCI patients is frequently observed by sperm chromatin structure assay. This increase is not correlated to the abstinence delay or to the removal of dead sperm and leukocytes by semen processing.42,43 High sperm DNA fragmentation index (over 30%) is associated to reduced pregnancy rates, even in patients with normal semen parameters.44 Testicular oxidative stress in SCI patients induces a higher sperm apoptotic DNA fragmentation

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in sperm, determined by the TUNEL assay, compared to fertile non-SCI patients43; ROS also induce nucleotide oxidation in sperm nuclei. Sperm DNA fragmentation and nucleotide oxidation may result in promutagenic effects.45 A higher aneuploidy rate was recently described in the sperm of chronic SCI patients, compared to healthy, fertile normospermic men. Aneuploidy is correlated with reproductive failure. This result could be associated to a poor testicular environment (hyperthermia, oxidative stress), leading to meiosis impairment.46

Evolution of semen characteristics during the chronic phase of SCI Only two retrospective studies examined the evolution of semen parameters during the chronic phase of SCI; they concluded that semen parameters do not significantly decrease during long-term evolution of SCI patients. Brackett et  al. performed a retrospective study in 125 SCI patients, on at least 2 specimens collected for up to 24 months after the first specimen. The mean age of the patients was 32.5 ± .6 years and 72% of them had an incomplete SCI. The semen quality was analyzed as a function of years postinjury, and no difference was assessed over time from SCI in sperm concentration, total sperm count, and motility.47 The same team published another longitudinal retrospective study on 87 SCI patients, on two or more specimens spaced 3 years apart or more. The mean age of the patients was 23 ± 6.4 years and 72% of them had a complete SCI. Iremashvili et al.20 showed a mild but statistically significant decrease in sperm concentration with time (2.2 × 106 per mL per year), but no significant change in other semen parameters. However, the total sperm count did not decrease statistically and the authors considered that the decrease of sperm concentration was “not significant from a clinical point of view.” These two studies led authors to conclude that fertility preservation by early sperm banking is not indicated in SCI patients. Nevertheless, in both studies, the mean number of years between SCI and the first semen collection analyzed was higher than 7 years: respectively 7.99 years (minimum 6  weeks, maximum 26.8 years) and 7.1 years (minimum 1 year, maximum 26 years). Moreover, as both studies were realized in the same center, this could induce a selection bias; indeed, the population of SCI treated in such an experienced center could differ from other SCI patients with lower quality follow-up. Prospective studies on the evolution of semen parameters during the postinjury phase of SCI are needed to provide more robust data, including the evolution of sperm DNA damage, which is unknown.

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Biological fatherhood after SCI Having children: An important part of the rehabilitation program SCI mainly affects young men of parenting age, who are expected to live many decades after injury. For most of them, biological fatherhood and family foundation are of utmost importance, as a way to rebuild a life project after the spinal injury.48 Consequently, male SCI fertility should be considered as an important item of the rehabilitation program.49 As very few SCI patients can achieve antegrade ejaculation by masturbation and/or sexual intercourse and a great many present impaired semen parameters,50 the majority of them require medical care to obtain a pregnancy.

from ejaculated semen or nonprogressive sperm extracted from bladder/seminal tract/testis). ART aims at restoring the fertility in the couple intimacy, as much as possible; indeed, when couple can safely manage self-insemination at home and when the male and female characteristics give reasonable chances of pregnancy, this easy and affordable ART should be attempted.5 After male and female evaluation, ART using fresh semen is usually proposed. When ejaculation cannot be obtained by masturbation, PVS with midodrine adjunction, or EEJ, then a sperm surgical retrieval from seminal tract/testis is proposed.51–53 Surgical sperm extraction is also used in case of azoospermia or severe necrospermia. ART usually uses fresh sperm. Nevertheless, in case of worsening of semen and/or patient’s ability to retrieve sperm by ejaculation, ART can use cryopreserved sperm, when semen has been previously banked (Figure 68.1).49

Male and female evaluation

Strategy to obtain biological fatherhood Only 10% of male SCI patients can achieve pregnancy without medical assistance.2 Consequently, when a chronic SCI patient starts a parental project, an ART is very often required.5 The ART mainly depends on the origin and characteristics of sperm (progressive sperm

The ability of patient to retrieve ejaculated semen, the semen parameters and the feminine characteristics are analyzed to choose the ART leading to the best pregnancy chances in the couple. Feminine characteristics should be carefully studied; indeed, age, ovulation, uterus, and tube permeability are of utmost importance for ART indication. For example, in case of tubal obstruction, self-inseminations at home

Chronic spinal cord injury and parental project

Masturbation No ejaculation

Ejaculation

Penile vibratory stimulation (PVS) No ejaculation

Ejaculation

PVS + Midodrine No ejaculation

Ejaculation

Semen analysis

Choice of the best ART technique

PVS « sandwich » + midodrine No ejaculation

Ejaculation

Assisted reproductive technique with fresh or frozen-thawed sperm

Ejaculation Electroejaculation No ejaculation

Surgical sperm extraction

Sperm banking

Figure 68.1 Protocol of sperm retrieval for assisted reproductive techniques in male chronic spinal cord-injured patients.

Fertility issues in men with spinal cord injury and IUIs would not be proposed, because the preg­nancy chances would be null. Consequently, only in vitro fertilization (IVF) using sperm selected from ejaculated semen or intracytoplasmic sperm injection (ICSI) using ejaculated or surgically retrieved sperm could be considered to achieve biological fatherhood.5,51,52 When the patient is able to retrieve semen by antegrade ejaculation, the ART is chosen according to the results of semen parameters analysis:5,54 ••

•• ••

When a sufficient count of progressive motile sperm is present in the ejaculate and when feminine characteristics are favorable, self-inseminations at home and/or IUI should be proposed. When a sufficient count of progressive motile sperm is present in the ejaculate and when feminine characteristics are not optimal, IVF should be proposed. When a low count of motile sperm is present in the ejaculate and when feminine characteristics allow it, ICSI should be proposed.

Sperm retrieval by ejaculation In a recent meta-analysis, Chéhensse et  al.9 concluded that 16% of SCI patients (complete and incomplete injuries) can obtain antegrade ejaculation by masturbation and/or sexual intercourse: 12% of patients with complete SCI and 33% of patients with incomplete SCI (Table 68.1). In other SCI patients, PVS (100 Hz, peak-to-peak amplitude of 2.5 mm) applied to the dorsum or frenulum of the glans and on the penis, is a simple and efficient technique to induce antegrade ejaculation.55 As a first-line treatment, PVS allows 52% of SCI patients to obtain antegrade ejaculation: 47% of patients with complete SCI and 53% of patients with incomplete SCI9 (Table 68.1). The ejaculation success rate is also related to the patients’ injury level and extent: Brackett et  al.50 showed in a large retrospective study that ejaculation is obtained by PVS in more than 80% of complete and incomplete SCI patients with an injury level above T10, and in 21% with an injury level T11 or below.9 In complete SCI patients, the ejaculation success depends on the integrity of spinal ejaculation centers (Table 68.2): Chéhensse et al.9 confirmed that for emission, the T12–L2 segments have to be infralesional and that for expulsion, the S2–S4 segments have to be infralesional. In complete and incomplete SCI patients failing to ejaculate during masturbation or sexual intercourse without medication, the use of acetylcholine esterase inhibitors was demonstrated to be more efficient in obtaining ejaculation than the use of PVS.9 However, acetylcholine esterase inhibitors are not currently used because of a high risk of autonomic dysreflexia. For patients not responding to PVS, the adjunction of midodrine is safe and efficient to improve ejaculation rates.51 In case of failure to ejaculate after PVS with one

759

Table 68.1   E  jaculation rates in complete and incomplete SCI patients, according to the stimulation technique Stimulation technique

SCI type: complete/ incomplete (n)

Ejaculation rate (%, CI)

Masturbation/ coitus

C+I

16 (2.5–19.5)

C (1161)

11.8 (10.1–13.8)

I (343)

33.2 (28.5–38.4)

C+I

52.1 (45.3–58.9)

C (597)

47.4 (43.4–51.4)

I (305)

52.8 (47.2–58.3)

PVS

Source: Adapted from Chéhensse C, Bahrami S, Denys P, Clément P, Bernabé J, Giuliano F, Hum Reprod Update, 2013, 19(5), 507–26. With permission. C, complete; CI, confidence interval; I, incomplete; PVS, penile vibratory stimulation; SCI, spinal cord injury.

Table 68.2  E  jaculation rates in complete SCI patients after PVS, according to the status of SECs SEC status in complete SCI patients

Technique

Ejaculation rate (%, CI)

Complete lesion of T12–S5 segment (n = 21)

PVS

0 (0–13.5)

T12–S5 segment infralesional (n = 53)

PVS

73.6 (60.3–83.7)

Lesion encompassing T12–L2 segment (n = 5)

PVS

0 (0–48.9)

T12–L2 segment infralesional (n = 30)

PVS

90 (73.6–97.3)

Lesion encompassing S2–S4 segment (n = 4)

PVS

0 (0–54.6)

S2–S4 segment infralesional (n = 47)

PVS

76.6 (62.6–86.6)

Source: Adapted from Chéhensse C, Bahrami S, Denys P, Clément P, Bernabé J, Giuliano F, Hum Reprod Update, 2013, 19(5), 507–26. With permission. SCI, spinal cord injury; SEC, spinal ejaculation center; PVS, penile vibratory stimulation.

vibrator, the simultaneous use of two vibrators (sandwich method) may also improve ejaculation.56 Symptoms of autonomic dysreflexia due to the stimulation can be safely managed.57 As a second-line treatment, EEJ induces an ejaculation in more than 91% of patients.5,50,54 This technique is based on the rectal insertion of a probe containing electrodes, followed by the delivery of electric current until ejaculation occurs. The use of an intermittent current induces

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a higher proportion of sperm in the antegrade fraction, compared to continuous current delivery.58 When EEJ equipment lacks, the finger massage of prostate and seminal vesicle through the rectum may be useful to drain sperm into the urethra after PVS.59 When only retrograde ejaculation can be obtained, it is possible to retrieve spermatozoa in the bladder for ART.52 Due to its high osmolarity and low pH, urine is cytotoxic to spermatozoa.60 Several protocols have been described to allow a better survival of sperm in the b ­ ladder. The oral adjustment of urinary pH and ­osmolarity by ­various methods (NaHCO3 tablets, carbonated beverages, “Liverpool solution”) is simple and inexpensive, but there is no consensus for a validated method. Moreover, these methods include the ingestion of rather important ­quantity of beverage, according to a precise ingestion ­calendar, which may be difficult to follow; osmolarity is not always corrected, leading to failures to retrieve motile sperm in the bladder.61,62 Alternatively, the ­instillation of sterile medium in the empty bladder before ejaculation is simple, efficient, and may allow sperm cryopreservation for subsequent use in ART.63,64 The use of various media has been described; media a­ssociated to ART success (live births) are Earle’s balanced salt solution buffered with HEPES (4-(2-hydroxyethyl)-1-­ piperazineethanesulfonic acid),65 .32 mol/L glucose solution,66 human tubal fluid + .5% bovine serum albumin67 and Ferticult© IVF medium (FertiPro N.V., BeernemBelgium).63 Semen parameters in bladder samples show normal sperm ­concentration (25–34 M/mL), but low progressive ­motility (4%–40%).65,68,69 It is worth mentioning that in SCI patients, semen parameters are related to the method of semen collection: Brackett et al.70 demonstrated that sperm viability was statistically higher in samples obtained by PVS versus by EEJ, and in samples obtained by antegrade versus retrograde ejaculation.

Sperm retrieval by surgical extraction Kafetsoulis et  al.5 highlighted that in the United States, 28% of fertility centers proposed surgical sperm retrieval as a first line of treatment to SCI patients, because they lacked equipment and training to obtain ejaculated semen by PVS and/or EEJ. This management of SCI patients’ fertility is not patient-centered; indeed, surgery should be restricted to rigorous indications in SCI,71 and surgical sperm retrieval yields smaller quantity of poorer quality sperm than ejaculation, which involves the use of more invasive and expensive ART.72 Nevertheless, in a minority of SCI patients, ejaculated sperm cannot be obtained and/or azoospermia or severe necrospermia is found; consequently, sperm surgical extraction is needed. Several studies showed that this procedure is successful for more than 85% of patients.30,73

In SCI patients, motility and viability of sperm extracted from vas deferens are statistically higher than ejaculated sperm.22

Fertility success rates of ART in couples with SCI male partner Couples who are able to manage PVS and risk of autonomic dysreflexia and who meet the clinical and biological eligibility criteria for semen self-insemination at home show 29% of pregnancy per couple and 22% of life birth per couple.5,54 The results of IUI in couples with SCI male partner are comparable to those in non-SCI infertile couples: 9%–18% pregnancy per cycle and 30%–60% cumulative pregnancy rate per couple.5,74 Similarly, the results of IVF and ICSI in couples with SCI male partners are comparable to those in non-SCI infertile couples;74,75 fecundation rates obtained by ICSI of sperm retrieved from the bladder and from surgical extraction are comparable to those obtained by ICSI of ejaculated sperm.63,74 In total, ICSI constitutes a cumulative pregnancy rate of 57% per couple and a cumulative life birth rate of 50% per couple.54

Should patients bank sperm after SCI? As previously stated, two retrospective studies suggested that semen parameters are stable during the chronic phase of SCI, except a mild but significant decrease in sperm concentration; however, most authors consider that preventative sperm banking is not useful for male SCI patients’ fertility management.20,47,54 Nevertheless, some authors also suggest that the fertility of SCI patients during the chronic phase is at higher risk than in non-SCI infertile patients. In SCI patients, impairment of basic semen parameters is very frequent; higher levels of oxidative stress and sperm DNA damage are also widely described.10,20,46,47,76 Though no clinically significant decrease in basic semen parameters was assessed by retrospective studies,20,47 there is no scientific evidence that sperm DNA damage remain stable during the chronic phase of SCI. Sperm DNA damage in SCI patients is at least in part related to oxidative stress; as the incidence of seminal tract and accessory glands infections is higher in chronic SCI patients (28%–38%) than in infertile non-SCI patients (10%),27,32,33 the question of the evolution of DNA damage during the chronic phase of SCI is raised. Orchitis and epididymitis also induce a higher risk of semen impairment and obstructive sequelae, leading to possible oligo/azoospermia.33,77,78

Fertility issues in men with spinal cord injury

761

Spinal cord injury End of the spinal shock phase* Masturbation No ejaculation

Ejaculation

Penile vibratory stimulation (PVS)

No ejaculation

Ejaculation No

PVS + Midodrine

Sperm banking

Parental project ? Yes

No ejaculation

Ejaculation Assisted reproductive technique with fresh or frozen-thawed sperm

Parental project ? No

Yes Electroejaculation

STOP until parental project arises

Ejaculation No ejaculation

Surgical sperm extraction

Figure 68.2

Proposition of a patient-centered management of male spinal cord-injured (SCI) patients’ fertility by early sperm banking. *As soon as a dysreflexia is observed below the level of injury (end of the spinal shock phase), patient should be informed that SCI increases the risk of impaired fertility and an attempt to ­masturbate can be proposed.

Moreover, the increasing use of intradetrusor injection of botulinum toxin for the treatment of overactive bladders could lead to retrograde ejaculation in many patients. Indeed, the toxin was suspected to diffuse to the bladder neck and sexual accessory tract, which resulted in an increased incidence of retrograde ejaculation and to a significant decrease of ejaculate volume.79 All these factors may induce the use of bladder or surgically retrieved sperm for ART and commit couples to ICSI.49 From the patients’ perspective, this scenario should be avoided because ICSI treatments are very expensive and more invasive for the female partner than IUI and selfinseminations at home. As SCI patients’ fertility is at higher risk compared to non-SCI patients, sperm banking has been proposed to insure a patient-centered care of these patients.49 The protocol proposes early sperm banking to all SCI patients after the phase of spinal shock, while they still stay in rehabilitation center. Indeed, the achievement of ejaculation in SCI patients is easier with specialized equipment and trained multidisciplinary staff: in case of ejaculation failure after masturbation, PVS ± midodrine ± sandwich technique can be proposed. When ejaculated sperm are retrieved, they are frozen and stored. EEJ and surgical sperm extraction are only proposed to SCI patients who desire biological

parenthood. When the SCI patient starts infertility treatment, fresh or frozen-thawed sperm may be used, according to the ability of patient to ejaculate, to semen parameters, and to sperm DNA damage (Figure 68.2). As soon as the rehabilitation center can provide proper equipment and trained staff, sperm banking is simple and affordable and could benefit to some SCI patients by avoiding surgical sperm extraction and ICSI.49

Conclusion Semen parameters are rapidly impaired by SCI. During the acute phase, spermatogenesis, blood–testis barrier, and seminal vesicle function are impacted. During the chronic phase, patients face a markedly decreased sperm motility and viability due to various testicular and seminal factors including autoimmune, oxidative, and heat stresses. The management of SCI patients’ fertility involves a multidisciplinary staff and should be patient centered. As robust scientific data are lacking about the evolution of semen parameters and sperm DNA damage during the chronic phase, early sperm banking may be proposed. The ART management of male SCI patients should use the better quality sperm available (fresh or frozen-thawed)

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and the technique should be carefully adapted to feminine characteristics: patient-centered care gives the best pregnancy chances to the couple and avoids preventable surgical sperm extractions. The results of ART treatments in couples with male SCI partner are expected to be comparable to those of non-SCI couples.

Acknowledgment The authors thank JM Soler, G Karsenty, B Bernuz, and J  Saïas-Magnan for helpful discussion and collaboration for the management of SCI patients’ fertility.

References 4891. National Spinal Cord Injury Statistical Center. NSCISC 2012 Annual Report [Internet]. University of Alabama at Birmingham, 2013. https://www.nscisc.uab.edu/reports.aspx [cited 20 July 2013]. 4892. Elliott SP. Sexual dysfunction and infertility in men with spinal cord disorders. In: Lin V, ed. Spinal Cord Medicine: Principles and Practice. New-York, NY: Demos Medical Publishing, 2003: 349–65. 4893. Brindley GS. The actions of parasympathetic and sympathetic nerves in human micturition, erection and seminal emission, and their restoration in paraplegic patients by implanted electrical stimulators. Proc R Soc Lond B 1988; 235(1279): 111–20. 4894. Momen MN, Fahmy I, Amer M, Arafa M, Zohdy W, Naser TA. Semen parameters in men with spinal cord injury: Changes and aetiology. Asian J Androl 2007; 9(5): 684–9. 4895. Kafetsoulis A, Brackett NL, Ibrahim E, Attia GR, Lynne CM. Current trends in the treatment of infertility in men with spinal cord injury. Fertil Steril 2006; 86(4): 781–9. 4896. Dimitriadis F, Karakitsios K, Tsounapi P, Tsambalas S, Loutradis D, Kanakas N et  al. Erectile function and male reproduction in men with spinal cord injury: A review. Andrologia 2010; 42(3): 139–65. 4897. Brackett NL, Lynne CM, Ibrahim E, Ohl DA, Sønksen J. Treatment of infertility in men with spinal cord injury. Nat Rev Urol 2010; 7(3): 162–72. 4898. Da Silva BF, Borrelli M Jr, Fariello RM, Restelli AE, Del Giudice PT, Spaine DM et al. Is sperm cryopreservation an option for fertility preservation in patients with spinal cord injury-induced anejaculation? Fertil Steril 2010; 94(2): 564–73. 4899. Chéhensse C, Bahrami S, Denys P, Clément P, Bernabé J, Giuliano F. The spinal control of ejaculation revisited: A systematic review and meta-analysis of anejaculation in spinal cord injured patients. Hum Reprod Update 2013; 19(5): 507–26. 4900. Iremashvili VV, Brackett NL, Ibrahim E, Aballa TC, Lynne CM. A minority of men with spinal cord injury have normal semen ­quality—Can we learn from them? A case-control study. Urology 2010; 76(2): 347–51. 4901. Lee S, Miselis R, Rivier C. Anatomical and functional evidence for a neural hypothalamic-testicular pathway that is independent of the pituitary. Endocrinology 2002; 143(11): 4447–54. 4902. Ottenweller JE, Li MT, Giglio W, Anesetti R, Pogach LM, Huang HF. Alteration of follicle-stimulating hormone and testosterone regulation of messenger ribonucleic acid for Sertoli cell proteins in the rat during the acute phase of spinal cord injury. Biol Reprod 2000; 63(3): 730–5. 4903. Huang HF, Linsenmeyer TA, Li MT, Giglio W, Anesetti R, von Hagen J et al. Acute effects of spinal cord injury on the pituitarytesticular hormone axis and Sertoli cell functions: A time course study. J Androl 1995; 16(2): 148–57. 4904. Dulin JN, Moore ML, Gates KW, Queen JH, Grill RJ. Spinal cord injury causes sustained disruption of the blood-testis barrier in the rat. PLoS ONE 2011; 6(1): e16456.

4905. Ohl DA, Sønksen J, Wedemeyer G, Zaborniak MC, Dam TN, Menge AC et al. Canine model of infertility after spinal cord injury: Time course of acute changes in semen quality and s­ permatogenesis. J Urol 2001; 166(3): 1181–4. 4906. Linsenmeyer TA, Pogach LM, Ottenweller JE, Huang HF. Spermato­ genesis and the pituitary-testicular hormone axis in rats during the acute phase of spinal cord injury. J Urol 1994; 152(4): 1302–7. 4907. Huang HFS, Li M-T, Wang S, Pogach LM, Ottenweller JE. Alteration of cyclic adenosine 3’,5’-monophosphate signaling in rat testicular cells after spinal cord injury. J Spinal Cord Med 2003; 26(1): 69–78. 4908. Dashtdar H, Valojerdi MR. Ultrastructure of rat seminal vesicle epithelium in the acute phase of spinal cord transection. Neurol Res 2008; 30(5): 487–92. 4909. Wang S, Wang G, Barton BE, Murphy TF, Huang HFS. Beneficial effects of vitamin E in sperm functions in the rat after spinal cord injury. J Androl 2007; 28(2): 334–41. 4910. Iremashvili V, Brackett NL, Ibrahim E, Aballa TC, Lynne CM. Semen quality remains stable during the chronic phase of spinal cord injury: A longitudinal study. J Urol 2010; 184(5): 2073–7. 4911. Mallidis C, Lim TC, Hill ST, Skinner DJ, Brown DJ, Johnston WI et al. Collection of semen from men in acute phase of spinal cord injury. Lancet 1994; 343(8905): 1072–3. 4912. Brackett NL, Lynne CM, Aballa TC, Ferrell SM. Sperm motility from the vas deferens of spinal cord injured men is higher than from the ejaculate. J Urol 2000; 164(3 Pt 1): 712–5. 4913. Brackett NL, Davi RC, Padron OF, Lynne CM. Seminal plasma of spinal cord injured men inhibits sperm motility of normal men. J Urol 1996; 155(5): 1632–5. 4914. Barbonetti A, Vassallo MRC, Di Rosa A, Leombruni Y, Felzani G, Gandini L et  al. Involvement of mitochondrial dysfunction in the adverse effect exerted by seminal plasma from men with spinal cord injury on sperm motility. Andrology 2013; 1(3): 456–3. 4915. Bennett CJ, Seager SW, Vasher EA, McGuire EJ. Sexual dysfunction and electroejaculation in men with spinal cord injury: Review. J Urol 1988; 139(3): 453–7. 4916. Paul C, Teng S, Saunders PTK. A single, mild, transient scrotal heat stress causes hypoxia and oxidative stress in mouse testes, which induces germ cell death. Biol Reprod 2009; 80(5): 913–9. 4917. Rolf C, Kenkel S, Nieschlag E. Age-related disease pattern in infertile men: Increasing incidence of infections in older patients. Andrologia 2002; 34(4): 209–17. 4918. Sakkas D, Mariethoz E, St John JC. Abnormal sperm parameters in humans are indicative of an abortive apoptotic mechanism linked to the Fas-mediated pathway. Exp Cell Res 1999; 251(2): 350–5. 4919. Naderi AR, Safarinejad MR. Endocrine profiles and semen quality in spinal cord injured men. Clin Endocrinol (Oxf) 2003; 58(2): 177–84. 4920. Elliott SP, Orejuela F, Hirsch IH, Lipshultz LI, Lamb DJ, Kim ED. Testis biopsy findings in the spinal cord injured patient. J Urol 2000; 163(3): 792–5. 4921. Padron OF, Brackett NL, Sharma RK, Lynne CM, Thomas AJ Jr, Agarwal A. Seminal reactive oxygen species and sperm motility and morphology in men with spinal cord injury. Fertil Steril 1997; 67(6): 1115–20. 4922. Ku JH, Jung TY, Lee JK, Park WH, Shim HB. Influence of ­bladder management on epididymo-orchitis in patients with spinal cord injury: Clean intermittent catheterization is a risk factor for ­epididymo-orchitis. Spinal Cord 2006; 44(3): 165–9. 4923. Mirsadraee S, Mahdavi R, Moghadam HV, Ebrahimi MA, Patel HRH. Epididymo-orchitis risk factors in traumatic spinal cord injured patients. Spinal Cord 2003; 41(9): 516–20. 4924. Depuydt CE, Bosmans E, Zalata A, Schoonjans F, Comhaire FH. The relation between reactive oxygen species and cytokines in andrological patients with or without male accessory gland infection. J Androl 1996; 17(6): 699–707.

Fertility issues in men with spinal cord injury 4925. Tremellen K. Oxidative stress and male infertility—a clinical perspective. Hum Reprod Update 2008; 14(3): 243–58. 4926. Basu S, Aballa TC, Ferrell SM, Lynne CM, Brackett NL. Inflammatory cytokine concentrations are elevated in seminal plasma of men with spinal cord injuries. J Androl 2004; 25(2): 250–4. 4927. Brackett NL, Cohen DR, Ibrahim E, Aballa TC, Lynne CM. Neutralization of cytokine activity at the receptor level improves sperm motility in men with spinal cord injuries. J Androl 2007; 28(5): 717–21. 4928. Zhang X, Ibrahim E, de Rivero Vaccari JP, Lotocki G, Aballa TC, Dietrich WD et al. Involvement of the inflammasome in abnormal semen quality of men with spinal cord injury. Fertil Steril 2013; 99(1): 118–24. 4929. Patki P, Woodhouse J, Hamid R, Craggs M, Shah J. Effects of spinal cord injury on semen parameters. J Spinal Cord Med 2008; 31(1): 27–32. 4930. Zhu J, Brackett NL, Aballa TC, Lynne CM, Witt MA, Kort HI et al. High seminal platelet-activating factor acetylhydrolase activity in men with spinal cord injury. J Androl 2006; 27(3): 429–33. 4931. Sønksen J, Ohl DA, Giwercman A, Biering-Sørensen F, Skakkebaek  NE, Kristensen JK. Effect of repeated ejaculation on semen quality in spinal cord injured men. J Urol 1999; 161(4): 1163–5. 4932. Brackett NL, Ibrahim E, Grotas JA, Aballa TC, Lynne CM. Higher sperm DNA damage in semen from men with spinal cord injuries compared with controls. J Androl 2008; 29(1): 93–9; discussion 100–1. 4933. Restelli AE, Bertolla RP, Spaine DM, Miotto A Jr, Borrelli M Jr, Cedenho AP. Quality and functional aspects of sperm retrieved through assisted ejaculation in men with spinal cord injury. Fertil Steril 2009; 91(3): 819–25. 4934. Evenson DP, Wixon R. Clinical aspects of sperm DNA fragmentation detection and male infertility. Theriogenology 2006; 65(5): 979–91. 4935. Sakkas D, Moffatt O, Manicardi GC, Mariethoz E, Tarozzi N, Bizzaro D. Nature of DNA damage in ejaculated human spermatozoa and the possible involvement of apoptosis. Biol Reprod 2002; 66(4): 1061–7. 4936. Qiu Y, Wang L-G, Zhang L-H, Li J, Zhang A-D, Zhang M-H. Sperm chromosomal aneuploidy and DNA integrity of infertile men with anejaculation. J Assist Reprod Genet 2012; 29(2): 185–94. 4937. Brackett NL, Ferrell SM, Aballa TC, Amador MJ, Lynne CM. Semen quality in spinal cord injured men: Does it progressively decline postinjury? Arch Phys Med Rehabil 1998; 79(6): 625–8. 4938. Anderson KD. Targeting recovery: Priorities of the spinal cordinjured population. J Neurotrauma 2004; 21(10): 1371–83. 4939. Karsenty G, Bernuz B, Metzler-Guillemain C, Grillo J-M, SaïasMagnan J, Rigot J-M et al. Should sperm be cryopreserved after spinal cord injury? Basic Clin Androl 2013; 23(1): 6. 4940. Brackett NL, Ibrahim E, Iremashvili V, Aballa TC, Lynne CM. Treatment for ejaculatory dysfunction in men with spinal cord injury: An 18-year single center experience. J Urol 2010; 183(6): 2304–8. 4941. Soler JM, Previnaire JG, Plante P, Denys P, Chartier-Kastler E. Midodrine improves ejaculation in spinal cord injured men. J Urol 2007; 178(5): 2082–6. 4942. Perrin J, Saïas-Magnan J, Thiry-Escudié I, Gamerre M, Serment G, Grillo J-M et al. [The spinal cord injured patient: Semen quality and management by Assisted Reproductive Technology]. Gynécologie Obstétrique Fertil 2010; 38(9): 532–5. 4943. Soler JM, Previnaire JG. Ejaculatory dysfunction in spinal cord injury men is suggestive of dyssynergic ejaculation. Eur J Phys Rehabil Med 2011; 47(4): 677–81. 4944. DeForge D, Blackmer J, Garritty C, Yazdi F, Cronin V, Barrowman N et  al. Fertility following spinal cord injury: A systematic review. Spinal Cord 2005; 43(12): 693–703.

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4945. Sønksen J, Biering-Sørensen F, Kristensen JK. Ejaculation induced by penile vibratory stimulation in men with spinal cord injuries. The importance of the vibratory amplitude. Paraplegia 1994; 32(10): 651–60. 4946. Brackett NL, Kafetsoulis A, Ibrahim E, Aballa TC, Lynne CM. Application of 2 vibrators salvages ejaculatory failures to 1 vibrator during penile vibratory stimulation in men with spinal cord injuries. J Urol 2007; 177(2): 660–3. 4947. Brackett NL, Ferrell SM, Aballa TC, Amador MJ, Padron OF, Sonksen J et al. An analysis of 653 trials of penile vibratory stimulation in men with spinal cord injury. J Urol 1998; 159(6): 1931–4. 4948. Brackett NL, Ead DN, Aballa TC, Ferrell SM, Lynne CM. Semen retrieval in men with spinal cord injury is improved by interrupting current delivery during electroejaculation. J Urol 2002; 167(1): 201–3. 4949. Arafa MM, Zohdy WA, Shamloul R. Prostatic massage: A simple method of semen retrieval in men with spinal cord injury. Int J Androl 2007; 30(3): 170–3. 4950. Makler A, David R, Blumenfeld Z, Better OS. Factors affecting sperm motility. VII. Sperm viability as affected by change of pH and osmolarity of semen and urine specimens. Fertil Steril 1981; 36(4): 507–11. 4951. Aust TR, Brookes S, Troup SA, Fraser WD, Lewis-Jones DI. Development and in vitro testing of a new method of urine preparation for retrograde ejaculation; the Liverpool solution. Fertil Steril 2008; 89(4): 885–91. 4952. Scammell GE, Stedronska-Clark J, Edmonds DK, Hendry WF. Retrograde ejaculation: Successful treatment with artificial insemination. Br J Urol 1989; 63(2): 198–201. 4953. Perrin J, Saïas-Magnan J, Lanteaume A, Thiry-Escudié I, Serment G, Bladou F, et  al. [Initial results of a novel technique for sperm retrieval in male infertility due to refractory retrograde ejaculation]. Progrès En Urol J Assoc Française Urol Société Française Urol 2011; 21(2): 134–8. 4954. Jefferys A, Siassakos D, Wardle P. The management of retrograde ejaculation: A systematic review and update. Fertil Steril 2012; 97(2): 306–12. 4955. Ranieri DM, Simonetti S, Vicino M, Cormio L, Selvaggi L. Successful establishment of pregnancy by superovulation and intrauterine insemination with sperm recovered by a modified Hotchkiss procedure from a patient with retrograde ejaculation. Fertil Steril 1995; 64(5): 1039–42. 4956. Saito K, Kinoshita Y, Yumura Y, Iwasaki A, Hosaka M. Successful pregnancy with sperm retrieved from the bladder after the introduction of a low-electrolyte solution for retrograde ejaculation. Fertil Steril 1998; 69(6): 1149–51. 4957. Silva PD, Larson KM, Van Every MJ, Silva DE. Successful treatment of retrograde ejaculation with sperm recovered from bladder washings. A report of two cases. J Reprod Med 2000; 45(11): 957–60. 4958. Glezerman M, Lunenfeld B, Potashnik G, Oelsner G, Beer R. Retrograde ejaculation: Pathophysiologic aspects and report of two successfully treated cases. Fertil Steril 1976; 27(7): 796–800. 4959. Jimenez C, Grizard G, Pouly JL, Boucher D. Birth after combination of cryopreservation of sperm recovered from urine and intracytoplasmic sperm injection in a case of complete retrograde ejaculation. Fertil Steril 1997; 68(3): 542–4. 4960. Brackett NL, Bloch WE, Lynne CM. Predictors of necrospermia in men with spinal cord injury. J Urol 1998; 159(3): 844–7. 4961. Klotz R, Joseph PA, Ravaud JF, Wiart L, Barat M. The Tetrafigap Survey on the long-term outcome of tetraplegic spinal cord injured persons: Part III. Medical complications and associated factors. Spinal Cord 2002; 40(9): 457–67. 4962. Fode M, Krogh-Jespersen S, Brackett NL, Ohl DA, Lynne CM, Sønksen J. Male sexual dysfunction and infertility associated with neurological disorders. Asian J Androl 2012; 14(1): 61–8.

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4963. Kanto S, Uto H, Toya M, Ohnuma T, Arai Y, Kyono K. Fresh testicular sperm retrieved from men with spinal cord injury retains equal fecundity to that from men with obstructive azoospermia via intracytoplasmic sperm injection. Fertil Steril 2009; 92(4): 1333–6. 4964. Nyboe Andersen A, Goossens V, Bhattacharya S, Ferraretti AP, Kupka MS, de Mouzon J et  al. Assisted reproductive technology and intrauterine inseminations in Europe, 2005: Results generated from European registers by ESHRE: ESHRE. The European IVF Monitoring Programme (EIM), for the European Society of Human Reproduction and Embryology (ESHRE). Hum Reprod Oxf Engl 2009; 24(6): 1267–87. 4965. Chung PH, Palermo G, Schlegel PN, Veeck LL, Eid JF, Rosenwaks Z. The use of intracytoplasmic sperm injection with e­ lectroejaculates from anejaculatory men. Hum Reprod Oxf Engl 1998; 13(7): 1854–8.

4966. Qiu Y, Wang L-G, Zhang L-H, Zhang A-D, Wang Z-Y. Quality of sperm obtained by penile vibratory stimulation and percutaneous vasal sperm aspiration in men with spinal cord injury. J Androl 2012; 33(5): 1036–46. 4967. Haidl G, Allam JP, Schuppe H-C. Chronic epididymitis: Impact on semen parameters and therapeutic options. Andrologia 2008; 40(2): 92–6. 4968. Christiansen E, Tollefsrud A, Purvis K. Sperm quality in men with chronic abacterial prostatovesiculitis verified by rectal ultrasonography. Urology 1991; 38(6): 545–9. 4969. Caremel R, Courtois F, Charvier K, Ruffion A, Journel NM. Side effects of intradetrusor botulinum toxin injections on ejaculation and fertility in men with spinal cord injury: Preliminary findings. BJU Int 2012; 109(11): 1698–702.

69 Pregnancy in spinal cord injury Carlotte Kiekens

Introduction In Western countries, traumatic spinal cord injury (SCI) is a relatively rare condition with an average incidence of 4  per 100,000 inhabitants per year in the United States1 and somewhat lower in Europe, for example 2.6 per 100,000 inhabitants in Norway.2 Eighty percent of the ­subjects are male.1 There is trend of increasing mean age at injury as well as proportion of women.3 For non-traumatic SCI, no clear data are available but, in general, mean age is higher, as well as the percentage of women.1 The mean age at onset being the early thirties, sexuality and fertility issues are relevant, but literature concerning these topics in women is scarce. However, motherhood is an important issue for the quality of life of these disabled women and their ­motivation to carry on with their lives after such a devastating event. The scientific literature concerning female fertility issues such as pregnancy rates, live births, and complications or obstetric management following SCI, mainly consists of case reports and opinion articles. Recently, however, some reviews and studies have been published, for example, with regard to the urological management of pregnant, spinal cord injured women as will be discussed in the Section “Pregnancy.”

duration of amenorrhea of 7.96 (±10.9) months, independent of the level of injury.7 The same pattern of regularity or irregularity then usually appears and the level and completeness of the lesion do not seem to influence the menstrual cycle.6 A multicenter survey in 472  women, published by Jackson and Wadley in 1999, showed that menstrual cramping is less frequent after SCI, which is in contrast to an increase in premenstrual syndrome.5 Exacerbation of autonomic symptoms occurs at particular times in the cycle. These spinal cord injured women had fewer gynecologic check-ups, mammographies, and PAP smears post-injury. Menopause was induced by SCI, immediately or within 12 months, in 14% of the subjects, but except for an increase in mood disorders, menopausal symptoms were fairly comparable in women with or without an SCI.5 The use of oral contraceptives may be contraindicated because of the challenged cardiovascular status and increased risk of deep venous thrombosis. Especially in women who smoke or are over 35 years of age, the risks are increased.8 As a result of sensory loss, intrauterine devices (IUDs) can be dangerous in case of urogenital infection or other complications.4 Condoms can be used and offer the additional benefit of protection from sexually transmitted disease.9 Persons with spina bifida very often exhibit latex allergy, so for them condoms should be latex-free. Also, in adult SCI patients, especially with pediatric-onset SCI, it may be wise to avoid frequent latex exposure.

Menstruation, fertility, and contraception

Pregnancy

Menarche has been reported to occur normally in girls who have been injured as preadolescents. When an SCI is sustained after menarche, it is usually followed by an episode of amenorrhea. On average, women resume menses after 3–6 months, with 50% of the women presenting menses at 6 months and 90% of the women by 1 year after injury. At that moment, fertility status returns to the premorbid status.4–6 A retrospective study of 128 women with SCI published in 2008 by Burghi et al. showed a longer mean

Pregnancy rate is lower in women with SCI. For instance, in the study by Burghi 20% of the women became pregnant after the period of transient amenorrhea.7 Pregnancy rate was higher when the SCI was sustained at a younger age while the level of injury had no influence. This does not seem to be due to fertility problems but rather to secondary factors such as decreased sexual activity, decreased involvement in relationships, not wanting children, or perceived difficulty in caring for the children.5

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Different problems can occur during pregnancy and a regular follow-up by a multidisciplinary team is mandatory. This team should at least be composed of the general practitioner, a gynecologist, and a physician specialized in physical medicine and rehabilitation. Ideally, also the urologist, anesthesiologist, physical therapist, occupational therapist, and midwife are involved. Tebbet and Kennedy state that services and professionals should approach these women with specific needs and wishes within a biopsychosocial framework.10 Where possible, it is optimal to give preconceptual counseling. This counseling comprises an evaluation of the medication scheme of the mother to avoid teratogenous effects on the fetus. Women with a spinal cord lesion “due to spina bifida” should take folic acid in a dose of 4 mg daily.11 Psychological aspects can be discussed in preparation of pregnancy, particularly in women who might not be able to care independently for their baby. A peer mentor system, promoting positive experiences in other women has been experienced as very beneficial and may help to improve self-efficacy and preparation for the experience of childbirth.10 Finally, a renal/urologic and pulmonary assessment in the preconception phase is appropriate. The following information is mainly based on the review on pregnancy and SCI published in 1996 by Baker and Cardenas,12 and the data reported, respectively, by Charlifue et  al. in 1992,5 Jackson and Wadley in 1999,4 Ghidini et  al.,13 and Skowronski et  al. in 2008.14 During pregnancy, weight gain can decrease mobility and independence for activities of daily living (ADL; e.g., transfers and wheelchair propulsion). Extra help as well as technical aids sometimes need to be provided, as can be the case for tetraplegic mothers for the care of the baby. As a result of sensory loss, fetal movements might not be perceived. In that case, the mother should be taught to feel these movements by palpating the abdominal wall. Bladder management is often disturbed: incontinence increases and more frequent intermittent catheterization may be necessary. As the presence of asymptomatic bacteriuria and urinary tract infection (UTI) increases, it is important to ensure sufficient fluid intake and to minimize residual volumes to avoid pyelonephritis, as this may induce preterm labor and delivery. Indwelling or suprapubic catheters are contraindicated and frequent surveillance of cultures is advised. Some suggest to switch from “clean” to “sterile” intermittent catheterization, for example, using a self-contained “touch-less” catheter and bag.6 A systematic literature review by Pannek et al. in 2011 confirmed that the majority of the women (64%) had at least one symptomatic UTI during pregnancy.15 Unfortunately, because of the small study samples and low level of evidence in all studies, no evidence-based recommendations could be made. In 2009, a French team published encouraging results of a prospective observational study in six women with SCI.16 A weekly oral cyclic antibiotic program showed a significant reduction of UTI without obstetric complications and good infant outcomes. They

are currently using the protocol. Because of a decrease in gastric motility during pregnancy, bowel management requires prevention of constipation with, again, sufficient fluid (and fiber) intake and, if necessary, mild laxatives. The pregnant woman with SCI often shows anemia and fatigue, water retention, and edema of the lower extremities. Augmented spasticity and pain have also been described. These factors, together with the decreased mobility, can cause decubitus ulcers. The risk for thromboembolism increases and compression stockings as well as LMWH (low-molecular-weight heparin) administration from the 4th month on until the end of the postpartum period are recommended. In high thoracic and cervical lesions, respiratory capacity is challenged during pregnancy, requiring adapted respiratory rehabilitation. Spasticity can be exacerbated during pregnancy, but oral baclofen can have side-effects for the fetus. Roberts et al. reported on two cases where an intrathecal baclofen (ITB) pump was implanted before or during pregnancy, and one case where ITB was administered via an external catheter with good tolerance and good effect on spasticity.17 Morton et  al. described another three patients with spasticity, of which one with a T5 paraplegia, who became pregnant and delivered with an ITB pump.18 In their clinical review, they ask attention for the position of the pump, the risk for catheter problems due to the change in abdominal shape, and care not to enter the pump pocket in case of a caesarean delivery. Spinal or epidural anesthesia needles should not pierce the catheter. The most important and dangerous complication during pregnancy (and delivery) is autonomic dysreflexia.19 This is a syndrome characterized by a sudden exaggerated reflex increase in blood pressure known as an important and possibly life-threatening complication, for the mother as well as the baby. It is reported to occur in 48%–85% of all SCI patients with an SCI at T6 or above, but isolated cases in patients with SCI as low as T8 have been reported. Any stimulus below the lesion that enters the spinal cord through intact peripheral nerves, such as a distended bladder or bowel, a UTI, a pressure sore, or labor, can trigger the sympathetic nervous system (segments T1–T5) and induce an uncontrolled increase in blood pressure due to the lack of inhibitory descending tracts. The symptoms are those of an infralesional vasoconstriction with supralesional vasodilatation. General symptoms are systemic hypertension, compensatory bradycardia, and anxiety. Above the lesion, we notice pounding headache, flushing, sweating, and, if the lesion is higher than T1, mydriasis. Below the lesion the patient presents mainly cool extremities and piloerection. Possible complications include retinal, subarachnoidal, or intracerebral hemorrhage; myocardial infarction; seizure; and death. During pregnancy, differential diagnosis has to be made with preeclampsia, of which the treatment is different.8 Prevention of autonomic dysreflexia by avoiding irritations, such as a full bladder or bowel, infection,

Pregnancy in spinal cord injury constipation, or skin ulcers, is absolutely mandatory. When treating autonomic dysreflexia, antihypertensive agents with rapid action and short duration are preferred (mostly nifedipine or captopril), but hypotension should be avoided as this is more poorly tolerated by the fetus then acute hypertension.

Labor and delivery Labor and delivery depend on the level of the lesion. The uterus is innervated by the segments T10–L1. Women presenting lesions lower than L1 have preservation of uterine sensibility. Women with a lesion in T10–L1 may present insufficient labor. When the lesion is situated in L1 or above, the onset of labor may not be perceived due to the sensory impairment. As is the case during pregnancy, women with lesions at T6 or higher present a risk for autonomic dysreflexia. Different authors report an increase in preterm labor and delivery. Labor indicators differ greatly following SCI and can have pain above the level of injury, abnormal pain, ruptured membranes (which can be confused with urinary incontinence), significantly increased spasticity (usually of the legs or the abdomen), respiratory changes, symptoms of autonomic dysreflexia, and increased bladder spasms.4,5,13 Some women report normal labor sensation but others do not experience any type of labor sensation, depending on the level and completeness of the lesion. Unattended delivery should be avoided in patients who are unable to sense contractions reliably. Therefore, cervical e­ xaminations once or twice weekly are recommended after 28 weeks, and hospitalization after 36 weeks or earlier if labor begins or the cervix dilates or is effaced.8,13,14 The patient should be taught uterine palpation techniques, and home uterine activity monitoring can be beneficial. Labor duration does not differ signifi­ cantly even though the clinical perception of labor may be present only at advanced labor and not at latent labor.12 During labor and delivery, rigorous prevention of pressure ulcers is of extreme importance, and a special support, regular changes in position, and skin examination are mandatory. Frequent bladder emptying by intermittent or continuous catheterization will prevent overdistention of the bladder, which is important as an (over) distended bladder can induce autonomic dysreflexia. In the series published by Charlifue et  al., 53% of the women had vaginal deliveries without forceps, 22% with forceps assistance, and 25% were cesarean deliveries. Of the cesarean deliveries, 5 were done by physician choice, 2 to deliver transverse lying twins, 2 for autonomic dysreflexia during delivery, 1 because of placenta previa, and 1 because of prolonged labor.5 Cross et  al. reported cesarean section in 43% of the patients for the following reasons: breech presentation, transverse presentation, lack of progress, onset of labor one day post-spinal fusion, and a mother’s request to have tubal ligation.8 Finally, Pereira

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described rates of spontaneous vaginal delivery in 37% of SCI women, assisted vaginal delivery in 31%, and cesarean delivery in 32%.11 If autonomic dysreflexia can occur, this means, in all women with a lesion at or above T6, an epidural anesthesia and continuous blood pressure monitoring are necessary.14 To avoid skin breakdown at the episiotomy site, the use of nonabsorbable sutures has been recommended, especially in denervated areas.6 There are some specificities concerning women presenting a cauda equina syndrome.20 Women who preserved an ability for walking often lose this at the end of the pregnancy. Sensibility of the internal genital organs is preserved, meaning that fetal movements as well as onset of labor will be perceived, so early hospitalization is usually not necessary in this group of patients. The abdominal muscles will help to expel the baby. However, the risk of perineal distention or even rupture is increased due to hypotonia of the pelvic floor and the cicatrization of episiotomy can be problematic. A cesarean section might be indicated to protect the fragile pelvic floor. Another issue applies to women with lower urinary tract (LUT) reconstruction. This technique has been increasingly performed over the last two decades, mainly in children and young adults. Some series on pregnancy and LUT reconstruction have been published, mostly with satisfying results.21–23 Monitoring and even prophylaxis of UTIs is important during pregnancy in these patients.23 Some had problems with clean intermittent catheterization, especially when the stoma was orthotopic. Elective cesarean section can be advised although vaginal delivery has also been reported with good results.22,23 Multidisciplinary follow-up including the urologist is crucial and his presence is necessary in case of a cesarean section: the augmented bladder or urinary reservoir should then be moved away after a midline incision.23 Although these series include several patients with spinal dysraphism, we only found one case of a spinal cord injured woman.22 She had an assisted vaginal delivery (forceps) at 39 weeks and afterward her continence was unchanged. She presented frequent episodes of febrile UTI and a severe pyelonephritis at 28 weeks. A final issue concerns women with Malone antegrade continence enema (MACE). A case report by Wren et al. in 2003 describes an excellent fecal continence during pregnancy and an uncomplicated vaginal delivery in a women with an injury of the sacral nerve roots.24

Postpartum and breastfeeding During the postpartum period, the risk for thromboembolic disease remains increased. Patients should be assessed for bladder distention, and bladder management has to be adapted. Bowel management also still requires extra attention.11,12 In case of impaired balance or upper limb function, extra help needs to be organized for the care

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Milk production

T4 – T6

Sympathetic input from suckling

Figure 69.1 Under normal conditions, the sympathetic input from suckling enters the spinal cord at the level of T4–T6 and from there travels up to the hypothalamus, which in turn induces oxytocin production and increases milk production. In lesions at or above T6, this normal pathway is partially or completely interrupted, which can result in a decrease of milk production.

of the baby. This may require some psychological adaptation of the mother. Technical aids, and tips and tricks can be given by the occupational therapist. Breastfeeding is possible even though milk production might be decreased in lesions above T6 due to decreased nipple sensation. In neurologically intact mothers, infant suckling activates tactile receptors in the breast. This signal is carried via afferent nerves in the T4–6 dorsal roots to the spinal cord and then to neurons in the hypothalamus (Figure 69.1), which release oxytocin in the bloodstream, triggering milk ejection from the breast.25 Cowley reported on three tetraplegic women maintaining breastfeeding for an extended period (12–54 weeks). One of them used mental imaging and relaxation techniques and another needed oxytocin nasal spray to facilitate the letdown reflex. In Charlifue’s series of 29 women who breastfed their infants, only 4 were reported to have insufficient milk.5 Halbert drew attention to the fact that additional support with breastfeeding aids, such as pillows to support the baby or adapted nursing bras with easy opening and closing, might be necessary.26

Motherhood Literature on the impact of SCI on mothering is very scarce. In 1994, an article was published on 26 mothers with SCI with 47 children.27 No women felt that their family roles and the relationships between family members differed from

those of other families. Neither did they have the impression that their children were unable to participate in regular activities because of their SCI. The 10 children who were able to fill out the questionnaire did not perceive their mothers as different from other mothers because of their SCI. Fathers did not report that they felt they had more responsibilities than partners of able-bodied women. In some other studies, very few problems were reported by mothers with SCI. One woman noted that she had problems going on field trips. Another woman, though, stated that having a child actually provided a motivation to stay healthy.6 In Ghidini’s study, 23 out of 24 women who gave birth reported that being a parent increased the quality of their life and that given the chance they would want to have a child again.13 In 2002, Alexander et  al. published a randomized controlled trial of mothers with SCI and their children, matched to able-bodied mothers and their children on key demographic variables.28 Eighty-eight mothers, 46 of their partners, and 31 of their children participated. In this study, SCI did not appear to affect their children adversely in terms of individual adjustment, attitudes toward their parents, self-esteem, gender roles, and family functioning. Moreover, SCI mothers saw their children as being less rigid and more comfortable in adjusting to novel situations in their environment. SCI mothers did not show more stress than the able-bodied mothers, even if they were more likely to report feeling a lack of emotional and active support from their partners in the area of child management. Partners of SCI mothers, however, seemed to enjoy more satisfying relationships with their children. Just the presence of maternal SCI does not predict difficulties in children’s psychological adjustment, nor does it lead to problems in areas of parenting satisfaction, parenting stress, marital adjustment, or family functioning.

Summary SCI is a relatively rare condition and mainly strikes men. Literature on pregnancy in SCI is very scarce and consists mainly of case reports and opinion articles. However, motherhood is an important topic for women with SCI. After an episode of amenorrhea, fertility returns to the premorbid status. Contraception should be prescribed if necessary, taking into account the specific risks of each method. Pregnancy rates are lower in women with SCI. During pregnancy, appropriate multidisciplinary follow-up is mandatory. The most dangerous complication is autonomic dysreflexia, which can occur in patients with a lesion at T6 or above. Other potential complications are bladder and bowel problems, pressure sores, anemia and fatigue, increased spasticity or pain, decreased respiratory capacity, and thromboembolic events. Extra monitoring is advised from the 28th week and hospitalization at 36 weeks to prevent preterm delivery. Delivery depends on the level of the lesion, the innervation of the uterus being autonomic and situated in

Pregnancy in spinal cord injury T10–L1. Even though spontaneous vaginal delivery is often possible, there is an increased percentage of assisted vaginal delivery or cesarean delivery. In patients presenting a lesion at T6 or above, continuous monitoring of blood pressure and epidural anesthesia is necessary during delivery because of the risk for autonomic dysreflexia. Breastfeeding is recommended because of its beneficial effects for the mother as well as the baby. In patients with a lesion above T6, the hypothalamus reaction to suckling-induced oxytocin production might be decreased, with insufficient milk production as a consequence. With some extra care, though, most of the women succeed in breastfeeding. The presence of maternal SCI does not seem to predispose for psychological adjustment problems in their children, nor does it lead to decreased parenting satisfaction or family functioning. Pregnancy and motherhood are certainly possible for women with SCI, but multidisciplinary follow-up with prevention of possible complications during pregnancy, labor, and delivery is mandatory.

References 4970. DeVivo MJ. Epidemiology of traumatic spinal cord injury: Trends and future implications. Spinal Cord 2012; 50: 365–72. 4971. Hagen EM, Eide GE, Rekand T et  al. A 50-year follow-up of the ­incidence of traumatic spinal cord injuries in Western Norway. Spinal Cord 2010; 48: 313–8. 4972. O’Connor PJ. Trends in spinal cord injury. Accident Anal Prev 2006; 38: 71–7. 4973. Jackson AB, Wadley V. A multicenter study of women’s self-reported reproductive health after spinal cord injury. Arch Phys Med Rehabil 1999; 80: 1420–8. 4974. Charlifue SW, Gerhart KA, Menter RR et al. Sexual issues of women with spinal cord injuries. Paraplegia 1992; 30: 192–9. 4975. Linsenmeyer TA. Sexual function and infertility following spinal cord injury. Phys Med Rehab Clin N Am 2000; 11: 141–56. 4976. Burghi S, Shaw SJ, Mahmood G et al. Amenorrhea, pregnancy, and pregnancy outcomes in women following spinal cord injuy: A retrospective cross-sectional study. Endocr Pract 2008; 14: 437–41. 4977. Cross LL, Meythaler JM, Tuel SM et al. Pregnancy, labor and delivery post spinal cord injury. Paraplegia 1992; 30: 890–902. 4978. Sipski ML. Spinal cord injury and sexual function: An educational model. In: Sipski ML, Alexander CJ, eds. Sexual Function in People with Disability and Chronic Illness. Gaitherburg, MD: Aspen Publishers, Inc., 1997: 149–76.

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4979. Tebbet M, Kennedy P. The experience of childbirth for women with spinal cord injuries: An interpretative phenomenology analysis study. Disabil Rehabil 2012; 34: 762–9. 4980. Pereira L. Obstetric management of the patient with spinal cord injury. Obstet Gynaecol Survey 2003; 58: 678–86. 4981. Baker ER, Cardenas DD. Pregnancy in spinal cord injured women. Arch Phys Med Rehab 1996; 77: 501–7. 4982. Ghidini A, Healy A, Andreani M et al. Pregnancy and women with spinal cord injuries. Acta Obstet Gynecol Scand 2008; 87: 1006–10. 4983. Skowronski E, Hartman K. Obstetric management following traumatic tetraplegia: Case series and literature review. Aust. ­ N Z J Obstet Gynaecol 2008; 48: 485–91. 4984. Pannek J, Bertschy S. Mission impossible? Urological management of patients with spinal cord injury during pregnancy: A systematic review. Spinal Cord 2011; 49: 1028–32. 4985. Salomon J, Schnitzler A, Ville Y et  al. Prevention of urinary tract infection in six spinal cord-injured women who gave birth. Int J Infect Dis 2009; 13: 399–402. 4986. Roberts AG, Graves CR, Konrad PE et al. Intrathecal baclofen pump implantation during pregnancy. Neurology 2003; 61: 1156–7. 4987. Morton CM, Rosenow J, Wong C et al. Intrathecal baclofen administration during pregnancy: A case series and focused clinical review. PM R 2009; 1: 1025–9. 4988. Campagnolo DI, Merli GJ. Autonomic and cardiovascular complications of spinal cord injury. In: Kirshblum S, Campagnolo DI, De Lisa JA, eds. Spinal Cord Medicine. Philadelphia, PA: Lippincott Williams & Wilkins, 2002: 123–34. 4989. Perrouin-Verbe B, Labat JJ. Sexualité et procréation des syndromes de la queue de cheval. In: Costa P, Lopez S, Pélissier J, eds. Sexualité, Fertilité et Handicap. Paris, France: Masson, 1996: 81–8. 4990. Greenwell TJ, Venn SN, Creighton S et  al. Pregnancy after lower urinary tract reconstruction for congenital abnormalities. BJU Int 2003; 92: 773–7. 4991. Quenneville V, Beurton D, Thomas L et al. Pregnancy and vaginal delivery after augmentation cystoplasty. BJU Int 2003; 91: 893–4. 4992. Hensle TW, Bingham JB, Reiley EA et  al. The urological care and outcome of pregnancy after urinary tract reconstruction. BJU Int 2004; 93: 588–90. 4993. Wren FJ, Reese CT, Decter RM. Durability of the Malone antegrade continence enema in pregnancy. Urology 2003; 61: 644iv. 4994. Cowley KC. Psychogenic and pharmacological induction of the ­let-down reflex can facilitate breastfeeding by tetraplegic women: A report of 3 cases. Arch Phys Med Rehab 2005; 86: 1261–4. 4995. Halbert LA. Breastfeeding in the woman with a compromised ­nervous system. J Hum Lact 1998; 14: 327–31. 4996. Westgren N, Levi R. Motherhood after traumatic spinal cord injury. Paraplegia 1994; 32: 517–23. 4997. Alexander CJ, Hwang K, Sipski M. Mothers with spinal cord injuries: Impact on marital, family, and children’s adjustment. Arch Phys Med Rehab 2002; 83: 24–30.

Part XI Prognosis and follow-up

70 Evolution and follow-up of lower urinary tract dysfunction in spinal cord–injured patients Marc Le Fort, Marie-Aimée Perrouin-Verbe, and Jean-Jacques Labat

Introduction Neurological lesions can disrupt bladder-sphincter functioning and its central neurological control. Consequently, these problems can alter the quality of life by inducing incontinence and even threatening the upper urinary tract, particularly of spinal cord injury (SCI) patients. For a long time, urinary complications have been the leading cause of death in SCI. Today, this is not the case. Better knowledge of the evolution and prognostic factors of neurological bladder has enabled the development of pertinent follow-up strategies, screening for risky situations, and taking account of aging urinary systems as well as aging SCI patients themselves. Neurourological assessment is never definitive. The evolution of therapeutic methods will permit new, more adequate treatments for use tomorrow.

Background In 1927, Harvey Cushing observed that 80% of SCI patients died within weeks after the trauma because of infections, urinary catheters, and bedsores. The mortality rate during the acute phase has evolved over the years due to improved care management. It has dropped from 60% to 80% during World War II to 30% in the 1960s and 6% in the 1980s.1 The decrease in mortality of urinary origin is partly responsible for this survival gain. In SCI patients who survived World War II and the Korean war,2 deaths from urinary causes were estimated to be 43%. Then, they declined with time, with the rate not exceeding 10% in the 1980s and 1990s.3 In 50 years of follow-up, the risk of death attributed to urinary factors has diminished by half in each successive decade.4 This favorable evolution in terms of mortality is also seen for morbidity, with preventive measures tending to

replace hospitalization for urological complications. The ­leading cause of rehospitalization, reported at 1–10–15–20 (except 5) year follow-ups, was diseases of the genitourinary system, including urinary tract infections.5 At present, 43% of rehospitalizations are for urinary reasons (the leading cause of rehospitalization),6 but in most cases, they are more for a check-up than for care. The average length of hospitalization is 7.9 days with a median length of 3 days. These figures thus confirm that there has been a progression from care to prevention, showing the importance of bladder-sphincter follow-up.

Prognostic factors in upper urinary tract changes Follow-up objectives There are many neurogenic bladder classifications, but they do not enable prognostic assessment because even if they do identify the dysfunction type, they do not estimate the balance of urodynamic forces present. The classical criteria of bladder disequilibrium, which are postvoid residual urine, urinary infection, vesicoureteral reflux, ureterohydronephrosis, lithiasis, and incontinence, reflect the deterioration when they occur, but they do not have good prognostic value. The follow-up objectives are thus to solve the problems encountered by SCI patients with lower urinary tract dysfunction, meaning: improvement of urinary continence, restriction of infections, facilitation of micturition while preserving patient autonomy. It is equally important to strive for an equilibrated bladder today without any risks for tomorrow, that is, to protect the upper urinary tract apparatus. This equilibrium is not a constant, but a daily balance cannot be considered as unchanging.

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The role of elevated intravesical pressure during the storage phase In 1981, MacGuire et al.7 brilliantly illuminated the harmful role of elevated intravesical pressures in SCI patients. When detrusor leak point pressure (DLPP) is lower than or equal to 40 cm H20, there is no vesicoureteral reflux and only 10% of dilatation on intravenous pyelography (IVP). When DLPP is more than 40 cm H20, we find 61% of reflux and 81% of upper urinary tract dilatation. We have confirmed these data in a retrospective study of 200 myelomeningocele patients,8 followed for a period of 3–17 years (average 9.02 years). The prognostic value of DLPP is demonstrated by the study of survival curves testing the rate of upper urinary tract degradation according to its dilatation and the DLPP: if DLPP rises during the follow-up, the probability of an undilated upper urinary tract at 12 years posttrauma is no more than 20%, while it is 86% if DLPP stays low; a patient with DLPP exceeding 40 cm H20 has 7 times more risk of upper urinary tract damage than someone with stable DLPP. SCI patients show a correlation between vesicoureteral reflux and elevated intravesical pressure:9 when bladder pressure exceeds 60 cm H20, 22% have reflux, but when the pressure is normal, reflux occurs in only 5%. In detrusor overactivity, we find upper urinary tract alteration in 16% and a normal upper urinary tract in 84%, corresponding to patients whose DLPP is, respectively, 115 cm H20 and 72  cm H20 on average.10 Similarly, in detrusor areflexia, the upper urinary tract is altered in 18% and normal in 82%. The corresponding DLPP values are, respectively, 58 cm and 24 cm H20. DLPP is thus an essential prognostic factor with a particularly bad significance when it exceeds 40 cm H20.

Physiopathology of upper urinary tract damage Bladder hyperpressure, either related to detrusor overactivity (SCI patients with prolonged and strong amplitude bladder contractions) or related to poor bladder compliance in case of detrusor areflexia (particularly in myelomeningocele), will have a dual effect: hydrodynamic perturbations and morphological changes. Bladder hyperpressure will alter urethral flow, as the latter occurs at low pressure; in the beginning, the ureter compensates by an increased amplitude and frequency of contractions; then, above 40 cm H20, statis presents with dilatation (or even vesicoureteral reflux). The situation will deteriorate rapidly if the duration of exposure to high pressure is prolonged. This upper urinary tract alteration is initially reversible by continuous catheterization or by restoring detrusor pressure to an acceptable level.

Detrusor hyperpressure can be the consequence but, above all, the cause of bladder wall deformities (trabeculae, diverticula); these may sometimes affect the water-tightness of the vesicoureteral junction and induce vesicoureteral reflux. They will facilitate the development of infectious sites, increasing hyperreflectivity. Collagen will seep progressively into and accumulate between smooth muscle fibers, which become rarified. These structural changes may have variable repercussions. When the bladder is active, they induce a decrease of detrusor contractility and lead to a new pressure equilibrium, a veritable homeostasis phenomenon aimed at protecting the upper urinary tract. More deformed bladders are not always the most poorly tolerated by the upper urinary tract level. The collagen excess also favors irreversible detrusor fibrosis, particularly in inactive or congenital neurobladders. This fibrosis, which thickens the detrusor wall, contributes to stenosis of the lower ureter and hydronephrosis. After bladder wall lesions are definitively installed, treatment of overactivity cannot stop the vesicoureteral reflux.

Context and antecedents Age at onset Children In childhood-acquired paraplegia, the prognosis of lower urinary tract dysfunction is relatively good compared to paraplegia occurring during adulthood.11 In the long-term (6–30 years), 10.4% of childhood paraplegics12 will incur a Bricker’s diversion, which has a lower rate than for adults in the same reference period (1960s–1980s).

Elderly Spinal cord lesions in the elderly mean complications. Rehabilitation failure is common because of difficulties in adapting to the new situation, a lower urinary tract altered by age (prostate hyperplasia, cystocele, sphincter failure) with slower reflexes and detrusor hypoactivity. These elements explain the frequency of surgical procedures in men and the use of indwelling catheters. When the lesion occurs after age 60, 50% have an indwelling catheter, and 50% of men undergo a de-obstruction procedure. Traditional rehabilitation often fails.13 The prognosis for old people, is, therefore, linked more to personal factors than to the neurourological situation itself.

Sex Studies published a few years ago show that women are less exposed than men to urological complications. In 1983, 99% of 200 SCI women who survived the initial phase retained

Evolution and follow-up of lower urinary tract dysfunction in spinal cord–injured patients a normal IVP for the following 20 years,14 the woman/man complication rate was 1 for 4.4; 1 woman died of renal failure for every 19 men. This difference may have improved since, as it has not been seen in recent years: in 1992, the urological complication rate with time was not significantly different between men and women, and renal failure was no higher in women with an indwelling catheter than in men with a condom catheter.15 A review of literature showed that male sex had been identified as an “additional” risk factor besides four main risk factors of urinary tract complications in multiple sclerosis (MS), which were MS duration, indwelling catheter, high-amplitude neurogenic detrusor contractions, and permanent high detrusor pressure.16 The drainage method significantly influences the complication rate, and the harmful role of indwelling catheters can be found here compared to reflex voiding or intermittent catheterization. This was very significant in a population of 70 SCI women followed for 11–13 years.17 It raises questions as to better choices of treatment, given the absence of urine collectors for women.

Neurological lesion In a study by Gerridzen et al.9 of 140 SCI patients, 62% were tetraplegic and 38% paraplegic. Somewhat surprisingly, 51% of paraplegics had detrusor overactivity versus 49% who presented with detrusor areflexia. Among the tetraplegics, 86% had detrusor overactivity and 14% had bladder areflexia. Eight years after the lesion, alterations of the upper urinary tract were 2 times more frequent among tetraplegics, as 17% of them had a damaged upper urinary tract versus 8% of paraplegics. The incidence of reflux is higher in complete than in incomplete SCI,18 but the frequency is identical in paraplegics and tetraplegics. It is probable that the perception of an equivalent of a micturition need limits the risk of increased intravesical pressure because the patient can urinate sooner.

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indwelling catheter (changed every month), 92 practiced proper intermittent catheterization, 74 voided spontaneously (defined as reflex micturition with postvoid residual urine volume less than 100 cc and voiding pressure less than 40 cm H20), and 36 carried a suprapubic catheter. A total of 398 urological complications occurred in 126 patients. The complications were more frequent in patients with continuous bladder drainage because 53.5% of these cases had 236 of the complications (61 patients), 4.4% of suprapubic catheter patients had 48 complications (16 patients), 32.4% of patients who voided spontaneously had 57 complications (24 patients), and 27.2% of intermittent catheterization patients had 57 complications (25 patients).

Tetraplegic cases The independence of tetraplegics is more or less limited, and so the choice of their micturition mode is necessarily influenced by voiding autonomy. Among 73 SCI patients of more than 20 years duration,21 32 had an indwelling catheter, and 41 another mode of micturition (reflex voiding, sphincterotomy, intermittent catheterization): there was no difference between the two groups for creatinine level, but the indwelling catheter group had a higher rate of hydronephrosis and renal atrophy. Alternatively to indwelling catheters, suprapubic catheters seemed to be a good drainage method as 34 of 61 tetraplegics used this mode for an average of 8.6 years (for 27 intermittent catheterizations, the average was 9.9 years), and no upper urinary tract deterioration was observed in any of these groups.22 However, we noted a much higher frequency of lithiasis in the suprapubic catheter group, and more frequent urinary infections with intermittent catheterization. Intermittent catheterization seems to be the safest method for SCI patients in terms of urological complications. In contrast, indwelling catheters appear to incur the highest rate of complications, particularly in the long term.

In the initial stage

Urinary infection Symptomatic infections

The complication rate in the initial period after the trauma is closely linked to the bladder drainage method, with particularly high risks of damage from indwelling catheters:19 acute pyelonephritis, purulent cystitis, paraurethral abscess, ureteral fistula, urethral strictures, and severe hematuric cystitis.

The elements that indicate urinary infections in SCI patients sometimes clearly appear with fever and shivering, smelly urine, or hematuria but are most often subtle: intense renal or bladder pain, urinary leakage or micturition changes, increased spasticity, lethargy, general malaise, and discomfort.

In the long term

Asymptomatic infections

In a very large study of 316 exclusively male SCI patients, Weld20 examined the influence of drainage methods on urological complications. A total of 114 patients had an

It is extremely difficult to find a consensus concerning the criteria of asymptomatic urinary infection in SCI patients and, above all, to see them applied, even if only

Drainage method

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to clinical studies. Nevertheless, criteria have been defined in a National Institute on Disability and Rehabilitation Research Consensus Statement23 according to the micturition mode and can be viewed as extremely rigorous: bacteriuria exceeding 102/mL in intermittent catheterization patients, greater than 104/mL in patients with a condom catheter, and no matter what the concentration is when patients have an indwelling catheter. The banality of asymptomatic infections is such that they may be neglected most of the time.

Universally accepted risk factors The risk factors of urinary infections have been classified universally by Cardenas and Hooton:24 bladder distension, vesicoureteral reflux, elevated intravesical pressure, postvoid residual urine volume, stones, lower bladder outlet obstruction, decreased immunity, pregnancy, repeated urethral traumas, anatomical anomalies of the urinary tract, perineum hygiene, and presence of an indwelling or suprapubic catheter. We must also consider some of the more subjective elements, including possible behavioral risks as well as psychological factors: degree of patient comprehension, inactivity, self-esteem, social acceptance. Finally, intermittent catheterization is a source of increased infections only when it is done for tetraplegics by untrained persons (in this case, with infection risk even higher than with indwelling catheters).

Infectious complications Epididymitis was found in 16.1% of patients, and pyelone­ phritis in 3.5%. A total of 94% of patients had been treated at least once for lower urinary tract infection. Indwelling catheters are the main cause of infectious complications: pyelonephritis and especially epididymitis. Intermittent catheterization leads to less epididymitis than reflex voiding.19

Renal function All bladder drainage methods may preserve the upper urinary tract, but continuous drainage is a risk factor for upper urinary tract damage and renal failure. With continuous bladder drainage, 18.6% of patients undergo upper urinary tract changes. This rate is 7.8% with reflex voiding, and 6.5% with intermittent catheterization.25 Among the associated factors, patient age and lesion duration are correlated with higher blood creatinine, lower creatinine clearance, and frequent proteinuria. Vesicoureteral reflux is correlated with renal function damage and radiological anomalies of the upper urinary tract. Blood creatinine levels alone seem not to be a very sensitive factor in early deterioration of the upper urinary

tract compared with proteinura, creatinine clearance, and upper urinary tract imaging. The two most sensitive methods of screening for renal function deterioration are creatinine clearance and isotopic scintigraphy. Blood creatinine declines with age and body mass reduction; hence, it can remain normal despite decreasing glomerular filtration, and is not sensitive enough. Measurement of endogenous creatinine clearance is acceptable, but poses a problem of 24-hour urine collection in SCI patients. Isotopic clearance (Tc DTPA) seems to be the best method of examination. Renal scintigraphy represents the most sensitive screening procedure for renal function changes. Effective renal plasma flow (ERPF) decreases by 4.5 mL per year in the 10 years following spinal cord lesion.26 The factors associated with declining ERPF are age, female sex, renal or bladder lithiasis, tetraplegia, frequent shivering, and fever episodes, but there is no relationship with lesion age, bacteriuria, and no link with lesion severity.

Radiology Urethral complications Urethral stricture has been noted in 11.7% of patients, and periurethral abscess in 2.8%.19 Indwelling catheters cause many urethral strictures, and intermittent catheters two times less, but significantly more than suprapubic catheters or reflex micturition.

Lithiasis Upper urinary tract lithiasis has been found in 35.1% of patients,19 and lower urinary tract lithiasis in 14.6%. Indwelling catheters lead to significantly more lithiasis complications of the upper urinary tract and bladder than intermittent catheterization and spontaneous micturition. Recurrent urinary tract infections, indwelling catheters, vesicoureteral reflux, and immobilization hypercalcuria are a few of the major risk factors for the development of urolithiasis among SCI patients.26 Temporal evolution shows that lithiasis risk is always present27—3.1% at 5 years, 5.1% at 10 years, 6% at 15 years, and 10.8% at 20 years— but with significant variations according to the voiding method: suprapubic and indwelling catheters represent a high risk while intermittent catheterization has negligible risk. In men who cannot use intermittent catheterization or when the bladder cannot empty spontaneously, suprapubic cystostomy is better than urethral catheterization to avoid renal stone formation.28

Upper urinary tract changes Vesicoureteral reflux has been found in 15.8% of patients, and upper urinary tract alteration in 26.3%.18 Intermittent

Evolution and follow-up of lower urinary tract dysfunction in spinal cord–injured patients catheterization and reflex micturition are accompanied by significantly less reflux than indwelling or suprapubic catheters. Injuries between Th10 and L2 involve the sympathetic nervous system; patients with such injuries often exhibited vesicoureteral reflux in the early stage of SCI.29

Urodynamics Postvoid residual urine Contrary to what we have always thought, even if postvoid residual urine volume is a sign of bladder-sphincter dysfunction, it is not a prognostic factor. The upper urinary tract can deteriorate without any residual volume; the bladder may work to avoid residual urine volume, but this exhausts the urinary system in the long term. In 1977, 38% of dilatation was found 2–6 years after SCI in the absence of residual volume.30 However, major, chronic postvoid urine volume can be tolerated perfectly for years, especially in hypoactive bladders with high compliance. The prognosis is thus not linked to postvoid residual volume, but depends on urodynamic balance. Postvoid urine volume is a sign of obstruction because it is also a function of adaptation to detrusor contraction. It is as much the consequence of primary insufficient detrusor contraction or decompensation as obstruction. It can be particularly dangerous if there is an associated compliance deficit, or if there are prolonged dyssynergic contractions, as the bladder is then subjected permanently to high pressures.

Bladder reflectivity and contractility The complication rate of upper urinary tract damage is clearly higher in patients with reflex micturition (32%) compared to patients who void spontaneously (0%) or who have an inactive detrusor or a detrusor inactivated by anticholinergics (7%).31 All overactivities are not dangerous in the same way: they will be more hazardous if the contractions are strong, prolonged, and frequent; otherwise, they may just manifest as a brief peak of hyperpressure but much less harmful than hyperpressure of the filling phase. In paraplegics, there is a correlation between high intravesical pressure and reflux with 22% of reflux occurring when intravesical pressure is greater than 60 cm H20 versus 5% when it is lower than this value.32

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dyssynergia. Complete spinal cord lesion is usually accompanied by continuous dyssynergia, whereas intermittent dyssynergia is seen only with incomplete lesion. Dyssynergia is associated with complete lesions, with high intravesical pressure, and with upper urinary tract complications. These associations are more pronounced in continuous dyssynergia than in intermittent dyssynergia. The proportion of patients suffering from a particular type of bladder-sphincter dyssyn­ergia has not changed with time. These parameters are, in fact, correlated. Indeed, dyssynergia is responsible for high intravesical pressures, which are themselves a source of risk for the upper urinary tract.

Compliance Measurement of compliance deficiency seems less significant than DLPP, but explores high pressures in the same way during the filling phase and their danger. In contrast, flaccid and compliant bladders, due for instance to a cauda equina syndrome after a disk herniation, do not develop any changes of the bladder wall and upper urinary tract. Evaluation of compliance is difficult in SCI patients because of overactivity, and studies are rare. Hypocom­pliant bladders are seldom found in SCI patients.34 In the population with initially normal compliance (higher than 20%), the upper urinary tract remains normal 3 years later in 78% of cases, but when initial compliance is low (17%), we find only 23% with a normal upper urinary tract after this period.35 A threshold of 12.5 mL/cm H20 significantly indicates the presence of various upper urinary tract complications: vesicoureteral reflux, upper urinary tract distension, pyelonephritis, and upper urinary tract lithiasis.36 In suprasacral lesions (complete and incomplete), bladder hypocompliance is more frequent in patients with continuous drainage than in those who use intermittent catheterization. Whatever the drainage method, low compliance is more frequent in sacral lesions than in suprasacral lesions and in complete than in incomplete lesions. Regression curve analysis shows that compliance is more often altered with time in the continuous drainage group than in the reflex micturition and intermittent catheterization groups. The risk of altered compliance with indwelling catheters increases by 23% every 5 years. The evolution of bladder compliance thus appears to be a fundamental element of surveillance for all neurological bladders.

Dyssynergia

Cytology and cystoscopy

Detrusor-sphincter dyssynergia

The risk of bladder tumor37 is high in aging SCI patients and notably in those with indwelling catheters (over 8 years) or bladder lithiasis.38 Groah et al.39 examined 3670 SCI patients by cystoscopy showing that the risk of bladder cancer with SCI using indwelling catheter is 77 per 100,000  person-years. This corresponds to an age- and

Bladder overactivity is harmful in SCI patients because it is associated with bladder-sphincter dyssynergia. In suprasacral lesions,33 7.4% of patients have no dyssynergia, 80.3% have intermittent dyssynergia, and 12.3% have continuous

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gender-adjusted standardized morbidity ratio of 25.4 when compared with the general population. After adjusting for age at injury, gender, level and severity of SCI, history of bladder calculi, and smoking, those using solely indwelling catheter had a risk of bladder cancer 4.9 times than those using non-indwelling methods. However, the incidence of invasive bladder cancer in European population appears to be lower than that reported in other series.40 Gross hematuria in individuals with SCI warrants aggressive assessment for bladder cancer.41 These findings suggest a screening by annual cystoscopy after 8 years of indwelling catheter use in the at-risk patient group (lithiasis, repeated infections, etc.). The BTA (bladder tumor antigen) stat, survivin assay, and urine cytology were unable to predict bladder cancer cases in patients with SCI.42 Cystoscopy, therefore, remains the gold standard for bladder cancer surveillance in patients with SCI.

Longitudinal follow-up Patient compliance in follow-up Clinical practice demonstrates the importance of some elements that are difficult to quantify.43 Patient compliance in follow-up is one of these parameters. The three most significant elements of complication occurrence are ignorance of follow-up importance, lack of confidence in their general practitioner, and examination cost.44 The other significant elements are living far from services, transport difficulties, and length of time since the accident. Changing of bladder-emptying method among SCI individuals over time is common. At least 10 years after a traumatic SCI: the use of clean intermittent catheterization (CIC) rose from 11% at the initial discharge to 36% at the time of follow-up. The use of suprapubic tapping fell from 57% to 31% in the same period, whereas the use of Crede maneuver rose from 5% to 19%. During followup, 46% changed bladder-emptying method. The results showed the following trends in change of method: a high proportion of discontinuation in normal bladder emptying, suprapubic tapping and abdominal pressure, and a high proportion of continuation when using CIC.45,46

Aging of urinary tract Mean age of SCI population is increasing and, over the age of paraplegia, neurourological status and, thus, previously secure bladder may get destabilized. Overall, 28.8% of bladder management method may change with time, particularly those using straining or balanced reflex voiding. The probability of change increases with age and postinjury delay. Reasons for change of bladder management method are various and there is no precise association between reason for change and bladder management method.46

Detrusor contractility may worsen and emptying bladder reflexes can deteriorate, requiring a recourse to catheterization. This may sometimes be the result of the development of posttraumatic syringomyelia (see Chapter 28); any change of neurourological status should systematically be monitored by a spinal MRI. During urodynamic follow-up, voiding pressure may decrease, that may be correlated to the posttraumatic delay and related to a detrusor depletion. The combination of two phenomena (detrusor exhaustion and obstructive syndrome) leads to an increasing dysuria and to an increased risk of urinary tract infections especially after an age of 60 years and/or between the first and third posttraumatic decade.

Delayed complications Radiologically, 63% of SCI patients have bladder anomalies—wall deformities, lithiasis, upper urinary ­ tract changes—that appear in 3/4 of cases in the first year, especially in patients who had an indwelling catheter for a prolonged initial period (more than 8 weeks). In contrast, new radiological anomalies occur in only 1% of cases after 10 years.47 Upper urinary tract complications (23.7% of 105 SCI patients)48 can present at any time of follow-up, between 1 month and 34 years, with an average of 10.4 years. A total of 44% of reflux appears during the first two years, and 23% during the two following years with the rates decreasing regularly with time.17 Thus, the first years after the trauma are the most dangerous. If we compare drainage methods,19 we find that the complication rate increases in the indwelling catheter group 5 years after the trauma, and after 15 years in patients with suprapubic catheters, with no significant changes in time for the two other groups (intermittent catheterization and spontaneous micturition), which, therefore, remain safe methods for the long term.

Patients at risk It is possible to define SCI populations at higher risk of urinary complications.

Tetraplegic patients have a higher risk9,18 Tetraplegic patients have a higher risk because they frequently have bladder overactivity, and because they do not take any anticholinergics to facilitate spontaneous micturition in a condom catheter.

Paraplegic patients have a relative decrease in risk9,20 The decreased risk in paraplegics is linked to a lower frequency of overactivity with high pressures because these patients are treated with intermittent catheterization and anticholinergics.

Evolution and follow-up of lower urinary tract dysfunction in spinal cord–injured patients In this group, the only deterioration occurs in patients not taking anticholinergics.

Men have more risks than women14,16 The caricatural difference of a few years ago is subsiding, thanks to progress made in the follow-up of SCI patients.

Surveillance will be especially close as intravesical pressures are high34,35 In overactivity, dyssynergia is responsible for type 3 high pressures according to Blaivas’ classification.49 This is characteristic of complete lesions. In areflexia, low compliance of the peripheral bladder is the source of high pressures. In all cases, it is important to suspect compliance