Neurologic Aspects of Systemic Disease Part III [1st Edition] 9780702044342, 9780702040887

Table of contents :
Content:
Series PagePage ii
CopyrightPage iv
Handbook of Clinical Neurology 3rd SeriesPage v
ForewordPage viiMichael J. Aminoff, François Boller, Dick F. Swaab
PrefacePage ixJosé Biller, José M. Ferro
ContributorsPages xi-xiv
Chapter 77 - Brain metastasesᾠPages 1143-1157Jaime Gállego Pérez-Larraya, Jerzy Hildebrand
Chapter 78 - Paraneoplastic disorders of the central and peripheral nervous systemsPages 1159-1179Adrien Didelot, Jérôme Honnorat
Chapter 79 - Radiation therapy in neurologic diseasePages 1181-1198Edward Melian
Chapter 80 - Neurologic complications of chemotherapy and other newer and experimental approachesPages 1199-1218Riccardo Soffietti, Elisa Trevisan, Roberta Rud`
Chapter 81 - Neurologic aspects of palliative care: the end of life settingPages 1219-1225Eefje M. Sizoo, Wolfgang Grisold, Martin J.B. Taphoorn
Chapter 82 - Neurologic aspects of heart transplantationPages 1229-1236Alain Heroux, Salpy V. Pamboukian
Chapter 83 - Clinical neurology in lung transplantationPages 1237-1243Christopher H. Wigfield, Robert B. Love
Chapter 84 - Neurologic complications in renal transplantationPages 1245-1255Kavitha Potluri, David Holt, Susan Hou
Chapter 85 - Neurologic complications of liver transplantationPages 1257-1266Eelco F.M. Wijdicks, Sara E. Hocker
Chapter 86 - Neurologic complications of intestinal transplantationPages 1267-1276Andrea Stracciari, Maria Guarino
Chapter 87 - Neurologic complications of pancreas and small bowel transplantationPages 1277-1293Michael Jacewicz, Christopher R. Marino
Chapter 88 - Neurologic complications of bone marrow transplantationPages 1295-1304Tulio E. Rodriguez
Chapter 89 - Neurologic aspects of multiple organ transplantationPages 1305-1317Saša A. Živković
Chapter 90 - Neurologic diseases in HIV-infected patientsPages 1321-1344Mohammed Bilgrami, Paul O’keefe
Chapter 91 - Measles, mumps, rubella, and human parvovirus B19 infections and neurologic diseasePages 1345-1353James F. Bale Jr.
Chapter 92 - Neurologic manifestations of diphtheria and pertussisPages 1355-1359Viraj Sanghi
Chapter 93 - Bacterial meningitisPages 1361-1375Sebastiaan G.B. Heckenberg, Matthijs C. Brouwer, Diederik van de Beek
Chapter 94 - EncephalitisPages 1377-1381Karen L. Roos
Chapter 95 - Fungal infections of the central nervous systemPages 1383-1401J.M.K. Murthy, C. Sundaram
Chapter 96 - Rickettsiae, protozoa, and opisthokonta/metazoaPages 1403-1443Erich Schmutzhard, Raimund Helbok
Chapter 97 - NeurocysticercosisPages 1445-1459Oscar H. Del Brutto
Chapter 98 - NeurosyphilisPages 1461-1472Joseph R. Berger, Dawson Dean
Chapter 99 - Nervous system Lyme diseasePages 1473-1483John J. Halperin
Chapter 100 - TuberculosisPages 1485-1499Juan Carlos Garcia-Monco
Chapter 101 - Rabies, tetanus, leprosy, and malariaPages 1501-1520J.M.K. Murthy, Faram D. Dastur, Satish V. Khadilkar, Dhanpat K. Kochar
Chapter 102 - Tropical myelopathiesPages 1521-1548Gustavo C. Román
Chapter 103 - Neurologic complications of vaccinationsPages 1549-1557Augusto A. Miravalle, Teri Schreiner
Chapter 104 - NeurodermatologyPages 1561-1594Jean-Philippe Neau, Gaëlle Godeneche, Stéphane Mathis, Gérard Guillet
Chapter 105 - Neurology of pregnancyPages 1595-1622H. Steven Block, José Biller
Chapter 106 - NeuroanesthesiaPages 1623-1633W. Scott Jellish, Steven Edelstein
Chapter 107 - Iatrogenic neurologyPages 1635-1671Luciano A. Sposato, Osvaldo Fustinoni
Chapter 108 - Neuromuscular complications in intensive care patientsPages 1673-1685Zohar Argov, Nicola Latronico
Chapter 109 - Posterior reversible encephalopathy syndromePages 1687-1701C. Lamy, C. Oppenheim, J.L. Mas
Chapter 110 - Neuro-Behçet syndromePages 1703-1723Sabahattin Saip, Gulsen Akman-Demir, Aksel Siva
Chapter 111 - Reversible cerebral vasoconstriction syndromePages 1725-1741Anne Ducros
Chapter 112 - Complications of neuroimagingPages 1743-1750Jordan D. Rosenblum, Olga Pasternak, Myrosia T. Mitchell
Chapter 113 - NeurotraumatologyPages 1751-1772Edward C. Perry III, Hazem M. Ahmed, Thomas C. Origitano
Chapter 114 - Neurology in the developing worldPages 1773-1782B.S. Singhal, Satish V. Khadilkar
IndexPages I1-I46

Citation preview

HANDBOOK OF CLINICAL NEUROLOGY Series Editors

MICHAEL J. AMINOFF, FRANC¸OIS BOLLER, AND DICK F. SWAAB VOLUME 121

EDINBURGH LONDON NEW YORK OXFORD PHILADELPHIA ST LOUIS SYDNEY TORONTO 2014

ELSEVIER B.V. Radarweg 29, 1043 NX, Amsterdam, The Netherlands © 2014, Elsevier B.V. All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Permissions may be sought directly from Elsevier’s Rights Department: phone: (þ1) 215 239 3804 (US) or (þ44) 1865 843830 (UK); fax: (þ44) 1865 853333; e-mail: [email protected]. You may also complete your request on-line via the Elsevier website at http://www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein). ISBN: 9780702040887 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging in Publication Data A catalog record for this book is available from the Library of Congress Notice Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the contributors or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. The Publisher

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Handbook of Clinical Neurology 3rd Series Available titles Vol. 79, The human hypothalamus: basic and clinical aspects, Part I, D.F. Swaab ISBN 9780444513571 Vol. 80, The human hypothalamus: basic and clinical aspects, Part II, D.F. Swaab ISBN 9780444514905 Vol. 81, Pain, F. Cervero and T.S. Jensen, eds. ISBN 9780444519016 Vol. 82, Motor neurone disorders and related diseases, A.A. Eisen and P.J. Shaw, eds. ISBN 9780444518941 Vol. 83, Parkinson’s disease and related disorders, Part I, W.C. Koller and E. Melamed, eds. ISBN 9780444519009 Vol. 84, Parkinson’s disease and related disorders, Part II, W.C. Koller and E. Melamed, eds. ISBN 9780444528933 Vol. 85, HIV/AIDS and the nervous system, P. Portegies and J. Berger, eds. ISBN 9780444520104 Vol. 86, Myopathies, F.L. Mastaglia and D. Hilton Jones, eds. ISBN 9780444518996 Vol. 87, Malformations of the nervous system, H.B. Sarnat and P. Curatolo, eds. ISBN 9780444518965 Vol. 88, Neuropsychology and behavioural neurology, G. Goldenberg and B.C. Miller, eds. ISBN 9780444518972 Vol. 89, Dementias, C. Duyckaerts and I. Litvan, eds. ISBN 9780444518989 Vol. 90, Disorders of consciousness, G.B. Young and E.F.M. Wijdicks, eds. ISBN 9780444518958 Vol. 91, Neuromuscular junction disorders, A.G. Engel, ed. ISBN 9780444520081 Vol. 92, Stroke – Part I: Basic and epidemiological aspects, M. Fisher, ed. ISBN 9780444520036 Vol. 93, Stroke – Part II: clinical manifestations and pathogenesis, M. Fisher, ed. ISBN 9780444520043 Vol. 94, Stroke – Part III: Investigations and management, M. Fisher, ed. ISBN 9780444520050 Vol. 95, History of neurology, S. Finger, F. Boller and K.L. Tyler, eds. ISBN 9780444520081 Vol. 96, Bacterial infections of the central nervous system, K.L. Roos and A.R. Tunkel, eds. ISBN 9780444520159 Vol. 97, Headache, G. Nappi and M.A. Moskowitz, eds. ISBN 9780444521392 Vol. 98, Sleep disorders Part I, P. Montagna and S. Chokroverty, eds. ISBN 9780444520067 Vol. 99, Sleep disorders Part II, P. Montagna and S. Chokroverty, eds. ISBN 9780444520074 Vol. 100, Hyperkinetic movement disorders, W.J. Weiner and E. Tolosa, eds. ISBN 9780444520142 Vol. 101, Muscular dystrophies, A. Amato and R.C. Griggs, eds. ISBN 9780080450315 Vol. 102, Neuro-ophthalmology, C. Kennard and R.J. Leigh, eds. ISBN 9780444529039 Vol. 103, Ataxic disorders, S.H. Subramony and A. Durr, eds. ISBN 9780444518927 Vol. 104, Neuro-oncology Part I, W. Grisold and R. Sofietti, eds. ISBN 9780444521385 Vol. 105, Neuro-oncology Part II, W. Grisold and R. Sofietti, eds. ISBN 9780444535023 Vol. 106, Neurobiology of psychiatric disorders, T. Schlaepfer and C.B. Nemeroff, eds. ISBN 9780444520029 Vol. 107, Epilepsy Part I, H. Stefan and W.H. Theodore, eds. ISBN 9780444528988 Vol. 108, Epilepsy Part II, H. Stefan and W.H. Theodore, eds. ISBN 9780444528995 Vol. 109, Spinal cord injury, J. Verhaagen and J.W. McDonald III, eds. ISBN 9780444521378 Vol. 110, Neurological rehabilitation, M. Barnes and D.C. Good, eds. ISBN 9780444529015 Vol. 111, Pediatric neurology Part I, O. Dulac, M. Lassonde and H.B. Sarnat, eds. ISBN 9780444528919 Vol. 112, Pediatric neurology Part II, O. Dulac, M. Lassonde and H.B. Sarnat, eds. ISBN 9780444529107 Vol. 113, Pediatric neurology Part III, O. Dulac, M. Lassonde and H.B. Sarnat, eds. ISBN 9780444595652 Vol. 114, Neuroparasitology and tropical neurology, H.H. Garcia, H.B. Tanowitz and O.H. Del Brutto, eds. ISBN 9780444534903 Vol. 115, Peripheral nerve disorders, G. Said and C. Krarup, eds. ISBN 9780444529022 Vol. 116, Brain stimulation, A.M. Lozano and M. Hallett, eds. ISBN 9780444534972 Vol. 117, Autonomic nervous system, R.M. Buijs and D.F. Swaab, eds. ISBN 9780444534910 Vol. 118, Ethical and legal issues in neurology, J.L. Bernat and H.R. Beresford, eds. ISBN 9780444535016 Vol. 119, Neurologic Aspects of Systemic Disease, J. Biller and J.M. Ferro, eds. ISBN 9780702040863 Vol. 120, Neurologic Aspects of Systemic Disease, J. Biller and J.M. Ferro, eds. ISBN 9780702040870

Foreword

Although neurology and psychiatry are closely linked specialties, many neurologists see their specialty as part of internal medicine. Indeed, neurology departments in the United States often began as divisions within departments of internal medicine, attesting to their special relationship. With the evolution of neurology as an independent discipline, it has become particularly important for its practitioners to remain familiar with the neurologic aspects of systemic diseases as well as with the systemic aspects of neurologic disorders. This has been recognized since the Handbook of Clinical Neurology was founded by Pierre Vinken and George Bruyn, with volume 1 appearing in December 1968. That first series concluded in 1982 and was followed by a second series, edited by them, that concluded—in turn—in 2002. We then took over as editors of the current third series, with volume 79 appearing in late 2003 and several volumes appearing annually since then. Two volumes (38 and 39) were published in the first series of the Handbook, focusing on the neurologic manifestations of systemic diseases. The second series included a further three volumes (63, 70, and 71) on the same topic, published in 1993 and 1998, with one of us (MJA) serving as an editor of those volumes. Advances in the field, but especially in immunology, genetics, imaging, pharmacotherapeutics, and intensive care, since that time have necessitated a reappraisal of the field and the publication of three new volumes on the topic. We are therefore particularly delighted at the publication of this scholarly contribution to the medical and neurologic literature and welcome it as part of the Handbook. We believe that it will appeal not only to neurologists but to physicians in all specialties, helping in their interactions with each other and with their patients. Professors Jose´ Biller and Jose´ M. Ferro have together produced an authoritative, comprehensive, and up to date account of the topic and have assembled a truly international group of authors with acknowledged expertise to contribute to these important multifaceted volumes. We are grateful to them and to all the contributors for their efforts in creating such an invaluable resource. We are confident that clinicians in many different disciplines will find much in these volumes to appeal to them. It is a pleasure, also, to thank Elsevier, our publishers – and in particular Tom Stone, Michael Parkinson, and Kristi Anderson – for unfailing and expert assistance in the development and production of these volumes. Michael J. Aminoff Franc¸ois Boller Dick F. Swaab

Preface

Medicine has always been in a state of evolution and today, more than ever, with the accelerated growth of scientific knowledge, patients are evaluated and treated by teams of physicians. The extensive body of knowledge and the major scientific and clinical advances in neurology and internal medicine are again drawing both specialties closer together. Whatever the subspecialty area of interest, the nature of modern clinical medicine calls for multidisciplinary collaborative efforts to better meet the needs of individual patients. The aim of these three volumes of the third series of the Handbook of Clinical Neurology is to integrate and provide a thorough framework of the core neurologic manifestations of a wide array of systemic disorders. Each chapter provides a critical appraisal and extensive background information regarding the variety of presentations of each disorder, the characteristic clinical course, the typical neurologic manifestations of each disease, and current therapeutic strategies. Comprehensive and updated references also bring forth valuable resources for further topical reading and research. Our intended audience includes experienced practitioners and residents in neurology, neurosurgery, and internal medicine, as well as other health care professionals in different subspecialties caring for these challenging patients. We have purposely divided these three volumes into chapters uniformly organized by organ system, which are further divided by specific conditions and disease categories. Volume I is dedicated to the neurologic aspects of cardiopulmonary diseases, renal disorders, and selective rheumatologic and musculoskeletal disorders. Volume II encompasses core neurologic aspects of gastrointestinal and hepatobiliary disorders, endocrinologic diseases, and a gamut of metabolic, nutritional and environmental conditions. Volume III concentrates on the neurologic aspects of hematologic and oncologic disorders, organ transplantation, infectious diseases, and tropical neurology. It also includes a miscellaneous group of disorders including neurodermatology, neurological complications of pregnancy, iatrogenic neurology, neuromuscular disorders in the intensive care setting, posterior reversible leukoencephalopathy and reversible cerebral vasoconstriction syndromes, neuro-Behcet’s, complications of neuroimaging, neurotraumatology, and observations pertaining to neurology in the developing world. These volumes go beyond the scope of classic neurology and examine the neurologic manifestations of a wide range of medical conditions, spanning most areas of medicine, that neurologists, neurosurgeons, internists, and other specialists must diagnose and treat in everyday practice. We are hopeful that these three volumes will contribute to the best possible care of patients with these disorders, and that the readership will find the material informative, authoritative, reliable, and stimulating We are extremely grateful to all the contributors from across the globe, who by sharing their knowledge and expertise made these volumes possible. To bring to fruition a work of this magnitude requires a highly professional editorial effort, and for this we thank Linda Turner for her wonderful organizational skills and administrative expertise, and Mike Parkinson and the editorial staff at Elsevier for their unfailing dedication, professionalism, and expert assistance in the development and production of these three volumes. Jose´ Biller, MD Jose´ M. Ferro, MD

Contributors

H.M. Ahmed Department of Neurological Surgery, Loyola University Medical Center, Maywood, IL, USA

D. Dean Department of Internal Medicine, Indiana University, Indianapolis, IN, USA

G. Akman-Demir Department of Neurology, School of Medicine, Istanbul Bilim University, Istanbul, Turkey

O.H. Del Brutto School of Medicine, Universidad de Especialidades Espiritu Santo and Department of Neurological Sciences, Hospital Clinica Kennedy, Guayaquil, Ecuador

Z. Argov Department of Neurology, Hadassah–Hebrew University Medical Center, Jerusalem, Israel J.F. Bale, Jr. Departments of Pediatrics and Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA J.R. Berger Department of Neurology, University of Kentucky College of Medicine, Lexington, KY, USA M. Bilgrami Department of Medicine, Loyola University Medical Center, Maywood, IL, USA

A. Didelot Centre de Re´fe´rence, de Diagnostic et de Traitement des Syndromes Neurologiques Parane´oplasiques and INSERM U842, UMR-S842, Lyon, France A. Ducros Department of Neurology, Hoˆpital Gui de Chauliac, Montpellier, France S. Edelstein Department of Anesthesiology, Loyola University Medical Center, Maywood, IL, USA

J. Biller Department of Neurology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA

O. Fustinoni INEBA Institute of Neurosciences and Faculty of Medicine, University of Buenos Aires, Buenos Aires, Argentina

H.S. Block Department of Neurology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA

J.C. Garcia-Monco Service of Neurology, Hospital de Galdacano, Galdacano, Vizcaya, Spain

M.C. Brouwer Department of Neurology, Academic Medical Center, Amsterdam, The Netherlands

G. Godeneche Department of Neurology, CHU La Mile´trie, Poitiers, France

F.D. Dastur Department of Medicine, P. D. Hinduja National Hospital, Mumbai, India

W. Grisold Department of Neurology, Kaiser Franz Josep Hospital, Vienna, Austria

xii

CONTRIBUTORS

M. Guarino Neurology Unit, S. Orsola-Malpighi University Hospital, Bologna, Italy

W.S. Jellish Department of Anesthesiology, Loyola University Medical Center, Maywood, IL, USA

G. Guillet Department of Dermatology, CHU La Mile´trie, Poitiers, France

S.V. Khadilkar Department of Neurology, Grant Medical College and Sir J. J. Group of Hospitals and Bombay Hospital Institute of Medical Sciences, Mumbai, India

J.J. Halperin Department of Neurosciences, Overlook Medical Center, Summit, NJ, USA S.G.B. Heckenberg Department of Neurology, Kennemer Gasthuis, Haarlem, The Netherlands R. Helbok Department of Neurology, Medical University Hospital Innsbruck, Innsbruck, Austria A. Heroux Heart Failure and Heart Transplant Program, Loyola University Medical Center, Maywood, IL, USA J. Hildebrand{ Fe´de´ration de Neurologie Mazarin, Groupe Hospitalier Pitie´-Salpeˆtrie`re, Paris, France S.E. Hocker Division of Critical Care Neurology, College of Medicine, Mayo Clinic, Rochester, MN, USA D. Holt Department of Surgery, Loyola University Medical Center, Maywood, IL, USA J. Honnorat Centre de Re´fe´rence, de Diagnostic et de Traitement des Syndromes Neurologiques Parane´oplasiques and INSERM U842, UMR-S842, Lyon, France

D.K. Kochar Medical Research, Rajasthan University of Health Sciences, Jaipur, India C. Lamy Department of Neurology, Universite´ Paris Descartes, Hoˆpital Sainte-Anne, Paris, France N. Latronico Department of Anesthesia Intensive Care and Postoperative Care, Division of Neuroanaesthesia and Neurocritical Care, University of Brescia, Spedali Civili, Brescia, Italy R.B. Love Department of Cardiothoracic Surgery, Medical College of Wisconsin, Milwaulkee, WI, USA C.R. Marino Department of Medicine, University of Tennessee Health Science Center, Memphis, TN, USA J.L. Mas Department of Neurology, Universite´ Paris Descartes, Hoˆpital Sainte-Anne, Paris, France S. Mathis Department of Neurology, CHU La Mile´trie, Poitiers, France E. Melian Department of Radiation Oncology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA

S. Hou Department of Medicine, Division of Nephrology and Hypertension, Loyola University Medical Center, Maywood, IL, USA

A.A. Miravalle Department of Neurology, University of Colorado School of Medicine, Aurora, CO, USA

M. Jacewicz Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA

M.T. Mitchell Department of Radiology, Advocate Christ Hospital, Oak Lawn, IL, USA

{

(deceased)

CONTRIBUTORS xiii J.M.K. Murthy G.C. Roma´n Continental Institute of Neurosciences & Rehabilitation, Department of Neurology, Weill Cornell Medical Continental Hospitals, IT & Financial District, College, Methodist Neurological Institute, Houston, Gachibowli, Hyderabad, India TX, USA J-P. Neau Department of Neurology, CHU La Mile´trie, Poitiers, France

K.L. Roos Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA

P. O’Keefe Department of Medicine, Loyola University Medical Center, Maywood, IL, USA

J.D. Rosenblum Department of Radiology, Loyola University Chicago, Stritch School of Medicine, Chicago, IL, USA

C. Oppenheim Department of Neurology, Universite´ Paris Descartes, Hoˆpital Sainte-Anne, Paris, France T.C. Origitano Department of Neurological Surgery, Loyola University Medical Center, Maywood, IL, USA S.V. Pamboukian Section of Advanced Heart Failure, Cardiac Transplant, Mechanical Circulatory Support and Pulmonary Vascular Disease, University of Alabama at Birmingham, Birmingham, AL, USA O. Pasternak Department of Radiology, Loyola University Chicago, Stritch School of Medicine, Chicago, IL, USA J. Ga´llego Pe´rez-Larraya Department of Neurology and Neurosurgery, Clinic of the University of Navarra, University of Navarra, Pamplona, Spain and Fe´de´ration de Neurologie Mazarin, Groupe Hospitalier Pitie´-Salpeˆtrie`re, Paris, France E.C. Perry III Department of Neurological Surgery, Loyola University Medical Center, Maywood, IL, USA K. Potluri Department of Medicine, Division of Nephrology and Hypertension, Loyola University Medical Center, Maywood, IL, USA T.E. Rodriguez Bone Marrow Transplantation Program, Loyola University Medical Center and Department of Medicine, Loyola University Chicago, Stritch School of Medicine, Chicago, IL, USA

R. Ruda` Division of Neuro-Oncology, Department of Neuroscience, University and San Giovanni Battista Hospital, Turin, Italy S. Saip Department of Neurology, Cerrahpasa School of Medicine, Istanbul University, Istanbul, Turkey V. Sanghi Division of Neurology, Bombay Hospital and Medical Research Centre, KEM Hospital and Seth G.S. Medical College, Mumbai, India E. Schmutzhard Department of Neurology, Medical University Hospital Innsbruck, Innsbruck, Austria T. Schreiner Department of Neurology, Children’s Hospital, Aurora, CO, USA B.S. Singhal Department of Neurology, Bombay Hospital Institute of Medical Sciences. Mumbai, India A. Siva Department of Neurology, Cerrahpasa School of Medicine, Istanbul University, Istanbul, Turkey E.M. Sizoo Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands R. Soffietti Division of Neuro-Oncology, Department of Neuroscience, University and San Giovanni Battista Hospital, Turin, Italy

xiv

CONTRIBUTORS

L.A. Sposato Department of Clinical Neurological Sciences, London Health Sciences Centre, University of Western Ontario, London, Ontario, Canada A. Stracciari Neurology Unit, S. Orsola-Malpighi University Hospital, Bologna, Italy C. Sundaram Department of Pathology Nizam’s Institute of Medical Sciences, Panjagutta, Hyderabad, India M.J.B. Taphoorn Department of Neurology, Medical Center Haaglanden, The Hague, Netherlands E. Trevisan Division of Neuro-Oncology, Department of Neuroscience, University and San Giovanni Battista Hospital, Turin, Italy

D. van de Beek Department of Neurology, Academic Medical Center, Amsterdam, The Netherlands E.F.M. Wijdicks Division of Critical Care Neurology, College of Medicine, Mayo Clinic, Rochester, MN, USA C.H. Wigfield Department of Surgery, Section of Cardiac & Thoracic Surgery, University of Chicago, Chicago, IL, USA ˇ ivkovic´ S.A. Z Neurology Service, Department of Veterans Affairs and Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 77

Brain metastases{ 1

JAIME GA´LLEGO PE´REZ-LARRAYA1,2* AND JERZY HILDEBRAND2 (deceased) Department of Neurology and Neurosurgery, Clinic of the University of Navarra, University of Navarra, Pamplona, Spain 2

Fdration de Neurologie Mazarin, Groupe Hospitalier Piti-Salptrire, Paris, France

INTRODUCTION Despite better prevention and treatment advances achieved during the last decades, cancer is still a major public health concern and remains one of the leading causes of death worldwide (Lopez et al., 2006). The central nervous system (CNS) is a frequent target for metastases from systemic cancer. The most common location of CNS metastases is the brain parenchyma, followed by the leptomeningeal space. Parenchymal metastases differ from leptomeningeal disease in clinical presentation, treatment modalities, and prognosis. However, their combination is common: on one hand, superficial brain lesions may invade the subarachnoid space, and on the other hand, primary leptomeningeal carcinomatosis often invades the brain parenchyma via perivascular Virchow–Robin spaces. This chapter deals only with metastases restricted to the brain parenchyma.

INCIDENCE AND PRIMARY TUMORS The exact incidence of metastatic brain tumors is unknown. Most epidemiologic studies may underestimate their true incidence, in part because some brain metastases remain asymptomatic, in part because even symptomatic lesions are often ignored in severely ill patients with advanced primary disease (Gavrilovic and Posner, 2005). Autopsy and clinical studies suggest that brain metastases occur in 10–30% of adult patients with systemic malignancies (Posner and Chernik, 1978; Schouten et al., 2002), thus representing by far the most frequent neurologic complication of systemic cancer

and the most common type of brain tumor in adults. They exceed the number of primary brain tumors at least fourfold. The incidence of brain metastases is thought to be rising in the last few decades due to a combination of factors other than population aging. First, improvements in and wider use of neuroimaging have resulted in an increased and earlier detection of clinically silent metastases. For example, routine brain scans are performed during the staging evaluation in neurologically asymptomatic patients with newly diagnosed lung cancer (Shi et al., 2006) or metastatic melanoma (Gavrilovic and Posner, 2005). Second, more effective treatments for systemic disease have extended survival of cancer patients, leading to a larger population at risk for brain metastases. Third, some highly effective anticancer agents poorly cross the blood–brain barrier (BBB), and are thereby unable to eradicate dormant micrometastases in patients with controlled systemic disease. Every malignant tumor is able to metastasize to the brain. However, only a limited number account for the vast majority of brain metastases. In adults, three tumors, lung and breast carcinomas and malignant melanoma, account for up to 75% of brain metastases (Nussbaum et al., 1996; DeAngelis and Posner, 2009). In children and very young adults, the primary tumors most likely to metastasize to the brain are sarcomas (osteogenic sarcoma, rhabdomyosarcoma, and Ewing’s sarcoma) and germ cell tumors (Kebudi et al., 2005). Lung cancers are the most common source of brain metastases, accounting for at least one half of the cases

*Correspondence to: Jaime Ga´llego Pe´rez de Larraya, M.D., Ph.D., Department of Neurology and Neurosurgery, Clı´nica Universidad de Navarra, Universidad de Navarra, Avd. Pı´o XII, 36, Pamplona 31008, Spain. Tel: þ34-948-255400, Fax: þ34-948296500, E-mail: [email protected] {

This chapter is dedicated to the memory of Professor Jerzy Hildebrand

1144 J. GA´LLEGO PE´REZ-LARRAYA AND J. HILDEBRAND (Soffietti et al., 2006). Patients with small-cell lung candestruction of the CNS structures, and by ischemia cer (SCLC), which accounts for only 15% of all lung can(DeAngelis and Posner, 2009). Through mass effect cers, are at special risk as up to 50% of them eventually and obstruction of cerebrospinal fluid (CSF) circulation, develop brain metastases (Seute et al., 2004). Among brain metastases may also cause intracranial hypertennon-small-cell lung cancers (NSCLC), adenocarcinomas sion, obstructive hydrocephalus, brain herniations, and metastasize to the brain more frequently than squamous false localizing signs such as sixth nerve palsy. cell carcinomas (Shi et al., 2006). Most symptoms and signs caused by brain metastases Breast cancer is the second most common source, evolve progressively over days to weeks. But some have responsible for about 15% of all brain metastases a stroke-like onset caused by tumor hemorrhage, tumor (Soffietti et al., 2006; DeAngelis and Posner, 2009). emboli, or acute rise in intracranial pressure. However, The risk is increased in estrogen receptor-negative in the authors’ experience, the mechanism of acute neuand HER2/neu-positive tumors. Patients with HER2/ rologic deficit remains often unexplained and could be neu-positive breast cancer are treated with trastuzumab related to acute worsening of edema. (Herceptin®), and in that group the incidence of brain Brain metastases may be located in all sites of the metastases is high. This may be due to increased patient brain, and are multiple in about 50% of the cases survival and to the fact that trastuzumab, which does not (Nussbaum et al., 1996). Therefore, any new neurologic cross the BBB, is unable to eradicate micrometastases manifestation occurring in a patient with cancer should (Stemmler et al., 2007). raise the possibility of a metastatic brain tumor. Certain Melanoma represents the third most common cause features, however, are particularly common. They of brain metastases, accounting for 5–10% of the cases, include headache, seizures, focal signs, cognitive and despite its comparably low incidence (Majer and behavioral changes, and gait disorders. Samlowski, 2007). But its propensity to form brain Headache is the most common presenting symptom, metastases is very high, and 50% of patients dying of occurring in approximately 50% of the patients (Forsyth melanoma have brain lesions (Amer et al., 1978). and Posner, 1993). It is more common in patients with Genitourinary tract cancers, mainly renal carcinoma, multiple and/or posterior fossa lesions. Headache and colorectal cancers come respectively as the fourth caused by brain metastases is usually mild but increases and fifth sources of brain metastases. In patients with in intensity and duration with time. Typically, it appears prostate cancer, small-cell or neuroendocrine carcinoin the early morning, worsens with maneuvers that mas represent less than 1% of the tumors, but are responincrease intracranial pressure such as straining, sible for 26% of brain metastases caused by prostate bending, or coughing, and may be accompanied by malignancies (Flannery et al., 2010). drowsiness, nausea, and vomiting. However, this “typiIn up to 15% of the patients with histologically cal” presentation occurs in only one-quarter to one-third proven brain metastases, physical examination and labof the patients. In the majority of the cases headaches oratory investigations fail to identify the site of the priresemble primary disorders such as tension-type headmary tumor in the early course of the disease (Nussbaum aches, and occasionally migraine (Forsyth and Posner, et al., 1996). During follow-up most of these patients are 1993). Thus headache characteristics, other than recent eventually found to have lung cancer (Ruda et al., 2001). worsening, fail to predict reliably the presence of brain metastases, unless focal deficits or papilledema coexist (Argyriou et al., 2006). Nowadays, papilledema CLINICAL FINDINGS is found in less than 10% of the patients due to earlier diagnosis of brain tumors (Young et al., 1974; Approximately two-thirds of brain metastases become DeAngelis and Posner, 2009). symptomatic in the course of the malignant disease Seizures occur as the first manifestation of brain (Cairncross et al., 1980). Most of them are diagnosed metastases in 20% of the patients and appear during in patients with already known systemic cancer the course of the disease in a similar percentage of cases (metachronous presentation) or found during diagnostic (Lynam et al., 2007). Patients with multiple lesions or procedure of the malignant disease (synchronous premetastatic melanoma have an increased seizure risk sentation). The discovery of brain metastases before that (Oberndorfer et al., 2002). Metastasis-related seizures of the underlying cancer (precocious presentation) is are essentially focal with or without secondary generalless common but this situation may prevail in departization, and thus have a localizing value. The most ments of neurosurgery and neurology. characteristic presentation is sensorimotor focal fits Tumor tissue plus the surrounding vasogenic edema with Jacksonian progression pattern. Postseizure palsy and, in some cases, intratumor hemorrhage produce and dysphasia are common in patients with underlying focal neurologic signs by compression rather than

BRAIN METASTASES tumor and may last longer than 24 hours (DeAngelis and Posner, 2009). The differential diagnosis of tumorrelated focal seizures and nonepileptic fluctuation of focal deficits such as worsening of aphasia or focal weakness is often very difficult in patients with language or other cognitive disorders including memory impairment. Nonconvulsive status epilepticus, which may be caused by unknown brain metastases, is another challenging but less common diagnostic issue (Blitshteyn and Jaeckle, 2006). Focal neurologic deficits such as weakness of one limb or hemiparesis with or without sensory changes, language disorders, and deficits of visual fields are common presenting signs occurring in up to 40% of the patients (Kaal et al., 2005). Cognitive decline, including memory impairment or lack of concentration, and behavioral disturbances ranging from personality changes to depression are extremely frequent. They have been reported in up to two-thirds of patients with brain metastases (Young et al., 1974; Mehta et al., 2003; Chang et al., 2007), but are largely underdiagnosed because they may be subtle, are reported more often by family members than by the patient himself, and may occur in absence of other neurologic signs. Gait disorders may be the initial manifestation of brain metastases even in the absence of lower limb weakness. They are typically caused by multiple, bilateral, small size metastases (Fig. 77.1). The patients usually complain of unsteadiness, and their gait is characterized by short steps and moderate widening of lower limbs.

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PATHOPHYSIOLOGYAND PATHOLOGY The metastatic process is a highly selective and nonrandom phenomenon, governed by a cascade of molecular and genetic changes (Chiang and Massague, 2008). The propensity to generate brain metastases differs not only between tumor types but also between cells of a single tumor. Not all cells of a given tumor are able to reach the CNS, and of those that do, not all will survive in the brain (Nathoo et al., 2005). Therefore primary tumors and their corresponding brain metastases can be biologically different, even when they appear pathologically similar (Morita et al., 1998). This seed (the metastasis) and soil (the brain) phenomenon is complex and not yet fully understood. It consists of a series of linked sequential steps: (1) cell detachment from the primary tumor by downregulation of adhesion molecules (Bremnes et al., 2002), and invasion of the host tissue through upregulation of matrixdegrading enzymes such as metalloproteases (Egeblad and Werb, 2002); (2) entry into the bloodstream through more permeable tumor-induced endothelial cells (Chang et al., 2000); (3) escape from destruction in the circulation, mainly by the immune system (natural killer cells) (Nieswandt et al., 1999) but also by mechanical forces; (4) arrest and early extravasation from brain microvessels (Kienast et al., 2010), favored by specific adhesion to brain endothelial cells (Pasqualini and Arap, 2002); and (5) survival and proliferation in the brain tissue by production of appropriate growth factors and promotion of angiogenesis or vessel co-option (Marchetti et al., 2003; Kienast et al., 2010). Cell predisposition to

Fig. 77.1. Contrast-enhanced T1-weighted MRI of a 67-year-old man with multiple brain metastases originating from lung adenocarcinoma. Unsteady gait was the only presenting sign. Note the ring-like enhancement of the largest lesion with central necrosis. (Reproduced courtesy of Prof. D. Bale´riaux.)

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metastasize is determined by genetic alterations, and changes that predict brain metastases from lung (Kikuchi et al., 2006) and breast cancer (Albiges et al., 2005) have been identified. Every step of this cascade is relatively inefficient and must be accurately completed for the final development of a brain metastasis. This explains why only a very tiny percentage of primary tumor cells is able to form viable brain metastases (Liotta and Kohn, 2003). Brain metastases are solid, usually rounded and well circumscribed space-occupying lesions (Wesseling et al., 2007). When present, the infiltration of the brain does not exceed 1 mm, except in metastases from SCLC and melanoma which may show a diffuse infiltration (Baumert et al., 2006). Distant infiltration may account for tumor recurrence after local therapy. Because tumor growth disrupts the BBB, brain metastases are often surrounded by vasogenic edema. Its extent, however, is not always proportional to the size of the malignant lesion. Large and rapidly growing metastases may contain central necrosis. Metastases of adenocarcinomas may contain collections of mucoid material (Wesseling et al., 2007). Microbleeds are common, and can be due either to invasion of blood vessel walls or to associated neovascularization. Large bleeds occur in up to 50% of metastases of melanoma and choriocarcinoma, followed by renal, thyroid, and testicular tumors (Mandybur, 1977). Metastases of lung cancers bleed in about 5% of the cases, but are a leading cause of tumor hemorrhage because of their high frequency. A recent study has shown an unexpectedly high rate of intratumoral hemorrhage in patients with metastases of breast or prostate cancers (Navi et al., 2010), but this observation is unusual and may reflect local experience. The histological appearance of brain metastases is generally similar to that of the primary tumor, even though they may differ biologically and genetically. In patients with unknown primary cancer and uninformative histological examination, appropriate immunostaining can suggest the nature and the location of the primary tumor (Becher et al., 2006). Brain metastases tend to develop at the junction between gray and white matter (Delattre et al., 1988; Hwang et al., 1996). Melanoma metastases are more likely than other metastatic tumors to invade the gray matter. Although direct extension into the CNS occasionally occurs from local tumors, most brain metastases reach the brain through hematogenous spread, and are believed to be entrapped in small size terminal arteries (Kienast et al., 2010). This mechanism may explain the propensity of brain metastases to develop in watershed zones of the cerebral circulation. The distribution of brain metastases, however, is roughly proportional to brain volume and blood flow: 80% are located in

the cerebral hemispheres, 15% in the cerebellum, and 5% in the brainstem. One study indicates that tumors arising in the pelvis, mainly prostate or uterine cancers, or colorectal cancer have a special affinity for the cerebellum (Delattre et al., 1988). The reason for this predilection is unknown. Based on imaging and autopsy data, one-half of patients with brain metastases have a single lesion (Posner and Chernik, 1978; Nussbaum et al., 1996), and an additional 20% two or three metastatic lesions (Delattre et al., 1988). Metastases from renal and colorectal tumors are often single, whereas lung cancers and melanoma are more likely to generate multiple lesions (Delattre et al., 1988).

DIAGNOSTIC PROCEDURES In patients with known cancer the purpose of diagnostic examinations is to identify and locate brain metastases. In individuals not known to have a malignant disease and in whom neuroimaging suggests brain metastases, the aim is to rule out other brain diseases, and to determine the nature and the location of the primary tumor.

Patients with known cancer Magnetic resonance imaging (MRI) is the best technique for detecting brain metastases, although there are no pathognomonic MRI features. MRI is superior to computed tomography (CT), even with double-dose delayed contrast, in visualizing small metastases and posterior fossa lesions (Schellinger et al., 1999). MRI has indeed a higher resolution, superior tissue contrast, and no bone artifacts. Furthermore, its versatile and multiplanar capabilities are useful in differential diagnosis and in planning surgery or stereotactic radiosurgery. Standard MRI includes T1WI (T1-weighted imaging) with and without contrast agent, T2WI (T2-weighted imaging), and FLAIR (fluid-attenuated inversion recovery) sequences. Most brain metastases generate low or intermediate intensity signal on T1WI. An increased intensity may correspond to a recent hemorrhage or to melanin deposit. Peritumoral edema appears as an area of decreased intensity. Brain metastases that reach a certain volume are enhanced after injection of paramagnetic contrast agent. Most brain metastases are spherical and sharply delineated. They may show peripheral ring enhancement with a nonenhancing core corresponding to central necrosis (Fig. 77.1). The enhancement is more conspicuous with magnetization transfer suppression (Knauth et al., 1996) and triple contrast dose (Sze et al., 1998), which may reveal very small lesions but also lead to false-positive findings. Conversely, treatment of the primary tumor with antiangiogenic agents may decrease

BRAIN METASTASES contrast enhancement of metastatic brain lesions (Karimi et al., 2009). T2WI and FLAIR sequences usually demonstrate an area of increased intensity encompassing both the tumor and the surrounding edema. The extent of edema is better appreciated on T2WI and FLAIR than on T1WI. Diffusion-weighted MRI (DW-MRI) is especially useful in the differential diagnosis of ring-enhancing cerebral lesions. It shows high-intensity signal in abscesses (restricted diffusion, low signal on apparent coefficient diffusion (ADC) map), compared to low-intensity signal (unrestricted diffusion, high signal on ADC map) in cystic or necrotic tumors (Fig. 77.2). Solid brain metastases can appear as hyperintense lesions (restricted diffusion) depending on their cellularity, in which case DW-MRI is unable to differentiate metastatic lesions from acute or subacute ischemic stroke (Geijer and Holtas, 2002).

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Perfusion MRI often shows an elevated relative cerebral blood volume (rCBV) in both metastatic and primary tumors. However, beyond the contrast-enhancing margins of the lesion, rCBV is usually increased in infiltrating primary tumors and decreased by edema in minimally invasive metastases (Law et al., 2002). The MRI spectroscopy profile of solid metastases is characterized by increased choline peak, and decreased or even absent N-acetylaspartate and creatine levels. In metastases with necrotic areas, elevated lactate and lipid peaks may be found (Fig. 77.3). These findings are not specific and are also seen in primary tumors. Likewise in rCBV study, peritumoral measurements may help to differentiate primary from secondary brain tumors, thanks to their different infiltration capacity. Spectroscopic imaging demonstrates elevated choline levels in the peritumoral region of gliomas but not of metastases (Law et al., 2002).

Fig. 77.2. Cerebral lesions with ring-enhancing appearance on contrast-enhanced T1- weighted image (upper images of panels (A) and (B)). The lesion in panel (A) is a breast adenocarcinoma metastasis, and its core is characterized by high signal on apparent diffusion coefficient (ADC) map (unrestricted diffusion). The lesion on panel (B) is an abscess, and its core is hypointense on ADC map (restricted diffusion). (Reproduced courtesy of Prof. M. Lemort.)

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Fig. 77.3. MRI spectroscopy of a brain metastasis, with increased choline peak, decreased N-acetylaspartate and creatine levels, and elevated lipid peak corresponding to necrosis. Cho, choline; Cr, creatine; NAA, N-acetylaspartate; Lip, lipids. (Reproduced courtesy of Dr. R. Guillevin.)

CT scan with and without iodine contrast is used when MRI is not available or when its use is prohibited by the presence of magnetic material. On nonenhanced CT scan, brain metastases appear as hypo- or isodense mass lesions, except when there is intratumoral bleeding or calcification. Lesion density is increased after contrast injection. Brain positron emission tomography (PET) using 18 F-fluorodeoxyglucose (18 F-FDG) or amino acid tracers can be useful to differentiate hypometabolic postradiation focal necrosis from hypermetabolic malignant lesion (Hustinx et al., 2005).

When MRI or CT scan show, in an appropriate clinical setting, multiple mass lesions located near the gray–white matter junction and surrounded by an often disproportionate edema, the diagnosis of brain metastases is usually accepted without pathological confirmation. However, diagnostic biopsy may be indicated in certain circumstances such as: (1) atypical neuroimaging, (2) controlled systemic malignancy without evidence of pulmonary tumor, (3) primary cancer with low propensity to form CNS metastases, and (4) high risk of vascular or infectious brain lesion.

BRAIN METASTASES 1149 In brain metastases without leptomeningeal involvePrimary brain gliomas and primary CNS lymphoma ment, CSF changes are characterized only by an (PCNSL) with atypical radiological presentation may be increased protein level. But lumbar puncture for CSF extremely difficult to differentiate from brain metastaanalysis may be hazardous and is not recommended. ses despite progress made in DW-MRI, perfusion MRI, EEG is helpful to support the diagnosis of epileptic and MR spectroscopy (see diagnostic procedures), and seizures especially in patients with confusion, language definite diagnosis may require biopsy. or memory disorders, and unreliable history. But its Hemorrhage caused by a small and previously uniinterpretation is often complicated by nonepileptiform dentified metastasis may closely resemble primary brain abnormalities due to the underlying tumor. hematoma. In some patients the definite diagnosis is made only after a prolonged follow-up. In most ischemic lesions the shape, the location, and Patients not known to have cancer the lack of early contrast enhancement helps to differenIn patients without obvious cancer, the identification of tiate vascular from malignant disease. But in cases with the primary tumor is part of the diagnostic procedure. delayed neuroimaging, contrast enhancement and The major dilemma is how far to pursue systemic invesedema may mislead the diagnosis. Occasionally, systigations, which may delay potentially curative treatment temic tumors may generate emboli made of malignant such as radiosurgery and jeopardize its efficacy. The cells and/or mucin (mucin-secreting cancers) plus fibrin, which occlude cerebral arteries of various sizes and diagnostic work-up before considering surgery should cause symptomatic stroke. In these patients, malignant consist of at least a clinical examination including fullmass may develop subsequently on the site of the ischebody skin scrutiny, chest and abdomen CT, and wholebody 18 F-FDG PET if accessible. Chest CT is the most mic territory (Nielsen and Posner, 1983). fruitful and simple examination (van de Pol et al., Brain abscesses are rare (1/100 000 per year), but 1996), as about 60% of patients with brain metastases their incidence is increased after neurosurgical procehave primary or metastatic lung tumor. CT of abdomen dures (bacteria) and in immunosuppressed patients and pelvis occasionally shows an unsuspected cancer. (fungi such as aspergillus). In about 15% of the cases brain abscesses are cryptogenic, and in patients Whole-body 18 F-FDG PET scan is a sensitive tool for without identified infectious source, inflammatory labdetecting systemic cancer, but its specificity in differenoratory changes are subtle or even absent, making the tiating malignant from benign or inflammatory lesions is relatively low (Lan et al., 2008). When these examinadiagnosis difficult. Nowadays DW-MRI allows the distions are inconclusive brain tumor resection or stereotinction between infectious and malignant disease tactic biopsy is recommended. Both procedures help (Fig. 77.2). Also in tuberculomas, inflammatory tests to establish histological diagnosis and orient to the locaare often unable to distinguish tuberculous from neotion of the primary tumor (Becher et al., 2006). In addiplastic lesions. Most CSF analysis shows only an increased protein level because concomitant tuberculous tion, neurosurgery may be the first therapeutic step. meningitis is present in less than 10% of the patients Specific serum tumor markers such as a-fetoprotein (Arseni, 1958). and b-human chorionic gonadotrophin for germ cell tumors, and other markers including CA 15.3 for breast, Due to migration, neurocysticercosis is no longer CA 19.9 for pancreatic, and CA 125 for ovarian carcilimited to endemic areas (Latin America, Africa, and noma may help to orient the diagnosis of the primary Eastern Europe). Multiple brain cysts occasionally cancer. mimic metastatic lesions. The diagnosis is based on the occurrence of chronic seizures and serologic criteria. Two viral CNS diseases may have a pseudotumoral DIFFERENTIAL DIAGNOSIS presentation: herpes simplex encephalitis (HSE) and Up to 10% of structural brain lesions seen in cancer progressive multifocal leukoencephalopathy (PML). patients may not be metastatic, and correspond to priBoth diseases may be diagnosed with polymerase chain mary tumors, vascular, infectious, granulomatous, or reaction. However, the diagnosis may be challenging in demyelinating lesions (Patchell et al., 1990). They are HSE patients with minimal infectious signs, and in more likely to occur in patients with specific risk factors patients with PML who can mount an inflammatory for these complications, in individuals with controlled reaction allowing enhancement of MRI lesions. systemic cancer without evidence of primary or metaSarcoidosis is a systemic disease characterized by static pulmonary lesions, and in tumors with low propennoncaseous granulomas which involve leptomeninges sity to invade the CNS. In patients who have undergone and cerebral parenchyma in up to 10% of the patients. prior brain irradiation, clinical and radiological features Occasionally, parenchymal location is the only obvious of necrosis may resemble tumor progression. manifestation of the disease and may be mistaken for

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a neoplastic lesion. The diagnosis may require biopsy, and is sometimes made on surgical material. Recent multiple sclerosis plaques are contrastenhanced and may be occasionally mistaken for brain metastases. However, in our experience, the most likely diagnostic error is PCNSL, because in both diseases the lesions are multiple and have, typically, a periventricular location. Brain lesions due to late-delayed toxicity of radiation therapy usually appear over 1 year following treatment, and therefore are not frequent in patients with brain metastases. The most common complication is diffuse leukoencephalopathy, causing cognitive and gait disorders which may mimic tumor progression. The main risk factors for this pathology are age, vascular risk factors, and concomitant chemotherapy. Focal radionecrosis is uncommon in patients treated with whole-brain irradiation using 30 Gy delivered in 10 days. But it occurs in up to 10% of individuals treated with stereotactic irradiation. Radiation-induced meningioma or glioma develop after a delay of 10–15 years.

TREATMENT Several therapeutic options are available to treat brain metastases. Their choice is guided by following factors: 1. 2. 3.

the extent, control, and pathology of the primary tumor the size, location, and number of brain metastases prior anticancer treatments.

A meta-analysis of the RTOG studies defined four independent prognostic factors for survival of patients with brain metastases: (1) age, (2) extent of systemic

disease, (3) one versus several brain metastases, and (4) performance status (PS). Median survival of patients with four favorable factors was 7 months, whereas patients with only one favorable factor survived only 3 months (Diener-West et al., 1989). Treatment of brain metastases cannot be considered in isolation as in about half of the patients death is caused by extraneural lesions. In most patients with widespread and uncontrolled cancer, the survival is unlikely to be significantly prolonged even by the most effective therapy of the cerebral disease. In such patients the primary aim of treatment of brain metastases is to improve or stabilize the neurologic deficit and the quality of life, with minimal inconvenience and morbidity. Whole-brain radiation therapy (WBRT) and corticosteroids usually fulfill these requirements. For example, in melanoma patients on fotemustine (a nitrosourea derivative) (Mornex et al., 2003) or in SCLC patients on teniposide (a podophyllotoxin) (Postmus et al., 2000), WBRT significantly prolongs the time to progression of brain metastases. By contrast, in patients in whom the primary tumor is either undiagnosed or well controlled, who have a PS of 70% or more, and between one and three brain metastases, both quality of life and survival are primarily related to the treatment of malignant brain lesions. In such patients aggressive treatment of CNS-disease is warranted and several options summarized in the therapeutic algorithm are available (Fig. 77.4).

External whole-brain radiation therapy WBRT is a mainstay of treatment and is used at some stage in malignant brain disease in most patients. The standard dose is 30 Gy delivered in 10 daily fractions.

Fig. 77.4. Treatment algorithm in brain metastases. SCLC, small-cell lung cancer; PS, performance status; ChT, chemotherapy; SRS, stereotactic radiosurgery; WBRT, whole-brain radiation therapy.

BRAIN METASTASES There is no clear evidence to support that modified dose or fractionation schedule results in significantly better control of brain disease, longer median survival, or better cognitive outcome (Borgelt et al., 1980; Kurtz et al., 1981). Also there is no evidence that particular dose or fractionation should be based either on tumor pathology or radiosensitivity of the primary tumor, but this may be due to the limited number of studies explicitly addressing the issue. The main indications for WBRT are as follows: ●

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As already mentioned, patients with poor outcome: advanced age, uncontrolled systemic cancer, low PS ( 113 months and > 69 months, respectively) ing that Yo-Abs may be directly involved in the pathothan Hu-Abs (median: 7 months) or Yo-Abs (median: genesis of paraneoplastic cerebellar degeneration 13 months) patients (Shams’ili et al., 2003). Cerebellar (Greenlee et al., 2010). Nonetheless, no study to date symptoms can be isolated or associated with signs of has demonstrated a clear benefit of immunotherapy widespread nervous system dysfunction depending on on the neurologic outcome. the associated Ab. The CSF analysis is rarely normal (less than 20%), and typically shows pleocytosis, increased Amphiphysin-Abs protein concentration, increased IgG level, and the presence of oligoclonal bands. Brain imaging by computed Even though targeting an intracellular epitope, tomography (CT) or magnetic resonance imaging amphiphysin-Abs was shown to induce stiff person (MRI) is typically normal early in the disease. Cerebellar syndrome-like symptoms when intrathecally infused in atrophy may be observed during the course of the disrats (Geis et al., 2010). Moreover, a reduced presynaptic ease, but is never seen at the onset of the cerebellar GABAergic inhibition was identified in this rodent ataxia. Nonspecific abnormalities such as white matter model leading to the assumption that GABAergic synapor cerebellar cortex T2 abnormal hyperintense signals ses are vulnerable to defective endocytosis induced by have occasionnally been reported. anti-amphiphysin immunoglobulin G (Geis et al., 2010).

SPECIFIC PARANEOPLASTIC NEUROLOGIC SYNDROMES Paraneoplastic disorders of the central nervous system SUBACUTE CEREBELLAR DEGENERATION Clinical and biological characteristics of patients with paraneoplastic cerebellar ataxia The first case of paraneoplastic cerebellar syndrome described was in 1919, that of a 60-year-old woman who suffered from pelvic cancer (Brouwer, 1919). The concept of paraneoplastic subacute cerebellar degeneration (SCD) was only demonstrated in 1983 with the description of anti-Yo antibodies (Greenlee and Brashear, 1983). SCD represents one of the most common PNS (Furneaux et al., 1990b; Graus et al., 2004; Giometto et al., 2010). The mean age of SCD patients is 63 (Shams’ili et al., 2003). The sex ratio is dependent on the antibody and the type of associated tumor (see below). SCD onset is typically subacute and becomes severe and debilitating within a few weeks or months. A faster onset within hours or days (Anderson et al.,

Clinical specificities according to the type of onconeuronal antibody The most common antibodies associated with SCD described in the literature are Yo-Abs and Hu-Abs, which are detected in 70% of cases (Shams’ili et al., 2003). However, some Abs were not detected by all the laboratories suggesting some biais in the diagnosis. Some antibodies are specific to cerebellar syndromes (Yo-Abs, Tr-Abs, ZIC4-Abs) and some others are frequently observed, but not specific (Hu-Abs, CV2/CRMP5-Abs). SCD with Yo-Abs The cerebellar syndrome is most often pure and isolated, usually severe enough to cause major handicap, with 79% of the patients bedridden within a few weeks (Shams’ili et al., 2003). In 50% of the patients death is related to the neurologic symptoms (Peterson et al., 1992; Shams’ili et al., 2003). Survival is longer in patients with breast cancer (median: 100 months) than in patients with ovarian cancer (median: 22 months) (Rojas et al., 2000). The presence of Yo-Abs is significantly associated with the presence of a gynecologic cancer. The most frequent

1164 A. DIDELOT AND J. HONNORAT tumors are ovarian carcinoma (38–47% of tumors) and (Honnorat et al., 2009). Patients with CV2/CRMP5-Abs breast cancers (27–35%) (Peterson et al., 1992; Rojas are mainly males (70%) with a mean age of 62 years et al., 2000). Other gynecologic tumors may be respon(Rogemond and Honnorat, 2000). The cerebellar syndrome sible for SCD with Yo-Abs, such as cancers of the endois generally less severe than that observed with Yo-Abs. metrium, fallopian tubes, or cervix (Peterson et al., 1992; Other associated neurologic symptoms may be observed Rojas et al., 2000). In case of negative results from such as LE, chorea, or visual symptoms such as retinopathy mammography, chest, abdominal and pelvic CT, and or uveitis (de la Sayette et al., 1998; Rogemond and ultrasound, it is advisable to perform an exploratory Honnorat, 2000). LEMS and peripheral neuropathy are also laparotomy to examine the ovaries and uterus frequently associated with the cerebellar ataxia (Honnorat (Peterson et al., 1992; Didelot and Honnorat, 2009). et al., 2009). The most frequently associated tumor is SCLC (60%), but malignant thymoma and uterine sarcoma have been described (Honnorat et al., 1996, 2009; Rogemond and SCD with Hu-Abs Honnorat, 2000). A cerebellar syndrome is observed in 22% of the patients with Hu-Abs (Honnorat et al., 2009). Unlike patients SCD with VGCC-Abs with Yo-Abs, extracerebellar signs are frequently observed from the beginning of the neurologic sympAntibodies to calcium channels, particularly those toms, such as LE, cranial nerve involvement, brainstem directed against the P/Q type, have been primarily disorders, dysautonomia, LEMS, or pure sensory described in association with Lambert–Eaton myasneuronopathy (Honnorat et al., 2009). These symptoms thenic syndrome (LEMS) (Lennon et al., 1995; are associated with extensive inflammation of the Motomura et al., 1997). However, studies showed that central nervous system, and neuronal destruction is not the incidence of cerebellar ataxia was particularly high restricted to the cerebellum and Purkinje cells (Dalmau in patients with LEMS (Clouston et al., 1992). In addiet al., 1992). Tumors associated with Hu-Abs are mainly tion, patients with ataxia associated with LEMS prelung cancer, and small-cell lung cancer (SCLC) is sented more frequently with cancer than patients with observed in 70% of cases (Honnorat et al., 2009). isolated LEMS (Clouston et al., 1992). Antibodies to calSCD with Tr-Abs The first case of SCD associated with Hodgkin’s disease and confirmed by autopsy was published in 1957. The association of Tr-Abs and SCD in patients suffering from Hodgkin’s disease was identified in 1997 (Graus et al., 1997). However, Tr-Abs identification is technically difficult. Suspicion of cerebellar syndrome with Tr-Abs (young man and/or known lymphoma) consequently requires special tests and must be clearly spelled out in the search for onconeuronal antibodies. Clinically, cerebellar syndromes with Tr-Abs are characterized by subacute ataxia with, in some cases, diplopia, oscillopsia, vertigo, or influenza-like illness and headache (Bernal et al., 2003). SCD associated with Tr-Abs occurs mainly among young men with Hodgkin’s disease (Bernal et al., 2003; Shams’ili et al., 2003). Two studies revealed that in 83–86% of cases, the cerebellar syndrome preceded the diagnosis of Hodgkin’s disease (Bernal et al., 2003; Shams’ili et al., 2003). SCD with CV2/CRMP5-Abs CV2/CRMP5-Abs were initially identified in a patient with cerebellar ataxia, uveitis, peripheral neuropathy, and metastatic undifferentiated adenocarcinoma (Antoine et al., 1993). Cerebellar ataxia was observed in 46% of the patients with CV2/CRMP5-Abs

cium channels of the P/Q type were also reported in patients with SCLC and SCD in the absence of LEMS (Mason et al., 1997). A study involving 39 patients with a cerebellar syndrome and lung cancer showed that 16 patients (41%) had antibodies to calcium channels of the P/Q type, while nine (23%) had exhibited Hu-Abs (Graus et al., 2002). Reported patients generally developed a pure cerebellar ataxia with a subacute onset. SCD with Ri-Abs A study of 50 patients with SCD showed that six of them had Ri-Abs (Shams’ili et al., 2003). Cerebellar syndrome may be isolated but is most often associated with other neurologic signs, such as opsomyoclonus and/or brainstem encephalitis. Ri-Abs are strongly associated with breast and lung cancers. Other autoantibodies associated with paraneoplastic cerebellar ataxia A few observations of SCD have been reported in association with anti-amphiphysin (Antoine et al., 1999a) or anti-Ma2 (Dalmau et al., 1999) antibodies. Some cases have also been reported with other autoantibodies, but in many cases, the specificity of these antibodies is unclear because only one or two cases have been identified.

PARANEOPLASTIC DISORDERS OF THE CENTRAL AND PERIPHERAL NERVOUS SYSTEMS Two patients with Ab directed against mGluR1, a metabotropic receptor of glutamate, have been reported (Sillevis Smitt et al., 2000). This antibody seems interesting because it could be directly responsible for cerebellar ataxia, as demonstrated by injection into rat cerebellum (Sillevis Smitt et al., 2000). However, since 2000, only one further case has been published (Marignier et al., 2010). Although the first two cases were associated with Hodgkin’s disease, the last one published had no cancer (Marignier et al., 2010). In the two first cases published, Hodgkin’s disease seemed not to be related to the cerebellar ataxia, suggesting that mGluR1-Abs antibodies could be associated with nonparaneoplastic SCD. Anti-Zic antibodies are described in SCD with SCLC (Bataller et al., 2004; Sabater et al., 2008a). A recent study showed that these antibodies were observed in 15% of SCD patients with lung cancer (Graus et al., 2008). However, the diagnostic role of these antibodies is not clear (Graus et al., 2010) because they are also detected in patients who have lung cancer without associated neurologic syndromes. One SCD patient with lung adenocarcinoma was described with antibodies against protein kinase C g (Sabater et al., 2006), and other isolated cases have been published with uncharacterized antibodies. Although the significance of these antibodies is unknown, their presence indicates an unusual activation of the immune system that may play a role in the onset of cerebellar ataxia. Seronegative SCD. It is interesting to note that a significant percentage (probably over 50%) of patients with SCD have no identified circulating neuronal antibodies (Anderson et al., 1988a; Mason et al., 1997). The etiology of the cerebellar ataxia in these patients without autoantibodies remains speculative; however, an autoimmune origin of the neurologic symptoms is probable because most of these patients have CSF inflammation, and pathologic lesions are not different from those seen in patients with onconeuronal antibodies (Mason et al., 1997). The clinical course of these patients is still difficult to discern owing to the lack of data.

PARANEOPLASTIC ENCEPHALOMYELITIS Paraneoplastic encephalomyelitis (PEM) is defined by disseminated neuronal loss and simultaneous inflammatory lesions in different parts of the nervous system. PEM may concern areas such as the hippocampus, the lower brainstem, the spinal cord, or dorsal root ganglia (Bataller et al., 2004). In patients with brainstem encephalitis, the pontine dysfunction precedes downward evolution in a half of the patients (Saiz et al., 2009). Sensory neuronopathy, LE, and cerebellar ataxia are the most common clinical syndromes observed in PEM. A failure of the autonomic nervous system is

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observed in 30% of the patients (orthostatic hypotension, urinary retention, pupillary abnormalities, impotence, and dry mouth) (Wabbels et al., 2004). Most of the patients present Hu-Abs, CV2/CRMP5-Abs or amphiphysin-Abs but a recent report shows a clinical pattern specific to Hu-Abs and CV2/CRMP5-Abs, respectively (Honnorat et al., 2009). A review of 200 patients suffering from PEM associated with Hu-Abs described comprehensively the clinical and paraclinical features associated with this disease (Graus et al., 2001). In this cohort, the mean age was 63 and 75% of cases were men. A subacute sensory neuropathy occurred in more than a half of the patients (54%), followed by cerebellar ataxia (10%), limbic encephalitis (9%), and multifocal involvement (11%). Interestingly in patients in whom the tumor diagnosis was the first event, PEM onset followed the progression or relapse of the underlying tumor. In 75% of the patients with PEM the underlying neoplasm is a SCLC. The treatment of the associated tumor, with or without immunotherapy, was an independent predictor of improvement of the neurologic symptoms. The factors independently associated with a higher mortality are: age over 60, a Rankin score over 3 at diagnosis, more than one area of the nervous system being affected, and the absence of treatment (Graus et al., 2001).

LIMBIC ENCEPHALITIS Limbic encephalitis (LE) is defined by an acute or a subacute anterograde amnesia associated with epileptic seizures and psychiatric disorders. Each symptom varies according to the associated Ab. Moreover, this concept is currently moving to a wider term of encephalitis due to the description of cases where observed symptoms suggested a widespread involvement of neurologic structures beyond the limbic structures. Hu-Abs, CV2/ CRMP5-Abs and Ma2-Abs presented the vast majority of patients with LE until the recent description of Ab directed against synaptic proteins or receptors such as NMDAr, AMPAr or GABABr, Lgi1 and CASPR2 proteins. The clinical course and the specificity of LE according to the associated Ab are discussed below (Table 78.4).

LE with NSA-Abs Since 2004, NSA-Abs have been described in some patients with LE. The clinical features and outcome of LE vary between patients with NSA-Abss and ON-Abs. In other words, many patients presenting with LE and NSA-Abs have no associated tumor and LE is often responsive to immunologic therapy.

Table 78.4 Main features of limbic encephalitis (adapted from Didelot and Honnorat, 2011) NMDAr-Abs Antibody

Female

Children

Male

VGKC/ LGI1-Abs

Hu-Abs

Ma2-Abs

GABABr-Abs

AMPAr-Abs

None

CV2-Abs

Amphiphysin-Abs

Published cases Antigenic target Age (range) Sex ratio (M/F) Percentage of cancer Type of associated tumor

248

150

29

217

88

65

17

10

8

6

6

EP

IC

IC

SCA

SCA

–

IC

IC

56 (24–75) 0.9 47%

57 (38–87) 1/9 70%

56 (28–67) 1 12%

54 1 100%

61 (55–68) 1 83%

SCLC

prostate cancer

Malignant thymoma and SCLC

SCLC

75% 100%

66% 100%

50% 50%

na

100%

100%

SCA 24 (18–80) – 58%

14 1/3 25%*

na – 5%

64 (9–84) 1 12%

Teratoma

Teratoma and neuroblastoma

SCLC, Hodgkin, testicular germ cell tumor

SCLC and malignant thymoma

na 51 (22–82) na 2.5 Almost 92% all cases SCLC Testicular cancer, SCLC

43% 78%

Frequent Frequent

78% 74%

85% 65%

Malignant thymoma, breast cancer, lung cancer 90% 60%

71%

50%

100%

100%

75%

Abnormal CSF 80% Abnormal MRI 50% at diagnosis Abnormal EEG 94%

SCA, cell surface antigen; EP, excreted protein; IC, intracellular antigen; na: not available; SCLC small-cell lung cancer; CSF, cerebrospinal fluid; EEG, electroencephalogram; MRI, magnetic resonance imaging; Abs, antibodies; r, receptor. *Girls in all but two of the paraneoplastic cases of encephalitis with N-methyl-D-aspartate receptor antibodies in childhood.

PARANEOPLASTIC DISORDERS OF THE CENTRAL AND PERIPHERAL NERVOUS SYSTEMS LE with VGKC-Abs, Lgi 1-Abs and CASPR2-Abs Antibodies supposed to react against voltage-gated Kþ channel (VGKC-Abs) were first described in 1995 in patients with neuromyotonia (Shillito et al., 1995; Hart et al., 1997; Vernino and Lennon, 2002), and few years later in some cases of Morvan’s disease (Lee et al., 1998; Barber et al., 2000; Liguori et al., 2001). In 2004, a larger published series of patients suggested a relationship between VGKC-Abs and LE (Vincent et al., 2004). However, recent immunologic findings have clearly demonstrated that voltage-gated Kþ channel was not the direct target for the Ab. The accurate target of this NSA-Ab eventually proved to be leucine-rich gliomainactivated 1 protein (Lgi1) in the case of LE (Irani et al., 2010a; Lai et al., 2010); contactin-associated protein 2 (CASPR2) is another epitopic target which may be more specific for neuromyotonia or Morvan’s disease (Irani et al., 2010a). The mean age of patients with Lgi1-Abs and LE is 62 years (Irani et al., 2010a; Lai et al., 2010) and 67% of the patients are males. The clinical features are characterized by memory loss, epileptic seizures, and delusion. Sleep disorders such as insomnia may be observed and are probably due to a hypothalamic dysfunction. A hyponatremia is frequent (55%) and is due to antidiuretic hormone secretion (Pozo-Rosich et al., 2003). Brain MRI is abnormal in 69% of cases, showing a limbic hypersignal in T2-weighted sequences, although other brain regions such as the frontal lobes or the cerebellum may also be involved. CSF analysis is normal in 59% of cases. A tumor was identified in 5% of the reported patients with Lgi1-Abs and LE: two thyroid, one lung, one thymoma, one ovarian teratoma, and one renal cell carcinoma. A significant clinical improvement was observed in 78% of cases with immunomodulator treatments such as corticosteroids, plasma exchanges, or intravenous immunoglobulins (Lai et al., 2010). LE with Neuropil-Abs This subtype of LE was described in 2005 with the identification of antibodies reacting against neuronal surface cell antigens with a different pattern than the one observed with VGKC-Abs (Ances et al., 2005; Vitaliani et al., 2005). Some Abs initially described as NeuropilAbs were revealed to be NMDAr-Abs (Vitaliani et al., 2005), GABABr-Abs (Lancaster et al., 2010), or AMPAr-Abs (Lai et al., 2009). The subgroup of Neuropil-Abs should consequently cease to be used in future, with the more accurate identification of the antigens.

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LE with NMDAr-Abs Between 1997 and 2006, numerous cases of women presenting with ovarian teratoma and LE were reported (Nokura et al., 1997; Aydiner et al., 1998; Lee et al., 2003; Stein-Wexler et al., 2005; Yang et al., 2006; van Altena et al., 2008). All these cases occurred in young women and included psychiatric disorders such as delusions or behavioral disturbances. No antibody was described but NSA-Abs were not looked for. In 2005, four cases gave a clue to an association between this syndrome and antibodies reacting against the membrane of hippocampal neurons (Vitaliani et al., 2005). This was supported by another study (Shimazaki et al., 2007) in which isolated antibodies happened to colocalize with a brain-specific protein involved in the regulation of the dendritic development of hippocampal neurons (Vitaliani et al., 2005; Koide et al., 2007). Finally, by analogy of staining, a NR1 subunit of the N-methyl-Daspartate glutamate receptor (NMDAr) was identified as a main target for these Abs (Dalmau et al., 2007). This subunit of the glutamate receptor is expressed at an elevated level in the associated ovarian teratoma as well (Dalmau et al., 2007). The prevalence of LE appears to be higher with NMDAr-Abs than in the previously described groups of Abs. In fact the first 100 patients were reported within less than 1 year after the NMDAr-Abs discovery (Dalmau et al., 2008) and more than 400 patients with NMDAr-Abs were diagnosed within 3 years by the group of Josep Dalmau (Dalmau et al., 2011). NMDAr-Abs were mainly observed in females (84%) who presented with stereotypical clinical features associating acute psychiatric disorders (delirium with visual or auditory delusions, mood disorders such as aggressiveness or irritability) followed by loss of consciousness and eventually epileptic seizures (Dalmau et al., 2011). A dysautonomia and/or an acute central respiratory failure occurred in one-third of patients and required ressuscitation. Recent findings suggested that the disease should progress through two main stages (Irani et al., 2010b). The first stage comprises psychiatric and epileptic symptoms and is associated with CSF lymphocytosis; the second is represented by movement disorders, loss of consciousness, dysautonomia, and the presence of oligoclonal bands in the CSF. Brain MRI was normal in 45% of cases and the CSF examination revealed clues for inflammation in more than 90% (elevated white cell count, mainly lymphocytes, mild hyperproteinorachia and/ or oligoclonal bands). Electroencephalogram was abnormal in more than 90% but remained unspecific. A paraneoplastic origin was observed in 60% of cases, the majority of which were associated with a teratoma (58% of all cases).

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Even though LE with NMDAr-Abs was first described as a disease in young women, two other subgroups of patients could still be individualized. The first subgroup gathered LE with NMDAr-Abs in childhood and was described in a case series of 32 children aged 2–14 years (Florance et al., 2009). Clinical symptoms were similar to those observed in young women. However, brain MRI was more frequently normal (69% of cases) and EEG and CSF were abnormal in 100% and 94% of cases, respectively (Florance et al., 2009). LE and NMDAr-Abs in children were much less often paraneoplastic and a cancer was found in only nine children of the 33 reported cases (27%): eight teratomas and one neuroblastoma (Florance et al., 2009; Lebas et al., 2010). LE with NMDAr-Abs has also been identified in a few men. Again no significant clinical differences were observed as compared to the previous subgroups but only two of the nine reported men (22%) presented a cancer (a SCLC and an immature teratoma of testis) (Dalmau et al., 2008). A good response to immunotherapy is observed in almost half of the patients. However, no study has yet demonstrated the superiority of one treatment over another. Intravenous immunoglobulin, plasmatic exchange, and corticosteroids are the most commonly used. LE with AMPAr-Abs To date, 12 patients (11 women) with AMPAr-Abs associated LE have been reported (Lai et al., 2009; Bataller et al., 2010; Graus et al., 2010). An accurate clinical description is difficult to obtain with these few cases. However, amnesic symptoms were constant and epileptic seizures occurred in only five cases (42%). CSF examination showed a mild lymphocytic pleocytosis (6–75 cells/mm3) in nine of the 12 cases (75%). Eight of the 11 patients (73%) in whom brain MRI was available showed T2-weighted and FLAIR (fluid attenuated inversion recovery) sequence abnormalities within the temporomesial structures. Eight patients had a cancer (four malignant thymoma, two breast cancers, one SCLC, and one non-SCLC), which had already been diagnosed at the time of LE in all but two cases (Lai et al., 2009; Graus et al., 2010). The first episode of LE responded positively in all patients, following immunotherapy and cancer treatment, suggesting that LE with AMPAr-Abs seemed to be associated with a good neurologic prognosis; however, the risk of relapse is high. For instance, many described patients had one to three relapses after the first episode of encephalitis (Lai et al., 2009). Recently, two cases of women over 50, presenting AMPAr-Abs and an acute late-onset psychosis, have been recently reported (Graus et al., 2010). This

finding suggests that AMPAr-Abs could be present in patients with a larger clinical spectrum than isolated LE. Further clinical studies will be necessary in order to characterize clinical specificities of these patients.

LE with GABABr-Abs GABABr-Abs has been identified in 2010 and targets the GABAB1 and GABAB2 receptor subunits (Lancaster et al., 2010). Patients with LE and GABABr-Abs were characterized by early and prominent seizures as first symptoms in 15 of the 17 cases (88%) described to date (Lancaster et al., 2010). The brain MRI was abnormal in 11 patients (65%) and showed mesiotemporal hypersignal in T2weighted sequences. The CSF examination was abnormal in 11 of the 13 patients in whom data were available (65%) and mainly showed an elevated white blood cell count and a mild hyperproteinorachia. Oligoclonal bands were present in five of the six patients (83%) who underwent this analysis. Interestingly, other antibodies can be associated with GABABr-Abs in 60% of the patients (i.e., 9/17). GAD-Abs were found in five cases, TPO-Abs in four, VGCC-Abs in three, and Sox1 in one case (some patients had more than one associated antibody). Seven (41%) of the 17 patients with GABABr-Abs had a cancer (six SCLC and one mediastinal adenopathy without histologic result). Eight of the 17 patients (i.e., 47%) experienced substantial improvement or fully recovered under various regimens of corticosteroids (65% of the patients received this therapy), intravenous immunoglobulins (35%), or plasma exchanges (two patients received this treatment, i.e., 12%) (Lancaster et al., 2010).

LE with ON-Abs LE with Hu-Abs. Hu-Abs-associated LE was the most frequent type of LE before the description of NSA-Absa. LE is observed in 21.3% of PNS associated with Hu-Abs and its prevalence remains equal across several case series (Dalmau et al., 1992; Honnorat et al., 2009). The other main neurologic symptoms associated with Hu-Abs are sensory neuronopathies, observed in 86.1%, and cerebellar ataxia in 21.6% of the patients (Honnorat et al., 2009). In Hu-Abs patients with LE, the temporal symptoms are rarely isolated and other neurologic symptoms such as cerebellar ataxia or a subacute sensory neuropathy are frequently present. An electroneuromyogram must consequently be performed in all cases in order to rule out an associated neuropathy. The association of LE with any other neurologic symptom must lead to the diagnosis of paraneoplastic encephalomyelitis (Graus et al., 2004).

PARANEOPLASTIC DISORDERS OF THE CENTRAL AND PERIPHERAL NERVOUS SYSTEMS LE with Ma2-Abs. MA2-Abs was first described in 1999 in patients with testicular teratoma, limbic and brainstem encephalitis, and testicular cancer (Voltz et al., 1999). Ma2-Abs is rare and represents less than 5% of the patients with PNS reported in the European database (Giometto et al., 2010). An involvement of the limbic structures was observed in about 75% of the patients with Ma2-Abs (Rosenfeld et al., 2001); however, an isolated LE occured in only 11% of the patients with Ma2-Abs (Dalmau et al., 2004). Testicular cancer, which is present in 53% of cases, must be ruled out in any man presenting Ma2-Abs. SCLC is the second most frequent associated tumor (21%) (Dalmau et al., 2004). Ma2-Abs are clearly associated with PNS even if 12% of the patients remained free of cancer after comprehensive carcinologic investigations; a neurosarcoidosis was reported in a woman with Ma2-Abs (Desestret et al., 2010). In male patients, the combination of the immunologic treatment with orchidectomy significantly improved clinical outcome in one-third of cases (Dalmau et al., 2004). LE with CV2/CRMP5-Abs. The first case of LE with CV2/CRMP5-Abs has been described in a patient with malignant thymoma (Antoine et al., 1995). In a recent study of 37 patients with PNS and CV2/CRMP5-Abs, five (13.5%) patients had LE (Honnorat et al., 2009). More recently, another case of CV2/CRMP5-Abs was associated with myasthenia gravis and thymoma (Monstad et al., 2009). Unlike LE with Hu-Abs, CV2/ CRMP5-Abs-related LE is more frequently isolated, even though a neuropathy was found in some cases (Honnorat et al., 2009). In two of the three cases where clinical features were available, it consisted of sudden psychiatric disorders with agitation and hallucinations. Memory loss was the most prominent symptom while epileptic seizures were less marked (Antoine et al., 1995). Brain MRI showed a limbic involvement in all patients but CSF was sometimes normal. LE with Amphiphysin-Abs. To date, only six cases of LE with Amphiphysin-Abs have been reported in case series gathering 77 patients (Antoine et al., 1999a; Dorresteijn et al., 2002; Pittock et al., 2005). Three among them had other associated autoantibodies: VGKC-Abs, VGCC-Abs, CV2/CRMP5-Abs, Hu-Abs and GAD-Abs (Dorresteijn et al., 2002; Pittock et al., 2005). LE was the sole symptom in only one patient (Antoine et al., 1999a); in the other cases it was associated with various neurologic syndromes such as a sensorimotor neuropathy, a cerebellar ataxia, axial or limb stiffness, myoclonus, or choreoathetosis. Five of the six described patients with LE and Amphiphysin-Abs presented a SCLC and no tumor was found in the last

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patient (Antoine et al., 1999a; Dorresteijn et al., 2002; Pittock et al., 2005). Paraneoplastic LE without antibody The percentage of “seronegative” paraneoplastic LE is difficult to evaluate. Before the description of NSAAbs, a retrospective study between 1987 and 1997, reporting 14 cases of LE with SCLC, described 50% of “seronegative” LE (Alamowitch et al., 1997). No relevant difference was observed between Hu-Abs positive and “seronegative” patients in terms of frequency of psychiatric disorders, percentage of abnormal CSF, or abnormal brain MRI. Even if the reported clinical features are too weak to form conclusions, most of these “seronegative” LE could be expected to belong to the later described antibody-associated PNS as seen with ONAbs or NSA-Abss. Moreover “seronegative” LE without cancer has also been described (Bien et al., 2000) and the clinical features of some reported patients may correspond to VGKC-Abs patients presenting with LE. In recent years, the frequency of “seronegative” LE decreased with the description of NSA-Abss. The immunologic findings in a case series of 39 patients with LE confirmed this assumption because only three of these patients (8%) eventually remained “seronegative” after immunochemistery screening (Bataller et al., 2007). Moreover, a recent study evaluated the prevalence of NSA-Abss in 45 patients suffering from LE, independently of the presence or not of ON-Abs (Graus et al., 2008). After NSA-Abss were identified in 29 patients, only five cases (17%) remained definitively “seronegative” despite comprehensive immunologic evaluations. The number of “seronegative” LE patients may continue to taper down with more antibodies to be discovered in the coming years. Nevertheless, the findings previously reported may still support the assumption that some LE genuinely are seronegative. This suggests that these LE may result from different mechanisms, which need to be characterized. Interestingly, within the eight “seronegative” cases which benefited from both ON-Abs and NSA-Abss screening, only one case was paraneoplastic (prostate adenocarcinoma) (Bataller et al., 2007; Graus et al., 2008). “Seronegative” LE thus seems to be rarely paraneoplastic. Conversely, the clinical outcome could be worse than in LE with NSA-Abs since only one of the eight reported cases (12%) improved following immunologic therapies (Bataller et al., 2007; Graus et al., 2008).

OPSOCLONUS MYOCLONUS Opsoclonus myoclonus (OM) associates large amplitude synchronic and chaotic eye movements (opsoclonus) with spontaneous muscle jerks (myoclonus) and ataxia. The eye movements are present during fixation, smooth

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pursuit, and convergence, and persist during sleep or eyelid closure. The large amplitude and high frequency (10–15 Hz) of the eye movements may cause visual blurring and oscillopsia. Even though the pathophysiology of OM remains unclear, several studies provided clues to an involvement of the cerebellar vermis (van Toorn et al., 2005) and a disinhibition of the cerebellum fastigial nucleus underlying the oculomotor symptoms (Huang et al., 2005; Ramat et al., 2005). Paraneoplastic OM is rare (Ki Pang et al., 2010) and is usually observed in pediatric patients with neuroblastoma (Rothenberg et al., 2009) or adult females with Ri-Abs and breast cancer (Weissman et al., 1989; Luque et al., 1991). Other etiologies such as infection (Lyme disease, varicella-zoster infection, streptococcal infection and West Nile virus), celiac disease, or metabolic disorders must be considered and ruled out (Wong, 2007). Most of the ON-Abs have been described as being associated with OM in single case reports and several other epitopic targets have also been proposed such as Zic2 (Bataller et al., 2003), neurofilaments (Noetzel et al., 1987), neuroleukin (Candler et al., 2006) or cell surface antigens (Blaes et al., 2005). However, the antibodies reacting against these different targets are not necessarily observed in paraneoplastic cases and none of them seems to be specific of this neurologic syndrome (Pranzatelli et al., 2002). Only a few adult patients presenting with seronegative paraneoplastic OM have been reported (Bataller et al., 2003). In theses cases, a SCLC was almost always diagnosed. Long-term outcome for children with paraneoplastic OM seems to be dominated by cognitive and behavioral problems rather than ataxia (Klein et al., 2007). In adults, relapses of opsoclonus may occur and residual gait ataxia tends to persist. Most patients who underwent treatment of the underlying tumors had complete or partial neurologic recovery (Bataller et al., 2001). Immunotherapy (such as corticosteroids or immunoglobulins) may also help recovery. A recent study provided clues to the efficiency of a combined treatment associating immunoglobulins, ACTH, and rituximab (Pranzatelli et al., 2010). The clinical improvement correlates with B cell reduction in the CSF (Pranzatelli et al., 2005, 2006, 2010).

Paraneoplastic disorders of the peripheral nervous system SUBACUTE SENSORY NEURONOPATHY Subacute sensory neuronopathy (SSN) is characterized by primary damage of the sensory nerve cell body of the dorsal root ganglia by cytotoxic T lymphocytes (Kuntzer et al., 2004). A paraneoplastic origin is only

one of the causes of SSN (Molinuevo et al., 1998). The clinical presentation may vary between patients, but a recent study has put forward a fairly specific clinical and electrophysiologic pattern specific to SSN (Camdessanche´ et al., 2009). In this the clinical pattern would be an acute or subacute onset of painful paresthesias of all limbs with absent deep-tendon reflexes and impairment of all sensory modalities, in particular joint position sense. This clinical presentation differs from those observed in other neuropathies. Thus a large majority of patients present with sensory abnormalities which involve the distal part of the four limbs with a nonlength-dependent distribution, and paresthesia are very frequent. Ataxia is observed in more than two-thirds of the cases and may involve the upper as much as the lower limbs. A neuropathic pain is reported in about half of cases. Asymmetric distribution was present in 42% of patients. Increased proteins in CSF and an oligoclonal CSF pattern are significantly more frequent as compared to nonparaneoplastic SSN (Camdessanche´ et al., 2009). The electrophysiologic hallmark of SSN is a severe and diffuse alteration of sensory nerve action potentials. Motor conduction velocities are normal or mildly altered (Camdessanche´ et al., 2002). CSF can show elevated concentrations of protein, pleocytosis, or oligoclonal bands. The tumor most often associated with paraneoplastic SSN is SCLC (Dalmau et al., 1992). More than 86% of the patients with Hu-Abs present with a SSN (Honnorat et al., 2009). This neuropathy is the most common symptom of the anti-Hu syndrome, but it is isolated in only 24% of the patients, the others having various combinations of central and PNS involvement (Graus et al., 2001). Other patients mostly present CV2/CRMP5-Abs (Antoine et al., 1999b) or amphiphysin-Abs. Yo-Abs and Ma2-Abs have been reported in only few cases (Tracy et al., 2006; Waragai et al., 2006). However, the peripheral neuropathies occurring in 57% of the patients with CV2/CRMP5-Abs are a little bit different than those observed in patients with Hu-Abs (Antoine et al., 2001). In patients with CV2/CRMP5-Abs the neuropathies are sensory or sensorimotor and predominate in the lower limbs. Furthermore, electroneuromyography shows an axonal or mixed axonal and demyelinating pattern (Antoine et al., 2001). Neuropathies associated with CV2/CRMP5-Abs are typically associated with cerebellar ataxia, limbic encephalitis, or ocular involvement.

NONCLASSIC PARANEOPLASTIC NEUROPATHIES Motor nerves or motor neurons can also be affected in patients with PNS resulting in a motor or sensorimotor polyneuropathy (Antoine and Camdessanche´, 2007).

PARANEOPLASTIC DISORDERS OF THE CENTRAL AND PERIPHERAL NERVOUS SYSTEMS A predominant or pure motor neuron syndrome is much less common (Verma et al., 1996). Lower motor neuron disease is reported in several cases of late-onset second PNS in patients with Hu-Abs and prolonged survival without tumor relapse (Ducray et al., 2010). A recent publication provides clues for an interaction between the so-called “survival motor neuron” gene and the HuD protein (Hubers et al., 2011). Hu-Abs may thus play a specific role in the pathophysiology of this disease. Nerve vasculitis and demyelinating neuropathies are reported but are a very unusual presentation (Younger et al., 1994; Antoine, 1998). Neuropathies that occurred shortly after the discovery of cancer tended to be inflammatory, including those with Guillain–Barre´ syndrome, chronic inflammatory demyelinating polyneuropathy, and neuropathies with vasculitis (Antoine, 1999b). The improvement of the neuropathy after treatment of the tumor is a major criterion for the diagnosis of paraneoplastic disorders. Ganglionic cholinergic receptor antibodies have been reported in patients with autonomic neuropathies and malignancies but these antibodies are not specific to cancer (Vernino and Lennon, 2000). Conversely, antiganglioside antibodies have been specifically associated with both cancer and neuropathy in few patients with melanoma (Weiss et al., 1998; Kloos et al., 2003).

LAMBERT–EATON MYASTHENIC SYNDROME Lambert–Eaton myasthenic syndrome (LEMS) is an autoimmune disorder of the neuromuscular junction characterized by muscle weakness and autonomic dysfunction (O’Neill et al., 1988; Newsom-Davis, 2004). First described in 1953 (Anderson et al., 1953), its electromyographic features were subsequently described, allowing differenciation of LEMS from myasthenia gravis (Lambert et al., 1956). Difficulty in walking because of proximal leg weakness is nearly always the first symptom (O’Neill et al., 1988). Proximal arm weakness is common, but ocular symptoms are less common than in myasthenia gravis. In rare cases, respiratory muscles can be affected (Nicolle et al., 1996). The cardinal features on examination are the augmentation of strength that occurs during the first few seconds of a maximum effort and the depressed deep-tendon reflexes that may show post-tetanic potentiation. Autonomic symptoms, even moderate (dry mouth, constipation, or erectile failure), are present in almost all cases (Khurana et al., 1988; O’Neill et al., 1988). In rare patients with paraneoplastic LEMS, a cerebellar ataxia can be observed (Fukuda et al., 2003; Romics et al., 2011). Conversely, some patients with paraneoplastic cerebellar degeneration can have VGCC-Abs but without clinical signs or symptoms of LEMS (Graus et al., 2002).

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On electroneuromyographic examination, the compound muscle action potential has a small amplitude which increases from 100% to 1000% after maximum voluntary contraction. This facilitation phenomenon is also observed after repetitive nerve electrical stimulations at high frequencies (between 20 and 50 Hz). Nonetheless a decrease in the amplitude of the compound muscle action potentials occurs with repetitive nerve stimulations at low frequencies (between 1 and 5 Hz), as seen in myasthenia gravis. Almost all patients have a decremential response to low-frequency nerve stimulation in at least one hand muscle; in these patients a reproducible postexercise increase in compound muscle action potentials is considered to be specific to LEMS and is more easily demonstrated in distal muscles (Sanders, 2003). Almost 60% of the patients with LEMS are paraneoplastic and SCLC is the main associated cancer, which will be detected mostly within the 2 years following the diagnosis of LEMS (O’Neill et al., 1988; NewsomDavis, 2004). A prospective study in a cohort of patients presenting with SCLC showed the prevalence of LEMS to be 3% (Elrington et al., 1991). VGCC-Abs (voltagegated calcium channel antibodies) are present in nearly all patients with LEMS, and these Abs do not differentiate between paraneoplastic and nonparaneoplastic forms. Sox1-Abs have been identified as a specific marker of paraneoplastic forms of LEMS (Graus and Saiz, 2005). In fact Sox1-Abs are present in 64% of the patients presenting LEMS and SCLC (Sabater et al., 2008b); on the other hand only one patient has been described to date with Sox1-Abs and an idiopathic LEMS (Titulaer and Verschuuren, 2008). Although more investigations are needed, Sox1-Abs seem to show a strong association with paraneoplastic LEMS (Tschernatsch et al., 2009). Two randomized controlled trials have demonstrated a beneficial role for 3,4-diaminopyridine (McEvoy et al., 1989; Sanders et al., 2000). Symptomatic improvement can sometimes be obtained with a mild dose of pyridostigmine, but it is less effective than in myasthenia gravis. Guanidine can be used, either alone or with pyridostigmine, but its adverse effects include bone marrow suppression and renal failure. In LEMS patients with severe or life-threatening weakness, intravenous immunoglobulin therapy will often be followed by several weeks of improvement (Lang et al., 1981; Newsom-Davis and Murray, 1984; Bain et al., 1996).

AUTONOMIC NEUROPATHY Pandysautonomia, autoimmune autonomic neuropathy, idiopathic autonomic neuropathy, or subacute autonomic neuropathy were also used for this clinical pattern, which rarely occurs solely. Autonomic neuropathy may overlap

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with other paraneoplastic neuropathies. However, pure dysautonomia was reported associated with acetylcholine receptor-Abs (Vernino et al., 1998). Hu-Abs, CV2/ CRMP5-Abs and ganglionic acetylcholine receptor-Abs are commonly present in autonomic neuropathy with a respective frequency of 25%, 31%, and 21% of cases (Koike et al., 2011). The diagnosis of autonomic neuropathy is of importance since PNS with automonic neuropathy has been shown to be associated with a worse prognosis than the others (Giometto et al., 2010).

AUTONOMIC NEUROPATHY WITH

PSEUDO-OBSTRUCTION

Autonomic neuropathy with pseudo-obstruction may start as an isolated and severe constipation. The clinical symptoms then evolve to dysphagia and vomiting. Patients with autonomic neuropathy and pseudoobstruction present with weight loss, persistent constipation, and abdominal distension due to neuronal damage of the enteric plexuses (De Giorgio et al., 2004; Lorusso et al., 2007). Some patients may present with dysphagia, nausea, and vomiting due to esophageal dysmotility or gastroparesis. Radiologic studies show bowel, colonic, or gastric dilatation; esophageal manometry may disclose spasms or achalasia. The most common Abassociated tumor (mainly Hu-Abs) is SCLC.

DERMATOMYOSITIS Dermatomyositis is defined by the association of a proximal motor weakness, Gottron’s papules (myxedematous lichen planus) over the knuckles, photosensitive erythematous patches spreading from the face to the upper limb, and a periorbital violaceous inflammation. The latter is almost pathognomonic (Cherin, 2004). In addition, a periungual erythema with a classic pressure-induced pain is highly suggestive of this diagnosis. The cutaneous signs may precede the myositis by several months. Patients may also present with asthenia, fever, and weight loss. A cardiac involvement with conduction disorders is not uncommon (15–20%). Respiratory disorders occur in 45% of cases and represent the second cause of death after cancer in dermatomyositis specially when resulting from a pharyngeal involvement. In 1916, a published case of a dermatomyositis associated with a gastric cancer was the first to suggest the association between dermatomyositis and malignancy. According to the results of several subsequent studies, 25–30% of patients presenting with a dermatomyositis had an associated tumor (Sigurgeirsson et al., 1992). The resulting standardized incidence ratios of associated malignancies vary within four to six in those patients compared to the general population (Chow et al., 1995; Buchbinder et al., 2001). The excess of cancer incidence

is maximal at the onset and within the first 3 years of dermatomyositis then it decreases with time. Conversely, more than a half of the cancers are diagnosed before the onset of the dematomyositis (Buchbinder et al., 2001). The more frequently associated tumors are ovaries, lung, colorectal, and breast cancers (Buchbinder et al., 2001). The proportion of gastric cancer was particularly elevated (41%) among paraneoplastic dermatomyositis patients in a Japanese cohort (Azuma et al., 2011). P155-Abs was shown to be specifically associated with myositis and cancer in adult patients (Targoff et al., 2006). Some recent studies proposed that these Abs may be involved in the transforming growth factor-b signaling pathway, which is inactivated in some malignancies (Vincent et al., 2009). A comprehensive cancer screening must be repeatedly performed in patients with p155-Abs. However, positron emission tomography (PET) scanning may be done only at the onset of dermatomyositis if these Abs are absent (Selva-O’Callaghan et al., 2010).

CLINICAL MANAGEMENT AND PRINCIPLES OF TREATMENT Identification of the tumor Detection of the associated cancer remains the main step in the treatment of patients suffering from PNS. In fact, PNS mostly precedes the diagnosis of the cancer, which is often of limited spread (Chartrand-Lefebvre et al., 1998) and could consequently be cured at a local stage. The type of carcinologic screening depends on the isolated Ab. There is an increasing number of Ab which are rarely associated with tumors. In cases such as GAD-Abs or NMDAr-Abs in children, a comprehensive carcinologic screening seems unnecessary. Conversely Hu-Abs and CV2/CRMP5-Abs are strongly associated with SCLC and screening for small mediastinal lymph nodes must be considered (Honnorat et al., 2009). YoAbs and SCD are highly suggestive of a gynecologic cancer and if mammography or pelvic examination is negative a surgical exploration of the pelvis must be discussed (Peterson et al., 1992; Rojas et al., 2000). Ma2-Abs in a male patient with risk of testicular cancer must lead to an orchidectomy if echography is not conclusive (Mathew et al., 2007). Women with NMDAr-Abs must have endovaginal ultrasound and pelvic MRI to rule out ovarian teratoma (Dalmau et al., 2008). Whole-body positron emission tomography with fluorodeoxyglucose (FDG-PET) is required in patients with paraneoplastic Ab when conventional imaging fails to identify a tumor or when lesions are difficult to reach for biopsy (Younes-Mhenni et al., 2004; Basu and Alavi, 2008).

PARANEOPLASTIC DISORDERS OF THE CENTRAL AND PERIPHERAL NERVOUS SYSTEMS

Treatment In case of ON-Abs, the best chance to stabilize or improve the syndrome remains induction of a complete response of the tumor (Keime-Guibert et al., 2000). The specific treament for PNS is based on immunologic therapies but no randomized double-blind studies are available because of the low incidence of PNS. However, the European Federation of Neurological Societies (EFNS) Task Force published some recommendations for treatment (Vedeler et al., 2006). These suggest that the response to the treatment mainly depends on the subtype of Ab associated with the PNS. PNS with NSA-Abss may thus improve significantly under immunomodulatory treatment whereas the latter is inefficient for PNS associated with ON-Abs. A delayed response to the treatment may be observed in the particular case of LE with NMDArAbs in which repeated injections of immunoglobulins may be required before observing an improvement. Another publication of the EFNS Task Force reviews the indications for intravenous immunoglobulins in neurology (Elovaara et al., 2008). This treatment shows efficacy for paraneoplastic LEMS and opsoclonus myoclonus especially in pediatric neuroblastoma patients. In contrast, intracellular Ab-associated PNS are inconstantly responsive to immunosuppressor treatment such as cyclophosphamide. Patients with Tr-Abs and Ma2-Abs and testicular cancer are more likely to improve than those with other intracellular Ab (Bernal et al., 2003; Dalmau et al., 2004). According to these considerations, PNS management must be organized depending on the associated Ab. In some cases, LE may be associated with several subtypes of Ab (Bataller et al., 2007). Their prognosis and response to treatment seem to depend on the presence or absence of ON-Abs, which probably lead to a poorer outcome, when present. Due to the low number of cases, the management of subacute cerebellar degeneration has not been codified. As a general rule a prompt treatment of the cancer is essential for neurologic stabilization in PNS. A study conducted on 50 patients demonstrated a neurologic improvement in only seven cases. All patients received antitumor treatment and were in complete remission (Shams’ili et al., 2003). The sensitivity to treatment is variable depending on the type of associated onconeuronal antibodies. In patients with Yo-Abs or Hu-Abs, improvement is rather rare, while a better outcome can be expected in Tr-Abs patients (Bernal et al., 2003). Regarding the specific management of PCD, immunomodulatory treatment or immunosuppressants may be proposed. Some clues based on case reports suggest a possible neurologic improvement with corticosteroids, cyclophosphamide (Thone et al., 2008), intravenous immunoglobulins (Phuphanich and

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Brock, 2007), or rituximab (Esposito et al., 2008). In cerebellar ataxia with anti-GAD, the effectiveness of immunoglobulins and steroids is often claimed but appears to be inconsistent. In some cases, periodic alternating nystagmus, reversible under GABAergic medication, has been reported (Tilikete et al., 2005). Finally, the management should be supplemented with the appropriate rehabilitation and psychological counseling.

ABBREVIATIONS Abs AMPA CASPR 2 CNS CSF CT FDG PET GABAA GABAB GAD IgGs IVIg LE LEMS Lgi1-Abs mGuR1 NMDAr NSA OM ON PCR PEM PNS SCD SCLC SSN VGCC VGKC

antibodies a-amino-3-hydroxy-5-methyl-4isoxazolepropionic acid contactin-associated protein 2 central nervous system cerebrospinal fluid computed tomography fluorodeoxyglucose positron emission tomography g-aminobutyric acid A receptor g-aminobutyric acid B receptor glutamic acid decarboxylase immunoglobulin Gs intravenous immunoglobulin limbic encephalitis Lambert–Eaton myasthenic syndrome leucine-rich glioma inactivated 1 protein metabotropic glutamate receptor 1 N-methyl-D-aspartate glutamate receptor neuronal cell surface antigen opsoclonus myoclonus onconeuronal polymerase chain reaction paraneoplastic encephalomyelitis paraneoplastic neurologic syndrome subacute cerebellar degeneration small-cell lung cancer subacute sensory neuronopathy voltage-gated calcium channel voltage-gated potassium (Kþ) channel.

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Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 79

Radiation therapy in neurologic disease EDWARD MELIAN* Department of Radiation Oncology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA

INTRODUCTION Therapeutic radiation has a major role in the treatment of neurologic diseases. It is also capable of causing neurologic injury by its effects on normal tissues. The modern neurologist needs to be aware of the role of radiation in neurologic disease and the potential for deleterious effects as well. In this chapter we describe the current process of modern radiotherapy, review some basics of radiobiology, describe its indications for neurologic disease, and review the pertinent sideeffects of treatment. Radiation therapy has undergone a dramatic evolution in the past few decades. The advent of advanced imaging combined with real time three-dimensional treatment planning on high tech computer systems has allowed for increases in target doses and decreases in acute and late complications. Multimodality treatments of surgery and radiation (with or without chemotherapy) have replaced more radical surgeries in many tumor sites, while in other disease sites, combinations of chemotherapy and radiation have shown improved outcomes over surgery or radiation alone while allowing for organ preservation. Radiation has also shown efficacy in the treatment of some non-neoplastic disease entities such as trigeminal neuralgia.

PROCESS OF IRRADIATION In the mid 1980s fluoroscopic set-up of the irradiated volume with field shaping based on two-dimensional oblique films images, and a single point dose calculation along the correct axis of the tumor was standard of care. Current standard definitive radiotherapy treatments begin with strict immobilization of the patient. In the head thermoplastic molds conformed to the anterior and posterior contours of the face and skull are used for most fractionated treatments. These provide 2–3 mm

reproducibility. For single dose radiosurgery treatments invasive stereotactic headframes are placed under local anesthesia. These frames give a reproducibility of < 1 mm. Invasive stereotactic frames are used in the treatment of small intracranial lesions. For the treatment of body lesions polyurethane foaming agents are typically used. These are used to create molds which are shaped to the individual patient. The entire mold is then “indexed” (reproducibly attached) to a specific location on the treatment table to eliminate possible rotational errors. Beanbag-like vacuum-formed molds are also used for similar purposes. Recently, mechanisms to limit respiratory motion, such as mechanical compression or vacuum compression, have been shown improve patient immobilization even further (Han et al., 2010). These devices are used when the target moves with respirations such as lesions in the lung, liver, or upper abdomen. Once the patient is immobilized the next step in the process is the acquisition of three-dimensional imaging. For most treatment sites this is done in a dedicated computed tomography (CT) scanner. The CT scan is taken across the entire body circumference in the region of the target. This allows for beams to be brought in from all directions and dose to be calculated. In some pelvic sites such as prostate brachytherapy ultrasound is the three-dimensional imaging method of choice. Magnetic resonance imaging (MRI) is used as the base planning scan in some stereotactic brain radiosurgery planning systems. Thin cuts are obtained as these allow for greater precision in dose calculation and better resolution with image reconstruction. The three-dimensional data from the simulation CT scan is transferred to a treatment planning computer. On the treatment planning computer the target lesion and critical normal tissues are delineated. Margins are added to gross tumor to account for microscopic spread

*Correspondence to: Edward Melian, M.D., Department of Radiation Oncology, Loyola University Chicago, Stritch School of Medicine, 2160 S. First Ave., Maywood, IL 60153, USA. E-mail: [email protected]

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Fig. 79.1. Initial gross tumor volume (GTV) (red), clinical target volume (CTV) (yellow), planning target volume (PTV) (purple) and boost GTV (orange), CTV (green), and PTV (blue) for a glioblastoma.

of disease and then additional margin for daily set-up error. The terms gross tumor volumes (GTV), clinical target volume (CTV), and planning target volume (PTV) are used to describe these volumes (Fig. 79.1). A fourth term, internal target volume (ITV), is used to describe the volume needed to be covered to account for clinical target deviations created by internal motion, typically secondary to respiration (Underberg et al., 2005). Once the target and critical normal tissue are delineated the treatment process begins. Fixed beams and/ or arcing beams are created. Each beam is individually shaped to match the target contours either manually or by automated means. The decision of which type, energy, and angle of each beam is made dependent upon clinical situation and availability. The computer then calculates a threedimensional dose display of the resulting plan. An interactive process then occurs of adjusting the beam’s variables to achieve the goal of covering the target and limiting the dose to normal tissues ensues until an

acceptable plan is achieved. The major advancement to improving therapy was the ability to calculate and display the dose throughout the volume. By using the Hounsfield units (the electron density of the tissue) of the treatment CT scan accurate dose can be calculated and sophisticated computer graphics power allows it to be displayed. The realization of deficits in target coverage with the three-dimensional dose calculations has led in turn to another advancement known as intensity-modulated radiotherapy (IMRT). This combines breaking each beam into multiple small beams called beamlets and then allowing the computer to create the best fit of the target dose to the target volume by controlling the dose delivered in each beamlet. Similarly the beamlet dose can be adjusted to spare critical normal tissues. It can be delivered by stationary or arcing beams (Low et al., 2011). As treatment planning and delivery is becoming faster with computer-driven delivery, as well as planning, IMRT is being used more frequently (Jin et al., 2011). Data on improvement in quality of life and decrease

RADIATION THERAPY IN NEUROLOGIC DISEASE in acute and late side-effects is beginning to be seen (McCormick and Hunt, 2011; Tribius and Bergelt, 2011). In contrast to the more commonly employed fractionated radiotherapy, the process of radiosurgery involves placing one (or at most a few) fractions of radiation precisely into a small volume with a sharp dose gradient at the edge of the target. Today’s radiation oncologists use both radiosurgery and radiotherapy. At the time of radiation delivery, real time image guidance through the use of kilovoltage X-rays, on board cone beam CT scanners, implanted electromagnetic transponders for ultrasound, and combinations of the above have added another layer of accuracy to patient treatment (Kim et al., 2011). Each of these technologies requires some form of rapid, typically automated matching to the simulation imaging used for the treatment planning. This has only become possible with the development of robust and efficient software tools (Xing et al., 2007; Ruan et al., 2011).

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Fig. 79.2. Stereotactic radiotherapy on a linear accelerator.

The process of radiotherapy attempts to take advantage of both of these factors.

PHYSICS BIOLOGY Radiation primarily interacts with the tissue it passes through by ionizing the local molecules. The radiation may directly ionize a molecule or may indirectly ionize a molecule by creating free radicals in adjacent molecules (usually water) which then cause the biologic damage to the target molecule. The biologic effects of radiation are caused by these direct and indirect ionizations leading to breaks in cellular DNA. Solitary single strand DNA breaks are typically repaired. Double strand DNA breaks are less likely to be repaired and are the event that leads to cell death (Thompson and Schild, 2001, 2002). Oxygen has been shown to increase the efficacy of ionizing radiation by “fixation” of the DNA strand break. While this mechanism is not certain, the clinical benefit appears to be true (Barilla and Lokajı´cek, 2000; Overgaard, 2011). Single large doses of radiation are more potent than the same dose delivered in multiple fractions. Single large doses are also more toxic to normal tissues. Although less effective dose per dose, treating with multiple fraction of radiation allows cells to move into a more radiosensitive portion of the cell cycle. Late G2 and mitotic phases are the most radiosensitive parts of the cycle, less so the late G1/early S phase, and least radiosensitive is the late S/early G2 phase (Pawlik and Keyomarsi, 2004). A therapeutic advantage can be gained by the use of fractionation when the normal tissue repairs the irradiation injury better than the target tissue. A therapeutic advantage can also be gained when a greater dose can be placed into the target tissues while limiting the dose to the adjacent normal tissues.

The majority of current day radiotherapy is delivered in the form of photons, high energy electromagnetic waves created by linear accelerators. Fig. 79.2. These devices accelerate electrons to high speeds in powerful electric fields created using microwaves technology. The electrons then collide with a heavy metal target. This collision creates the high energy photons used for treatment. The photon beam is then shaped to match the geometry of the target by passing through adjustable heavy metal collimators. The heavy metal target can be removed to allow for direct treatment with the electron particle. Electron beam radiation has a limited depth of penetration proportioned to the energy of the accelerator. Electrons are therefore typically used to treat more superficial lesions. Recently, the refinement of high-powered large accelerators featuring cyclotrons capable of accelerating heavier particles has led to increased use of proton beam therapy (Kagan and Schulz, 2010). While photon beams create a path of energy deposition through the body, proton particles deposit most of their energy at a depth proportional to their level of acceleration. This limits the volume receiving high radiation dose by decreasing the entrance dose and nearly eliminating the exit dose. Carbon ions beams have similar advantages and a sharper fall off of dose at the beam edge, but require very high energy acceleration (Suit et al., 2010). Cost and technology have limited the use of carbon ions to a few centers worldwide. If clinical improvements can be documented the future of radiotherapy may see greater incorporation of these heavier particles in patient care. Proton radiobiology is similar to photon therapy, but does have unique differences (Gerweck and Paganetti, 2008).

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THE USE OF RADIOTHERAPY IN THE TREATMENT OF NEUROLOGIC DISEASE Tumors The use of radiotherapy as the primary or adjuvant treatment of brain tumors dates to Harvey Cushing and before (Kunschner, 2002). In this section we describe the use of radiation against the most common tumors afflicting the central nervous system with the exception of metastases which is addressed in a separate chapter.

Malignant tumors GLIOBLASTOMA AND ANAPLASTIC ASTROCYTOMA Glioblastoma is the most common malignant brain tumor accounting for over 50% of glial tumors in most series. Anaplastic astrocytomas usually account for another 5%. Radiation, although used for a half century before, was not definitively shown to improve survival until the late 1970s. Randomized trials by the Brain Tumor Study Group (Walker et al., 1978) and the Scandinavian Glioblastoma Study Group (Kristiansen et al., 1981) proved the value of external beam radiotherapy. These studies showed that doses of 60 Gy would double the median survival of these patients from 4–5 months to 8–11 months. Improvement in the time spent with good performance status was also shown. Attempts at increasing the dose further both in the 1980s with the external beam standards of the time and then in the 1990s and 2000s using more conformal therapy (Chan et al., 2002), brachytherapy (LaPerriere et al., 1998), or radiosurgery (Souhami et al., 2004) did not lead to further improvement. The use of chemotherapy with the radiation was controversial until 2005 when an international randomized trial clearly showed a 3 month improvement in median survival from 12 to 15 months with the use of temozolomide during and after radiotherapy (Stupp et al., 2005). These data have held up and at 3 and 5 years survival was 16% and 10 % with temozolomide versus 4% and 2% with radiation alone (Stupp et al., 2009). Current trials are evaluating the role of bevacizumab, a vascular endothelial growth factor inhibitor, in addition to temozolomide and radiation at initial diagnosis (Vredenburgh et al., 2011). The volumes typically irradiated consist of the T2 abnormality on MRI and a 1–2 cm margin and a boost to the T1 region of enhancement with a 1–2.5 cm margin. These margins are built upon pattern of failure studies which show that the vast majority of the recurrences are with a few centimeters of the original tumor (Hochberg and Pruitt, 1980; Wallner et al., 1989). A recent series of patients treated with concurrent temozolomide proposes that margins could be made a little more narrow (McDonald et al., 2011) as even with 0.7 cm T2 initial volume margins and 0.5 cm T1 boost

volume margins the vast majority of patients still failed locally. At the same time others have found that in patients treated with conformal radiotherapy and temozolomide the distant (out of the high-dose volume) failure rate is close to 10% (Minniti et al., 2010; Dobelbower et al., 2011) which might argue in favor of considering larger volumes.

LOW-GRADE GLIOMAS The role, or perhaps more specifically the timing, of radiotherapy in low-grade gliomas is not as clear. A decrease in neurologic symptoms including seizures after wide local field radiotherapy is repeatedly reported. Radiotherapy after diagnosis has been shown to improve disease-free, although not overall survival (van den Bent et al., 2005). Doses of 45–50 Gy have been shown to be equally effective as higher doses (60–65 Gy) with less toxicity (Kiebert et al., 1998; Shaw et al., 2002). Prognostic features such as tumor size, age, presence of symptoms, extent of surgery, presence of 1p, 19q deletions, and the crossing of midline have been used to determine which patients should be treated initially and which might be able to be observed until clinical or radiographic progression. In clinical practice, most patients over 40 and those with clinical symptoms receive upfront treatment. Younger patients without symptoms may be observed until either MRI or clinical progression is noted. An abstract from RTOG study 9802 has shown an improvement in disease-free survival for PCV chemotherapy in high-risk patients (Shaw et al., 2008) when added to radiation. Volumes treated are similar to higher grade gliomas due to the infiltrative nature of the disease.

OLIGODENDROGLIOMAS These lesions are very radioresponsive and chemoresponsive. They are associated with the favorable 1p,19q gene deletion. Radiotherapy improves symptoms and disease-free survival similar to other gliomas. Two randomized trials evaluating the use of procarbazine, lomustine, and vincristine (PCV) before and after radiotherapy for anaplastic oligodendrogliomas and oligodendrogliomas showed no overall survival benefit compared to radiotherapy alone, but did show a benefit in disease-free survival (van den Bent et al., 2006). Updates to both of these trials in 2012 have now shown an overall survival benefit to the use of PCV which interestingly did not begin to declare itself until seven to eight years post treatment. (Cairncross et al., 2013. van den Bent et al., 2013). Temozolomide is now being substituted for the PCV (Vogelbaum et al., 2009) due to less toxicity and similar efficacy. Grade for grade patients with oligodendrogliomas respond to treatment better than other gliomas and have longer survivals regardless of modality of therapeutic intervention.

RADIATION THERAPY IN NEUROLOGIC DISEASE 1185 The Mayo Clinic reported a median survival rate of rates of recurrence (Balmaceda et al., 1996; Kellie et al., nearly 10 years for low-grade oligodendrogliomas. The 2004). Whether chemotherapy adds enough in upfront dose of radiation given mirrors that of low and high-grade treatment to give it in addition to whole brain or whole gliomas about 50 Gy to low-grade lesions and 60 Gy to ventricular radiation is an issue of controversy. In the high-grade lesions. The current issue being addressed is setting of nonseminomatous germ cell tumors the results the sequencing of treatment with an international trial with radiation alone are not as good, with disease-free comparing radiation alone to temozolomide alone to survival of 20–50%. Combined modality therapy with concurrent temozolomide and radiation (NCCTG, 2009). chemotherapy before, after, and/or during radiotherapy Practically in the single modality arms of the trial the is used for the nonseminomatous tumors. These include other modality will most likely be used at progression. the endodermal sinus tumors, the choriocarcinomas, the malignant teratomas, and the malignant immature teraEPENDYMOMAS tomas. For germinomas, the excellent response and local control rates with radiotherapy have defined the role of Ependymomas tend to act akin to low-grade infiltrative surgery to be to obtain a diagnosis. The nongeminomagliomas. As they are hypothesized to come from the tous tumors with their less satisfactory control rates same glial stem cell, this is not unexpected. While gross should be considered more strongly for attempts at total resection can provide control for many years, late resection when possible. recurrences can and do occur. Intracranial ependymomas are usually recommended to have postoperative PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMAS radiotherapy (Rogers et al., 2005; Armstrong et al., 2010) as resection is rarely complete due to the infiltraPrimary central nervous system lymphomas (PCNSL) are tive nature of the disease. Radiotherapy doses of predominately B cell lymphomas. They were treated with 45–54 Gy improve the recurrence-free interval in most whole brain radiotherapy until the last decade of the 20th series (Akyurek et al., 2006) and in retrospective comparcentury. Improvement in control and survival was seen isons have been shown to improve survival (Metellus in doses up to 50 Gy, but boosting beyond 50 Gy gave et al., 2010). Fifty gray has been shown to be better than no further benefit (Nelson et al., 1992), most likely due lower doses. Due to the long time to recurrence some to failures outside of the boosted region. Median surbelieve radiotherapy can be delayed if the patient is vival was about 12 months with radiotherapy alone. observed carefully by serial MRI scans. If CSF sampling Attempts to add chemotherapy to the radiation failed is negative and MRI shows no evidence of diffuse craprior to incorporating high-dose methotrexate into the niospinal axis involvement, radiation is now given locally treatment regimen (Schultz et al., 1996; Mead et al., to the tumor bed with margin even in the anaplastic sub2000). The addition of high-dose systemic methotrexate type (Wallner et al., 1986; Merchant et al., 2004). Spinal with intrathecal methotrexate to 45 Gy of radiotherapy cord ependymomas can be treated with surgery alone made a marked improvement in survival with median followed by observation as long as gross total resection survival going to 3 years (DeAngelis et al., 1992, is achieved. Subtotally resected spinal cord lesions 2002). Soon though, it became apparent that this was and myxopapillary subtypes should be considered for at the price of dementia among many of the survivors postoperative radiotherapy (Pica et al., 2009). (DeAngelis et al., 2002; O’Brien et al., 2006). Dropping out the radiation reduced median survival to 18–24 GERM CELL TUMORS months in some trials, and controversy remained as to These lesions are divided into the germinomas and the the best upfront treatment. A 551 patient randomized nongerminomatous germ cell tumors. They are the most trial from Germany looking at high-dose methotrexate common tumors of the pineal region. While the pineal with or without 45 Gy whole brain radiotherapy found region accounts for about 60% of the cases in most a decrease in progression-free survival when omitting series, about 30% are found in the suprasellar region. the whole brain radiation from 18 months to 12 months, Germinomas are the most common of the germ cell but no difference in overall survival (32 months with tumors. While craniospinal radiation alone yields crawhole brain radiotherapy and 37 months without radioniospinal control rates of 98%, more limited fields of therapy) the endpoint of the trial. Treatment-related neuwhole brain radiotherapy or total ventricular radiation rotoxicity was doubled in those receiving whole brain can give nearly equal control with substantially less acute radiotherapy 49% versus 26%. This trial is critiqued in toxicity and decreased risks of second malignancy. that only 318 patients, of the original 551 enrolled, which Relapse-free survival of about 90–95% is seen and a were treated per protocol were analyzed, and the nonin5 year survival of greater than 95% (Rogers et al., feriority endpoint of the trial was not reached. Neverthe2005). Chemotherapy alone or with less than whole venless, it adds to the data favoring an initial approach with tricular irradiation has been found to yield unacceptable chemotherapy alone (Thiel et al., 2010). The current

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RTOG study incorporates a lower dose of 24 Gy whole brain radiotherapy in addition to a multidrug regimen. For older patients and others who may not tolerate chemotherapy as well, radiation alone in a more modern series has yielded a better survival rate (18 months median) than historically reported, and when selected for younger patients with better performance status which would have been eligible for chemotherapy trials, overall survival improved to 26 months and 5 year survival to 24% (Shibamoto et al., 2005). In the salvage setting after primary chemotherapy has failed radiation has been shown to obtain a response rate near 80% with half of those being complete responders. Median survival after radiotherapy salvage was 11 months in one series and 16 months in another (Nguyen et al., 2005; Hottinger et al., 2007). Reported neurotoxicity in these series was 15% and 22%.

SPINAL CORD COMPRESSION Malignant spinal cord compression is an oncologic emergency for which treatment should be initiated within 24 hours. Radiation therapy is indicated for the treatment of acute spinal cord compression syndrome due to tumor in patients who are not surgical candidates or have radiosensitive tumors. It is also indicated after surgery as an adjuvant treatment when surgery is incorporated. A randomized trial (Patchell et al., 2005) shows better survival and neurologic function when surgery is added to radiation as long as an aggressive removal of compressing tumor is possible (as opposed to simple laminectomy). As many patients have advanced systemic disease and poor overall survival, surgery is often not able to be employed. Doses of 30 Gy in 10 fractions are most commonly used, but more prolonged courses of up to 50 Gy in 25 fractions are used for better prognosis patients, and a shorter single dose course of 8 Gy in a single fraction are advocated by some for poorer prognosis patients

(Abraham et al., 2008). A study of 98 patients showed motor function improvements in 86% of the patients after a slow (>14 days) development of motor deficits before radiotherapy, in 29% after a relatively fast (8–14 days) development of motor deficits, and in 10% after a very fast (1–7 days) development of motor deficits (p < 0.001). The corresponding post-treatment ambulatory rates were 86%, 55%, and 35%, respectively (p ¼ 0.026) (Rades et al., 2002, 2006). Thus a more rapid onset of symptoms should lead one to consider surgery more strongly in borderline cases. When surgery is used radiotherapy should start as soon as the wound is healed, typically at about 2 weeks. Single dose and few fraction stereotactic radiosurgery is now being used to treat spinal cord compression as well. These techniques allow a greater dose to be given to the tumor while maintaining a relatively lower dose to the spinal cord (Fig. 79.3). An epidural tumor response rate of 80%, with a 27% complete response, has been reported in a 62 patient study with a progression rate of only 6% (Ryu et al., 2010). While at this time radiosurgical techniques are usually reserved for previously treated patients or radioresistant histologies, if the increased dose can be shown to give greater local control it may come into more widespread use.

Benign tumors PITUITARY ADENOMAS Radiotherapy has long been a mainstay of treatment of these lesions. In recent years improvements in medical management and surgical technique have decreased the need for radiation for some patients. Microadenomas should be resected and if there is no residual and hormones normalize no further treatment is necessary. Macroadenomas that are prolactin or growth hormone secreting may be treated with upfront medical treatment; should they be controlled they are maintained

Fig. 79.3. Standard two-dimensional and intensity modulated treatment plans for a paravertebral/vertebral body metastasis (yellow). Light blue represents 20 Gy isodose. The intensity modulated radiotherapy (IMRT) plan gives twice the dose to the lesion while giving equivalent spinal cord and bowel doses as the two-dimensional plan.

RADIATION THERAPY IN NEUROLOGIC DISEASE on medical treatment. The most effective duration of treatment is not clear. Radiotherapy and radiosurgery are used in the setting of gross residual disease which cannot be medically controlled or for patients with secreting tumors which cannot be medically controlled. Side-effects in general are limited to hypopituitarism. Radiosurgery may normalize secreting lesions faster than radiotherapy, but at a few years control rates are similar. The trend now is to use the same stereotactic techniques developed for radiosurgery, but delivered in a fractionated method to increase safety to normal tissues (Fig. 79.4).

MENINGIOMAS Meningiomas are the most common primary intracranial tumor. Until recently they were not followed in most tumor registries, but recent compilations such as the Central Brain Tumor Registry in the United States (CBTRUS), have quantified an incidence of 3.9 per 100 000 person-years. This is higher than Danish data showing an incidence of 2.4 per 100 000 person-years. The Danish data show an increasing incidence over the last few decades, perhaps due to more frequent use of CT and MR imaging. While the primary treatment modality for these lesions is surgery there is a significant

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role for radiotherapy. Subtotal resection plus fractionated radiotherapy yields long-term progression-free survival rates equal to or better than gross total resection alone and significantly better than subtotal resection alone (Condra et al., 1997). Even gross total resection has recurrence rates of 7–12% at 5 years, increasing to 20–25% at 10 years. With the advent of improved imaging such as MRI and thin cut CT scans it is now possible to observe some of these lesions after subtotal resection or after serendipitous diagnosis until documented progression prior to intervention. Doses given are in the range of 50–60 Gy using fractionated radiotherapy with doses less than 50 Gy having been found to be inferior. As meningiomas are slow growing, long-term follow-up is important to judge results. A study of 101 patients with 10 and 15 year follow-up found local control rates of 92% and 87% at 10 and 15 years (Mendenhall et al., 2003). Stereotactic fractionated radiotherapy has been shown to yield even better local control rates with 94% progression-free survival at 5 and 10 years in a series of 180 patients first reported in 2001 (Debus et al., 2001) and updated in 2005; with median follow-up of 6 years and 317 patients local control remained 93% (Milker-Zabel et al., 2005). A smaller series of 53 patients showed a 93% progression-free survival with fractionated stereotactic

Fig. 79.4. Treatment beams and isodoses for fractionated stereotactic treatment of a pituitary adenoma. Note shaping at brainstem and optic chiasm.

1188 E. MELIAN radiotherapy (Minniti et al., 2011). These series currently control rates but unacceptable rates of fifth, seventh, have the deficit of shorter follow-up. Complications in and eighth nerve injury. The current day standard is these series are currently 2–7%, with the exception of pitu12–14 Gy to the periphery and yields 90% local control itary insufficiency which went as high as 19%. As meninrates with < 5% rate of fifth and seventh nerve injury giomas often have irregular geometry, especially along and a hearing preservation rate of over 50% at 3–5 years, the skull base, IMRT can be used to improve the conformbut declining to less than 50% by 10 years (Chopra et al., ality of the high-dose region (Milker-Zabel et al., 2007). 2007). Fractionated radiotherapy at doses of 50–54 Gy at The information on the treatment of meningiomas comes 1.8 Gy a day yields similar results with perhaps a greater from retrospective studies and no large prospective series chance of hearing preservation. No randomized trials have been reported although one is underway. between fractionated and single dose radiosurgery exist. Single dose radiosurgery shows similar excellent conTwo single institution retrospective comparisons showed trol rates for small ( 400–500 mg/m2 of cisplatin in 3–6 months (Walsh et al., 1982; Thompson et al., 1984), the neuropathy is predominantly sensory with initial complaints of paresthesias in the distal parts of the extremities. Although all sensory modalities are involved, a loss of large-fiber sensory function is prominent, which often results in sensory ataxia. Lhermitte’s phenomenon is common and is probably an expression of spinal cord involvement. Neuropathic symptoms can

Channelopathy, axonopathy Axonopathy Axonopathy Microtubule disruption Microtubule disruption Axonopathy/neuronopathy? Secondary demyelination Axonopathy Microtubule disruption Axonopathy Axonopathy Axonopathy Ganglionopathy?

Demyelination Axonopathy Axonopathy, secondary segmental demyelination

progress up to 2 months after cessation of therapy (“coasting”). Then, gradual improvement occurs but the symptoms can last for several years. However, because the underlying pathology is a ganglionopathy, recovery may be incomplete, especially in more severe cases. Motor involvement is rare, while autonomic neuropathy is infrequent and can cause dizziness, palpitations, or impotence (Hansen, 1990). Electrophysiologic features for platinum compounds are mostly axonal changes with a predominance of sensory fibers. Nerve biopsies have shown a loss of large myelinated fibers (Roelofs et al., 1984).

CARBOPLATIN Carboplatin is less neurotoxic (McKeage, 1995) but in higher cumulative doses produces a sensory neuropathy. When combined with paclitaxel, 20% of patients develop moderate to severe sensory neuropathies.

OXALIPLATIN Cumulative toxicity resembles cisplatin-induced neuropathies. The long-term use of oxaliplatin is associated with mild, sensory, and motor axon loss (Burakgazi

NEUROLOGIC COMPLICATIONS OF CHEMOTHERAPY Table 80.2 Clinical syndromes of central nervous system toxicity from antineoplastic dugs Acute (reversible) encephalopathy

Methotrexate (MTX) Ifosfamide Paclitaxel 5-Fluorouracil (5-FU) Cytarabine (Ara-C) Procarbazine Nitosoureas (high dose) Interferon-a Interleukin-2 Tamoxifen (high dose) Etoposide (VP-16) (high dose) High dose steroids with stem cell transplantation Subacute encephalopathy MTX Cis-platinum Chronic encephalopathy MTX intravenously/ intrathecally Infrequently others High dose polychemotherapies Reversible posterior (leuko) Ciclosporin, other encephalopathy immunosuppressants, syndrome (PRES) combination therapy including cyclophosphamide, Ara-C, cis-platinum, cyclophophamide, ifosfamide, vincristine, gemcitabine, bevacizumab Multifocal Capecitabine leukoencephalopathy Thrombotic Mitomycin-C microangiopathy Gemcitabine Ciclosporin Cerebral infarcts MTX Ciclosporin Platinum derivatives Cortical blindness Platinum derivatives Fludarabine (high dose) Bevacizumab Optic neuropathy Tamoxifen Visual disturbances Pseudotumor cerebri Retinoids Cerebral venous thrombosis L-asparaginase Cerebellar dysfunction Ara-C 5-FU Infrequently vincristine, ciclosporin Seizures MTX, etoposide, VP-16 (high dose), cis-platinum, vincristine, asparaginase, carmustine, dacarbazine, amsacrine, AMSA, busulfan (high dose), ciclosporin, misonidazole, paclitaxel Aseptic meningitis MTX, Ara-C (intrathecally)

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et al., 2011). Oxcarbazepine has been shown to be effective in prophylaxis (Argyriou et al., 2006). In addition to dose-dependent neuropathies, about 60–80% of patients develop a cold-induced acute toxicity characterized by paresthesias in the throat, mouth, face, and hands occurring within 30–60 min after application and also includes muscle cramps and fasciculations. The sensations are described as a tingling or burning induced by contact with cold surfaces or cold liquids. They appear acutely and typically remit a few days after the infusion is completed. Spontaneous activity has been observed in the EMG during the attacks (Hill et al., 2010). Oxaliplatin affects voltage-gated sodium channels and interferes with axonal ion conductance (Webster et al., 2005). Oxaliplatin is transformed into oxalate that chelates calcium and has an effect on inward sodium channels (Gamelin et al., 2007; Park et al., 2011). Intravenous calcium gluconate and magnesium sulfate lower acute oxaliplatin symptoms (Gamelin et al., 2002).

Other alkylating agents IFOSFAMIDE Neuropathy can develop in about 8% of patients (Klastersky, 2003). The onset is gradual, with paresthesias and pain in the feet. The type of sensory loss is panmodal. Neuropathic pain can be a problem; tendon reflexes are reduced; weakness is rare. Recovery after termination of treatment is slow.

PROCARBAZINE Procarbazine is widely used in hematologic malignancies and in the treatment of brain tumors. Mild peripheral neuropathy has been described but is rarely problematic (Spivack, 1974). Myalgias can also occur.

THIOTEPA A motor neuropathy has been rarely described after intrathecal thiotepa (Martin Algarra et al., 1990).

Mitotic spindle inhibitors VINCA ALKALOIDS Vinca alkaloids interfere with microtubule assembly and mitotic spindle formation. They also influence axonal transport (Paulson and McClure, 1975). As with most toxic neuropathies, longer axons are more susceptible. Vincristine, vinblastine, and their semisynthetic derivatives, vindesine and vinorelbine, are predominantly used for the treatment of leukemias, lymphomas, and sarcomas. All are given by intravenous infusion and

1202 R. SOFFIETTI ET AL. produce a dose-related sensorimotor neuropathy reactions; the other is Abraxane, a protein-bound pacli(Schaumburg, 2000). Vincristine and vindesine cause taxel which avoids the side-effects of Cremaphor but the most severe neurotoxicity, while vinblastine and unfortunately causes polyneuropathies. vinorelbine are less toxic. Taxanes hyperstabilize microtubule subunit crossPolyneuropathies present usually within the first 3 linking and decrease the ability of the cell to dynamically months of treatment. Early symptoms are paresthesias reorganize the cytoskeleton. Also, the formation of crysand pain in the hands and feet, and distally accentuated talline arrays of microtubule subunits in the cell or axon hyperesthesia. Weakness may also occur, in particular in occurs (Apfel, 2000), which disrupts the axonal transwrist extensors and dorsiflexors of the toes. Tendon port, the retrograde transport of trophic factors, and reflexes are lost early on. Muscle cramps in distal musother vesicular components. Both processes interfere cles (e.g., feet) are frequent, often persisting long after with axonal transport and result in neuropathy. In additreatment cessation. Mononeuropathies (femoral, perition to microtubule changes, the ubiquitin-proteasome toneal nerves) and cranial nerve lesions (with diplopia, system (UPS) in axons, with local activation of calvocal cord paralysis, facial nerve palsy, and hearing loss) pain/caspase cell and apoptosis, may also be activated. have been reported (Sanderson et al., 1976; Kalcioglu Sensory symptoms are common and dose-related et al., 2003). Autonomic damage can result in gastroin(Postma et al., 1995). Both drugs induce paresthesias, testinal symptoms, such as paralytic ileus or megacolon loss of sensation, and dysesthetic pain in the feet and (Low et al., 2003). Bladder atony, impotence, orthostatic hands. Gait unsteadiness can be a result of sensory hypotension, and cardiac problems have also been ataxia. At examination, the vibratory threshold increases reported. Rarely, severe neuropathy with quadriparesis and perceptions of light touch and pin decrease in the occurs (Moudgil and Riggs, 2000). Inherited neuropafeet more than in the hands. Deep tendon reflexes at thies (Chauvenet et al., 2003) may aggravate the expresthe ankle may be lost but more proximal reflexes may sion of neuropathies and need to be considered before be preserved. starting chemotherapy. Weakness is absent or mild, although motor neuNerve conduction studies show axonal neuropathies ropathies have been observed (Freilich et al., 1996). Lherwith a reduced amplitude of motor and sensory action mitte’s phenomenon can appear. Autonomic symptoms potentials, and mildly reduced conduction velocities. have been described, as well as gastrointestinal sympThere are no pharmacologic treatments to reduce or toms and cardiac arrhythmia. prevent polyneuropathies induced by vinca alkaloids. A An acute toxicity, caused by mitochondrial damage pharmacologic approach with lacosamide has been proand small-fiber type lesions with upregulation of posed to reduce pain and allodynia in animal models PGP9.5 in the Langerhans cells, has been described (Geis et al., 2011). Reducing dose levels and frequency (Siau et al., 2006) and as the lesions are restricted to of application may be of benefit. After cessation of therthe afferent axon’s terminal arbor, it was suggested that apy, coasting has been described (Verstappen et al., this should be named “terminal arbor degeneration” 2005). In severe cases, improvement occurs over months (Bennett et al., 2011). to several years and may be incomplete. A decreased risk Treatment with taxanes can also cause a proximal of neuropathy and a more rapid recovery may exist in weakness syndrome independently of sensory symptoms. African Americans with at least one CYP3A5*1 allele Creatine kinase (CK) is normal and weakness improves (Egbelakin et al., 2011). after cessation of therapy. Myalgia/arthralgia syndromes are more frequent with paclitaxel, beginning 2–3 days after administration and lasting several days. TAXANES Electrophysiologic testing typically demonstrates Both paclitaxel and docetaxel are widely used, either that sural nerve potentials are reduced or absent in sympalone or in combination, for the treatment of breast, tomatic patients with signs of axonal neuropathy. ovarian, lung, and many other forms of cancer. PacliConcurrent cis-platinum or alcohol abuse increases taxel may produce more neuropathies than docetaxel the risk of neuropathy. ABCB1-allelic variation nega(Hilkens et al., 1997). Taxanes are frequently used in tively influences the effect of docetaxel treatment combination with other agents that cause toxicity to (Sissung et al., 2008). PNS. It is unclear whether additive or synergistic neuropThe sensory symptoms can be troublesome and typiathy results from these combinations. There are two cally remit within several weeks after treatment has been important issues concerning the transport vehicle of completed. Lowering the dose and lengthening the treatthe drugs: one is Cremophor (Scripture et al., 2005), a ment may reduce symptoms. Long-term follow-up nonionic surfactant and a polysaturated castor oil examinations report individuals with a prolonged effect which has side-effects of its own, in particular allergic (Thornton et al., 2008).

NEUROLOGIC COMPLICATIONS OF CHEMOTHERAPY

OTHER MICROTUBULE-STABILIZING AGENTS Podophyllin is an alkaloid extracted from the Mayapple or American mandrake and is considered both a spindle as well as a topoisomerase inhibitor. Etoposide (VP-16) and teniposide (VM-26) are agents derived from podophyllin. They disrupt mitotic spindle formation and inhibit topoisomerase II as well. The drugs are extensively used in different forms of cancer, often in combination with drugs that cause polyneuropathies. Although peripheral toxicity is generally accepted, data from large studies are missing. Ixabepilone, an epothilone B analog, which is used for breast cancer, induces a severe predominant sensory neuropathy in up to 15% of patients (Lee et al., 2006). Sensory symptoms tend to be cumulative, but improve substantially within 1–2 months of discontinuation or dose reduction. Eribulin is a nontaxane microtubule inhibitor used in the treatment of patients with locally advanced or metastatic breast cancer who have previously been treated with other chemotherapies. Peripheral neuropathy (incidence 5%) is the most common adverse event. In animal experiments, eribulin seems less toxic compared to other drugs (Wozniak et al., 2011).

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Usually, it is a reversible neuropathy, whose severity depends on duration of treatment (Argyriou et al., 2008; Sonneveld and Jongen, 2010). In a few cases, demyelinating neuropathies, which are probably dysimmune, have been observed (Ravaglia et al., 2008; St€ ubgen, 2011). Electrophysiologic changes demonstrate an axonal loss (Chaudhry et al., 2008). Pretreatment with thalidomide is a serious risk factor for the development of polyneuropathy.

CARFILZOMIB Carfilzomib is an irreversible proteasome inhibitor with less neurotoxic side-effects (O’Connor et al., 2009).

Antibiotics Several antibiotics have antineoplastic effects. The most important is doxorubicin. Although doxorubicin can induce DRG changes in animals, this is not an issue in clinical practice. Other antibiotics, such as actinomycin, anthracyclines, daunorubicin, valrubicin, idarubicin, and epirubicin, rarely cause peripheral neurologic complications.

Antimetabolites Proteasome inhibitors BORTEZOMIB Bortezomib is a polycyclic derivative of boronic acid that inhibits the mammalian 26S proteasome. The 26S proteasome is a large complex that is part of the ubiquitin degradation pathway. It regulates the homeostatic level of many intracellular proteins including those involved in cell-cycle regulation and apoptosis. The proteasome degrades the intracellular inhibitor of NF-kB (IkB). Bortezomib increases the level of the inhibitor and decreases the activity of NF-kB. This downregulates the expression of proteins that promote cell division and proliferation and enhances apoptosis. Also, secretion of cytokines in the bone marrow is suppressed. It also enhances oxidative stress by upregulation of p53, p21, p27, p38, MAPK, and JNK. The neuropathy is predominantly sensory, dose-related, and cumulative (Broyl et al., 2010). Genetic factors may be implicated in the susceptibility (Becker, 2011; Corthals et al., 2011). It often causes neuropathic pain, probably due to small-fiber involvement. Patients experience sensory loss (numbness) and pain, which is perceived as burning, sharp, cold, or electric (Farquhar-Smith, 2011). Autonomic changes with postural hypotension have been reported; increased age is an additional risk factor. In trials, neuropathy occurred in 37–44% of patients with multiple myeloma (Cavaletti and Jakubowiak, 2010).

Antimetabolites are compounds more commonly associated with central rather than peripheral neurotoxicity. Methotrexate is a folate antagonist that inhibits dihydrofolate reductase, a key enzyme in the synthesis of nucleotides. Peripheral neurotoxicity is rare. Although IT treatment is a routine procedure, it can be associated with complications such as spinal arachnoiditis and myelopathy. Cytosine arabinoside (Ara-C) is a pyrimidine antagonist that blocks synthesis of cytosine, thymidine, and uridine. Peripheral neurotoxicity is rare. There are several case reports of various neuropathies associated with the use of high-dose Ara-C (Openshaw et al., 1996). Depot Ara-C (DepoCyt®) is increasingly used for patients with neoplastic meningitis: the drug may cause a cauda equina syndrome (Ga´llego Pe´rez-Larraya et al., 2011; Ostermann et al., 2011) in some patients. Gemcitabine is a deoxycytidine analog structurally related to Ara-C. In many patients, it causes systemic symptoms of low-grade fever, fatigue, malaise, and arthralgias. In about 10%, a sensory neuropathy with paresthesias can develop. Autonomic involvement has also been observed. Muscle symptoms can appear as myalgias. Magnetic resonance imaging (MRI) can show edema of the affected muscle and CK can be elevated. Gemcitabine is often used in combination with taxanes, platinum compounds, or vinca alkaloids, all of which cause neuropathies but the association does not seem to increase the risk.

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5-Fluorouracil (5-FU) is a pyrimidine antagonist. A small number of cases of polyneuropathies have been reported after treatment with 5-FU (Stein et al., 1998). Capecitabine is metabolized to 5-FU. Toxicity to PNS is unlikely (Saif et al., 2004). Cranial nerve lesions appear rarely (Dasgupta et al., 2010). The “hand-foot syndrome,” or “palmar-plantar erythrodysesthesia” (PPE), has been observed in up to 10% of patients treated with capecitabine, but is not specific and also appears with other drugs. Administration of the drug is followed within days by palmar and plantar paresthesias and itching, followed by the development of an erythematous and occasionally bullous palmar and plantar rash. It is thought to be due to a local skin reaction, but a relationship to neuropathy or damaged small skin nerves is postulated (Stubblefield et al., 2006). Cladribine can be rarely associated with a Guillain– Barre´ syndrome. Nelarabine, a new purine nucleoside analog, used for T cell leukemia and lymphomas, can cause a poorly characterized peripheral neuropathy with leg weakness and paresthesias (Cohen et al., 2008); on rare occasions symptoms can be severe and mimic Guillain–Barre´syndrome.

Micellaneous THALIDOMIDE AND LENALIDOMIDE Thalidomide has been used as a potent vascular endothelial growth factor (VEGF) inhibitor in multiple myeloma, Waldenstr€ om’s macroglobulinemia, myelodysplastic syndromes, acute myeloid leukemia, myelofibrosis, graft-versus-host disease, prostate cancer, renal cell cancer, malignant brain tumors, and Kaposi sarcoma. The type of neuropathy is predominantly sensory, with numbness and pain in hands and feet. All sensory qualities are affected, though reflexes may be preserved. Cramps of small foot muscles occur. Neuropathies develop in 20–40% of patients (Mazumder and Jagannath, 2006). The frequency of neuropathy increases with age and cumulative doses or duration of treatment; the vulnerability of elderly people is a major concern (Palumbo et al., 2011). Lenalidomide is an analog (a-3-aminophthalimidoglutarimide) which is less neurotoxic to the PNS (Mateos, 2010).

SURAMIN Suramin can cause two types of peripheral neuropathy: a mild distal axonal neuropathy and an acute form resembling acute polyradiculitis (Chaudhry et al., 1996).

ARSENIC TRIOXIDE Arsenic trioxide has recently been introduced for the treatment of refractory forms of cancer. It is an inorganic arsenic compound that has been known for many years to cause severe, and sometimes fatal peripheral neuropathies. A recent single-agent trial, however, described few neurotoxic effects (Zhou et al., 2010).

TOPOISOMERASE INHIBITORS Type-I topoisomerase inhibitors are camptothecin irinotecan and topotecan, and type-II inhibitors are etoposide and teniposide. Overall, minor neuropathies have been reported (Garcia et al., 2005).

Biologic and targeted therapies INTERFERON-a Interferon-a is used in the treatment of leukemias and lymphomas as well as hepatitis C. It can cause a distal symmetric sensory neuropathy, with pain and paresthesias, and mild loss of pain and temperature perception (Toyooka and Fujimura, 2009).

HORMONES Endocrine therapy using aromatase inhibitors (anastrozole and exemestane) in patients with ER-positive and/ or PgR-positive breast cancer showed grade 2 neuropathies occurring in 30% of patients receiving chemotherapy while hormonal treatment was well tolerated (Semiglazov et al., 2007). Focal neuropathies, such as the carpal tunnel syndrome, may increasingly occur during aromatase therapy (Nishihori et al., 2008).

RADIOSENSITIZERS Misonidazole has been used as a radiosensitizer. It causes a sensory, often painful, neuropathy that is dose-related (Melgaard et al., 1988). The incidence can be up to 30% if the maximum cumulative dose has been reached.The more recent radiosensitizer motexafin gadolinium has not yet been reported to cause neuropathies.

RETINOIDS Retinoids are used in hematologic diseases. Not only muscle cramps and myalgias but also sensory symptoms have been reported. The mechanism is not fully understood. Conversely, in animal experiments, a protective effect of retinoids in regard to toxicity to PNS has been hypothized (Arrieta et al., 2011).

NEUROLOGIC COMPLICATIONS OF CHEMOTHERAPY

MONOCLONAL ANTIBODIES Bevacizumab is anti-VEGF monoclonal antibody. As of August 2011, 13 485 persons have reported side-effects: 16 individuals (0.12%) had a sensory neuropathy, which occurred in the first month, which makes a cumulative effect unlikely (http://www.ehealthme.com). Other concomitant drugs were also used, which makes it difficult to evaluate the individual toxicity. A possible association with paclitaxel has been observed. Brentuximab is an anti-CD30 monoclonal antibody used in the treatment of Hodgkin’s lymphoma. Sensory neuropathies have been described (Foyil and Bartlett, 2011). Trastuzumab is employed for treatment of HER-2 positive breast cancer patients. As of August 2011, 64 443 persons have reported side-effects: among them, eight individuals (0.12%) reported a sensory neuropathy (http://www.ehealthme.com). Unlike bevacizumab, the neuropathy was most often observed after 1 year (50%) and 2 years (25%), which makes a cumulative effect likely.

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COMPLICATIONS OF CHEMOTHERAPY IN THE CENTRAL NERVOUS SYSTEM Antimetabolites METHOTREXATE Methotrexate (MTX) is an antimetabolite compound that inhibits the enzyme dihydrofolate reductase, thereby preventing the conversion of folic acid into tetrahydrofolate, and inhibiting DNA synthesis in the S-phase of the cell cycle. MTX is used for systemic malignancies such as leukemia, lymphoma, and breast cancer, and is also the most effective chemotherapeutic agent for primary CNS lymphoma. The drug does not cross the BBB very well, being highly ionized and somewhat hydrophobic. Therefore, CNS toxicity is uncommon unless MTX is administered intravenously (IV) at high doses ( 1 g/m2) or via the intrathecal (IT) route. MTX-induced CNS toxicity is often divided into acute (during or within hours of administration), subacute (after days to weeks), and chronic (after months to years) effects.

SMALL TYROSINE KINASE INHIBITORS Imatinib is an oral compound that inhibits the constitutively active fusion product of the BCR-ABL translocation in Philadelphia chromosoma-positive leukemia as well as C-KIT in gastrointestinal tumors. Muscle cramping or myalgias occur in up to 50% and 20% of the patients, respectively: these symptoms are generally mild and responsive to calcium, magnesium, or quinine. Creatinine kinase elevation, muscle edema, and rhabdomyolysis with myoglobinuria are very rare. Tipifarnib is an oral nonpeptidomimetic farnesyl transferase inhibitor used in both solid tumors and hematologic malignancies such as acute myeloid leukemia. Toxicity is predominantly hematologic but mild neuropathies have been reported.

The issue of prevention and rehabilitation Despite encouraging results from prospective studies, at present the data are insufficient to conclude whether any agent is actually able to prevent damage to the peripheral nervous system from chemotherapeutic agents (Walker and Ni, 2007; Wolf et al., 2008). In small clinical trials vitamin E appeared to afford some neuroprotection in cisplatin-treated patients (Pace et al., 2003; Argyriou et al., 2005). Erythropoietin has been shown to be of potential benefit as well (Kassem and Yassin, 2010). As chemotherapy-induced polyneuropathies are often not completely reversible and may leave patients distinctly disabled (Hile et al., 2010), rehabilitation deserves particular attention (Grisold et al., 2007; Stubblefield, 2011).

Acute/subacute effects After IT administration, MTX can induce a chemical meningitis in approximately 10% of patients (Vezmar et al., 2003). The diluent used in the MTX solution is thought to possibly play a role in the development of the syndrome. Symptoms include headache, stiff neck, meningismus, and low-grade fever, arising within a few hours of drug infusion. The cerebrospinal fluid (CSF) typically demonstrates a mild pleocytosis, with negative viral and bacterial cultures. The reaction appears to be idiosyncratic, usually does not recur with subsequent cycles of IT treatment, and does not seem to be dose-related. If corticosteroids are administered before or during the IT instillation of MTX, chemical meningitis may be quite mild or not occur at all. Patients that have had an acute reaction to IT MTX do not appear to be predisposed to developing a late or chronic effect of the drug. Less common acute and subacute side-effects of IT and systemic MTX include seizures, encephalopathy, transient focal neurologic deficits, and transverse myelopathy (Vezmar et al., 2003). Seizures can rarely occur after IT administration. The most extensive experience with this complication has been in pediatric patients receiving IT MTX for treatment of acute leukemia. Acute and subacute encephalopathy can occur in the setting of high-dose IV MTX (3–12.5 g/m2; 2.5–15% of patients), often as part of a multiagent regimen for patients with primary CNS lymphoma (Green et al., 2006). The clinical presentation typically includes

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somnolence, focal signs such as hemiparesis, dysphasia, and dysarthria, as well as occasional seizure activity. MRI demonstrates transient white matter abnormalities, or is normal in some cases. MRI diffusion within 1 hour of onset of the syndrome has revealed bilateral, symmetric restricted diffusion involving white matter of the cerebral hemispheres, without evidence of vasospasm or perfusion defect (Eichler et al., 2007), probably due to a transient cytotoxic edema. Electroencephalography (EEG) usually shows diffuse slowing of the background. The syndrome is not correlated with serum or CSF levels of MTX, and can occasionally recur with subsequent courses of treatment. In most cases, there is complete resolution of the clinical and imaging abnormalities; rarely, a chronic leukoencephalopathy can follow. MTX-induced leukoencephalopathy and demyelination had been linked to functional polymorphisms in enzymes influencing the methionine-homocysteine pathway, such that reduction of S-adenosylmethionine (SAM), the only methyl-group donor in the CNS, is reduced (Linnebank et al., 2005; Linnebank et al., 2009) and levels of homocysteine (Becker et al., 2007) may be increased. A rare but devastating complication of intrathecal therapy with MTX, alone or associated with Ara-C, is acute myelopathy with ascending para- or tetraparesis (Beretta et al., 1996; DeAngelis and Posner, 2009; Kwong et al., 2009). This can occur even after a single dose exposure, and could involve the brainstem and lead to a locked-in syndrome or even death due to acute “encephalomyelitis” (DeAngelis and Posner, 2009). Possible risk factors are extensive meningeal disease, irradiation of the CNS and childhood or old age. There are reports of patients having severe reactions to overdosage, with rapidly progressive encephalopathy and death. Potential treatment options for patients with an overdose of IT MTX would include CSF drainage and ventriculolumbar perfusion. The pathologic findings are those of a necrotizing myelopathy; efficient therapies have not been established. However, a recent case has been reported of a 54-year-old woman with MTX-induced severe myelopathy who showed partial remission of symptoms beginning 3 days after continuous substitution of S-adenosylmethionine (SAM) 3  200 mg/day, folic acid 4  20 mg/day, cyanocobalamin 100 mg/day, and methionine 5 g/day (intravenously for 1 week, then orally) (Ackermann et al., 2010). Given the lack of other established treatment, substitution of these derivates of the folic acid and methionine/homcysteine metabolic pathway may be tried as well as complete CSF “exchange.”

Chronic effects Chronic or late side-effects of IT and IV MTX manifest 6 months or longer after initial drug exposure (Vezmar et al., 2003). The most characteristic syndrome is a leukoencephalopathy, which is well described in children with acute leukemia, but can also occur in adults (Price and Jamieson, 1975). In children, the clinical presentation includes progressive learning disorders, memory loss, gait difficulty, and urinary incontinence. The presentation is similar in adults, with confusion and memory loss that often progresses to dementia, as well as somnolence, irritability, impaired vision, seizures, and ataxia. MRI reveals diffuse white matter damage, cortical atrophy, ventricular enlargement, and punctate areas of calcification within the basal ganglia and deep white matter. In addition, asymptomatic patients who have received high-dose IV or IT MTX may demonstrate similar, but much milder, damage to the white matter on imaging studies. The leukoencephalopathy is most likely to occur after combination treatment with high-dose IV MTX, IT MTX, and cranial irradiation (45%), with a much lower incidence for high-dose MTX and/or IT MTX alone (2% or less) (Bleyer, 1981). Neurotoxicity is especially enhanced when the patient receives irradiation before the administration of MTX. The mechanisms underlying this synergistic toxicity remain unclear, but may be related to a radiationinduced increase in the permeability of the BBB, reduced clearance of MTX from the CSF, increased passage of MTX into the white matter through the ependymal–brain barrier, and potential direct cellular toxicity caused by irradiation (Vezmar et al., 2003). Neuropathologic changes are most notable in the periventricular white matter and deep centrum semiovale, and include demyelination, multifocal white matter necrosis, gliosis, dystrophic calcification of deep microvessels, and axonal damage; inflammatory cellular infiltration is typically not present. There is no effective treatment for this disorder.

CYTOSINE ARABINOSIDE Cytosine arabinoside (Ara-C) is a pyrimidine analog that is metabolized into Ara-CTP, the active moiety that inhibits DNA polymerase. It is commonly used in multiagent chemotherapy regimens for the treatment of leukemia and lymphoma, as well as for neoplastic meningitis. Central neurotoxicity from Ara-C is usually noted in the context of high-dose IV therapy ( 3 g/m2 every 12 hours  4–6 days), and typically presents with a subacute pancerebellar syndrome (Baker et al., 1991). In most cases, the symptom onset is within hours to days of completion of the infusion; rarely, it can occur during the

NEUROLOGIC COMPLICATIONS OF CHEMOTHERAPY infusion. The size of a given individual dose may be more important than the cumulative dose of the drug. Patients with renal failure are at increased risk of developing the syndrome. Symptoms include dysarthria, dysmetria, ataxia, and nystagmus. Signs of cerebral dysfunction, such as somnolence, headache, and seizures, can be noted in some patients. Symptoms usually resolve after discontinuation of Ara-C. The most common neuropathologic findings are cerebellar cortical atrophy and Purkinje cell loss. Intrathecal use of Ara-C can be associated with a mild chemical meningitis, similar to MTX (Baker et al., 1991). It is more common with the liposomal, sustained-release preparation of Ara-C (i.e., DepoCyt), and can recur with subsequent doses of the drug. Rarely, seizures and confusional syndromes can occur with IT usage. An acute myelopathy can occur as well.

5-FLUOROURACIL 5-Fluorouracil (5-FU) is a fluorinated pyrimidine analog of uracil that inhibits the enzyme thymidylate synthetase, thereby interfering with DNA and RNA synthesis (Hammack, 2005). The drug is commonly used for the treatment of head and neck, breast, and gastrointestinal cancers. CNS toxicity is most likely in patients receiving high-dose IV 5-FU or in those with a deficiency of dihydropyrimidine dehydrogenase, a key enzyme involved in 5FU metabolism (Takimoto et al., 1996). The most common form of neurotoxicity associated with 5-FU is an acute or subacute pancerebellar syndrome, with an estimated incidence of 2–4% and clinical features of limb and gait ataxia, nystagmus, and dysarthria (Pirzada et al., 2000). The onset of symptoms is usually during or immediately after the infusion of the drug. Clinical investigations with MRI and CSF are generally unremarkable. Typically, there is complete reversal of clinical findings after several days to weeks. However, if the patient is treated with 5-FU again, the syndrome may recur. Other forms of neurotoxicity associated with 5-FU include headache, seizures, and diffuse encephalopathy, as well as rarer entities such as optic neuropathy, extrapyramidal disorders, and leukoencephalopathy (Pirzada et al., 2000). Similar to the pancerebellar syndrome, the onset of encephalopathy is usually acute, either during or just after infusion of the drug. It presents with acute confusion, disturbances of cognition and mentation, and altered sensorium. The leukoencephalopathy can occur with 5-FU alone or in combination with other drugs, in particular levamisole (Choi et al., 2001). This syndrome is characterized by impaired cognitive function, loss of memory, abulia, ataxic gait, and akinetic mutism. The biochemical basis of 5-FU neurotoxicity remains unknown (Pirzada et al., 2000). Pathologic examination

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of the brains of patients with 5-FU reveals minimal if any abnormalities. Numerous theories have been proposed, including blockade of the Krebs cycle by fluoroacetate. Another hypothesis is that the drug may induce neurologic toxicity via an acute deficiency of thiamine, since 5-FU is able to block the production of thiamine phosphate, the active form of the vitamin (Askoy et al., 1980). The differential diagnosis of 5-FU neurotoxicity is broad, and covers a wide range of disease processes, including cerebellar metastases, paraneoplastic cerebellar syndromes, vertebrobasilar ischemia, and intoxication by other medications.

CAPECITABINE Capecitabine is an oral, flouropyrimidine carbamate prodrug that is converted to 5-FU after enzymatic metabolism in the liver; it is used for the treatment of colorectal, breast, and ovarian cancers (McKendrick and Coutsouvelis, 2005). It is generally not associated with significant risk for neurotoxicity, but there are several reports of encephalopathy and cerebellar toxicity in patients with breast and colon adenocarcinoma (Videnovic et al., 2005).

FLUDARABINE Fludarabine phosphate is a synthetic purine nucleoside that inhibits DNA polymerase and is used for treatment of chronic lymphocytic leukemia (Roback et al., 2006). The most common form of fludarabine neurotoxicity involves delayed and progressive deterioration of vision, in the form of photophobia, in combination with either optic neuritis or cortical blindness (Chun et al., 1986). Seizures, ataxia, tremor, and myelopathy may also occur. In most patients, the onset of toxicity is during treatment with fludarabine. However, in some cases, toxicity can be delayed for several months after the discontinuation of chemotherapy. Severe cases of fludarabine neurotoxicity appear to be dose-related. MRI may demonstrate diffuse or multifocal white matter abnormalities on T2 or fluid-attenuated inversion recovery (FLAIR) images; the regions of signal abnormality do not enhance after infusion with gadolinium. The CSF is usually normal. Neuropathologic examination reveals multifocal or diffuse demyelination with macrophage infiltration and necrosis, mainly in the occipital and parietal lobes (Spriggs et al., 1986). The optic nerves, brainstem, and spinal cord can also be affected.

CLADRIBINE Cladribine is a purine nucleoside analog that inhibits DNA synthesis and ribonucleotide reductase, which is

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used for the treatment of leukemia and lymphoma (Roback et al., 2006). In general, neurotoxicity is uncommon when cladribine is used within the routine dose ranges. At higher doses, headache and generalized “weakness” have been reported (Cheson et al., 1994). Rarely, a myelopathy can occur.

PENTOSTATIN Pentostatin is a purine analog that inhibits DNA synthesis and is used for the treatment of hairy cell leukemia (Roback et al., 2006). Similar to cladribine, neurotoxicity is infrequent when pentostatin is used within the typical dose range. At higher doses, some patients can manifest symptoms such as somnolence, seizures, and coma (Cheson et al., 1994).

GEMCITABINE Gemcitabine is a purine nucleoside analog of deoxycytidine that is toxic to cells during DNA synthesis. It is used for treatment of solid tumors, such as pancreatic, nonsmall-cell lung, and ovarian cancers. Neurotoxicity from gemcitabine has been very rare, with only one report of a patient with headache, seizures, and a reversible posterior leukoencephalopathy syndrome (Russell et al., 2001).

HYDROXYUREA Hydroxyurea is a urea-derived drug that inhibits ribonucleotide reductase and DNA synthesis. It is used most often for the treatment of hematologic malignancies, but has also been applied to HIV infection, sickle cell disease, and inoperable meningiomas. Significant central neurotoxicity is very uncommon, with only rare reports of mild encephalopathy and headache (Barry et al., 1999).

NELARABINE AND CLOFARABINE Nelarabine can have CNS toxicity, in addition to PNS damage. Altered consciousness and headache are common, and seizures can occur. The mechanism of neurotoxicity is unknown, although nelarabine has excellent penetration of the intact BBB. Clofarabine, an analog of nelarabine used for treatment of pediatric acute lymphoblastic leukemia, which has a much lower CNS penetration, commonly causes mild to moderate headache but never other severe CNS symptoms.

Alkylating agents PLATINUM COMPOUNDS CNS neurotoxicity is very important in some patients, and depends on the dose and route of administration (IV versus intra-arterial (IA)). Seizures and diffuse encephalopathy are the most common forms of CNS toxicity associated with cisplatin (Markman, 2003). They can occur as a result of acute injury to neural tissues, induction of systemic metabolic derangements, or a combination of both. Hypomagnesemia is noted in 55– 60% of patients receiving IV cisplatin, and is caused by impaired magnesium reabsorption in the proximal renal tubule. Also, a diffuse muscle weakness can occur, depending on the severity of the magnesium deficit. Patients are also at risk for hyponatremia, which can result from the syndrome of inappropriate antidiuretic hormone (SIADH), excessive hydration with hypotonic fluids during cisplatin infusion, or severe cisplatininduced emesis (Berghmans, 1996). In rare patients, especially those with intracranial space-occupying lesions, excessive hydration during cisplatin infusion can result in cerebral edema, somnolence, seizures, and tonsillar herniation (Walker et al., 1988). Encephalopathy can occur as a direct toxic effect during IV treatment, but is even more common during IA infusion. Other symptoms that can arise during or within hours to days of IV cisplatin include stroke, cortical blindness, retinal toxicity, dysphasia, and focal motor deficits. The neurologic injury usually resolves without specific treatment and may not recur with subsequent cycles of cisplatin. In patients with stroke, angiography may reveal branch occlusion or, in some cases, be completely normal. The cause of cisplatin-induced stroke remains unclear: mechanisms include vasospasm in the setting of hypomagnesemia, coagulopathy, and drug-induced endothelial injury. Intra-arterial cisplatin is associated with a broad range of CNS neurologic complications, including encephalopathy and confusional states, seizures, stroke, chronic leukoencephalopathy, and ocular toxicity (Newton, 2006). The ocular injury can manifest as optic neuropathy and/or retinopathy, and may include retinal infarcts. The risk for ocular toxicity is reduced if the catheter is placed beyond the origin of the ophthalmic artery. However, supraophthalmic delivery of cisplatin is associated with more severe neurologic toxicity. Carboplatin, via the IA route, has less neurotoxicity than cisplatin (Newton et al., 2003).

NITROSOUREAS The nitrosoureas are a class of drugs that alkylate DNA and RNA, and include carmustine (BCNU), lomustine

NEUROLOGIC COMPLICATIONS OF CHEMOTHERAPY (CCNU), semustine (methyl-CCNU), nimustine (ACNU), fotemustine, and streptozotocin. They have a high lypophilicity and excellent penetration of the blood–brain barrier (BBB), with CSF drug levels approximately 15–30% of plasma levels. Nitrosoureas are used predominantly for the treatment of high-grade gliomas, melanoma, and lymphoma. When used at conventional IV doses, the incidence of CNS toxicity is very low. High-dose IV BCNU has been associated with optic neuropathy and leukoencephalopathy (Schold and Fay, 1980). CNS and ocular toxicity is more likely to occur when nitrosoureas (BCNU, ACNU) are administered to brain tumors via the IA route (Newton, 2006). Ocular toxicity includes acute orbital pain during drug infusion, along with optic neuropathy and retinal injury. These symptoms could be mitigated with supraophthalmic delivery of the drug. Cerebral symptoms include focal or generalized seizures, encephalopathy, focal weakness, stroke. In some patients this constellation of symptoms and signs can be caused by a necrotizing leukoencephalopathy, a relatively common and occasionally fatal complication of IA BCNU (Rosenblum et al., 1989). Concurrent irradiation increases the risk of developing the complications. The onset of symptoms is often delayed after drug administration, up to 6 months in some cases. MRI demonstrates prominent edema in the ipsilateral hemisphere, and gyral enhancement may be present. Pathologic examination reveals focal necrosis and mineralizing angiopathy. The mechanism of injury could be similar to MTX, and related to a combination of a direct neurotoxic effect of the drug and endothelial damage. BCNU can be administred to brain tumor patients in wafer form, implanted directly into the resection cavity (Raza et al., 2005): in general, there is only a mild risk of neurotoxicity in this setting, with the potential for transitory increased cerebral edema, seizures, and new focal neurologic deficits after wafer placement.

TEMOZOLOMIDE AND DACARBAZINE Temozolomide is an alkylating agent that methylates DNA on N7-guanine, N3-adenine, and O6-guanine positions and is used for the treatment of high-grade gliomas, melanomas, and brain metastases. Central neurotoxicity appears to be very uncommon, with rare reports of headache, seizures, and exacerbation of focal neurologic deficits (Yung et al., 2000). However, it is difficult to rule out if these symptoms might have been related to the underlying brain tumor, in addition to or instead of the drug. Rarely, transient neurologic deterioration can occur at the onset of therapy, the so called “tumor flare” syndrome (Rosenthal et al., 2002). Dacarbazine is an alkylating agent that is used for the treatment of melanomas, solid tumors, and lymphoma.

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Significant neurotoxicity appears to be extremely uncommon, with only rare reports of dementia and seizures. Mild symptoms, such as headache and malaise, are more common and generally self-limited.

MECHLORETHAMINE Mechlorethamine is the original nitrogen mustard and is still used in the treatment of Hodgkin’s disease and other lymphomas. Used at conventional IV doses, mechlorethamine does not cause any CNS toxicity. When used in high-dose IV regimens, such as in preparation for bone marrow transplantation (BMT), the drug has been reported to cause, headache, seizures and encephalopathy. The symptom onset is usually within a few days of treatment and spontaneous recovery is typical.

ESTRAMUSTINE Estramustine is a nitrogen mustard with a linkage to estradiol, allowing the drug to function as an alkylating agent and a microtubule poison. It is used mainly for treatment of refractory prostate cancer and is not associated with any significant CNS toxicity except rare cases of thrombotic microangiopathy with cerebral infarction (Halevy et al., 2002).

CHLORAMBUCIL Chlorambucil is an orally administered nitrogen mustard that is used in combination regimens for the treatment of leukemia and lymphoma. At conventional doses, there is very little risk for CNS toxicity. During high-dose therapy or overdosage, neurotoxicity can include seizures, delirium, myoclonus, optic neuropathy, and retinopathy (Salloum et al., 1997).

THIOTEPA Thiotepa is related to nitrogen mustard and can easily cross the BBB. It can be administered IV at conventional doses for breast and ovarian cancers, and lymphoma. In addition, high-dose IV thiotepa is often included in multiagent chemotherapy regimens prior to BMT, and can be administered IT to patients with leptomeningeal metastases. CNS toxicity is very rare at conventional IV doses. However, with high IV dosing, a diffuse encephalopathy can occur. Neurotoxicity is more likely when thiotepa is administered IT, with symptoms similar to MTX and Ara-C, including a mild, reversible chemical meningitis and, in rare cases, a transient or persistent myelopathy.

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HEXAMETHYLMELAMINE Hexamethylmelamine is an alkylating agent that is mainly used as second-line therapy for recurrent ovarian cancer. Although the drug does not cross the BBB very well, its metabolites can readily enter the CNS. The most common neurotoxic effects include headache and mild encephalopathy. Less frequent forms of toxicity include seizures, ataxia, tremor, and parkinsonism. The symptoms are reversible and improve once the drug has been discontinued.

IV ifosfamide. The toxicity is more likely to occur when IV therapy is continuous over several days or given in a large bolus dose, as opposed to fractionated schedules. The most common symptoms include delirium, mutism, visual hallucinations, seizures, focal motor deficits, facial nerve palsy, and aphasia. Symptoms usually develop during or immediately after the infusion of ifosfamide. Treatment with benzodiazepines results in rapid clinical improvement. Similarly, treatment with methylene blue, either before or after the onset of symptoms, may be of benefit.

BUSULFAN Busulfan is a non-cell-cycle specific alkylating agent that interacts with cellular thiol groups and nucleic acids, producing cross-links between DNA molecules. It is used orally for the treatment of chronic myelogenous leukemia and IV in conditioning regimens for BMT. Busulfan is known to easily cross the BBB, with a CSF to plasma ratio of 1:1. Approximately 10% of patients receiving high-dose oral or IV busulfan will develop generalized seizures, and this is more likely to occur in adults than children. The seizures are dose-dependent and appear within 48 hours of drug administration. Prophylaxis with anticonvulsants, such as lorazepam, can minimize the risk for seizures (Chan et al., 2002).

PROCARBAZINE Procarbazine is thought to function as an alkylating agent after activation in the liver, and is used for treatment of lymphoma and gliomas. High-dose oral procarbazine can cause CNS toxicity, including somnolence, depression, obtundation, and psychosis (Postma et al., 1998). In addition, due to its weak activity as a monoamine oxidase (MAO) inhibitor, procarbazine can cause hypertensive encephalopathy, headache, and delirium when administered in combination with sympathomimetic agents or after consumption of tyraminecontaining foods.

CYCLOPHOSPHAMIDE AND IFOSFAMIDE Cyclophosphamide (CTX) is an antineoplastic agent that requires activation in the liver and is used in combination chemotherapy regimens for numerous solid tumors. Neurotoxicity is very uncommon, but may present during high-dose IV infusions as a mild, reversible encephalopathy with dizziness, blurred vision, and confusion. Ifosfamide is an alkylating agent structurally similar to CTX that is used for treatment of many solid and hematopoietic tumors, known to frequently cause CNS toxicity (Nicolao and Giometto, 2003). Central neurotoxicity occurs in 20–40% of patients that receive high-dose

Mitotic spindle inhibitors VINCA ALKALOIDS Due to poor penetration of the BBB, vinca alkaloids are only associated with occasional episodes of CNS toxicity. There have been reports of seizures, with or without encephalopathy, as well as transient cortical blindness suggestive of posterior reversible leukoencephalopathy. Other rare neurologic symptoms and signs include unilateral or bilateral optic neuropathy, ataxia, visual hallucinations, tremor, and parkinsonism. Vinca alkaloids are known to produce SIADH, which can secondarily lead to encephalopathy and seizures, especially in patients receiving aggressive hydration with their chemotherapy regimens. In addition, these drugs can cause severe neurotoxicity if given IT, with ascending myelopathy, coma, and death (Bleck and Jacobsen, 1991). Pathologic analysis demonstrates diffuse necrosis in the brain and spinal cord in regions exposed to the CSF.

TAXANES Both paclitaxel and docetaxel cross the BBB poorly, and have indetectable CSF levels after an IV injection. Neurotoxicity has been very uncommon with paclitaxel, mainly affecting the visual system. Reports have included transient scintillating scotomas and occasional visual loss (Capri et al., 1994). Visual evoked potentials were abnormal in some of the patients, while electroretinograms were intact in the same cohort, suggesting that the optic nerve was the region of injury. The visual symptoms resolved in most patients after discontinuation of the drug. Generalized seizures and encephalopathy have also been reported in rare cases after paclitaxel administration. Docetaxel is less neurotoxic than paclitaxel, and only rarely causes CNS toxicity, such as seizures or encephalopathy.

OTHER MICROTUBULE-STABILIZING AGENTS Etoposide (VP-16) and teniposide (VM-26) are semisynthetic derivatives of podophyllotoxin and inhibit the enzyme topoisomerase II, thus inducing single- and

NEUROLOGIC COMPLICATIONS OF CHEMOTHERAPY 1211 double-strand breaks in DNA and DNA-protein crossL-Asparaginase is a bacterial-derived enzyme that links (Martincic and Hande, 2005). Both drugs are highly hydrolyzes L-asparagine into aspartic acid and ammoprotein-bound and poorly penetrate the BBB: CSF levels nia. It is capable of depleting the extracellular supply are only 0.3–5% of concurrent plasma levels. CNS toxicof L-asparagine, thereby “starving” tumor cells of the ity with either drug is very rare when used at convenamino acid and inhibiting protein synthesis (Verma tional doses. On occasion, severe headache, seizures, et al., 2007). L-Asparaginase is a large molecule with and encephalopathy can develop during or after highminimal penetration of the BBB: minimal CSF levels dose IV infusion. are detected after an IV infusion. However, despite its inability to traverse the BBB, the drug is associated with several forms of central neurotoxicity, including Antibiotics diffuse encephalopathy, cerebral venous thrombosis BLEOMYCIN with venous infarction, and cerebral hemorrhage. The Bleomycin causes single-strand breaks in DNA and also encephalopathy can be acute or subacute and appears inhibits DNA-directed RNA polymerase. It is used in to be dose-related. Although the mechanism remains multiagent regimens for lymphomas, germ cell tumors, unclear, it may be due to hepatic toxicity and hyperamand head and neck cancer. Central neurotoxicity is very monemia. Encephalopathy can develop in 35–60% of rare, and may be more likely due to coadministered patients receiving high-dose treatment, often within the first 24 hours after drug administration. Symptoms agents (e.g., cisplatin). Reported neurologic symptoms include visual dysfunctions, seizures, encephalopathy, are variable, and can range from mild lethargy and perand cerebral infarction. sonality changes to frank coma. Focal neurologic deficits and seizures may also be noted. EEG usually DOXORUBICIN AND DAUNORUBICIN demonstrates diffuse slowing with triphasic waves. The majority of patients with encephalopathy have eleDoxorubicin and daunorubicin are antibiotics that vated levels of ammonia. Improvement in symptoms bind nucleic acids, disrupting the structural integrity usually occurs within a few days of discontinuation of of DNA, which are used for the treatment of L-asparaginase. More modern protocols use lower doses numerous hematologic and solid malignancies. During of L-asparaginase and are much less likely to induce IV infusion, neither drug is able to penetrate the encephalopathy. BBB to any significant degree: central neurotoxicity Cerebrovascular complications related to Lhas not been reported. However, when administered asparaginase can be quite severe in some patients, but IA to brain tumor patients, doxorubicin has been linked are less common. The drug depletes serum levels of sevto cerebral infarcts and hemorrhagic necrosis (Neuwelt eral hemostatic factors, including fibrinogen, antithromet al., 1983). Inadvertent IT injection of either drug can bin III, protein C, protein S, factors IX and X, and lead to an acute or subacute ascending myelopathy fibrinolytic enzymes (e.g., plasminogen). As a result, and encephalopathy, which can be fatal (Mortensen the serum prothrombin time (PT) and partial thromboplaset al., 1992). tin time (PTT) are typically elevated during treatment, even in asymptomatic patients. The most common cereMITOMYCIN C brovascular complication of L-asparaginase is cerebral Mitomycin C is an antineoplastic antibiotic that funcvenous or dural sinus thrombosis, with secondary venous tions as an alkylating agent and inhibits DNA synthesis. infarction (Lee et al., 2000). Headache is typically the first It is only known to cause central neurotoxicity in the consymptom, often associated with nausea, emesis, and text of mitomycin-induced disseminated intravascular visual obscuration. Generalized or partial seizures and coagulation and thrombotic microangiopathy, which somnolence are also frequently noted, as well as focal can lead to headache and other CNS symptoms (Pisoni neurologic deficits and papilledema. Cranial computed et al., 2001). tomography (CT) and MRI may be able to demonstrate venous infarction adjacent to the thrombosed vein or Miscellaneous agents dural sinus. MRI is more sensitive than CT, especially in conjunction with a magnetic resonance venogram L-ASPARAGINASE (MRV), which is able to clearly demonstrate the filling L-Asparagine is an amino acid required for the synthesis void of the involved sinus. Initial treatment consists of disof many important cellular proteins in normal human continuation of L-asparaginase and anticoagulation with cells. Many tumor cells do not have this capacity, due heparin (providing there is no evidence of frank hemora lack of the enzyme L-asparagine synthetase, and thererhage). Fresh-frozen plasma may also be of benefit to prefore require an exogenous supply of the amino acid. vent extension of the thrombus.

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TOPOISOMERASE INHIBITORS Irinotecan, topotecan, and rubitecan are all inhibitors of topoisomerase I, and prevent the religation of singlestrand breaks in DNA during DNA synthesis. The drugs are used to treat lymphomas, leukemias, and refractory solid tumors. Topotecan does not appear to have any significant central neurotoxicity except for very rare reports of headache and lethargy. Irinotecan has been associated with nonspecific dizziness and insomnia as well as occasional episodes of dysarthria, either alone or in combination with other drugs. The dysarthria completely resolves after discontinuation of the drug. Mitoxantrone is an intercalating agent that induces DNA strand breaks and inhibits topoisomerase II, which is used for the treatment of acute leukemia, lymphoma, prostate cancer, and various other solid tumors. It is not associated with any central neurotoxicity when given systemically, but may cause a myeloradiculopathy if administered intrathecally.

and psychiatric side-effects appear to be dose-related and are more likely in elderly patients and in those with underlying brain disease. Symptoms generally resolve after discontinuation of the drug.

TAMOXIFEN Tamoxifen is a nonsteroidal estrogen receptor antagonist that is mainly used for the treatment of estrogen receptor-positive breast cancer. It also inhibits protein kinase C, an important component of several signal transduction pathways. CNS neurotoxicity is relatively infrequent. Headache is one of the most common side-effects, especially in patients with a history of migraine. Visual system dysfunction is also described, with damage to the retina or optic nerves (Nayfield and Gorin, 1996). Retinal injury is more common, and presents with reduced visual acuity and central scotoma. Ophthalmic evaluation may reveal retinal edema and pigmentary changes; electroretinograms are often abnormal.

RADIOSENSITIZERS

INTERLEUKINS

Misonidazole and metronidazole are antimicrobial and antiprotozoal agents that are also used as radiation sensitizers, due to their selectivity for hypoxic cells and ability to impair nucleic acid synthesis and induce DNA strand breakage (Hammack, 2005). CNS toxicity is very rare, with scattered reports of generalized seizures and encephalopathy.

The interleukins (IL) are another family of cytokines with potent immunomodulatory and antineoplastic properties. IL-2 and IL-4 are used for their antineoplastic activity, while IL-3, IL-6, and IL-11 have applications as hematopoietic growth factors in support of chemotherapy. IL-2 is known to increase capillary permeability, which can lead to increased peritumoral edema and an elevation of intracranial pressure in patients with primary and metastatic brain tumors. Resulting symptoms can include headache, nausea, vomiting, seizures, exacerbation of focal deficits, and somnolence. In addition, other neuropsychiatric symptoms, such as depression, delusions, hallucinations, cognitive impairment, and focal neurologic deficits, may be noted. MRI may be normal or reveal multifocal regions of high signal abnormality on T2 images. In most cases, neurologic manifestations resolve after discontinuation of IL-2. IL-4 has less severe CNS toxicity, and is known to cause headache, lethargy, and fatigue.

THALIDOMIDE Thalidomide is a drug with antiangiogenetic and immunomodulatory properties, used for the treatment of myeloma, sarcoma, breast and prostate cancer, and high-grade astrocytomas (Melchert and List, 2007). Central neurotoxicity is generally mild, with varying degrees of somnolence. At high doses (i.e., 400 mg/day or above), the somnolence can be quite severe.

Biologic and targeted therapies INTERFERONS

RETINOIDS

The interferon family includes INF-a, INF-b, and INF-g, and represents a diverse group of cytokines with oncologic, immunoregulatory, and antiviral activity (ChelbiAlix and Wietzerbin, 2007). The most common CNS side-effects include headache, somnolence, cognitive slowing, and personality changes. Depression, mania, movement disorders, visual dysfunction, and other neuropsychiatric symptoms can also occur. The neurologic

The retinoids, including tretinoin and alitretinoin, are synthetic analogs of vitamin A (i.e., retinol) that induce cellular differentiation in tumors such as Kaposi’s sarcoma and acute promyelocytic leukemia. All of the retinoids are easily able to cross the BBB. The most common form of central neurotoxicity is headache, which affects 50–80% of patients on higher dose regimens, and can often be dose limiting. In most patients, there

NEUROLOGIC COMPLICATIONS OF CHEMOTHERAPY is no clinical evidence of elevated intracranial pressure. However, a small percentage of these patients can develop the syndrome of retinoid-induced pseudotumor cerebri, with symptoms of severe headache and visual impairment (Visani et al., 1996). Retinoids may induce the syndrome by reducing CSF resorption at the level of the arachnoid granulations. Discontinuation of the retinoid will result in resolution of headache, even if associated with pseudotumor cerebri. For patients that require continued treatment with retinoids, serial lumbar punctures and CSF drainage may be of benefit. Other less common neurologic side-effects of retinoids include abnormal color vision, transient visual loss, oculogyric crisis, and ataxia.

MONOCLONAL ANTIBODIES AND SMALL INHIBITORS (ANTIANGIOGENIC DRUGS) Most, if not all, anti-VEGF agents cause hypertension. Poorly controlled hypertension can lead to the development of posterior reversible encephalopathy syndrome (PRES). It is not the absolute blood pressure that predisposes patients to developing PRES but the change of blood pressure from baseline; patients can present with modest diastolic increase. PRES has been described after treatment with bevacizumab (Allen et al., 2006; Glusker et al., 2006; Ozcan et al., 2006; Koopman et al., 2008), sorafenib (Govindarajan et al., 2006), and sunitinib (Kapiteijn et al., 2007; Martin et al., 2007). PRES manifests clinically with the following symptoms: relative hypertension, cortical blindness, seizures, and confusion. Typically, MRI shows abnormalities on T2-weighted sequences limited to parieto-occipital white matter bilaterally, but occasionally anterior regions are involved. Timely initiation of antihypertensive therapy can probably prevent the occurrence of PRES. With some agents that cause PRES (for example, ciclosporin) retreatment at a lower dose has been possible following recovery, but similar data for VEGF inhibitors are lacking. Most patients recover fully with discontinuation of the causative agent and supportive management of hypertension and seizures. After initial reports (Kilickap et al., 2003; Johnson et al., 2004) mentioning an increased risk of intratumoral bleeding with the anti-VEGF monoclonal antibody bevacizumab, many trials of VEGF antagonists excluded patients with CNS metastases. However, an analysis identifying four trials of anti-VEGF therapy in patients with brain metastases found a negligible rate of intracranial bleeding (Carden et al., 2008). There is, therefore, no reason to exclude all patients with CNS metastases from treatment with

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bevacizumab, although caution is advised with tumors with a strong hemorrhagic tendency, such as renal cell carcinoma or melanoma. Similarly, a retrospective study suggests that bevacizumab can safely be combined with anticoagulants such as warfarin and enoxaparin in patients with brain tumors (Nghiemphu et al., 2008). Sunitinib is a polytyrosine kinase inhibitor that inhibits the intracellular tyrosine kinase domain of VEGF, platelet-derived growth factor, and c-KIT receptor, and it received US Food and Drug Administration (FDA) approval in 2006 for gastrointestinal stromal tumors and advanced kidney cancer. The occurrence of cognitive disorders in sunitinib-treated patients with pre-existing arteriosclerotic leukoencephalopathy has been described in three patients aged 74–84 (van der Veldt et al., 2007) who developed confusion, hallucinations, or an extrapyramidal syndrome that was rapidly reversible upon sunitinib discontinuation. All developed moderate hypertension during treatment and manifested leukoencephalopathy on MRI; none underwent repeat MRI after sunitinib discontinuation. In view of the clinical scenario, these patients conceivably suffered from a PRES variant.

CHEMOBRAIN The concept of “chemobrain” has evolved over the past decade and remains a hot topic in the literature. It is defined as a cognitive impairment in the absence of a direct involvement of the CNS by systemic tumor in the context of chemotherapy treatment. It was originally described among breast cancer patients in several longitudinal, cross-sectional studies with concomitant neuropsychological testing (Phillips and Bernhard, 2003; Hurria et al., 2007). Many of the studies have reported a subtle but significant impairment of memory, processing speed, and executive function among patients receiving chemotherapy in comparison to control subjects. The level of impairment did not seem to correlate with anxiety, depression, fatigue, or menopausal symptoms. On the other hand, there was a correlation with the intensity of chemotherapy. Patients were more likely to be impaired if they received high-dose regimens in comparison to those treated with standard regimens. These cognitive defects may persist more than 20 years after treatment (in particular with cyclophosphamide, methotrexate, and fluorouracil) (Koppelmans et al., 2012), are correlated with structural changes of the white matter tracts on MRI (Deprez et al., 2012), and could be attributable to a decline in neurogenesis in the hippocampus (Christie et al., 2012).

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Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 81

Neurologic aspects of palliative care: the end of life setting EEFJE M. SIZOO1*, WOLFGANG GRISOLD2, AND MARTIN J.B. TAPHOORN3 Department of Neurology, VU University Medical Center, Amsterdam, The Netherlands

1

2

Department of Neurology, Kaiser Franz Josep Hospital, Vienna, Austria

3

Department of Neurology, Medical Center Haaglanden, The Hague, Netherlands

INTRODUCTION The concept “palliative care” in neurologic patients is often a matter of debate. The perceived boundaries between active treatment and palliative care are often not well defined as for many neurologic diseases, there are no curative treatment options at present. Some authors suggest that palliative care in specific neurologic diseases describes the whole process of treatment, others associate the term palliative care only with the end of life (EOL) setting. This chapter on neurologic aspects of palliative care will mainly be focused on common aspects of the EOL setting of patients with neurologic diseases. The occurrence and supportive treatment of common neurologic signs and symptoms (such as increasing intracranial pressure, seizures, confusion and cognitive deficits, and disability), advance care planning with the focus on patients with progressive cognitive deficit, as well as EOL decision making will be discussed.

NEUROLOGIC SIGNS AND SYMPTOMS IN THE END OF LIFE PHASE Raised intracranial pressure Raised intracranial pressure may be present in the EOL phase of patients with brain tumors or other space-occupying lesions, such as intracerebral hemorrhage, brain abscess or massive venous infarction. Furthermore, obstruction of the normal cerebrospinal fluid circulation may also result in raised intracranial pressure. Compared to intracranial hemorrhage with an acute rise in intracranial pressure, the increase of intracranial pressure in patients with brain tumors is more gradual. It should be noted, however, that

spontaneous bleeding may occur in (rapidly) growing brain tumors with a similar acute rise in intracranial pressure to that in other causes of intracranial hemorrhage. High intracranial pressure results in (acute) headache, visual disturbances, nausea and vomiting, somnolence, and finally loss of consciousness. Decreasing level of consciousness often impairs the patient’s ability to communicate. In brain tumor patients, headache is a common presenting symptom (30–40%), and a new increase of headache points to a change in the oncologic situation, most often underlying brain edema or tumor recurrence (Behin et al., 2003). Increased intracranial pressure is common in the EOL phase of patients with high-grade gliomas; 36–62% of patients have headaches, and in the last week before death, decreased consciousness is present in 85–94% of patients (Oberndorfer et al., 2008; Pace et al., 2009; Sizoo et al., 2010).

Seizures Epileptic seizures in the EOL phase are common in patients with brain tumors: 30–58% of patients have seizures in the last month before death (Faithfull et al., 2005; Oberndorfer et al., 2008; Pace et al., 2009; Sizoo et al., 2010) and may even occur de novo in these patients. In contrast to classic partial or generalized seizures, patients may have nonconvulsive seizures which may easily be mistaken for decreased consciousness. Also, the postictal phase in brain tumor patients may be prolonged with only slow recovery of deficit. Although data on the incidence of seizures in the EOL phase of patients with other neurologic diseases are lacking, one can expect seizures to occur in diseases with progressive cortical damage (e.g., Alzheimer’s disease,

*Correspondence to: Eefje M. Sizoo, M.D., Department of Neurology, VU University Medical Center, P.O. Box 7057, 1007 MB Amsterdam, Netherlands. Tel: þ31-20-444-4219, Fax: þ31-20-444-2800, E-mail: [email protected]

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stroke, prion disease). When patients with a history of seizures develop problems with swallowing in the EOL phase – for example due to decreasing consciousness or oral candidiasis – the administration of medication is often withdrawn. Since discontinuation of antiepileptic drugs (AED) may induce seizures, it may be argued that daily AED should be administered via alternative routes (Krouwer et al., 2000). Patients with brain tumors and their partners often fear seizures in the EOL phase (Hildebrand, 2004; Mason, 2003).

Confusion and cognitive deficits Cognitive deficits are common in patients with brain diseases, and are most prominent in patients with dementia, stroke, or brain tumors. Patients with frontal lobe pathology (frontotemporal dementia, frontal brain tumors) may either express disinhibited behavior or present with a lack of motivation and activity. In patients with Alzheimer’s disease, memory deficits are the hallmark, whereas in other degenerative diseases (Parkinson’s disease, multiple stroke patients) mental slowing may be most prominent (Clare, 2010). In particular in brain tumor patients, cognitive deficits are global, not restricted to the brain tumor area, and due to both the disease itself and its treatment (Taphoorn and Klein, 2004). Cognitive deficits may eventually impair and distort personality and negatively influence communication (Lipsman et al., 2007), in particular in the terminal phases of the disease. Furthermore, in the EOL phase patients can be confused or agitated as a result of a delirium, although data on the incidence of a terminal delirium in neurologic patients are lacking. However, delirium is a common symptom in patients dying from systemic cancer (Ross and Alexander, 2001) and is often associated with the presence of brain metastases (Sarhill et al., 2001). The frequency of delirium is considerably higher in patients with primary or metastatic brain tumors (36%) as compared to cancer patients without brain involvement (18%) (Cobb et al., 2000). The presence of delirium, restlessness, or behavioral disturbances will have a negative impact on a peaceful and dignified experience of dying, affecting both the patients and their relatives (Morita et al., 2007; Namba et al., 2007; Bruera et al., 2009). Communication with the terminal neurologic patient may, apart from decreased consciousness and confusion, also be severely hampered due to dysphasia as a result of stroke, brain tumor, or Alzheimer’s disease.

Impaired motor functioning and immobility Progressive motor weakness leading to severe disability is the hallmark of patients with amyotrophic lateral sclerosis (ALS). In the EOL phase, these patients become

completely immobile and often unable to swallow and talk (Shoesmith and Strong, 2006; Wood-Allum and Shaw, 2010). Furthermore, paralysis of respiratory muscles causes respiratory insufficiency and is the cause of death in a large proportion of patients with ALS (McCluskey, 2007). Another respiratory abnormality in the terminal (neurologic) patient is the death rattle, caused by the accumulation of saliva in the throat. Other causes of (motor) disability in neurologic patients are brain tumor or stroke. Hemiparesis, but also sensory problems or lack of coordination, may result in immobility. Immobility has a severe negative impact on the patient’s quality of life (Osoba et al., 1997), and is often associated with loss of self-esteem and dignity. Limitations in the capability of personal care, continence, and hygiene are additional burdens. Immobility may lead to bodily pain due to skin ulcerations, spasticity, and limb contractures.

SUPPORTIVE TREATMENT OF NEUROLOGIC SYMPTOMS In the EOL phase, the physician’s duty is to reduce suffering as much as possible. Treatment should be aimed at relieving symptoms, maintaining quality of life, and facilitating a peaceful and dignified way of dying. The proper judgment and logistics (steering) of this situation requires an experienced team of doctors and nurses. Procedures vary among countries and cultures. Of paramount importance for the healthcare team is to stay in touch with the patient and the patient’s family, discussing all relevant issues concerning the EOL phase (Docherty et al., 2008). Especially in this phase, any investigation and treatment should be carefully considered, weighing any benefits against the disadvantages for the patient. In deciding on interventions postponing death, physicians should weigh the potential benefits of treatment against the quality of the patients’ remaining life. These decisions are based on medical and legal issues, but are also influenced by opinions from the family, who may wish to continue therapy as long as possible (Oberndorfer et al., 2008).

Increased intracranial pressure Headache due to increased intracranial pressure should be relieved by treatment with analgesics such as paracetamol and opioids, and nausea can be reduced by antiemetic drugs (Daly and Schiff, 2007). Especially in brain tumor patients, corticosteroids (dexamethasone) may relieve symptoms resulting from high intracranial pressure by reducing vasogenic edema surrounding the tumor. In approximately 70–80% of brain tumor patients significant symptom improvement is noticeable within 6–24 hours following the first dose (Kaal and

NEUROLOGIC ASPECTS OF PALLIATIVE CARE: THE END OF LIFE SETTING Vecht, 2004; Sinha et al., 2004). In selected cases a neurosurgical intervention (such as cerebrospinal fluid drainage) should be considered if corticosteroids are insufficient. In the EOL phase, the majority of brain tumor patients are on permanent corticosteroid treatment (Bausewein et al., 2003; Oberndorfer et al., 2008; Pace et al., 2009; Sizoo et al., 2010). When consciousness is decreasing and patients are no longer able to swallow, steroids are often discontinued. Acute withdrawal of corticosteroids, however, may result in rebound symptoms of increased intracranial pressure and/or adrenal insufficiency.

Seizures There is a lack of studies concerning seizure management in the EOL phase. As long as patients with a history of seizures are able to swallow, AED should be continued. However, many patients with neurologic diseases develop dysphagia as death approaches, due to pseudobulbar paresis, mesencephalic compression, or decreasing consciousness (White et al., 2008). Oral infections (e.g., candidiasis) are a non-neurologic cause of dysphagia to be considered. Dysphagia may cause problems in taking AEDs, especially in the home care setting. Current recommendations are based on expert opinion and common sense. If patients become unable to swallow, it is suggested the physician should reassess the necessity for continued AED use (Krouwer et al., 2000). Sometimes, AED are prescribed prophylactically, for example, in brain tumor patients without a history of seizures. At present, there is no evidence favoring prophylactic prescription of AED in brain tumor patients (Tremont-Lukats et al., 2008). However, the high incidence of seizures in the EOL phase of brain tumor patients suggests AED should be continued until death in patients with previous seizures. If oral administration is no longer possible, patients can be switched to rectal administration (valproic acid, carbamazepine, and phenobarbital are available as suppositories) (Krouwer et al., 2000) or intranasal or sublingual midazolam or clonazepam. Seizures may be treated with rectal diazepam, subcutaneous midazolam, or sublingual clonazepam (Krouwer et al., 2000). In the hospital setting, intravenous infusion of AEDs may be an option (Krouwer et al., 2000). The management of status epilepticus in the EOL phase may be a difficult decision, since admittance to the intensive care unit should preferably be avoided.

Cognitive deficits and delirium Cognitive deficits, if caused by progressive brain edema in brain tumor patients, may be alleviated with corticosteroids. Studies in various palliative care populations

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yielded recommendations concerning treatment and care of delirious patients in the EOL phase (Breitbart and Alici, 2008). A standard approach to the management of delirium involves a search for possible reversible underlying causes of delirium, such as pain, drugs, or bladder dilatation and metabolic causes (Voltz and Borasio, 1997). When symptoms are refractory, the medication of first choice is usually a neuroleptic drug such as haloperidol (Casarett and Inouye, 2001). However, neuroleptics can lower seizure threshold and should be prescribed very cautiously in patients with frequent seizures (Voltz and Borasio, 1997). In approximately 30% of dying patients with delirium, symptoms are not adequately controlled by antipsychotic medication. In such cases and in patients with disinhibited behavior, sedative drugs (midazolam, lorazepam) are reasonable options. Paradoxical reactions to benzodiazepines in geriatric patients, and prolonged deposit of these drugs in fatty tissue need to be considered. In studies evaluating palliative sedation, delirium is the most common underlying refractory symptom requiring sedation (Engstrom et al., 2007).

IMPAIRED MOTOR FUNCTIONING AND IMMOBILITY Motor disability in patients with ALS cannot be treated, but swallowing problems can be circumvented by enteral tube feeding and, in case of respiratory failure, (noninvasive) mechanical ventilation may support the patient and reduce dyspnea (Wood-Allum and Shaw, 2010). These measures may prolong life, but clearly have no influence on the course of disease (McCluskey, 2007). Severe sialorrhea as a result of swallowing problems may be treated with medication (e.g., botulin toxin) or radiation of the salivary glands (Guy et al., 2011). Since immobility and spasticity can be painful, positioning and physiotherapy are important aspects of supportive care. If motor disability is caused or aggravated by vasogenic edema surrounding a progressive brain tumor, dexamethasone may effectively, but only temporarily, relieve symptoms in the EOL phase (Kaal and Vecht, 2004).

END OF LIFE DECISIONS EOL decisions include withholding or withdrawing potentially life-prolonging treatment no longer considered to be useful (for example, the withdrawal of food and fluid), alleviation of pain and other symptoms with a potentially life-shortening agent (often opioids), continuous deep sedation, and, in a restricted number of countries, physician-assisted death (van der Heide et al., 2007). Attitudes regarding EOL decisions vary widely among countries and cultures (van der Heide

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et al., 2003). The withdrawal of nutrition in the EOL phase is more readily accepted than fluid withdrawal. The main goal of medical decision making at the EOL is to improve the quality of life of patients through the prevention and relief of suffering, even if this might hasten death. In several countries and cultures, however, the attitude towards the preservation of life, even under grim circumstances, averts any death “hastening” activities. It is often assumed the prescription of opioids and sedative drugs inevitably results in shortening of life. However, there is no evidence that initiation or increasing doses of opioids or sedative drugs at the EOL is associated with precipitation of death (Sykes and Thorns, 2003). In 2010, the American Academy of Neurology (AAN) ethics section discussed the practice of palliative sedation, and the majority of members agreed that terminal sedation was a useful option to reduce suffering (Russell et al., 2010). The use of opioids and sedative drugs in terminally ill patients is increasingly becoming accepted practice in EOL care. In some countries (Switzerland, the Netherlands, Belgium, and Luxemburg), physician-assisted death as euthanasia or physician-assisted suicide are allowed under strict conditions upon a well-considered request. The proportion of patients in whom nonsudden death is preceded by an EOL decision ranged, among six European countries, from 21% (Italy) to 51% (Switzerland) (van der Heide et al., 2007). Considering neurologic diseases, extensive data regarding EOL decisions are available in ALS patients. In these patients, EOL practices are very common, which is probably due to the restricted prognosis and the retained capacity for decision-making until dying (Gordon, 2011). On the other hand, in chronic progressive neurologic diseases such as dementia, advanced stages of Parkinson’s disease, or Huntington’s disease, the course may be protracted. The transition into the EOL phase may be sudden (e.g., due to infection) and unpredictable. Probably for this reason, EOL decision making in dementia is not very well documented and patients often receive poor EOL care, related to the unpredictable course of disease and patients dying as a result of poor intake of food and fluids, cachexia, and dehydration (Ostgathe et al., 2008).

Nontreatment decisions Nontreatment decisions in patients with a dismal prognosis due to any disease are defined as withholding or withdrawing life-sustaining treatment, such as cardiopulmonary resuscitation, antibiotic drugs, and admission to an intensive care unit or to a hospital. Nontreatment decisions in neurologic patients often encompass withholding or withdrawing artificial

administration of fluids and nutrition. Sufficient intake of food and fluids may be restricted in neurologic patients due to dysphagia, decreased consciousness, and cognitive failure. A specific EOL decision for ALS patients is whether or not to start or continue (non)invasive mechanical ventilation (Maessen et al., 2009), whereas in brain tumor patients use of dexamethasone is an important issue in EOL decisions (Pace et al., 2009).

Palliative sedation Palliative sedation is often started in delirious patients in the EOL phase, such as in patients with brain tumors. In high-grade glioma patients it was applied in 13% of cases and even, in a Dutch cohort, as many as 30% (Pace et al., 2009; Sizoo et al., 2012). Compared to brain tumor patients, the figures for palliative sedation in ALS patients are lower, ranging from 3.3% in Italy (Spataro et al., 2010) to 14.8% in the Netherlands (Maessen et al., 2009). Such figures on palliative sedation are not available in patients with dementia, but in a survey studying palliative sedation in Dutch nursing homes, dementia was the underlying disease in 20% of patients (van Deijck et al., 2010).

Euthanasia or physician-assisted suicide Data regarding euthanasia or physician-assisted suicide (PAS) are available in the Netherlands. In a cohort of ALS patients who died between 2000 and 2005, 16.8% opted for euthanasia or PAS (Maessen et al., 2009). Relatives frequently reported that reasons for patients with amyotrophic lateral sclerosis (ALS) to ask for these lifeshortening practices were fear of choking, progressive deterioration, loss of dignity, and being dependent on others (Maessen et al., 2009). Concerning patients with high grade glioma (HGG) and dementia, the cognitive impairment, in particular in the terminal stages, makes patient autonomy questionable. In a population of Dutch HGG patients, euthanasia or PAS occurred in 7% of patients. Cognitive disturbances and decreasing consciousness were reported as reasons for refusing euthanasia or PAS in these patients (Sizoo et al., personal communication). Despite the fact that many patients with dementia have an advance euthanasia directive, life termination hardly ever takes place, and never in incompetent patients (De Boer et al., 2010).

DECISION MAKING AND ADVANCE CARE PLANNING Confusion, cognitive deficits, communication deficits, and decreasing levels of consciousness are common problems in the EOL phase of many patients with neurologic diseases, although ALS may be regarded as an

NEUROLOGIC ASPECTS OF PALLIATIVE CARE: THE END OF LIFE SETTING exception in this respect. These symptoms may impair the patients’ competence to participate in EOL decision making (Kerrigan and Ormerod, 2010). Given that patient autonomy is increasingly important, and considering that the large majority of brain tumor patients and patients with dementia become incompetent in participating in shared treatment decisions in the EOL phase, advance care planning (ACP) involving the patient and the patient’s family is of major importance (Congedo et al., 2010). The aim is to reach a consensus about possible EOL decisions between all participants, respecting the values of both the patients and their families (Bausewein et al., 2003; Pace et al., 2010). Given the possibility that the patient will become incompetent regarding EOL decision making in the late stages of their illness, it is important to discuss the subject at a relatively early stage. In a randomized controlled trial evaluating ACP in patients with glioblastoma multiforme, patients were asked during treatment about their preferences if their disease became uncontrollable. Of all patients approached, 68% participated in the study, though at least 12% of patients were unwilling to participate and discuss the subject. Patients who participated were assigned to intervention or standard supply of information. Intervention included watching a video explaining different goals of care: life-prolonging care (including cardiopulmonary resuscitation), basic medical care (hospital care), or comfort care (symptom relief). Patients who had watched the video opted for “comfort care only” in more than 90% of cases (El Jawahri et al., 2010). None of the patients felt uncomfortable watching the video. This study underscores the importance and applicability of ACP: the majority of patients are willing to discuss potential EOL scenarios and, once the various treatment options have been made clear, the majority prefer comfort care over life-prolonging treatment. ACP varies among countries and cultures (Jox et al., 2008; Kerrigan and Ormerod, 2010; van Wijmen et al., 2010). In the Netherlands, where euthanasia and PAS are allowed under strict conditions upon a voluntary and well-considered request, ACP is dominated by the issue of euthanasia (van Wijmen et al., 2010). The directives are often written in a very general way, and may apply to patients with systemic cancer and probably for ALS, but become unclear with respect to patients with cognitive impairment or confusion (dementia patients, brain tumor patients). If a patient has a written advance euthanasia directive, ethically the question arises whether the person who made the directive is still the same person once they reach the final life phase. As written advanced directives rarely address the exact clinical situation under which the patient would have asked

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for euthanasia or PAS, these practices will often not be carried out in patients unable to assess their own situation (De Boer et al., 2010; Rurup et al., 2010; Sizoo et al., submitted).

BEREAVEMENT CARE Although bereavement is part of the daily routine in dealing with severely ill or dying patients, comparatively little attention is devoted to this important phase for the caregivers. Doctors have an important role in bereavement, and consultation with relatives and other carers is usually incorporated in the process of treatment (Smeding, 2006). Davies and Clarke have investigated this important, and often neglected issue (Davies and Clarke, 2005). Conversely the analysis of the bereavement process can serve as a feedback for the professional team.

CONCLUSION Palliative care and treatment issues in the EOL phase are important parts of neurologic care. Supportive treatment is aimed at preserving quality of life as long as possible, rather than being aimed at prolonging life as such. End of life decisions are common. In patients with a neurologic disease with a high chance of progressive cognitive decline along the disease process, it is important to anticipate and discuss EOL preferences relatively early in the disease.

REFERENCES Bausewein C, Hau P, Borasio GD et al. (2003). How do patients with primary brain tumours die? Palliat Med 17: 558–559. Behin A, Hoang-Xuan K, Carpentier AF et al. (2003). Primary brain tumours in adults. Lancet 361: 323–331. Breitbart W, Alici Y (2008). Agitation and delirium at the end of life: “We couldn’t manage him”. JAMA 300: 2898–2910. Bruera E, Bush SH, Willey J et al. (2009). Impact of delirium and recall on the level or distress in patients with advanced cancer and their family caregivers. Cancer 115: 2004–2012. Casarett DJ, Inouye SK (2001). Diagnosis and management of delirium near the end of life. Ann Intern Med 135: 32–40. Clare L (2010). Awareness in people with severe dementia: review and integration. Aging Ment Health 14: 20–32. Cobb JL, Glantz MJ, Nicholas PK et al. (2000). Delirium in patients with cancer at the end of life. Cancer Pract 8: 172–177. Congedo M, Causarano RI, Alberti F et al. (2010). Ethical issues in end of life treatments for patients with dementia. Eur J Neurol 17: 774–779. Daly FN, Schiff D (2007). Supportive management of patients with brain tumors. Expert Rev Neurother 7: 1327–1336. Davies E, Clarke C (2005). Views of bereaved relatives about quality of survival after radiotherapy for malignant cerebral glioma. J Neurol Neurosurg Psychiatry 76: 555–561.

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de Boer ME, Dr€oes RM, Jonker C et al. (2010). Advance directives for euthanasia in dementia: do law-based opportunities lead to more euthanasia? Health Policy 98: 256–262. Docherty A, Owens A, Asadi-Lari M et al. (2008). Knowledge and information needs of informal caregivers in palliative care: a qualitative systematic review. Palliat Med 22: 153–171. El-Jawahri A, Podgurski LM, Eichler AF et al. (2010). Use of video to facilitate end-of-life discussions with patients with cancer: a randomized controlled trial. J Clin Oncol 28: 305–310. Engstrom J, Bruno E, Holm B et al. (2007). Palliative sedation at end of life – a systematic literature review. Eur J Oncol Nurs 11: 26–35. Faithfull S, Cook K, Lucas C (2005). Palliative care of patients with a primary malignant brain tumour: case review of service use and support provided. Palliat Med 19: 545–550. Gordon PH (2011). Amyotrophic lateral sclerosis: pathophysiology, diagnosis and management. CNS Drugs 25: 1–15. Guy N, Bourry N, Dallel R et al. (2011). Comparison of radiotherapy types in the treatment of sialorrhea in amyotrophic lateral sclerosis. J Palliat Med 14: 391–395. Hildebrand J (2004). Management of epileptic seizures. Curr Opin Oncol 16: 314–317. Jox RJ, Hessler HJ, Borasio GD (2008). End-of-life decisions, powers of attorney, and advance directives. Nervenarzt 79: 729–737. Kaal EC, Vecht CJ (2004). The management of brain edema in brain tumors. Curr Opin Oncol 16: 593–600. Kerrigan S, Ormerod I (2010). Advance planning in end-of-life care: legal and ethical considerations for neurologists. Pract Neurol 10: 140–144. Krouwer HG, Pallagi JL, Graves NM (2000). Management of seizures in brain tumor patients at the end of life. J Palliat Med 3: 465–475. Lipsman N, Skanda A, Kimmelman J et al. (2007). The attitudes of brain cancer patients and their caregivers towards death and dying: a qualitative study. BMC Palliat Care 6: 7. Maessen M, Veldink JH, Onwuteaka-Philipsen BD et al. (2009). Trends and determinants of end-of-life practices in ALS in the Netherlands. Neurology 73: 954–961. Mason WP (2003). Anticonvulsant prophylaxis for patients with brain tumours: insights from clinical trials. Can J Neurol Sci 30: 89–90. McCluskey L (2007). Amyotrophic lateral sclerosis: ethical issues from diagnosis to end of life. NeuroRehabilitation 22: 463–472. Morita T, Akechi T, Ikenaga M et al. (2007). Terminal delirium: recommendations from bereaved families’ experiences. J Pain Symptom Manage 34: 579–589. Namba M, Morita T, Imura C et al. (2007). Terminal delirium: families’ experience. Palliat Med 21: 587–594. Oberndorfer S, Lindeck-Pozza E, Lahrmann H et al. (2008). The end of-life hospital setting in patients with glioblastoma. J Palliat Med 11: 26–30.

Osoba D, Aaronson NK, Muller M et al. (1997). Effect of neurological dysfunction on health-related quality of life in patients with high-grade glioma. J Neurooncol 34: 263–278. Ostgathe C, Gaertner J, Voltz R (2008). Cognitive failure in end of life. Curr Opin Support Palliat Care 2: 187–191. Pace A, Lorenzo CD, Guariglia L et al. (2009). End of life issues in brain tumor patients. J Neurooncol 91: 39–43. Pace A, Metro G, Fabi A (2010). Supportive care in neurooncology. Curr Opin Oncol 22: 621. Ross DD, Alexander CS (2001). Management of common symptoms in terminally ill patients. Part II. Constipation, delirium and dyspnea. Am Fam Physician 64: 1019–1026. Rurup ML, Pasman HR, Onwuteaka-Philipsen BD (2010). [Advance euthanasia directives in dementia rarely carried out. Qualitative study in physicians and patients]. Ned Tijdschr Geneeskd 154: A1273. Russell JA, Williams MA, Drogan O (2010). Sedation for the imminently dying: survey results from the AAN Ethics Section. Neurology 74: 1303–1309. Sarhill N, Walsh D, Nelson KA et al. (2001). Assessment of delirium in advanced cancer: the use of the bedside confusion scale. Am J Hosp Palliat Care 18: 335–341. Shoesmith CL, Strong MJ (2006). Amyotrophic lateral sclerosis: update for family physicians. Can Fam Physician 52: 1563–1569. Sinha S, Bastin ME, Wardlaw JM et al. (2004). Effects of dexamethasone on peritumoural oedematous brain: a DT-MRI study. J Neurol Neurosurg Psychiatry 75: 1632–1635. Sizoo EM, Braam L, Postma TJ et al. (2010). Symptoms and problems in the end-of-life phase of high-grade glioma patients. Neuro Oncol 12: 1162–1166. Sizoo EM, Pasman HRW, Buttolo J et al. (2012). Decisionmaking in the end-of-life phase of high-grade glioma patients. Eur J Cancer 48: 226–232. Smeding R (2006). Bereavement. In: R Catani, N Cherny, M Kloke et al. (Eds.), ESMO Handbook of Advanced Cancer Care. Taylor and Francis, London, New York, pp. 243–246. Spataro R, Lo Re M, Piccoli T et al. (2010). Causes and place of death in Italian patients with amyotrophic lateral sclerosis. Acta Neurol Scand 122: 217–223. Sykes N, Thorns A (2003). The use of opioids and sedatives at the end of life. Lancet Oncol 4: 312–318. Taphoorn MJB, Klein M (2004). Cognitive deficits in adult patients with brain tumours. Lancet Neurol 3: 159–168. Tremont-Lukats IW, Ratilal BO, Armstrong T et al. (2008). Antiepileptic drugs for preventing seizures in people with brain tumors. Cochrane Database Syst Rev CD004424. van Deijck RH, Krijnsen PJ, Hasselaar JG et al. (2010). The practice of continuous palliative sedation in elderly patients: a nationwide explorative study among Dutch nursing home physicians. J Am Geriatr Soc 58: 1671–1678. van der Heide A, Deliens L, Faisst K et al. (2003). End-of-life decision-making in six European countries: descriptive study. Lancet 362: 345–350.

NEUROLOGIC ASPECTS OF PALLIATIVE CARE: THE END OF LIFE SETTING van der Heide A, Onwuteaka-Philipsen BD, Rurup ML et al. (2007). End-of-life practices in the Netherlands under the Euthanasia Act. N Engl J Med 356: 1957–1965. van Wijmen MP, Rurup ML, Pasman HR et al. (2010). Advance directives in the Netherlands: an empirical contribution to the exploration of a cross-cultural perspective on advance directives. Bioethics 24: 118–126.

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Voltz R, Borasio GD (1997). Palliative therapy in the terminal stage of neurological disease. J Neurol 244 (Suppl 4): S2–S10. White GN, O’Rourke F, Ong BS et al. (2008). Dysphagia: causes, assessment, treatment, and management. Geriatrics 63: 15–20. Wood-Allum C, Shaw PJ (2010). Motor neurone disease: a practical update on diagnosis and management. Clin Med 10: 252–258.

Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 82

Neurologic aspects of heart transplantation 1

ALAIN HEROUX1* AND SALPY V. PAMBOUKIAN2 Heart Failure and Heart Transplant Program, Loyola University Medical Center, Maywood, IL, USA

2

Section of Advanced Heart Failure, Cardiac Transplant, Mechanical Circulatory Support and Pulmonary Vascular Disease, University of Alabama at Birmingham, Birmingham, AL, USA

INTRODUCTION Approximately 5 million Americans have heart failure, with National Hospital Discharge Survey data from 1979 to 2004 indicating that the number of hospitalizations with any mention of heart failure tripled from 1 274 000 in 1979 to 3 860 000 in 2004 (Roger, 2010). Currently, heart transplantation remains the best longterm therapy for patients with end-stage heart failure who have failed conventional medical therapies. However, due to organ shortages and other factors, heart transplant rates have remained static. In 2008, approximately 2000 heart transplants were performed in the US (Wolfe et al., 2010). Therefore, the appropriate selection of patients with the best chance of survival after cardiac transplantation is an important part in the allocation of this limited resource. The neurologic evaluation of the potential transplant recipient includes evaluation by a multidisciplinary team including the transplant cardiologist, neurologist, and neurosurgeon. The presence and severity of concomitant neurologic conditions must be defined in order to determine if outcome after cardiac transplant would be adversely affected, making cardiac transplantation ill advised.

PREOPERATIVE EVALUATION OF NEUROLOGIC DISEASE Central neurologic disease A detailed history regarding possible previous neurologic events, such as stroke or transient ischemic attack (TIA), or concomitant diseases that can have central manifestations should be obtained. Examples of diseases that have central nervous system manifestations and could impact on post-transplant survival would

include vascular diseases, connective tissue diseases, dementias, multiple sclerosis, sarcoidosis, and amyloidosis. In conjunction with a detailed history, thorough physical examination should be performed. After history and physical examination have been performed, imaging studies should follow. Because many, if not all, endstage heart failure patients have implantable cardiac defibrillators and/or pacing devices, magnetic resonance imaging (MRI) may not be feasible as many consider these devices a contraindication. (Farling et al., 2010) Therefore, unenhanced and/or enhanced head computed tomography (CT) should be obtained. Patients who have had previous stroke, age > 40, or who are at risk of vascular disease (for example, those with known coronary artery disease or diabetes), should have carotid artery imaging. If an abnormality is found, it is important to assess the extent of disease burden. In general, dementias, systemic diseases limiting survival, or systemic diseases exacerbated by immunosuppressive therapy post-transplant are considered contraindications to cardiac transplantation. Previous stroke is not an absolute contraindication to cardiac transplantation, unless there are significant neurologic sequelae and late effects. Patients with significant cognitive impairment and limited potential for cardiac rehabilitation are not considered appropriate for transplant in most centers. The presence of high-grade, asymptomatic, focal carotid artery disease may not preclude cardiac transplantation, but may require revascularization, either with carotid endarterectomy, or alternatively stenting, depending on the patient’s clinical condition (Hertzer, 2010). In contrast, diffuse disease may progress post-transplant in the presence of steroid therapy, drug-induced diabetes, hypertension, and dyslipidemia, and may render cardiac transplant ill advised.

*Correspondence to: Alain Heroux, M.D., Professor, Heart Failure/Heart Transplant Program, Loyola University Medical Center, 2160 South First Avenue, Maywood, IL 60153, USA. E-mail: [email protected]

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Peripheral nervous system disease As above, a detailed history and physical examination assessing for the presence of peripheral nervous system disease should be performed at the time of heart transplant evaluation. Systemic diseases with peripheral nervous system manifestations that would preclude long-term survival post-transplant or interfere with rehabilitation would be considered contraindications to heart transplant. Many patients with diabetes mellitus and concomitant heart disease are referred for heart transplant evaluation, therefore peripheral neuropathy as a complication of diabetes is the most commonly encountered peripheral neurologic disorder in this population. Patients with uncomplicated diabetes have been shown to do well after cardiac transplantation although they may be at increased risk of infections (Marelli et al., 2003; Russo et al., 2006). However, in one large study of over 20 000 heart transplant recipients transplanted between 1995 and 2005, patients with increased severity of diabetes characterized by the presence of obesity (BMI
35 kg/m2), previous stroke, renal insufficiency (creatinine
2.5 mg/dL) or peripheral vascular disease had lower median survival post-transplant, with decreasing survival for each diabetes-related complication present (Russo et al., 2006). Those without diabetes had a median survival of 10.1 years versus 3.6 years for those with two or more diabetic-related complications (Russo et al., 2006). Traditionally, individuals with peripheral neuropathy as a complication of diabetes have been declined heart transplantation, and therefore excluded from published series. However, extrapolating from published data, the presence of peripheral neuropathy (characterized by nerve conduction study) as a marker of worse disease severity would need to be carefully considered along with other disease indicators to determine suitability for cardiac transplantation.

POSTOPERATIVE NEUROLOGIC COMPLICATIONS Central Perioperative cerebrovascular complications are more common after cardiac transplantation compared to routine cardiac surgery such as coronary artery bypass grafting (van de Beek et al., 2008). Rates range from 4% to 42% (Andrews et al., 1990; Jarquin-Valdivia et al., 1999; Malheiros et al., 2002; Perez-Miralles et al., 2005; van de Beek et al., 2008). Ischemic stroke is the most common cerebrovascular complication (Perez-Miralles et al., 2005; van de Beek et al., 2008) and may result from anoxic-hypoperfusion events resulting in watershed infarcts. Other cerebrovascular complications include hemorrhagic stroke,

encephalopathy, and TIA. Early perioperative hemorrhagic stroke may occur in the setting of pretransplant low cardiac output followed by post-transplant relative hyperperfusion associated with disordered cerebral autoregulatory pressor response (Sila, 1989a; Zivkovic, 2007). Transcranial Doppler ultrasound after heart transplantation shows an increase of velocity of up to 50% or higher (Massaro et al., 2006). Seizures and posterior reversible encephalopathy syndrome (PRES) may occur perioperatively, likely related to the introduction of immunosuppressive agents, specifically calcineurin inhibitors (CNI), in the early postoperative period. Substitution of one CNI for another with close monitoring of drug levels may be necessary. Perioperative stroke is associated with 1 year mortality in contrast to perioperative delirium or encephalopathy, diseases of peripheral nerves and muscles, and seizures, which are not associated with worse outcome (van de Beek et al., 2008). CNS infections are relatively uncommon early posttransplant, but are associated with decreased survival (van de Beek et al., 2008). Imaging studies including head CT (unenhanced or enhanced) should be undertaken, but may be nondiagnostic. MRI can be performed as pacing/defibrillating devices were removed at the time of cardiac transplant; however, it may be limited by the clinical condition and the patient’s ability to lie in the scanner for a prolonged period. The evaluation of possible neurologic complication post-transplant should include expert input from a neurologist familiar with issues related to solid organ transplantation.

Peripheral nervous system complications Postoperative peripheral nervous system complications most commonly include brachial plexopathy, peroneal nerve mononeuropathy, critical illness neuropathy or myopathy, (Adair et al., 1993; Perea et al., 2001; Mateen et al., 2009), and vocal cord paralysis (van de Beek et al., 2008). Although patient survival after transplantation may not be affected by these complications, they do contribute to the morbidity of the procedure and prolong rehabilitation time. With careful patient management and attention to patient positioning and monitoring, most of these complications are avoidable.

LONG-TERM NEUROLOGIC ASPECTS OF HEART TRANSPLANTATION The incidence of neurologic complications following solid organ transplantation is frequent. Approximately one-third of recipients (10–59%) present with neurologic symptoms (van de Beek et al., 2008; Marco et al., 2009). It is most frequently related to side-effects of the immunosuppressive regimen, drug toxicity, and complications

NEUROLOGIC ASPECTS OF HEART TRANSPLANTATION 1231 due to immunosuppression. Symptoms related to the increasing endothelium, with secondary increase of tromimmunosuppressive regimen following heart transplanboxane and decrease in nitric oxide. The drugs may also tation include tremors, seizures, strokes, central nervous cause an impairment of neuronal transmission by (1) system infections, encephalopathy, and tumors (van de decreasing g-aminobutyric acid which can lead to Beek et al., 2008). Risk factors that may enhance neuroincreased seizure activity, (2) decreasing neuronal serotologic complications following heart transplantation nin leading to more susceptibility to depression and include pre-existing conditions such as a prior sroke tremor, and (3) the inhibition of glutaminergic Nand comorbidities such as diabetes, hypertension, and methyl-D-aspartate receptors which could be a possible hypercoagulable states. Neurologic complication is the cause of delirium (Bechstein, 2000). primary cause of death in 20% of transplant recipients The treatment of neurotoxic side-effects related to (Perez-Miralles et al., 2005). calcineurin inhibitors consists of switching from ciclosporin to tacrolimus or vice versa, decreasing the dose of the drugs or switching from mycophenolate mofetil or Current immunosuppression azathioprine to a Thor inhibitor such as evrolimus or The current immunosuppressive regimen in solid organ sirolimus to decrease the level of calcineurin inhibitors. transplantation can be divided into three phases: inducb-Blockers can also be used to decrease tremors. tion, maintenance, and rescue. The induction phase The use of steroids in the induction, maintenance, and occurs at the time of transplantation and consists of rescue phases can cause behavioral disorders such as the use of monoclonal antibodies such as OKT3 and confusion, mood disturbances, manic states, and psydacluzimab or polyclonal antibodies such as antithymochosis. These can be exacerbated by underlying metacyte globulin (ATG). The aim of induction is to prevent bolic abnormalities. Treatment consists of lowering the the early occurrence of acute cellular rejection. It is given dose or stopping intravenous steroids and correcting over the course of a few days while the serum level of the underlying metabolic abnormalities. maintenance immunosuppressive agent can be raised to Monoclonal and polyclonal antibodies used during therapeutic levels to prevent rejection. the induction and rescue phases of immunosuppression Maintenance immunosuppressive regimen consists of: can cause acute aseptic meningitis in 5–10% of patients (1) calcineurin inhibitors such as Cyclosporine and tacroli(Adair et al., 1991; Pittock et al., 2003). These symptoms mus (FK506); (2) mycophenolate mofetil (MMF) and azaare due to proinflammatory cytokine release, due to T thioprine; (3) mTOR (mammalian target of rapamycin) cell lysis with OKT3 and lymphocyte inactivation with inhibitors such sirolimus and everolimus; (4) steroids. ATG. The symptoms resolve without stopping the drugs. Finally, the rescue phase of immunosuppression is Inhibitors of DNA synthesis such mycophenolate related to the treatment of acute cellular rejection and mofetil and azathioprine work by selective and nonseleccirculating antibody-mediated rejection. Intravenous or tive blocking of enzymes involved in purine synthesis. oral steroids, monoclonal or polyclonal antibodies, are They inhibit both T cells and B cells. Mycophenolate the most frequently used agents. mofetil use has been reported as a cause of progressive Calcineurin inhibitors (CNI) such as ciclosporin and multifocal encephalopathy resulting from the activation tacrolimus inhibit T cell proliferation and activation by of the JC virus. Finally, Thor inhibitors such as sirolimus inhibiting the transcription of cytokine genes that proand evrolimus have not been reported as a cause of duce lymphocyte-specific growth factor interleukin 2 neurologic symptoms following transplantation. (IL2). Both drugs have similar toxicity profiles although Although calcineurin inhibitors are the most frequent neurotoxicity is more frequent and more severe with culprits for neurologic side-effects, the incidence can tacrolimus. Approximately 10–28% of patients on calciincrease due to drug interactions (Lake and Canafax, neurin inhibitors experience neurotoxic side-effects 1995) that increase their concentration, such as erythromy(Bechstein, 2000). Symptoms range from mild to severe cin, increase absorption of ciclosporin, such as Metoand include tremors, insomnia, nightmares, headaches, clopramide, and agents that decrease the metabolism vertigo, dysesthesia, photophobia, mood disturbances, of ciclosporin, such as diltiazem, nicardipine, rapamil, akinetic mutism, seizures, cortical blindness, focal neuketoconazole, fluconazole, itraconazole, erythromycin, rologic deficit, psychosis, and encephalopathy. josamycin, oral contraceptives, and tacrolimus (FK506). The mechanism of neurotoxicity with calcineurin It is also important to note that the use of antiseizure inhibitors may be related to binding with immunophilins, medications can decrease the level of ciclosporin and which facilitate protein folding and transportation. increase the risk of rejection. Phenytoin decreases abWhen bound to calcineurin inhbilitors, immunophilins sorption and increases the metabolism of ciclosporin. are less available for normal physiologic processes. CalPhenobarbital and carbamazepine both increase the cineurin inhibitors cause vasoconstriction of vessels by metabolism and decrease the serum level of ciclosporin.

1232 A. HEROUX AND S.V. PAMBOUKIAN Finally neurologic complications of the immunoreactivation of Mycobacterium tuberculosis rarely suppressive regimen are also related to the state causes brain abscesses. Its incidence has been reported of immunosuppression rather than side-effects from at 1%. Listeria monocytogenes can manifest itself immunosuppressive drugs or drug toxicity. They include with symptoms of meningitis but also with brainstem central nervous system infection, stroke, and tumors. encephalitis with cranial nerve palsy and cerebellar signs. Opportunistic infections caused by a Candida Encephalopathy species rarely cause central nervous system infections. Aspergillus fumigatus is the most frequent cause of Following heart transplantation, patients can present fungal brain abscesses (Hotson and Enzmann, 1988b). with mildly altered level of consciousness to delirium Like Nocardia, the route of entry for Aspergillus is and coma (Chang et al., 2001). This can be associated the lung. There is evidence of pulmonary infection in with impaired vision, tremor, multifocal myoclonous, 83–90% of patients. Aspergillus CNS infection can chorea, and seizures. Electrolyte, glucose, and other cause ischemic or hemorrhagic infarction and multiple metabolic disorders as well as ciclosporin, tacrolimus, abscesses. Patients can present with altered mental state and to a lesser extent OKT3 have been associated with (86%), seizures (41%), focal neurologic deficits (32%), these symptoms. Levels of these drugs can be elevated and meningeal signs (19%). Cryptococcus neoformans but symptoms can occur with normal serum levels. is an encapsulated yeast. It is a rare cause of CNS infecThe EEG usually shows a diffuse slowing and correction tion (0.36%). Symptoms develop between 2 and 90 days of the underlying metabolic abnormalities and modifyafter infection and are compatible with subacute mening the immunosuppressive regimen can reverse the ingitis (Wu et al., 2002). symptoms. Infection with a protozoal agent is also increased in immunocompromised patients. Toxoplasma gondii is Central nervous system infections an obligate intercellular parasite. It is the second cause Central nervous system infections occur in 5–7% of solid of meningeal encephalitis and brain abscesses. Brain organ transplant patients (Sila, 1989a). Patients affected abscesses are usually multiple. It can also, like the other with central nervous system infections have a high moragents, cause other infections such as chorioretinitis, tality. Infections usually occur 2—6 months after transmyocarditis, and pneumonitis. plantation. Bacterial infections occur with a higher Focal encephalitis is the usual presentation of patients incidence early, between 0 and 2 months. Viral and funwith herpes virus (HSV) and HHV-6 agent. Cytomegalogal infections occur later, with a higher incidence at 6 virus (CMV) is an uncommon cause of CNS infection months post-transplantation. Their occurrence is related due to prophylaxis with valganciclovir (Valcyte). The risk to higher dose of immunosuppression especially early of infection is increased in patients who are CMVafter transplantation and are associated with systemic negative at the time of transplantation receiving an infections. They are often caused by opportunistic organ from a CMV-positive donor. There is an increased agents. These can be bacterial, such as Nocardia, Mycorisk of reactivation in CMV-positive recipients who do bacterium tuberculosis (Singh and Paterson, 1998), not receive Valcyte prophylaxis or patients who are Listeria monocytogenes; fungal, such as Cryptococcus receiving intense immunosuppression as rescue therapy neoformans (Wu et al., 2002), Aspergillus fumigatus for rejection of the heart. Finally, JC polyomavirus (Hall et al., 1989b), candida, and Pneumocystis carinii; causes progressive multifocal leukoencephalopathy and viral, such as cytomegalovirus (CMV), varicella zos(PML) with symptoms of dementia, ataxia, visual disturter, Epstein–Barr virus (EBV), herpes type 1, 2, 6 (Nash bances, and progression to a vegetative state in 6 months. et al., 2004), and less frequently, JC polyomaviruses There is no treatment for a polyoma infection (Hall et al., (Lewis et al., 1993). Patients can present symptoms com1988a; van de Beek et al., 2007). patible with meningitis, encephalitis (Murtagh et al., It is important to remember that the symptoms of 2005), and focal deficit with the presence of an abscess CNS infection can be subtle due to the presence of the (Weigel et al., 2003; Marchiori et al., 2007). These sympimmunosuppressive drugs. A high degree of suspicion toms may be blunted because of immunosuppression must be exercised to changes in mental status or focal which decreases symptoms related to inflammation. signs in the context of the systemic infection. Diagnostic Bacterial opportunistic infection by Nocardia has imaging should be used early and diagnostic invasive been reported in 16% of solid organ transplant patients. procedures such as lumbar puncture and brain biopsy The usual route of entry is through the lungs. After an to identify the opportunistic agent should be used if initial pneumonia the most frequent secondary dissemiother sites such as the lungs do not show evidence of nation site is the central nervous system. It can cause infection that would be amenable to a diagnostic a single or multiple brain abscesses. An infection or procedure.

NEUROLOGIC ASPECTS OF HEART TRANSPLANTATION

Stroke Strokes are rare but a significant cause of morbidity and mortality following heart transplantation (JarquinValdivia et al., 1999). The incidence is reported to be between 3% and 10%. Underlying etiologies for strokes are the presence of atherosclerosis, vasculitis, arrhythmias, hypercoagulable states, and endocarditis. A retrospective study of 314 patients having undergone heart transplantation (46  14 years of age; 78% male) between 1984 and 2002 with a mean follow-up of 54  57 months have shown a 7% incidence of patients presenting symptoms compatible with a cerebral vascular accident (Belvis et al., 2005). Of these, 60% were ischemic stroke, 28% were transient ischemic attack (TIA), and 12% were hemorrhagic. Early postoperative strokes (less than 2 weeks) occurred in 20% of this population whereas late stroke incidence accounted for 80%. The clinical presentation of ischemic strokes was compatible with occlusion of the total anterior circulation in 23.1%, partial occlusion of the anterior circulation in 38.4%, lacunar infarction in 15.4%, and posterior circulation occlusion in 23.1%. The etiology of ischemic stroke was related to large artery atherosclerosis in 15.4% of the patients, cardioembolism in 14.4%, small vessel disease in 15.4%, unusual causes in 15.4%, and undetermined etiology in 38.4%. The presence of a prior stroke increased the risk of stroke after heart transplantation. The risk of developing a stroke 5 years after heart transplantation was 4.1% in patients who had a prior stroke compared to 1.1% of patients without a history of stroke. The incidence of echo contrast or thrombi in the left atrium is significantly lower in patients having undergone the bicaval anastomosis technique at the time of transplantation then the standard biatrial anastomosis. Older age and the presence of extracranial carotid artery stenosis over 50% seems to increase the risk of stroke. The recurrence of stroke was 18% in patients having presented with a stroke following heart transplantation.

Central nervous system malignancies Patients having undergone solid organ transplantation are three to four times more at risk of developing central nervous system (CNS) malignancies than the general population. The most common type of malignancies are lymphomas and gliomas. The incidence of posttransplant lymphoproliferative disorder (PTLD) is 5% in the Registry of the University of Cincinnati (Penn, 2000). Heart and lung transplant recipients are at an increased risk of developing PTLD. Based on the University of Cincinnati’s Tumor Registry, nonrenal transplant recipients account for 45% of the total reported cases of

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PTLD compared to renal transplant recipients, who account for 12%. A heavy immunosuppression regimen increases the potential for the development of PTLD. PTLD is diagnosed in 1% of renal, 3% of heart, 3% of liver, 8% of lung, and 19% of intestinal transplant recipients. Positive seroconversion to the Epstein–Barr virus (EBV), especially if the recipient was seronegative at the time of transplantation, has been reported as a risk factor for the development of PTLD. Cytomegalovirus (CMV) infection may be a cofactor with EBV as a risk. This may be due to an increase in immunosuppression. The presence of an increased EBV load increases the incidence of B cell lymphoma. Based on the Cardiac Transplant Research Database (CTRD), pediatric transplant recipients are at higher risk. The high occurrence may be related to the fact that children have more lymphoid tissue.

CLASSIFICATION OF POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER

1.

2.

Hyperplasia: these types of lymphoproliferation are all polyclonal. Examples are infectious mononucleosis and plasma cell hyperplasia. Neoplasia: these types of malignancies can be polymorphic or monomorphic, such as B cell, T cell, natural killer, and all plasma cell lymphomas. Other forms include myeloma, plasmacytomas, and Hodgkin’s disease, which are uncommon. Some 4% of PTLDs are myeloma and 3% are Hodgkin’s disease.

The detection of the disease is based on clinical symptoms and imaging. The final diagnosis is based on brain biopsy. The treatment of PTLD is based on the cellular type and may include radiation therapy, chemotherapy, and surgery. Early PTLD (up to 24 months) are more frequently EBV þ, affect children more frequently, and have a tendency to respond to a decrease in immunosuppression and the use of antiviral agents. Late PTLD (25–300 months) are usually EBV  and do not respond to a decreased immunosuppression and the use of antiviral agents.

Seizures Seizures following heart transplantation are usually related to immunosuppression toxicity, electrolyte or osmolar changes, CNS infection, ischemic or hemorrhagic stroke, tumor, and a history of epilepsy prior to transplantation. (van de Beek et al., 2007; Zierer et al., 2007; Zivkovic, 2007; Navarro et al., 2010). Seizures are partial or generalized, usually tonic-clonic, and rarely nonconvulsive. In the majority of patients they

1234 A. HEROUX AND S.V. PAMBOUKIAN are usually isolated events that usually do not require left heart syndrome not corrected (n ¼ 6), (2) hypoplastic long-term therapy. Investigation of seizures should left heart syndrome with Norwood repair (n ¼ 3), and (3) include an EEG, CT and MRI of the head (Zivkovic, cardiomyopathy (n ¼ 8). Overall the population had an 2007), serum chemistry for magnesium, sodium, and 82% survival rate during follow-up. One patient in group glucose, and a lumbar puncture if the patient has signs 1 presented with a stroke followed by seizures necessitatof meningismus. ing long-term antiepileptic therapy. Three had minor At the moment, there is no controlled drug trial for neurologic abnormalities such as tremors and absent the management of seizures after orthotopic heart transreflexes, and seven had normal neurologic examination. plantation. It is important to remember that there is an Risk factors for seizures have been reported by Raja interaction between antiepileptic therapy and immunoet al. (2003). This study population included 127 infants suppressive medications. Phenytoin, phenobarbital, who had undergone orthotopic heart transplantation due and carbamazepine can decrease the ciclosporin serum to hypoplastic left heart syndrome (HLHS). Their ages level by decreasing the absorption or by increasing the ranged from 9 to 90 days at the time of transplantation. metabolism of ciclosporin. Thus it is important to check Seizures occurred in 27 patients (21%) during follow-up. drug levels for both antiseizure and immunosuppressive The group was compared to 27 patients of comparable regimen. First-line therapy includes phenytoin, phospheage who had undergone heart transplantation without nytoin, and phenobarbital that can be administered intraseizures. The study concluded that risk factors for seivenously. Seizures lasting more than 4–5 minutes or zures included a prolonged total cardiopulmonary progressing into status epilepticus require prolonged antibypass time, especially if it was associated with the presepileptic drug treatment with oral medications such as ence of other complications following transplantation. gabapentin, levetiracetam, carbamazepine, valproic acid, Deep hypothermic circulatory arrest was inversely correand other agents (Chabolla and Wszolek, 2006). Status lated with seizure severity. Infants presenting with an epilepticus represents 16–25% of all poststroke seizures. abnormal pretransplantation EEG and a high total Most poststroke seizures are focal and typically controlled bypass time had a higher frequency of seizures requiring with intravenous phenytoin, phosphophenytoin, and valprolonged use of antiepileptic therapy. Abnormalities in proic acid. This intravenous treatment would be followed post-transplantation EEGs were not associated with the by an oral monotherapy. Hemodialysis should be consineed for continued antiepileptic treatment. dered for drug-induced seizures, especially if renal failure Acute myopathy of intensive care has been described reduces drug elimination. Finally, patients with a history of with an acute onset of hypotonia and flaccid quadriplegia seizures pretransplantation may warrant prophylactic use (Chetaille et al., 2000). The patient had undergone a preof antiepileptic drug therapy, especially early following operative muscle biopsy because of family history of heart transplantation when drug levels of immunosupperipheral myopathy. The biopsy was near normal with pressive medications such as ciclosporin and FK506 are nonspecific mitochondrial disorder. Postoperatively with at their higher serum levels and predispose the patient to symptoms of flaccid quadriplegia, the biopsy showed seizures along with metabolic changes occurring early severe loss of myosin and ATPase activity in type 2 fibers. after heart transplantation. The patient had normal nerve conduction and the electromyogram showed myopathic changes. Recovery Peripheral nervous system complications occurred within 3 weeks and the biopsy performed a few months later was normal. Progressive visual deterioPeripheral nervous system complications following heart ration due to pseudotumor cerebri leading to blindness transplantation can present with peripheral neuropathy has been reported (Schowengerdt et al., 1993), as well associated with immunosuppressive regimens as previas Friedreich’s ataxia presenting clinically after cardiac ously discussed and complications related to comorbidtransplantation (Leonard and Forsyth, 2001). In this case ities such as diabetes and osteopenia (Malheiros et al., the patient underwent a muscle biopsy preoperatively 2002). Compression of nerve roots by an infectious probecause of weakness. The biopsy and histochemical stains cess or a tumor, although less frequent, should also be were normal. The weakness was felt to be due to congesconsidered (Malheiros et al., 2002). tive heart failure. The patient underwent successful orthotopic heart transplantation and continued to develop Neurologic complications in children muscle weakness with normal allograft function. Genetic It has been reported that up to 50% of children undergostudies performed were compatible with Friedreich’s ing heart transplantation had neurologic complications ataxia. Finally, neurodevelopmental outcome in two (Starnes et al., 1989; Martin et al., 1992). A study by groups of age-matched pediatric patients has been Lynch et al. (1994) reported a 60 month follow-up in 17 described (Fleisher et al., 2002). The investigator compatients divided into three populations: (1) hypoplastic pared 18 pediatric patients who had undergone heart

NEUROLOGIC ASPECTS OF HEART TRANSPLANTATION transplantation versus 18 who had undergone cardiopulmonary bypass for nontransplant cardiac procedures. Pediatric patients having undergone orthotopic heart transplantation had difficulties with growth and development, an increase in neurologic abnormalities as well as speech, language delays, and hearing problems. Comparison of neurologic complications between adults and children having undergone heart transplantation has been described (Mayer et al., 2002). A 14 year retrospective study (1986–2000) consisted of 184 patients (107 adults and 77 children). Forty-seven neurologic complications occurred in 29.9% of adults whereas 22 complications occurred in 18 children (23.4%). Peripheral neuropathy was the most frequent neurologic complication in adults and seizures the most frequent complication in children. Other complications such as infections, encephalopathy, cerebral vascular accidents, and neoplasm were comparable in both groups. Early complications ( 40 years and Despite the long list of esoteric neurologic problems seen peripheral vascular disease being the strongest predicamong transplant recipients, many of the most common tors for stroke in this population (Oliveras et al., problems, specifically the metabolic causes, are similar 2003). There are conflicting data regarding the risk of to those seen in the general population. Patients with stroke and intracranial hemorrhage in renal transplant renal disease, with or without a renal transplant, have recipients with autosomal dominant polycystic kidney a more profound response to metabolic events than disease (ADPKD). While a few reports suggested an those without renal disease with the sole exception of increased risk of stroke (Pirson et al., 1996) and intracrasevere hyperglycemia in dialysis patients, who are spared nial bleed in this patient group (Wijdicks et al., 1999; volume contraction from osmotic diuresis. Transplant Oliveras et al., 2003), others did not find any such assorecipients are frequently monitored for such changes ciation and reported ADPKD renal transplant patients to and so many of the metabolic problems do not pose a be more susceptible to ischemic than hemorrhagic diagnostic dilemma. strokes (Adams et al., 1986; Watschinger et al., 2008). Although uremia certainly causes neurologic sympRegardless of the risk, as in the general population, renal toms, the elevated blood urea nitrogen (BUN) and creattransplant recipients with ADPKD should have brain inine levels are rarely the cause of lethargy and mental imaging done when there is a family history of intracrastatus changes. Myoclonus, tremors, and asterixis are nial hemorrhage. Mortality has been reported to be high commonly seen with high BUN and creatinine levels. in transplant patients with stroke, with one US study There is no definite cut-off value for BUN as symptoms attributing 8% of deaths in kidney transplant recipients of uremia have appreciable interpatient variation and to stroke (Howard et al., 2002). Efforts to prevent stroke depend on the rapidity of renal failure, the age of the include aggressive control of hypertension, diabetes, and patient, and any underlying CNS disease (Bleck et al., hyperlipidemia. There is no contraindication to the use of 1993). Since metabolism of most drugs is affected in low-dose aspirin, even in transplant recipients with renal renal failure, it might be difficult to distinguish uremia insufficiency. from effects induced by medications. Acute uremic encephalopathy generally reverses with dialysis (with PERIPHERAL NEUROPATHY an occasional lag period of 1–2 days) and other etiologies Uremic polyneuropathy seen in patients with advanced need to be pursued when this does not happen. renal failure generally improves after transplantation Hyperglycemia is common as many patients develop but may persist in patients who have been on dialysis post-transplant diabetes mellitus, for which they are roufor years prior to the transplant. tinely monitored. This is more common in the immediate The incidence of Guillain–Barre´ syndrome (GBS) in post-transplant period as a result of medication sidesolid organ transplant is unknown although commonly effects and restoration of normal kidney function which reported in bone marrow transplant patients. Published shortens the half-life of insulin. Accordingly, diabetic cases in such a setting suggest a higher incidence in renal transplant recipients are instructed to monitor their males and association with CMV infection at or before blood sugar at home even if they did not require any the onset of GBS (El-Sabrout et al., 2001). medicines while on dialysis. Acute femoral neuropathy in the immediate postHypercalcemia can occur when hypertrophied paratransplant period may occur in 2% of renal transplant thyroid glands continue to secrete the parathyroid

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hormone (PTH) even in the setting of near normal renal function. PTH levels generally drop in few weeks but some patients may have tertiary hyperparathyroidism leading to symptomatic hypercalcemia (anxiety, confusion, and in severe cases, stupor and coma as well). Hypomagnesemia due to calcineurin inhibitors frequently coexists leading to muscle weakness, behavioral changes, and seizures. Profound muscle weakness leading to paralysis due to hypo- or hyperkalemia can occur, although rarely, because these conditions are generally detected and treated before potassium levels are so profoundly abnormal. Hyponatremia and hypernatremia are rare with normal renal function but should always be considered in patients with mental status changes, especially in the elderly. In either case, restoring normal serum sodium levels at no more change than 10–12 mEq per day should be aimed for, to prevent central pontine myelinolysis and cerebral edema respectively. Renal transplant recipients are more prone to developing rhabdomyolysis leading to profound muscle weakness from the combination of calcineurin inhibitors and statins. The muscle weakness may take longer to resolve than the renal function abnormalities. Although liver failure can occur when hepatotoxic drugs are used in patients with underlying liver disease, it rarely occurs, as liver function tests are closely monitored in transplant patients.

DIAGNOSTIC APPROACH A detailed history including recent and remote travel as well as exposure to mosquitoes, pets, and bird and rodent droppings should be obtained as atypical infections are common in transplant patients. History should also include a careful review of occupational hazards, gardening, agricultural and home remodeling projects. Medication history should be reviewed for any drugs known to cause neurologic symptoms with the recognition that sedatives and narcotics have an exaggerated and prolonged response in patients with kidney disease despite being metabolized by the liver. Pretransplant workup generally includes serology for EBV, CMV, HSV, varicella, RPR, and PPD status. Donor serologies for EBV and CMV are generally available if evaluated at US transplant centers. Clinical features might be similar in many different illnesses and neurologic examination alone may not clarify the etiology. A careful search for evidence of systemic or focal disease outside the CNS may be helpful for diagnosis or at least providing tissue for diagnosis. CSF examination is essential in determining the nature of infectious processes but may be nonspecific in immunocompromised patients (Table 84.2). CT or MRI of the head is indicated in most patients unless there is a clear-cut metabolic abnormality. Radiologic studies will also be needed in asymptomatic patients with systemic illnesses that have a high propensity for CNS involvement as management or duration

Table 84.2 Diagnostic findings in central nervous system disorders in renal transplant recipients

Tuberculosis

Crypotococcus

Toxoplasmosis Listeria

Cerebrospinal fluid

Radiologic studies

Glucose: 80% þ ve Glucose: mild abnormality Protein: mild abnormality Mononuclear cells: 50–75% Cryptococcal Ag: 90% Culture: 90–100% Protein elevated Mononuclear pleocytosis Protein elevated Glucose: low in 50% PMN predominant

Tuberculomas 5–10% Hydrocephalus Cerebral infarcts Basilar meningeal enhancement

Mass lesion 10%

Ring enhancing lesions

NEUROLOGIC COMPLICATIONS IN RENAL TRANSPLANTATION

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Table 84.2 Continued Cerebrospinal fluid

Radiologic studies Hyperintense lesions in white matter

Nocardia Lymphoma

Protein 60–140 mg/dL Glucose: normal WBC: mixed differential Protein elevated Glucose: normal Lymphocytic pleocytosis PCR > 95% þve Generally unremarkable Unremarkable

Luekoencephalopathy

Unremarkable

West Nile virus

Herpes simplex virus encephalitis

Temporal lobe lesions

Single or multiple loculated abscesses Enhancing lesions Multifocal 75% Hyperintense lesions in white matter

PMN, polymorphonuclear leukoctes (neutrophils); PCR, polymerase chain reaction; AFB, acid-fast bacilli; Ag, antigen; WBC, white blood cell count.

and mode of therapy (intravenous or oral) might change in such a case. Brain biopsy might be necessary to make a diagnosis of malignancy, and less commonly in infection. However, the risk of morbidity and sometimes even mortality associated with brain biopsy is so high that every effort should be made to establish a diagnosis with other tests when possible.

TREATMENT Most of the infectious problems respond to specific antimicrobial therapy but in life-threatening infection, reduction of immunosuppression will be necessary. Drug toxicity can be addressed by reducing the dose or changing to a different class of drugs when possible. If resolution of drug-related symptoms is slow even after adjustments are made, other possibilities need to be explored. Correction of metabolic abnormalities is done along the same lines as in the general population. Decreasing immunosuppression is almost always a part of treating malignancy. Further management (surgery versus chemotherapy versus immunotherapy) is based on the type and aggressiveness of the tumor. Treatment of cerebrovascular disease is similar to that in the general population, with the recognition that aggressive treatment of risk factors is needed.

SUMMARY Renal transplant recipients are at increased risk of a wide range of conditions that can lead to neurologic symptoms. Decreased cellular immunity-accelerated atherosclerotic vascular disease, the need for multiple drugs, and the frequency of metabolic abnormalities are the most common

predisposing factors for neurologic abnormalities in this population. Effective treatment requires early recognition of life-threatening conditions requiring early specific treatment from easily treated or self-limited infections. The time frame for diagnosis and treatment is often hours to a few days except in tumors, but early diagnosis improves prognosis even in such patients. CSF analysis and neuroimaging are key to making a diagnosis and in some cases, repeated CSF examinations will be needed. A clear collaboration between transplant physicians and neurologists is necessary for heightened vigilance, and a thorough familiarity with these problems.

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Benziada-Boudour A, Schmitt E, Kremer S et al. (2010). Tacrolimus-associated posterior reversible encephalopathy syndrome after solid organ transplantation. Eur Neurol 64: 169–177. Besenski N, Rumboldt Z, Emovon O et al. (2005). Brain MR imaging abnormalities in kidney transplant recipients. AJNR Am J Neuroradiol 26: 2282–2289. Biovin G (2004). Diagnosis of herpesvirus infections of the central nervous system. Herpes 11 (Suppl 2): 48A–56A. Bleck TP, Smith MC, Pierre-Louis SJ et al. (1993). Neurologic complications of critical medical illnesses. Crit Care Med 21: 98–103. Brennan DC (2001). Cytomegalovirus in renal transplantation. J Am Soc Nephrol 12: 849–855. Burke A, Cunha MD (2001). Central nervous system infections in the compromised host: a diagnostic approach. Infect Dis Clin North Am 15: 567–590. Cohen SM, Minkove JA, Zebley JW 3rd et al. (1984). Severe but reversible neurotoxicity from acyclovir. Ann Intern Med 100: 920. Currie AC, Knight SR, Morris PJ (2010). Tuberculosis in renal transplant recipients. The evidence for prophylaxis. Transplantation 90: 695–704. Dawson TM, Steiner JP, Lyons WE et al. (1994). The immunophilins, FK 506 binding protein and cyclophilin are discretely localized in the brain: relationship to calcineurin. Neuroscience 62: 569–580. Detry O, Honore´ P, Hans MF et al. (2000). Organ donors with primary central nervous system tumors. Transplantation 70: 244–248. Dhillon SS, Sarac E (2002). Lumbosacral plexopathy after dual kidney transplantation. Am J Kidney Dis 36: 1045–1048. El-Agroudy AE, Refaie AF, Moussa OM et al. (2003). Tuberculosis in Egyptian transplant recipients: study of clinical course and outcome. Nephrology 16: 404–411. El-Sabrout RA, Radovancevic B, Ankoma-Sey V et al. (2001). Guillain–Barre´ syndrome after solid organ transplantation. Transplantation 71: 1311–1316. Fishman J, Rubin R (1998). Infection in organ-transplant recipient. N Engl J Med 338: 1741–1751. Flynn JT, Bunchman TE, Sherbotic JR (2001). Indications, results and complications of tacrolimus conversion in pediatric renal transplantation. Pediatr Transplant 5: 439–446. Gomez E, Santiago M, Aguado S et al. (1997). Herpes simplex virus encephalitis in a renal transplant patient: diagnosis with PCR chain detection of HSV DNA. Am J Kidney Dis 30: 423–427. Hauben M (1996). Cyclosporine neurotoxicity. Pharmcotherapy 16: 576–583. Hellden A, Odar-Cederlof I, Diener P et al. (2003). High serum concentrations of the acyclovir main metabolite 9carboxymethoxymethylguanine in renal failure patients with acyclovir-related neuropsychiatry side effects: an observational study. Nephrol Dial Transplant 18: 1135–1141.

Hinchey J, Chaves C, Appignani B et al. (1996). A reversible posterior leucoencephalopathy. N Engl J Med 334: 494–500. Howard RJ, Patton PR, Reed AI et al. (2002). The changing causes of graft loss and death after kidney transplantation. Transplantation 73: 1923–1928. Iwamoto M, Jernigan DB, Guasch A et al. (2003). Transmission of West Nile virus from an organ donor to four transplant recipients. N Engl J Med 348: 196–203. Kashtan CE, Cook M, Chavers BM et al. (1997). Outcome of chicken pox in 66 pediatric renal transplant recipients. J Pediatr 131: 874–877. Ketteler M, Kunter U, Floege J (2003). An update on herpes virus infections in graft recepients. Nephrol Dial Transplant 18: 1703–1706. Kiberd D, Forward K (2004). Screening for West Nile virus in organ transplantation: a medical decision analysis. Am J Transplant 4: 1296–1301. Koukourgianni F, Pichault V, Liutkus A et al. (2009). HHV-6 infection in a pediatric kidney transplant patient. Pediatr Nephrol 24: 2445–2448. Kumar D, Drebot MA, Wong SJ et al. (2004). A seroprevalence study of West Nile virus infection in solid organ transplant recipients. Am J Transplant 4: 1883–1888. Lee VH, Wijdicks EF, Manno EM et al. (2008). Clinical spectrum of reversible posterior leukoencephalopathy syndrome. Arch Neurol 65: 205–210. Lopez-Montes A, Gallego E, Lopez E et al. (2004). Treatment of tuberculosis with rifabutin in a renal transplant recipient. Am J Kidney Dis 44: 59–63. Lyson T, Ermel LD, Belshaw PJ et al. (1993). Cyclosporine and FK-506 induced sympathetic activation correlated with calcineurin mediated inhibition of T-cell signaling. Circ Res 73: 596–602. Margreiter R (2002). Tacrolimus versus Cyclosporine Renal Transplant Study Group. Efficacy and safety of tacrolimus compared with cyclosporine micro emulsion in renal transplantation: a randomized multicentre study. Lancet 359: 741–746. Martin MA, Massanari RM, Nghiem DD et al. (1988). Nosocomial aseptic meningitis associated with administration of OKT3. JAMA 259: 2002–2005. Mason WJ, Nickols HH (2008). Images in clinical medicine. Crystalluria from acyclovir use. N Engl J Med 358: e14. Moskowitz A, Nolan C, Lis E et al. (2007). Posterior reversible encephalopathy syndrome due to sirolimus. Bone Marrow Transplant 39: 653–654. Muller MP, Richardson DC, Walmsley SL (2001). Trimethoprim-sulfamethoxazole induced aseptic meningitis in a renal transplant patient. Clin Nephrol 55: 489–490. Nahmias AJ, Whitley RJ, Visintine AN et al. (1982). Herpes simplex virus encephalitis: laboratory evaluations and their diagnostic significance. J Infect Dis 145: 829–836. Oliveras A, Roquer J, Puig JM et al. (2003). Stroke in renal transplant recipients: epidemiology, predictive risk factors and outcome. Clin Transplant 17: 1–8.

NEUROLOGIC COMPLICATIONS IN RENAL TRANSPLANTATION Opelz G, Dohler B (2004). Lymphomas after solid organ transplant: a collaborative transplant study report. Am J Transplant 4: 222–230. Ozt€ urk S, Tufan F, Alis¸ir S et al. (2006). A case of isolated Nocardia asterioides brain abscess in a kidney transplant recipient. Transplant Proc 38: 3121–3124. Parvex P, Pinsk M, Bell LE et al. (2001). Reversible encephalopathy associated with tacrolimus in pediatric renal transplant patients. Pediatr Nephrol 16: 537–542. Pilmore H, Collins J, Dittmer I et al. (2009). Fatal human herpes virus-6 infection after renal transplantation. Transplantation 88: 762–765. Pirson Y, Christophe JL, Goffin E (1996). Outcome of renal replacement therapy in autosomal dominant polycystic kidney disease. Nephrol Dial Transplant 11 (Suppl 6): 24–28. Qin W, Tan CY, Huang X et al. (2011). Rapamycin-induced reversible posterior encephalopathy in a kidney transplant patient. Int Urol Nephrol 43: 913–916. Riska H, Gronhagen-Riska C, Ahonen J (1987). Tuberculosis and renal allograft transplantation. Transplant Proc 19: 4096–4097. Rogers NM, Peh CA, Faull R et al. (2008). Transmission of toxoplasmosis in two renal allograft recipients receiving an organ from the same donor. Transpl Infect Dis 10: 71–74. Roth C, Febert A (2010). Posterior reversible leucoencephalopathy: long term follow-up. J Neurol Neurosurg Psychiatry 81: 773–777. Salahudeen AK, Woods HF, Pingle A et al. (1990). High mortality among recipients of bought living unrelated donor transplants. Lancet 336: 725–728. Schuchat A, Deaver KA, Wenger JD et al. (1992). Role of foods in sporadic listeriosis. I. Case-control study of dietary risk factors. The Listeria Study Group. JAMA 267: 2041–2045. Schwartz RB, Bravo SM, Klufas RA et al. (1995). Cyclosporine neurotoxicity and its relationship to hypertensive encephalopathy: CT and MR findings in 16 cases. Am J Roentgenol 165: 627–631. Senzolo M, Ferronato C, Burra P (2009). Neurologic complications after solid organ transplantation. Transpl Int 22: 269–278.

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Sharma KR, Cross J, Santiago F et al. (2002). Incidence of acute femoral neuropathy following renal transplantation. Arch Neurol 59: 541–545. Snanoudj R, Durrbach A, Leblond V et al. (2003). Primary brain lymphomas after kidney transplantation: presentation and outcome. Transplantation 76: 930–937. Srinivasan A, Burton CE, Kuehnert JM et al. (2005). Transmission of rabies virus from an organ donor to four transplant recipients. N Engl J Med 352: 1103–1111. Tan CS, Koralnik IJ (2010). Progressive multifocal luekoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis. Lancet Neurol 9: 425–437. Thwaites GE, Bang ND, Dung NH et al. (2004). Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 351: 1741–1751. Torre D, Casari S, Speranza F et al. (1998). Randomized trial of trimethoprim-sulfamethoxazole versus pyrimethaminesulfadiazine for therapy of toxoplasmic encephalitis in patients with AIDS. Italian Collaborative Study Group. Antimicrob Agents Chemother 42: 1346–1349. United States Renal Data System, annual data report (2010). www.usrds.org. Vilchez RA, Fung J, Kusne S (2002). Cryptococcus in organ transplant recipients: an overview. Am J Transplant 2: 575–580. Wang FZ, Linde A, Hagglund H et al. (1999). Human herpes virus 6 DNA in cerebrospinal fluid specimens from allogenic bone marrow transplant patients: does it have clinical significance? Clin Infect Dis 28: 562–568. Watschinger AS, Konstantin H, Demetriou D et al. (2008). Pre-transplant predictors of cerebrovascular events after kidney transplantation. Nephrol Dial Transplant 23: 1429–1435. Wijdicks EF, Torres VE, Schievink WI et al. (1999). Cerebral hemorrhage in recipients of renal transplantation. Mayo Clin Proc 74: 1111–1112. Wilson JP, Turner HR, Kirchner KA et al. (1989). Nocardia infections in renal transplant recipients. Medicine 68: 38–57. Yoshikawa T, Suga S, Asano Y et al. (1992). A prospective study of human herpes virus-6 infection in renal transplantation. Transplantation 54: 879.

Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 85

Neurologic complications of liver transplantation EELCO F.M. WIJDICKS* AND SARA E. HOCKER Division of Critical Care Neurology, College of Medicine, Mayo Clinic, Rochester, MN, USA

INTRODUCTION Most major medical centers have developed a logistically successful liver transplantation program with good outcomes (Mandell et al., 2002). Yet, neurologic complications continue to dominate the postoperative care of patients. In the earlier days some of these manifestations were dramatic, unexpected, and even fatal (Adams et al., 1987; Vogt et al., 1988; Gridelli et al., 1994; Pujol et al., 1994; Vecino et al., 1999; Wijdicks, 1999; Bronster et al., 2000a). Most instructive were patients who would develop refractory status epilepticus and remained in a coma after large intravenous doses of immunosuppressive drugs. Now, in the modern era, next to seizures, “encephalopathy” is the major concern of the liver transplant surgeon and the postoperative medical team (Lewis and Howdle, 2003; Kim et al., 2007; Fernandez et al., 2010). In fact, acute confusional state occurs in more than 50% of patients who have a transplantation for alcoholic liver disease (Buis and Wijdicks, 2002). Any critically ill patient after a solid organ transplant is at risk of neurologic complications, but there are specific problems in liver recipients. First and urgently challenging is the management of acute fulminant hepatic failure that can only be treated with acute liver transplantation. When cerebral edema occurs patients present with multiple medical problems that are not only demanding to the medical team, but also to the neurosurgeon, who has to place an intracranial pressure monitor, and to the consulting neurologist, who has to advise on management of increased intracranial pressure while trying to make sense of a sedation-confounded neurologic examination. Second, liver transplantation has been used to treat Wilson’s disease (Stangou and Hawkins, 2004; Erol

et al., 2008) and amyloidosis, linking liver transplantation with a major disabling but curable disease. Third, with the increase in liver transplantation for patients with prior alcoholism, critical illness neuropathy and myopathy can be expected to occur more often as a direct result of their emaciated state. This subsection summarizes the major neurologic complications after liver transplantation.

LIVER TRANSPLANTION: PAST AND PRESENT For a long time liver transplantation was considered technically and medically too formidable and certain to fail. The development of liver transplantation can be credited to Dr. Thomas Starzl at the University of Colorado. In 1963, he pioneered liver transplantation in several patients, but all patients died from postoperative complications. Starzl recollects that, with this depressing first experience, most surgeons felt that liver transplantation was simply not feasible (Starzl and Fung, 2010). Nevertheless, several European teams in the early 1970s – and Starzl again – went on with a second try; this time, with much more effective immunosuppressive agents and a dedicated team of hepatologists and immunologists, patients survived. Liver transplantation has remained a major surgical procedure and continues to place patients at significant risk of complications – as opposed to kidney transplantation, which now rarely has recipients in an intensive care unit (ICU) for a prolonged period of time. Indications for liver transplantation are regional. In the UK, where acetaminophen/paracetamol intoxication is prevalent, approximately two-thirds of the liver transplantations are performed for that indication. Outside the UK and in the US, hepatitis C, B, and alcoholic cirrhosis are

*Correspondence to: Eelco F.M. Wijdicks, M.D., Ph.D., F.A.C.P., Professor of Neurology, Chair, Division of Critical Care Neurology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Tel: þ1-507-284-4741, Fax: þ1-507-266-4419, E-mail: [email protected]

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Fig. 85.1. Example of split liver transplantation. (Reproduced from Wijdicks, 2009, with the permission of the Mayo Foundation for Medical Education and Research. All rights reserved.)

the major indications for liver transplantation. In pediatric transplantation, the most common indications are extrahepatic biliary atresia and total parenteral nutrition (TPN) cholestasis (Gridelli et al., 1994). In some of these children with TPN cholecystasis progression can be rapid and liver cirrhosis may develop in a few months. (These children have been treated with TPN for acute and chronic intestinal failure.) The initial liver transplantation was orthotopic, where the patient liver is removed and replaced by a whole or partial donor liver. Over the years changes in technique have occurred that included a split liver technique (Fig. 85.1). The donor liver is attached through anastomosis of the suprahepatic and intrahepatic inferior vena cava, hepatic artery, portal artery, and bile duct (Fig. 85.1). As expected, the immediate postoperative care is predominated by the care of a coagulopathy, ventilatory management, and management of blood pressure and fluid balance. Most patients may have a severe coagulopathy in the first postoperative days until clotting factors are produced by the new liver. The fluid status is unstable with episodes of hypervolemia associated with hypertension. All these changes with blood pressure, oxygenation, and clotting can cause neuronal injury, but it is surprising how many patients do well after this major surgical procedure. Infections are rare and probably a result of preemptive gut decontamination and antifungal prophylaxis. The most challenging category of patients is patients with fulminant hepatic failure. Fulminant hepatic failure can lead to rapid neurologic deterioration attributed to brain edema. At some point during the course of time, a metabolic derangement (hepatic encephalopathy) progresses toward a structural lesion (cerebral edema) that causes permanent brainstem injury. Brain edema is more common in patients who have a short interval between the onset of jaundice and signs of encephalopathy, when

there is an associated infection, need for vasopressors, or when there is associated renal failure. Increased arterial ammonia at presentation in fulminant hepatic failure is a strong predictor for more severe manifestations of cerebral edema. Over the years neurologic complications have decreased and most of the complications now are mostly postoperative agitation, encephalopathy, and seizures. Major structural brain lesions are incidental and may involve intracranial hemorrhage or a posterior reversible encephalopathy syndrome due to immunosuppressive drugs. More recent studies suggest neurologic complications may reach up to one in four patients. Only seizures have declined over the years and all other complications have remained quite prevalent (Table 85.1).

CLINICAL FEATURES Any neurologist evaluating a neurologic complication for liver transplantation is expected to have a good knowledge of the pretransplant setting, reasons for transplantation, perioperative complications, and most importantly, polypharmacy use in the postoperative setting. One should anticipate great difficulties with understanding the patient’s condition and the spectrum of neurologic complications varies widely. One could expect to see a mildly confused patient or a comatose patient, a single seizure or status epilepticus, a recovering compression neuropathy or a severe flaccid quadriplegia. Patients may do well initially only to deteriorate later in the early postoperative course and some may develop a neurologic manifestation years after liver transplantation. How the prevalence of complications has evolved over time is difficult to gather from the existing literature. Most series involve thousands of patients over many years with many significant changes in postoperative care. Most reported early neurologic complications after liver transplantation are altered

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Table 85.1 Neurologic complications of liver transplantation over time

Reference

Time epoch

N

Seizure

Encephalopathy

Stroke*

CPM

Peripheral nerve

Other

Adams et al., 1987 Guarino et al., 1996 Vecino et al., 1999 Lewis and Howdle, 2003 Dhar et al., 2008

1982–1986 1986–1993 1996–1998 1990–2000 2000–2002

52 199 43 627 101

25% 6% 7% 6% 4%

8% 24% 16% 11% 28%

6% 3% 9% 4% 0

2% 0.5% 0 2% 0

0 4% 0 4% 0

2% 4% 2% 6% 0

*Ischemic and hemorrhagic combined. CPM, central pontine myelinolysis.

Table 85.2 Neurologic complications after transplantation: classification by neurologic signs and symptoms and common diagnostic considerations Sign or symptom

Consideration

Failure to awaken

Hypoxic-ischemic encephalopathy, central pontine myelolysis, anesthetic agents, air embolism, acute graft failure Intracranial hemorrhage, seizures, drug toxicity Immunosuppressive toxicity, acute hypoglycemia, hyperglycemia, corticosteroids, fungal meningitis Ciclosporin or tacrolimus toxicity, intracranial hemorrhage, lymphoma, meningitis Ciclosporin or tacrolimus toxicity Cardiac arrest, ciclosporin toxicity, posterior reversible encephalopathy syndrome (PRES) Ischemic or hemorrhagic stroke, neoplasm, brain abscess Immunosuppressive drugs Hypoxic-ischemic encephalopathy, ketamine or cephalosporin intoxication Acute liver (rejection) disease Haloperidol overdose, malignant hyperthermia Acute critical illness polyneuropathy, polymyositis, corticosteroids, associated myopathy, neuromuscular blocking agents Fungal meningitis, muromonab-CD3 toxicity, ciclosporin or tacrolimus use, lymphoma, astrocytoma

Loss of consciousness Confusional state Seizures Mute or stuttering Cortical blindness Hemiparesis Tremors Myoclonus Asterixis Rigidity Muscle weakness Headaches

consciousness, seizures, agitation, and encephalopathy and, occasionally, acute neuromuscular weakness. Late complications may involve central nervous system (CNS) infections and de novo brain tumors. The most frequently seen neurologic complications and presumed causes are shown in Table 85.2.

ABNORMAL CONSCIOUS STATE Neurologists will have difficulty defining an abnormal conscious state in a liver transplant recipient. Even an acute confusional state might be difficult to define but can be considered if it lasts for several days and is associated with agitation, acute disorientation, and sometimes hallucinations. Acute confusional state after

a liver transplant can be due to alcoholic liver disease and in fact is quite common in these patients. In our study, confusion occurred as early as 3 days after transplantation for alcoholic liver disease and was associated with increased levels of serum ammonia and also brain atrophy on CT scan, all suggesting a predisposition (Buis et al., 2002). In some patients, a high dose of corticosteroids in the setting of an immunosuppressive regimen could lead to an agitated confusional state but this complication is rare in our experience. The use of calcineurin inhibitors is most likely the most common cause for abnormal level of consciousness (Freise et al., 1991). Ciclosporine and tacrolimus are usually part of a postoperative immunosuppressive regimen and neurologic symptoms often

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occur during intravenous loading of these drugs (Small et al., 1996). Over the years there has been far more experience with titrating these drugs and therefore the incidence of severe neurotoxicity has declined substantially. In addition, newer drugs such as sirolimus are not associated with neurotoxicity. This is explained by a different mechanism of action – sirolimus blocks interleukin 2 and does not inhibit calcineurin. Immunosuppressive toxicity has a colorful display of symptoms and its clinical features are similar in any transplant recipient (de Groen et al., 1987; Wijdicks et al., 1999; Wijdicks, 2001). Most of the time patients start with a progressive position tremor that is then followed by visual hallucinations and development of a language or speech abnormality (Bird et al., 1990; Reyes et al., 1990). Mostly, articulation abnormalities are seen; in the past this has been called a “foreign accent syndrome.” Some patients become mute and develop a frontal syndrome with marked abulia (Valldeoriola et al., 1996; Laureno and Karp, 1997). When not recognized and calcineurin inhibitors are continued seizures appear and may become recurrent. Unusual manifestations of calcineurin inhibitors are visual hallucinations, grimacing, tongue protrusion, opsoclonus, and cortical blindness (Ghalie et al., 1990; Steg and Garcia, 1991; Marchiori et al., 2004). All these clinical features can be located to a specific area in the brain, predominantly the brainstem or occipital lobe. The challenge is to “prove” neurotoxicity in a liver transplant recipient and this is difficult because neurologic findings correlate poorly with serum levels of ciclosporin or tacrolimus. Even a marked increase in dose or level does not necessarily predispose the patient to toxicity and in fact, rapidly titrating towards increasing plasma levels is a crucial part of early postoperative management. Moreover MR imaging can be normal in a patient with neurotoxicity but in a patient with an abnormal level of consciousness and seizures, normal MR imaging makes neurotoxicity a much less likely possibility. If present, the MRI abnormalities can be profound and involve typical features known to occur in a posterior reversible encephalopathy syndrome (Truwit et al., 1991). There is abnormal signal in the subcortical white matter predominantly in the occipital regions bilaterally (Fig. 85.2), which may extend into the frontal regions and into the thalamus. There is typically no restricted diffusion or abnormal enhancement and the abnormalities fairly rapidly resolve after the immunosuppressive drug is replaced. Switching from one calcineurin inhibitor to another may also be successful (Emre et al., 2000; Jain et al., 2000). Currently there is a growing incentive to avoid calcineurin inhibiting agents and replace these drugs with sirolimus or CellCept (mycophenolate mofetil) (Maramattom and Wijdicks, 2004). However, sirolimus

Fig. 85.2. MRI image showing marked hyperintensities due to vasogenic edema associated with use of calcineurin inhibitor.

is not an innocuous drug having major problems with skin lesions (Montalbano et al., 2004). The mechanisms of ciclosporin and tacrolimus toxicity have not been resolved but breakdown of the blood–brain barrier is needed for ciclosporin to enter the brain. Ciclosporin is very lipophilic and therefore cannot cross the blood–brain barrier because of tight junctions. It has been speculated that impairment of the blood–brain barrier due to surgery associated with ischemic insult due to hypotension might have predisposed the patient in the postoperative phase; however, it is not a common occurrence. Most of the abnormalities are simply fluid extravasation and not neuronal destruction causing cytotoxic edema. There are no neuropathology studies in a series of patients that could explain the true nature of this disorder. A second common cause of altered consciousness is accumulation of sedation. Mostly drugs such as midazolam or propofol have been used and their pharmacokinetics might be difficult in any transplant patient. Midazolam is a complicated drug in a patient who has just received a liver graft because it is highly proteinbound and pre-existing protein levels may increase its sedative effect. Opioids can be used in the postoperative phase and also may cause a significant decrease in response, certainly when used in combination with

NEUROLOGIC COMPLICATIONS OF LIVER TRANSPLANTATION midazolam. Another cause of postoperative stupor after liver transplant is central pontine myelinolysis (CPM). This has been typically associated with rapid correction of hyponatremia but this relationship between hyponatremia and CPM after liver transplantation has never been definitively established. Fluid shifts from major compartments occur after liver transplantation but CPM is very uncommon with only a few cases seen in many thousands of liver transplant patients. The diagnosis may not be recognized if an MRI scan is not performed and the patient may present with stupor alone (Boon et al., 1991; Buis et al., 2002; Guo et al., 2006). Abnormal level of consciousness can also be due to graft failure and presents itself with liver function tests rapidly becoming abnormal and a patient who lapses into a higher clinical stage of encephalopathy. The patient may be drowsy with slowing immediately after surgery but then deteriorate into a state with less orientation, pronounced confusion, new development of asterixis and eventually, lapsing into an unresponsive comatose state. Finally, and most unfortunately, some patients might be brain dead after liver transplantation. This scenario is relatively uncommon in patients who have had an emergent liver transplantation for fulminant hepatic failure. The clinical scenario here is that patients developed a massively increased intracranial pressure (ICP) that required barbiturate treatment. Failure to obtain a reliable neurologic examination or any additional ancillary tests may have led to proceeding with liver transplantation leaving only a patient without demonstrable brain function in the postoperative phase. In some patients a marked ICP rise during transplantation may have tipped the balance and resulted in loss of all brainstem function. The evaluation of patients with an abnormal conscious state should also include consideration of anoxic-ischemic injury. In liver transplantation this is highly unusual but mostly seen if there has been an intraoperative cardiorespiratory arrest shortly after transplantation. Sudden loss of consciousness in the liver transplantation patient is typically due to catastrophic intracranial hemorrhage. Cerebral hematoma is particularly common in patients after liver transplantation with coagulopathy and bacterial sepsis syndrome, but fungal infections, such as an overwhelming Aspergillus fumigatus infection, may present with a massive intracranial hemorrhage. Coagulopathy plays a role but bacteremia or fungemia was found in a large proportion of our patients who presented with intracranial hemorrhage (Wijdicks et al., 1995a).

SEIZURES A new seizure in a transplant recipient should foretell a major medical or neurologic problem. Seizures have been reported frequently in a liver transplant recipient

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and in some series may have been seen in up to 10–20% of patients (Wijdicks et al., 1994; Wijdicks et al., 1996a). In the early days of transplantation seizures were associated with neurotoxicity and this has remained a strong consideration in any patient with liver transplant. Other, less common causes are acute hyponatremia, hypomagnesemia, and hyperglycemia, but all published recent information is poorly detailed and seizures have been mostly linked to neurotoxicity. In any event, a new structural lesion should be documented or at least excluded and some cases may have an intracranial hemorrhage or a CNS infection. Seizures may also occur in patients with a rapidly evolving rejection recognized by increasing arterial ammonia. Management of seizures in a transplant recipient is typically an antiepileptic drug if there is a structural lesion. If antiepileptic drugs are considered, intravenous levetiracetam is probably the best agent to use and the least hepatotoxic. Failure rapidly to correct a metabolic cause, probability of drug toxicity, and whether electroencephalography (EEG) shows epileptiform abnormalities are also reasons to treat patients. Long-term management is rarely warranted.

BRAIN EDEMA The postoperative management of brain edema in patients who received a liver to replace an acutely necrotic liver is another major neurologic issue. Management has already begun in the pretransplantion phase but needs continuation in the days after transplantation (Daas et al., 1995; Auzinger and Wendon, 2008). Brain edema after fulminant hepatic failure is prominent in patients with stage III/IV hepatic encephalopathy (Fraser and Arieff, 1985) and in fact those are usually the patients who are acutely listed for transplantation (Emond et al., 1989; Russo et al., 2004; Khanna and Hemming, 2010). The potential mechanism for brain edema involves both a vasogenic and a cytotoxic component (Ritt et al., 1969; Blei, 2007, 2008). Current leading explanations are that there is an osmotic and oxidative stress neuronal damage. Glutamine has been the major responsible substance and a significant increase of glutamine in the brain precedes increase in brain water in many experimental models (Raabe, 1987; Albrecht and Norenberg, 2006). Ammonia diffuses through the bloodstream barrier, causes a rise in glutamine which attracts water due to its function as an osmolite (Bhatia et al., 2006; Bernal et al., 2007). Brain edema can be very rapid and cause a significant problem with management of increased ICP. A protocol for management is shown in Table 85.3. Placement of an intracranial pressure monitoring device is necessary to control ICP during the perioperative phase. There is an

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Table 85.3 Treatment options for brain edema in fulminant hepatic failure Propofol infusion (start with 30 mg/kg per minute and may increase to 200 mg/kg per minute for brief periods of time) Moderate hypothermia (33–35 C) with cooling blankets, alcohol rubbings, and ice lavage Pentobarbital bolus of 3–5 mg/kg intravenously followed by 1–3 mg/kg per hour up to normalizing of intracranial pressure Mannitol, 0.5–1 g/kg every 6 hours if plasma osmolality is < 310 mOsm/L

understandable reluctance by neurosurgeons to place ICP monitors due to the associated coagulopathy with nearly absent liver function, but with the use of recombinant factor VIIa, coagulopathy can be controlled (Shami et al., 2003). The risk of a clinically relevant probe-associated hemorrhage is approximately 10–20%. On the other hand, losing a patient with rapid brain edema that could have been detected and controlled is equally problematic. Most experts in this field feel that ICP monitoring should be present in a patient lapsing into stupor necessitating intubation and mechanical ventilation. Monitoring ICP in fulminant hepatic failure remains essential to shepherd the patient through surgery (LeRoux et al., 1990; Brandsaeter et al., 2002). A sudden increase in ICP has been noted during transplantation and these surges of ICP do occur after reperfusion of the transplanted liver and may even extend through the first day after liver transplantation (Montalti et al., 2005). Table 85.3 shows options for treatment of brain edema. Propofol may be useful and in small doses has reduced intermittent increases in ICP. With a dosage of 1–3 mg/kg we were able to control ICP satisfactorily (Wijdicks and Nyberg, 2002). Treatment is typically the use of osmotic drugs (Raghaven and Marik, 2006; O’Grady, 2007). However, the use of hypertonic saline and mannitol may be initially problematic if the patient has developed a hepatorenal syndrome but not with continuous renal replacement therapy. There is a current interest in quickly using hypothermia (33–34 C) in combination with high-dose barbiturates (Stravitz et al., 2007). Further data are forthcoming as to whether hypothermia should be standard in the management of brain edema in fulminant hepatic failure. Monitoring EEG with pentobarbital may be useful but ICP may still be elevated in burst suppression patterns and it is better to be guided by the ICP tracing. What remains unclear is how many patients are able to be salvaged when frank edema and crowding of the basal cisterns appear on a

repeat CT scan (Wijdicks et al., 1995b; Lee and Wijdicks, 2008). In many of these patients transplantation may come too late. In these urgent situations a hepatic bridging device would be ideal, but it has long been a holy grail for hepatologists and transplant surgeons (Van de Kerkhove et al., 2004; Park and Lee, 2005).

CENTRAL NERVOUS SYSTEM INFECTIONS A patient with a recent organ transplantation and treated with immunosuppression is at increased risk of opportunistic infections, and they can rapidly become quite serious (Feltracco et al., 2010). In the early postoperative phase (less than 1 month) infections are usually systemic bacterial or fungal infections and the brain and spinal cord is mostly spared. Most of the neurologic infectious diseases cause substantial morbidity and mortality and it would require systemic autopsy studies to tabulate them accurately. When a CNS infection intervenes, parasitic infections (Hoare et al., 2006), viral infections, and fungal infections predominate. Most series of liver transplant patients will, fortunately, only have a few patients with devastating infections. Not infrequently, these infections occur in patients with a complicated postoperative clinical course and already long ICU stays. CNS infections present as a meningoencephalitis with treatment-refractory headache, behavior changes, and less commonly localizing signs such a hemiparesis. Intracerebral hemorrhage may be associated with fungal infections (Wijdicks et al., 1995a). The most frequently encountered pathogen is Aspergillus fumigatus and it may be rapidly invasive and fatal (Boon et al., 1990). The diagnosis is very difficult to make intra vitam and more commonly autopsy will be able to show the widely disseminated angioinvasive hyphae. In our experience we have seen only sporadic cases in liver transplant recipients, but when it occurred no patient survived the concomitant multiorgan involvement. Other causes are Cryptococcus neoformans and a variety of other fungal infections but mostly reported as anecdotes in the literature. MR imaging can be helpful in documenting multiple small abscesses, but there are no distinguishing features. CSF will invariably show a lymphocytic pleocytosis and a biopsy or immunodiffusion tests for the detection of antibodies. CSF India ink (with suspicion of Cryptococcus neoformans) is frequently positive and helpful clinically (Wu et al., 2002). Disseminated viral infections have also been described with very high mortality rates, but again no systemic studies have been reported. A viral encephalopathy that has emerged more recently is a human herpes virus 6 (HHV-6) (Seeley et al., 2007). This infection may be seen several weeks after transplantation and is often

NEUROLOGIC COMPLICATIONS OF LIVER TRANSPLANTATION 1263 unrecognized or initially misdiagnosed as a metabolic Meningeal involvement may produce headache. The derangement or neurotoxicity from immunosuppressive diagnosis can only be considered if the CT scan shows agents. A confusional state with disorientation may a new mass lesion in the periventricular region and with be the only clinical sign. Isolation by PCR is necessary a proportionally large amount of perilesional edema. A and no other tests have any key features. Mortality is biopsy might be necessary to find the lesion followed by high, with about 80% of the patients remaining comaaggressive treatment with radiation. Outcome, however, tose. Foscarnet has been tried in some cases but there remains very poor with ultimate demise in all patients. is as yet little experience. Another concern is the transmission of a primary high Another under-recognized infection is cytomegalovigrade CNS tumor of a donor to a liver recipient and multiple rus (CMV) encephalopathy. Approximately 80% of liver single cases have been reported. A recent study evaluated recipients have reactivation of a latent CMV that may the risk and found it to be very low (less than 3%). Nonetheoccur several weeks after transplantation. Again the less molecular chimera studies have proved malignant brain diagnosis of CMV encephalitis is notoriously difficult tumors came from the donor (Kashap et al., 2009). with a presentation that is baffling to most clinicians. Some patients present with focal findings such as dysarNEUROMUSCULAR COMPLICATIONS thria, spasticity and rigidity, and tremor, and others Liver transplantation should spare muscle and nerve. develop fever and neck stiffness. CMV chorioretinitis may be demonstrated, but CMV encephalitis may occur However, neuropathies may occur due to cannulation, without this manifestation. In all these opportunistic coagulation-induced compressive hematomas (Wijdicks infections recent availability of PCR technology has et al., 1996a; Campellone et al., 1998). The relationship increased recognition but there is as yet no evidence that between immunosuppressive agents and development early treatment improves outcome. of a neuromuscular disorder has never been established Progressive multifocal leukoencephalopathy caused and should be considered unlikely. Most neuropathies are due to stretch with surgery or by a JC virus is another unusual complication after transpositioning and possibly preventable. A brachial plexoplantation and only a few well-documented cases have been reported. Behavioral change and dementia are compathy can be due to a shoulder hyperabduction but axilmon due to demyelination of the frontal lobe. The MRI lary vein cannulation is less commonly used in liver scan shows characteristic increased signal in the white transplantation. Ulnar and radial neuropathies are matter and brain biopsy can demonstrate in situ hybriduncommon after liver transplant surgery and are noticed ization for JC virus. Cytarabine is used to temporize by the patient usually as significant hand muscle weakthe tumor growth but with little success and most ness and more often painful tingling. Bilateral peroneal palsies are far more common after liver transplantation patients have not survived more than a year after the due to prolonged immobility during surgery in patients diagnosis. already predisposed as a result of marked weight loss. All these neuropathies have a good outcome over time. CENTRAL NERVOUS SYSTEM In our series, we found coagulopathy-associated psoas MALIGNANT TUMORS hematomas causing a femoral hematoma but this may Any transplant recipient is at risk of developing B cell only be seen in the more severe cases with rejection after lymphomas or glioblastoma multiforme or progressive liver transplantation. Chronic inflammatory demyelinatmultifocal leukoencephalopathy (PML) (Schiff et al., ing polyneuropathy has been reported in patients after 2001). These disorders are extremely uncommon, but reduction of immunosuppressive drugs. The true incican present within weeks after transplantation. Most dence is not known, nor how an immunologic response notorious is the occurrence of CNS lymphoma several to multiple nerves emerges (Taylor et al., 1995). weeks after transplantation (occurrence may vary from Any patient that develops a postoperative sepsis is at a few weeks to more than two decades after transplanrisk of critical illness polyneuropathy and presents tation). Most post-transplantation lymphomas are with severe quadriplegia. Rhabdomyolysis is also a premonoclonal B cell lymphomas, but multiclonal B cell sentation of severe sepsis but is less commonly seen lymphomas or T cell lymphomas have been reported. after liver transplantation. In cases reported certain Epstein–Barr virus infection has been linked to B cell drugs may have contributed (i.e., combination of statins lymphoma. CNS lymphoma represent with both brain and antibiotics). Patients may have considerable weakand spinal cord involvement, but presentation is nonspeness and muscle pain. Muscles are tender to touch but cific with new behavioral changes, visual hallucinations, this may be an unreliable sign in a critically ill patient or focal signs such as hemiparesis. In most patients a who just underwent a major transplantation procedure. change in personality may be the only key sign. Rhabdomyolysis cannot be clinically differentiated from

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critical illness myopathy, which is more common in patients with sepsis, use of neuromuscular blockade and prolonged bed rest, and from corticosteroid-induced necrotic myopathy. In both, EMG will show a myopathic pattern (short duration motor units and fibrillation potentials) and creatine phosphokinase (CPK) values can be elevated. Outcome is favorable and rapid and muscle biopsies are usually deferred. The outcome of patients with critical illness polyneuropathy after liver transplantation is not known but likely not different from other clinical situations. There is generally little concern with neuromuscular disorders in liver transplant recipients and they rarely impact on mobility or function.

CONCLUSIONS There are specific neurologic problems with liver transplant recipients. The most challenging are: (1) treatment of acute fulminant liver failure and cerebral edema; (2) treatment of recurrent seizures and recognition of immunosuppressive neurotoxicity; (3) treatment and evaluation of agitation and postoperative confusion; (4) CNS infections, which are uncommon in the postoperative phase but can occur later, and often cause fatality. Neurologic complications after liver transplantation have declined, mostly as a result of better postoperative titration of immunosuppressive agents, critical care management, and possibly better selection of patients undergoing liver transplantation. Moreover, the spectrum of neurologic complications may change over time with liver transplant surgeons now mostly concerned with postoperative confusion and agitation. Neurologists seeing patients in a transplant unit should be prepared to see critically ill patients with multiple medical problems, procedures, and polypharmacy. Neurologists may also provide specific management recommendations and even be closely involved with the day to day care.

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NEUROLOGIC COMPLICATIONS OF LIVER TRANSPLANTATION Fraser CL, Arieff AI (1985). Hepatic encephalopathy. N Engl J Med 313: 865–873. Freise CE, Rowley H, Lake J et al. (1991). Similar clinical presentation of neurotoxicity following FK 506 and cyclosporine in a liver transplant recipient. Transplant Proc 23: 3173–3174. Ghalie R, Fitzsimmons WE, Bennett D et al. (1990). Cortical blindness: a rare complication of cyclosporine therapy. Bone Marrow Transplant 6: 147–149. Gridelli B, Lucianetti A, Rodriguez G et al. (1994). Neurologic complications following pediatric orthotopic liver transplantation. Transplant Proc 26: 193. Guarino M, Stracciari A, Pazzaglia P et al. (1996). Neurologic complications of liver transplantation. J Neurol 243: 137–142. Guo Y, Hu JH, Lin W et al. (2006). Central pontine myelinolysis after liver transplantation: MR diffusion, spectroscopy and perfusion findings. Magn Reson Imaging 24: 1395–1398. Hoare M, Gelson WT, Antoun N et al. (2006). Early recurrence of neurocysticercosis after orthotopic liver transplant. Liver Transpl 12: 490–491. Jain A, Brody D, Hamad I et al. (2000). Conversion to Neoral for neurotoxicity after primary adult liver transplantation under tacrolimus. Transplantation 69: 172–176. Kashap R, Ryan C, Sharma R et al. (2009). Liver grafts from donors with central nervous system tumors: a single-center perspective. Liver Transpl 15: 1024–1208. Khanna A, Hemming AW (2010). Fulminant hepatic failure: when to transplant. Surg Clin North Am 90: 877–889. Kim BS, Lee SG, Hwang S et al. (2007). Neurologic complications in adult living donor liver transplant recipients. Clin Transplant 21: 544–547. Laureno R, Karp BP (1997). Cyclosporine mutism. Neurology 48: 296–297. Lee WM, Wijdicks EFM (2008). Fulminant hepatic failure: when the hepatologist meets the neurointensivist. Neurocrit Care 9: 1–2. LeRoux PD, Elliott JP, Perkins JD et al. (1990). Intracranial pressure monitoring in fulminant hepatic failure and liver transplantation. Lancet 335: 1291. Lewis MB, Howdle PD (2003). Neurologic complications of liver transplantation in adults. Neurology 61: 1174–1178. Mandell MS, Lezotte D, Kam I et al. (2002). Reduced use of intensive care after liver transplantation: influence of early extubation. Liver Transpl 8: 676–681. Maramattom BV, Wijdicks EFM (2004). Sirolimus may not cause neurotoxicity in kidney and liver transplant recipients. Neurology 63: 1958–1959. Marchiori PE, Mies S, Scaff M (2004). Cyclosporine A-induced ocular opsoclonus and reversible leukoencephalopathy after orthotopic liver transplantation: brief report. Clin Neuropharmacol 27: 195–197. Montalbano M, Neff GW, Yamashiki N et al. (2004). A retrospective review of liver transplant patients treated with sirolimus from a single center: an analysis of sirolimusrelated complications. Transplantation 78: 264–268. Montalti R, Nardo B, Beltempo P et al. (2005). Liver transplantation in fulminant hepatic failure: experience with 40 adult patients over a 17-year period. Transplant Proc 37: 1085–1087.

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O’Grady J (2007). Modern management of acute liver failure. Clin Liver Dis 11: 291–303. Park JK, Lee DH (2005). Bioartificial liver systems: current status and future perspective. J Biosci Bioeng 99: 311–319. Pujol A, Gratis F, Rimola A et al. (1994). Predictive factors of in-hospital CNS complications following liver transplantation. Neurology 44: 1226–1230. Raabe W (1987). Synaptic transmission in ammonia intoxication. Neurochem Pathol 6: 145–166. Raghaven M, Marik PE (2006). Therapy of intracranial hypertension in patients with fulminant hepatic failure. Neurocrit Care 4: 179–189. Reyes J, Gayowski T, Fung J et al. (1990). Expressive dysphasia possibly related to FK506 in two liver transplant recipients. Transplantation 50: 1043–1045. Ritt DJ, Whelan G, Werner DJ et al. (1969). Acute hepatic necrosis with stupor or coma. An analysis of thirty-one patients. Medicine (Baltimore) 48: 151–172. Russo MW, Galanko JA, Shrestha R et al. (2004). Liver transplantation for acute liver failure from drug induced liver injury in the United States. Liver Transpl 10: 1018–1023. Schiff D, O’Neill B, Wijdicks EFM et al. (2001). Glioma arising in organ transplant recipients: an unrecognized complication of transplantation? Neurology 57: 1486–1488. Seeley WW, Marty FM, Holmes TM et al. (2007). Posttransplant acute limbic encephalitis: clinical features and relationship to HHV6. Neurology 69: 156–165. Shami VM, Caldwell SH, Hespenheide EE et al. (2003). Recombinant activated factor VII for coagulopathy in fulminant hepatic failure compared with conventional therapy. Liver Transpl 9: 138–143. Small SL, Fukui MB, Bramblett GT et al. (1996). Immunosuppression-induced leukoencephalopathy from tacrolimus (FK506). Ann Neurol 40: 575–580. Stangou AJ, Hawkins PN (2004). Liver transplantation in transthyretin-related familial amyloid polyneuropathy. Curr Opin Neurol 17: 615–620. Starzl TE, Fung JJ (2010). Themes of liver transplantation. Hepatology 51: 1869–1884. Steg RE, Garcia EG (1991). Complex visual hallucinations and cyclosporine neurotoxicity. Neurology 41: 1156. Stravitz RT, Kramer AH, Davern T et al. (2007). Intensive care of patients with acute liver failure: recommendations of the U.S. Acute Liver Failure Study Group. Crit Care Med 35: 2498–2508. Taylor BV, Wijdicks EFM, Poterucha JJ et al. (1995). Chronic inflammatory demyelinating polyneuropathy complicating liver transplantation. Ann Neurol 38: 828–831. Truwit CL, Denaro CP, Lake JR et al. (1991). MR imaging of reversible cyclosporin A-induced neurotoxicity. AJNR Am J Neuroradiol 12: 651–659. Valldeoriola F, Graus F, Rimola A et al. (1996). Cyclosporineassociated mutism in liver transplant patients. Neurology 46: 252–254. Van de Kerkhove MP, Hoekstra R, Chamuleau RA et al. (2004). Clinical application of a bioartificial liver support systems. Ann Surg 240: 216–230.

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Vecino MC, Cantisani G, Zanotelli ML et al. (1999). Neurological complications in liver transplantation. Transplant Proc 31: 3048–3049. Vogt DP, Lederman RJ, Carey WD et al. (1988). Neurologic complications of liver transplantation. Transplantation 45: 1057–1061. Wijdicks EFM (Ed.), (1999). Neurologic Complications in Organ Transplant Recipients. Butterworth-Heinemann, Boston. Wijdicks EFM (2001). Neurotoxicity of immunosuppressive drugs. Liver Transpl 7: 937–942. Wijdicks EFM (2009). Neurologic Complications of Critical Illness. 3rd edn. Oxford University Press. Wijdicks EF, Nyberg SL (2002). Propofol to control intracranial pressure in fulminant hepatic failure. Transplant Proc 34: 1220–1222. Wijdicks EFM, Wiesner RH, Dahlke LJ et al. (1994). FK506induced neurotoxicity in liver transplantation. Ann Neurol 35: 498–501.

Wijdicks EFM, de Groen PC, Wiesner RH et al. (1995a). Intracerebral hemorrhage in liver transplant recipients. Mayo Clin Proc 70: 443–446. Wijdicks EFM, Plevak DJ, Rakela J et al. (1995b). Clinical and radiologic features of cerebral edema in fulminant hepatic failure. Mayo Clin Proc 70: 119–124. Wijdicks EFM, Wiesner RH, Krom RA (1995c). Neurotoxicity in liver transplant recipients with cyclosporine immunosuppression. Neurology 45: 1962–1964. Wijdicks EFM, Litchy WJ, Wiesner RH et al. (1996a). Neuromuscular complications associated with liver transplantation. Muscle Nerve 19: 696–700. Wijdicks EFM, Dahlke LJ, Wiesner RH (1999). Oral cyclosporine decreases severity of neurotoxicity in liver transplant recipients. Neurology 52: 1708–1710. Wu G, Vichez RA, Eidelman B et al. (2002). Cryptococcal meningitis: an analysis among 5,521 consecutive organ transplant recipients. Transpl Infect Dis 4: 183–188.

Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 86

Neurologic complications of intestinal transplantation ANDREA STRACCIARI* AND MARIA GUARINO Neurology Unit, S. Orsola-Malpighi University Hospital, Bologna, Italy

INTRODUCTION The first attempts at intestine transplantation (ITx) in humans were made during the 1960s, but intestinal transplants were not successful until the 1990s, when potent immunosuppressive drugs became available along with improved methods to prevent infections. In particular, the introduction of FK506 (tacrolimus) led to a consistent improvement in ITx outcome, significantly lengthening patient and graft survival, due also to the refinement of surgical techniques and better clinical management. Notwithstanding, ITx remains a difficult procedure and the results are still inferior to those of other organ transplants, especially in terms of long-term outcome and multivisceral transplants, due to a high risk of immunologic complications, and the subsequent need for profound immunosuppression with its attending sideeffects such as malignancies, infections, and drug toxicity. After ITx, patients may experience various medical and surgical complications, the commonest including infections, rejection, intestinal ischemia, and leaks from the anastomoses. There are treatment options for all of these complications, but in some cases they result in graft loss or even the death of the patient. Among ITx complications, neurologic problems have received little attention to date, especially when compared to those occurring after other solid organ transplantations. Prior to a detailed analysis, a short survey of the general aspects of ITx may be useful.

GENERAL REMARKS Indications and contraindications for intestinal transplantation ITx is indicated in patients with chronic, irreversible intestinal failure associated with failure or severe complications of parenteral nutrition. Intestinal failure

may result from a variety of anatomic and functional conditions, the leading cause being the short bowel syndrome, which results from inadequate bowel length due to the primary disease or surgical resections. The functional condition results from inadequate bowel function due to neuromuscular or mucosal disease, although bowel length may be completely preserved. A list of common indications for ITx is presented in Table 86.1. As with other solid abdominal organ transplants (Steinman et al., 2001), absolute contraindications to ITx include life-threatening and other irreversible disease not related to the digestive system such as severe cardiopulmonary disease, severe systemic infections with multiple organ failure, aggressive malignancy, profound neurologic disabilities, and importantly, insufficient vascular patency to guarantee vascular access for up to 6 months after transplant (Caicedo and Iyer, 2005; Braun et al., 2007; Vianna et al., 2008; Millar et al., 2009). A relative contraindication may be excessive narcotic dependency and usage in children with chronic intestinal pseudo-obstruction (CIPO) (Millar et al., 2009), a heterogeneous group of rare disorders presenting with symptoms and signs of intestinal obstruction, but without a mechanical basis.

Surgical procedures and complications Three different approaches are currently adopted for ITx: (1) isolated intestinal transplant – to date estimated at 30% (Berg et al., 2009) – for those patients presenting only intestinal failure; (2) combined liver and intestine transplant, when intestinal and end-stage liver failure coexist; (3) multivisceral transplant, when multiorgan failure requires transplantation of at least three organs, including the intestine. Surgical complications are common, occurring in 50% of transplanted patients, but rarely hampering the

*Correspondence to: Dr. Andrea Stracciari, Unita` Operativa di Neurologia, Policlinico S. Orsola-Malpighi, via Albertoni 15, 40138 Bologna, Italy. Phone: þ39-051-636-2643, Fax: þ39-051-636-2640, E-mail: [email protected]

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Table 86.1 Causes of intestinal failure requiring intestine transplantation Children

Adults

Gastroschisis Volvulus Necrotizing enterocolitis Intestinal atresia Pseudo-obstruction Microvillus inclusion disease Intestinal polyposis Aganglionosis/Hirschsprung disease Trauma Tufting enteropathy

Superior mesenteric artery and venous thrombosis Crohn disease Intestinal dysmotility Trauma Volvulus Desmoid tumor Familial polyposis Gastrinoma Budd–Chiari disease Intestinal adhesions Pseudo-obstruction Inflammatory bowel disease Radiation enteritis

transplant success. The main complications are postsurgery anastomotic haemorrhage, vascular occlusion, and biliary loss or obstruction, whereas intestinal perforations, wound dehiscence, and wound infections are less common (Guaraldi et al., 2005; Braun et al., 2007; Millar et al., 2009). Most adult intestine recipients have had multiple abdominal surgeries before reaching ITx and have developed dense adhesions, which may result in significant blood loss and hemodynamic instability at the time of transplant. In addition, intestinal transplant recipients may have a poor nutritional status, which directly impacts on wound and anastomotic healing. The post-transplant clinical course is frequently complicated by extensive metabolic, toxic, and infectious disorders related to previous dependence on total parenteral nutrition, frequent severe hepatic cholestasis, and the strong immunosuppression required to prevent and/or control rejection. The intestine is more difficult to transplant than other solid organs, some of the reasons possibly being the large number of white cells in the bowel which provides a strong stimulus for rejection, and the large number of bacteria in the gut, which increases the risk of infection after transplantation. Because of the degree of immunosuppression used, typical and atypical postoperative infections are likely to occur after ITx (Kusne et al., 1996; Guaraldi et al., 2005; Fryer, 2008), and sepsis/multiorgan failure continues to be the leading cause of death (Fryer, 2008). Approximately half of the deaths in intestinal transplant patients have been clearly attributed to sepsis, while another quarter have been attributed to multiorgan failure to which sepsis was likely a contributing factor (Fryer, 2008). The most common locations of infections

are the bloodstream, central venous catheters (CVC), respiratory tract, wound and intra-abdominal cavity (Guaraldi et al., 2005; Tzakis et al., 2005; Oltean et al., 2006; Kimura et al., 2009). Another common post ITx complication is rejection (Grant et al., 2005; Fryer, 2008; Mazariegos et al., 2010), which can lead to graft failure and death. Some forms of acute rejection occur in up to 90% of intestinal transplant recipients. Acute cellular allograft rejection can occur at any time but is most common in the first year. Chronic rejection, demonstrated in 10–13% of intestine-only transplants (Fryer, 2008), consists of the sum of persistent episodes of acute rejection, presenting with diarrhea, weight loss, intermittent fever, abdominal pain, and gastrointestinal hemorrhage.

Immunosuppression ITx presents a greater immunologic challenge than other solid organs transplants (Pirenne and Kawai, 2009), being still characterized by a higher incidence of rejection due to the susceptibility of the intestinal graft, a large amount of donor lymphoid tissue, and the colonization of bacteria which can translocate into the circulation once the integrity of the intestinal mucosal barrier is disrupted. This is why ITx patients usually need more profound immunosuppression than other solid organ transplant recipients. The immunosuppressive history of successful ITx began with the clinical introduction of tacrolimus, which still represents the core immunosuppression used for maintenance therapy. Subsequently, induction therapy combined with immune modulation became the standard protocol. To date, induction therapy has been adjusted to minimize the dosage of immunosuppression, and consists of monoclonal (e.g., muromonab (OKT3)) or polyclonal antibody preparations, or antilymphocyte agents. Steroids are usually also included in most postoperative immunosuppressive regimens. Sirolimus has been used in combination with tacrolimus and may help prevent chronic rejection (Fishbein et al., 2002; Fryer, 2008) and reduce the dependence on tacrolimus and steroids. The risk of complications associated with immunosuppressive agents, especially tacrolimus, is not negligible. Chronic renal damage is particularly frequent and dangerous. In general, average serum levels for this drug are maintained at higher levels in intestinal transplant recipients compared with levels for other solid organ recipients, thereby explaining why a decline in renal function is more common and precipitous after ITx (Kato et al., 2006; Watson et al., 2008).

NEUROLOGIC COMPLICATIONS Unlike other types of solid organ transplantation, the literature on neurologic complications after ITx is scant.

NEUROLOGIC COMPLICATIONS OF INTESTINAL TRANSPLANTATION 1269 A review updated to December 2010 found few case Etiology reports and only three case series, all retrospective. Of As for other organ transplants, the etiology of neurothese, one is autoptic (Idoate et al., 1999), another conlogic complications appears to be heterogeneous, often cerns a population of children who received liver and multifactorial, and varies depending on the phase liver plus small bowel transplant (Fernandez et al., considered. 2010), with data presented all together for both types During the organ transplant procedure neurologic of transplantation, thereby concealing the complications problems may occur due to the pre-existing conditions strictly related to ITx. The only informative study on of the patient as well as the long duration and complexity clinical neurologic complications after ITx is that by of the operation, and are more frequent in multivisceral Zivkovic´ et al. (2010). transplantation. Patients may experience increased intracranial pressure, with a severely compromised cerebral Epidemiology perfusion pressure. Hypovolemia and hypercarbia may complicate surgery, with a further reduction in The few available data seem to indicate that the neurocerebral blood flow. Hypotension may develop, leading logic complications of ITx are more common than those to a hypoxic-ischemic event. For these reasons, surgeryaffecting other solid organ transplant recipients. In their related neurologic complications mostly affect the sample, including 23 isolated ITx, 16 with liver plus intescentral nervous system (CNS), mainly causing cerebrotine transplantation, and seven multivisceral transplants, vascular injury. Peripheral nervous system (PNS) damexamined retrospectively with a median follow-up of 25 age may also occur, presenting with mononeuropathies months, Zivkovic´ et al. (2010) found that 46 of 54 recipcaused by stretching, compression, or direct injury, espeients (85%) developed one or more neurologic complicacially in the case of prolonged and complex surgery, such tions. This overall rate of neurologic complications is as multivisceral transplants. consistently higher than that reported with other transIn the early postsurgical phase (100 days post-HSCT. 30% developed irreversible neurotoxicity despite Infections during the pretransplant period are related discontinuation of the drug. After interruption of the to the underlying disease and how competent the immune calcineurin inhibitor therapy, 54% of patients who develsystem of the patient is at that time. Patients with neoplasoped neurotoxicity before day 100 post-transplantation tic conditions associated with hypogammaglobulinemia developed graft-versus-host disease even though might develop infections due to encapsulated bacteria. alternative immunosuppressive therapy was initiated. Patients with acute myeloid leukemia might develop invaMortality was observed in 80% of the patients approxisive fungal infections due to prolonged neutropenia. Aermately 30 days after the development of neurotoxicity. obic Gram-negative bacilli, such as Klebsiella species and Most patients died of graft-versus-host disease (54%), Escherichia coli are frequently observed during this relapse disease (20%), or multiorgan failure/thrombotic period (Sable and Donowitz, 1994). However, most infecthrombocytopenic purpura (20%). The rest died from tious processes will be local infections and associated veno-occlusive disease. The majority of patients in this severity and mortality rates are low. Neurologic complicastudy achieved resolution of their symptoms after distions are not frequent during this period. continuation or dose adjustment of the drug. However, The pre-engraftment period is characterized by the half of those patients developed recurrence of their presence of neutropenia and disruption of mucosal barsymptomatology after reintroduction of the drug or an riers due to cytotoxic chemotherapy of radiation therapy. alternate calcineurin inhibitor. The high incidence of The use of central venous catheters is also a contributing graft-versus-host disease and subsequent mortality factor for the development of infections. The predomiwas not surprising considering that patients identified nant infections during this phase of transplantation are for this analysis were those with significant neurotoxicbacterial, occurring in 15–50% of recipients of bone marity and incapable of tolerating without interruption one row transplant (Sable and Donowitz, 1994). In the 1980s, of the most effective preventive therapies against graftGram-negative bacteria were a frequent source of morbidversus-host disease. Perhaps, knowing that graft-versusity and mortality in cancer patients, including recipients of host disease is one of the leading causes of mortality in HSCT. However, with the frequent use of prophylaxis patients who developed calcineurin inhibitor neurotoxicbased on quinolones and common utilization of indwelling ity, efforts should be directed at identifying alternate catheters, Gram-positive organisms became an important effective regimens for this vulnerable group of patients. source of infections during this period. Sepsis-related encephalopathy may be observed during this period. Invasive fungal infections are observed during this INFECTIONS ASSOCIATED WITH period as well and are one of the most lethal complicaNEUROTOXICITY IN HEMATOPOIETIC tions. The most common pathogens affecting recipients STEM CELL TRANSPLANTATION of HSCT are Candida species and Aspergillus species. Infections in hematopoietic stem cell transplant patients Invasive candidiasis is the most frequent mycosis affectare frequent causes of morbidity and mortality. As ing hematologic and hematopoietic stem cell transplant expected, the transplant-related mortality associated recipients. The wide use of fluconazole prophylaxis in with infections is directly proportional to the degree of HSCT patients is responsible for a higher incidence of immunosuppression and time of immune reconstitution species other than Candida albicans, as, for example, of the recipient. Infections as the main cause of mortalCandida glabrata and Candida krusei. The CNS may ity in HSCT transplant patients occur in approximately be involved by disseminated infection. The initial symp8% of autologous HSCT, 12% of HLA-matched sibling toms of meningitis secondary to Candida are

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indistinguishable from those related to bacterial infections (Henao and Vagner, 2011). The initial symptoms of acute meningitis related to Candida are indistinguishable from those produced by bacterial infections. A negative CSF does not rule out the infection, especially in the presence of pleocytosis. Involvement of the CSF by Candida species is relatively infrequent. On the other hand, Aspergillus species account for 30–50% of CNS infections caused by an invasive fungal infection. Fluconazole has no activity against Aspergillus species and the echinocandins, such as caspofungin, mycafungin, and anidulafungin, are mainly fungistatic against this organism. Current guidelines recommend using triazoles, e.g., voriconazole, for the management of invasive fungal infections due to Aspergillus species (CDC, 2000). Infections due to Zygomycetes have emerged more frequently due to improvements in survival of transplant patients and the frequent use of fungal prophylaxis using fluconazole and voriconazole (Fig. 88.2). Zygomycosis has been found postmortem in up to 8% of patients with leukemia and 2%

of patients after allogeneic hematopoietic stem cell transplantation. Viral infections may be observed in the preengraftment period. These include human simplex virus and human simplex virus 2. The postengraftment period is characterized by resolution of the neutropenia and discontinuation of the protective isolation imposed on most patients during their conditioning regimen and pre-engraftment period. During this time, graft-versus-host disease and its therapy become important sources of morbidity and mortality. Immunosuppressive therapy increases the incidence of fungal infections and viral infections. Bacterial infections are less frequent. A significant association between pretransplant viral status, defined as a higher number of positive herpes group viral serologies in the recipient before transplantation, and the development of neurologic complications has been observed. There is also a significant association between cytomegalovirus seropositivity and the incidence of neurologic complications (Rubin et al., 2005). The late post-transplantation period is characterized by a relative immune reconstitution compared to prior transplant phases. Nevertheless, the development of graft-versus-host disease and its management may predispose patients to fungal, viral, and even bacterial infections due to the functional asplenia that characterizes the disorder.

NEUROLOGIC COMPLICATIONS ASSOCIATED WITH CHRONIC GRAFT-VERSUS-HOST DISEASE

Fig. 88.2. MRI of a central nervous system zygomycosis infection. Gadolinium ring enhancement lesion documented in the left frontal lobe. Invasive fungal infection was diagnosed by left frontal craniotomy in this 61-year-old man with a history of non-Hodgkin lymphoma and autologous hematopoietic stem cell transplantation who was requiring intermittent steroid therapy due to refractory idiopathic thrombocytopenic purpura post-transplantation.

Chronic graft-versus-host disease is a complication of allogeneic HSCT that is frequently preceded by acute graftversus-host disease. Most cases are diagnosed within the first year post-transplantation. Chronic graft-versus-host disease most often involves the skin and mouth, but almost any other organ system can be involved. Correct diagnosis is critical so that appropriate therapy can be started promptly to minimize symptoms and prevent irreversible organ damage (Lee and Flowers, 2008). First-line therapy is based on corticosteroids with or without calcineurin inhibitors (Grauer et al., 2010). The use of steroids is associated with significant morbidity and mortality including opportunistic infections, steroid-induced myopathy, and steroid-induced encephalopathy. Other neurologic complications associated with chronic graft-versus-host disease are polymyositis and immune-mediated neuropathies, such as Guillain–Barre´ syndrome (GBS) and myasthenia gravis (MG).

NEUROLOGIC COMPLICATIONS OF BONE MARROW TRANSPLANTATION

CONCLUSION Neurologic complications in hematopoietic stem cell transplant recipients are important causes of treatment-related morbidity and mortality. More than half of the patients undergoing hematopoietic stem cell transplantation will experience a neurologic complication. The incidence relates to the degree of HLA disparity and the risk status of the underlying disease. Recipients of alternate stem cell donors appear to be at a higher risk compared to recipients of HLA-matched sibling donors. The diagnosis of neurologic complications in hematopoietic stem cell transplant patients could be elusive. Patients undergoing stem cell transplantation are frequently under sedative hypnotic drugs or neuromuscular blocking agents. Other common non-neurologic complications such as hypoxemia, hypotension, renal or hepatic failure, and metabolic abnormalities, might complicate even further the recognition of neurologic dysfunction. Therefore, clinicians should keep a high level of suspicion for neurologic complications especially if the patient is the recipient of an alternate HLA-matched donor transplant. Common risk factors for the development of neurologic complications should be kept in mind. Some of the common risk factors are sepsis, TBI, or busulfan-containing regimen, the use of calcineurin inhibitors, graft-versus-host disease, prolonged immunosuppression, and infections. Prompt neurologic assessment and initiation of antibiotic therapy are of paramount importance in preventing morbidity and mortality of hematopoietic stem cell transplant recipients.

REFERENCES Andersson BS, Kashyap A, Gian V et al. (2002). Conditioning therapy with intravenous busulfanand cyclophosphamide (IV BuCy2) for hematologic malignancies prior to allogeneic stem cell transplantation: a phase II study. Biol Blood Marrow Transplant 8: 145–154. Bacigalupo A, Ballen K, Rizzo D et al. (2009). Defining the intensity of conditioning regimens: working definitions. Biol Blood Marrow Transplant 15: 1628–1633. Barba P, Pin˜ana JL, Valca´rcel D et al. (2009). Early and late neurological complications after reduced intensity conditioning allogeneic stem cell transplantation. Biol Blood Marrow Transplant 15: 1439–1446. Bleggi-Torres LF, de Medeiros BC, Werner B et al. (2000). Neuropathological findings after bone marrow transplantation: an autopsy study of 180 cases. Bone Marrow Transplant 25: 301–307. Bolton CF, Young B (2007). Managing the nervous system effects of sepsis. Chest 131: 1273–1274. Carson SS, Kress JP, Rodgers JE et al. (2006). A randomized trial of intermittent lorazepam versus propofol with daily interruption in mechanically ventilated patients. Crit Care Med 34: 1326–1332.

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CDC (2000). Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Recomm Rep 49: 1–125, CE 1–7. Cohen J, Drage S (2011). How I manage haematology patients with septic shock. Br J Haematol 152: 380–391. de Brabander C, Cornelissen J, Smitt PA et al. (2000). Increased incidence of neurological complications in patients receiving an allogenic bone marrow transplantation from alternative donors. J Neurol Neurosurg Psychiatry 68: 36–40. Dicke KA, Zander AR, Spitzer G et al. (1979). Autologous bone marrow transplantation in relapsed adult acute leukemia. Exp Hematol 7 (Suppl 5): 170–187. Dohgu S, Sumi N, Nishioku T et al. (2010). Cyclosporin A induces hyperpermeability of the blood–brain barrier by inhibiting autocrine adrenomedullin-mediated up-regulation of endothelial barrier function. Eur J Pharmacol 644: 5–9. Eberly AL, Anderson GD, Bubalo JS et al. (2008). Optimal prevention of seizures induced by high-dose busulfan. Pharmacotherapy 28: 1502–1510. Garrick R (2000). Neurological complications. In: K Atkinson et al. (Eds.), Clinical Bone Marrow and Blood Stem Cell Transplantation. Cambridge University Press, Cambridge, pp. 958–979. Grauer O, Wolff D, Bertz H et al. (2010). Neurological manifestations of chronic graft-versus-host disease after allogeneic haematopoietic stem cell transplantation: report from the Consensus Conference on Clinical Practice in chronic graft-versus-host disease. Brain 133: 2852–2865. Hansen JA, Clift RA, Mickelson EM et al. (1981). Marrow transplantation from donors other than HLA identical siblings. Hum Immunol 2: 31–40. Henao NA, Vagner B (2011). Infections of the central nervous system by Candida. J Infect Dis Immun 3: 79–84. Iacobone E, Bailly-Salin J, Polito A et al. (2009). Sepsis associated encephalopathy and its differential diagnosis. Crit Care Med 37 (Suppl): S331–S336. Jacobson LO, Marks EK, Robson MJ et al. (1949). Effect of spleen protection on mortality following X-irradiation. J Lab Clin Med 34: 1538–1543. Kumar A, Roberts D, Wood KE et al. (2006). Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 34: 1589–1596. La Morgia C, Mondini S, Guarino M et al. (2004). Busulfan neurotoxicity and EEG abnormalities: a case report. Neurol Sci 25: 95–97. Larson RA, Geller RB, Janisch L et al. (1995). Encephalopathy is the dose-limiting toxicity of intravenous hepsulfam: results of a phase I trial inpatients with advanced hematological malignancies. Cancer Chemother Pharmacol 36: 204–210. Laupacis A, Keown PA, Ulan RA et al. (1982). Cyclosporin A: a powerful immunosuppressant. Can Med Assoc J 126: 1041–1046. Lee SJ, Flowers ME (2008). Recognizing and managing chronic graft-versus-host disease. Hematology Am Soc Hematol Educ Program 2008: 134–141.

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Lin MY, Weinstein RA, Hota B (2008). Delay of active antimicrobial therapy and mortality among patients with bacteremia: impact of severe neutropenia. Antimicrob Agents Chemother 52: 3188–3194. Lindboe CF, Loberg EM (1989). Wernicke’s encephalopathy in nonalcoholics. An autopsy study. J Neurol Sci 90: 125–129. Lorenz E, Uphoff D, Reid TR et al. (1951). Modification of irradiation injury in mice and guinea pigs by bone marrow injections. J Natl Cancer Inst 12: 197–201. Majolino I, Caponetto A, Scime´ R et al. (1990). Wernicke-like encephalopathy after autologous bone marrow transplantation. Haematologica 75: 282–284. McCune JS, Gibbs JP, Slattery JT (2000). Plasma concentration monitoring of busulfan: does it improve clinical outcome? Clin Pharmacokinet 39: 155–165. Openshaw H, Slatkin NE (1999). In: ED Thomas, KG Blume, SJ Foreman (Eds.), Hematopoietic Cell Transplantation. 2nd edn. Blackwell Science, Malden, MA, pp. 659–673. Papadopoulos MC, Davies DC, Moss RF et al. (2000). Pathophysiology of septic encephalopathy: a review. Crit Care Med 28: 3019–3024. Pasquini MC, Wang Z (2011). Current use and outcome of hematopoietic stem cell transplantation: CIBMTR Summary Slides. Available at: http://www.cibmtr.org. Rubin J, Wide K, Remberger M et al. (2005). Acute neurologicalcomplications after hematopoietic stem cell transplantation in children. Pediatr Transplant 9: 62–67. Sable CA, Donowitz GR (1994). Infections in bone marrow transplant recipients. Clin Infect Dis 18: 273–281. Siegal D, Keller A, Xu W et al. (2007). Central nervous system complications after allogeneic hematopoietic stem cell transplantation: incidence, manifestations, and clinical significance. Biol Blood Marrow Transplant 13: 1369–1379. Speck B, Zwaan FE, van Rood JJ et al. (1973). Allogeneic bone marrow transplantation in a patient with aplastic anemia

using a phenotypically HL-A-identical unrelated donor. Transplantation 16: 24–28. Takeshima K (1953). Studies on bone marrow blood of atomic bomb victims who showed epilation. Acta Pathol Jpn 3: 124–132. Thomas ED, Buckner CD, Banaji M et al. (1977). One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood 49: 511–533. Till JE, McCulloch EA (1963). Early repair processes in marrow cells irradiated and proliferating in vivo. Radiat Res 18: 96–105. Uckan D, Cetin M, Yigitkanli I et al. (2005). Life-threatening neurological complications after bone marrow transplantation in children. Bone Marrow Transplant 35: 71–76. Valca´rcel D, Martino R, Sureda A et al. (2005). Conventional versus reduced-intensity conditioning regimen for allogeneic stem cell transplantation in patients with hematological malignancies. Eur J Haematol 74: 144–151. van Rossum HH, de Fijter JW, van Pelt J (2010). Pharmacodynamic monitoring of calcineurin inhibition therapy: principles, performance, and perspectives. Ther Drug Monit 32: 3–10. Vriesendorp HM (2003). Aims of conditioning. Exp Hematol 31: 844–854. Weber C, Schaper J, Tibussek D et al. (2008). Diagnostic and therapeutic implications of neurological complications following paediatric haematopoietic stem cell transplantation. Bone Marrow Transplant 41: 253–259. Yamashita M, Katsumata M, Iwashima M et al. (2000). T cell receptor-induced calcineurin activation regulates T helper type 2 cell development by modifying the interleukin 4 receptor signaling complex. J Exp Med 191: 1869–1879. Young GB, Bolton CF, Austin TW et al. (1990). The encephalopathy associated with septic illness. Clin Invest Med 13: 297–304.

Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 89

Neurologic aspects of multiple organ transplantation SASˇA A. ZˇIVKOVIC´* Neurology Service, Department of Veterans Affairs and Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

INTRODUCTION The field of organ transplantation remains one of the most dynamic areas in medicine, with ever changing protocols and improved outcomes (Linden, 2009a). Availability of more potent immunosuppressants and better understanding of pathogenesis of allograft rejection have facilitated the development of more effective immunosuppressive protocols and prophylactic regimens decrease the impact of opportunistic infections. Such improvements have established organ transplantation as a valid treatment option for patients with irreversible end-organ failure. Transplantations of kidney, heart, and liver have been well established for more than two decades, and more recently transplantation of intestine became accepted as a rescue treatment for patients with intestinal failure who failed parenteral nutrition (Grant et al., 2005; AbuElmagd, 2006; Abu-Elmagd et al., 2009a; Fishbein, 2009). Multisystemic medical conditions (e.g., amyloidosis, diabetes) may compromise the function, or even lead to failure of several different organs. Multiorgan failure requires complex multidisciplinary care and may necessitate simultaneous transplantation of several organs, including combinations of heart–lung allograft, heart–liver, kidney–pancreas, or multivisceral transplantation (Table 89.1). Additionally, combined hematopoietic stem cell and solid organ transplantations have been performed in an attempt to modulate the postoperative immunologic response and induce the tolerance of allograft with decreased immunosuppression needs (Starzl and Zinkernagel, 1998; Starzl, 2004). Postoperative clinical course after organ transplantation is frequently marred by various surgical and medical complications, and it has been estimated that up to 30–60% of patients may develop some type of

post-transplant neurologic complications (Patchell, 1994; Bronster et al., 2000; Lewis and Howdle, 2003; Zˇivkovic´ and Abdel-Hamid, 2010). Overall, neurologic complications associated with organ transplantation typically stem from (1) the transplant procedure, (2) metabolic insult created by the underlying primary disease, (3) opportunistic infections, and (4) neurotoxicity of immunosuppressive medications (Zˇivkovic´ and AbdelHamid, 2010). Most commonly, neurologic complications do not determine the outcome of transplantation except in some patients with opportunistic CNS infections. In more recent years, as transplantation outcomes and survival continued to improve, the spectrum of post-transplant neurologic complications started to shift from acute postoperative complications to chronic complications which are increasingly encountered in an outpatient setting. The most commonly reported neurologic complications after transplantation are still alterations of consciousness, seizures, and neuromuscular complications (Zˇivkovic´ and Abdel-Hamid, 2010).

MULTIVISCERAL TRANSPLANTATION Intestinal failure is frequently accompanied by dysfunction and failure of other abdominal organs requiring liver–intestine or multivisceral transplantation (Abu-Elmagd et al., 2009a; Fishbein, 2009). Intestinal failure is defined as an “inability to maintain proteinenergy, fluid, electrolyte, or micronutrient balance” as a result of obstruction, dysmotility, surgical resection, congenital defect, or disease-associated loss of absorption (O’Keefe et al., 2006). The most common cause of intestinal failure requiring transplantation is short bowel syndrome (SBS), present in more than 70% of allograft recipients, followed by functional intestinal problems (e.g., dysmotility) in 20%, and “other” causes

*Correspondence to: Sasˇa A. Zˇivkovic´, M.D., Ph.D., PUH F878, 200 Lothrop St, Pittsburgh, PA 15213, USA. Tel: þ1-412-647-1706, Fax: þ1-412-647-8398, E-mail: [email protected]

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S.A. ZˇIVKOVIC´

Table 89.1

Table 89.2

Multiorgan transplantations in US in 2009

Neurologic manifestations of nutritional deficiencies

Kidney–heart Kidney–intestine Kidney–lung Liver–heart Liver–intestine Multivisceral and intestinal Liver–kidney–heart Liver–kidney–pancreas–intestine Liver–lung Liver–lung–heart Liver–pancreas–intestine Pancreas–kidney Pancreas–intestine Heart–lung

60 5 3 11 4 180 4 9 10 1 76 854 9 30

Copper Selenium Chromium Carnitine Vitamin B1 Vitamin B2 Vitamin B3 Vitamin B6 Vitamin B12

Vitamin D Vitamin E

(UNOS OPTN Annual Report, 2009)

in the remaining of 10% of recipients (Hanto et al., 2005). Loss of functioning bowel in SBS requires complex dietary and medical management needed to alleviate severe disability and failure to thrive (Matarese et al., 2005). Intestinal failure may precipitate nutritional deficiencies or affect absorption of medications (O’Keefe et al., 2006; Ward, 2010). Malnutrition and various dietary deficiencies can precipitate a wide spectrum of neurologic disorders (Table 89.2). In adult patients, SBS is most often caused by Crohn’s disease, mesenteric thrombosis, or volvulus (Table 89.3). More recently, complications of surgeries for treatment of obesity have been recognized as another iatrogenic cause of SBS. Management of intestinal failure is based on trying to maintain balance of fluid, electrolytes, and nutrients and most patients will require nutritional support with total parenteral nutrition (TPN), at least temporarily. It has been estimated that more than 10 000 patients in the US are currently treated with long-term TPN, and 15–20% are deemed potential candidates for intestinal or multivisceral transplantation (DiBaise and Scolapio, 2007). Chronic TPN use may precipitate cholestatic liver injury, or even hepatic failure, but the pathophysiology of liver injury is still not well understood. Liver injury related to TPN is indicative of a poor outcome and these patients may require liver replacement (Pironi et al., 2011). Other frequent complications of TPN include malnutrition (if not properly formulated) and recurrent infections complicating venous access. Patients on TPN need continuous dietary monitoring to avoid sequelae of inadequate nutritional support (Mikalunas et al., 2001). Recurrent bloodstream infections have been reported in two-thirds of patients with long-term TPN (Marra et al., 2007). Patients who can no longer be maintained on TPN will require intestinal transplantation as a

Myeloneuropathy/myelopathy Myopathy Neuropathy Myopathy Wernicke–Korsakoff syndrome, peripheral neuropathy Optic neuropathy Encephalopathy, peripheral neuropathy, optic neuropathy Sensory neuropathy,* infantile seizures Subacute combined degeneration, dementia, peripheral neuropathy, autonomic neuropathy, optic neuropathy Myopathy, muscle cramps Retinitis pigmentosa, peripheral neuropathy, spinocerebellar degeneration

*Pyridoxine neurotoxicity may also cause sensory neuropathy. (Heller and Friedman, 1983; Cuba Neuropathy Field Investigation Team, 1995; Verhage et al., 1996; Chariot and Bignani, 2003; Orssaud et al., 2007; Kumar, 2010)

Table 89.3 Primary illnesses causing intestinal failure in pediatric and adult patients Children

Adults

Gastroschisis Necrotizing enterocolitis Intestinal atresia Volvulus Aganglionopathy Pseudo-obstruction

Mesenteric ischemia Inflammatory bowel disease Abdominal neoplasms Radiation enteritis Trauma Volvulus Pseudo-obstruction

(Abu-Elmagd et al., 2009a; Nayyar et al., 2010)

rescue therapy (Abu-Elmagd, 2006). Transplantation of small intestine (jejunoileum) is performed as an isolated intestinal transplantation procedure, or in combination with transplantation of other abdominal organs. It may be combined with liver allograft, and it is also the essential part of multivisceral transplantation (Abu Elmagd, 2006; Fishbein, 2009). Multivisceral and intestinal (MVI) transplantations are usually grouped together when outcomes of transplantation are considered. Multivisceral transplantation (also used synonymously is the term multiorgan transplantation) is performed simultaneously in contrast to sequential transplantations in patients developing organ failures at different times after initial transplantation (e.g., kidney failure related to calcineurin inhibitor (CNI) toxicity). Multivisceral

NEUROLOGIC ASPECTS OF MULTIPLE ORGAN TRANSPLANTATION transplantation offers immunologic protection to the intestinal allograft and is associated with lower rejection rate when compared to isolated intestinal transplantation (de Vera et al., 2000). Surgical complexity and formidable immunologic challenges has precluded wider use of multivisceral transplantation since 1987, when Dr Starzl and his team performed the first successful multivisceral transplantation (Starzl et al., 1989). Soon thereafter, Drs. Goulet and Grant and their groups performed the first successful isolated intestine and small intestine–liver transplantations, respectively (Grant et al., 1990). Continued advances in surgical technique and immunosuppression strategies established the role of MVI transplantation as a viable option for patients with complex multiorgan failures (Abu-Elmagd et al., 2009a, b, 2012). Development of improved and more potent immunosuppressive protocols based on recipient pretreatment and reduced maintenance immunosuppression enabled improved survival and reduction of organ rejection and post-transplant complications (Abu-Elmagd et al., 2009a, b, 2012). In the last few years, post-transplant survival at 1 and 5 years has reached 92% and 70%, which is comparable to other types of solid organ allografts (Abu-Elmagd et al., 2009a). However, the complexities of surgery and postoperative care are still largely limiting these procedures to a small number of academic centers, and more than 80% of MVI transplantations in the US have been performed by only 10 transplant centers (Grant et al., 2005). Currently there are close to 200 intestinal and multivisceral transplantations performed annually in the US, compared to more than 6000 liver transplantations (UNOS OPTN Annual Report, 2009). In August of 2010, there had only been 1988 intestinal and multivisceral transplantations performed in the US since 1990 (UNOS OPTN Annual Report, 2009). Immunogenicity of transplanted abdominal organs necessitates intensive immunosuppressive therapy which is associated with significant risks of immunosuppressant toxicity and opportunistic infections (Abu-Elmagd et al., 2009a, b). More recently, conditioning and tolerogenic immunosuppression strategies have tried to circumvent the need for such aggressive approach and allow effective use of lower intensity immunosuppression (Starzl et al., 2003; Abu-Elmagd et al., 2009a, b). This approach has allowed the use of lower doses of corticosteroids and CNIs and reduction of their toxicity. While close monitoring of nutritional status is still needed, successful transplantation is followed by nutritional autonomy in 90% of survivors and significant improvement and quality of life (AbuElmagd et al., 2012). Candidates for MVI transplantation frequently have an extensive history of abdominal surgeries, including

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intestinal resection, and complex pretransplant morbidities. Most common primary diseases leading to underlying organ failure differ in children and adults (Table 89.3). In children the most common underlying conditions include gastroschisis, necrotizing enterocolitis, and intestinal atresia. In the adult population the most common causes are inflammatory bowel disease, mesenteric artery thrombosis caused by hypercoagulable state, and abdominal tumors. Complex pretransplant morbidities and metabolic disturbances present unique challenges in post-transplant care of these patients (Hopfner et al., 2013). There are very few reports of neurologic complications after intestinal and multivisceral transplantation, consisting of individual case reports and one larger retrospective study (Mendez et al., 2006; Zˇivkovic´ et al., 2010). The rate of neurologic complications after MVI transplantation was reported as 86%, which is higher than the 30–60% usually reported with liver, kidney, or other solid organ transplantations (Patchell, 1994; Zˇivkovic´ and Abdel-Hamid, 2010; Zˇivkovic´ et al., 2010). Autopsy series showed frequent brain atrophy in deceased MVI allograft recipients, explained by long-standing metabolic disturbances and nutritional deficiencies (Idoate et al., 1999). Most commonly reported post-transplant neurologic complications in MVI allograft recipients include alterations of consciousness, seizures, and cerebrovascular complications (Zˇivkovic´ et al., 2010). The rate of opportunistic CNS infections with MVI in early series was higher than with other types of transplantation (Fishman, 2007; Zˇivkovic´ et al., 2010). However, the use of less intense immunosuppression in recent years will probably reduce the frequency of neurologic complications in line with other types of allografts.

Multivisceral transplantation Multivisceral transplantation is usually described as en bloc transplantation of three or more abdominal organs, including stomach, but at this time there is still no consensus on the definition of multivisceral allograft (Fig. 89.1; Table 89.4). The graft is modified according to the individual patient’s need with inclusion or exclusion of one or more abdominal organs, including the liver and kidney. Inclusion of the small bowel (jejunoileum) is essential to consider the graft as multivisceral. A variant known as “cluster transplantation” includes only liver, pancreas, duodenum, and possibly stomach. Preservation of native pancreas may improve posttransplant glucose control, but its impact on neurologic complications is uncertain (Cruz et al., 2010). The posttransplant course after multivisceral transplantation does not differ significantly in its spectrum from the complications seen after isolated intestine or

S.A. ZˇIVKOVIC´

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Gastrostomy tube

Duodenojejunal anastomosis PV Aorta Vascular graft, SMV

PV Jejunostomy tube Vascular graft, SMA

Aortic Condult

Chimney ileostomy

JPC

Ileocolic anastomosis Transplanted Native

A

B

C

Fig. 89.1. Intestinal and multivisceral allografts. The three main different types of intestinal transplantation are (1) isolated intestine; (2) combined liver–intestine; (3) multivisceral transplantation containing the stomach, duodenum, pancreas, small bowel, and liver. PV, portal vein; SMA, superior mesenteric artery; SMV, superior mesenteric vein. (Modified from Abu-Elmagd et al., 2009b.) Table 89.4 Definitions of multivisceral allograft Definition of multivisceral allograft

Source (Grant et al., 2005) (UNOS OPTN Annual Report, 2009) (Tzakis et al., 2005)

Includes stomach as part of composite visceral graft Includes liver, intestine and either pancreas or kidney Replacement of all organs dependent on the celiac and superior mesenteric arteries

liver–intestine transplantation, including neurologic complications (Abu-Elmagd et al., 2009a, b, 2012; Zˇivkovic´ et al., 2010; Hopfner et al., 2013).

Isolated intestine transplantation Intestine allograft transplantation is an integral part of multivisceral transplantation, but if function of other abdominal organs is preserved, some patients may undergo isolated intestine transplantation. This may be the preferred procedure for patients who need transplantation in the near future before multivisceral allograft

may become available (Fishbein, 2009). Isolated transplantation of the intestine is typically performed in patients that have (relatively) intact function of other abdominal organs or if the patient cannot wait for availability of compatible multivisceral allograft (Fishbein, 2009). When compared to multivisceral and liver– intestine allografts, there is an increase of risk of graft rejection and loss with isolated intestinal allograft (AbuElmagd et al., 2009a). As a result of improved surgical and immunosuppression protocols, intestinal transplantation is associated with improved survival rates compared to nontransplanted candidates (Pironi et al., 2008; Abu-Elmagd et al., 2009a, b). Most transplant recipients achieve TPN-independence after transplantation and improved quality of life (Rovera et al., 1998). Transplantation of isolated intestinal allograft is more commonly performed in adults than in children due to more frequent liver dysfunction in pediatric patients and a different spectrum of underlying primary diseases leading to intestinal failure.

Liver–intestine transplantation Combined liver–intestine transplantation is pursued in patients with intestinal failure and liver dysfunction. At this time there is no consensus on definition of the extent of liver dysfunction required for

NEUROLOGIC ASPECTS OF MULTIPLE ORGAN TRANSPLANTATION liver–intestine allograft transplantation (Fishbein, 2009). Liver–intestine transplantation is also considered in patients with liver failure and concurrent portomesenteric thrombosis. When compared to isolated small bowel transplantation, composite liver–intestine and multivisceral transplantation procedures are associated with improved allograft tolerance (de Vera et al., 2000; Abu-Elmagd et al., 2009a).

Pediatric intestinal and multivisceral transplantation Intestinal failure and SBS are relatively rare in children, but if present are associated with severe morbidity and a profound impact on growth and development. Intestinal failure in this population is defined as an inability to achieve adequate weight and growth without parenteral nutritional support. Medical management of pediatric intestinal failure may enable some patients to achieve enteral autonomy, but intestinal (or multivisceral) transplantation may be required in more than one-third of patients (Nucci et al., 2008). Early referral for transplantation is recommended to avoid more extensive morbidity which may also affect the outcome of transplantation. High morbidity associated with transplantation is countered frequently with abysmal prognosis of many nontransplanted patients. Almost a half of pediatric patients on long-term TPN develop liver disease, and in the presence of cirrhosis 1 year mortality may amount to 70–80% (Goulet et al., 2004). At this time transplantation pediatric allograft recipients comprise 55–60% of all MVI transplantations (UNOS OPTN Annual Report, 2009). Pediatric MVI transplantation differs from the same procedures in adult recipients in underlying etiologies of intestinal failure and its profound impact on and pre- and posttransplant morbidity and growth and development of allograft recipients (Kato et al., 2006; Mazariegos et al., 2008; Nayyar et al., 2010). Pediatric MVI transplant patients may present unique challenges in the acute postoperative phase or later, especially with multiple preexisting morbidities and late transplant referrals (Hauser et al., 2008). Outcome of MVI transplantation will directly affect the future growth and development of allograft recipients, and while most allograft recipients improve after transplantation, they may still not be able to catch up with their healthy age-matched controls (Sudan et al., 2000; Abu-Elmagd et al., 2009a). In recent years, protocols using lower doses of corticosteroids seemed to have improved post-transplant growth in pediatric intestinal transplant recipients (Ueno et al., 2006). Cognitive developmental delay and psychiatric disorders have been reported in up to 37% of pediatric MVI allograft

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recipients (Abu-Elmagd et al., 2012). Chronic malnutrition and lack of adequate social support in some patients may also contribute to developmental delays and challenges. Despite the high prevalence of psychiatric and developmental disorders in this population, almost one-third (31%) will later graduate from college and an additional 35% will finish an equivalent of high school (Abu-Elmagd et al., 2012). At this time there are no published systematic studies describing neurologic complications following intestinal and multivisceral transplantation in pediatric MVI allograft recipients.

NEUROLOGIC COMPLICATIONS OF MULTIVISCERAL AND INTESTINAL TRANSPLANTATION Neurologic complications of organ transplantation are a frequent cause of morbidity in early and late postoperative clinical course. Due to complex metabolic disturbances, nutritional insufficiencies, and high immunosuppression requirements the rate of neurologic complications after MVI transplantation is relatively high when compared to transplantations of liver, lung, or heart (Lewis and Howdle, 2003; Zierer et al., 2007; Zˇivkovic´ et al., 2010). The most commonly described complications include alterations of consciousness, headaches, and seizures (Table 89.5) (Zˇivkovic´ et al., 2010). While complex nutritional deficiencies in MVI transplant candidates invoke similarities with bariatric surgery patients, the observed spectrum of related neurologic complications is different (Thaisetthawatkul et al., 2004; Juhasz-Pocsine et al., 2007; Kazemi et al., 2010; Zˇivkovic´ et al., 2010). Half of adult MVI allograft recipients still receive vitamin D and B6 supplementation after successful surgery (Abu-Elmagd et al., 2012). Lack of reported complications attributable to malnutrition after MVI transplantation is also related to strict monitoring of nutritional parameters, similarly to the recommendations with bariatric surgery (Matarese et al., 2005, 2007; Thaisetthawatkul et al., Table 89.5 Neurologic complications after intestinal and multivisceral transplantation Altered consciousness Seizures Ischemic stroke Intracerebral hemorrhage CNS infection Peripheral neuropathy Headaches (Zivkovic et al., 2010)

43% 17% 4% 2% 7% 7% 50%

1310 S.A. ZˇIVKOVIC´ 2010). However, we also have to acknowledge that it consciousness and behavior (Small et al., 1996; would be difficult to compare bariatric procedures Bartynski et al., 2008). Neurotoxicity of other medicawith over 100 000 cases yearly with the 300 annual cases tions is less common. Antiviral medications and antibiof MVI transplantation. Additionally, as complications otics (e.g., aciclovir, cephalosporins) may also of bariatric surgery such as copper-deficiency precipitate toxic encephalopathy, especially in patients myeloneuropathy may manifest 9 years or longer after with hepatorenal dysfunction (Grill and Maganti, the gastric bypass, it will be essential to compare long2008). Opportunistic infections may precipitate alterterm surveillance results for meaningful comparison ations of consciousness via direct spreading to central of outcomes. nervous system or by triggering septic encephalopathy. Complexity of pretransplant morbidities and posttransplant complications may also help to explain high Alterations of consciousness and behavior levels of stress and frequent psychiatric disorders in Encephalopathy defined as an alteration of consciousMVI allograft recipients (Stenn et al., 1992; DiMartini ness or behavior is quite common in transplant recipiet al., 1996; Surman et al., 2009). ents, including multivisceral allograft recipients. Etiologies vary widely, from drug toxicities and metabolic abnormalities to opportunistic infections (with or Epilepsy without direct involvement of CNS) (Zˇivkovic´ et al., Epileptic seizures occur commonly in transplant recipi2010). Liver failure may also precipitate hepatic encephents and most frequent causes include toxic-metabolic alopathy, similar to that in liver transplant recipients disturbances, CNI neurotoxicity, and CNS infections (Guarino et al., 2006). Liver dysfunction in MVI trans(Estol et al., 1989; Wijdicks et al., 1996). In MVI recipiplant recipients is commonly related to cholestatic ents, seizures were reported in up to 17% of recipients TPN-related liver injury, but it is not the only possible (Zˇivkovic´ et al., 2010). Generalized tonic-clonic seizures cause of hyperammonemic encephalopathy. Etiology are most common. Nonconvulsive status epilepticus may of hyperammonemia may be quite complex and also be difficult to distinguish from toxic-metabolic encephrelated to: (1) hepatic allograft rejection, (2) liver cirrhoalopathy, even with careful review of video-EEG recordsis, (3) bacterial overgrowth, and (4) urea cycle enzyme ing (Brenner, 2005). Electroencephalographic findings abnormalities. Bacterial overgrowth in strictured bowel are frequently not specific, and repeated studies are with intestinal transplant-related portocaval shunt may often needed to demonstrate epileptiform changes on precipitate relapsing encephalopathy associated with EEG (Steg and Wszolek, 1996). Neurotoxicity of CNIs hyperammonemia (Shah et al., 2003). Partial urea cycle may precipitate seizures, with or without PRES. At this enzyme abnormalities may also, under stress conditions, time it remains unclear when it is safe to discontinue trigger hyperammonemia which may be difficult to antiepileptics after resolution of PRES, and recomtreat. Successful use of hemodialysis and nitrogen waste mended durations of treatment after clinical resolution agents has been reported in one patient with hyperammoof PRES vary from several weeks to several months. Seinemic coma after heart–lung transplantation (Berry zures associated with structural brain abnormalities et al., 1999). In addition to hyperammonemic encephacaused by PRES, ischemic stroke, or cerebral hemorlopathy, other toxic-metabolic encephalopathies may rhage may warrant long-term antiepileptic treatment. stem from hyper- or hypoglycemia, electrolyte disturTreatment of status epilepticus after MVI transplanbances, drug toxicity, and opportunistic infections. Clintation does not differ from standard treatment protoically it may be difficult to distinguish metabolic (or cols, but maintenance antiepileptic regimens have to toxic) encephalopathy from nonconvulsive status epileptake into consideration possible hepatic, renal, and/or ticus and the role of EEG in such settings cannot be overintestinal dysfunction, and also altered absorption of emphasized. However, caution is needed in the orally administered medications. Traditionally used antiinterpretation of EEG findings as electroencephaloepileptic medications phenytoin and carbamazepine may graphic patterns may be difficult to distinguish with ceraffect metabolism of CNIs and there is a risk of hepatotainty (Brenner, 2005). Neurotoxicity of calcineurin toxicity. The use of topiramate in this population is usuinhibitors (CNIs), tacrolimus and cyclosporine (CNI), ally precluded by its appetite-suppressing properties is particularly common in first 30 days after transplanwhich are problematic in such patients who are already tation when higher dosing is used (Zˇivkovic´ et al., at risk from nutritional deficiencies. As with other types 2010). Clinical manifestations of CNI neurotoxicity of transplants, levetiracetam is being used more freinclude altered mental status, tremor, and posterior quently, especially since it is now available in intravereversible encephalopathy syndrome (PRES), characternous preparation as well (Chabolla and Wszolek, 2006). ized by typical imaging findings and alterations of

NEUROLOGIC ASPECTS OF MULTIPLE ORGAN TRANSPLANTATION 1311 54 adult MVI allograft recipients at the University of Cerebrovascular complications Pittsburgh showed a prevalence of CNS opportunistic Post-transplant stroke is more common than in general infections of 7%, which is higher than with other types population and affects up to 2–4% of non-heart allograft of allografts (Fishman, 2007; Zˇivkovic´ et al., 2010). In recipients (Zˇivkovic´ and Abdel-Hamid, 2010; Zˇivkovic´ recent years, improvements in immunosuppressive reget al., 2010). Uncontrolled hyperlipidemia and hypertenimens and routine prophylactic therapy have reduced the sion, which may be aggravated by immunosuppressive prevalence of opportunistic CNS infections, down to medications, increase the risk of cardiovascular and 1–2% in recent reported series with other types of solid cerebrovascular disease. Post-transplant hypertension organ transplants (Lewis and Howdle, 2003; Zierer et al., has been reported in up to 51% of adult MVI allograft 2007). A similar reduction in CNS infections was recipients (Abu-Elmagd et al., 2012). Despite frequent observed in MVI allograft recipients more recently infections in this group, so far there have been no reports (author’s unpublished observation). of an increased rate of infective endocarditis. HypercoaChronic immunosuppression may diminish the gulability is relatively frequent in MVI allograft recipiinflammatory response, altering typical clinical signs ents and mesenteric artery thrombosis related to an or even radiologic features of an infection (Linden, underlying hypercoagulable condition is one of the more 2009b). Additionally, complex toxic-metabolic disturcommon indications for MVI transplantation. Common bances may also mask the signs of infection and delay causes of hypercoagulable state include antithrombin the diagnosis. The spectrum of infection causes also deficiency, factor V Leiden mutation, and protein C changes depending on time after transplantation, intenand S deficiencies (Giraldo et al., 2000). These patients sity of immunosuppression and exposures, with inclumay require lifelong anticoagulation, even after liver sion of opportunistic pathogens and atypical transplantation, and are at an increased risk of deep presentations (Fishman, 2007). Therefore, to prevent venous thrombosis and pulmonary embolism (Giraldo infections, different prophylactic protocols are routinely et al., 2000). Deep venous thrombosis may precipitate used in the treatment of transplant recipients and the use stroke via shunt (paradoxical embolism) through a patof individual medications will depend on specific expoent foramen ovale, which may be present in up to 25% sures and comorbidities. In the specific population of of the general population (Kent and Thaler, 2010). While intestinal and multivisceral allograft recipients, the proxclinical significance of hypercoagulable conditions in the imity of intestinal bacterial load and impaired defensive pathogenesis of arterial cerebrovascular thrombosis barriers due to inflammation and rejection create an remains somewhat controversial (Levine, 2005), ischeenvironment with a high risk of bacterial and fungal mic strokes might be more frequent in MVI allograft infections. Bacterial and fungal systemic infections recipients with underlying hypercoagulable conditions are very common, and increasing incidence was (Zˇivkovic´ et al., 2010). observed 3 months or longer after transplantation; this Cerebrovascular complications related to thrombotic pattern was explained by chronic intense immunosupmicroangiopathy have not been reported in this populapression (Kusne et al., 1994). Fatal infections have been tion. Thrombotic microangiopathy may present with a associated with graft failure in 11% of recipients, and stuttering clinical course and is usually considered as were most commonly bacterial (61%), followed by funsimilar to thrombotic thrombocytopenic purpura gal (31%) and viral infections (7%) (Abu-Elmagd et al., (TTP) (Dawson et al., 1991; Scully and Machin, 2009). 2009a). Bacterial CNS infections are overall uncommon Thrombotic microangiopathy may improve with in transplant recipients except with some specific enviwithdrawal of CNIs. ronmental exposures (e.g., unpasteurized dairy and listeHigh prevalence of hypercoagulable conditions, freriosis), and timely treatment will reduce the morbidity. quent infections, and dehydration (diarrhea) predisposes However, there is an increased risk of fungal opportumultivisceral and intestinal transplant recipients to nistic CNS infections which carry a high mortality even higher risk of venous blood clotting, including cerebral with an early diagnosis. The port of entry for fungal venous sinus thrombosis. However, so far there are only infections is usually the respiratory system, and most rare reports of cerebral venous sinus thrombosis in this patients have clinical signs of respiratory infection. population (Zˇivkovic´ et al., 2010). Infrequently, fungal sinusitis may go unnoticed and precipitate catastrophic CNS infection in transplant recipients (van de Beek et al., 2008). Fatal fungal and Opportunistic infections protozoal CNS infections were reported in MVI alloOpportunistic infections are a significant source of morgraft recipients, and reported frequency of opportunisbidity after MVI transplantation (Kusne et al., 1996; tic CNS infections is higher than observed with other Guaraldi et al., 2005). Retrospective study of the first types of allografts (Mendez et al., 2006; Fishman,

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2007). In reported series, CNS aspergillosis was the most commonly reported opportunistic CNS infection in MVI transplant recipients (Nishida et al., 2002; Zˇivkovic´ et al., 2010). Parasitic infections are also fortunately rare, but mortality is very high (Campbell et al., 2006; Mendez et al., 2006). The most common parasitic infection in transplant recipients is toxoplasmosis, while amebiasis and strongyloidosis are rare. Solid organ transplant recipients are also at risk of viral encephalitides most commonly caused by cytomegalovirus (CMV), varicella zoster (VZV) and herpes simplex (HSV) viruses (Fishman, 2007). EBV infection may be associated with post-transplant lymphoproliferative disorder (PTLD). In the early years of MVI transplantations, CMV infections had a significant negative impact on transplantation outcomes, but this was not related to associated CNS infections (Furukawa et al., 1996). In subsequent years, implemented surveillance and prophylactic measures diminished the impact of CMV infections (Abu-Elmagd et al., 2009a, b). Progressive multifocal leukoencephalopathy (PML) has a very high mortality, but it is fortunately rare in HIV-negative solid organ transplant recipients (Amend et al., 2010). PML is caused by JC virus, and the same virus was also implicated in the pathogenesis of chronic intestinal pseudo-obstruction, which may cause intestinal failure leading to transplantation (Selgrad et al., 2009). However, to date there have been no reports of MVI transplant recipients with a firmly established diagnosis of PML, although there is a report of a single patient with PML-like leukoencephalopathy improving after allograft was removed (Idoate et al., 1999). Rarely, back pain and weakness may be caused by infectious discitis or vertebral osteomyelitis caused by bacterial or fungal infections (Gerlach et al., 2009).

Headaches Migraines are very common in the population as a whole, including MVI transplant candidates, and allograft recipients will commonly report worsening of preexisting or new onset of migraines after transplantation, especially with the use of calcineurin inhibitors. New onset or worsening of headaches always present a diagnostic and treatment challenge in transplant patients. Post-transplant headaches significantly worsen the quality of life of one-third of affected allograft recipients (Uutela et al., 2009). Interestingly, a high frequency of headaches was reported in intestinal and multivisceral transplant recipients but the underlying pathophysiology remains unclear (Zˇivkovic´ et al., 2010). Possible explanations include chronic use of pain medications in many patients and higher doses of tacrolimus than used with other types of transplantation. Rarely, new onset of

headaches in transplant patients may signify the presence of a severe neurologic condition, including CNS infection, fungal sinusitis, or calcineurin-inhibitor toxicity, especially when accompanied by other neurologic symptoms (e.g., confusion, focal weakness, seizures) (Kiemeneij et al., 2003; Mendez et al., 2006). Early diagnosis of opportunistic CNS infections is an imperative to allow early diagnosis and prompt treatment. Treatment decisions in transplant patients with headaches are frequently guided by limitations imposed by the transplant status. Topiramate is frequently avoided in intestinal and multivisceral transplant recipients due to its potential weight-losing properties. Additionally, topiramateinduced kidney stones were observed in 1.5% of treated epilepsy patients (Shorvon, 1996). Valproate may interact with tacrolimus or cyclosporine and is potentially hepatotoxic. Other options for treatment of migraines include riboflavine (200 mg twice daily) and magnesium (Peikert et al., 1996; Stracciari et al., 2006). Magnesium is sometimes used for headache prevention and it is already typically included in standard maintenance regimens of many transplant recipients treated with tacrolimus or cyclosporine to prevent CNI-induced hypomagnesemia. A short course of corticosteroids may be used for abortive treatment of migraines. Acetaminophen/ paracetamol and nonsteroidal anti-inflammatory medications are usually avoided due to potential hepato- and nephrotoxicity. Other options include preventive use of tricyclic antidepressants and b-blockers, but we should always investigate possible drug–drug interactions or consequences of suboptimal liver and kidney function. Additionally, tricyclics may slow intestinal motility and careful dosing is needed. Triptans should be used cautiously for abortive treatment, and we also have to consider altered enteral absorption in patients with allograft rejection or chronic diarrhea. Continued use of opioid medications for chronic pain, frequently related to prior abdominal surgeries, may also complicate headache treatment.

Neuromuscular complications Complex metabolic and toxic disturbances following intestinal and multivisceral transplantation create an environment rich in risk factors for development of various neuromuscular disorders. Neuromuscular complications after bariatric surgery have been well described and attributed to nutritional deficiencies and metabolic imbalance (Thaisetthawatkul et al., 2004; Rudnicki, 2010). We could possibly expect a similar spectrum of neuromuscular complications following frequent long-standing nutritional imbalance in MVI allograft recipients. Somewhat surprisingly there is a

NEUROLOGIC ASPECTS OF MULTIPLE ORGAN TRANSPLANTATION low reported prevalence of neuromuscular complications in intestinal and multivisceral transplant recipients, amounting only to up to 7% (Zˇivkovic´ et al., 2010). A complicated post-transplant course requiring prolonged stay in intensive care units increases the risk of critical illness myopathy, similarly as in other transplant patients (Campellone et al., 1998). Critical illness myopathy is frequently accompanied by its neuropathic counterpart, critical illness polyneuropathy (Visser, 2006). Other more frequent causes of polyneuropathy include diabetic and uremic neuropathies, and toxic neuropathies related frequently to the use of neurotoxic antibiotics. Frequent bacterial infections may necessitate the use of potentially neurotoxic antibiotics (e.g., metronidazole, linezolid), and the risk may be increased with prolonged use. Despite frequent nutritional deficiencies, there are no published reports of neuropathy directly attributable to defined nutritional deficiency in this population. Posttransplant diabetes has been described in 11% of MVI allograft recipients increasing the risk of diabetic neuropathy (Abu-Elmagd et al., 2012).

Other complications Post-transplant lymphoproliferative disorder (PTLD) remains relatively common after intestinal transplantation, especially in pediatric patients and with multivisceral allografts (Grant et al., 2005; Abu-Elmagd et al., 2009c). It has been reported that overall, up to 13% of MVI graft recipients may develop PTLD, and nonlymphoid neoplasms have been reported in an additional 3% of patients (Abu-Elmagd et al., 2009c). In MVI recipients, PTLD is typically associated with EBV infection (Abu-Elmagd et al., 2009a). Overall, CNS involvement in PTLD has been reported in up to 15% of patients with various types of allografts, and is usually associated with a poor prognosis (Buell et al., 2005). However, some patients may recover with decreased immunosuppression (Castellano-Sanchez et al., 2004). Lymphoid content of intestinal allograft increases the risk of graft-versushost disease (GVHD), which is more common than with other types of solid organ allografts and has been reported in up to 9% of MVI allograft recipients compared to 1–2% with liver transplantation (Wu et al., 2011). The risk of GVHD seems to be higher with multivisceral allografts when compared to isolated intestine and liver-intestine transplantation (Abu-Elmagd et al., 2009a). There are no reports of GVHD involving peripheral or central nervous system in MVI transplant recipients, but other previously reported cases of GVHD with neurologic involvement ranged from myositis and vasculitic neuropathy to cerebral vasculitis (Parker et al., 1996; Ma et al., 2002).

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Movement disorders are usually not a significant source of morbidity in intestinal transplant patients. Tremor is frequent with the use of CNIs, but only rarely is it severe enough to consider modification of immunosuppression. Use of metoclopramide to promote motility may precipitate tardive dyskinesia which may be difficult to treat (Zˇivkovic´ et al., 2008).

HEART^LUNG TRANSPLANTATION Combined heart–lung transplantation is most commonly performed for the treatment of congenital heart disease, cystic fibrosis, and idiopathic pulmonary arterial hypertension (Christie et al., 2010). Outcomes are usually grouped together with lung transplantations, and the long-term mortality is mostly related to infections and bronchiolitis obliterans, as with lung transplantation. In the early post-transplant course, morbidity is higher than with lung transplantation and this may be somewhat attributable to pre-existing heart failure and complex technical aspects of surgery and postsurgical care. The number of combined heart–lung transplantations has decreased in recent years by 50% when compared to the earlier peak in the 1990s (Christie et al., 2010). It seems that combined transplantation of lungs and heart offers some immunologic benefits and onset of cardiac vasculopathy is typically delayed when compared to transplantation of the heart alone. In the first year after transplantation, PTLD is the most common malignancy, and CNS involvement has been reported in 13% of heart or lung allograft recipients (Buell et al., 2005). Long-term survivors are exposed to an increased risk of malignancies, which have been reported in up to 40% of heart–lung transplant recipients after 15 years (Deuse et al., 2010). There have been no systematic studies of neurologic complications following heart–lung transplantation, and the spectrum of neurologic complications largely overlaps post-transplant complications in lung and heart allograft recipients. Postoperative phrenic nerve injury seems to be more common than after lung transplantation and this may be attributed to the more extensive surgical procedure (Ferdinande et al., 2004).

KIDNEY^PANCREAS TRANSPLANTATION Combined kidney–pancreas transplantation is the most commonly performed multiorgan transplantation procedure. Typical indication is kidney failure caused by diabetic nephropathy with poorly controlled diabetes. Simultaneous kidney–pancreas has better outcomes than sequential transplantation of kidney and pancreas on two different occasions (Wiseman, 2010).

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There have been no systematic studies of neurologic complications following kidney–pancreas transplantation. However, the postoperative course is similar to the clinical course following kidney transplantation. Worsening of weakness was reported after kidney– pancreas transplantation and this was attributed to myopathy as there was no associated worsening of neuropathy (Dyck et al., 2001). Diabetic neuropathy usually gets better following kidney–pancreas transplantation as glycemic control improves, but the extent of improvement is variable in individual patients. Vascular complications are relatively common in patients with diabetes, including ischemic strokes. Slower progression of macrovascular disease, including cerebrovascular complications, was demonstrated in kidney–pancreas transplant recipients when compared to patients with only kidney allograft (Biesenbach et al., 2005). Nevertheless, cerebrovascular complications remain a significant source of morbidity after kidney–pancreas transplantation and were still reported as a cause of death in almost 2% of allograft recipients (Sollinger et al., 2009). Benefit of a successful combined kidney–pancreas transplant becomes more apparent after 5 years or longer post-transplantation. There are no published systematic reports on occurrence of PTLD after kidney–pancreas transplantation, but more frequent CNS involvement was reported for both pancreas (27%) and kidney (18%) allograft recipients with PTLD (Buell et al., 2005).

COMBINED SOLID ORGAN AND HEMATOPOIETIC STEM CELL TRANSPLANTATION Combination of solid organ and hematopoietic stem cell transplantation(HSCT) has been pursued to improve allograft tolerance and reduce immunosuppression after transplantation (Starzl, 2004). Experimental studies on laboratory animals demonstrated induction of tolerance of allograft when donors’ bone marrow transplant was combined with solid tumor transplantation (Gozzo et al., 1970). Subsequent clinical studies showed a decrease of the rate of rejection, lower immunosuppression requirements, and even complete immunosuppression withdrawal in some patients (Zeevi et al., 1997; Delis et al., 2006). However, longer follow-up will be needed to establish the magnitude of benefit and risks of complications. Combined solid organ and hematopoietic stem cell transplantation may be complicated by acute and chronic GVHD with a reaction of the donor’s immune system attacking the host’s organs. Most recent reports record a decrease in risk with improved HSCT protocols and only 2% of allogeneic hematopoietic stem cell transplant recipients develop severe acute GVHD

(Gooley et al., 2010). At this time it is still not known if the risk of GVHD is changed after combined HSCT and solid organ transplantation. So far, there are no reports of GVHD related to HSCT-augmented solid organ transplantation. There are also no published systematic studies of neurologic complications of HSCTaugmented solid organ transplantation.

ACKNOWLEDGEMENTS The authors take full responsibility for the contents of this article, which do not represent the views of the Department of Veterans Affairs or the United States Government.

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van de Beek D, Patel R, Campeau NG et al. (2008). Insidious sinusitis leading to catastrophic cerebral aspergillosis in transplant recipients. Neurology 70: 2411–2413. Verhage AH, Cheong WK, Jeejeebhoy KN (1996). Neurologic symptoms due to possible chromium deficiency in longterm parenteral nutrition that closely mimic metronidazole-induced syndromes. JPEN J Parenter Enteral Nutr 20: 123–127. Visser LH (2006). Critical illness polyneuropathy and myopathy: clinical features, risk factors and prognosis. Eur J Neurol 13: 1203–1212. Ward N (2010). The impact of intestinal failure on oral drug absorption: a review. J Gastrointest Surg 14: 1045–1051. Wijdicks EF, Plevak DJ, Wiesner RH et al. (1996). Causes and outcome of seizures in liver transplant recipients. Neurology 47: 1523–1525. Wiseman AC (2010). The role of kidney-pancreas transplantation in diabetic kidney disease. Curr Diab Rep 10: 385–391. Wu G, Selvaggi G, Nishida S et al. (2011). Graft-versus-host disease after intestinal and multivisceral transplantation. Transplantation 91: 219–224. Zeevi A, Pavlick M, Banas R et al. (1997). Three years of follow-up of bone marrow-augmented organ transplant recipients: the impact on donor-specific immune modulation. Transplant Proc 29: 1205–1206. Zierer A, Melby SJ, Voeller RK et al. (2007). Significance of neurologic complications in the modern era of cardiac transplantation. Ann Thorac Surg 83: 1684–1690. Zˇivkovic´ SA, Abdel-Hamid H (2010). Neurologic manifestations of transplant complications. Neurol Clin 28: 235–251. Zˇivkovic´ SA, Costa G, Bond G et al. (2008). Treatment of tardive dyskinesia with levetiracetam in a transplant patient. Acta Neurol Scand 117: 351–353. Zˇivkovic´ SA, Eidelman BH, Bond G et al. (2010). The clinical spectrum of neurologic disorders after intestinal and multivisceral transplantation. Clin Transplant 24: 164–168.

Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 90

Neurologic diseases in HIV-infected patients MOHAMMED BILGRAMI AND PAUL O’KEEFE* Department of Medicine, Loyola University Medical Center, Maywood, IL, USA

INTRODUCTION Since the introduction of highly active antiretroviral therapy (HAART) there has been an improvement in the quality of life of people with human immunodeficiency virus (HIV) infection. Despite this progress, about 70% of HIV-infected patients develop neurologic complications. They originate either in the central or the peripheral nervous system (Sacktor, 2002) and are divided into primary and secondary disorders. The primary disorders result from the direct effects of the virus and include HIV-associated neurocognitive disorder (HAND), HIV-associated vacuolar myelopathy (VM), and distal symmetric polyneuropathy (DSP), which are prevalent at all levels of immune function (CD4 þ T cell counts). Secondary disorders result from marked immunosuppression and include opportunistic infections and primary central nervous system lymphoma (PCNSL). It is challenging to evaluate and manage HIV-infected patients who present with neurologic signs and symptoms. Diagnostic testing is more valuable when a prioritized differential diagnosis is kept in mind. It can be accomplished by detailed history, neurologic examination, and having a good understanding of the role of HIV in various neurologic disorders. A broad, unfocused diagnostic evaluation will result in unnecessary testing and possibly confuse the clinical picture.

ETIOLOGYAND DIAGNOSTIC APPROACH A recommended initial approach is to attempt to narrow the focus to one of the broad categories outlined in Table 90.1.

PATHOGENESIS OF NEUROLOGIC COMPLICATIONS OF HIV Neurologic complications of HIV may result from direct effects of HIV on the central nervous system. They may also result from HIV-related immune dysfunction with CD4 cell depletion and its associated increased host susceptibility to neurologic opportunistic infections, diseases, and neoplasms. HIV infection of the central nervous system (CNS) leads to immune activation and overexpression of inflammatory cytokines, resulting in cellular and tissue dysfunction with damage to the blood–brain barrier (BBB), surrounding glial cells and neurons. The primary HIV- associated neurologic disorder of the brain is HIV-associated dementia whereas HIV infection involving the spinal cord causes HIVassociated myelopathy. With the widespread use of antiretroviral therapy, the incidence and prevalence of neurologic opportunistic infections has declined (Maschke et al., 2000). Conditions due to direct effects of HIV itself on the CNS, such as HIV-associated dementia or sensory neuropathies, have also declined but remain a source of considerable morbidity. HIV uses at least two surface receptors to enter the target cell. The primary receptor is the CD4 molecule which is expressed on the surface of CD4 lymphocytes, dendritic cells, and monocytes/macrophages. After the virus binds to its primary receptor, it binds to one of two co-receptors, either CCR5 or CXCR4. These corecetptors are chemokine receptors. HIV that utilize CCR5 are also called R5 or M tropic whereas those utilizing CXCR4 are called X4 or T tropic (Albright et al., 2003). CCR5-tropic virus is commonly transmitted during primary infection whereas CXCR4-tropic virus is

*Correspondence to: Paul O Keefe, M.D., Loyola University Medical Center, 2160 S. First Avenue, Building 102, Room 7604, Maywood, IL 60153, USA. Tel: þ1-708-216-9453, E-mail: [email protected]

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Table 90.1

Table 90.2

Neurologic manifestations of HIV infection

CNS cell types involved in HIV neuropathogenesis

Clinical syndrome

Etiologic agent or disease Cell type

Cerebrovascular disease

Dementia Encephalitis

Mass lesion in brain

Meningitis

Myelopathy/radiculopathy

Peripheral neuropathy

Cytomegalovirus HIV Infective endocarditis with emboli Mycobacterium tuberculosis Treponema pallidum Varicella zoster virus HIV Treponema pallidum HIV (acute HIV infection) Cytomegalovirus Herpes simplex West Nile virus Toxoplasma gondii JC virus (the cause of progressive multifocal leukoencephalopathy) Primary central nervous system lymphoma Cryptococcus neoformans HIV Mycobacterium tuberculosis Treponema pallidum Cytomegalovirus HIV Varicella zoster virus HIV Medications (didanosine, stavudine) Toxins (alcohol) Vitamin deficiencies (B12, folate)

(Reproduced with permission from Clinical Care Options: CCO HIV, inPractice, 2011, available at www.inpractice.com)

transmitted less often. As HIV infection progresses in the individual, the R5 phenotype may be replaced by X4 due to selective pressure. The more pathogenic X4 phenotype induces syncytial formation among HIVinfected and uninfected cells. These multinucleate giant cells are dysfunctional and rapidly die. Fusion of microglia and brain macrophages, resulting in multinucleated giant cells in the CNS, is a distinct feature of HIVassociated encephalitis (Rock et al., 2004). Macrophages are derived from peripheral monocytes which enter the CNS and differentiate into perivascular microglia as well as perivascular, meningeal, and choroid plexus macrophages. Microglia are phagocytic cells in the CNS, which, like monocytes in the periphery, remove pathogens and debris from the local site. These cells exhibit bidirectional BBB passage.

Astrocytes Endothelial cells Microglia Monocytes/ macrophages Neurons Oligodendrocytes

HIV infection

Nature of infection

Yes Yes Yes Yes

Restricted, nonproductive Possibly productive Productive Productive

No No

(Reproduced with permission from Clinical Care Options: CCO HIV, inPractice, 2011, available at www.inpractice.com)

Table 90.2 shows the various cell types in the central nervous system. Microglia express only the CCR5 coreceptor and are the primary target cells of HIV. Monocytes and macrophages in the CNS express both CXCR4 and CCR5 co-receptors and thus bind both R5 and X4 virus. Similar to microglia they support HIV growth and replication (Gartner and Liu, 2002). Astrocytes, well represented in the CNS, are capable of being infected but do not support growth and replication of the HIV. This restricted infection may contribute to neuronal dysfunction (Brack-Werner, 1999). Endothelial cells express both co-receptors and are capable of being infected. Whether they support HIV replication or not is still unclear. Neurons and oligodendrocytes are not known to be infected by HIV. CNS cell types involved in HIV neuropathogenesis are depicted in Table 90.2. Brain parenchyma is separated from the systemic circulation by the BBB which is composed of tightly bound endothelial cells. Passage of proteins and some drugs, including certain antiretrovirals, into the CNS is limited by the BBB. Immune cells which develop and differentiate in the periphery exhibit bidirectional movement between the systemic circulation and the CNS. HIV enters the CNS by infecting monocytes which can cross the BBB (the Trojan horse model) (Haase, 1986). Cytokine expression as well as toxic products of HIV infection can damage neurons and glial cells resulting in a more porous BBB. This may allow entry of cell free HIV virions into the CNS. Once within the CNS, HIV can damage neurons. One model suggests that HIV-infected microglia and macrophages release various neurotoxic viral proteins such as HIV envelope glycoprotein 160 (gp 160) and its cleavage products gp 120 and gp 41 or regulatory proteins including Tat, Nef, and Vpr (Li et al., 2005). Other studies have shown that inflammatory cytokines from glial cells or macrophages or other soluble products are released in response to HIV infection. Most importantly these include tumor necrosis factor-a (TNF-a) and interleukin 1 (IL-1).

NEUROLOGIC DISEASES IN HIV-INFECTED PATIENTS Glial cells and macrophages also release other cytokines and other factors including b-chemokines such as MIP (macrophage inflammatory protein)-1a, MIP-1b, and RANTES (regulated on activation normal T cell expressed and secreted); the a-chemokine interferon-g-inducible protein(IP)-10; arachidonic acid; platelet-activating factor; quinolinic acid; nitric oxide; and superoxide anions. Significantly elevated concentrations of all of these factors have been found in the brain or cerebrospinal fluid (CSF) of HIV-infected persons (Smith et al., 2001).

OPPORTUNISTIC INFECTIONS Toxoplasmosis Toxoplasmosis is caused by an intracellular protozoan, Toxoplasma gondii, and has a worldwide distribution. Seroprevalence in the US is about 15% but reaches 50–75% in some European and resource-limited countries. Its prevalence is increased in areas of the world that have hot, humid climates and lower altitudes. Toxoplasmosis is the most common parasitic opportunistic infection (OI) involving the CNS in persons with AIDS with the frequency progressively increasing as CD4 counts reach 100 and lower. Nearly all episodes of toxoplasmosis occur as a result of reactivation of latent infection acquired some time earlier. Toxoplasmosis is not transmitted from person to person, except in instances of mother to child (congenital) transmission, blood transfusion, or organ transplantation. Most human infections occur by one of two routes: (1) consumption of undercooked, contaminated meat (especially pork, lamb, and venison) containing encysted organisms, or (2) accidental ingestion of oocysts shed in cat feces through such activities as cleaning a litter box or ingestion of oocysts in contaminated soil or water.

TOXOPLASMA GONDII: HUMAN INFECTION After ingestion, T. gondii are carried by monocytes to the liver and then can spread throughout the body. Among HIV-infected persons, latent infection in the brain can reactivate with severe immunodeficiency and cause toxoplasma encephalitis. In recent years, the incidence of toxoplasma encephalitis has declined substantially due both to the widespread availability of antiretroviral therapy and the common practice of employing the drug trimethoprim/sulfamethoxazole (TMP-SMX) for the prevention of pneumonia due to Pneumocystis jiroveci. In a study that tracked opportunistic infections during the years 1994–2007, the incidence of CNS toxoplasmosis decreased from 4.1 per 1000 person-years in the years 1994–1997 to 1.3 per

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1000 person-years in 1998–2002. It declined further to 0.5 per 1000 person-years in 2003–2007 with the widespread use of highly active antiretroviral therapy (HAART) (Buchacz et al., 2010). Among HIV-infected patients the seroprevalence of toxoplasmosis mirrors the rate of seropositivity in the general population. Among 2525 women in the US the seroprevalence was 15% and was not different in HIV-positive versus HIV-negative women in the sample (Falusi et al., 2002). Age over 50 or being born outside of the US were both associated with a greater likelihood of seropositivity (Falusi et al., 2002). In patients with AIDS, cat ownership was not associated with greater risk of toxoplasmosis (Wallace et al., 1993). Because the parasite can reactivate and cause disease in persons with AIDS, all persons with HIV should be screened for toxoplasma antibodies (IgG). Seropositive persons have an approximately 30% chance of reactivation in the CNS if not on effective prophylaxis (Luft and Remington, 1992).

CLINICAL MANIFESTATIONS In immunocompetent people, infection with T. gondii is usually asymptomatic. Some individuals develop a mononucleosis-like illness with enlarged, tender lymph nodes, muscle aches and fever that lasts for several weeks. Others may develop chorioretinitis. Once a person is infected, the parasite remains in an inactive state and can reactivate if the person becomes immunosuppressed e.g., HIV with CD4 counts less than 100 cells/mm3. Toxoplasmosis in immunocompromised patients is usually acute, generalized, and commonly involves the brain in the form of toxoplasma encephalitis (TE). TE is the most common AIDS-defining disease affecting the central nervous system (Montoya and Liesenfeld, 2004). Other less common but important sites include the lungs (pulmonary toxoplasmosis) and the eye (retinitis), and some patients develop multiorgan disease. Patients with TE typically present with fever, headache, and confusion. Focal neurologic deficits or seizures are also common. In one retrospective review of 115 cases, 55%, 52%, and 47% had headache, confusion, and fever, respectively (Porter and Sande, 1992). In recent studies conducted during the HAART era, reported inpatient mortality has been around 15% (Miro and Murray, 2008). Clinical signs of toxoplasmosis are nonspecific and mimic other CNS diseases including lymphoma, progressive multifocal leukoencephalopathy, mycobacterial infection, or cryptococcosis. Diagnosis is established by (1) compatible clinical findings, (2) neuroimaging, (3) specific diagnostic testing including serology, biopsy findings, or molecular (DNA) methods, and (4) response to therapy

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NEUROIMAGING Contrast MRI is more sensitive than contrast CT scanning and is recommended as the study of choice for initial assessment and for following response to therapy. In following response to therapy, clinicians should not compare MRI to CT scans as CT can miss lesions which are seen with MRI. The most common MRI findings with CNS toxoplasmosis, seen in 90% of patients, are multiple enhancing lesions that often involve basal ganglia and the gray–white junction (Fig. 90.1). Mass effect secondary to toxoplasmosis is not as commonly seen as it is in lymphoma. In order to differentiate toxoplasmosis from lymphoma, clinicians have utilized other imaging techniques. Magnetic resonance spectroscopy, both single-photon emission computed tomography (SPECT) using thallium 201 and positron emission tomography (PET) using labeled substrates such as 2-fluorodeoxyglucose, appears useful. In patients with mass lesions on CT or MRI, the absence of increased uptake on thallium 201 single-photon emission computed tomography scanning, or decreased activity on positron emission tomography scans (“cold” or hypometabolic lesions) are characteristic of infection. By contrast, lymphoma is almost invariably associated with increased uptake using these two scanning techniques (Skiest et al., 2000).

LABORATORY DIAGNOSIS About 95% of patients with acute toxoplasma encephalitis will have antitoxoplasma IgG antibodies using ELISA and about 85% have detectable antibodies using an IFA assay. Antitoxoplasma IgM has minimal value in

Fig. 90.1. Brain MRI: T2-weighed image of a patient with cerebral toxoplasmosis showing numerous hyperintense signal abnormalities predominately in the subcortical gray–white junction and basal ganglia.

diagnosis. Lumbar puncture can provide useful information to rule out other diagnoses. The cell count and Epstein–Barr virus (EBV) polymerase chain reaction (PCR) is helpful in ruling out CNS lymphoma which may mimic toxoplasma encephalitis clinically and radiographically. EBV PCR in CSF is very sensitive and specific for CNS lymphoma. PCR testing for T. gondii is available, but the test lacks sensitivity (Nogui et al., 2009).

APPROACH WITH SUSPECTED TOXOPLASMA ENCEPHALITIS

Factors that suggest toxoplasma encephalitis include a positive IgG serology for T. gondii, non-use of toxoplasma prophylaxis, the presences of multiple enhancing brain lesions, and a positive CSF PCR for T. gondii. Most experts would recommend a trial of empiric therapy for toxoplasma encephalitis in patients who are toxoplasma seropositive and have multiple enhancing brain lesions. Brain biopsy carries significant risk and should generally be reserved for patients who do not demonstrate clinical or radiographic improvement after 10–14 days of antitoxoplasma therapy. This delayed biopsy approach is not appropriate in cases in which clinical, laboratory, and radiographic indicators strongly point to a diagnosis of lymphoma (Antinori et al., 1997).

TREATMENT Guidelines for the treatment of toxoplasmosis in HIVinfected persons have been published by the US Centers for Disease Control and Prevention (CDC), National Institutes of Health (NIH), and the HIV Medicine Association of the Infectious Diseases Society of America (Kaplan et al., 2009). The treatment of choice for patients with toxoplasmosis is a combination of sulfadiazine plus pyrimethamine plus leucovorin (folinic acid) for 6–8 weeks (Table 90.3). Leucovorin is given to avoid hematologic toxicity. If intracranial hypertension is present, corticosteroids are recommended, as are anticonvulsants if the patient experiences seizures. Valproic acid is the recommended antiepileptic for patients receiving antiretroviral therapy with non-nucleoside reverse-transcriptase inhibitors (NNRTIs) or protease inhibitors (PIs) to avoid the possible drug interactions with other antiepileptic agents. In case of sulfadiazine allergy or intolerance, clindamycin plus pyrimethamine plus leucovorin is the recommended regimen. Other alternatives are available. Patients receiving antitoxoplasma treatment should be monitored for toxicity because adverse effects are common with all regimens. If treatment failure is observed after 10–14 days, a brain biopsy is recommended in order to confirm toxoplasma encephalitis or to diagnose another AIDS-defining central nervous system disease. If the biopsy confirms the diagnosis of toxoplasma encephalitis after the 10–14 day trial

NEUROLOGIC DISEASES IN HIV-INFECTED PATIENTS Table 90.3 Treatment of CNS toxoplasmosis* Initial treatment 6 weeks; may be longer if clinical or radiologic disease is extensive or response is incomplete at 6 weeks Preferred therapy: Pyrimethamine 200 mg po  1 dose, then 50 mg (60 kg) po daily þ sulfadiazine 1000 mg (60 kg) or 1500 mg (>60 kg) po q 6 h þ leucovorin (folinic acid) 10–25 mg po daily Alternative therapy regimens: Pyrimethamine/leucovorin (above doses) þ clindamycin 600 mg IV or po q 6 h TMP-SMX (5 mg/kg TMP) IV or po bid Pyrimethamine/leucovorin (above doses) þ atovaquone 1500 mg po bid with food Atovaquone 1500 mg po bid with food Atovaquone 1500 mg po bid with food þ sulfadiazine 1000–1500 mg po q 6 h Pyrimethamine/leucovorin (above doses) þ azithromycin 900–1200 mg po daily Maintenance Preferred therapy: Pyrimethamine 25–50 mg po daily þ sulfadiazine 2–4 g po qd (in 2–4 divided doses) þ leucovorin 10–25 mg po daily Alternative therapy regimens: Pyrimethamine/leucovorin (above doses) þ clindamycin 600 mg po q 8 h Atovaquone 750 mg po q 6–12 h  either (pyrimethamine 25 mg po þ leucovorin 10 mg po daily) or (sulfadiazine 2–4 g po daily) *(2009 CDC/IDSA/NIH Guidelines for Prevention and Treatment of Opportunistic Infections in Adults with HIV Infection; Kaplan et al., 2009). po, oral; IV, intravenous; q, every; qd, daily; bid, twice daily; TMPSMX, trimethoprim/sulfamethoxazole.

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some experts recommend switching to an alternative antitoxoplasma regimen (Kaplan et al., 2009). Antiretroviral therapy-induced immune reconstitution inflammatory syndrome (IRIS) associated with toxoplasma encephalitis has been reported but appears to be rare. There are not enough cases to provide recommendations on how to manage toxoplasma encephalitisassociated IRIS.

RESPONSE TO INITIAL THERAPY More than 70% of patients show both clinical and radiographic improvement to initial therapy. In a retrospective study involving 35 patients, 86% showed improvement by day 7 and 91% showed improvement by day 14 (Luft et al., 1993).

PRIMARY PROPHYLAXIS All of the agencies that publish treatment recommendations also recommend that prophylaxis be prescribed for all toxoplasma-seropositive HIV-infected patients with CD4þ cell counts less than100 cells/mm3. Trimethoprimsulfamethoxazole, one double-strength tablet daily, used to prevent Pneumocystis jirovici pneumonia, also prevents toxoplasmosis. Toxoplasma-seropositive patients who are receiving pneumocystis pneumonia prophylaxis that is not active against toxoplasmosis, such as inhaled pentamidine, should either modify the prophylaxis or receive additional medication that will prevent toxoplasmosis if the CD4þ cell count declines below 100 cells/mm3 (see Table 90.4).

SECONDARY PROPHYLAXIS Secondary prophylaxis should be administered to all patients who have completed initial therapy for toxoplasma encephalitis. However, it can be discontinued if the patient’s CD4 þ cell count increases to over

Table 90.4 Primary prophylaxis of CNS toxoplasmosis Pathogen

Indication

First choice

Alternative

Toxoplasma gondii

Toxoplasma IgGpositive with CD4 < 100 cells/ mm3

Trimethoprimsulfamethoxazole (TMPSMX) 1 DS PO daily

TMP-SMX 1 DS PO three times weekly TMP-SMX 1 SS PO daily Dapsone 50 mg PO daily þ Pyrimethamine 50 mg PO weekly þ leucovorin (folinic acid) 25 mg PO weekly Dapsone 200 mg þ pyrimethamine 75 mg þ leucovorin 25 mg) PO weekly Atovaquone 1500 mg  pyrimethamine 25 mg þ leucovorin 10 mg) PO daily

(2009 CDC/IDSA/NIH Guidelines for Prevention and Treatment of Opportunistic Infections in Adults with HIV Infection; Kaplan et al., 2009) PO, oral; DS, dose; single strength.

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200 cells/mm3 for more than 6 months and if the HIV-1 RNA level remains undetectable with the use of antiretroviral therapy. Prophylaxis should be reintroduced if the CD4 þ cell count falls below 200 cells/mm3.

Primary central nervous system lymphoma Primary CNS lymphoma (PCNSL) is defined as nonHodgkin’s lymphoma (NHL) limited to the CNS. It is to be differentiated from systemic lymphoma with tumor spread to CNS. PCNSL is the second most common intracranial mass lesion seen in HIV patients besides CNS toxoplasmosis. It is usually seen with advanced HIV disease (CD4þ count less than 50 cells/mm3). It is an aggressive malignancy accounting for 15% of all NHL in HIV-infected patients. CNS lymphoma is about 1000 times more common in HIV-infected persons than in the general population. Although it is restricted to the CNS, it may spread to the leptomeninges, spinal cord, and eye. Before the HAART era PCNSL was seen in about 2—6% of HIV-infected persons (MacMahon et al., 1991). The incidence has declined in the HAART era but at a rate less than that seen with other HIV-related complications. CDC data have documented a decline from 8 per 1000 person-years in 1994 to 2.3 per 1000 person-years in 1997 (Kaplan et al., 2000).

PATHOGENESIS Virtually all cases of PCNSL are Epstein–Barr virusrelated. EBV-infected B cells may undergo monoclonal proliferation in the presence of immune dysregulation and a severely immunosuppressed state (CD4 þ count less than 50 cells/mm3).

CLINICAL PRESENTATION PCNSL usually presents within the fourth decade of life. It is more common in men than women (Surawicz et al., 1999). Signs and symptoms evolve over days to months. The presentation may be nonspecific with focal and/or nonfocal signs and symptoms including B symptoms in 80% of cases. Symptoms and signs include confusion, headache (30–40%), memory loss, aphasia, hemiparesis and/or seizures. Fever is notably absent in most patients. The CD4 count is generally less than 50 cells/mm3. Diagnosis of PNCSL involves neuroimaging, CSF analysis, and biopsy.

NEUROIMAGING MRI is more sensitive and more accurate in characterizing focal brain lesions such as PCNSL. MRI with contrast usually shows a single, irregular, contrast-enhancing lesion, but there can be multiple lesions in up to 50% of cases (Johnson et al., 1997). Contrast enhancement

can be in a ring or homogeneous pattern. These lesions usually involve the periventricular area, corpus callosum, or periependymal area; however, they can be anywhere. These lesions are generally 2–6 cm in diameter and are usually associated with impressive mass effect. Single photon emission computed tomography (SPECT) is useful (see section on toxoplasmosis). If lumbar puncture can be safely performed, then it is advised in order to facilitate the diagnosis of lymphoma and rule out other infectious complications. In addition to routine testing, CSF should be sent for cytology, and PCR assays for EBV (PCNSL), JC virus (progressive multifocal leukoencephalopathy (PML)), CMV (cytomegalovirus encephalitis) and Mycobacterium (CNS tuberculosis). PCR for EBV in CSF is a very helpful diagnostic test and carries a sensitivity of about 80% and a specificity of 94% (Skiest, 2002).

BRAIN BIOPSY Definitive diagnosis can be made by stereotactic brain biopsy either when CSF analysis is not possible or unrevealing or when patients have not responded to empiric antitoxoplasma treatment within 2 weeks.

MANAGEMENT There is no curative treatment at present. In the preHAART era, median survival for untreated PCNSL was 1–3 months and for treated PCNSL was up to 3.5 months (Fine and Mayer, 1993). Mortality is usually due to advanced immunodeficiency or to other opportunistic infections. Longer survival appears to be associated with HAART. In a retrospective analysis with a median follow-up of 667 days, six of seven HAART-treated patients with PCNSL were alive versus none of 18 patients not receiving HAART (Skiest and Crosby, 2003). Because of the diffuse nature of PCNSL aggressive surgical decompression is of no benefit. Until recently, high-dose radiation therapy was considered the standard treatment, but prospective studies done by the Radiation Therapy Oncology Group (RTOG) have shown that the disease recurs in the brain in 92% of patients (Nelson et al., 1992). All patients with PCNSL should be offered chemotherapy as first-line treatment when their performance status is adequate and if they have relatively high CD4 counts, i.e., greater than 100 and preferably greater than 200. Chemotherapy regimens should include high dose methotrexate often in combination with cytarabine. A retrospective review of 226 patients described better results with the use of high-dose methotrexate or cytarabine combined with radiation therapy than the results with other combination chemotherapy regimens. The CHOP regimen failed to show any benefit over radiation therapy alone. Currently multiple trials are ongoing

NEUROLOGIC DISEASES IN HIV-INFECTED PATIENTS employing various combination chemotherapies with good CNS penetration. Recent studies documenting better responses with combinations such as methotrexate and ifosfamide (Fischer et al., 2009) or with intra-arterial methotrexate plus intravenous etoposide and cyclophosphamide (MacNealy et al., 2008) are being reported. Corticosteroids can provide substantial but, unfortunately, short- lived remissions. Steroids should be avoided before brain biopsy as they may alter the histology and prevent adequate diagnosis (Johnson et al., 1997).

Progressive multifocal leukoencephalopathy EPIDEMIOLOGY Progressive multifocal leukoencephalopathy (PML) is a progressive, demyelinating disease caused by a human polyoma virus called John Cunningham virus (JCV). PML is the most common infiltrative disease of the brain seen in persons with HIV/AIDS. JC virus is ubiquitous; about 85% of healthy people are seropositive for JC virus. In the pre-HAART era the prevalence of PML was 1–10% among patients with AIDS. Once diagnosed, it was relentlessly progressive, usually resulting in death within a few months. Now, after introduction of HAART, the incidence of PML has decreased and survival has improved (Sacktor, 2002).

PATHOGENESIS About 85% of the normal population is asymptomatically infected with JCV in childhood or early adulthood (Kaplan et al., 2009). The virus remains latent in lymphoid tissue and the kidney. Latent JC virus reactivates in states of immunosuppression. It circulates in B lymphocytes and infects oligodendrocytes as well as astrocytes causing cell lysis and demyelination.

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headache are usually not seen with PML. When JC virus involves the cerebellum without white matter involvement on MRI and without classic PML histopathology, it is referred to as the cerebellar variant (Koralnik et al., 2005). Common presenting signs and symptoms in PML include motor weakness often with hemiparesis, dementia, speech disturbances including aphasia and dysarthria, vision abnormalities, and gait instability.

DIAGNOSIS The presumptive diagnosis can often be made by the clinical presentation along with neuroimaging studies and lumbar puncture results. CT scan typically reveals hypodense lesions of the white matter without enhancement or mass effect, but it can be normal. MRI is more sensitive and typically shows hypointensity on T1-weighted images and increased intensity on T2-weighted images (Fig. 90.2). Lesions are usually bilateral and multiple, but some patients may show a single focal lesion. The lesions may have a scalloped appearance on MRI because of involvement of subcortical white matter. Routine testing of CSF is usually not helpful, and it may be normal in many cases. Cell count may be normal or mildly elevated (less than 20 cells/mm3) and protein is normal or mildly elevated. PCR for JCV in CSF is a very helpful diagnostic test and carries a sensitivity of 70–80% and a specificity of 95–100% (Simona et al., 2005). Definite diagnosis is made by obtaining a brain biopsy showing the characteristic features consisting

CLINICAL PRESENTATION Clinical features are nonspecific and vary according to the area of the brain involved. PML should be suspected in HIV patients with focal neurologic symptoms and signs, especially with a CD4 count of less than 100 cells/mm3. However, in one reported series, 7–25% of HIV patients with PML had CD4 counts greater than 200 cells/mm3 (Skiest, 2002). JC virus causes white matter demyelination resulting in the classic clinical picture of focal neurologic deficits and cognitive impairment. The disease is characterized by progressive dementia with eventual coma and death. Symptoms are insidious in onset and progress over weeks to months as compared to other major opportunistic focal brain disorders in which symptoms progress in hours to days. Less commonly, patients with PML have a waxing and waning clinical course which may extend for years. Fever and

Fig. 90.2. Brain MRI: T2 FLAIR image of a patient with progressive multifocal leukoencephalopathy.

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of loss of myelin with enlarged, bizarre astrocytes and lipid-laden macrophages. Brain biopsy is not necessary in all patients with a classic presentation that includes cognitive deficits, focal neurologic findings, multiple nonenhancing white matter lesions and CSF PCR positive for JCV.

PROGNOSIS Prognosis of PML is poor with a median survival of 1–6 months after diagnosis. However, about 8% of patients with PML will have a benign course and even spontaneously recover (Skiest, 2002). Factors associated with longer survival include PML as the initial AIDS diagnosis, high CD4 count at diagnosis, patients on HAART, increase of CD4 count by greater than 100 from nadir, low HIV viral load, low levels of JCV in CSF, and lack of neurologic progression in the first 2 months after diagnosis.

TREATMENT There is no effective treatment for PML. HAART appears to prolong survival and improve neurologic deficits when immune reconstitution is achieved. Although HAART is considered the treatment of choice, some patients have progressed despite receiving HAART and others have even developed PML while receiving HAART (Cinque et al., 2001). Reports of treatment with prednisone, cytarabine, aciclovir, vidarabine, amantadine, interferon-a, cidofovir, topotecan, mirtazapine, or mefloquine did not benefit patients with PML (Kaplan et al., 2009). There have been reports of worsening of PML associated with immune reconstitution in patients placed on HAART. This is thought to result from enhanced inflammatory responses and is called the immune reconstitution inflammatory syndrome or IRIS (Cinque et al., 2001). As JC virus is ubiquitous and exposure to the virus cannot be prevented, initiation of HAART in persons with HIV infection will greatly lessen the likelihood of developing PML.

Cryptococcal meningitis EPIDEMIOLOGY Cryptococcus neoformans is a ubiquitous environmental encapsulated fungus found in abundant quantities in soil and bird feces. Transmission occurs via inhalation. C. neoformans is the most common cause of meningitis in HIV patients, occurring when CD4 þ counts decline below 100 cells/mm3. Because signs and symptoms of meningitis can be subtle in HIV-infected persons, isolation of Cryptococcus from any site must be followed by a lumbar puncture to rule out meningitis. Although seen

worldwide, the prevalence of cryptococcal disease varies in different regions. It is rare in Europe, occurs in 5–8% of AIDS patients in the US and in 20–30% of persons with HIV infection in sub-Saharan Africa and South Asia (Kaplan et al., 2009; Park et al., 2009). Since the introduction of antiretroviral therapy and widespread use of fluconazole for candidiasis, the incidence of cryptococcosis has decreased (Mirza et al., 2003). There are four different serotypes of Cryptococcus which can be differentiated based on serology. Serotypes A and D include the more common Cryptococcus neoformans var neoformans, whereas serotypes B and C include Cryptococcus neoformans var gattii. In recent years C. gattii has emerged in the Pacific Northwest, but the majority of cases did not have underlying HIV disease. Thus, C. neoformans causes the great majority of infections in persons with HIV/AIDS.

PATHOGENESIS Cryptococcus enters the body via inhalation. In the lungs it results in subclinical infection or overt pulmonary cryptococcosis. It can disseminate to other organs including blood, skin, meninges (the most common site), brain, eye, bone, prostate, and adrenals. Like other encapsulated organisms, C. neoformans infects the meninges where immunoglobulin and complement are lacking. Persons with HIV manifest infection with C. neoformans when CD4þ counts decline to below 100/ mm3 and particularly below 50/mm3 (Darras-Joly et al., 1996).

CLINICAL FEATURES In HIV patients, cryptococcosis most commonly occurs as a subacute meningitis or meningoencephalitis. Presentation is indolent often with symptoms present for 2–4 weeks before the diagnosis is made. Common symptoms include fever, malaise, and headache. Some patients demonstrate encephalopathic symptoms such as lethargy, altered behavior, personality changes, or memory loss which result from elevated intracranial pressure. Classic meningeal symptoms and signs of neck stiffness and photophobia are seen in only 25–33% of patients with cryptococcal meningitis (Darras-Joly et al., 1996). Most cases are associated with cryptococcemia, i.e., cryptococcus in the blood. Cryptococcal pneumonia may be the initial presentation manifesting as fever, cough, and shortness of breath with abnormal chest imaging. Features on chest imaging are indistinguishable from other infections, and sometimes Cryptococcus is isolated in respiratory cultures when the chest X-ray is normal. Interstitial and alveolar infiltrates are common in HIV patients with low CD4 counts and may mimic infection with Pneumocystis jiroveci. In one study,

NEUROLOGIC DISEASES IN HIV-INFECTED PATIENTS 78% of HIV patients with cryptococcal meningitis had pulmonary symptoms in the months before and/or at the time their cryptococcal infection was diagnosed (Batungwanayo et al., 1994). All patents with HIV and pulmonary cryptococcosis should undergo lumbar puncture to rule out CNS dissemination. Skin involvement is seen in about 10% of patients, and there are several different skin lesions described. The most common type resembles Molluscum contagiosum, but the lesions often progress to central necrosis or ulceration in cutaneous cryptococccosis, a finding not seen with Molluscum contagiosum (Murakawa et al., 1996).

DIAGNOSIS Cryptococcal antigen in serum and CSF can be detected by latex agglutination or other similar tests that identify cryptococcal polysaccharide. When there is a high clinical suspicion of cryptococcal infection, the serum cryptococcal antigen level is a very helpful initial screening test. It is sensitive and specific. The serum antigen is positive in over 95% of patients with cryptococcal meningitis whereas it is often negative in patients having only lung involvement (Feldmesser et al., 1996). Approximately 20% of patients with cryptococcal meningitis will have a normal CSF formula including cell count, protein, and glucose. Therefore a normal CSF formula does not rule out cryptococcal meningitis. CSF should be tested for cryptococcal antigen and cultured for fungus. The CSF cryptococcal antigen is positive in virtually all patients with cryptococcal meningitis. CSF opening pressure should be measured as it is elevated in the majority of patients with cryptococcal meningitis. Patients with elevated pressure may require specific treatment to

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lower the pressure and more frequent follow-up lumbar punctures (Perfect et al., 2010). Cryptococcus grows in blood cultures in 50–70% of patients with meningitis. A positive blood culture for cryptococcus in a patient with HIV infection should prompt a lumbar puncture to rule out meningitis.

IMAGING In order to rule out space-occupying mass lesions, CT or MRI should be obtained before performing a lumbar puncture in patients presenting with focal deficits or signs and symptoms suggestive of raised intracranial pressure.

TREATMENT Guidelines for the treatment of cryptococcal meningitis in HIV-infected persons have been published by the CDC, NIH, and the HIV Medicine Association of the Infectious Diseases Society of America (Kaplan et al., 2009). The principles of treatment for patients with cryptococcal meningitis include: (1) antifungal therapy, (2) lowering elevated intracranial pressure, (3) initiating or optimizing antiretroviral therapy to improve immune function, and (4) management of immune reconstitution if it develops. Antifungal therapy is divided into induction, consolidation, and maintenance phases as shown in Table 90.5. In general, amphotericin B can clear cryptococcus more rapidly from CSF than fluconazole (Bicanic et al., 2007) and amphotericin B plus flucytosine more rapidly than amphotericin B alone (Brouwer et al., 2004). At the present time, most centers use lipid formulations of amphotericin B in lieu of the older, more toxic

Table 90.5 Treatment of cryptococcal meningitis Preferred regimen

Alternative therapy

Induction ( for at least 2 weeks) Amphotericin B 0.7 mg/kg IV daily þ flucytosine 100 mg/kg PO daily in four divided doses or lipid amphotericin B 4–6 mg/kg IV daily þ flucytosine Consolidation (start after significant clinical improvement and negative CSF culture) Fluconazole 400 mg PO daily for 8 weeks Maintenance therapy: continue fluconazole 200 mg PO daily until patient is asymptomatic, has completed induction and consolidation therapy, and has a CD count over 200 for 6 months on antiretroviral therapy (Vibhagool et al., 2003)

1. Amphotericin þ fluconazole 400 mg PO or IV daily 2. Amphotericin or lipid amphotericin alone 3. Fluconazole 400–800 mg daily IV or PO þ flucytosine for 4–6 weeks* Itraconazole 200 mg PO bid for 8 weeks

Continue itraconazole 200 mg PO daily (consider for persons unable to tolerate or unresponsive to fluconazole)

*For persons unable to tolerate or unresponsive to amphotericin B (2009 CDC/IDSA/NIH Guidelines for Prevention and Treatment of Opportunistic Infections in Adults with HIV Infection; Kaplan et al., 2009) PO, oral; bid, twice daily; IV, intravenous; CSF, cerebrospinal fluid.

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deoxycholate form (Hamill et al., 2010). Additionally, fluconazole plus flucytosine is less effective than amphotericin B (Bicanic et al., 2007). Induction therapy, usually with amphotericin B and flucytosine, is continued for at least 2 weeks in patients showing improvement, but longer in those remaining seriously ill. When patients improve, consolidation therapy followed by long-term maintenance therapy is continued, usually with fluconazole. During all three phases of therapy, patients should be monitored for side-effects. With regard to the newer azole antifungals, including voriconazole and posaconazole, limited data documenting their efficacy in treatment of cryptococcal meningitis exist. Finally, echinocandins are not active against C. neoformans.

MANAGEMENT OF ELEVATED INTRACRANIAL PRESSURE All patients with cryptococcal meningitis should have lumbar puncture with measurement of opening pressure in the lateral decubitus position. Elevated opening pressure (greater than 25 cm H2O) is associated with more clinical signs and higher mortality. More than 90% of reported deaths within first 2 weeks and 40% of deaths in weeks 3–10 were due to raised intracranial pressure (Graybill et al., 2000). Thus clinicians should manage elevated pressure very aggressively with daily lumbar punctures. High opening pressure can be reduced to half by removal of 20–30 mL of CSF. If repeated lumbar punctures cannot be accomplished or fail to reduce symptoms or cerebral edema, placement of a lumbar drain, ventricolostomy, or ventriculoperitoneal shunt should be considered.

ANTIRETROVIRAL THERAPY Antiretroviral therapy should be included in the treatment of all patients diagnosed with cryptococcal meningitis; however, the timing of initiation of antiretroviral therapy remains unclear. Concern about immune reconstitution inflammatory syndrome (IRIS) has led many experts to recommend deferring antiretroviral therapy for 2-10 weeks (until CSF cultures become negative) after initiating antifungal therapy. The incidence of IRIS after starting antiretroviral therapy in patients with cryptococcal meningitis is between 20% and 40%. The majority of patients who develop IRIS are antiretroviral naı¨ve and have higher HIV RNA levels (Shelburne et al., 2005). In addition, IRIS is associated with pre-ART increases in Th17 and Th2 responses (Boulware et al., 2010). Symptoms of IRIS resemble the initial presentation of cryptococcal meningitis and may suggest treatment failure. Lumbar puncture should be obtained and negative fungal cultures from the CSF along with rapid decline in HIV RNA levels and a marked improvement in CD4 counts all favor IRIS as the cause of the ambiguous

clinical picture. Appropriate management of IRIS is to continue both antiretroviral therapy and antifungal therapy. Some experts recommend corticosteroids for severe symptomatic cases of IRIS (Venkataramana et al., 2006).

PROPHYLAXIS Although controlled clinical trials have shown that fluconazole or itraconazole can reduce the frequency of primary cryptococcal infection in patients with CD4 þ cell counts of less than 50/mm3, primary prevention of cryptococcal infection in HIV-infected persons is not recommended due to the infrequency of cryptococcal disease, lack of survival benefit with prophylaxis, drug interactions, drug resistance and cost (Perfect et al., 2010). Before HAART was available, lifelong treatment with oral fluconazole, 200 mg daily, was used for secondary prophylaxis after control of the meningitis with induction and consolidation therapy. With HAART, secondary prophylaxis can be discontinued after the patient is asymptomatic, has completed induction and consolidation therapy (at least 10 weeks), and has a CD4 þ cell count over 200 for 6 months on ART (Vibhagool et al., 2003) (Table 90.5).

Cytomegalovirus encephalitis Cytomegalovirus (CMV) is a double-stranded DNA virus belonging to the herpesvirus family. Among patients with advanced immunosuppression, the virus can cause disseminated or localized end organ disease. Patients with CMV encephalitis may present with only encephalitis or may have associated CMV infection at other sites including the retina, GI tract (esophagus to colon), adrenals, or other less commonly involved sites. Risk factors for CMV include CD4 count less than 50/ mm3 (not on ART or not responding to current regimen), HIV RNA level over 100 000 copies/mL, history of previous opportunistic infection, or evidence or prior CMV infection, i.e., CMV IgG positive. Virtually all CMV infections in AIDS represent reactivation of latent infection. Since the introduction of highly active antiretroviral therapy (HAART), the incidence of new cases of CMV end organ disease has declined by 75–80%. Incidence is now estimated to be fewer than six cases per 100 personyears (Jabs et al., 2007). Mortality associated with CMV disease has also decreased (Palella et al., 1998).

CLINICAL FEATURES OF NEUROLOGIC CYTOMEGALOVIRUS DISEASE

CMV is responsible for three distinct neurologic syndromes. These include dementia, encephalitis with ventriculoencephalitis, and ascending polyradiculomyelopathy.

NEUROLOGIC DISEASES IN HIV-INFECTED PATIENTS Dementia presents as lethargy, confusion, and fever mimicking HIV dementia. CSF shows a lymphocytic pleocytosis, normal to elevated protein, and low to normal glucose. Ventriculoencephalitis has an acute onset with confusion, focal deficits, cranial nerve abnormalities, nystagmus, ataxia, and rapid progression to death. CSF typically demonstrates a lymphocytic pleocytosis and an elevated protein. However, the spinal fluid formula can be normal with CMV encephalitis and thus, normal CSF does not rule out CMV encephalitis. CT or MRI with contrast may demonstrate perivetricular enhancement which supports the diagnosis of CMV encephalitis but is not specific for the disease. Ascending polyradiculomyelopathy due to CMV results in a Guillain–Barre´like syndrome with ascending bilateral leg weakness along with bladder/bowel incontinence, radicular pain, and sensory deficits. CSF demonstrates neutrophilic pleocytosis.

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therapy (HART) can be delayed until there is symptomatic improvement (French et al., 2000).

PREVENTION Antiretroviral therapy with control of HIV replication and improved immune function will prevent CMV disease. Primary prophylaxis with anti-CMV medications is not recommended.

SPINAL CORD DISORDERS IN HIV PATIENTS/VACUOLAR MYELOPATHY EPIDEMIOLOGY Spinal cord disorders are less common than peripheral nervous system disorders in HIV patients. HIV-associated myelopathy occurs as a result of HIV infection and is also called vacuolar myelopathy (VM). VM can occur at any stage during the course of HIV infection but is more common with advanced immunosuppression.

DIAGNOSIS

INCIDENCE AND PREVALENCE

CMV viremia can be detected by PCR or by antigen assays. Viremia is usually observed with end organ disease, but it may also be present in the absence of end organ disease. CMV antibodies are not useful in diagnosis although a negative anti-CMV IgG makes CMV infection unlikely. Spinal fluid cultures are positive in less than 50% of cases with CMV encephalitis. Detection of CMV DNA by PCR in the CSF is positive in 80%. The specificity of spinal fluid PCR is 90% in CMV neurologic disease (Skiest, 2002). Definitive diagnosis, then, is based on a compatible clinical syndrome and demonstration of CMV in CSF or brain tissue after biopsy.

Reliable data on incidence and prevalence of myelopathy in HIV patients is not available. This is because of underdiagnosis or the lack of symptoms and signs in affected patients. One autopsy-based case control study documented VM in 46% of persons with AIDS (Dal Pan et al., 1994).

TREATMENT Anti-CMV therapy may be effective if given early in the course of disease although clinical response to therapy is unpredictable. As recommended in the treatment guidelines from the CDC, NIH and the HIV Medicine Association of the IDSA 2009, combination therapy with intravenous ganciclovir 5 mg/kg twice a day and intravenous foscarnet 90 mg/kg twice a day should be used to stabilize disease and maximize response. It should be continued until improvement is demonstrated, which might take weeks to months depending on the severity of neurologic disease. After symptomatic improvement oral valganciclovir 900 mg twice daily along with intravenous foscarnet once daily should be used for life unless there is evidence of immune recovery. Because of rare fatal cases of IRIS attributed to CMV infection of the CNS, initiation of Highly active antiretroviral

PATHOLOGY Vacuolar myelopathy is a pathologic diagnosis in which vacuolation of myelin in the posterior and lateral columns of the spinal cord, with or without inflammation, is seen. The upper thoracic levels of the spinal cord are commonly involved. The HIV virus does not directly involve the spinal cord. It facilitates the development of disease by stimulating macrophages to produce inflammatory cytokines. Clinically and pathologically, HIV myelopathy often resembles subacute combined degeneration of spinal cord as is seen with vitamin B12 deficiency (Petito et al., 1985).

CLINICAL FEATURES Vacuolar myelopathy is characterized by a subacute onset of clinical signs and symptoms, developing over weeks to months. Common symptoms include bilateral lower extremity weakness with spasticity. Patients also experience bowel, bladder, and erectile dysfunction with variable sensory disturbances. Deep tendon reflexes are hyperactive with an extensor plantar response (Babinski sign). Upper extremities are normal. Ambulatory patients may have unsteadiness of gait. When paresthesias or numbness are present, VM can be differentiated

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from peripheral neuropathy by noting the brisk reflexes with VM as opposed to depressed reflexes with peripheral neuropathy.

DIAGNOSIS Diagnosis of VM is by exclusion and requires ruling out other causes by measuring serum vitamin B12 levels, copper levels, rapid plasma reagin (RPR), and human T-lymphotrophic virus-1 (HTLV-1) antibodies before making the diagnosis. Lumbar puncture should be performed to rule out infection with herpes simplex virus, varicella zoster virus, CMV, and neurosyphilis. In VM the CSF may be normal, or it may show mild pleocytosis with mild elevation in protein. Similar CSF findings may be seen in asymptomatic HIV persons. Therefore, CSF is not helpful in making the diagnosis but remains important in excluding the above noted infections. The spinal MRI may be normal, or it may show spinal atrophy or patchy abnormalities on T2-weighted images. Somatosensory evoked potentials (SEP) help to confirm myelopathy, whereas nerve conduction studies can detect coexistent neuropathy if present.

TREATMENT There is no effective therapy that will reverse or eliminate HIV-associated vacuolar myelopathy. Symptomatic treatment with antispasticity agents such as baclofen, tizanidine, or botulinum toxin can relieve spasms. Routine care such as maintenance of skin integrity or prevention of urinary retention is essential. The role of antiretroviral therapy in improving VM has not been established (Geraci and Di Rocco, 2000). Trials with methionine supplements and corticosteroids have not shown benefit (Di Rocco et al., 2004). Trials with intravenous immunoglobulin (IVIG) are ongoing.

NEUROMUSCULAR DISORDERS Peripheral nervous system disorders causing pain, sensory disturbance, or motor weakness occur commonly in persons with HIV infection. They may be caused by HIV itself or may occur secondary to opportunistic infections or certain antiretroviral drugs. These disorders are further classified into four categories: (1) distal symmetric polyneuropathy (DSP), (2) inflammatory demyelinating polyneuropathy (IDP), (3) mononeuropathy and mononeuropathy multiplex, and (4) radiculopathies.

Distal symmetric polyneuropathy Distal symmetric polyneuropathy (DSP) is the most common form of neuropathy seen in HIV-infected patients. Although it can develop at any stage of HIV disease it is most commonly observed in advanced stages with

immunosuppression. Pathogenesis is complex, multifactorial and incompletely understood. DSP may be associated with other primary HIV-related neurologic disorders such as dementia or vacuolar myelopathy. Dideoxynucleoside reverse transcriptase inhibitors, such as stavudine and didanosine, are also implicated as causes of DSP. Once the mainstay of treatment, stavudine and didanosine are no longer recommended as preferred agents for the treatment of HIV infection (DHHS HIV Treatment Guidelines, 2012). Attributed to advanced immunosuppression in the pre-HAART era, DSP is now observed in patients with controlled infection and intact immune function suggesting that other causes have assumed a more significant role (Evans et al., 2011). In a study of 2141 patients who started antiretroviral therapy and were followed for at least 3 years between 2000 and 2007, the AIDS Clinical Trials Group demonstrated rates of peripheral neuropathy and symptomatic peripheral neuropathy of 32% and 8.6% respectively. Some 87% of the patients in the study had HIV RNA levels less than 400 and 70% had CD4 counts over 350 cells/mm3 (Evans et al., 2011). Risk factors for symptomatic peripheral neuropathy were older age, diabetes, and use of neurotoxic antiretrovirals including stavudine, didanosine, zalcitibine, and nevirapine.

CLINICAL FEATURES Symptoms are primarily sensory, beginning in the feet. Specific symptoms include symmetric numbness, tightness, pain, burning, and hyperalgesia. With progression, symptoms proceed proximally to involve ankles, calves, and finally the hands. Motor weakness is not seen. Physical examination demonstrates decreased vibratory and temperature sensation with either decreased or hyperalgesic pin-prick sensation. Deep tendon reflexes are decreased at the ankles compared to the knees.

DIAGNOSIS Diagnosis is clinical, but electrophysiologic testing such as nerve conduction studies and electromyography can help to confirm the diagnosis. Clinical signs and electrophysiologic evidence of DSP occur in the absence of symptoms in 25% of cases (Skopelitis et al., 2006).

TREATMENT Implicated reverse transcriptase inhibitors (stavudine, didanosine, and zalcitabine) should be stopped and alternative antiretrovirals substituted. Symptoms may persist for several weeks or may worsen after stopping the drugs. Otherwise, treatment is symptomatic aiming to reduce neuropathic pain. Nonsteroidal anti-inflammatory agents

NEUROLOGIC DISEASES IN HIV-INFECTED PATIENTS have been tried, but some patients require opioids. Gabapentin can be used, and it showed benefit in one placebo controlled trial (Hahn et al., 2004). Lamotrigine 25 mg twice daily increasing to 300 mg/day was found to be effective in clinical trials (Simpson et al., 2000). Pregabalin can also be used, though only US Food and Drug Administration (FDA) approved for diabetic neuropathy (Simpson et al., 2010). Antidepressants including nortriptyline, amytriptyline, imipramine, desipramine, and duloxetine are also used with benefit in some patients. Topical agents such as lidocaine and capsaicin have been tried but were not effective in clinical trials (Simpson et al., 2008).

Inflammatory demyelinating polyneuropathy Inflammatory demyelinating polyneuropathy (IDP) is an uncommon form of neuropathy seen in HIV-infected persons. It occurs in two forms: acute inflammatory demyelinating polyneuropathy (AIDP) or Guillain– Barre´ syndrome (GBS), and chronic inflammatory demyelinating polyneuropathy (CIDP). Acute inflammatory demyelinating polyneuropathy AIDP/GBS occurs early in the course of HIV infection particularly at the time of seroconversion, either as a part of the acute retroviral syndrome or in otherwise asymptomatic persons (Piette et al., 1986). Its incidence is unknown. Pathogenesis is complex and the role of HIV in the pathogenesis is not completely understood. It is postulated that HIV can trigger an immune-mediated or autoimmune process resulting in demyelination. Antibodies directed against peripheral nerve myelin have been described (Petratos et al., 1998). Clinically it manifests as rapid, symmetric, ascending motor weakness with generalized areflexia and relative sparing of sensation. Facial weakness and ophthalmoparesis can also be seen (Cornblath et al., 1987). Symptoms usually peak at 4 weeks after onset. Serious complications include respiratory compromise and autonomic dysfunction (Cornblath et al., 1987). Chronic inflammatory demyelinating polyneuropathy/CIDP can develop in early or in late stages of HIV infection. If symptoms and signs of AIDP persist beyond 8 weeks the condition is called chronic inflammatory demyelinating polyneuropathy. The course can be monophasic or relapsing. Diagnosis of AIDP is based on clinical presentation, CSF analysis, and electrophysiologic studies. The CSF typically shows an elevated protein and mild lymphocytic pleocytosis, usually 10–50 cells/mm3. In non-HIVinfected patients with AIDP or CIDP, the CSF is usually without cells. Nerve conduction studies show a conduction block with decreased nerve conduction velocity due to demyelination. Electromyography shows reduced

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action potential amplitudes in affected muscles (Alport and Sander, 2012).

TREATMENT Acute inflammatory demyelinating polyneuropathy is treated with IVIG 400 mg/kg/day for 5 days. Plasma exchange is also used (Kiprov et al., 1988). Chronic inflammatory demyelinating polyneuropathy is also treated with IVIG for 5 days. This may be followed up with maintenance IVIG every 3 weeks depending on the patient response (Malamut et al., 1992). Plasma exchange or prednisone 1 mg/kg/day, continued until therapeutic response, may also be tried (Leger et al., 1989).

Mononeuropathy and mononeuropathy multiplex Mononeuropathies are rarely seen in HIV-infected persons. They can be seen involving either cranial or peripheral nerves. The cause of these mononeuropathies is not always clear, but HIV itself, other infections, immunologic processes or compression from external structures have all been implicated (Verma et al., 2004). A common early presentation is unilateral or bilateral facial nerve palsy which is most commonly seen in acute HIV infection (Wechsler and Ho, 1989). In late stages of HIV infection, mononeuropathies are caused by other infections or processes such as varicella zoster virus (VZV) infection, syphilis, tuberculosis, or meningeal lymphoma (Verma et al., 2004). Examples of clinical presentations include wrist drop, foot drop, sensorineural hearing loss, and diaphragmatic paralysis (Piliero et al., 2004). Diagnosis is based on clinical presentation and electrophysiologic testing. Regardless of HIV status, treatment of mononeuropathies is the same. Corticosteroids may be effective, but antivirals have not been shown to provide benefit (Sullivan et al., 2007). Mononeuritis multiplex is classically associated with vasculitis. It is rare but when seen in HIV-infected persons it occurs either in early stages, due to immunologic factors, or in late stages, due to infections such as CMV, hepatitis B, hepatitis C, or VZV (Verma et al., 2004). Mononeuritis multiplex develops slowly, typically involving sensory, motor, and autonomic functions. It most commonly presents as a painful, asymmetric polyneuropathy affecting multiple nerves in a stepwise fashion (Verma et al., 2004). Diagnosis is established by the clinical presentation and electrophysiologic testing. In patients with low CD4 counts, CMV should be ruled out with CSF CMV PCR or nerve biopsy. If CMV is documented or in patients with CD4 counts less than 200 cells/mm3 where CMV is likely, either directed or empiric treatment for CMV infection (see section in this chapter on CMV infection) with ganciclovir should be

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started (Kaplan et al., 2009). In patients with CD4 counts over 200 cells/mm3 supportive treatment is recommended for this often self-limited condition. If a nerve biopsy discloses vasculitis, treatment with IVIG, plasma exchange, or corticosteroids is recommended (Brew, 2001).

prevent immune reconstitution (French et al., 2000). The neuropathies and radiculopathies associated with HIV infection are summarized in Table 90.6.

NEUROSYPHILIS Epidemiology and clinical manifestations

Radiculopathies PROGRESSIVE POLYRADICULOPATHY Polyradiculopathy is defined as inflammation and necrosis of nerve roots at the site of exit from the spinal cord. Progressive polyradiculopathy typically affects lumbosacral nerve roots and is characterized by radicular pain and sensorimotor deficits. In the pre-HAART era, CMV was the most common cause of progressive polyradiculopathy. It was typically seen in patients with advanced immunosuppression (CD4 counts less than 50 cells/ mm3) and evidence of CMV at other sites. In one report, CMV radiculopathy was found in 2% of patients with AIDS (Gans et al., 1990). Since the introduction of antiretrovirals the incidence of radiculopathy has decreased. Other causes of progressive polyradiculopathy are herpes simplex virus, varicella zoster virus, syphilis, tuberculous meningitis, and lymphomatous meningitis. The classic clinical presentation is that of a rapidly evolving cauda equina syndrome with weakness and numbness in the lower extremities, bowel and bladder sphincter dysfunction, radicular pain in the lower extremities in a cauda equina distribution, and saddle anesthesia (perineal area). Involvement of upper extremities and cranial nerves may occur in later stages. Prompt diagnosis is imperative in order to avoid irreversible nerve root necrosis. Lumbar puncture must be performed and CSF sent to rule out other etiologies by testing for CMV, HSV, and VZV by PCR, RPR, AFB culture, and cytology. The CSF in CMV polyradiculitis is characterized by a neutrophilic pleocytosis with elevated protein, normal to low glucose, and positive PCR. Viral cultures may not be helpful. Nerve conduction studies and electromyography will show multilevel nerve root involvement. MRI should be done to rule out compressive or space-occupying lesions of the cauda equina or lower thoracic spinal cord. On the MRI one may see thickening or enhancement of lumbosacral nerve roots. While awaiting results treatment should be started promptly as CMV polyradiculitis can be fatal. Combination therapy with intravenous ganciclovir plus foscarnet is recommended. Clinical trials with CMV polyradiculitis have not been done. Therefore benefits of single versus combination therapy have not been established and the optimal duration of therapy is not known. Antiretrovirals should be initiated or optimized several weeks after starting anti-CMV therapy to

Neurosyphilis refers to infection of the central nervous system caused by Treponema pallidum. It is a sexually transmitted infection in which the bacteria enter the body through skin abrasions or mucous membranes. Data are conflicting regarding the incidence, symptoms, severity, and treatment response in HIV-infected patients (Rolfs et al., 1997; Collis and Celum, 2001). HIV-infected patients with syphilis may present with atypical and more aggressive disease. Serologically they respond less well to therapy when compared to HIV-negative patients (Kingston et al., 2005). Based on small case series, the incidence of neurosyphilis was about 9% before introduction of HAART. Data on the incidence after HAART are lacking. Syphilis is classified as early, including primary and secondary stages, and late, which includes latent and tertiary stages. Classically, neurosyphilis is a late manifestation, but neurologic complications of early secondary syphilis including meningitis and stroke are seen more frequently in HIV-infected patients (Marra et al., 2004). The stages of neurosyphilis and associated clinical syndromes are depicted in Tables 90.7 and 90.8.

DIAGNOSIS Diagnosis of neurosyphilis is based on clinical presentation as well as CSF findings. Lymphocytic pleocytosis (WBC greater than 5/mm3) and elevated protein are the most common CSF abnormalities seen with neurosyphilis. T. pallidum cannot be cultured so the fluorescent treponemal antibody absorption test (FTA-ABS) and treponema particle agglutination tests (TPPA) and non-treponemal rapid plasma reagin (RPR) and Venereal Disease Research Laboratory (VDRL) serologic tests are used. The nontreponemal tests are quantitative and are used for screening and for post-treatment follow-up. Treponemal tests are used to confirm the screening nontreponemal test. They are also occasionally used for diagnosis of neurosyphilis when the nontreponemal CSF test is negative in a patient with symptoms suggestive of neurosyphilis. VDRL in CSF is specific but less sensitive whereas the CSF FTA-ABS test is very sensitive but less specific. Because false-negative CSF VDRL tests are not uncommon and pleocytosis and elevated protein are seen in many other conditions, diagnosis of neurosyphilis can be difficult. The indications for lumbar puncture in HIV-infected patients with

Table 90.6 Neuropathies and radiculopathies associated with HIV infection Etiology and pathogenesis

Disease

Symptom progression

Classic presentation

Management

Distal symmetric polyneuropathy

Months

Unknown, watch for neurotoxic antiretrovirals

Symmetric pain, numbness, burning of toes/feet No weakness Absent/decreased ankle reflex Rapid ascending weakness with generalized areflexia, relative sparing of sensation

NCV/EMG: axonal neuropathy Symptomatic (analgesics, anticonvulsants, antidepressants)

Inflammatory demyelinating polyneuropathy

Acute: peak in 4 weeks Chronic: >8 weeks

Immunologic and autoimmune process

Mononeuritis multiplex

Variable, over weeks to months

Rule out CMV and vasculitis

Asymmetric motor and sensory deficits

Progressive polyradiculopathy

Days to weeks

Rule out CMV

Rapid weakness and numbness in legs, perineal area with reduced or absent knee and ankle reflexes

NCV/EMG: demyelinating polyneuropathy CSF: pleocytosis, increased protein, cultures negative IVIG, plasma exchange NCV/EMG: asymmetric multifocal defects Rule out CMV (CSF/nerve biopsy) Treat for CMV if CD4 count < 50 NCV/EMG: multilevel nerve root involvement. CSF to rule out CMV. Ganciclovir  foscarnet for CMV polyradiculitis

CMV, cytomegalovirus; CSF, cerebrospinal fluid; NCV, nerve conduction velocities; EMG, electromyogram; IVIG, intravenous immunoglobulin.

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Table 90.7 Stages of neurosyphilis Neurosyphilis stage

Presentation

Sites affected in CNS

Clinical syndrome

Early stage

Within weeks to years but common < 1 year after initial infection

CSF Meninges Vasculature

Late stage

Years to decades after initial infection

Brain Spinal cord

Asymptomatic meningitis Symptomatic meningitis Cranial neuropathies Stroke Gummas (mass lesions) Optic disease General paresis of insane Tabes dorsalis (posterior column)

CNS, central nervous system; CSF, cerebrospinal fluid.

Table 90.8 Clinical features and laboratory findings in neurosyphilis CSF: cell count (lymphocytes), protein, VDRL

Early stage neurosyphilis

Clinical features

Asymptomatic meningitis Symptomatic meningitis Cranial neuropathies Ocular disease

Absent Headache, confusion and meningeal signs, hydrocephalus, seizures, syphilitic gumma as mass lesions Optic, facial, auditory nerves are commonly involved Posterior uveitis, chorioretinits, optic neuritis, etc. Ischemic stroke in young person (thrombosis, ischemia, infarction of cerebral vessel)

WBC < 100, protein < 100,  VDRL WBC 200–400, protein 100–200, VDRL positive

General paresis (dementia, personality changes)

CSF: WBC < 100, protein < 100, generally þ VDRL Imaging: cerebral atrophy CSF may be normal or show mild lymphocytic pleocytois and mild increased protein, 25% of cases will be VDRL negative

Meningovascular disease/stroke

Late stage neurosyphilis Brain parenchyma

Spinal cord parenchyma

Tabes dorsalis (ataxia, lancinating pains, papillary abnormalities

WBC < 100, protein 100–200,  VDRL

VDRL, Venereal Diseases Research Laboratory test; CSF, cerebrospinal fluid; WBC, white blood cell count.

syphilis are neurologic, ocular, or auditory signs and symptoms, evidence of tertiary syphilis (aortitis or gumma), and treatment failure. Treatment failure includes continued presence of signs or symptoms, or a fourfold rise in serum RPR or a failure of the serum RPR to decrease by fourfold within 2 years of treatment. Some studies have shown that development of neurosyphilis is more likely in HIV patients if the CD4 count is

less than 350/mm3 or if the RPR titer exceeds 1:32 (Ghanem et al., 2009).

TREATMENT Parenteral penicillin is the drug of choice for treatment of neurosyphilis. Recommended treatments from the CDC are shown in Table 90.9. According to the CDC

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Table 90.9 Treatment of neurosyphilis Disease

Preferred therapy

Alternate therapy

Neurosyphilis Some experts recommend benzathine benzylpenicillin (penicillin G) 2.4 million units IM weekly for 3 weeks after completion of recommended IV therapy

Aqueous crystalline benzylpenicillin 18–24 million units IV daily in divided doses given every 4 hours, or given by continuous infusion for 10–14 days

Procaine benzylpenicillin (penicillin G) 2.4 million units IM QD for 10–14 days þ probenecid 500 mg PO QID for 10–14 days or Ceftriaxone 2 g IV/IM QD for 10–14 days*

*Limited data on ceftriaxone in neurosyphilis. (2010 CDC STD Treatment Guidelines; Workowski and Berman, 2010) IM, itramuscular; IV, intravenous; PO, oral; qd, daily; qid, four times a day.

guidelines, CSF protein and glucose should be normal by 2 years. The cell count should show evidence of decline by 6 months.

TUBERCULOSIS OF THE CENTRAL NERVOUS SYSTEM Both in immunocompetent and immunocompromised individuals, Mycobacterium tuberculosis occurs within the central nervous system either by reactivation or by dissemination, usually from a primary focus in the lungs. Infections with HIV and M. tuberculosis tend to occur with greater frequency in areas of the world where tuberculosis is endemic. Some reports describing the manifestations of CNS tuberculosis in patients with and without HIV coinfection do not describe differences, whereas other reports describe distinct clinical, pathologic, and radiographic features in HIV-infected persons (Berenguer et al., 1992; Katrak et al., 2000). CNS tuberculosis generally manifests in advanced HIV disease with CD4 counts less than 200/mm3, but there are reports of the disease in patients with higher CD4 counts as well.

PATHOGENESIS Mycobacterium tuberculosis protein antigens spill into the subarachnoid space and cause intense inflammatory responses. This commonly occurs at the base of the brain leading to proliferative arachnoiditis and vasculitis. Hydrocephalus develops if the inflammatory exudate extends to the basilar cisterns. Varied clinical manifestations are seen depending on the location and extent of these changes.

CLINICAL FEATURES Clinical manifestations include meningitis, stroke, cerebral abscess, tuberculoma, or involvement of the spinal

cord. The most common signs of TB meningitis are headache and low grade fever. Meningitis is progressive with development of personality changes, followed by meningismus, lethargy, cranial nerve palsies, and hemiparesis. Late findings include delirium, stupor, coma, multiple cranial nerve palsies, and hemiplegia. Strokes result from vasospasm and thrombosis and typically involve the basal ganglia. Cerebral abscess is characterized by fever, headache, delirium, cranial nerve palsies, seizures, and hemiparesis. Tuberculomas may or may not have clinical manifestations. When present, clinical manifestations consist of focal symptoms and signs of an intracranial space-occupying mass lesion generally without systemic illness or meningeal inflammation. Spinal tuberculosis results in arachnoiditis and presents as meningitis or cord compression (Rock et al., 2008).

DIAGNOSIS Diagnosis of CNS tuberculosis is difficult and challenging. With high clinical suspicion antituberculosis therapy should be started empirically while waiting for CSF culture results. Delay in diagnosis is associated with high mortality. The CSF typically shows a lymphocytic pleocytosis with elevated protein and low glucose. A positive culture for Mycobacterium tuberculosis is the gold standard for diagnosis but takes 2–8 weeks. In addition the culture is not uniformly sensitive and, in patients in whom there is high clinical suspicion, some experts recommend a minimum of three lumbar punctures performed daily in order to improve the yield. Acid-fast smears from CSF are positive in only 25% of cases. PCR can be used to detect DNA of M. tuberculosis in AFB smear negative cases. The PCR is 56% sensitive and 98% specific (Pai et al., 2003). Therefore, when positive the test is very helpful in the diagnosis but, if negative, it does not rule out tuberculous meningitis. The

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chest X-ray is abnormal in about 50% of HIV-infected patients with CNS tuberculosis.

Table 90.11

NEUROIMAGING

CD4 count in HIV patient with TB

Timing of initiation of HAART after starting TB therapy

CD4 count < 200 cells/mm3 CD4 count 200–500 cells/mm3

Within 2–4 weeks 2–4 weeks or at least 8 weeks Within 8 weeks

Because of its greater sensitivity in detecting meningeal enhancement, MRI is preferred over CT. Other MRI findings with nervous system tuberculosis include small, enhancing lesions in the basal ganglia, brainstem, and spinal cord (Offenbacher et al., 1991). Tuberculomas appear as small, enhancing, space-occupying lesions without significant mass effect, whereas tuberculous cerebral abscesses are larger ring-enhancing lesions.

Initiation of HAART in the setting of HIV/TB coinfection

CD4 count > 500 cells/mm3

(DHHS HIV Management Guidelines 2012) HAART, highly active antiretroviral therapy; HIV, human immunodeficiency virus; TB, tuberculosis.

TREATMENT Treatment, depicted in Table 90.10, combines recommendations from the American and British Thoracic Societies, the CDC and the Infectious Diseases Society of America (ATS/CDC/IDSA Treatment Guidelines for Tuberculosis, 2003; Blumberg et al., 2003). Treatment should be initiated whenever there is strong clinical suspicion of CNS tuberculosis and should not be delayed until the infection is proven. It consists of an initial 2 month period of intensive therapy using four drugs which is followed by a prolonged continuation phase usually with two drugs lasting 7–10 months depending on clinical response and the established drug sensitivity of the isolate. Duration of therapy should be extended to 18 months in patients with tuberculoma whereas 18–24 months is recommended for drug-resistant organisms. Corticosteroids during the early phase of treatment of tuberculous meningitis have been shown to improve

Table 90.10 Treatment of CNS tuberculosis Initial phase Use 4 drugs for 2 months Continuation phase Use 2 drugs for 7–10 months Duration Drug-susceptible TB Drug-resistant TB (modify regimen accordingly) Tuberculoma Corticosteroids Dexamethasone, or Prednisone

Isoniazid, rifampicin, ethambutol and pyrizinamide Isoniazid with rifampicin (only if susceptible) 9–12 months depending on response 18–24 months 18 months 0.3–0.4 mg/kg, taper over 6–8 weeks 1 mg/kg for 3 weeks and taper over 3–5 weeks

(2003 ATS/CDC/IDSA Guidelines; Blumberg et al., 2003) CNS, central nervous system; TB, tunerculosis.

outcomes and decrease mortality (Thwaites et al., 2004). Factors associated with poor prognosis of CNS TB in HIV-infected patients include more severe illness at presentation, CD4 count less than 50/mm3, and the presence of multidrug-resistant strains (Thwaites et al., 2005; Cecchini et al., 2007). Initiation of HAART in patients with CNS tuberculosis may be associated with worsening due to the frequent occurrence of the immune reconstitution inflammatory syndrome (IRIS). With CNS tuberculosis, IRIS manifests as worsening of meningeal symptoms or expanding/new intracranial lesions (Lawn et al., 2005). The Department of Health and Human Services has published recommendations concerning timing of initiation of HAART in patients who are being treated for active tuberculosis (Table 90.11). If an HIV patient on HAART develops CNS tuberculosis, HAART should be continued but the doses modified in order to avoid drug–drug interactions. Interactions between rifampicin and the protease inhibitors are common, most often resulting in increased levels of rifampicin due to a decrease in its rate of metabolism. Levels of the protease inhibitors are decreased due to accelerated metabolism by rifampicin. Rifabutin is associated with reduced interactions and is often used in place of rifampicin in patients receiving protease inhibitors (Burman et al., 1999).

HIV-ASSOCIATED NEUROCOGNITIVE DISORDER HIV-associated neurocognitive disorder (HAND) is the result of neural damage caused by HIV replication and immune activation. HIV entry into the CNS and proposed mechanisms by which HIV promotes inflammation have been discussed in the introductory section of

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Table 90.12 Frascati classification of HIV-associated neurocognitive disorders HIV-associated neurocognitive disorder (HAND) subgroup Asymptomatic neurocognitive impairment (ANI) Mild neurocognitive disorder (MND) HIV-associated dementia (HAD)

Neuropsychological test

Daily functions

Mild impairment in test

No impairment in daily functions

Mild impairment in test Marked cognitive impairment

Mild functional impairment Marked functional impairment

(Antinori et al., 2007)

this chapter. Frascati has classified HAND into the three subgroups listed in Table 90.12.

PREVALENCE In the pre-HAART era, HIV-associated dementia (HAD) was seen in approximately 7% of persons with HIV/AIDS. The condition was seen with CD4 þ cell counts of less than 200 cells/mm3 and was characterized by rapid progression to death, usually within 6 months. With the introduction of antiretroviral drugs and then HAART, there have been changes in the epidemiology of HAD. Data from the CASCADE cohort (Concerted Action on Seroconversion to AIDS and Death in Europe) described a decline in the incidence of HAD from 20–30% to 10–15% in patients with advanced HIV disease (Bhaskaran et al., 2008). In the Multicenter AIDS Cohort study the incidence of HAD declined by 50% between the 1990–1992 period and the 1996–1998 period – again attributed to the introduction of antiretrovirals (Sacktor, 2002). The prevalence of severe HAD has clearly decreased but the prevalence of mild to moderate HAND has not changed during this same time period. Risk factors associated with development of HAND are as follows: low CD4 count, high HIV RNA levels in serum and CSF, older age at seroconversion, duration of HIV infection, anemia, pre-existing neurocognitive dysfunction, coexisting hepatitis C, and female sex (Stern et al., 2001). In the pre-HAART era higher CSF to serum ratios of HIV RNA levels correlated with the severity of cognitive impairment (Cinque et al., 1998) but after the introduction of HAART the correlation was no longer seen. Whereas in the pre-HAART era, HAD was driven by HIV, in the post-HAART era the driver for HAND is not as clear. Comorbid conditions including syphilis, CMV infection, hepatitis, drugs, trauma, or psychiatric conditions and their treatment have been proposed to play a role. Another possible cause is the virus itself.

HIV replication in the CNS occurs independent of replication in plasma. CNS replication may generate resistance mutations even with suppression of viral replication in the serum. Measurement of HIV replication in CSF may be indicated when a new neurologic problem occurs. However, the finding of discordant replication is rare and does not explain the frequency with which HAND is encountered. Inflammation, as identified by elevated levels of inflammatory markers in the CSF or by visualization of active microglial cells (Garvey, 2012), despite control of viral replication has also been proposed. Other suggested and studied possible causes include aging and vascular disease. Mild neurocognitive disorder and depression are the most accurate predictors of severity of HAD (Stern et al., 2001). Progression of neurocognitive disorders is variable; patients may have mild dysfunction over a long period of time or rapid progression with severe impairment. Studies done by Letendre (2004, 2010) showed that poor CNS penetration of antiretroviral regimens is associated with ongoing viral replication. This lower penetration is associated with increased risk of HAD although it has yet to be proven that use of antiretroviral agents with better CNS penetration leads to decreased risk of HAD.

CLINICAL FEATURES Mild neurocognitive disorder is subtle and often not recognized without testing. HAD is a subcortical dementia characterized by decreased concentration, motor slowing, and behavioral changes. Some of the subtle early, as well as the overt late symptoms are listed in Table 90.13.

DIAGNOSIS Diagnosis of HIV neurocognitive disorder is based on history, physical examination, and neuropsychological tests to assess neurocognitive function. Common screening tests include the HIV dementia scale (Diesing et al., 2002); the International HIV dementia scale (naming

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Table 90.13 Symptoms of HIV-associated dementia Early symptoms Subtle

Late symptoms Marked

Memory loss, unsteady gait, limb weakness, tremor, apathy, depression, anhedonia Global dementia, bradyphrenia, bradykinesia, saccadic eye movements, hyperreflexia, dysdiadokinesis, frontal release signs

(Antinori et al., 2007)

four objects, fingertapping, “Laura” psychomotor learning task (learning a sequence of hand positions), and recall of names (Berger and Brew, 2005; Sacktor et al., 2005); and the Montreal cognitive assessment (MoCA©), which takes 5–10 minutes to perform in clinic (©Z. Nasreddine 2003-2012. www.mocatest.org). Neuroimaging, preferably with MRI, should be done to rule out other etiologies. Common MRI findings with HAD are cerebral atrophy with diffuse periventricular white matter abnormalities.

TREATMENT HAART is the mainstay of treatment for HAND as it reduces viral load both in peripheral circulation and

the CNS thereby preventing widespread CNS HIV infection. There is debate over which agents are the most effective. In the pre-HAART era zidovudine was the most effective antiretroviral for reducing impairments caused by HAD (Sidtis et al., 1993). Subsequently other drugs such as protease inhibitors have been shown to be good options as well. Recent work by Letendre has shown that antiretrovirals with better CNS penetration are associated with lower CSF viral loads. He also developed the central nervous system penetration effectiveness scores (CPE scores) for individual antiretroviral drugs (Table 90.14). Using a 1 to 4 scale, the drugs in column 4 have the highest penetration. Adding the scores of all the drugs in a multiple drug regimen, a score greater than 7 was associated with CSF viral loads less than 2 copies/mL. This scoring system has been criticized as being simplistic and not proven. It needs to be evaluated prospectively to be recommended (Letendre et al., 2010). Many patients with HAND have associated psychiatric disorders, most commonly depression. These disorders should be appropriately treated. In summary, cognitive function may be impaired in treated HIV patients. Optimizing management by avoiding low CD4 þ counts, maintaining undetectable HIV RNA levels, minimizing chronic immune activation, and optimizing cerebral perfusion are all important goals. Finally, a healthy lifestyle, along with HIV control, should enhance neurologic function. (Clifford, 2012).

Table 90.14 Antiretoviral agents and CNS penetration effectiveness scores

Drug class Nucleoside reverse transcriptase inhibitors Non-nucleoside reverse transcriptase inhibitors (NNRTI) Protease inhibitors

Entry/fusion inhibitors Integrase inhibitors

3 Intermediate penetration

2 Intermediate penetration

Zidovudine

Abacavir Emtricitabine

Nevirapine

Delavirdine Efavirenz

Didanosine Lamivudine Stavudine Etravirine

Indinavir/r

Darunavir/r Fosemprenavir/r Lopinavir/r Maraviroc Raltegravir

4 High penetration

(Reproduced with permission from IAS–USA; Letendre et al., 2010.) r denotes Ritonavir.

1 Low penetration Tenofovir Zalcitabine

Atazanavir Atazanavir/r Fosamprenavir Enfuvirtide

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HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis 5: 361–373. Leger J, Bouche P, Bolgert F et al. (1989). The spectrum of polyneuropathies in patients infected with HIV. J Neurol Neurosurg Psychiatry 52: 1369–1374. Letendre S, McCutchan J, Childers M et al. (2004). Enhancing antiretroviral therapy for human immunodeficiency virus cognitive disorders. Ann Neurol 56: 416–423. Letendre S, Ellis R, Ances B et al. (2010). Neurologic complications of HIV disease and their treatment. Top HIV Med 18: 45–55. Li W, Galey D, Mattson M et al. (2005). Molecular and cellular mechanisms of neuronal cell death in HIV dementia. AIDS 19: 1367. Luft B, Remington J (1992). Toxoplasmic encephalitis in AIDS. Clin Infect Dis 15: 211–222. Luft B, Hafner R, Korzun A et al. (1993). Toxoplasmic encephalitis in patients with the acquired immunodeficiency syndrome. Members of the ACTG 077p/ANRS 009 Study Team. N Engl J Med 329: 995–1000. MacMahon E, Glass J, Hayward S et al. (1991). Epstein–Barr virus in AIDS-related primary central nervous system lymphoma. Lancet 338: 969–973. MacNealy M, Newton H, McGregor J et al. (2008). Primary meningeal CNS lymphoma treated with intra-arterial chemotherapy. J Neurooncol 90: 329–333. Malamut R, Leopold N, Chester P et al. (1992). The treatment of HIV-associated chronic inflammatory demyelinating polyneuropathy (HIV-CIDP) with intravenous immunoglobulin (IVIG). Neurology 42: 335. Marra C, Maxwell C, Smith S et al. (2004). Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features. J Infect Dis 189: 369–376. Maschke M, Kastrup O, Esser S et al. (2000). Incidence and prevalence of neurological disorders with HIV. J Neurol Neurosurg Psychiatry 69: 376–380. Miro J, Murray H (2008). Toxoplasmosis. In: R Dolin, H Masur, M Saag (Eds.), AIDS Therapy. 3rd edn. Churchill Livingstone, Philadelphia, pp. 659–681. Mirza S, Phelan M, Rimland D (2003). The changing epidemiology of cryptococcosis: an update from population-based active surveillance in 2 large metropolitan areas, 1992– 2000. Clin Infect Dis 36: 789–794. Montoya J, Liesenfeld O (2004). Toxoplasmosis. Lancet 363: 1965–1976. Murakawa G, Kerschmann R, Berger T (1996). Cutaneous Cryptococcus infection and AIDS. Report of 12 cases and review of the literature. Arch Dermatol 132: 545–548. Nelson D, Martz K, Bonner H et al. (1992). Non-Hodgkin’s lymphoma of the brain: can high dose, large volume radiation therapy improve survival survival? Report on a prospective trial by the Radiation Therapy Oncology Group (RTOG): RTOG 8315. Int J Radiat Oncol Biol Phys 23: 9–17. Nogui F, Mattas S, Junior G et al. (2009). Neurotoxoplasmosis diagnosis for HIV-1 patients by real-time PCR of cerebrospinal fluid. Braz J Infect Dis 13: 18.

NEUROLOGIC DISEASES IN HIV-INFECTED PATIENTS Offenbacher H, Fazekas F, Schmidt R et al. (1991). MRI in tuberculous meningoencephalitis: report of four cases and review of the neuroimaging literature. J Neurol 238: 340. Pai M, Flores L, Pai N et al. (2003). Diagnostic accuracy of nucleic acid amplification tests for tuberculous meningitis: a systematic review and meta-analysis. Lancet Infect Dis 3: 633–643. Palella F, Kathleen M, Moorman A et al. (1998). Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med 338: 853–860. Park B, Wannemuehler K, Marston B et al. (2009). Estimation of the current global burden of cryptococcal meningitis among persons living with HIV/AIDS. AIDS 23: 525–530. Perfect J, Dismukes W, Dromer F et al. (2010). Clinical practice guidelines for the management of cryptococcal disease: 2010 update by the infectious diseases society of America. Clin Infect Dis 50: 291–322. Petito C, Navia B, Cho E et al. (1985). Vacuolar myelopathy pathologically resembling subacute combined degeneration in patients with the acquired immunodeficiency syndrome. N Engl J Med 312: 874–879. Petratos S, Turnbull V, Papadopoulos R et al. (1998). Antibodies against peripheral myelin glycolipids in people with HIV infection. Immunol Cell Biol 76: 535–541. Piette A, Tusseau F, Vignon D et al. (1986). Acute neuropathy coincident with seroconversion for anti-LAV/HTLV-III. Lancet 1: 852. Piliero P, Estanislao L, Simpson D (2004). Diaphragmatic paralysis due to isolated phrenic neuropathy in an HIVinfected man. Neurology 62: 154–155. Porter S, Sande M (1992). Toxoplasmosis of the central nervous system in the acquired immunodeficiency syndrome. N Engl J Med 327: 1643–1648. Rock R, Gekker G, Hu S et al. (2004). Role of microglia in central nervous system infections. Clin Microbiol Rev 17: 942–964. Rock R, Olin M, Baker C et al. (2008). Central nervous system tuberculosis: pathogenesis and clinical aspects. Clin Microbiol Rev 21: 243–261. Rolfs R, Joesoef R, Hendershot E et al. (1997). A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. N Engl J Med 337: 307–314. Sacktor N (2002). The epidemiology of human immunodeficiency virus-associated neurological disease in the era of highly active antiretroviral therapy. J Neurovirol 8 (Suppl 2): 115–121. Sacktor N, Wong M, Nakasujja N et al. (2005). The international HIV dementia scale: a new rapid screening test for HIV dementia. AIDS 19: 1367–1374. Shelburne S, Darcourt J, White C et al. (2005). The role of immune reconstitution inflammatory syndrome in AIDS

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Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 91

Measles, mumps, rubella, and human parvovirus B19 infections and neurologic disease JAMES F. BALE, JR.* Departments of Pediatrics and Neurology, University of Utah School of Medicine, Salt Lake City, UT, USA

MEASLES AND MUMPS VIRUSES The myxoviruses, a name derived from the Greek mxyo, denoting mucus, consist of two families, Orthomyxoviridae, the influenza viruses, and Paramyxoviridae, a group of viruses that includes mumps, measles, parainfluenza, and respiratory syncytial viruses. Influenza viruses, as illustrated recently by outbreaks of the H1N1 strain, have considerable potential to induce neurologic disease in both children and adults (Ekstrand et al., 2010). The mumps and measles paramyxoviruses, although less frequently encountered currently because of compulsory immunization programs, remain potential causes of neurologic disease among human populations in many regions (Koskiniemi et al., 1991; WHO, 2007).

Epidemiology MEASLES Measles (also known as rubeola), a highly contagious human disease, spreads via respiratory secretions, especially during the catarrhal (exudative) phase of infection. Infected persons are most contagious during the interval 4 days before and 4 days after the onset of the rash. Before a vaccine was available, measles affected virtually all young children. Prior to the 1970s, millions of children in the US and other countries had measles annually, leading to hospitalization, neurologic complications, and occasionally, death. Vaccine programs have effectively reduced the rates of measles worldwide, and by 2010 approximately 85% of the world’s children had received at least one dose of measles vaccine by their first birthday (WHO, 2012a). Nonetheless, measles remains a

major public health concern in many regions, especially in parts of Africa and Asia; nearly 140 000 persons, mostly young children, died from measles and measles-related complications in 2010 (WHO, 2012a). In immunized populations, measles can affect adolescents or young adults, and outbreaks of measles have been reported in high schools or on college campuses (CDC, 1987). Subacute sclerosing panencephalitis (SSPE), a measles virus-induced “slow viral” disease, typically affects children at a median of 7–9 years of age, although onset in adulthood has been reported (Singer et al., 1977). Approximately one-half of the patients with SSPE experience wild measles virus infections before the age of 2 years (Jabbour et al., 1972), and for unknown reasons, cases in males exceed those in females by approximately 2.5:1. Most SSPE cases currently affect children living in Asia; fewer than 80 cases were reported in the US between 1989 and 2004, reflecting the impressive success of widespread vaccination of young children (Honarmand et al., 2004).

MUMPS Cases of mumps can occur throughout the year, peaking in the late winter and spring. Infected persons, usually children between the ages of 5 and 9 years, shed the mumps virus in the saliva and upper respiratory secretions and spread infection via respiratory droplets or fomites. In the prevaccine era the incidence of mumps was as high as 2000 cases per 100 000 population/year, corresponding to 200 000 or more cases annually in the US. The mumps virus accounted for as many as 30% of the cases of aseptic meningitis and encephalitis

*Correspondence to: James F. Bale, Jr., M.D., Pediatric Residency Office, Third Floor, Primary Children’s Medical Center, 100 N. Mario Capecchi Drive, Salt Lake City, Utah 84113, USA. Tel: þ1-801-662-5700, Fax: þ1-801-662-5755, E-mail: [email protected]

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in the US and other regions prior to the introduction of an effective mumps vaccine in the late 1960s (Koskiniemi et al., 1983). Despite the near-elimination or disappearance of mumps from the US and other countries with mumps immunization programs, the disorder retains worldwide public health importance, especially in Africa and certain areas of Asia. As of July 2012, 120 countries (62% of the world’s countries) had incorporated mumps vaccine into the national immunization schedules (WHO, 2012b).

Clinical manifestations MEASLES Approximately 10–14 days after exposure to the measles virus, infected persons have fever, conjunctivitis, cough, coryza, and the measles virus enanthem, Koplik spots, small, gray-white lesions that appear on the buccal mucosa adjacent to the lower molars. Fever, usually the first sign of measles, can last 4–7 days. The measles exanthem, an erythematous maculopapular rash, appears first on the face, spreads to the trunk and extremities, and gradually fades or desquamates over the subsequent 5–7 days. The neurologic complications of measles consist principally of three distinct disorders: (1) acute encephalomyelitis, (2) subacute measles encephalitis, and (3) subacute sclerosing panencephalitis (SSPE). Encephalomyelitis (also called measles virus-induced acute disseminated encephalomyelitis) complicates approximately 1 per 1000 cases of measles and usually begins 2–5 days after the rash appears (Johnson, 1998). The clinical features of measles encephalomyelitis consist of headache, irritability, seizures, and altered consciousness (Johnson et al., 1984); some children have ataxia, choreoathetosis, paralysis, or incontinence. While most patients with measles encephalomyelitis improve after 3–4 days, occasional children have severe illnesses with cerebral edema, intractable seizures, and occasionally, death (Johnson et al., 1984). Subacute measles encephalitis typically appears in measles-virus infected children or adults with disorders of cell-mediated immunity; rarely, the disorder can occur in otherwise healthy, immunocompetent individuals. Subacute measles encephalitis begins with focal seizures or encephalopathy and can progress relatively rapidly to a fatal coma (Mustafa et al., 1993; Croxson et al., 2002). Because of the temporal profile, beginning 1–7 months after exposure to the measles virus, this disorder can be differentiated from measles encephalomyelitis, a disorder that affects children during the acute stage of measles, and SSPE, a disorder that can occur in children or young adults several years after measles (Murphy and Yunis, 1976; Aicardi et al., 1977; Mustafa et al., 1993).

Table 91.1 Representative stages of subacute sclerosing panencephalitis Stage

Clinical features

IA

Cognitive and personality changes. Normal ambulation Cognitive and personality changes persist. Myoclonus begins, usually focally Continued dementia. Myoclonus generalizes. Ambulation difficult due to myoclonus Language difficulties; apraxias, ataxia, and spasticity appear. Needs assistance to walk Less verbal; vision deteriorates. Sits, but cannot walk independently. Myoclonus intensifies No spontaneous speech. Vision loss. Myoclonus persists. Bulbar dysfunction requires nasogastric or nasojejunal feedings Myoclonus ceases. Vegetative state

IB IIA IIB IIIA IIIB

IV

(Adapted from Aydin et al., 2003.)

Subacute sclerosing panencephalitis (SSPE) displays relatively distinct clinical stages (Aydin et al., 2003) (Table 91.1). The disorder typically begins insidiously with behavioral changes or intellectual decline, features that may mimic neurobehavioral disorders, or with visual symptoms or signs (Eroglu et al., 2008). Approximately 50% of patients with SSPE have chorioretinitis, optic atrophy, cortical blindness, nystagmus, or visual field deficits (La Piana et al., 1974; Gabay and Mayers, 1997). Myoclonus appears next, involves the extremities, head or trunk, and can be provoked by excitement, movement, or sensory stimuli. Generalized tonic-clonic or absence seizures may occur at this time, as well. As SSPE worsens, myoclonus intensifies, speech, coordination, and intellect deteriorate, and extrapyramidal features such as choreoathetosis, bradykinesia, or rigidity appear. Patients with SSPE ultimately experience profound dementia, paralysis, autonomic instability, and death. Occasional patients have atypical features, consisting of ataxia, focal signs, or rapid deterioration with intractable seizures, focal deficits, and cerebral edema (Demir et al., 2007). Although the exact pathogenesis of SSPE has not been established, defective viruses and altered host responses play important roles (Bale and Fujinami, 2008; Buchanan and Bonthius, 2012).

MUMPS Patients with mumps have low grade fever, anorexia, malaise, and headache beginning approximately 14 days after exposure to the virus. Parotitis appears soon thereafter in most cases, causing parotid gland enlargement,

MEASLES, MUMPS, RUBELLA, AND HUMAN PARVOVIRUS B19 INFECTIONS earache and facial tenderness; fever can be as high as 40 C. Other potential manifestations of mumps include orchitis (Ternavasio-de la Vega et al., 2010), epididymitis, prostatitis, hepatitis, pancreatitis, thyroiditis, deafness, aseptic meningitis, or mild encephalitis (Hviid et al., 2008); a substantial number of mumps infections lack recognizable symptoms or signs. Mumps-induced aseptic meningitis or encephalitis begins 3–14 days after the onset of parotitis, often after fever and parotitis have subsided (Koskiniemi et al., 1983). However, central nervous system (CNS) signs can be present concurrently with parotitis, and as many as 50% of patients with mumps meningitis lack a clear history of parotid gland involvement. Neurologic symptoms consist of headache, vomiting, back pain, stiff neck, or somnolence (Koskiniemi et al., 1983). Severe cases can be accompanied by coma, seizures, focal deficits (e.g., hemiparesis, aphasia, brainstem involvement), or poliomyelitis-like features.

Diagnosis MEASLES Laboratory studies in patients with acute measles encephalomyelitis may show peripheral leukopenia, and cerebrospinal fluid (CSF) studies can be normal or mimic those of other viral CNS infections with a mixed or lymphocytic pleocytosis and mild protein elevation. The diagnosis of measles encephalomyelitis can be made by detecting measles-specific IgM in serum or CSF or by detecting significant elevations of measles-specific IgG in paired acute and convalescent sera. Measles virus RNA can be detected in blood and saliva by reverse transcriptase (RT)-polymerase chain reaction (PCR) assay. Although measles virus can be isolated occasionally from brain tissue, immunologically mediated factors, rather than lytic infection of neural cells, cause measles encephalomyelitis (Gendelman et al., 1984). Magnetic resonance imaging (MRI) in measles encephalomyelitis can be normal or show white matter or cortical lesions consistent with acute disseminated encephalomyelitis. Subacute measles encephalitis can be diagnosed by detecting measles virus-specific IgG in CSF, paramyxovirus particles or measles virus antigens in brain tissue, or measles virus RNA in CSF or brain tissues by RT-PCR (Mustafa et al., 1993). Head computed tomography (CT) is normal, whereas brain MRI may be normal or show patchy hyperintense lesions in gray matter (Mustafa et al., 1993). Subacute sclerosing panencephalitis is best established by detecting high titers of measles virus-specific IgG in CSF. The CSF immunoglobulin levels are elevated, reflecting increased intrathecal synthesis of measles virus-specific immunoglobulin, and oligoclonal IgG bands are typically present (Akram et al., 2008). The CSF

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otherwise contains few cells and has a normal protein and glucose content. Serum measles virus antibody titers are also frequently elevated, and RT-PCR can be used to detect measles-virus RNA in neural tissues (Bale and Fujinami, 2008). The electroencephalogram (EEG), often the initial clue to the diagnosis of SSPE, shows bilaterally synchronous, high amplitude spike or slow wave bursts that may correlate with clinical myoclonus. As SSPE progresses, the background activity of the EEG deteriorates to a burst-suppression pattern. Neuroimaging studies in SSPE show nonspecific abnormalities or diffuse atrophy, and signal abnormalities can be detected symmetrically in the cerebral white matter (Figs 91.1 and 91.2) or multifocally in subcortical white matter or cortex by MRI using T2, FLAIR and diffusion-weighted sequences (Lum et al., 1986; Brismar et al., 1996; Bale and Fujinami, 2008). MR spectroscopy can demonstrate reductions in the N-acetylaspartate (NAA) peak and alterations of the choline and myoinositol peaks (Fig. 91.3). Early lesions of SSPE can be identified using F-18 fluorodeoxyglucose positron emission tomography (FDG PET) (Yilmaz et al., 2010), and diffusion tensor imaging can be used to define the extent of white matter tract disease in SSPE (Trivedi et al., 2006).

Fig. 91.1. Axial T2-weighted MRI shows nearly symmetric areas of signal hyperintensity in the cerebral white matter in a teenager with early subacute sclerosing panencephalitis.

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J.F. BALE, JR. titers in acute and convalescent sera; or (4) mumps virus RNA in CSF or buccal swabs by using RT-PCR (Hatchette et al., 2009). The CSF features of mumps meningitis and encephalitis consist of a normal protein content, normal or mildly depressed glucose content, and modest lymphocytic pleocytosis, usually between 50 and 300 WBC/mm3. Ependymal cells can sometimes be detected in the CSF. MRI can detect signal hyperintensities in brain or spinal cord compatible with acute disseminated encephalomyelitis (Sonmez et al., 2004).

Treatment, prognosis, and prevention MEASLES

Fig. 91.2. Coronal FLAIR MRI shows signal hyperintensity of cerebral white matter in a teenager with subacute sclerosing panencephalitis.

Fig. 91.3. Short TE magnetic resonance spectroscopy in the same teenager as in Figures 91.1 and 91.2 shows elevations of the myoinositol (MyoI) and choline (Cho) peaks, a reduction in the N-acetylaspartate (NAA) peak, and a lactate doublet (lactate). The creatine (Cr) peak is normal. The boxel was placed over the occipital white matter. These features indicate neuronal injury and degradation of white matter.

MUMPS Mumps virus infections are diagnosed by detecting (1) mumps virus in saliva, throat washings, or CSF; (2) mumps virus-specific IgM in serum specimens; (3) fourfold or greater elevations in mumps virus-specific IgG

Treatment of measles encephalomyelitis consists of supportive care and management of seizures or cerebral edema, potential complications in severe cases. Among populations with vitamin A deficiency two doses of vitamin A given 24 hours apart, using 50 000–100 000 IU orally for children < 12 months of age and 200 000 IU orally for older children (American Academy of Pediatrics, 1993; World Health Organization, 2013), are recommended for measles virus-infected children. Overall mortality for measles encephalomyelitis averages 10–15%. Developmental delay, seizures, motor dysfunction, and behavioral disturbances occur in as many as 50% of the children who survive severe measles encephalomyelitis (Johnson, 1998). Most individuals with subacute measles encephalopathy die (Mustafa et al., 1993; Croxson et al., 2002), although patients have improved during intravenous therapy with ribavirin. Subacute sclerosing panencephalitis displays considerable variability in its clinical course. Approximately 80% of patients with SSPE deteriorate relentlessly and die within 2 years of disease onset (Gascon, 1996); 10% have a fulminant course, with death within a few months; and 10% display a chronic course with exacerbations and spontaneous remissions lasting several years. Beginning with observations in the 1970s (Huttenlocher and Mattson, 1979), several studies suggest that patients with SSPE may benefit from therapy with isoprinosine (Inosiplex; Newport Synthesis, Ltd., Dublin, Ireland). Composed of inosine and the p-acetamidobenzoic acid salt of N, N-dimethylamido-2-propanol, isoprinosine has modest antiviral and immunomodulating effects (Ginsberg and Glasky, 1977) which contribute to the drug’s potential benefit in SSPE. In a large multicenter trial without a concurrent, placebo control group (Gascon, 2003) 35% of isoprinosine-treated subjects stabilized or improved, a rate substantially higher than the historical remission rates of 5–10%. Patients with probable or proven SSPE can be treated with isoprinosine 100 mg/kg/day (maximum of 3 grams/ day) in three equally divided doses. Potential side-effects

MEASLES, MUMPS, RUBELLA, AND HUMAN PARVOVIRUS B19 INFECTIONS include hyperuricemia and nephrolithiasis (Gascon, 2003). Ribavirin has been utilized as an adjunct to isoprinosine, although the added benefit of ribavirin in SSPE seems modest. Interferon (including intraventricular therapy with interferon-a2b), corticosteroids, intravenous immunoglobulin, amantadine do not modify the course of SSPE (Gascon, 2003; Tatli et al., 2012). Despite current therapies, the vast majority of persons with SSPE die within 5 years of disease onset (Gutierrez et al., 2010). Measles can be prevented by vaccination using the combined measles-mumps-rubella (MMR) vaccine, and the current two-dose strategy provides > 98% protection against measles virus infection (American Academy of Pediatrics, 2008; Sudfeld et al., 2010). In the US the first vaccination is recommended between 12 and 15 months of age, and the second is recommended prior to school entry, typically at the ages of 4–5 years. Occasional vaccinated children experience febrile seizures approximately 10–14 days after immunization (Barlow et al., 2001). Although considerable controversy has existed in the lay press regarding the safety of immunizations, current scientific evidence indicates that the MMR vaccine does not cause serious or permanent neurologic disorders (Institute of Medicine, 2004).

MUMPS Therapy of mumps consists of supportive care. Patients with CNS complications usually recover within 5–10 days, and residual deficits are uncommon. The most common late complication of mumps, with a prevalence of approximately 1 per 2000 cases of mumps, is permanent sensorineural hearing loss (Kanra et al., 2002). Although mumps-induced deafness is usually unilateral (Hashimoto et al., 2009), bilateral profound deafness requiring cochlear implantation has been reported (Wang et al., 2003). Optic atrophy, facial paralysis, hemiplegia, or behavioral disturbances have been reported following mumps encephalitis, and rarely, hydrocephalus develops as a consequence of mumps virus-induced ependymitis and aqueductal obstruction (Bray, 1972). Mumps can be prevented by the MMR immunization, although a recent resurgence of mumps cases among immunized adolescents and young adults in several areas, including Canada, the US, and the UK, has prompted a re-evaluation of immunization strategies to prevent mumps virus infections (Peltola et al., 2007; Dayan et al., 2008). In the US, the initial mumps vaccine dose is given between 12 and 15 months of age, and a second dose is given between the ages of 4 and 6 years (American Academy of Pediatrics, 2009a).

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RUBELLA Rubella virus, a non-arthropod-borne member of the RNA togavirus family, causes German measles, a mild exanthematous disorder of childhood. The relationship between rubella virus and severe human disease was first recognized in 1941 by the Australian ophthalmologist Sir Norman Gregg, who observed a high rate of congenital cataracts among women who had experienced German measles during their pregnancies (Gregg, 1941). Subsequent observations expanded considerably the clinical spectrum of the congenital rubella syndrome (CRS).

Epidemiology Rubella virus spreads by contact with infected upper respiratory tract secretions and typically infects school-age children in unimmunized populations and adolescents or adults in immunized populations. Before a vaccine became available, epidemics of German measles commonly took place in the winter and spring at 6–9 year intervals. During the last US pandemic in the 1960s, more than 13 million cases of rubella were reported (Herman, 1991). The incidence of rubella in the US declined dramatically during the 1970s after the introduction of the rubella vaccine, and immunization has nearly eliminated rubella and CRS in many other areas of the world. By 2009 approximately two-thirds of the world’s countries had incorporated the MMR into their national vaccine programs (WHO, 2012c). Since licensure of the rubella vaccine in 1969, the incidence of CRS in the US has declined from 1.72 cases per 100 000 live births to less than 0.1 per 100 000 (Herman, 1991; Centers for Disease Control, 2010a). The incidence of rubella and CRS reached historic lows in the late 1990s, indicating that CRS is nearing elimination in the Americas and many other regions (Centers for Disease Control, 2010a). Because endemic foci of rubella virus infections persist in various regions of the world, however, CRS remains a potential threat to pregnant women and unborn children among unimmunized populations. In rare instances, women with anticipated immunity who acquired rubella during their pregnancies have given birth to infants with CRS (Robinson et al., 1994).

Clinical manifestations ACQUIRED RUBELLA INFECTION The incubation period of rubella, a mild, systemic illness, averages 14–21 days. Lymphadenopathy, often the initial clinical clue to rubella, involves the posterior auricular, posterior cervical and suboccipital nodes. The erythematous, maculopapular rash of rubella, less intense and less likely to desquamate than the measles virus rash,

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begins on the face, spreads to the trunk, and disappears over 3–5 days. Low grade fever (rarely above 38.3 C), coryza, and conjunctivitis are variable. Neurologic complications of rubella include encephalitis, aseptic meningitis, myelitis, or Guillain–Barre´ syndrome (GBS) (Figueiredo et al., 2008). These complications, usually appearing within 6 days of the rash, consist of headache, vomiting, somnolence and seizures in cases of encephalitis or symmetric weakness with hyporeflexia, in the rare cases of GBS (Connolly et al., 1975). Overall, less than 0.1% of rubella cases are associated with neurologic complications.

CONGENITAL RUBELLA SYNDROME As many as 1% of the infants born to women pregnant during pandemics of rubella had CRS. The risk to the fetus correlates directly with the timing of maternal infection; infections prior to the 16th week produce fetal loss, cataracts, and/or heart disease, whereas infections after the 17th week are asymptomatic (Dudgeon, 1975; Ueda et al., 1979). The hallmark clinical features of CRS are cataracts, sensorineural hearing loss, and congenital heart disease, consisting of patent ductus arteriosus or septal defects. Although these features are the hallmarks, rubella virus can infect many tissues, causing intrauterine growth retardation, microphthalmia, chorioretinitis, hepatosplenomegaly, hepatitis, “blueberry muffin” rash, interstitial pneumonitis, osteopathy, or thrombocytopenia. Approximately 25% of infants with CRS have CNS involvement at birth, with lethargy, hypotonia, irritability, or seizures (Desmond et al., 1967).

Diagnosis Routine laboratory abnormalities associated with rubella include leukopenia, atypical lymphocytosis, or thrombocytopenia. The CSF abnormalities in aseptic meningitis consist of a lymphocytic pleocytosis and an elevated protein concentration. The virologic diagnosis of rubella infection can be supported by detecting rubella-specific IgM and confirmed by detecting rubella virus in throat washings or rubella virus RNA in CSF, urine, or saliva by using RT-PCR (Tipples and Hiebert, 2011). Genotyping of the rubella virus can provide useful epidemiological information. The CSF in CRS shows an increased protein concentration as well as a lymphocytic pleocytosis. Neuroimaging studies (ultrasonography, CT, or MRI) of children with CRS frequently reveal atrophy, calcifications, cystic lesions, or leukomalacia (Yamashita et al., 1991). CRS can be supported by detecting rubella-specific IgM in serum or CSF and confirmed by detecting rubella virus RNA in clinical samples or isolating rubella virus from urine, CSF, or throat washings. Infants with CRS

commonly shed the virus in urine or saliva for several months. Prenatal diagnosis of CRS is possible by detecting rubella virus in amniotic fluid or rubella-specific IgM in fetal blood.

Treatment, prognosis, and prevention The treatment of rubella virus infections, whether acquired or congenital, consists of supportive care; effective antiviral therapy is not currently available. Persons with acquired rubella virus infections and neurologic complications recover completely. By contrast, infants with CRS, especially those infected during the first trimester, often have microcephaly, developmental delay, epilepsy, growth impairment, behavioral abnormalities, or permanent deafness. Sensorineural hearing loss, the most frequent complication of CRS, affects 50–60% of infected infants and can be bilateral, profound, and occasionally, progressive (Wild et al., 1989). Children with CRS are at risk for late sequelae, including diabetes mellitus, thyroid dysfunction, and progressive postrubella panencephalitis, a rare neurodegenerative disorder that shares some clinical and EEG features with SSPE (Townsend et al., 1975). Both acquired rubella virus infections and the CRS can be prevented by administering the MMR vaccine.

HUMAN PARVOVIRUS B19 Human parvovirus B19, a small single-stranded DNA virus closely related to several animal parvoviruses, causes erythema infectiosum and erythroblastopenia in infected humans (Servant-Delmas et al., 2010). The virus, identified in the 1970s and linked to erythema infectiosum in the 1980s (Anderson et al., 1983), infects humans only and replicates in human erythroid progenitors; consequently the virus is also known as human B19 erythrovirus.

Epidemiology Parvovirus B19 can infect humans at any age, although the incidence of infection is highest between the ages of 5 and 15 years. By adolescence approximately 50% of the population is seropositive for parvovirus B19, indicating prior infection, and the majority of adults possess antibodies against the virus (American Academy of Pediatrics, 2009b). Approximately 1–2% of women become infected with parvovirus B19 during their pregnancies, and vertical transmission to the fetus occurs in approximately one-third of these infections (Al-Khan et al., 2003). Infection can be acquired through contact with respiratory secretions, blood, or blood products; the incubation period ranges from 4 to 21 days (American Academy of Pediatrics, 2009b).

MEASLES, MUMPS, RUBELLA, AND HUMAN PARVOVIRUS B19 INFECTIONS

Clinical manifestations The most common human disorder associated with parvovirus B19 is erythema infectiosum, a mild systemic illness associated with malaise, low grade fever and an erythematous rash that commonly affects the cheeks, hence the term “slapped cheek” rash (CDC, 2010b). The disorder is also called fifth disease, because erythema infectiosum was the fifth recognized childhood exanthematous disorder, after measles, scarlet fever, rubella and Dukes disease (an obscure condition most likely due to enteroviral infections). The facial rash of parvovirus B19 infections occurs more often in children, whereas adults are more likely to experience arthralgias or arthritis affecting the wrists, hands, knees, and ankles. Parvovirus B19-associated arthropathy lasts 1–3 weeks. Human parvovirus B19 can also cause a petechial/ purpuric rash of the hands and feet known as the “gloves and socks” syndrome (American Academy of Pediatrics, 2009b; Parez et al., 2009). Because the virus infects and destroys erythrocyte precursors, persons with immunocompromising conditions such as HIV/AIDS, who cannot clear viral infections, can have chronic anemia during infections with human parvovirus B19 (Morellis et al., 2007). Similarly, those with genetic conditions that predispose to anemia, such as sickle cell disease or thalassemia, are at risk of parvovirus-induced exacerbations of anemia due to aplastic crises (Slavov et al., 2011). Fetal death or intrauterine anemia causing hydrops fetalis can complicate infections of pregnant women (Al-Khan et al., 2003). Neurologic disorders potentially associated with parvovirus B19 infections include encephalitis, aseptic meningitis, stroke, and peripheral neuropathy (Douvoyiannis et al., 2009). These complications can affect previously healthy children or adults as well as children with underlying systemic or neurologic conditions. The clinical manifestations associated with encephalitis or aseptic meningitis include headache, vomiting, lethargy, irritability, poor oral intake, ataxia, seizures, or focal signs (Kerr et al., 2002). Stroke has been associated with parvovirus B19 infections in previously healthy children or adults and in children with sickle cell disease (Wierenga et al., 2001; Douvoyiannis et al., 2009).

Diagnosis The diagnosis of human parvovirus B19 infection can be established serologically by detecting human parvovirus B19-specific IgM in a patient’s serum or by detecting parvovirus B19 DNA in human serum, especially in immunocompromised hosts. The CSF findings in patients with encephalitis or aseptic meningitis can include a mild CSF lymphocytic or monocytic

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pleocytosis, and CNS infection can be confirmed by detecting human parvovirus DNA in CSF by using PCR (Kerr et al., 2002). The CSF in human parvovirus B19-induced Guillain–Barre´ syndrome can show an elevated protein in the absence of a cellular response (the albuminocytologic dissociation) (Yamaoka et al., 2000).

Treatment, prognosis, and prevention Treatment consists of supportive care and management of seizures, dehydration, respiratory failure, or anemia. Blood transfusions can be given to manage hydrops fetalis (Al-Khan et al., 2003) as well as to treat aplastic crises in children or adults. Although most children and adults with human parvovirus B19 infections, including those associated with neurologic complications, recover completely, deaths have been described, especially among children with underlying systemic or neurologic conditions (Kerr et al., 2002). At the present time, human infections with parvovirus B19 cannot be prevented by vaccination; hand washing and other hygienic measures may potentially reduce the risk of infection among vulnerable populations, such as pregnant women or persons with immunodeficiencies or hereditary conditions predisposing to anemia.

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Aydin OF, Senbil N, Kuyucu N et al. (2003). Combined treatment with subcutaneous interferon-alpha, oral isoprinosine, and lamivudine for subacute sclerosing panencephalitis. J Child Neurol 18: 104–108. Bale JF, Fujinami R (2008). Subacute sclerosing pancephalitis. In: CR Reiss (Ed.), Neurotropic Virus Infections. Cambridge University Press, Cambridge, pp. 26–34. Barlow WE, Davis RL, Glasser JW et al. (2001). The risk of seizures after receipt of whole-cell pertussis or measles, mumps, and rubella vaccine. N Engl J Med 345: 656–661. Bray PF (1972). Mumps: a cause of hydrocephalus? Pediatrics 49: 446–449. Brismar J, Gascon GG, von Steyern KV et al. (1996). Subacute sclerosing panencephalitis: evaluation with CT and MR. AJNR Am J Neuroradiol 17: 761–772. Buchanan R, Bonthius DJ (2012). Measles virus and associated central nervous system sequelae. Semin Pediatr Neurol 19: 107–114. Centers for Disease Control (1987). Measles prevention. MMWR 36: 423–425. Centers for Disease Control (2010a). Progress Toward Control of Rubella and Prevention of Congenital Rubella Syndrome – Worldwide, 2009. Accessed 12/24/2010, http://www.cdc. gov/mmwr/preview/mmwrhtml/mm5940a4.htm#tab. Centers for Disease Control (2010b). Parvovirus B19 (Fifth Disease). Accessed 122/24/2010, http://www.cdc. gov/ncidod/dvrd/revb/respiratory/parvo_b19.htm. Connolly JH, Hutchinson WM, Allen IV et al. (1975). Carotid artery thrombosis, encephalitis, myelitis, and optic neuritis associated with rubella virus infections. Brain 95: 583–594. Croxson MC, Anderson NE, Vaughan AA et al. (2002). Subacute measles encephalitis in an immunocompetent adult. J Clin Neurosci 9: 600–604. Dayan GH, Guinlisk MP, Parker AA et al. (2008). Recent resurgence of mumps in the United States. N Engl J Med 358: 1580–1589. Demir E, Aksoy A, Anlar B et al. (2007). Atypical presentations of SSPE: a clinic study in four cases. Turk J Pediatr 49: 295–300. Desmond MM, Wilson GS, Melnick JL et al. (1967). Congenital rubella encephalitis: course and early sequelae. J Pediatr 71: 311–331. Douvoyiannis M, Litman N, Goldman DL (2009). Neurological manifestations associated with parvovirus B19 infections. Clin Infect Dis 48: 1713–1723. Dudgeon JA (1975). Congenital rubella. J Pediatr 87: 1078–1086. Ekstrand JJ, Herbener A, Rawlings J et al. (2010). Heightened neurological complications in children with pandemic H1N1 infections. Ann Neurol 68: 762–768. Eroglu E, Gokcil Z, Bek S et al. (2008). Long-term follow-up of patients with adult-onset subacute sclerosing pancephalitis. J Neurol Sci 275: 113–116. Figueiredo CA, Klautau GB, Afonso AM et al. (2008). Isolation and genotype analysis of rubella virus from a case of Guillain–Barre´ syndrome. J Clin Virol 43: 343–345.

Gabay JE, Mayers M (1997). Ocular manifestations of systemic infections. Curr Opin Ophthalmol 8: 74–80. Gascon GG (1996). Subacute sclerosing panencephalitis. Semin Pediatr Neurol 3: 260–269. Gascon GG, the International Consortium on Subacute Sclerosing Panencephalitis (2003). Randomized treatment study of inosiplex versus combined inosiplex and intraventricular interferon-alpha in subacute sclerosing panencephalitis (SSPE): international multicenter study. J Child Neurol 18: 819–827. Gendelman HE, Wolinsky JS, Johnson RT et al. (1984). Measles encephalomyelitis: lack of evidence of viral invasion of the central nervous system and quantitative study of the nature of demyelination. Ann Neurol 15: 353–360. Ginsberg T, Glasky AJ (1977). Inosiplex: an immunomodulation model for the treatment of viral disease. Ann N Y Acad Sci 284: 128–138. Gregg NM (1941). Congenital cataract following German measles in the mother. Trans Ophthalmol Soc Aust 3: 34–45. Gutierrez J, Issacson RS, Koppel BS (2010). Subacute sclerosing panencephalitis: an update. Dev Med Child Neurol 52: 901–907. Hashimoto H, Fujioka M, Kinumaki H (2009). An office-based prospective study of mumps deafness. Pediatr Infect Dis J 28: 173–175. Hatchette T, Davidson R, Clay S et al. (2009). Laboratory diagnosis of mumps in a partially immunized population: the Nova Scotia experience. Can J Infect Dis Med Microbiol 20: e157–e162. Herman KL (1991). Rubella in the United States: toward a strategy for disease control and prevention. Epidemiol Infect 107: 55–61. Honarmand S, Glaser CA, Chow E et al. (2004). Subacute sclerosing panencephalitis in the differential diagnosis of encephalitis. Neurology 63: 1489–1493. Huttenlocher PR, Mattson RH (1979). Isoprinosine in subacute sclerosing panencephalitis. Neurology 29: 764–771. Hviid A, Rubin S, M€ uhlemann K (2008). Mumps. Lancet 371: 932–944. Institute of Medicine (2004). Immunization safety review: vaccines and autism. National Academy of Sciences, Washington DC. Jabbour JT, Duenas DA, Sever JL et al. (1972). Epidemiology of subacute sclerosing panencephalitis (SSPE): a report of the SSPE Registry. JAMA 220: 959–962. Johnson RT (1998). Viral Infections of the Nervous System. 2nd edn Lippincott-Raven, New York. Johnson RT, Griffin DE, Hirsch RL et al. (1984). Measles encephalomyelitis: clinical and immunologic studies. N Engl J Med 310: 137–141. Kanra G, Kara A, Cengiz AB et al. (2002). Mumps meningoencephalitis effect on hearing. Pediatr Infect Dis J 21: 1167–1169. Kerr JR, Barah F, Chiswick ML et al. (2002). Evidence for the role of demyelination, HLA-DR alleles, and cytokines in the pathogenesis of parvovirus B19 meningoencephalitis and its sequelae. J Neurol Neurosurg Psychiatry 73: 739–746.

MEASLES, MUMPS, RUBELLA, AND HUMAN PARVOVIRUS B19 INFECTIONS Koskiniemi M, Donner M, Petta O (1983). Clinical appearance and outcome in mumps encephalitis in children. Acta Paediatr Scand 72: 603–609. Koskiniemi M, Rautonen J, Lehtokoski- Lehtinieme E et al. (1991). Epidemiology of encephalitis in children: a 20 year survey. Ann Neurol 29: 492–497. La Piana FG, Tso MO, Jenis EH (1974). The retinal lesions of subacute sclerosing panencephalitis. Ann Ophthalmol 6: 603–610. Lum GB, Williams JP, Dyken PR et al. (1986). Magnetic resonance and CT imaging correlated with clinical status in SSPE. Pediatr Neurol 2: 75–79. Morellis P, Besstetti G, Longhi E et al. (2007). Persistent parvovirus B9-induced anemia in an HIV-infected patient under HAART. Case report and review of the literature. Eur J Clin Microbiol Infect Dis 26: 833–837. Murphy JV, Yunis EJ (1976). Encephalopathy following measles infection in children with chronic illness. J Pediatr 88: 937–942. Mustafa MM, Weitman SD, Winick NJ et al. (1993). Subacute measles encephalitis in the young immunocompromised host: report of two cases diagnosed by polymerase chain reaction and treated with ribavirin and review of the literature. Clin Infect Dis 16: 654–660. Parez N, Dehe´e A, Michel Y et al. (2009). Papular-purpuric gloves and socks syndrome associated with B19V infection in a 6-year-old child. J Clin Virol 44: 167–169. Peltola H, Kulkarni PS, Kapre SV et al. (2007). Mumps outbreaks in Canada and the United States: time for new thinking on mumps vaccines. Clin Infect Dis 45: 459–466. Robinson J, Lemay M, Vaudry WL (1994). Congenital rubella after anticipated maternal immunity: two cases and a review of the literature. Pediatr Infect Dis J 13: 812–815. Servant-Delmas A, Lefre`re JJ, Morinet F et al. (2010). Advances in human B19 erythrovirus biology. J Virol 84: 9658–9665. Singer C, Lang AE, Suchowersky O (1977). Adult-onset subacute sclerosing panencephalitis: case reports and review of literature. Mov Disord 12: 342–353. Slavov SN, Kashima S, Pinto AC et al. (2011). Human parvovirus B19: general considerations and impact on patients with sickle-cell disease and thalassemia and on blood transfusions. FEMS Immunol Med Microbiol 62: 247–262. Sonmez FM, Odemis E, Ahmetoglu A et al. (2004). Brainstem encephalitis and acute disseminated encephalomyelitis following mumps. Pediatr Neurol 30: 132–134. Sudfeld CR, Navar AM, Halsey NA (2010). Effectiveness of measles vaccination and vitamin A treatment. Int J Epidemiol 39: i48–i55. Tatli B, Ekici B, Ozmen M (2012). Current therapies and future perspectives in subacute sclerosis panencephalitis. Expert Rev Neurother 12: 485092.

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Ternavasio-de la Vega HG, Boronat M, Ojeda A et al. (2010). Mumps orchitis in the post-vaccine era (1967–2009): a single-center series of 67 patients and review of clinical outcome and trends. Medicine (Baltimore) 89: 96–116. Tipples G, Hiebert J (2011). Detection of measles, mumps and rubella viruses. Methods Mol Biol 665: 183–193. Townsend JJ, Baringer JR, Wolinsky JS et al. (1975). Progressive rubella panencephalitis: late onset after congenital rubella. N Engl J Med 292: 990–993. Trivedi R, Gupta RK, Agarawal A (2006). Assessment of white matter damage in subacute sclerosing panencephalitis using quantitative diffusion tensor MR imaging. AJNR Am J Neuroradiol 27: 1712–1716. Ueda K, Nishida Y, Oshima K et al. (1979). Congenital rubella syndrome: correlation of gestational age at time of maternal rubella with type of defect. J Pediatr 94: 763–765. Wang Y, Cao K, Yang W et al. (2003). Bilateral total deafness due to mumps and outcome of cochlear implantation. Lin Chuang Er Bi Yan Hou Ke Za Zhi 17: 602–603. Wierenga KJ, Serjeant BE, Serjeant BR (2001). Cerebrovascular complications and parvovirus infections in homozygous sickle cell disease. J Pediatr 139: 438–442. Wild NJ, Sheppard S, Smithelis RW et al. (1989). Onset and severity of hearing loss due to congenital rubella. Arch Dis Child 64: 1280–1283. World Health Organization (WHO) (2007). Mumps vaccine. Wkly Epidemiol Rec 82: 49–60. World Health Organization (WHO) (2012a). Accessed 10/29/ 2012. http://www.who.int/mediacentre/factsheets/fs286/ en/index.html. World Health Organization (WHO) (2012b). Accessed 10/29/2012 http://www.who.int/immunization_monitoring/ diseases/mumps/en/. World Health Organization (WHO) (2012c). Accessed 10/29/2012. http://www.who.int/immunization_monitoring/ diseases/Rubella_map_schedule.jpg. World Health Organization (WHO) (2013). Accessed 10/22/2013. http://:www.who.int/mediacentre/factsheets/ fs286/en. Yamaoka Y, Isozaki E, Kagamihara Y et al. (2000). A case of Guillain–Barre´ syndrome following human parvovirus B19 infection. Rinsho Shinkeigaku 40: 471–475. Yamashita Y, Matsuishi T, Murakami et al. (1991). Neuroimaging findings (ultrasonography, CT, MRI) in 3 infants with congenital rubella syndrome. Pediatr Radiol 21: 547–549. Yilmaz K, Yilmaz M, Mete A et al. (2010). A correlative study of FDG PET, MRI/CT, electroencephalography, and clinical features in subacute sclerosing panencephalitis. Clin Nucl Med 35: 675–681.

Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 92

Neurologic manifestations of diphtheria and pertussis VIRAJ SANGHI* Division of Neurology, Bombay Hospital and Medical Research Centre, KEM Hospital and Seth G.S. Medical College, Mumbai, India

DIPHTHERIA Diphtheria, an infectious disease caused by Corynebacterium diphtheriae, affects the nasopharynx and skin. C. diphtheriae is a Gram-positive bacillus. It does not form spores, is nonmotile, and is transmitted via aerosol pathways. Typically, the incubation period for respiratory disease is 2–5 days. Toxigenic strains of C. diphtheriae release a toxin that leads to formation of a pseudomembrane in the pharynx – pharyngeal diphtheria. In addition, the toxin also results in systemic toxicity, myocarditis, and polyneuropathy. Nontoxigenic strains commonly cause cutaneous diphtheria.

Epidemiology Before the development of a vaccine, diphtheria was a major cause of morbidity and mortality in children, especially in crowded urban areas. The development of diphtheria toxoid vaccine has led to the near elimination of diphtheria in Western countries (Bishai and Murphy, 2008). The annual peak incidence rate was 191 cases per 100 000 people in the US in 1921. Since 1980, this has fallen to fewer than five cases per 100 000 people. Between 1980 and 1995, only 41 cases of respiratory diphtheria were reported (Bisgard et al., 1998). However, pockets of colonization persist in North America, particularly in South Dakota, and Washington State in the US, and in the Province of Ontario in Canada. In the UK, the incidence of diphtheria is low. Since 1990, only 19 cases of toxigenic diphtheria have been reported in England and Wales and most of these were acquired abroad (McAuley et al., 1999). However, during the 1990s, diphtheria experienced a resurgence in both developed and developing countries where it had been well controlled. An epidemic that began in 1990 in the Newly

Independent States (NIS) of the former USSR affected almost 150 000 people with nearly 5000 deaths by the end of 1996 (Vitek and Wenger, 1998). More than 97 000 cases with 2500 fatal outcomes took place in Russia (Piradov et al., 2001). In Latvia, an epidemic started in 1994, with a secondary peak of 574 cases (with 38 deaths) between 1998 and 2000 (Krumina et al., 2005). In 2000, 231 diphtheria cases were registered at the Infectology Center in Riga, Latvia, the majority of which were cadets, soldiers, and other defense personnel from a single closed community. In Belarus, a total of 965 cases were reported from 1990 to 1998 (Filonov et al., 2000). In the Latvian epidemic, 80% of patients with diphtheritic polyneuropathy were between the ages of 41 and 60 years (Logina and Donaghy, 1999). In the Russian study of 32 patients, the age range of patients with diphtheritic polyneuropathy was 21–54 years (Piradov et al., 2001). Today, most children in industrial and postindustrial countries receive diphtheria toxoid. Without subsequent booster doses, adults progressively lose immunity. Decreased immunity in the adult population has resulted in the resurgence of diphtheria. Adults vaccinated in childhood do not continue to have sufficient immunity to protect against diphtheria once the infection returns to a community. In the US, 40–50% of adults above the age of 30 years are susceptible to diphtheria (Fontaranosa, 1995). Similar findings were reported from the UK (Maple et al., 1995), while a Danish study (Kjeldsen et al., 1985) showed that 22% of previously vaccinated adults were susceptible. The incidence of diphtheritic polyneuropathy is directly proportional to the severity of intoxication. Polyneuropathy is considered uncommon in mild diphtheria, but occurs in about 10% of cases of average severity and in up to 75% of severe cases (Holmes, 1997).

*Correspondence to: Dr. Viraj Sanghi, Consultant Paediatric Neurologist, Division of Neurology, Bombay Hospital and Medical Research Centre, KEM Hospital and Seth G.S. Medical College, Mumbai, India. Tel: þ91-93-2005-2518, Fax: þ91-22-2208-0871, E-mail: [email protected]

1356 V. SANGHI In the Latvian study, 15% of patients admitted to hospital Clinical features with diphtheria developed neurologic complications Diphtheria usually manifests as a pharyngeal, tonsillar, (Logina and Donaghy, 1999). Diphtheritic polyneuropaor nasal infection with early local toxic effects that often thy is more likely to occur in patients with severe infeclead to formation of a characteristic membranous exution, including those with “bull neck” and toxic shock. date. Cervical lymphadenopathy and soft tissue swelling may lead to the formation of a “bull neck.” This is followed by biphasic, secondary toxicity (early local and Pathogenesis and pathology late remote). Diphtheritic polyneuropathy and cardiomyopathy are Typically, a stereotypic pattern of bulbar symptoms caused by a toxic protein secreted by C. diphtheriae. occurs 3–6 weeks after initial infection with onset of The toxin is encoded by the tox bacteriophage gene. polyneuropathy at around 8 weeks (McDonald and Only those C. diphtheriae strains harboring this bacteriKocen, 1991). In 32 Russian patients (Piradov et al., ophage cause polyneuropathy and cardiomyopathy 2001), the latency between the first symptoms of diph(Pleasure and Messing, 2005). Diphtheria toxin comtheria and the development of diphtheritic polyneuropaprises two chains, A and B. The A chain is the catalytic thy varied from 18 to 46 (mean, 30 þ 8) days. In the domain. The B chain has two domains – the transmemLatvian study of 50 patients with diphtheritic polyneurobrane (T) domain and the receptor-binding (I) domain pathy, neurologic symptoms appeared 2–50 (median 10) (Ren et al., 1999). The T domain is a ligand for days after the onset of localized tonsillar and pharyngeal plasma membrane heparin-binding epidermal growth diphtheria (Logina and Donaghy, 1999). Typical initial factor (HB-EGF) receptors and plays a role in toxin symptoms include numbness of the tongue and face endocytosis. The I domain penetrates the endosomal and dysphonia. Bulbar symptoms include nasal or hoarse membrane and translocates the toxin into the cytosol. voice along with dysphagia and palatal paralysis. These In the cytosol, the toxin A chain then irreversibly symptoms vary from mild to severe and are seen in inhibits protein synthesis by NAD þ -dependent ADP almost all patients with diphtheritic polyneuropathy ribosylation of elongation factor 2 (Bishai and (Logina and Donaghy, 1999; Piradov et al., 2001). DysMurphy, 2008). Toxin-poisoned cells undergo death by phagia may be accompanied by excessive salivation apoptosis. and nasal regurgitation of fluid food or its aspiration Schwann cells are more susceptible and selectively into the airways, necessitating the usage of a nasogastric targeted by diphtheria toxin. They express abundant tube for feeding. HB-EGF receptors and are thus more capable of binding Symptoms of bulbar dysfunction recover during diphtheria toxin than most other cell types (Pleasure and weeks 5–10 with appearance of motor weakness worsenMessing, 2005). ing during weeks 6–9, reaching a maximum on day Local toxic effects occur by direct spread of the toxin 51 þ 10 of diphtheritic polyneuropathy (Piradov et al., and result in early bulbar dysfunction while generalized 2001). This characteristic, biphasic evolution of symppolyneuropathy arises from hematogenous disseminatoms has been described by other authors (McDonald tion (McAuley et al., 1999). The delay in development and Kocen, 1991; Logina and Donaghy, 1999). Single of the polyneuropathy as well as the proximal to distal case reports from the UK (McAuley et al., 1999), France spread relates to the long time for transport of newly (Creange et al., 1995), and Sweden (Solders et al., 1989) synthesized protein down the axons. have shown similar patterns of disease. Classically, diphtheritic polyneuropathy is considered Other cranial nerves are also involved. Oculomotor to be a pure demyelinating disease with sparing of the impairment, manifested by ptosis, anisocoria, and diploaxons. However, there is increasing suggestion in experpia, is described with varying frequency: in 84% of imental studies that axonal function is also affected with patients by Piradov et al. (2001) and 30% in a study by a loss of sensory neurons and motor axons (Pleasure and Logina and Donaghy (1999). Facial weakness is also well Messing, 2005). In a single case report (Solders et al., described. 1989), sural nerve biopsy showed signs of demyelination Limb symptoms typically occur 5–8 weeks after onset with short internodes. The fiber density was slightly of throat diphtheria (Logina and Donaghy, 1999; reduced. There was no infiltration of inflammatory cells. McAuley et al., 1999; Piradov et al., 2001; Krumina HLA-DR antigen staining showed expression of the antiet al., 2005). Thus during the second month of disease, gen on nonmyelinating Schwann cells and on macrofunctional recovery of cranial nerves is accompanied phages. Anterior tibial muscle biopsy showed signs of by worsening of motor weakness of the trunk and early neurogenic atrophy with scattered angular atrophic extremities. Proximal quadriparesis was seen in fibers. No signs of inflammation were seen. 60–90% of patients with diphtheritic polyneuropathy.

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The severity ranges from mild difficulty in walking to severe weakness and loss of ability to walk unaided. There appears to be an inverse relationship between latency and recovery of motor symptoms – a longer latency corresponds with an earlier regression of limb weakness (Piradov et al., 2001). In addition to motor weakness, sensory disturbance characterized by paresthesia, hypoesthesia, hyperesthesia or a diminished sense of joint position and vibration in distal parts of the extremities is seen in nearly all patients. Sensory ataxia may also be seen in some patients. Deep tendon reflexes are lost. Autonomic dysfunction is another complication of diphtheria. Circulatory disturbances such as tachycardia, arrhythmias and arterial hypotension are commonly seen; these may be difficult to distinguish from symptoms of diphtheritic myocarditis (Logina and Donaghy, 1999). Bladder dysfunction as well as blurred vision from impaired accommodation and abnormal pupil reactions may occur. Retention of urine requiring persistent catheterization of the bladder develops in one third of cases. Xeroderma and hyperkeratosis were reported in 24 of 32 patients, while hyperemia and hyperhidrosis in the face, neck, and chest were seen in 20 patients (Piradov et al., 2001). Respiratory muscle weakness is life-threatening and typically occurs in weeks 1–3 and maximizes during weeks 3–4 (Piradov et al., 2001). It necessitates the use of prolonged artificial ventilation. Myocarditis occurs frequently (in almost two-thirds of patients) in patients with diphtheritic polyneuropathy (Logina and Donaghy, 1999); pneumonia is also common.

Autonomic function tests show an early and prominent impairment of parasympathetic vagal functions (Solders et al., 1989). The R-R variations and heart reaction to the Valsalva maneuver are abnormal and the results of these tests follow clinical recovery.

Laboratory features

Outcome

Throat cultures provide an accurate means for diagnosis of diphtheria. However, false-negative results may be obtained if there is a delay in processing the specimen (Pleasure and Messing, 2005). Cerebrospinal fluid (CSF) studies may be normal or show elevated protein (albumin-cytologic dissociation). Occasionally, there may be a lymphocytic pleocytosis (Creange et al., 1995). Piradov et al. (2001) found an elevated CSF pressure in nine of 32 patients. Nerve conduction studies show slow conduction velocities (sensory and motor), prolonged distal motor latencies, multiple conduction blocks and prolonged F-response latencies (Solders et al., 1989; Logina and Donaghy, 1999). These findings are consistent with pathologic findings of a demyelinating polyneuropathy. Electrophysiologic studies show a maximum impairment at weeks 3–10 and then gradual improvement. Abnormal studies may persist beyond 100 days after the onset of polyneuropathy and occasionally even up to a year later.

Recovery of strength and sensations usually begins 2–3 months after the onset of neuropathic symptoms (Pleasure and Messing, 2005). In the Latvian study (Logina and Donaghy, 1999), the average duration of hospital stay was 34.4 (range 7–101) days. At the time of discharge, 24% of surviving patients were unable to walk independently. At 1 year, all surviving patients were able to walk 10 meters independently. However, two of these patients (6%) were unable to perform manual work. In Russian patients with diphtheritic polyneuropathy, motor symptoms started recovering at the end of month 2 and patients could walk without assistance 2 months later (Piradov et al., 2001). Mortality from diphtheria increases with the severity of local disease and toxicity produced. The mortality in patients with the toxic form of diphtheria was reported to be 25.7% from Russia (Rakhmanova et al., 1996). Logina and Donaghy reported a mortality of 16% in their study (1999).

Treatment Diphtheritic infection is treated by administration of intravenous penicillin and diphtheritic antitoxin at the time of the initial illness. Alternative treatment options for those who are allergic to penicillin include erythromycin, rifampin and clindamycin. The aim of antibiotic treatment is primarily to prevent transmission to other susceptible contacts (Bishai and Murphy, 2008). Antitoxin administration aims to block cellular binding and uptake of diphtheria toxin. It appears to be effective only when administered promptly in the early course of infection (Logina and Donaghy, 1999; McAuley et al., 1999; Pleasure and Messing, 2005; Bishai and Murphy, 2008). The antitoxin is a horse serum and may cause serum sickness in some individuals. A test dose must be administered to rule out immediate-type hypersensitivity. Those who exhibit hypersensitivity must be desensitized prior to receiving the full therapeutic dose. Glucorticoids may help in reducing the airway obstruction in acute laryngeal diphtheria but have not been shown to reduce the incidence of polyneuropathy (Pleasure and Messing, 2005; Bishai and Murphy, 2008). There is no specific treatment of the neurologic complications other than protection of the airway and physiotherapy (McAuley et al., 1999).

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V. SANGHI

PERTUSSIS Pertussis, or whooping cough, is an acute infectious disease of the respiratory tract caused by Bordetella pertussis or Bordetella parapertussis. These are Gram-negative, pleomorphic, and aerobic bacilli. Use of the pertussis vaccine has greatly reduced the incidence of the disease. In the US, the incidence of pertussis was 8.9 per 100 000 population in 2004 (Cherry, 2006). In the prevaccine era, the majority of cases occurred in children. Widespread vaccination in children has resulted in a shift in the age category with a reservoir of B. pertussis in older individuals. In the US, many cases of pertussis occur in teenagers or adults (Robbins, 1999). Similar findings have been reported from Europe (Schmitt-Grohe et al., 1995; Birkebaek, 1999). The incidence of pertussis in adults is underestimated because the diagnosis is often not considered in adults with cough, who frequently do not present with classic disease (Orenstein, 1999). Classic disease consists of severe paroxysms of coughing followed by a sudden, massive inspiratory effort, during which a characteristic whoop may occur. Paroxysms may occur several times per hour, during both day and night. Seizures and encephalopathy may occur as a complication. These may be due to cerebral hypoxia related to asphyxia. Tetanic seizures may be associated with severe alkalosis that results from the loss of gastric contents caused by persistent vomiting. Rarely, subarachnoid and intraventricular hemorrhage may occur (Cherry and Heininger, 2009). Neurologic complications occurred in 4% of Swedish patients hospitalized with pertussis (Romanus et al., 1987). Diagnosis may be established by culturing the organisms on appropriate media, by identifying their presence by polymerase chain reaction (PCR), or by demonstration of specific antibodies. Antibiotics are efficacious in treating pertussis. Erythromycin as well as newer macrolides, such as azithromycin and clarithromycin, are the drugs of choice. Alternatively, trimethoprimsulfamethoxazole can be used in those who cannot tolerate erythromycin (Cherry and Heininger, 2009).

recommended booster vaccine for older children, adolescents, and adults (Bishai and Murphy, 2008). Traditionally, there have been concerns regarding the safety of DTP vaccination (diphtheria and tetanus toxoids and whole-cell pertussis vaccine), especially the development of adverse neurologic events (Wilson, 1973). The risk of seizures and other neurologic events following diphtheria-tetanus-pertussis (DTP) immunization for 38 171 children who received 107 154 DTP immunizations in their first 3 years of life was studied (Griffin et al., 1990). The risk of febrile seizures in the 0 to 3 days following DTP immunization was increased. There was no evidence that the risk of afebrile seizures or acute symptomatic seizures was increased. In another large study (Barlow et al., 2001) that assessed the risks of DPT vaccination, 340 386 immunizations were studied. Receipt of DTP vaccine was associated with an increased risk of febrile seizures only on the day of vaccination. The number of febrile seizures attributable to the administration of DTP vaccine was estimated to be 6–9 per 100 000 children. The risk of nonfebrile seizures was not increased. As compared with other children with febrile seizures that were not associated with vaccination, the children who had febrile seizures after vaccination were not found to be at higher risk for subsequent seizures or neurodevelopmental disabilities. Berkovic et al. (2006) studied 14 patients with alleged vaccine encephalopathy in whom the first seizure occurred within 72 hours of vaccination. SCN1A mutations were identified in 11 of 14 patients. The authors postulated that cases of alleged vaccine encephalopathy could in fact be a genetically determined epileptic encephalopathy that arose de novo. Vaccination, however, might trigger earlier onset of Dravet syndrome in children who, because of an SCN1A mutation, are destined to develop the disease (McIntosh et al., 2010). However, vaccination should not be withheld from children with SCN1A mutations because there was no evidence that vaccinations before or after disease onset affect outcome. The consensus is that the risk of vaccine-induced encephalopathy and/or epilepsy, if it exists at all, is extremely low (Shorvon and Berg, 2008).

IMMUNIZATION AGAINST DIPHTHERIA AND PERTUSSIS

REFERENCES

Vaccination of children and adequate boosting vaccination of adults is necessary to reduce the incidence of diphtheria. At present diphtheria toxoid vaccine is coadministered with tetanus (with or without acellular pertussis) vaccine. DTaP (full-level diphtheria and tetanus toxoids and acellular pertussis vaccines, adsorbed) is the currently recommended vaccine for children up to the age of 7 years. Tdap (tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis vaccine) is the

Barlow WE, Davis RL, Glasser JW et al. (2001). The risk of seizures after receipt of whole-cell pertussis or measles, mumps, and rubella vaccine. N Engl J Med 345: 656–661. Berkovic SF, Harkin L, McMahon JM et al. (2006). De-novo mutations of the sodium channel gene SCN1A in alleged vaccine encephalopathy: a retrospective study. Lancet Neurol 5: 488–492. Birkebaek NH, Kristiansen M, Seefeldt T et al. (1999). Bordetella pertussis and chronic cough in adults. Clin Infect Dis 29: 1239–1242.

NEUROLOGIC MANIFESTATIONS OF DIPHTHERIA AND PERTUSSIS Bisgard KM, Hardy IR, Popovic T et al. (1998). Respiratory diphtheria in the United States, 1980 through 1995. Am J Public Health 88: 787–791. Bishai WR, Murphy JR (2008). Diphtheria and other infections caused by corynebacteria and related species. In: AS Fauci, E Braunwald, DL Kasper et al. (Eds.), Harrison’s Principles of Internal Medicine. Vol. 1. McGraw-Hill, New York, pp. 890–895. Cherry JD (2006). Epidemiology of pertussis. Pediatr Infect Dis J 25: 361–362. Cherry JD, Heininger U (2009). Pertussis and other bordetella infections. In: RD Feigin, JD Cherry, GJ Demmler-Harrison et al. (Eds.), Textbook of Pediatric Infectious Diseases. Vol. 1. Saunders Elsevier, Philadelphia, pp. 1683–1706. Creange A, Meyrignac C, Roulades B et al. (1995). Diphtheritic neuropathy. Muscle Nerve 18: 1460–1463. Filonov VP, Zakharenko DF, Vitek CR et al. (2000). Epidemic diphtheria in Belarus, 1992–1997. J Infect Dis 181 (Suppl 1): 41–46. Fontaranosa PB (1995). Diphtheria in Russia: a reminder of risk. JAMA 273: 1245. Griffin MR, Ray WA, Mortimer EA et al. (1990). Risk of seizures and encephalopathy after immunization with the diphtheriatetanus-pertussis vaccine. JAMA 263: 1641–1645. Holmes RK (1997). Diphtheria, other corynebacterial infections and anthrax. In: AS Fauci, E Braunwald, K Isselbacher et al. (Eds.), Harrison’s Principles of Internal Medicine. Vol. 1. McGraw-Hill, New York, pp. 892–899. Kjeldsen K, Simonsen O, Heron I (1985). Immunity against diphtheria 25–30 years after primary vaccination in childhood. Lancet 325: 900–902. Krumina A, Logina I, Donaghy M et al. (2005). Diphtheria with polyneuropathy in a closed community despite receiving recent booster vaccination. J Neurol Neurosurg Psychiatry 76: 1555–1557. Logina I, Donaghy M (1999). Diphtheritic polyneuropathy: a clinical study and comparison with Guillian–Barre´ syndrome. J Neurol Neurosurg Psychiatry 67: 433–438. Maple PA, Efstratious A, George RC et al. (1995). Diphtheria immunity in UK blood donors. Lancet 345: 963.

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McAuley JH, Fearnley J, Laurence A et al. (1999). Diphtheritic polyneuropathy. J Neurol Neurosurg Psychiatry 67: 825–826. McDonald WI, Kocen RS (1991). Diphtheritic neuropathy. In: PJ Dyck, PK Thomas (Eds.), Peripheral Neuropathy. Vol. 2. WB Saunders, Philadelphia, pp. 1412–1417. McIntosh AM, McMahon J, Dibbens LM et al. (2010). Effects of vaccination on onset and outcome of Dravet syndrome: a retrospective study. Lancet Neurol 9: 592–598. Orenstein WA (1999). Pertussis in adults: epidemiology, signs, symptoms, and implications for vaccination. Clin Infect Dis 28 (Suppl 2): 147–150. Piradov MA, Pirogov VN, Popova LM et al. (2001). Diphtheritic polyneuropathy. Arch Neurol 58: 1438–1442. Pleasure D, Messing A (2005). Diphtheritic polyneuropathy. In: PJ Dyck, PK Thomas (Eds.), Peripheral Neuropathy. Vol. 2. Elsevier Saunders, Philadelphia, pp. 2147–2151. Rakhmanova AG, Lumio J, Groundstroem K et al. (1996). Diphtheria outbreak in St. Petersburg: clinical characteristics of 1,860 adult patients. Scand J Infect Dis 28: 37–40. Ren J, Kachel K, Kim H et al. (1999). Interaction of diphtheria toxin T domain with molten globule-like proteins and its implications for translocation. Science 284: 955–957. Robbins JB (1999). Pertussis in adults: introduction. Clin Infect Dis 28 (Suppl 2): 91–93. Romanus V, Jonsell R, Bergquist SO (1987). Pertussis in Sweden after the cessation of general immunization in 1979. Pediatr Infect Dis J 6: 364–371. Schmitt-Grohe S, Cherry JD, Heininger U et al. (1995). Pertussis in German adults. Clin Infect Dis 21: 860–866. Shorvon S, Berg A (2008). Pertussis vaccination and epilepsy – an erratic history, new research and the mismatch between science and social policy. Epilepsia 49: 219–225. Solders G, Nennesmo I, Persson A (1989). Diphtheritic neuropathy, an analysis based on muscle and nerve biopsy and repeated neurophysiological and autonomic function tests. J Neurol Neurosurg Psychiatry 52: 876–880. Vitek C, Wenger J (1998). Diphtheria. Bull WHO 76 (Suppl 2): 129–130. Wilson J (1973). Proceedings: neurological complications of DPT inoculation in infancy. Arch Dis Child 48: 829–830.

Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 93

Bacterial meningitis SEBASTIAAN G.B. HECKENBERG1, MATTHIJS C. BROUWER2, AND DIEDERIK VAN DE BEEK2,* 1 Department of Neurology, Kennemer Gasthuis, Haarlem, The Netherlands 2

Department of Neurology, Academic Medical Center, Amsterdam, The Netherlands

INTRODUCTION Community-acquired bacterial meningitis continues to exact a heavy toll, even in developed countries. It is a neurologic emergency and the patients require immediate evaluation and treatment. The incidence of bacterial meningitis is about five cases per 100 000 adults per year in developed countries and may be 10 times higher in less developed countries (van de Beek et al., 2006a; Brouwer et al., 2010a). The predominant causative pathogens in adults are Streptococcus pneumoniae (pneumococcus) and Neisseria meningitidis (meningococcus), which are responsible for about 80% of all cases (van de Beek et al., 2006a; Brouwer et al., 2010a).

EPIDEMIOLOGY The incidence of acute bacterial meningitis is 5–10/ 100 000 persons per year in high income countries, resulting in 15 000–25 000 cases in the US annually (Durand et al., 1993; Hsu et al., 2009; Brouwer et al., 2010a). Vaccination strategies have substantially changed the epidemiology of community-acquired bacterial meningitis during the past two decades (Whitney et al., 2003; Hsu et al., 2009; Brouwer et al., 2010a). The routine vaccination of children against Haemophilus influenzae type B has virtually eradicated H. influenzae meningitis in the developed world (Peltola, 2000; Brouwer et al., 2010a). As a consequence, Streptococcus pneumoniae has become the most common pathogen beyond the neonatal period and bacterial meningitis has become a disease of predominantly adults. The introduction of conjugate vaccines against seven serotypes of S. pneumoniae that are among the most prevalent in children aged 6 months to 2 years has reduced the rate of invasive pneumococcal infections in young children

and in older persons (Whitney et al., 2003). The integration of the meningococcal protein–polysaccharide conjugate vaccines into vaccination programs in several countries further reduced the disease burden of bacterial meningitis in high- and medium-income countries (Snape and Pollard, 2005). S. pneumoniae affects all ages and causes the most severe disease in the very young and the very old (Weisfelt et al., 2006c). Of the > 90 pneumococcal serotypes, a few dominate as the causes of meningitis. The increase of drug-resistant strains of S. pneumoniae is an emerging problem worldwide. The prevalence of antibiotic-resistant strains in some parts of the US is as high as 50–70% with important consequences for treatment (Whitney et al., 2000). N. meningitidis is mainly responsible for bacterial meningitis in young adults; it causes sporadic cases and epidemics (Stephens et al., 2007). Its incidence shows a peak in winter and early spring and varies greatly around the world. Small outbreaks typically occur in young adults living in close quarters, such as dormitories of military camps or schools. Major epidemics have occurred periodically in sub-Saharan Africa (the so-called “meningitis belt”), Europe, Asia, and South America (Brouwer et al., 2010a). During these epidemics, attack rates can reach several hundred per 100 000, with devastating consequences. The group B streptococcus (S. agalactiae) is a pathogen of neonates and often causes a devastating sepsis and meningitis (Saez-Llorens and McCracken, 2003; Brouwer et al., 2010a). It colonizes the maternal birth canal, and is transmitted to the child during delivery. The colonized newborn can develop group B streptococcal disease of early onset (developing at less than 7 days of age; median 1 day) or late onset (developing later than 7 days of age). Listeria monocytogenes causes meningitis preferentially in neonates, in adults with

*Correspondence to: Diederik van de Beek, Academic Medical Center, Department of Neurology, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands. E-mail: [email protected]

1362 S.G.B. HECKENBERG ET AL. alcoholism, immunosupression, or iron overload, and in et al., 2010). In patients with sepsis due to N. meningitidis, pregnant women or the elderly (Brouwer et al., 2006). SNPs in cytokine and fibrinolysis genes have been There is often an encephalitic component to presentareported to influence mortality (Brouwer et al., 2010b). tion, with early mental status alterations, neurologic In bacterial meningitis research on genetic factors is deficits and seizures. In countries with routine vaccinalacking but may provide important pathophysiologic tion against H. influenzae type B it has become a rare insights. Bacterial meningitis is a complex disorder in disease (Peltola, 2000). In large parts of the world which injury is caused, in part, by the causative organism H. influenzae type B remains a major cause of pediatric and, in part, by the host’s own inflammatory response. meningitis, with high rates of mortality and hearing loss Recognition of particular subgroups of patients with a (Brouwer et al., 2010a). genetic predisposition to more severe illness may help Bacterial meningitis also occurs in hospitalized to individualize treatment and improve prognosis. Furpatients (“physician-associated meningitis” or “nosocother investigation is warranted to delineate the extend mial meningitis”). In a large city hospital, almost 40% of the genetic influence on susceptibility and outcome of cases may be nosocomial (Durand et al., 1993). Most in bacterial meningitis. cases occur in patients undergoing neurosurgical procedures, including implanting of neurosurgical devices, PATHOPHYSIOLOGYAND PATHOLOGY and in patients with focal infections of the head. Furthermore, patients with cerebrospinal fluid shunts are at conSpecific bacterial virulence factors for meningeal pathtinuous risk of developing drain associated meningitis ogens include specialized surface components that are (van de Beek et al., 2010a). The organisms causing crucial for adherence to the nasopharyngeal epithelium, nosocomial meningitis differ markedly from those the evasion of local host defense mechanisms, and subsecausing community-acquired meningitis and include quent invasion of the bloodstream (Scheld et al., 2002). Gram-negative rods (e.g., Escherichia coli, Klebsiella In pneumococcal disease, presence of the polymeric immunoglobulin A receptor on human mucosa, which spp., Pseudomonas aeruginosa, Acinetobacter spp., binds to a major pneumococcal adhesin, CbpA, correlates Enterobacter spp.), staphylococci and streptococci other than S. pneumoniae (Korinek et al., 2006; Weisfelt et al., with the ability of pneumococci to invade the mucosal 2007; van de Beek et al., 2010a). barrier. Viral infection of the respiratory tract may also Since the early antibiotic era, the emergence of antimipromote invasive disease (Weisfelt et al., 2006a). From crobial resistance has been a continuing problem. Pneuthe nasopharyngeal surface, encapsulated organisms mococcal resistance to penicillin, due to changes in its cross the epithelial cell layer and invade the small subepenicillin-binding proteins, started to appear in the pithelial blood vessels. Binding of bacteria to upregulated receptors (e.g., platelet-activating factor receptors) pro1960s and has since developed worldwide, often necessimotes migration through the respiratory epithelium and tating initial therapy with a combination of a thirdgeneration cephalosporin with vancomycin, instead of vascular endothelium, resulting in bloodstream invasion. monotherapy with penicillin (Brouwer et al., 2009a). In the bloodstream, bacteria must survive host defenses, including circulating antibodies, complementmediated bactericidal mechanisms, and neutrophil phagoGENETICS cytosis. Encapsulation is a shared feature of the principal Host genetic factors are major determinants of suscepmeningeal pathogens. To survive the various host conditibility to infectious diseases. The cause of these differtions they encounter during infection, pneumococci ences in susceptibility are single base-pair variations, undergo spontaneous and reversible phase variation, also known as single-nucleotide polymorphisms (SNPs), which involves changes in the amount of important surin genes controlling the host response to microbes. face components (Overweg et al.,2000; Weisfelt et al., Patients with recurrent or familial meningitis or sepsis 2006a). The capsule is instrumental in inhibiting neutrodue to S. pneumoniae or N. meningitidis are often found phil phagocytosis and complement-mediated bactericidal to have rare mutations that cause a substantial increase activity. Several defense mechanisms counteract the antiin susceptibility to infection (Brouwer et al., 2009). phagocytic activity of the bacterial capsule. Activation of These mutations are mostly founding genes coding for the alternative complement pathway results in cleavage of the complement system or Toll-like receptor (TLR) pathC3 with subsequent deposition of C3b on the bacterial surways. In the general population identified alterations face, thereby facilitating opsonization, phagocytosis, and include SNPs in the complement system, cytokines, intravascular clearance of the organism (Tuomanen et al., and TLRs (Brouwer et al., 2009). A genome-wide asso1986). Impairment of the alternative complement pathway ciation study has shown complement factor H SNPs occurs in patients with sickle-cell disease and those who decrease the risk of meningococcal disease (Davila have undergone splenectomy, and these groups of

BACTERIAL MENINGITIS patients are predisposed to the development of pneumococcal meningitis. Functional deficiencies of several components involved in the activation and function of complement-mediated defenses have been identified (i.e., mannose-binding lectin, properdin, terminal complement components), which increase the susceptibility for invasive meningococcal infections (Brouwer et al., 2009). The blood–brain barrier is formed by cerebromicrovascular endothelial cells, which restrict blood-borne pathogen invasion. Cerebral capillaries, as opposed to other systemic capillaries, have adjacent endothelial cells fused together by tight junctions that prevent intercellular transport (Kim, 2008). Bacteria are thought to invade the subarachnoid space via transcytosis. Nonhematogenous invasion of the CSF by bacteria occurs in situations of compromised integrity of the barriers surrounding the brain. Direct communication between the subarachnoid space and the skin or mucosal surfaces as a result of malformation or trauma gives rise to meningeal infection. Bacteria can also reach the CSF as a complication of neurosurgery or spinal anesthesia (van de Beek et al., 2010a). Physiologically, concentrations of leukocytes, antibodies, and complement components in the subarachnoid space are low, which facilitates rapid multiplication of bacteria. In the CSF pneumococcal cell-wall products, pneumolysin, and bacterial DNA induce a severe inflammatory response via binding to Toll-like receptor 2 (TLR) (Kim, 2008). Once engaged, this signaling receptor transmits the activating signal into the cell, which initiates the induction of inflammatory cytokines (Beutler and Rietschel, 2003). Endotoxin is a major component of the outer membrane of the meningococcus and is crucial in the pathogenesis of sepsis and meningitis (Stephens et al., 2007). The host responds to bacterial endotoxin with proinflammatory gene expression and activation of coagulation pathways. The subarachnoid inflammatory response is accompanied by production of multiple mediators in the CNS. Tumor necrosis factor-a (TNF-a), interleukin 1b, and interleukin 6 are regarded as the major early response cytokines that trigger the inflammatory cascade that induces various pathophysiologic alterations implicated in pneumococcal meningitis (Fig. 93.1) (Scheld et al., 2002). TNF-a and interleukin 1b stimulate the expression of chemokines and adhesion molecules, which play an important part in the influx of leukocytes from the circulation to the CSF. Upon stimulation with bacterial components, macrophages and granulocytes release a broad range of potentially tissue-destructive agents, which contribute to vasospasm and vasculitis, including oxidants (e.g., peroxynitrite) and proteolytic enzymes such as matrix metalloproteinases (MMP). MMP, zinc-dependent enzymes produced as part of the immune response to bacteria that degrade extracellular

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matrix proteins, also contribute to the increased permeability of the blood–brain barrier. The major element leading to increased intracranial pressure in bacterial meningitis is the development of cerebral edema, which may be vasogenic, cytotoxic, or interstitial in origin. Vasogenic cerebral edema is a consequence of increased blood–brain barrier permeability (van de Beek et al., 2006b). Cytotoxic edema results from an increase in intracellular water following alterations of the cell membrane and loss of cellular homeostasis. Cytotoxic mechanisms include ischemia and the effect of excitatory amino acids. Secretion of antidiuretic hormone also contributes to cytotoxic edema by making the extracellular fluid hypotonic and increasing the permeability of the brain to water. Interstitial edema occurs by an increase in CSF volume, either through increased CSF production via increased blood flow in the choroid plexus, or decreased resorption secondary to increased CSF outflow resistance. The exact mechanisms that lead to permanent brain injury are incompletely understood. Cerebral ischemic necrosis probably contributes to damage to the cerebral cortex (Fig. 93.1). Cerebrovascular complications occur in 15–20% of patients with bacterial meningitis (van de Beek et al., 2006a). Other abnormalities include subdural effusion or empyema, septic sinus thrombosis, subarachnoid hematomas, compression of intracranial structures due to intracranial hypertension, and herniation of the temporal lobes or cerebellum. Gross changes, such as pressure coning, are rare (Fitch and van de Beek, 2007). There is diffuse acute inflammation of the piaarachnoid, with migration of neutrophil leukocytes and exudation of fibrin into the CSF. Pus accumulates over the surface of the brain, especially around its base and the emerging cranial nerves, and around the spinal cord. The meningeal vessels are dilated and congested and may be surrounded by pus (Fig. 93.1). Pus and fibrin are found in the ventricles and there is ventriculitis, with loss of ependymal lining and subependymal gliosis. Infection may block CSF circulation, causing obstructive hydrocephalus or spinal block. In many cases death may be attributable to related septicemia, although bilateral adrenal hemorrhage (Waterhouse–Friederichsen syndrome) may well be a terminal phenomenon rather than a cause of fatal adrenal insufficiency as was once imagined. Patients with meningococcal septicemia may develop acute pulmonary edema.

CLINICAL PRESENTATION Community-acquired bacterial meningitis Early diagnosis and rapid initiation of appropriate therapy are vital in the treatment of patients with bacterial meningitis. A recent study provided a systematic

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Fig. 93.1. Multiple complications in a patient with pneumococcal meningitis. (A) T2-proton-density-weighted MRI of the brain shows a transverse view of a hyperintense signal (arrows) in the globus pallidus, putamen, and thalamus that indicates bilateral edema. (B) A postmortem view of the brain of the same patient shows yellowish-colored meninges as a result of extensive inflammation. (C) Confirmation of the bilateral infarction of globus pallidus, putamen, and thalamus (arrows). The microscopic substrate in the same patient shows a meningeal artery with (D) lymphocytic infiltration in and around the vessel wall, (E) extensive subpial necrotizing cortical inflammation, and (F) edema in the white matter.

assessment of the sequence and development of early symptoms in children and adolescents with meningococcal disease (encompassing the spectrum of disease from sepsis to meningitis) before admission to the hospital (Thompson et al., 2006). Classic symptoms of rash, meningismus, and impaired consciousness develop late in the prehospital illness, if at all. Early signs before admission in adolescents with meningococcal disease were leg pain and cold hands and feet. Bacterial meningitis is often considered but may be difficult to recognize. The clinical presentation of a patient with bacterial meningitis may vary depending

on age, underlying conditions, and severity of illness. Clinical findings of meningitis in young children are often minimal and in childhood bacterial meningitis and in elderly patients the classic symptoms such as headache, fever, nuchal rigidity, and altered mental status may be less common than in younger and middleaged adults (Weisfelt et al., 2006d; Brouwer et al., 2010a). Infants may become irritable or lethargic, stop feeding, and are found to have a bulging fontanel, separation of the cranial sutures, meningism, and opisthotonos; they may also develop convulsions. These findings are uncommon in neonates, who sometimes present with

BACTERIAL MENINGITIS respiratory distress, diarrhea, or jaundice (Saez-Llorens and McCracken, 2003; Brouwer et al., 2010a). In a prospective study on adults with bacterial meningitis, the classic triad of signs and symptoms consisting of fever, nuchal rigidity, and altered mental status was present in only 44% of the patients (Van de Beek et al., 2004a). Certain clinical features may predict the bacterial cause of meningitis. Predisposing conditions such as ear or sinus infections, pneumonia, immunocompromise, and dural fistulae are estimated to be present in 68–92% of adults with pneumococcal meningitis (Weisfelt et al., 2006c; Brouwer et al., 2010d). Rashes occur more frequently in patients with meningococcal meningitis, with reported sensitivities of 63–80% and with specificities of 83–92% (Heckenberg et al., 2008; Brouwer et al., 2010a).

Post-traumatic bacterial meningitis This is often indistinguishable clinically from spontaneous meningitis (Weisfelt et al., 2007; van de Beek et al., 2010a). However, in obtunded or unconscious patients who have suffered a recent or previous head injury, few clinical signs may be present. A fever and deterioration in the level of consciousness or loss of vital functions may be the only signs of meningitis. Finding a CSF leak adds support to the possibility of meningitis in such patients, but this is undetectable in most cases. The range of bacteria causing meningitis in these patients is broad and consideration should be given to broad spectrum antibiotics including metronidazole for anaerobic pathogens.

Infections of cerebrospinal fluid shunts Patients may present with clinical features typical of spontaneous meningitis, especially if virulent organisms are involved (van de Beek et al., 2010a). The more usual presentation is insidious, with features of shunt blockage such as headache, vomiting, fever, and a decreasing level of consciousness. Fever is a helpful sign, but is not a constant feature and may be present in as few as 20% of cases. Shunts can be infected without causing meningitis, in which event the features of the infection will be determined by where the shunt drains. Infection of shunts draining into the venous system produces a disease similar to chronic right-sided infective endocarditis together with glomerulonephritis (shunt nephritis), while infection of shunts draining into the peritoneal cavity produces peritonitis.

MANAGEMENT Given the high mortality of acute bacterial meningitis, starting treatment and completing the diagnostic process

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should be carried out simultaneously in most cases (Fig. 93.2) (van de Beek et al., 2006a). The first step is to evaluate vital functions, obtain two sets of blood cultures, and blood tests which typically should not take more than 1 or 2 minutes. At the same time, the severity of the patient’s condition and the level of suspicion for the presence of bacterial meningitis should be determined. Recommendations for cranial CT and fears of herniation are based on the observed clinical deterioration of a few patients in the several to many hours after lumbar puncture and the perceived temporal relationship of lumbar puncture and herniation, but proving a cause and effect association is very difficult based on the available data. Therefore, it is reasonable to proceed with lumbar puncture without a CT scan if the patient does not meet any of the following: patients who have newonset seizures (suggestive of focal brain lesions), an immunocompromised state, signs suspicious for space-occupying lesions (papilledema or focal neurologic signs – not including cranial nerve palsy), or moderate to severe impairment of consciousness (score on the Glasgow Coma Scale below 10) (van de Beek et al., 2006a; Fitch and van de Beek, 2007). Other contraindications to lumbar puncture include local skin sepsis at the site of puncture, a clinically unstable patient, and any clinical suspicion of spinal cord compression. Lumbar puncture may also be harmful in patients with coagulopathy, because of the chance of needle-induced subarachnoid hemorrhage or of the development of spinal subdural and epidural hematomas. Contraindications for (immediate) lumbar puncture are provided in Table 93.1 (van de Beek et al., 2006a). In patients with suspected bacterial meningitis who receive a CT scan before lumbar puncture, initial therapy consisting of adjunctive dexamethasone (10 mg intravenously) and empiric antimicrobial therapy (Fig. 93.2, Table 93.2) should always be started without delay, even before sending the patient to the CT scanner. Several studies have reported a strong increase in mortality due to a delay in treatment caused by cranial imaging (Proulx et al., 2005).

Cerebrospinal fluid analysis When CSF analysis shows increased white blood cell counts, confirming a diagnosis of meningitis, it is important to discriminate between the usually harmless viral and the life-threatening bacterial meningitis. The CSF abnormalities of bacterial meningitis include raised opening pressure in almost all patients, polymorphonuclear leukocytosis, decreased glucose concentration, and increased protein concentration. In bacterial meningitis, the white blood cell count is typically > 1000 cells/mL,

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S.G.B. HECKENBERG ET AL.

Fig. 93.2. Algorithm for the management of the patient with suspected community-acquired bacterial meningitis. DXM stands for dexamethasone.

while in viral meningitis it is < 300 cells/mL, although there is considerable overlap (Fitch and van de Beek, 2007; Brouwer et al., 2010a). The neutrophil count is higher in bacterial than in viral meningitis. More than 90% of cases present with CSF white cell counts of more

than 100/mL. In immunocompromised patients, CSF white blood cell counts may be lower, although acellular CSF is exceedingly rare, except in patients with tuberculous meningitis (Thwaites and Tran, 2005). The normal CSF glucose concentration is between 2.5 and 4.4 mmol/L,

BACTERIAL MENINGITIS Table 93.1 Contraindications for immediate lumbar puncture Signs suspect for space occupying lesion Papilledema Focal neurologic signs (excluding isolated cranial nerve palsies) Score on Glasgow Coma Scale below 10 Severe immunodeficiency (such as HIV) New onset seizures Skin infection puncture site Coagulopathy, e.g. Use of anticoagulant medication Clinical signs of diffuse intravascular coagulation Septic shock

which is approximately 65% of the serum glucose. In bacterial meningitis the glucose concentration is usually less than 2.5 mmol/L, or < 40% of the serum glucose. The CSF protein in bacterial meningitis is usually increased > 50 mg/dL (van de Beek et al., 2004a; Brouwer et al., 2010a). The CSF Gram stain identifies the cauasative microorganism in 50–90% of cases and CSF culture is positive in 80% of untreated patients, depending on the pathogen (van de Beek et al., 2004a; Brouwer et al., 2010a). Gram’s staining of CSF permits the rapid identification of the causative organism (sensitivity, 60–90%; specificity, >97%). The yield of CSF Gram staining is only marginally decreased if the patient received antibiotic treatment prior to the lumbar puncture (Brouwer et al., 2010a). Latex particle agglutination tests that detect antigens of N. meningitidis, S. pneumoniae, H. influenzae and S. agalactiae have been tested in bacterial meningitis patients. No incremental yield of this method was observed in several cohort studies. Therefore these tests are no longer advised (Brouwer et al., 2010a). In the past decade PCR has proven to provide additional yield in recognizing the causative pathogen in bacterial meningitis patients from CSF. The reported sensitivities and specificities are high for different organisms and therefore PCR can be used to detect patients in whom cultures remain negative or those who were pretreated with antibiotics. However, CSF culture will remain the “gold standard” for diagnosis as it is obligatory to obtain the in vitro susceptibility of the causative microorganism and to rationalize treatment (Brouwer et al., 2010a).

SERUM MARKERS OF INFLAMMATION In the distinction between viral and bacterial meningitis, serum inflammatory markers may suggest the diagnosis ( van de Beek et al., 2004a; Brouwer et al., 2010a). Retrospective studies showed that increased serum procalcitonin levels (>0.5 ng/mL) and C-reactive protein levels

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(>20 mg/L) were associated with bacterial meningitis (Sormunen et al., 1999; Dubos et al., 2008). Although elevated concentrations can be suggestive of bacterial infection, they do not establish the diagnosis of bacterial meningitis.

BLOOD CULTURE Blood cultures are valuable to detect the causative organism and establish susceptibility patterns if CSF cultures are negative or unavailable. Blood culture positivity differs for each causative organism and varies between 50% and 90%. The yield of blood cultures is decreased by 20% for patients who received pretreatment with antibiotics (Brouwer et al., 2010a).

SKIN BIOPSY Microbiological examination of skin lesions is routine diagnostic workup in patients with suspected meningococcal infection. It differentiates well between meningitis with and without hemodynamic complications, and the result is not affected by previous antibiotic treatment (van Deuren et al., 1993; Arend et al., 2006).

Antimicrobial therapy The choice of initial antimicrobial therapy is based on the most common bacteria causing the disease according to the patient’s age, on the clinical setting, and on patterns of antimicrobial susceptibility (Table 93.2). Once the pathogen has been isolated, specific treatment based on the susceptibility of the isolate can replace the empiric regimen (Table 93.3). The pharmacokinetics and dynamics of antimicrobial agents are important drug characteristics to base the empiric regimen on. Penetration of the blood–brain barrier (BBB) into the subarachnoid space is the first pharmacologic factor that determines whether an antimicrobial agent is able to clear bacteria from the CSF. BBB penetration is affected by lipophility, molecular weight and structure, and protein-bound fraction. Bacterial meningitis is a dynamic process and CSF penetration of antimicrobials is highly dependent on the breakdown of the BBB. Anti-inflammatory drugs such as dexamethasone might influence the breakdown of the BBB and thereby interfere with CSF penetration of antimicrobial agents. The activity of antimicrobial drugs in infected purulent CSF depends on a number of factors, such as activity in the environment of decreased pH, protein-bound fraction, bacterial growth rate and density, and clearance in the CSF. Mechanisms of antibiotic action are targeting the bacterial cell wall, targeting the bacterial cell membrane, or targeting biosynthetic processes. Whereas

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Table 93.2 Recommendations for empiric antimicrobial therapy in suspected bacterial meningitis Predisposing factor Age 50 years With risk factor present} Post-traumatic Postneurosurgery

CSF shunt

Common bacterial pathogens

Initial intravenous antibiotic therapy

Streptococcus agalactiae, Escherichia coli, Listeria monocytogenes Streptococcus pneumoniae, Neisseria meningitidis, S. agalactiae, Haemophilus influenzae, E. coli, L. monocytogenes S. pneumoniae, N. meningitidis, S. agalactiae, H. influenzae, E. coli N. meningitidis, S. pneumoniae N. meningitidis, S. pneumoniae, L. monocytogenes, aerobic Gram-negative bacilli S. pneumoniae, L. monocytogenes, H. influenzae

Ampicillin plus cefotaxime or an aminoglycoside Ampicillin plus vancomycin plus ceftriaxone or cefotaxime{

S. pneumoniae, H. influenzae Coagulase-negative staphylococci, Staphylococcus aureus, aerobic Gram-negative bacilli (including Pseudomonas aeruginosa) Coagulase-negative staphylococci, Staphylococcus aureus, aerobic Gram-negative bacilli (including Pseudomonas aeruginosa), Propionibacterium acnes

Vancomycin plus ceftriaxone or cefotaxime{ Vancomycin plus ceftriaxone or cefotaxime{ Vancomycin plus ceftriaxone or cefotaxime plus ampicillin{ Vancomycin plus ceftriaxone or cefotaxime plus ampicillin Vancomycin plus ceftriaxone or cefotaxime plus ampicillin Vancomycin plus ceftazidime

Vancomycin plus ceftazidime

{

In areas with very low penicillin-resistance rates (such as the Netherlands) monotherapy penicillin may be considered. In areas with very low penicillin-resistance and cephalosporin-resistance rates (such as the Netherlands) combination therapy of amoxicillin and third-generation cephalosporin may be considered. } Alcoholism, altered immune status. General recommendations for intravenous empirical antibiotic treatment have included penicillin, 2 million units every 4 hours; amoxicillin or ampicillin, 2 g every 4 hours; vancomycin, 15 mg/kg every 6–8 hours; third-generation cephalosporin: ceftriaxone, 2 g every 12 hours, or cefotaxime, 2 g every 4–6 hours; ceftazidime, 2 g every 8 hours. (This material was published previously in articles by van de Beek et al. as part of an online supplementary appendix to references 1 and 24. Copyright 2006 and 2010 Massachusetts Medical Society (van de Beek et al., 2006a and van de beek 2010a). All rights reserved.) {

Table 93.3 Recommendations for specific antimicrobial therapy in suspected bacterial meningitis Microorganism Haemophilus influenzae b-lactamase-negative b-lactamase-positive Neisseria meningitidis Penicillin MIC < 0.1 mg/mL Penicillin MIC 0.1–1.0 mg/mL Streptococcus pneumoniae Penicillin MIC < 0.1 mg/mL Penicillin MIC 0.1–1.0 mg/mL Penicillin MIC > 2.0 mg/mL or cefotaxime/ ceftriaxone MIC > 1.0 mg/mL Listeria monocytogenes Streptococcus agalactiae MIC, minimum inhibitory concentration.

Antimicrobial therapy

Duration of therapy

Amoxicillin Ceftriaxone or cefotaxime

7 days 7 days

Penicillin G (benzylpenicillin) or amoxicillin Ceftriaxone or cefotaxime

7 days 7 days

Penicillin G or amoxicillin Ceftriaxone or cefotaxime Vancomycin plus ceftriaxone or cefotaxime

10–14 days 10–14 days 10–14 days

Penicillin G or amoxicilline Penicillin G or amoxicillin

>21 days 7 days

BACTERIAL MENINGITIS bacteriostatic activity involves inhibition of growth of microorganisms, bactericidal antimicrobials cause bacterial cell death. Antibiotic-induced lysis of bacteria leads to the release of immunostimulatory cell-wall components and toxic bacterial products, which induce a severe inflammatory response that mainly occurs through binding to Toll-like receptors and the complement system. Neonatal meningitis is largely caused by group B streptococci, E. coli, and L. monocytogenes. Initial treatment, therefore, should consist of penicillin or ampicillin plus a third-generation cephalosporin, preferably cefotaxime or ceftriaxone, or penicillin or ampicillin and an aminoglycoside (Tunkel et al., 2004; van de Beek et al., 2006b; Brouwer et al., 2010a). In the community, children are at risk of meningitis caused by N. meningitidis and S. pneumoniae, and, rarely in Hib-vaccinated children, H. influenzae. Antimicrobial resistance has emerged among the three major bacterial pathogens causing meningitis. Although intermediate penicillin resistance is common in some countries, the clinical importance of penicillin resistance in the meningococcus has yet to be established. Because of the resistance patterns of these bacteria, thirdgeneration cephalosporins cefotaxime or ceftriaxone should be used in children (Saez-Llorens and McCracken, 2003; Tunkel et al., 2004; van de Beek et al., 2006b; Brouwer et al., 2010a). Spontaneous meningitis in adults is usually caused by S. pneumoniae or N. meningitidis. Due to the worldwide emergence of multidrug-resistant strains of S. pneumoniae, some experts recommend adding vancomycin to the initial empiric antimicrobial regimen in adult patients (Tunkel et al., 2004; van de Beek et al., 2006b; Brouwer et al., 2010a). Additionally, in patients aged over 50 years, treatment with ampicillin should be added to the above antibiotic regimen for additional coverage of L. monocytogenes, which is more prevalent among this age group. Although no clinical data on the efficacy of rifampicin in patients with pneumococcal meningitis are currently available, some experts would recommend the use of this agent in combination with a third-generation cephalosporin, with or without vancomycin, in patients with pneumococcal meningitis caused by bacterial strains that, on the basis of local epidemiology, are likely to be highly resistant to penicillin or cephalosporin. S. suis remains sensitive to the b-lactams and should be treated with penicillin, cefotaxime, or ceftriaxone. Fluoroquinolones may be an alternative. Nosocomial post-traumatic meningitis is mainly caused by multiresistant hospital-acquired organisms such as K. pneumoniae, E. coli, Pseudomonas aeruginosa, and S. aureus. Depending on the pattern of susceptibility in a given hospital unit, ceftazidime (2 g intravenously,

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every 8 hours), cefotaxime, ceftriaxone, or meropenem should be chosen. If P. aeruginosa infection seems likely, ceftazidime or meropenem is the preferred antibiotic (Tunkel et al., 2004; van de Beek et al., 2010a). Device- and shunt-associated meningitis is caused by a wide range of organisms, including methicillinresistant staphylococci (mostly coagulase-negative staphylococci) and multiresistant aerobic bacilli. Cases with shunts and an insidious onset are probably caused by organisms of low pathogenicity, and empiric therapy is a less urgent requirement. For postoperative meningitis the first-line empiric therapy should be cefotaxime, or ceftriaxone, or meropenem. If the patient has received broad-spectrum antibiotics recently or if P. aeruginosa is suspected, ceftazidime or meropenem should be given. Meropenem should be used if an extended-spectrum, b-lactamase organism is suspected, and flucloxacillin or vancomycin if S. aureus is likely. The infected shunt or drain will almost certainly have to be removed urgently (van de Beek et al., 2010a). Once the etiologic agent has been isolated and its susceptibilities determined, the empiric treatment should be changed, if necessary, to an agent or agents specific for the isolate (Table 93.3). The optimal duration of treatment has not been determined by rigorous scientific investigation; however, treatment regimens that are probably substantially in excess of the minimum necessary to achieve cure have been based on wide clinical experience. General recommendations for empiric antibiotic treatment have included ceftriaxone administered intravenously every 12 hours or intravenous cefotaxime every 4–6 hours, and/or ampicillin at 4 hour intervals, or penicillin G every 4 hours. There are no randomized comparative clinical studies of the various dosing regimens. In general, 7 days of antimicrobial therapy are given for meningitis caused by N. meningitidis and H. influenzae, 10–14 days for S. pneumoniae, and at least 21 days for L. monocytogenes. As these guidelines are not standardized it must be emphasized that the duration of therapy may need to be individualized on the basis of the patient’s response (Tunkel et al., 2004; van de Beek et al., 2006b; Brouwer et al., 2010a).

Adjunctive dexamethasone treatment Animal models of bacterial meningitis showed that bacterial lysis, induced by antibiotic therapy, leads to inflammation in the subarachnoid space. The severity of this inflammatory response is associated with outcome and can be attenuated by treatment with steroids (van de Beek and de Gans, 2006). On the basis

1370 S.G.B. HECKENBERG ET AL. of experimental meningitis studies, several clinical trials long-term cognitive outcome in adults after bacterial have been undertaken to determine the effects of adjunmeningitis (Hoogman et al., 2007). Since the publication ctive steroids in children and adults with bacterial of these results, adjunctive dexamethasone has become meningitis (Scheld et al., 1980; Brouwer et al., 2010c). routine therapy in most adults with suspected bacterial Of several corticosteroids, the use of dexamethasone meningitis (Brouwer et al., 2010d). in bacterial meningitis has been investigated most extRandomized studies in adults with bacterial meningiensively. Dexamethasone is a glucocorticosteroid with tis from Malawi and Vietnam have been published anti-inflammatory as well as immunosuppressive prop(Proulx et al., 2005; Nguyen et al., 2007). In the Malawi erties and has excellent penetration in the CSF. In a study dexamethasone was not associated with any signimeta-analysis of randomized trials since 1988, adjuncficant benefit (Scarborough et al., 2007), whilst in tive dexamethasone was shown to reduce meningitisVietnam a significant benefit in mortality (RR 0.43, associated hearing loss in children with meningitis due CI 0.2–0.94) was seen in patients with confirmed bactto H. influenzae type B (McIntyre et al., 1997). erial meningitis only (Nguyen et al., 2007; Hsu et al., As most available studies on adjunctive dexametha2009). A recent meta-analysis of individual patient sone therapy in adults with bacterial meningitis were limdata of five recent randomized controlled trials showed ited by methodological flaws, its value in adults no effect of adjunctive dexamethasone in meningitis remained a subject of debate for a long time. In 2002, (van de Beek et al.,2010b). Guidelines recommend results of a European randomized placebo-controlled routine use of adjunctive dexamethasone in adults trial showed that adjunctive treatment with dexamethawith pneumococcal meningitis in high-income countries sone, given before or with the first dose of antimicrobial (Tunkel et al., 2004; van de Beek et al., 2006a). Dexatherapy, was associated with a reduction in the risk of methasone therapy has been implemented on a large unfavorable outcome in adults with bacterial meningitis scale as adjunctive treatment of adults with pneu(relative risk [RR] 0.59; 95% confidence interval [CI] mococcal meningitis in the Netherlands (Brouwer 0.37–0.94) and with a reduction in mortality (RR 0.48; et al., 2010d). The prognosis of pneumococcal meningitis CI 0.24–0.96) (de Gans and van de Beek, 2002). This on a national level has substantially improved after the beneficial effect was most apparent in patients with introduction of adjunctive dexamethasone therapy with pneumococcal meningitis, in whom mortality was a reduction in mortality from 30% to 20%. decreased from 34% to 14%. The benefits of adjunctive Despite these encouraging results, the use of adjuncdexamethasone therapy were not undermined by an tive dexamethasone in bacterial meningitis remains conincrease of severe neurologic disability in patients who troversial in certain patients. Clearly the results from survived or by any corticosteroid-induced complication. studies in children and adults from Malawi suggests that In a post hoc analysis, which included only patients with there is no benefit in patients in that setting compared pneumococcal meningitis who died within 14 days after with the results from Europe and Vietnam and further admission, the mortality benefit of dexamethasone therwork is needed to determine if these differences in the apy was entirely due to reduced mortality from systemic efficacy of dexamethasone can be explained. Secondly, causes such as septic shock, pneumonia, or acute respipatients with septic shock and adrenal insufficiency benratory distress syndrome; there was no significant reducefit from corticosteroid therapy in physiologic doses and tion in mortality due to neurologic causes (van de Beek for > 4 days; however, when there is no evidence of reland de Gans, 2004). ative adrenal insufficiency, therapy with corticosteroids Results of a subsequent quantitative review on this may be detrimental. Results of a subsequent quantitative topic in adults, which included five clinical trials, conreview on this topic that included nine studies comparing firmed that treatment with corticosteroids was associmortality rates of corticosteroid treatment in sepsis or ated with a significant reduction in mortality (RR 0.6; septic shock showed a trend toward increased mortality CI 0.4–0.8) and in neurologic sequelae (RR 0.6; CI associated with their administration (Cronin et al., 1995). 0.4–1.0). The reduction in case fatality in patients with As controlled studies of the effects of corticosteroid pneumococcal meningitis was 21% (RR 0.5; CI therapy in a substantial number of patients with both 0.3–0.8) (van de Beek et al., 2004b). In meningococcal meningitis and septic shock are not available at present, meningitis, in which the number of events was smaller, treatment with corticosteroids cannot be recommended there were favorable point estimates for preventing morunequivocally for such patients. Third, corticosteroids tality (RR 0.9; CI 0.3–2.1) and neurologic sequelae (RR may potentiate ischemic and apoptotic injury to neurons. 0.5; CI 0.1–1.7), but these effects did not reach statistical In animal studies of bacterial meningitis corticosteroids significance. Adverse events were equally divided aggravated hippocampal neuronal apoptosis and learnbetween the treatment and placebo groups. Treatment ing deficiencies in dosages similar to those used in clinwith adjunctive dexamethasone did not worsen ical practice. Therefore, concerns existed about the

BACTERIAL MENINGITIS effects of steroid therapy on long-term cognitive outcome. To examine the potential harmful effect of treatment with adjunctive dexamethasone on long-term neuropsychological outcome in adults with bacterial meningitis a follow-up study of the European Dexamethasone Study was conducted (Weisfelt et al., 2006b). In 87 of 99 eligible patients, 46 (53%) of whom were treated with dexamethasone and 41 (47%) of whom received placebo, no significant differences in outcome were found between patients in the dexamethasone and placebo groups (median time between meningitis and testing was 99 months). Therefore, treatment with adjunctive dexamethasone does not worsen long-term cognitive outcome in adults after bacterial meningitis. By reducing permeability of the BBB, steroids can impede penetration of antibiotics into the CSF, as was shown for vancomycin in animal studies (Paris et al., 1994), which can lead to treatment failures, especially in patients with meningitis due to drug-resistant pneumococci in whom antibiotic regimens often include vancomycin. However, in an observational study, which included 14 adult patients admitted to the intensive care unit because of suspected pneumococcal meningitis, appropriate concentrations of vancomycin in CSF were obtained even when concomitant steroids were used (Ricard et al., 2007). The dose of vancomycin used in this study was 60 mg/kg/day. Although these results suggest that dexamethasone can be used without fear of impeding vancomycin penetration into the CSF of patients with pneumococcal meningitis (provided that vancomycin dosage is adequate), it is recommended that patients with bacterial meningitis due to nonsusceptible strains, treated with adjunctive dexamethasone, are carefully monitored throughout treatment.

Adjunctive glycerol treatment Glycerol is a hyperosmolar agent that has been used in several neurologic and neurosurgical disorders to decrease intracranial pressure. Although glycerol has no beneficial effect in experimental meningitis models, a small randomized clinical trial in Finland suggested that this drug might protect against sequelae in children with bacterial meningitis (Kilpi et al., 1995; Singhi et al., 2008). A large study in children with bacterial meningitis in several South American countries showed a significant decrease in sequelae, but there were several questions about the methodology of the trial (Peltola et al., 2007). A recent trial in Malawi in adults, however, showed that adjuvant glycerol was harmful and increased mortality (Ajdukiewicz et al., 2011). Therefore, there appears to be no role for treatment with adjuvant glycerol in bacterial meningitis in adults. For children the

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evidence is currently insufficient to justify routine glycerol treatment.

Other adjunctive therapies The management of adults with bacterial meningitis can be complex and common complications are meningoencephalitis, systemic compromise, stroke and raised intracranial pressure (Fig. 93.2). Various adjunctive therapies have been described to improve outcome in such patients, including anti-inflammatory agents, anticoagulant therapies, and strategies to reduce intracranial pressure (ICP) (van de Beek et al., 2006b). Few randomized clinical studies are available for other adjunctive therapies than corticosteroids in adults with bacterial meningitis. Recently a randomized controlled trial was published on adjuvant high dose paracetamol in children with bacterial meningitis in Luanda. The trial was performed in a 2
2 design in which simultaneously slow infusion of antibiotics was compared to bolus injection of antibiotics. No benefit on the primary endpoints were observed in any of the treatment groups (Pelkonen et al., 2011). A Dutch cohort study evaluated the effects of complications on mortality in patients with pneumococcal meningitis and compared these findings among different age groups. In older patients ( 60 years), death was usually a result of systemic complications, whereas death in younger patients (1200 mg per day encouraged) for 10–12 weeks; (5) itraconzole (200 mg twice per day orally) for 10–12 weeks, although the use of this drug is discouraged. Maintenance or suppressive therapy includes: fluconazole (200 mg/day) or itraconazole (200 mg twice per day orally). Consider discontinuing suppressive therapy during HAART in patients with a CD4 cell count 1100 cells/mL and an undetectable or very low HIV RNA level sustained for 3 months (minimum of 12 months of antifungal therapy); consider reinstitution of maintenance therapy if the CD4 cell count decreases to 2 weeks þþ Extracranial involvement  Cryptococcomas þþ Mortality þþ Raised intracranial pressure  Positive India ink 50% Cerebrospinal fluid antigen > 1:1024 þ Serum antigen þ Cerebrospinal fluid culture 75%

þ þþþþ  þþþ þþ 80% þþþþ þþþþ >90%

(Reproduced from Satishchandra et al., 2007, with permission.)

(II) Patients otherwise healthy hosts: the induction therapy consists of AmBd (0.7–1.0 mg/kg/day IV) plus flucytosine (100 mg/kg/day in four divided doses) for at least 4 weeks; this treatment is for patients without neurologic complications and CSF-negative yeast cultures after 2 weeks of treatment. Consider extending induction therapy for a total of 6 weeks, and lipid-based AmB may be given for the last 4 weeks of the prolonged induction period, followed by consolidation with fluconazole (400 mg per day) for 8 weeks. If the patient is AmBd intolerant, substitute liposomal AmB (3–4 mg/ kg/day IV) or ABLC (5 mg/kg/day IV). After induction and consolidation therapy, patients are kept on maintenance therapy with fluconazole (200 mg (3 mg/kg) per day orally) for 6–12 months. Elevated intracranial pressure is an important contributor to morbidity and mortality of cryptococcal meningitis, in both HIV-negative and HIV-positive patients. The guidelines (Saag et al., 2000; Perfect et al., 2010) for the management of elevated intracranial pressure in patients with cryptococcal meningitis, both HIVnegative and HIV-positive, include: (1) in patients with normal baseline opening pressure ( 400 mm H2O) may require lumbar drain. In patients in whom the above measures fail to control elevated pressure symptoms or when persistent or progressive neurologic deficits are present, a ventriculoperitoneal shunt is indicated. The reported mortality in HIV-associated cryptococcal meningitis even in the context of amphotericin Bbased therapy has ranged from 22% to > 40% (Imwidthaya and Poungvarin, 2000; Brouwer et al., 2004). In the US Mycoses Study Group treatment trial of HIV-associated cryptococcal meningitis had a mortality of 9.4% at 10 weeks (Van der Horst et al., 1997). Mortality associated with cryptococcal infection peaked in 1989 at 0.67 deaths per 100 000 persons; 96% of deaths were in HIV-positive patients (McNeil et al., 2001). The factors associated with mortality are poor mental status at presentation, elevated intracranial pressure, lack of headache, underlying hematologic malignancy (Kovacs et al., 1985; Pappas et al., 2001) and low CSF glucose levels and cell count (Diamond and Bennett, 1974). The neurologic sequelae in cryptococcal meningitis include cognitive impairment, visual loss, motor impairment, and cranial neuropathy (Satishchandra et al., 2007).

Central nervous system candidal infections Candida spp. form part of normal human microbial flora and rarely can cause invasive disease unless the host defenses have been compromised. Most cases are due to C. albicans, with very few reports of C. glabrata and other species causing infection. Patients with AIDS or neutropenia are at risk for candidial infections. Burns, critical illness, and the use of central venous catheters may allow systemic disease to develop in otherwise immunocompetent individuals. Candidial meningitis mostly occurs in neonates, neurosurgical patients, and immunocompromised patients (Black and Baden, 2007). CNS infection usually occurs as a manifestation of disseminated candidiasis and can also occur as a complication of a neurosurgical procedure, CSF shunt placement, or by direct inoculation during surgery, and rarely following head trauma. Candida seeding the CNS may lead to meningitis or abscesses, most commonly microabscesses throughout the brain parenchyma. Large solitary brain abscesses and epidural abscesses have been reported (Burgert et al., 1995; Bonomo et al., 1996; Sanchez-Portocarrero et al., 2000; Vazquez and Sobel, 2003). C. glabrata causes a more insidious form of meningitis (Perfect, 2004). Basal meningitis results in cranial neuropathies and sometimes stroke syndromes from an invasive arteritis (Burgert

FUNGAL INFECTIONS OF THE CENTRAL NERVOUS SYSTEM

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Table 95.3 Fungal pathogens and antifungal agents Antifungal agent Drug toxicity - type Polyene antibiotic Amphotericin B Nephrotic (þþþ/þþþþ)* Liposomal amphotericin Hepatic (þþ) Amphotericin B lipid complex Hematologic (þ) Electrolytic abnormalities (þþ/þþþþ)* Azole Voriconazole Hepatic (þ), electrolyte abnormalities (þ) Ketoconazole Itraconazole Hepatic (þ), electrolyte abnormalities (þ) Fluconazole Hepatic (þ) Posaconazole Hepatic (þ) Echinocandin Caspofungin Hepatic (þ), Hematologic (þ), Electrolyte abnormalties (þ) Micafungin Hepatic (þ), Hematologic (þ) Anidulafungin Hepatic (þ), electrolyte abnormalities (þ) Pyrimidine analog Flucytosine Hepatic (þþ), Hematologic (þþþ), electrolyte abnormalities (þ)

Fungal pathogen

Aspergillus, Candida, Cryptococcus Coccidioides, Blastomyces Histoplasma, Zygomycetes Dematiaceous fungi Aspergillus, Candida,Coccidioides Histoplasma, Paracoccidioides Blastomyces (normal host) Aspergillus Cryptococcus, Candida Coccidioides, Aspergillus

Candida, Aspergillus Candida Candida

Candida, Cryptococcus Aspergillus, Chromoblastomyces

Plus signs indicate the degree of toxicity: (þ) mild, (þþ) moderate, (þþþ) severe; electrolyte abnormalities include hypkalemia and hypomagesemia. *Nephrotoxicity and electrolyte abnormalities are less with liposomal amphotericin and amphotericin lipid complex.

et al., 1995). Candidal microabscesses have an even more subtle presentation: typically only fever and vague encephalopathy may be present and focal deficits are rare (Black and Baden, 2007). Infection of a neurosurgical device may manifest merely as shunt malfunction (Sanchez-Portocarrero et al., 2000). CSF typically demonstrates neutrophilic or monocytic cell response with low glucose. CSF adenosine deaminase levels may also be elevated. In severely immunocompromised individuals CSF may show almost no detectable CSF inflammatory response. Candida is identified by culture in most of the patients (Sanchez-Portocarrero et al., 2000; Davis et al., 2007). Neuroimaging is helpful in demonstrating meningeal enhancement, microabscess, or hydrocephalus (Fig. 95.3C, D) (Jain et al., 2007).

The primary treatment of CNS candidiasis includes liposomal AmB (3–5 mg/kg/day with or without flucytosine 25 mg/kg four times a day for several weeks followed by fluconazole 400–800 mg (6–12 mg/kg) daily. Alternative therapy for patients unable to tolerate liposomal AmB includes fluconazole 400–800 mg (6–12 mg/kg) daily. Treatment should be for the time all signs and symptoms, CSF abnormalities, and radiologic abnormalities have resolved. Removal of intraventricular devices is recommended (Pappas et al., 2009).

Central nervous system aspergillosis Aspergillus, a genus of filamentous fungi, is ubiquitous throughout the world and can be found in the air of most buildings, including hospitals. A. fumigatus is the most

1396 J.M.K. MURTHY AND C. SUNDARAM common pathogen; other identified pathogenic species Duration of therapy for most conditions for aspergillosis include A. flavus, A. terreus, and A. niger. Invasive has not been optimally defined. Most experts attempt to CNS aspegergillus infection is primarily seen in immutreat infection until resolution. nocompromised individuals, mostly neutropenic In most series of intracranial aspergillus granulomas, patients, and occurs by hematogenous spread, usually postoperatively IV conventional amphotericin B was the from a focus in the respiratory tract. CNS involvement standard treatment and the mortality with this therapy may also occur by direct extension of the infection from was very high (Rajshekhar, 2007). Preoperative adminissinuses, nose, and ear canal (Figs 95.1, 95.4A, 95.2B) and tration of intraconazole for a week has been shown to rarely by direct inoculation after head trauma or surgery. improve outcome in patients with intracranial aspergilloThe sinocranial form of CNS aspergillosis is often sis (Siddiqui et al., 2004). The pathology of aspergillus reported from countries with a temperate climate, often granulomas in otherwise immunocompetent individuals in immunocompetent individuals (Murthy et al., 2001; shows dense fibrosis. This may not permit the systemically Sundaram et al., 2006). The pathology of hematogenous administered amphotericin B to achieve intralesional therdissemination to CNS, because of the angioinvasive apeutic concentration (Murthy et al., 2001). To achieve character of Aspergillus, includes ischemic infarction maximum cure, radical resection of the lesion followed and hemorrhage, and the pathology in sinocranial asperby postoperative variconazole may be the treatment of gillosis is characterized by well formed granulomas choice in patients with intracranial aspergillomas. How(Fig. 95.4C, D) (Sundaram et al., 2006). ever, we need well designed trials to establish this treatThe clinical presentation of CNS invasive aspergilloment approach in these patients. sis is characterized by the angiinvasive predilection of the Aspergillus spp.; stroke-like syndromes: cerebral Rhinocerebral zygomycosis infarction, hemorrhage, mycotic aneurysm. Meningitis and meningoencephalitis can also occur. Rarely spinal The organisms of the class Zygomycetes are ubiquitous in soil and are commonly found in decaying organic matsyndromes can be the presenting feature (Murthy, ter, such as fruit and bread. Medically the most impor2007). Patients with sinocranial aspergillosis may present with features of intracranial focal mass lesions, skulltant pathogenic moulds include Mucor, Rhizopus, base syndromes: orbital apex syndrome, cavernous sinus Rhzomucor, Absidia, Cunninghamella spp. Clinical syndrome, proptosis with or without ocular nerve manifestations of zygomycosis can be classified by the palsies, polyneuritis cranialis, and orbitocranial syntissue site affected. Rhinocerebral disease is the most dromes (Murthy, 2007). common form of zygomycosis and most commonly In addition to cultures, CSF polymerase chain reacoccurs in the setting of diabetic ketoacidosis. Other risk factors include renal failure, injectable drug use, and tion and galactomannan antigen tests may be of help direct implant during neurosurgical procedures. In a in establishing the diagnosis (Maertens et al., 2001). Neuroimging, particularly in patients with sinocranial asperlarge series of zygomycosis, 283 cases involved the brain: gillosis, may be diagnostic (Jain et al., 2007). A definitive 87 cerebral only and 196 rhinocerebral. Of note, among diagnosis may require brain tissue for histopathologic injectable drug users, hematogenous spread was more examination. common, and 62% of the 45 cases were cerebral, with Variconazole (6 mg/kg IV every 12 hours for 1 day only 5% rhinocerebral (Roden et al., 2005). Manifestafollowed by 4 mg/kg IV every 12 hours, oral dosage tions of the disease may reflect the sequential involvement of the nose, sinuses, eye, and brain. 200 mg twice a day) is recommended for the primary Manifestations of cavernous sinus thrombosis include treatment of invasive aspergillosis, both pulmonary and extrapulmonary. Liposomal AmB (3–5 mg/kg/day loss of vision, internal and external ophthalmoplegia. IV) could be considered as alternative primary therapy Thrombosis of the internal carotid artery can also occur in some patients (Walsh et al., 2008). In a recent review, and causes contralateral hemiplegia. The complaints of of the 81 patients with cerebral aspergillosis treated with paranasal sinus symptoms, diplopia, or acute onset of variconazole, 28 (35%) patients had a positive response; blurred vision in a diabetic or immunocompromised indiall of them required surgical resection as well (Schwartz vidual should alert the clinician for early recognition of the disease (Fig. 95.8A–D). et al., 2005). Salvage therapy for patients refractory to or Neuroimaging is of help in visualizing the affected intolerant of primary antifungal therapy: liposomal AmB (3–4 mg/kg/day IV), ABLC (5 mg/kg/day IV), area and is also of help in obtaining the tissue for idenposaconazole (initially 200 mg/day oral then 400 mg tifying the organism by stains and cultures. Overall, cultwice a day oral), or micagungin (100–150 mg/day IV). tures are positive in 40–70% of biopsy-proven cases. Refractory infection may respond to a change to another More specific molecular methods such as nucleic acid drug or to a combination of agents (Walsh et al., 2008). amplification techniques are being investigated.

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Fig. 95.8. (A) Photomicrograph of a patient showing proptosis of left eye (rhino-orbital zygomycosis) and left facial weakness. (B) Photomicrograph showing necrotic palate (ishar) in a diabetic male with an acute right rhino-orbital zygomycosis. (C) Photomicrograph showing broad aseptate, irregularly branching hyphae of Zygomycetes (H&E 10). (D) Photomicrograph delineating the broad aseptate hyphae of Zygomycetes (Gomori’s methenamine silver 40).

Zygomycosis treatment requires aggressive surgical debridement of necrotic tissue and antifungal therapy. Antifungal therapy includes high-dose IV amphotericin B, 1.2–1.5 mg/kg/day of the conventional formulation or 3–10 mg/kg/day of lipid formulation. In most studies, a total dose of at least 2 g of amphotericin B is given; in some cases even up to 4 g. Posaconazole has been shown to be an effective therapy in zygomycosis including CNS zygomycosis. A typical oral daily dosage of posaconazole is 800 mg, given as two or four divided doses and therapy tends to be protracted (Black and Baden, 2007). Surgical debridement has been a key component of treatment of zygomycosis and survival rates are much better in patients treated with combined medical and surgical therapy than in patients treated with medical therapy only (Gonzalez et al., 2002). The estimated mortality associated with cerebral zygomycosis is 79% and for disseminated infection with CNS involvement is 98%, while morality for both localized cerebral and rhinocerebral infection is about 62% (Warwar and Bullock, 1998; Roden et al., 2005).

Blastomycosis B. dermatitidis is endemic in Africa and in certain parts of the Mississippi valley, north central states, and midAtlantic states in the continental US. CNS involvement with B. dermatitidis is an uncommon and potentially fatal complication of blastomycosis. It occurs in less than 5% among immunocompetent individuals and in

as high as 40% in patients with AIDS (Chapman et al., 2008). The neurologic presentations include: brain abscess, epidural abscess, meningitis, concomitant meningitis and mass lesions and osteomyelitis. CNS blastomycosis usually presents with evidence of infection at other sites (Bariola et al., 2010). Amphotericin B, lipid formulation, at a dosage of 5 mg/kg per day for 4–6 weeks followed by an oral azole is the recommended treatment. Possible options for azole therapy include fluconazole (800 mg per day), itraconazole (200 mg two or three times per day), or voriconazole (200–400 mg twice per day) for at least 12 months and until resolution of CSF abnormalities (Chapman et al., 2008). Surgical drainage of an epidural abscess or brain abscess may be necessary in limiting morbidity and mortality from this disorder (Serody et al., 1993).

Coccidioidomycosis C. immitis has geographic distribution in the southwestern US and in parts of Mexico and South America. Coccidioides species are the most common etiologic agents of chronic meningitis in regions endemic for coccidioidomycosis. Occasionally, even short-term travel to endemic regions results in the acquisition of meningeal disease. Immunocompromise, most commonly HIV/ AIDS, and chronic steroid therapy increase risk, but diabetes is also a risk factor. A male preponderance has been noted. The principal feature of CNS dissemination is chronic basilar meningitis with complications including

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hydrocephalus and vasculitic infarcts (Evans, 1909; Williams, 2007; Drake and Adam, 2009). CSF anticoccidioidal antibody and culture are frequently negative on presentation, but the serum antibody test is usually positive. Imaging studies are helpful in establishing the diagnosis, and most commonly demonstrate basilar meningitis or hydrocephalus (Drake and Adam, 2009). Fluconazole (400 mg per day) is the current preferred treatment. Itaconazole, administered in dosage of 400–600 mg per day, has also been reported to be comparably effective. Patients who respond to azole therapy should continue this treatment indefinitely. Patients who do not respond to fluconazole or itraconazole would be candidates for intrathecal amphotericin B, 0.1 mg and 1.5 mg per dose administered at intervals ranging from daily to weekly therapy with or without continuation of azole treatment. Hydrocephalus most often requires ventriculoperitoneal shunting (Galgiani et al., 2005). The prognosis depends on the early recognition and treatment of the disease. In those whose disease is identified early and who remain on lifelong treatment with azoles, the prognosis is typically good (Drake and Adam, 2009).

Histoplasmosis H. capsulatum is endemic in certain areas in the Ohio and central Mississippi valley and in Latin America. One-tenth to one-fourth of patients with disseminated histoplasmosis develops CNS histoplasmosis. Patients with AIDS are a higher risk to develop disseminated disease. However, it can also occur in apparently normal hosts. CNS histoplasmosis includes meningitis, parenchymal lesions of the brain and/or spinal cord, or both. The drug treatment of CNS histoplasmosis includes liposomal amphotericin B (5.0 mg/kg daily for a total of 175 mg/kg given over 4–6 weeks) followed by itraconazole (200 mg two or three times daily) for at least 1 year and until resolution of CSF abnormalities, including Histoplasma antigen levels. Blood levels of itraconazole should be obtained to ensure adequate drug exposure (Joseph-Wheat et al., 2007). CNS histoplasmosis has lower response and higher relapse rates to the available therapies than other forms of Histoplasma infections (CNS). Although resection of brain or spinal cord lesions has been reported, surgery is rarely needed and should be performed only with progressive clinical findings despite receipt of antifungal therapy (Joseph-Wheat et al., 2007).

CONCLUSION Fungal infections of the CNS have been increasingly recognized over the last few decades, mostly due to the expansion of the immunocompromised population at risk and also increased awareness and the advances in

the diagnostic techniques. However, there is considerable delay in the diagnosis as the available diagnostic techniques are often inadequate in most clinical circumstances. With the new antifungal drug development most of the fungal infections can be salvageable if suspected and diagnosed early.

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Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 96

Rickettsiae, protozoa, and opisthokonta/metazoa ERICH SCHMUTZHARD* AND RAIMUND HELBOK Department of Neurology, Medical University Hospital Innsbruck, Innsbruck, Austria

RICKETTSIAE (INFECTION WITH RHIZOBIALES) Introduction Rickettsiae are small, intracellularly growing bacteria which are transmitted by a wide variety of arthropods and cause acute disease with fever, headache, joint-ache, myalgia and frequently skin lesions. A specific peculiarity of rickettsial infections is complicating courses with diffuse hemorrhages, encephalitis, myo- or endocarditis, pancarditis, pneumonia, and involvement of other organs (Bernabeu-Wittel and Segura-Porta, 2005; Stein and Raoult, 2006; Moerman and Vogelaers, 2009; Glaser et al., 2010; Knobloch and L€ oscher, 2010; Raoult, 2010). A local skin lesion at the area of the arthropod bite is usually an important clue to diagnosis (so-called eschar or tache noire). The order Rickettsiales contains three genera, Rickettsia, Coxiella, and Orienta. In addition, Bartonella spp., Ehrlichia spp. and Anaplasma spp. are included in the group of rickettsial infections (Glaser et al., 2010; L€ oscher, 2010; Knobloch and L€ oscher, 2010). Rocky Mountain spotted fever, typhus, tsutsugamushi fever, Q fever, bartonelloses, ehrlichioses, and anaplasmoses are of potential importance to the neurologist (Parola et al., 2009; Glaser et al., 2010).

infectious disease and tropical medicine publications. Only those causing neurologic disease are discussed in more detail here (Parola et al., 2008, 2009; Socolovschi et al., 2009; Glaser et al., 2010; L€oscher, 2010). Table 96.1 lists the more important Rickettsia species causing human disease.

Clinical manifestations Rickettsiaceae/Rhizobiales are small Gram-negative rods which only can grow inside cells, except Bartonella and Wolbachia species. The clinical spectrum of Rhizobiales may be grouped as (Stein and Raoult, 2006; Suputtamongkol et al., 2009; Knobloch and L€oscher, 2010; L€oscher, 2010): ● ● ● ● ● ● ●

tick-borne rickettsial diseases ( ¼ spotted fever group) typhus group scrub typhus Q fever bartonellosis ehrlichiosis anaplasmosis.

Table 96.2 details the systemic and neurologic manifestations and their prognosis.

Therapy Pathogens Very recently, the order Rickettsiales has been renamed Rhizobiales, to which — in addition to the Rickettsiales – Bartonella, Ehrlichia and Anaplasma species also belong. Rhizobiales grow intracellularly, and usually a very low infectious dose is sufficient to cause disease. The taxonomic peculiarities as well as the majority of the infections by Rhizobiales (Rickettsiaceae) will not be discussed in this chapter; for this the reader is referred to

Early recognition and appropriate treatment reduces morbidity and mortality of rickettsial infections of the nervous system. Rational antimicrobial therapy for rickettsioses would be doxycycline in mild cases and a combination of a third-generation cephalosporin (either cefotaxime or ceftriaxone) with doxycycline in severe cases, i.e., in the typical case of rickettsial infection of the nervous system. Azithromycin can be considered as an alternative treatment when doxycycline allergy is

*Correspondence to: Erich Schmutzhard, M.D., Department of Neurology, Medical University Hospital Innsbruck, Anichstrasse 35, A-6020 Innsbruck, Austria. Tel: þ43-512/504-23853, Fax: þ43-512/504-24243, E-mail: [email protected]

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Table 96.1 Rickettsiales (Rhizobiales), epidemiologic features

Clinical group

Disease

Pathogen of (potentially) neurologic importance

Typhus group Rickettsiales

Epidemic typhus

Rickettsia prowazekii

Louse borne

Murine (endemic) typhus Rocky Mountain spotted fever (RMSF) Many other spotted fevers, including new rickettsioses (e.g., R. africa, R. helvetica, R. slovaca, etc.) Scrub typhus (tsutsugamushi fever)

R. typhi ( ¼ R. mooseri) R. rickettsii

Flea borne (rarely louse borne) Tick borne

See specific infectious disease literature (very rarely affecting the nervous system)

Tick borne (rickettsial pox: transmitted by mite)

Usually: R. species named after their geographical distribution

Orienta tsutsugamushi

Mite (larvae)

Coxiellosis (Q fever)

Coxiella burnetii

Bartonellosis

Cat scratch fever

Ehrlichia

Human monocytic ehrlichiosis

Anaplasmosis

Human granulocytic anaplasmosis

B. bazilliformis B. elizabethae B. henselae B. quintana and others Ehrlichia spp., e. g., E. chaffeensis and others Anaplasma phagocytophilum and others

Tick borne or by aerosol Phlebotomes Flea borne Louse borne Partially not known

South-, South-East-, East-Asia, Papua New Guinea Worldwide

Spotted fever group Rickettsiales

Scrub typhus (tsutsugamushi fever) Coxiellosis (Q fever)

suspected or when doxycycline should not be given. In most instances both therapeutic regimens should be curative, leading to defervescence and improvement of neurologic signs and symptoms within 2–3 days. Little is known about the optimal duration of therapy. Doxycycline should be given – in a dosage of 200 mg/day in the adult – for 5–10 days. Azithromycin is given in a dosage of 500 mg daily; again not much is known about the optimal duration of this therapy. In contrast, Q fever endocarditis, caused by Coxiella burnetii infection, requires a long-term (months) antimicrobial chemotherapy, e.g. doxycycline 200 mg/day, combined with hydroxychloroquine (200 mg three times a day). Alternatively rifampicin (300 mg/day) can be combined with doxycycline (200 mg/day) or ciprofloxacin (750 mg/day). This antimicrobial chemotherapy must be continued until the

Transmission

Tick borne

Tick borne

Geographical distribution Focal areas, worldwide Focal areas, worldwide US, Central America, Brazil

South America Worldwide

US Europe Asia US Europe Asia

specific phase I IgA serum antibodies drop to levels of 1:50 (or likewise: phase IgG serum antibodies to levels of 1:200) (Shaked, 1991; Stein and Raoult, 2006; Knobloch and L€oscher, 2010; L€oscher, 2010).

PROTOZOA AND METAZOA (OPISTHOKONTA) OF THE NERVOUS SYSTEM For reasons of tradition, in medicine and veterinary medicine, protozoa and opisthokonta (metazoa) are subsumed under the term “parasites.” Among these are numerous pathogens, particularly in tropical and subtropical regions, that cause disease, neurologic long-term sequelae, and millions of deaths per year. Even in central Europe and in North America parasites exist that cause

Table 96.2 Rickettsiales (Rhizobiales): clinical manifestations Disease

Pathogen

Systemic manifestations

Neurologic features

Death rate

Epidemic typhus

R. prowazekii

Encephalopathy Meningovasculitis

Up to 15%

Endemic (murine typhus) Rocky Mountain spotted fever

R. typhi R. rickettsii

Usually mild rash (hemorrhagic) High fever “Typhus” See epidemic typhus, but definitely milder Severe myalgia, maculopapular, pupuric rash, multiorgan involvement

Scrub typhus (tsutsugamushi fever) Coxiellosis (Q fever)

R. tsutsugamushi

General rash, tache noire

C. burnetii

Bartonellosis Wolhynian fever Carrio´n disease (Oroya fever, verruga peruana) Cat scratch disease

B. quintana B. bacilliformis

B. henselae

Acute Q fever “Nonspecific” flu-like illness, hepatitis, atypical pneumonia endocarditis Fever, myalgia Multiorgan failure Hemolytic anemia Pneumonia, myocarditis Skin lesions Bacillary angiomatosis

Ehrlichiosis

E. chaffeensis

Human anaplasmosis

Anaplasma spp.

Human monocytotrophic ehrlichiosis (HME) unspecific symptoms, fever, rash, multiorgan involvement, anemia, granulocytopenia, thrombopenia See human monocytotrophic ehrlichiosis

Severe headache Severe quantitative (delirium) and qualitative (coma) impairment of consciousness, seizures, focal signs (!meningovasculitis or encephalitis) Meningitis, encephalitis, deafness Headache, cardiac embolism Very rarely: meningoencephalitis

93% respectively (da Silva Ribeiro et al., 2010; Deckers and Dorny, 2010; Handali et al., 2010). Antigen ELISA may add to diagnostic accuracy, even in the absence of neuroimaging (Gabriel et al., 2012). In rare cases calcified Cysticercus cellulosae cysts can be found in the skeletal muscles, allowing easy bioptic proof. In case of obstructive hydrocephalus (intraventricular cyst) leading to hydrocephalus, or in case of intractable increased intracranial pressure, neurosurgical intervention may be necessary to relieve the acute lifethreatening condition, and will also allow neuropathologic

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Fig. 96.3. Intracranial calcification with perifocal edema in a student from India with focal motor seizures.

Fig. 96.4. Racemose form of neurocysticercosis presenting as chronic meningitis and lower brain stem/upper cervical medullary syndrome.

proof of the disease. Rarely encephalitic and angiitic courses have been described (Serpa et al., 2006). Treatment. Both the location of the parasitic cyst and the stage determine the treatment of neurocysticercosis. Generally, the best clinical management of neurocysticercosis includes anthelmintic drugs, anti-inflammatory

drugs, antiepileptic drugs, and, if indicated, surgery/ neurosurgery. Praziquantel and albendazole are the most commonly used drugs in the treatment of neurocysticercosis. Both drugs are satisfactorily efficacious and equally satisfactorily tolerated. Praziquantel is given in a dosage of 50 mg/kg bw per day for 15 days, although other doses and other durations have also proven to be efficacious and tolerable. Albendzole should be given in a dose of 15 mg/kg bw per day for at least 1 week, possibly for up to 1 month. The comparison between praziquantel and albendazole has produced conflicting results, although albendazole seems to be more efficacious than praziquantel (Abba et al., 2010). It seems to be beyond doubt that anthelminthic therapy should be used in patients with viable or degenerating cysts in the brain parenchyma or in the subarachnoid space. Whether anthelmintic drugs should accompany the neurosurgical excision of a single ventricular cyst has not been adequately studied; however, it is recommended, since in rare cases a viable cyst might rupture during its neurosurgical extraction, possibly causing spread of the scolices. Corticosteroids are recommended in the therapy of active neurocysticercosis (Ramirez-Zamora and Alarcon, 2010). Antiepileptic therapy must be given to all neurocysticercosis patients with epilepsy, even if antiparasitic therapy may play a role in reducing the frequency of seizures. The fact that patients who were seizure-free while under antiepileptic treatment suffered relapses after drug discontinuation indicates that even dead intracranial cysticerci may be a permanent substrate for seizures (Nash et al., 2006). It is recommended that patients with epilepsy and neurocysticercosis should be kept on anticonvulsive therapy as long as any other patient with symptomatic epilepsy (Sinha and Sharma, 2009). Neurosurgery still plays an important role in relieving acute intracranial hypertension secondary to ventricular cysticerci or due to an agglomoration of several cysts. An obstructive hydrocephalus may need both cyst removal and shunt placement during the same neurosurgical session. Concurrent administration of anthelmintic drugs and/or steroids is advisable. Very recently endoscopic resection of intraventricular cysts has been employed successfully resulting in fewer sequelae than open surgery (Rajshekhar, 2010). Prevention. Human neurocysticercosis has been identified as a potentially eradicable disease. On the other hand in certain geographic areas, such as central and especially eastern Africa, this disease is rising steeply due to the introduction of pig husbandry to bring about improvements in nutrition and living, but in the absence of close veterinary monitoring of slaughterhouses, abattoirs, etc. The current global efforts to eradicate taeniasis and neurocysticercosis are so far unsatisfactory although in certain regions nationwide control programs, strict

RICKETTSIAE, PROTOZOA, AND OPISTHOKONTA/METAZOA 1425 meat inspection, and improving sanitary conditions have symptoms of cystic echinococcosis of the CNS are virtubeen implemented; nevertheless the situation in rural ally always those of an extremely slowly growing spaceareas has not markedly changed, with pigs raised and occupying lesion (Turgut, 2002; Kalkan et al., 2007; slaughtered under traditional husbandry practices. In Midyat et al., 2009; Duishanbai et al., 2010; Limaiem some rural areas of tropical countries latrines are et al., 2010; Nourbakhsh et al., 2010). In extremely rare uncommon, and pigs still roam freely, conditions which cases spontaneous or trauma-induced cyst rupture facilitate the transmission of T. solium between humans may release protoscolices or smaller cysts which can and pigs (Willingham et al., 2010). The practice of using grow into larger cysts. In cyst leakage or rupture sysfresh human feces to fertilize crops may counteract all temic or neurologic “immunological responses” may official efforts to contain this helminthic disease, to occur, leading to acute inflammation, or even anaphybreak the transmission cycle and to render cysticercosis laxis (Rumana et al., 2006; Tuzun et al., 2010). control sustainable. Diagnosis. The definitive diagnosis of cystic echinococcosis of the nervous system – in a patient with the typEchinococcosis ical signs and symptoms of an extremely slowly growing space-occupying lesion – is established by neuroimaging, Two major species of medical and public health imporcerebral CT scanning or MR imaging being equally capatance exist, Echinococcus granulosus, causing cystic ble of detecting these intracranial cysts with “daughter” echinococcosis, and Echinococcus multilocularis, causcysts and protoscolices. In case of an intracranial or ing alveolar echinococcosis. Both may cause serious disintraspinal cyst, ultrasound (or CT) of the abdomen ease, the former more frequently affecting the CNS than and the thorax should be done in order to visualize the the latter, but the latter carrying a poor prognosis if manusually present hepatic (or pulmonary) cysts. aged incorrectly. Neither imaging technique is capable of assessing Cystic echinococcosis (hydatid disease) of the parasite viability; in case of only mildly symptomatic nervous system. Epidemiology — geographical distrior accidentally detected cystic echinococcosis of the bution. Echinococcus granulosus has been reported CNS follow-up CTs are recommended to assess the profrom more than 100 countries (Raether and Ha¨nel, gression of the cyst and thereby the viability of the par2003), including temperate, subtropical, tropical and asite (T€ uz€ un et al., 2002; B€ ukte et al., 2004; Tlili-Graiess even polar areas. The highest prevalences are found in et al., 2006; Kovoor et al., 2007). Serologic testing may parts of Europe, Asia, eastern Africa and South support the clinical signs and symptoms and the images; America. however, lumbar puncture for serodiagnostic tests of the The pathogenic agent. When ingested, Echinococcus CSF is usually contraindicated. Enzyme-linked immunogranulosus eggs hatch in the intestine and the released sorbant assay (ELISA), indirect hemagglutination antiembryos, called onchospheres, migrate through the mucosa body assay, latex agglutination test, immunoblot test, into the circulation, being spread to various internal organs immunofluorescence antibody test and arc-5 immunowhere they develop into cysts. These hydatid cysts develop electrophoresis are immunologic/serologic methods to mainly in the liver, rarely in the lungs of humans which are detect IgG serum antibodies. Hytatid cyst fluid, if availusually a dead end for the parasite. The regular intermediable, is the best material for immunodiagnosis. Beside ate hosts are sheep and other animals, whose offal is frethe techniques mentioned above, the lipoproteins antigen quently fed to the principal host, the dog. In dogs the B and antigen 5 – major components of hydatic cyst fluid – cestode develops in the intestine into the adult form, proare currently widely used for immunodiagnosis of ducing eggs, shed by the feces of the dogs, thus completing cystic echinococcosis (El-Arousy and Ismail, 2005; the life cycle. There are at least 10 distinct genetic types of E. Gavidia et al., 2008). Serodiagnosis may be hampered granulosus, some of them being more likely to have sheep, by cross-reactivity with antigens from other parasites, some cattle, and others horses as their intermediate host. in particular other taenidae. Molecular methods for The knowledge of these facts facilitates possible preventive direct detection of Echinococcus granulosus DNA by measures in highly endemic areas. means of PCR provides a highly sensitive and specific Clinical manifestations of hydatid disease (cystic approach, even being capable of differentiating cystic echinococcosis). The primary infection with Echinococechinococcosis from alveolar echinococcosis. cus granulosus goes unnoticed; small cysts never induce Therapy of hydatid disease. Incidentally detected signs and symptoms and may last for years. More than hydatid cysts do not need immediate treatment. Chemo90% of the cysts occur in the liver or lungs, or both. In therapy and surgery should be reserved for symptomatic other organs these cysts are rarely seen, and in maxilesions, especially in case of intracranial or intraspinal mally 2% these cysts are located in the brain, spinal space-occupying effect. Presurgical chemotherapy has canal, or skeletal muscles. The presenting signs and reduced recurrence rates by > 25%. Multiple cysts or

1426 E. SCHMUTZHARD AND R. HELBOK cysts in specific anatomic localizations may be inaccesVery recently, novel chemotherapeutic agents have sible for neurosurgical intervention. Strenuous efforts been identified, e.g., the pyridinyl imidazoles, the should be made to avoid intraoperative rupture. Without mitogen-activated protein kinases, amino acid transpreoperative chemotherapy the initial puncture and aspiporters and even the well known antimalarials dihydroarration technique to facilitate the in toto extirpation of the temisinin and artesunate (Hemphill et al., 2007; cyst may lead to recurrent cysts within the subarachnoid Gelmedin et al., 2008; Spicher et al., 2008). These drugs space, spinal canal, etc. The puncture, aspiration, injecneed further prospective evaluation. tion (of a protoscolicidal substance, e.g., 95% ethanol) and reaspiration ( ¼ so-called PAIR technique) is not Alveolar echinococcosis (central nervous practical in intracranial or intraspinal cysts, although system infestation by Echinococcus the PAIR technique in combination with chemotherapy multilocularis). Alveolar echinococcosis is caused by has been shown to be the most effective treatment stratEchinococcosus multilocularis which has extensive egy in hepatic cystic echinococcosis (Smego et al., 2003). endemic regions in central Europe, northern and central Mebendazole has been the cornerstone of anthelmintic Asia and parts of North America, and is virtually absent chemotherapy for cystic echinococcosis; in the last decade in the southern hemisphere. albendazole (10 mg/kg bw in divided doses, usually The pathogenic agent. The life cycle of Echinococcus 400 mg twice daily) reduces the size in up to three-quarters multilocularis is very similar to that of Echinococcosus and leads to complete disappearance in almost half of the granulosus, with the exception that in most cases the patients. Duration of albendazole therapy may be necesadult worms live in the intestine of wild carnivores, in sary for up to 6 months; the originally proposed 3 to 6 four particular foxes, and only extremely rarely in domestic weeks cycles with intervals of 14 days does not improve animals such as dogs. Accordingly, the animals that efficacy and does not decrease the rate of adverse effects. are their prey, namely rodents, are the principal intermeIn more than 90% the cysts are no longer viable after 3 diate hosts, the human intermediate host being a “dead months of therapy. Adverse effects of albendazole include end.” Infection may be acquired by eating wild bluenausea, neutropenia, hepatotoxicity, and alopecia. The berries, cranberries, etc. freshly contaminated with fox combination of albendazole with praziquantel (25 mg/ feces containing the eggs of E. multolocularis. kg/day) has shown a better efficacy than albendazole Clinical manifestations. Echinococcus multilocualone. Recently a newer benzimidazole compound (flularis causes alveolar echinococcosis with an incubation bendazole) has been used both alone and in combination period of up to 15 years and a subsequent chronic course, with ivermectin. Another biochemically similar comthe sixth and seventh decade being the typical peak for pound, oxfendazole, has been proven to be an adequate clinical presentation. The metacestodes develop almost treatment for animal cystic echinococcosis, though human exclusively in the liver of any intermediate host, i.e., also studies are still lacking. In pregnant women and in patients humans. In very rare cases alveolar echinococcosis prewith chronic hepatic diseases or bone marrow depression, sents as multiorgan disease and single cases of a “tumorbenzimidazole compounds should not be used (Chang and like” infiltration of the brain or spine have been reported Ko, 2000; del Brutto, 2006; Gavidia et al., 2010). so far, causing the signs and symptoms of a (very) slowly Chemotherapy should be initiated prior to neurosurgrowing space occupying tumor, the neurologic features gery; however, it is unknown how many days or weeks depending on its localization and possible secondary prior to neurosurgery should be recommended; simieffects (to blood vessels, cerebrospinal fluid flow, larly, little is known of how efficaciously benzimidazole etc.) (Yang et al., 2005; Senturk et al., 2006). compounds penetrate the blood–brain barrier. Within Diagnosis. The diagnosis of alveolar echinococcosis 1 month 70%, within 3 months more than 90% of extrashould be considered in a patient with an infiltratively cranial cysts are rendered nonviable. If the neurologic growing intracranial or intraspinal tumor who also signs and symptoms, in particular the space-occupying suffers from the same type of tumor in the liver and effect, allow a preneurosurgical chemotherapy of at has lived (even decades ago) in an area endemic for least 1 (perhaps even better up to 3) month(s), such an Echinococcus multilocularis (Kern, 2010). Neuroimaganthelminthic chemotherapy should be employed to ing allows “staging” of the disease, the WHO having reduce the danger of recurrence in case of aspiration proposed the PNM system (P ¼ parasitic mass in the being necessary or accidental cyst rupture during surliver, N ¼ involvement of neighboring organs, and gery. The latter necessitates continuing neuroimaging M ¼ metastasis) (Kern et al., 2006)), neurologic alveolar monitoring and continuing anthelmintic chemotherapy, echinococcosis usually qualifying as PNM stage 3. Simthe duration of which may be limited by adverse events ilar to cystic echinococcosis, serologic testing provides and should be guided by clinical and, in particular, close an adjunctive role in early, i.e., possibly presurgical, neuroimaging follow-up. detection of the infection. Early diagnosis is of utmost

RICKETTSIAE, PROTOZOA, AND OPISTHOKONTA/METAZOA 1427 importance since alveolar echinococcosis carries a high cases in international travelers or migrants. Most cases fatality rate. are reported from the Far East. It is estimated that Treatment. Earliest possible diagnosis of alveolar around 5% of all sparganosis cases present with CNS echinococcosis possibly reduces the rate of unresectinvolvement (Wiwanitkit, 2005). Noninvasive neuroimable lesions. Pre-, peri- and postoperative long-term aging techniques, such as CT and MRI, allow more accuchemotherapy with albendazole (20 mg/kg bw/day) rate diagnosis of all types of intracranial helminthic has improved survival. So far, this drug has been shown infection (Song et al., 2007), and also sparganosis. to be the only parasitostatic agent against these metaConsumption of frogs and snakes are known risk faccestodes and in any case of E. multilocularis infestators, but infections due to the consumption of meat from tion chemotherapy must be continued for at least 2 other animals definitely occur. In China infection rates years postneurosurgery. So far, no technique is availof > 60% in frogs offered in markets (Berger et al., able to determine the appropriate point of time when 2009) have been reported. Since many snakes prey on it may be stopped. Very recently, a combination therfrogs, the infection rate in snakes is high. More than a apy of albendazole with an antitumor compound third of sparganosis patients from China have a history (2-methoxyes-tradiol) (Spicher et al., 2008) as well as of recently eating frogs and snakes (Ou et al., 2010). Raw drugs aiming at some E. multilocularis amino acid snake blood and snake bile are even popular in some transporters and the antimalarials dihydroartemisinin areas. Eating live tadpoles as a traditional remedy, or and artesunate have been tested, holding some promise the application of raw frog meat or tadpoles onto skin of efficacy, warranting further urgent investigation in ulcers, open wounds or even oral ulcers definitely constihumans (Kern, 2010). tute ways to acquire this disease. Prevention of human echinococcosis. Occupational Pathogen. Human neurosparganosis is caused by the and behavioral factors may influence exposure to Echisparganum of Spirometra spp. The life cycle of Spironococcus eggs. Being the owner of a dog, taking one’s metra is complex, involving three hosts. The adult worms water supply from wells, and having no knowledge of live in the intestine of carnivores (dogs, cats), their eggs echinococcosis or Echinococcus species (as parasites) being passed in the feces into fresh water where they have been shown to be risk factors for developing both hatch releasing the first stage larvae, the coracidia. cystic or alveolar echinococcosis (Yang, 2006). Avoiding The first intermediate host, Cyclops spp., consume these contact with dog or fox feces, reducing the respective larvae, which develop into the procercoids dwelling in animal populations, hand washing and improved water these cyclops. When these cyclopses are ingested by supply and sanitation as well as treating the dogs with the second intermediate host, such as frogs, the larvae anthelmintic drugs and incinerating infected organs of penetrate the intestinal wall, migrate to other organs, intermediate hosts (e.g., of sheep with cystic echinococin particular skeletal muscles, where procercoids cosis) and, of utmost importance, health education may develop into spargana. A wide variety of paratenic hosts be efficacious control measures to reduce prevalence of are known; they include reptiles, amphibians, and even cystic and/or alveolar echinococcosis (Yang et al., 2010). mammals. As soon as the second intermediate host or In geographically well circumscribed areas such control paratenic host is preyed upon by a cat or dog the sparmeasures have been successful, leading even to the elimgana develop into adult tape worms in their intestine ination of the disease (e.g., in Iceland, New Zealand, within up to 3 weeks. The adult worms have a life span Tasmania, Cyprus, provinces of Argentina and Chile of up to 4 years. Humans become accidental definitive (Craig et al., 2007). Control of E. multilocularis is much hosts, but also second intermediate hosts or “paratenic more difficult since the principal cycle is mostly sylvatic host” depending at which point of time during this cominvolving foxes and rodents, animals much more diffiplex life cycle of Spirometra they “enter the floor.” cult to approach compared to sheep and dogs. PraziquanAdult worms parasitizing the intestines of humans result tel baits may prove of value to control E. multilocularis in virtually no health problems whereas spargana (when infections in foxes. So far, only in one Japanese island the human is second intermediate host) may invade any has E. multilocularis been eliminated successfully, this organ or tissue, thus causing disease. How spargana having been achieved by completely eliminating the migrate to the CNS is not known. Summing up, humans fox and dog population from the island. are infected, first, by drinking water containing infected Cyclops spp., or, second, by ingesting the flesh of second intermediate or paratenic hosts harboring spargana Sparganosis (ingesting raw meat) and, third, by applying the flesh Epidemiology. More than 1400 human cases of spargaor skin of infected intermediate hosts as a poultice to nosis, rarely in the central nervous system, have been an open wound, or ulcers, allowing the sparganum to reported from almost 40 countries, including imported directly invade human tissue. Washing the eyes or rinsing

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the mouth with contaminated, cyclops-containing water may also be a way to acquire sparganosis. Clinical — neurologic manifestations. Neurosparganosis may have an extremely variable incubation period, even decades having been reported (Song et al., 2007). Subcutaneous sparganosis usually has an incubation period of weeks to months. The neurologic manifestation depends on the anatomic regions involved, focal neurologic signs and symptoms, headache and seizures being the most common neurologic features. The vast majority present with a long-standing history of seizures. In advanced diseases cognitive decline has also been reported. Very rarely, involvement of the spinal cord can be seen (Kwon and Kim, 2004), the signs and symptoms depending also on the location of the lesion. Diagnosis. A definitive diagnosis of sparganosis of the CNS relies on the histologic proof of a sparganum, either by surgery of a space-occupying, mainly cystic lesion, or by autopsy. History of exposure, clinical manifestations, focal neurologic lesions and neuroimaging might suggest the preoperative diagnosis, in particular, a history of specific behavior such as eating raw frogs, tadpoles, and snakes or drinking snake bile and blood (Lv et al., 2010). Eosinophilia may be present; however, because of the usually long duration of illness, a marked eosinophilia is frequently absent. Neuroimaging shows usually nodular or irregularly enhancing space-occupying lesions with spotty calcifications, sometimes extremely extensive and multifocal (Song et al., 2007). In the earlier course of CNS sparganosis extensive or multifocal areas of rather low density within the white matter, even focal cortical atrophy and ventricular dilatation may be seen (Wiwanitkit, 2010; Deng et al., 2011). Where available, MRI may be superior in sensitivity; however, its specificity has never been calculated or reported. Serologic testing for Sparganum-specific IgG antibodies has been used in specific areas (e.g., China); however, there is crossreactivity between Spirometra spp. and Taenia spp. In postcontrast MRI the so-called tunnel sign may be highly suggestive for sparganosis (Song et al., 2007). Intracranial primary or secondary brain tumors being the likeliest differential diagnosis, it seems to be worthwhile to note that in the earlier phase of CNS sparganosis imaging signs of larval migration (which is usually associated with eosinophilia) might hold, along with the appropriate history, an important differential diagnostic clue. Treatment. No systematic evaluation of anthelmintic drugs has been carried out so far, although single case reports indicate that praziquantel was not able to kill living spargana. If neurosurgical intervention succeeds in removing the living worms or the entire granuloma, the outcome may be improved (Nobayashi et al., 2006; Deng et al., 2011).

Coenurosis of the central nervous system The larval metacestode usually takes the form of a single cyst with multiple invaginated protoscolisces. This cyst may be several centimeters in diameter. The adult worm, T. multiceps, is a cestode of dogs, with sheep being the main intermediate host. Epidemiology. Single human cases have been reported from Africa, South America, North America, and southern Europe, mainly the island of Sardinia (Malomo et al., 1990; Ing et al., 1998; El-On et al., 2008). Pathogen. T. multiceps and possibly other closely related T. species are parasites of dogs, sheep being the principal intermediate host. The ingestion of eggs leads to the larval stage, i.e., the development of cysts with protoscolisces. The larval parasite has a clear tropism for the brain and eyes, although in very rare cases also intramuscular and other extracranial sites have been described (Benifla et al., 2007). Signs and symptoms. The typical signs and symptoms of coenurosis, i.e., the infection with the larva of Taenia multiceps and other Taenia species, are those of an intracranial space-occupying lesion with varying degrees of perifocal inflammation. Due to reasons not yet known, these cystic lesions are particularly common in the basal cisterns, leading frequently to a potentially lifethreatening compression of brainstem and occlusive hydrocephalus. The involvement of an eye may cause blindness. Diagnosis. The clinical signs and symptoms of a slowly growing space-occupying lesion should prompt neuroimaging, on CT (or MR) cysts > 2 cm without a clear internal structure may suggest cerebral coenurosis (Schellhas and Norris, 1985; Benifla et al., 2007). The diagnosis can only be confirmed by histological examination which allows the discrimination from neurocysticercosis, intracranial hydatidosis, and any other “tumor”. Treatment. No prospective randomized trials exist, Praziquantel has been given and appears to be effective against the parasite. Accompanying steroid therapy is recommended. The treatment of choice should be neurosurgical excision, the only curative option in many cases.

SECONDARY EFFECT OF INFESTATION WITH DIPHYLLOBOTRIUM LATUM Epidemiology. Diphyllobothrium latum occurs in many parts of the world, mainly in northern Asia, round the Baltic Sea, but also in the Danube delta, and even in fresh waters such as the Alpine lakes in upper Italy, Switzerland, and France. Rarely, it has also been found in northern America, in African countries, in Australia, Papua New Guinea, and South America. In the sub-Arctic

RICKETTSIAE, PROTOZOA, AND OPISTHOKONTA/METAZOA regions D. dendriticum and other species may cause infestation. Dogs, cats, bears, i.e., mammals feeding on fish, are the reservoir hosts (Lee et al., 2007). Pathogen. Raw or undercooked fish may be infected by plerocercoids of D. latum, which develop rapidly into adults in the small intestine (within less than 4 weeks). This tapeworm survives for many years and may produce up to a million eggs per day. The eggs are excreted with the feces; the first-stage larva, usually hatching in fresh water, is ingested by Cyclops species, which are in turn ingested by small fish which serve as prey for larger fish, In this way larvae may accumulate in large numbers in the meat of fish eaten by humans (Dick et al., 2001; Arizono et al., 2009). Clinical manifestations. In humans the adult worms reside in the small intestine, depending heavily on the host’s vitamin B12 supply and eventually causing vitamin B12 deficiency. This occurs mainly if the adult worm is located in the ileum; when D. latum resides in the duodenum, the risk of vitamin B12 deficiency is less. Since the adults may live for many years, even decades, the host may eventually develop the clinical signs and symptoms of polyneuropathy, funicular myelosis, and even optic nerve atrophy. Rarely, these neurologic signs and symptoms occur without manifest pernicious anemia (Markkanen et al., 1965; Scholz et al., 2009; Kim and Lee, 2010). Diagnosis. The detection of the typical eggs, in rare cases proglottids, in the feces is diagnostic. Serodiagnostic tests are of no use; sophisticated molecular biologic methods may be used to differentiate the various subspecies of Diphyllobothrium. The diagnostic workup of other causes for anemia and funicular myelosis includes gastroscopy, Schilling test, etc. It is noteworthy that in the case of Diphyllobothriasis the Schilling test does not show normalization by adding intrinsic factor. Therapy. A single dose of praziquantel (10 mg/kg bw) is the anthelmintic drug of choice with cure rates of more than 90%. Substituting vitamin B12 is done according to the hematologic and neurologic signs and symptoms.

Nematodes (roundworms) Thousands of nematodes may infest human beings causing an extremely wide variety of diseases ranging from mild to potentially fatal clinical manifestations. Some of the nematodes occur in strictly defined regions, others worldwide, nevertheless the majority of round worms affecting the CNS occur in tropical countries. In rare instances an immunosuppressive state enhances the invasiveness of round worms, e.g., in Strongyloides stercoralis hyperinfection syndrome. The mode of transmission is extremely diverse, ranging from ingestion of insufficiently cooked meat, playing with or handling dogs, cats, or racoons, insufficient sanitation, active

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penetration of the larva through the skin to infection by means of mosquito bites (Walker and Zunt, 2005).

NEUROFILARIOSES – LYMPHATIC FILARIOSES Epidemiology. Wuchereria bancrofti, occurring in tropical Africa, parts of Central and South America, as well in South-East Asia, Brugia malayi, occurring in South and South-East Asia, as well as Brugia timori (occurring on the island of Timor) are the causative agents of lymphatic filarioses. Prevalence of filarioses in endemic areas is high, reaching peak prevalence rates in the second decade (in up to 50% of the local population). The microfilariae are transmitted by mosquito bites (Anopheles spp. and/or Culex spp., with regional differences) (Taiwo and Tamiowo, 2007; Utzinger et al., 2010). Pathogen. Female and male adults, up to 100 mm long, live within lymph nodes and lymph vessels, mainly in the lower extremities and intra-abdominally. They produce, over years, thousands of microfilariae which circulate periodically in the peripheral blood (mainly nighttime). All stages of these filariae contain bacterial endosymbionts (genus Wolbachia) which are essential for the embryogenesis in the adult females. The average lifespan of female adults is 5 years; those potentially invading the CNS are seen within 6–9 months of infection. Clinical manifestations. The typical clinical signs and symptoms of lymphatic filariasis are not the subject of this chapter, lymphadenopathy, hydroceles, lymphatic varices, chyluria, elephantiasis, etc., being the main clinical manifestations. In very rare situations microfilariae may invade the eyes and, theoretically, also the CNS, causing the signs and symptoms of “larva migrans cerebralis.” Diagnosis. The history of exposure, the presence of other clinical signs and symptoms and eosinophilia (blood and CSF) may guide the diagnostic considerations. Recently, serologic tests (ELISA) as well as PCR techniques have supplemented the hitherto widely accepted diagnostic mean of night-blood film examination (Aron et al., 2002). Therapy. Diethylcarbamacin is the first drug of choice; however, it should be accompanied by doxycycline which depletes Wolbachia and leads in > 85% to the death of the adult worms. Ivermectin should be given whenever a rapid reduction of microfiliaria is urgent (e.g., in intracranial or intraocular manifestations); however, it should be accompanied by corticosteroids and doxycycline (del Brutto, 2006).

NEURO-ONCHOCERCOSIS In western African countries the Onchocerca volvulus eradication campaign has been started, involving the

1430 E. SCHMUTZHARD AND R. HELBOK treatment of the entire population in well defined may serve as intermediate and/or paratenic hosts, verteWest African areas with ivermectin once a year. This brate species may be naturally infected by the third stage has led to the impression of a reduction of the prevalence larvae of G. spinigerum; freshwater fish show high infecof epilepsies in the respective target populations. tion rates (Sieu et al., 2009). The increasing economic Neither serologic nor neuroimaging techniques have importance of aquaculture may even increase the risk of been employed in order to substantiate this assumption, developing gnathostomiasis (Rojekittikhun et al., 2004). which is based only these epidemiological observations Humans may acquire the infection through various food (Boussinesq et al., 2002; Druet-Cabanac et al., 2004; items and increased travel may be the explanation of Marin et al., 2006; Pion et al., 2009). an increasing percentage of travelers infected with In eastern Africa, southern Tanzania, and the Gnathostoma spp. (Samarasinghe et al., 2002; Cle´mentMahenge district, it has been known for several decades Rigolet et al., 2004; Ligon, 2005; Schmutzhard, 2007; that in the Wapogoro tribe (people living in the very Herman and Chiodini (2009) and Herman et al., 2009). remote Mahenge hills) both onchocercosis and epilepsy This is particularly true of travelers who mix with the are extremely prevalent. This fact eventually prompted a local population, consume local delicacies, and accept detailed evaluation of onchocercosis possibly causing local cultural habits (Herman et al., 2009; Katchanov epilepsy. More than 200 epilepsy patients were thoret al., 2011). Nevertheless, in certain areas, such as Japan, oughly investigated by neurologists, detailed histories the prevalence of G. spinigerum has declined over the past were taken, and in virtually all patients lumbar puncture decades. was done. Those showing either focal neurologic signs Pathogen. Gnathostomiasis of the nervous system is and symptoms or diffuse encephalopathy were subjected caused by the larval migration of various Gnathostoma to MRI of the brain. In all patients skin snips were taken, species. G. spinigerum, is the most common species yielding a positive result for the presence of Onchocerca parasitizing humans, but G. hispidum, G. doloresi volvulus microfilaria in > 60%. Microfilaria were isoand G. nipponicum have also been reported to cause lated and finally used as antigen for serologic testing human disease. G. spinigerum is a common intestinal of both CSF and serum as well as for the development parasite of cats and dogs. Eggs are passed to the enviof a polymerase chain reaction test. In none of those ronment via the feces of the carnivorous mammals, and patients suffering from both epilepsy and onchocercosis when reaching fresh water they hatch within a week, of the skin could the presence of onchocercal microfilarreleasing free larvae which are then ingested by the first ial DNA or Onchocerca volvulus-specific antibodies in intermediate host, the copepods (water fleas), where the CSF be objectivized (K€ onig et al., 2010). they develop into second stage larvae. The infected For this reason a positive proof of the existence of a copepods are then ingested by the second intermediate disease called neuro-onchocercosis causing epilepsy is host, frogs, eels, snakes, fish, and reptiles, where they highly unlikely to exist. How the epidemiologic observadevelop into third stage larvae which start migrating tion in western Africa can be explained remains specuthrough the tissue of their second intermediate host, lative. It is possible that the improved medical and encyst in their host’s musculature. However, infecattention through this eradication program may have tive third stage larvae can also be passed from one host led to improved supply of anticonvulsive treatment, thus to another via predation and scavenging, thus making reducing the incidence of epileptic seizures in this popchicken and ducks feeding on frogs or snails paratenic ulation (K€ onig et al., 2010). hosts. Humans serve as nonpermissive definitive hosts or as “second intermediate host;” in the latter case the third stage larvae migrate through subcutaneous or visGNATHOSTOMIASIS OF THE NERVOUS SYSTEM ceral tissues, eventually reaching the central nervous Epidemiology. Human gnathostomiasis mainly occurs in system. Most likely the third stage larvae penetrate South-East and East Asia, but cases have been reported along nerve roots into the CNS (Punyagupta et al., from Central America, and very recently from southern 1990). Very rarely humans serve as definitive hosts, Africa. The cutaneous and visceral form is predominant; developing a tumorous lesion in the stomach wall where CNS involvement has been reported in large numbers the adult worms lodge. Since up to almost 50 vertebrate from Thailand, but in only a few cases from outside this species have been found to be naturally infected with country so far. A possible explanation could be that Gnathostoma species (Rojekittikhun et al., 2002), the Gnathostoma spinigerum is the most common species infection route of humans seems to be even more comresponsible for human cases in Thailand, whereas plicated. In rare cases drinking fresh water contamiother Gnathostoma species (G. hispidum, G. doloresi, nated with infected copepods (the first intermediate G. nipponicum, G. malaysiae, etc.) are more prominent host) has also been suggested as a route of infection; in other areas of endemicity. A large variety of animals possibly this route of infection is associated with a

RICKETTSIAE, PROTOZOA, AND OPISTHOKONTA/METAZOA 1431 higher risk of CNS gnathostomiasis (Samarasinghe In rare cases larvae can be isolated from subcutaneous et al., 2002). creeping eruptions, and even more rarely directly from Clinical manifestations. The incubation period of neuCSF. Immunologic tests for the diagnosis exist; however, rologic manifestations of gnathostomiasis is not known, there is cross-reactivity with other parasitic infections, ranging from weeks to possibly years. G. spinigerum mainly nematodes (Herman and Chiodini (2009), invades the CNS while migrating through the human body, Intapan et al., 2010). However, the typical signs and sympmostly by accident. The first signs and symptoms of larva toms of gnathostomiasis of the nervous system in associmigrans (migratory swellings) occur within 3 weeks after ation with a hemorrhagic CSF, its pleocytosis being consumption of raw fish and can reappear for another 10 predominantly eosinophilic and eosinophilic in the periphweeks. At any time the larvae may penetrate into the CNS. eral blood, are highly suggestive for this disease in a The main findings in gnathostomiasis of the CNS are patient having travelled to endemic areas. Serologic testradiculitis, radiculomyelitis, encephalitis, subarachnoid ing is locally available. Magnetic resonance imaging or hemorrhage, even obstructive hydrocephalus and cerebral/spinal CT are helpful (Fig. 96.5). Spinal cord hemorrhagic encephalitis (Schmutzhard et al., 1988; enlargement with diffuse high signal intensity, hemorPunyagupta et al., 1990; Bunyaratavej et al., 2008; rhagic tracts, and scattered deep hemorrhages with spotty Ramirez-Avila et al., 2009). The signs and symptoms white matter lesions are found in spinal or cerebral are of sudden onset, presenting with severe radicular gnathostomiasis (Sawanyawisuth et al., 2005, 2009a). pain and/or headache, radicular motor (and sensory) All those nematode larvae which cause larva migrans signs and symptoms, cranial nerve palsies, and even – visceralis may be considered in differential diagnosis, in the case of intracranial hemorrhage or obstructive Angiostrongylus cantonensis being the most important hydrocephalus – impairment of consciousness. The one. The sparganum of Spirometra mansoni or even radiculitis/myelitis/encephalitis and even subarachnoid Toxocara canis or cati and, in very rare instances, hemorrhage is usually accompanied by a varying degree Anisakis spp. may also be considered in the differential of eosinophilic pleocytosis in the CSF. Radiculitis and/or diagnosis. Geographical and history of exposure myelitis may lead to monoplegia, triplegia and even tetstrongly support the correct diagnosis. However, it must raplegia; similar to cranial nerve palsies these disease be noted that very recently G. spinigerum has been found manifestations carry a rather poor prognosis and are in patients who have only travelled to southern Africa or not, or only insufficiently, reversible. In rare cases Botswana. G. spinigerum may “travel” to or through the optic Treatment. A wide variety of anthelmintic drugs has nerve, leading to impairment of vision or segmental been used in single cases, the antimalarial drug quinine visual field impairment. In up to 60% either hemorrhagic clearly failing to show appreciable efficacy, with metroor xanthochromic spinal fluid is seen; the eosinophilia nidazole, diethyl-carbamazine, praziquantel and tiabenmust be specifically looked for. Gnathostomiasis of the dazole similarly lacking noticeable effect. Currently, brain carries a mortality of up to 12%, and long-term moralbendazole and ivermectin are in use. Albendazole bidity of 40% in the surviving patients has been reported has been tested so far in subcutaneous gnathostomiasis, (Schmutzhard et al., 1988). At postmortem the hallmark with a dosage of 400 mg once or twice a day, for 3 days, signs of gnathostomiasis of the CNS are hemorrhagic successfully reducing the intensity and the frequency of tracts throughout the spinal cord, nerve roots, cranial symptoms and lowering the eosinophilia. Although data nerves, and cerebral tissue. These tracts may be visualized for G. spinigerum infestation of the CNS are incomplete, by MRI or at autopsy (Sawanyawisuth et al., 2004). such patients should be treated with albendazole However, if the disease is diagnosed very early and (Schmutzhard, 2007). A similar efficacy has been treated appropriately myelitic, radicular or even encephreported for ivermectin (Nontasut et al., 2005). It must alitic signs and symptoms may be contained and longbe stressed that for these two drugs the sample size of term residua be minimal. single studies does not exceed 20 patients, although very Diagnosis. The diagnosis of nervous system gnathosobvious adverse events have not been reported in either tomiasis is based upon travel history, recent history of drug, with the exception that with ivermectin patients exposure, such as eating undercooked freshwater fish, more frequently develop a local skin reaction (in case swamp eels, snakes, snails, frogs, or undercooked of cutaneous gnathostomiasis) when compared to albenchicken or duck in endemic areas, or even drinking fresh dazole (Nontasut et al., 2000, 2005). Thus, in case of conwater in endemic areas in a patient with the typical signs comitant ocular or CNS involvement, close observation and symptoms (see above) and peripheral and CSF eosinis recommended. Even corticosteroids should be considophilia. Migratory swellings in subcutaneous tissue or ered in such patients (Bussaratid et al., 2005), as they eyelids occurring in a few patients with CNS gnathostoeffectively prevent inflammation in cerebrospinal fluid, miasis may underline the diagnosis. although one prospective observational study failed to

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E. SCHMUTZHARD AND R. HELBOK

Fig. 96.5. Visceral larva migrans, eosinophilic radiculomyelitis (lower cervical spine and upper thoracic spine syndrome) due to Gnathostoma spinigerum.

show conclusive results when using corticosteroids alone versus placebo (Punyagupta et al., 1990), however, without any specific anthelmintic drug.

INFESTATIONS WITH STRONGYLIDA HOOKWORMS Ancylostoma duodenale, Ancylostoma brasiliense, Necator americanus and others usually cause, during their course of development, a cutaneous larva migrans, finally settling in the small intestine causing hookworm disease with the prominent feature of anemia (Saathoff et al., 2004; Bethony et al., 2006). The other members of this family, Angiostrongylus cantonensis and Angiostrongylus costaricensis, may involve the central nervous system during their migration, causing a wide variety of neurologic signs and symptoms, mainly eosinophilic meningitis. Angiostrongylus cantonensis (costaricensis) Epidemiology. More than three-quarters of the cases have been reported from tropical South-East and East Asia. Again, Thailand seems to be the highest endemic area. In recent years angiostrongyliasis has also been documented in eastern Africa and in Central America (Angiostrongylus costaricensis). The prevalence of angiostrongyliasis in these areas is strongly associated with cultural habits and eating habits, both being rooted in local culture and taboos. Freshwater and terrestrial snails are the most common source of infection, but also

terrestrial slugs, frogs, and lizards may be a source of infection (Wan and Weng, 2004). These animals are sometimes part of traditional medicine treatments, sometimes being ingested in parallel with strong alcohol as part of a traditional ritual. Since chicken and duck may also feed on these snails, slugs and frogs, the consumption of undercooked meat of chicken or ducks may also be a source of infection. The extension of tourism, the spread of snail species, and the consumption of exotic foods have also become driving factors to spread angiostrongyliasis, as may be long distance food transport (Prociv and Carlisle, 2001; Slom et al., 2002; Ba¨rtschi et al., 2004; Schmutzhard, 2007; Malvy et al., 2008; Luessi et al., 2009). Pathogen. The human disease of angiostrongyliasis is caused by the rat lung worms A. cantonensis and A. costaricensis. Whereas A. cantonensis frequently causes eosinophilic meningitis, A. costaricensis mainly causes eosinophilic infiltrations in the intestinal wall. Very recently A. malayensis in South-East Asia and A. mackerras in Australia have been suspected to be the cause of neurologic signs and symptoms (Prociv et al., 2000). Adult Angiostrongylus worms parasitize the pulmonary arteries and cardiac cavities of rats and release their eggs into the bloodstream. After hatching, the L1 larvae penetrate the capillary blood vessels and enter the airways. They are found in the rat sputum and excreted directly in the sputum or, much more often, they are swallowed and pass the intestine and finally are

RICKETTSIAE, PROTOZOA, AND OPISTHOKONTA/METAZOA released in the feces. These freely moving first stage larvae enter their mollusc intermediate hosts, e.g., snails, frogs, slugs, etc., where they develop finally into third stage infective larvae. Either by eating these mollusc intermediate hosts (snails or slugs) or by eating paratenic hosts such as shrimps, crabs, fish, frogs, and even chicken and ducks which have fed upon them, humans can become infected. It must be noted that infective third stage larvae live for weeks without further development in their paratenic hosts. When rats ingest intermediate or paratenic hosts harboring the infective third stage larvae, these larvae penetrate the stomach or intestinal walls, migrating through their host’s body and the life circle is completed (Pien and Pien, 1999; Prociv et al., 2000). A. cantonensis is highly neurotropic (much more intensively than G. spinigerum). This means that larvae aim directly into the CNS where they have obviously optimal conditions to survive for long duration. Humans being nonpermissive hosts for this nematode, the larvae enter the human central nervous system but do not develop further (as in rats). They do not enter the pulmonary arteries in humans; such a development, typical for the final hosts, rats, can rarely be seen in small children where the larvae may migrate into the pulmonary vessels and may induce even potentially fatal inflammation of the lungs. The typical course in human beings is that of a larva migrans within the CNS. Clinical manifestations. Angiostrongylus species induce inflammation in cerebral, spinal, meningeal tissue, typically leading to extremely increased eosinophilic pleocytosis and very frequently causing meningitis. Thus, eosinophilic meningitis in a patient with the appropriate history of exposure is in most instances due to A. cantonensis. The incubation period is not known, possibly a few days, most likely between 1 and 4 weeks (Qu et al., 2011). In rare cases incubation periods of even several months have been reported. Most likely the incubation period depends on the intermediate host having been consumed and carrying the infective third stage larva. In addition, the number of ingested larvae may also play a decisive role for the duration of the incubation period. The typical clinical neurologic entity is that of an eosinophilic meningitis (Sawanyawisuth et al., 2009b). In rare cases, meningoencephalitis and even radiculomyelitis, cranial nerve lesions, and ocular manifestations may be seen. As rare complications, nasal and pulmonary infections have been described, mainly in young children. In most cases CNS angiostrogyliasis is a selflimiting disease (Wang et al., 2006), and the patients recover usually without long-term sequelae. However, if the infection intensity is high, the patients may develop a possibly fatal encephalitis (Chotmongkol and Sawanyawisuth, 2002).

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Cerebrospinal fluid inflammation may result in increased cranial pressure leading to headache, nausea, or vomiting. Most of the patients report neck stiffness, some of them observe hyperesthesia or itching, or a sensation like “worms crawling under the skin.” Adult patients rarely have a high-grade fever, whereas children may experience high body temperature. Diagnosis. The recovery of the larvae from CSF is the definitive proof of angiostrongyliasis, but this is achieved only in a minority of cases (up to 5%). It seems to be easier to recover the third stage larvae in children than in adults. Usually, the diagnosis is made upon history, i.e., eating snails, slugs, paratenic hosts, clinical signs and symptoms, and examination of the cerebrospinal fluid showing a high level of eosinophilic pleocytosis. As well as the CSF eosinophilia an at least transitory eosinophilia in the blood is regularly noted. Several serologic tests have been studied, such as enzyme linked immunoassay (ELISA), and very recently a polymerase chain reaction (PCR) has been developed, but sensitivities and specificities are not yet clear (Dekumyoy et al., 2000; Kittimongkolma et al., 2007). Other causes of eosinophilic meningitis, in particular, in the main area of angiostrongyliasis may be G. spinigerum, even toxocarosis or anisakiasis. Therapy. As yet the best possible anthelmintic drug is not known. Albendazole and mebendazole have been used leading to a reduction of headache, with shorter duration and lower frequency. In an observational study albendazole has been used satisfactorily in children (Jitpimolmard et al., 2007). Levamisole has shown good efficacy in children, whereas tiabendazole did not show any effect when administered at a dosage of 50 mg/kg bw/day for 3 days. Corticosteroids can reduce concomitant complaints such as headache and intensity of pleocytosis, but relapses were reported (Chotmongkol et al., 2006). Currently a combination of anthelmintic drugs and corticosteroids is recommended, though which anthelmintic drug should be used (most likely abendazole or ivermectin) still is under discussion (Sawanyawisuth and Sawanyawisuth, 2010).

ASCARIDIA Ascaris lumbricoides, one of the most common round worms worldwide, has been reported in single cases as being erroneously migrating into sinuses, body cavities, bile and pancreatic duct, causing septicemia with the potential to involve secondarily the central nervous system presenting as bacterial meningitis.

TRICHINELLOSIS Trichinellosis, a zoonosis with a worldwide occurrence (Gottstein and Piarroux, 2008; Gottstein et al., 2009) is

1434 E. SCHMUTZHARD AND R. HELBOK potentially caused by eight species of the genus Trichicorticosteroids (Keiser and Utzinger, 2010; Odermatt nella, most of them showing distinct geographical et al., 2010). distributions. It comprises the species T. spiralis, T. nativa, T. pritori, T. murelli, T. nelsoni, T. pseudospirTOXOCARA CANIS, TOXOCARA CATI alis, T. papae and T. zimbabwensis (Kusolsuk et al., 2010). Pathogen. Trichinella spp. are most commonly Epidemiology. These nematodes mainly occur in regions acquired by ingesting raw or undercooked pork or other with temperate climates. Usually, it is mainly toddlers and infants who are at risk since the ingestion of these meat containing encysted Trichinella larvae (Gottstein eggs is frequently by geophagy (PICA), or when playet al., 2009; Lo et al., 2009). Such encysted larvae excyst upon ingestion in the human small intestine, penetrating grounds are contaminated by dog (or cat) feces. the intestinal wall and causing an acute enteric phase. Rarely infection via contaminated water and contamAfter having matured, the adults mate, and the female inated food has been reported. In rabbits these larvae worms reside in the intestine, producing larvae which survive, and undercooked rabbit meat may also cause migrate into the lymphatic and blood vessels, finally Toxocara canis infestation (rabbits serving as paratenic encysting in striate muscles. This migration may last hosts). Infection rates in puppies may be as high as more than 50%. Seroepidemiological examinations have for weeks or even months. The encystment specifically shown a very high percentage of seropositives, with only occurs in the skeletal muscle, and the cysts calcify over years. In rare cases the larvae may migrate into the cenfew patients suffering from overt clinical disease tral nervous system causing both acute eosinophilic (Rubinsky-Elefant et al., 2010). meningoencephalitis and, eventually, cyst formation Pathogen. Toxocara canis is the most frequent path(Gottstein et al., 2009). ogenic agent causing visceral larva migrans syndrome. Clinical manifestations of neurologic involvement in However, T. cati (cat nematode and Baylisascaris protrichinosis. The intensity of disease is directly related to cyonis (raccoon nematode)) (Gavin et al., 2005) may also cause a larva migrans syndrome. The eggs of Toxocara the number of larvae ingested. Most infections will go spp. are excreted by lactating dogs and by puppies. When unnoticed or with minor symptoms. In case of highgrade ingestion of larvae, the signs and symptoms of being excreted into the appropriate environment it takes the migratory phase comprise severe myalgia, conjunctiup to 5 weeks of embryo forming before the eggs contain vitis, periorbital edema, and fever. During this phase the infectious larvae. When the embryonated Toxocara blood eosinophilia is high. Beside this “eosinophilic myoeggs are ingested, the second stage larvae hatch, penesitis,” migration of the larvae into CNS may cause diftrate the intestinal mucosa and migrate actively or hemafuse encephalopathy, even diffuse encephalitis. togeneously or lymphogenously into virtually all organs. In humans these larvae may survive for years, with the Quantitative and qualitative impairment of consciousinner organs, the eyes and the central nervous system ness, focal neurologic signs and symptoms, as well as epileptic seizures may be caused by these migratory larall being potential targets of the migrating larvae. vae, especially in high-grade infestation (Pozio et al., The number of migrating larvae and the immunologic 1993; Suwansrinon et al., 2007). reaction against the larvae determine the clinical signs Diagnosis. The diagnosis of nervous system trichinoand symptoms. Frequently inflammatory and/or immusis rests upon the combination of epidemiologic data nologic reaction to migrating ( ¼ living) larvae is minor, (several patients showing comparable signs and sympwhereas dying larvae, liberating a large amount of antigen, may lead to eosinophilic granulomatous inflammatoms having been exposed to the same food, sharing tory reaction. Such inflammatory granulomata may the same dishes, or coming from the same household), the typical features of migrating larvae (skeletal muscause disease in eyes, brain, spinal cord, etc. Eventually, cles, brain), high-grade eosinophilia; it may be additionthese granulomas turn into fibrotic tissue, and calcificaally based on serologic testings. Muscle biopsies provide tion may ensue. a specific diagnosis but lack sensitivity (sensitivity Clinical manifestations. In most cases Toxocara50%, specificity 100%) (Akisu et al., 2006). In larger induced (as well as Baylisascaris procyonis-associated) outbreaks biopsy is particularly important in order to larva migrans remains asymptomatic. However, when a large number of larvae start migrating, fever, abdominal determine the Trichinella spp. and to allow preventive discomfort, pulmonary signs and symptoms, including measures. Imaging does not show specific changes, but may help in planning best possible biopsy sites lung infiltrates and uncharacteristic malaise may be (del Brutto, 2006). major presenting signs and symptoms (Moreira-Silva Therapy. Trichinosis is usually a self-limiting disease, et al., 2004; Wise et al., 2005). It is mainly the affected but in case of CNS involvement (as in severe pneumonia, organ that further defines the clinical features. These myocarditis, etc.) albendazole may be given along with include lymphadenopathy, hepatomegaly, splenomegaly,

RICKETTSIAE, PROTOZOA, AND OPISTHOKONTA/METAZOA 1435 myocardiopathy and even focal neurologic signs and Thus, the very rare case of CNS anisakiasis may remain symptoms (Helbok et al., 2007) such as seizures, hemiparundiagnosed, or the definitive proof of the presence of esis, transverse myelitis, etc. Involvement of the retina larvae in the intestinal wall (endoscopy–biopsy) may sugmay lead to impairment of vision, retinal detachment, gest an association with a concomitant CNS manifestaor uveitis. In rare cases amaurosis has been reported tion (Bouree et al., 1995; Petithory, 2007). (Marx et al., 2007; Ota et al., 2009). Therapy. No specific anthelmintic therapy exists; in Diagnosis. Only very rarely can the living larvae be individual cases (perforation, pericarditis, obstructive seen intra vitam (in biopsies, CSF, pleural fluid). Intraileus, etc.) surgery may be essential and life-saving. cranial or spinal granulomas can be diagnosed by neuroimaging, cerebral Computertomography (cCT) and STRONGYLOIDES STERCORALIS INFECTION Magnetic Resonance Tomography (MRT), showing contrast-enhancing granulomas. The larva migrans itself Epidemiology. S. stercoralis can be found in virtually all (migrating tracts, etc.) usually cannot be visualized. tropical and subtropical regions, probably infecting up to High-grade eosinophilia in the peripheral blood and in 100 million humans. Regional prevalence rates of more the CSF might guide the diagnostic direction. Serology than 30% have been reported (Einsiedel and Spelman, 2006; Malnick et al., 2009; Montes et al., 2010). (ELISA, immunoblot) may confirm the diagnosis. Pathogen. Infection with S. stercoralis occurs only in Therapy. The patient showing the clinical signs and symptoms of acute inflammatory reaction will benefit humans, when larvae penetrate the intact skin. The larfrom corticosteroids. The evidence for the efficacy of vae migrate via lung and the bronchial system into the anthelminthic therapy is rather low, nevertheless albenesophagus, finally reaching the small intestine. The dazole (400 mg twice a day for 2–4 weeks) is recomadults, lodging in the small intestine, begin oviposition. mended. Thiabendazole and ivermectin have also A specific feature of Strongyloides spp. is the internal shown some efficacy (in case series). autoinfection: rhabditiform larvae develop into filariform infectious larvae, which start the full cycle, as do Regular deworming of dogs and cats as well as ensurthose filariform infectious larvae which penetrate the ing that dogs (and cats) do not contaminate children’s playgrounds are effective prophylactic measures skin. This internal autoinfectious cycle is most likely (Moreira-Silva et al., 2004; del Brutto, 2006). responsible for the very long persistence of infection with S. stercoralis (Montes et al., 2010). When immunosuppression-specific and nonspecific ANISAKIS INFESTATION (ANISAKIASIS) defense mechanisms which usually control this internal Epidemiology. Infestation of marine fishes with Anisakis autoinfectious cycle are not able to contain it, this may species is very frequent. Humans may be infected when lead eventually to a potentially life-threatening hyperineating raw or undercooked fish. fection syndrome (Keiser and Nutman, 2004; Bava and Pathogen. Herring and cod may harbor the larvae of Troncoso, 2009; Altintop et al., 2010; Basile et al., 2010). Anisakis simplex. The adults lodge in the intestinal tract Clinical manifestations. The acute infection with of marine mammals. The infectious third stage larvae filariform larvae of S. stercoralis may cause a bronchitis are ingested by humans when they eat raw fish. Most and pneumonia, i.e., the typical Loeffler syndrome. An of these vital larvae are not capable of penetrating the uncomplicated chronic intestinal infection leads to intestinal walls, leading to an eosinophilic inflammatory unspecific abdominal discomfort. However, in case of reaction, and rarely causing ulcerations and perforations immunosuppression, the larvae may be disseminated (Auer et al., 2009). into all organs, usually accompanied by Gram-negative Clinical manifestations. Usually anisakiasis causes bacteremia, sepsis, meningitis, etc. These filariform laracute abdominal pains, either acute or chronic gastroenvae may enter the CNS and cause acute or peracute menteritis. The acute intestinal anisakiasis starts within days ingitis, since they carry with them Gram-negative after ingestion of the raw fish. Very rarely the first stage bacteria from the large intestine. Thus, the eosinophilic larvae penetrate the intestinal wall leading to the clinical meningitis is usually aggravated by a pyogenic meningisigns and symptoms of larva migrans. Theoretically the tis, sepsis syndrome and/or even abscess formation CNS may be involved. (Newberry et al., 2005; Shorman and Al-Tawfiq, 2009). Diagnosis. In humans with a history of ingesting raw The mortality rate in S. stercoralis hyperinfection fish, acute intestinal signs and symptoms, leukocytosis syndrome reaches more than 70%. and eosinophilia may be important diagnostic features. Diagnosis. In case of immunosuppression any acute Endoscopy and biopsy confirm the diagnosis. In the or peracute pyogenic meningitis, sometimes accompavery rare cases of larva migrans the eosinophilia may nied by a transitory eosinophilia, is suggestive for a be more pronounced, but serologic tests do not exist. S. stercoralis hyperinfection syndrome. The presence

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of a colitis (as evidenced by imaging or colonoscopy) and the proof of larvae in colonic lavage or feces strengthens or even confirms the suspected diagnosis. Therapy. Every patient with S. stercoralis infection, especially anyone at risk of or definitely showing immunosuppression, needs immediate therapy with ivermectin (200 mg/kg bodyweight for 2 days, which should be repeated within 2–3 weeks). Such therapeutic cycles should be repeated in case of survival of a hyperinfection syndrome. As an alternative, albendazole may be given.

METAZOA Pentastomiasis The tongue worms, Pentastomatidae, are arthropods and part of a subgenus of Crustaceae. The two species, Armillifer armillatus and Linguatula serrata, may cause pathology in humans (Tappe and B€ uttner, 2009).

LINGUATULA INFESTATION Dogs, foxes, and wolves harbor, within their nasopharynx, the adults of Linguatula serrata. Eggs are excreted either by feces or via sputum/saliva of the host. Intermediate hosts may be rodents, sheep, and goats. The disease rarely occurs in West African countries, but also in the Middle East (e.g., Lebanon, Sudan) (Drabick, 1987). If the eggs are ingested they may penetrate the intestinal wall, migrating to the liver lymph nodes and other organs, including CNS, causing the so-called visceral form of Linguatula infestation. If the uncooked liver of the intermediate hosts (sheep, goats) is eaten, the larvae may attach to the mucosa of the pharynx and larynx, causing focal lesions and even allergic reactions including Quincke edema, facial edema, and epistaxis (Morsy et al., 1999). Removal of the larvae (in case of nasopharyngeal linguatulosis) or surgical extirpation from lymph node, tissue, etc. is the only causative therapy. Encapsulated, calcified larvae may be left in situ. An antiparasitic chemotherapeutic agent is not known.

POROCEPHALOSIS (INFESTATION WITH ARMILLIFER POROCEPHALUS SPP.)

SPP. AND

African snakes may serve as final host of Armillifer spp. or Porocephalus spp. The female adults of Armillifer armillatus parasitize the respiratory tract of snakes, intermediate hosts being frequently rodents where the larvae encyst in various tissues. If humans ingest raw snake meat or food contaminated with the feces of snakes, the eggs hatch in the upper intestine, migrate into various tissues such as liver, lungs, eyes, brain, and other organs. In most instances, the infection is asymptomatic; organ-specific

signs and symptoms may occur if the parasitic load is big, or if the nymphae cause space-occupying, inflammatory reaction in the respective tissue, e.g., CNS (Lavarde and Fornes, 1999; Dakubo et al., 2006; du Plessis et al., 2007; Yao et al., 2008; Chen et al., 2010). The diagnosis can be established by the visualization of calcified larvae (up to 2 cm in diameter); typically, Armillifer does not enter striated muscles (in contrast to cysticercosis). Hence, in a patient with focal neurologic signs and symptoms and/or focal seizures, showing such calcifications with a history of having lived in West Africa or East Asia and having ingested snake meat, the diagnosis of a porocephalosis might be considered. The diagnosis can be confirmed only by histologic workup of the surgically resected nymph. There is no specific antiparasitic therapy (Lai et al., 2010).

Myiasis Larvae of flies invading various parts of the human body may cause a disease called myiasis. Usually the larvae of tumbu fly (Cordylobia anthroprophaga) or botfly (Dermatobia hominis) are the most important causes of cutaneous or subcutaneous myiasis, rarely ophthalmomyiasis and, even rarer, secondary infection in the periorbital tissue, including meninges. The same applies to infestation with screwworms (genus Callitroga) and related species which usually affect sheep, cats, dogs, etc., in rare cases also malnourished humans. These larvae lead to purulent rhinitis, even sinusitis, osteomyelitis, and finally potentially fatal meningitis. The sheep botfly (Oestrus ovis, rarely also Wohlfahrtia species) may cause ophthalmomyiasis externa or interna which, per se, can lead in malnourished patients to periorbital invasion, secondary infection, and even meningitis and brain abscess (Jelinek et al., 1995; Robbins and Khachemoune, 2010). Similarly, a chronic otitis may be the “ground” for myiasis leading to exacerbation of the external otitis leading to otitis media and even mastoiditis and progression into the intracranial space, causing meningitis, epidural or subdural empyema, or even brain abscess (Sampson et al., 2001; Messahel et al., 2010). Radical extirpation/removal of all maggots may prevent further spread of secondary infections (Clyti et al., 2008).

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Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 97

Neurocysticercosis OSCAR H. DEL BRUTTO* School of Medicine, Universidad de Especialidades Espiritu Santo and Department of Neurological Sciences, Hospital Clinica Kennedy, Guayaquil, Ecuador

HISTORY Taeniasis and cysticercosis have been mentioned since the beginning of the recorded history. Tapeworms and cysticerci have been found in mummies from Ancient Egypt (Bruschi et al., 2006). Arab writers, during the first millennium AD, recognized tapeworm proglottids and called them “cucurbitine,” because of their similarity with pumpkin seeds (Cucurbita pepo). The occurrence of swine cysticercosis (measly pork) was common knowledge among the Ancient Greeks and Romans (Nieto, 1982). Indeed, swine were considered impure in Ancient Greece, and it may have been for that reason that the Qur’an prohibited the consumption of pork, since many Greek ideas were adopted by the prophet Muhammad (570–632 AD), the founder of the Islamic religion. The first human cases of neurocysticercosis were described during the 16th century. By that time, however, vesicles found in some autopsied brains were not identified as parasites (Nieto, 1982). The association between taeniasis and cysticercosis in the same individual was probably first described by the Peruvian Hipo´lito Unanue in 1792, as he published the case of a soldier with taeniasis who died following a seizure (Deza, 1987). During the 19th century, morphologic similarities between the head of the adult Taenia solium and the scolex of cysticercus were recognized. In Germany, K€ uchenmeister (1855) demonstrated that oral consumption of cysticercus from pork meat resulted in intestinal taeniasis. A few days before a convict’s death, a man was fed with cysticerci obtained from a pig slaughtered 60 hours previously. At autopsy, performed 48 hours after execution, the author found a Taenia attached with its rostellum to the duodenal mucosa. This report suggested that human taeniasis is acquired by consumption of cysticercus from infected pork.

Knowledge of the life cycle of Taenia solium was completed during the second half of the 19th century by experiments demonstrating than when Taenia eggs obtained from proglottids passed by infected humans were fed to pigs, the animals develop cysticercosis. Relevant advances during those years included the description of meningeal cysticercosis, the first classification of the clinical syndromes of cysticercosis, and the description of cysticercotic angiitis (Trelles and Trelles, 1978). The prestigious Handbuch der Neurologie included a chapter on cysticercosis that listed more than 200 references mainly from Europe, where this pathology was well recognized at the turn of the 20th century (Henneberg, 1912). The work of Yoshino (1933), who infected himself with Taenia solium cysticerci to study the life cycle of the cestode, must also be mentioned. With the introduction of the complement fixation test, the diagnosis of cysticercosis could, for the first time, be established without the need of histologic demonstration of the parasite. (Weinberg, 1909). The extensive work of Dixon and Lipscomb (1961) described in detail the public health consequences of mass travel to endemic areas and its impact on the prevalence of cysticercosis in Western countries, and contributed to our current knowledge about the natural history of this parasitic disease. Thereafter, the introduction of computed tomography (CT) allowed the visualization of intracranial cysticerci and improved the diagnosis of neurocysticercosis (Carbajal et al., 1977). Finally, the advent of specific therapy for human cysticercosis (Robles and Chavarrı´a, 1979) heralded a new era in the history of this ancient scourge.

EPIDEMIOLOGY With the exception of Muslim countries, cysticercosis is endemic in most of the developing world. While the exact

*Correspondence to: Oscar H. Del Brutto, M.D., Air Center 3542, P.O. Box 522970, Miami, FL 33152-2970, USA. Tel: þ593-42-2857-90, E-mail: [email protected]

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prevalence of neurocysticercosis is largely unknown, it is estimated that millions of people living in Latin America, Africa, and Asia are infected by this parasite, and that many of them, at any point of their lives, experience the clinical consequences of this infection (Ndimubanzi et al., 2010). Population-based studies carried out in rural villages of endemic countries have shown that neurocysticerosis is the principal cause of the excess fraction of epilepsy seen in these areas, when compared to the prevalence of epilepsy in developed countries (Del Brutto et al., 2005; Medina et al., 2005; Montano et al., 2005). The disease is also a health problem in urban centers of developing countries, where neurocysticercosis is still a major cause of hospital admissions to neurologic centers (Fleury et al., 2010). Neurocysticercosis (NCC) was rare in the US and Europe up to 30 years ago. Together with the growing number of immigrants from endemic areas, there has been an increase in the number of patients with NCC in these countries. In the US, most cases have been reported from the southwestern states where more than 20 million Mexican Americans live. Almost 90% of neurocysticercosis patients diagnosed in the US are immigrants from Mexico or South America (White, 2000; Serpa et al., 2011). However, some cases have been recognized in American citizens with no history of travel to endemic areas. Most of these patients acquired the disease through a household contact infected with Taenia solium (Sorvillo et al., 2011). A similar scenario has been observed in Canada, Australia, and some European countries, where mass immigration of people from South America has caused a recent increase in the prevalence of this parasitic disease (Esquivel et al., 2005; MassSese et al., 2008; Del Brutto, 2012a, b, c). It has also been noted that there is an increased prevalence of NCC among international travelers from nonendemic to diseaseendemic areas; most of these patients develop the disease months to years after returning home and present with benign forms of NCC (single cysticercus granulomas), strongly suggesting that the most common form of disease acquisition was through sporadic contact with a Taenia carrier while abroad (Del Brutto, 2012d).

proglottids. T. solium inhabits the small intestine of humans, where it is attached to the intestinal wall by its suckers and hooks. Every day, some gravid proglottids are detached from the distal end of the worm and are passed with the feces. Each proglottid liberates thousands of fertile eggs which are resistant to the environment. In places with deficient disposal of human feces, pigs are fed with human feces containing T. solium eggs. Once in the intestinal tract of the pig, the eggs lose their coat and liberate embryos (oncospheres) which cross the intestinal wall and enter the bloodstream, from where they are carried to the tissues and evolve forming larvas (cysticercus). Under these circumstances, pigs become intermediate hosts in the life cycle of T. solium (Del Brutto et al., 1988c). Human consumption of improperly cooked infected pork (Fig. 97.1) results in release of cysticerci in the small intestine where, by the action of digestive enzymes, their scolices evaginate and attach to the intestinal wall. After the scolex is attached, the proglottids begin to multiply and will become mature approximately 4 months after infection. Humans can also act as intermediate hosts for T. solium after ingesting its eggs. Under these circumstances, human cysticercosis develops. The mechanisms by which eggs cross the intestinal wall and lodge in human tissues are the same as those described in the pig. Humans acquire cysticercosis from ingestion of food contaminated with T. solium eggs and by the fecal-oral route in individuals harboring the adult

ETIOPATHOGENESIS Life cycle of Taenia solium The tapeworm T. solium has a complex life cycle involving two hosts, humans and pigs. Humans are the only definitive hosts for the adult cestode, whereas both pigs and humans may act as intermediate hosts for the larval form called cysticercus. The adult T. solium has a head (scolex) that consists of four suckers and a double crown of hooks, a narrow neck, and a large body formed by several hundred

Fig. 97.1. Infected pork meat showing multiple cysticerci.

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parasite in the intestine. While the former was considered the most common form of transmission, recent epidemiologic studies showing clustering of patients with cysticercosis around taeniasic individuals have changed previous concepts crediting the environment as the main source of human contamination with T. solium eggs. Human cysticercosis should now be considered as a disease mostly transmitted from person to person, and the role of infected pigs is to perpetuate the infection (Gonzalez et al., 2006).

Characteristics of cysticerci Cysticerci are small vesicles that consist of two parts, the vesicular wall and the scolex (Willms, 2008). The scolex has an armed rostellum and a rudimentary body. In some cysticercus the scolex cannot be identified. These parasites are composed of membranes attached to each other that tend to group in clusters resembling a bunch of grapes. This form is often called the racemose form of cysticerci, and is usually observed in parasites located within the cerebrospinal fluid (CSF) cisterns at the base of the brain, where they may attain a large size. While the mechanisms responsible for the transformation of cysticerci from single vesicles to the racemose form are not totally understood, it is likely that the scolices disappear as the result of a degenerative process, called hydropic degeneration, caused by the continuous entrance of CSF inside the vesicles (Escobar and Weidenheim, 2002).

Stages of involution of cysticerci After entering the central nervous system (CNS), cysticerci are in a vesicular (viable) stage in which the parasites have a transparent membrane, a clear vesicular fluid, and a normal invaginated scolex. Cysticerci may remain viable for years or, as the result of the host’s immunologic attack, enter in a process of degeneration that ends with their transformation into inert nodules. The first stage of involution of cysticerci is the colloidal stage, in which the vesicular fluid becomes turbid, and the scolex shows signs of hyaline degeneration. Thereafter, the wall of the cyst thickens and the scolex is transformed into mineralized granules; this stage, in which the cysticercus is no longer viable, is called the granular stage. Finally, the parasite remnants appear as a mineralized nodule (calcified stage) (Escobar and Weidenheim, 2002). The duration of each of these stages has not been established, although it is believed that considerable differences exist among individuals. Furthermore, pathologic studies have shown cysticerci in different stages of involution in the same individual (Fig. 97.2). Whether this represents cysts of different ages from recurrent infections or a single infection in which only some cysts have been attacked by the host’s

Fig. 97.2. Brain slice showing parenchymal cysticerci in different stages of involution.

immune system remains unknown. It has recently been suggested that not all cysticerci go through these four orderly stages of involution. Indeed, it is possible that some metacestodes are attacked by the host’s immune system as soon as they enter the nervous system, and are transformed into granulomas without going through the vesicular and colloidal stages. This alternative hypothesis of cysticerci involution is supported by the younger age of patients with cysticercus granulomas (when compared with those with vesicular cysts), by the higher prevalence of a single cysticercus granuloma in populations who are exposed to low parasite loads, and by the low sensitivity of serologic assays in patients with a single cysticercus granuloma (Garcia et al., 2010).

Tissue reaction around cysticerci Parenchymal brain cysticerci in the vesicular stage elicit a scarce inflammatory reaction in the surrounding tissue that is mainly composed of plasma cells, lymphocytes, and eosinophils. Colloidal cysticerci are surrounded by a thick collagen capsule and by a mononuclear inflammatory reaction that usually includes the parasite itself. The surrounding brain parenchyma shows an astrocytic gliosis associated with microglial proliferation, edema, neuronal degenerative changes, and perivascular cuffing of lymphocytes. When parasites enter into the granular and calcified stages, the edema subsides but the astrocytic changes in the vicinity of the lesions may become more intense, and epithelioid cells appear and coalesce to form multinucleated giant cells (Pittella, 1997). Meningeal cysticerci usually elicit a severe inflammatory reaction in the subarachnoid space with formation of an exudate composed of collagen fibers, lymphocytes,

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Fig. 97.3. Cysticerci membranes in subarachnoid space (black arrows) surrounded by inflammatory reaction (white arrowheads).

multinucleated giant cells, eosinophils, and hyalinized parasitic membranes leading to abnormal thickening of the leptomeninges (Fig. 97.3). This inflammation may be disseminated, inducing damage in structures distant to the site where the parasites lodge. The optic chiasm and cranial nerves arising from the brainstem are encased in this leptomeningeal thickening. The foramina of Luschka and Magendie may also be occluded by the thickened leptomeninges and parasitic membranes with the subsequent development of obstructive hydrocephalus. Small penetrating arteries arising from the circle of Willis may also be affected by the subarachnoid inflammatory reaction. This may cause occlusion of the lumen of the vessel with the subsequent development of a cerebral infarction (Del Brutto, 2008). Ventricular cysticerci may also elicit an inflammatory reaction if they are attached to the choroid plexus or to the ventricular wall. The ependymal lining is disrupted and proliferating subependymal glial cells protrude toward the ventricular cavities blocking the transit of CSF, particularly when the site of protrusion is at or near the foramina of Monro or the cerebral aqueduct (Pittella, 1997).

Immune response against cysticerci Some cysticercal antigens stimulate the production of specific antibodies that form the basis for the immunologic diagnosis of cysticercosis, while others play a role in the evasion of the immune surveillance against cysticerci. One of these antigens, a paramyosin called antigen B, has affinity for collagen and may bind to C1q, inhibiting the classic pathway of complement activation. As destruction of cysticerci seems to be mediated by activation of the complement cascade, antigen B could play a role in the protection of cysticerci against the host’s

immunologic attack. Despite the presence of specific antibodies against cysticerci in most patients with neurocysticercosis, there is no correlation between the severity of parasite destruction and the overall titers of such antibodies. Indeed, immunoglobulins have been more frequently found around living parasites than surrounding dead cysts, suggesting that cysticerci use the host’s immunoglobulins as a screen to avoid recognition from the immune system (Del Brutto et al., 1988c; Flisser et al., 2002). Some reports suggest the presence of cellular immune dysfunction in patients with neurocysticercosis. This impairment results from an increase in the subpopulations of CD8 T lymphocytes, impaired proliferation of lymphocytes, and abnormal concentration of cytokines. The depressed cellular immunity may be responsible for the reported association of neurocysticercosis with conditions resulting from immunodeficiency states. In addition, some studies showed a higher prevalence of cerebral glioma among neurocysticercosis patients than in the general population (Del Brutto et al., 1997). In these patients, the intense glial proliferation around the parasites, along with the suppression of the cellular immune responses may cause inhibition of the immunologic surveillance against cancer, leading to malignant transformation of astrocytes (Del Brutto et al., 2000).

CLINICAL MANIFESTATIONS Neurocysticercosis may present with a variety of clinical manifestations, a pleomorphism that is related to individual differences in the number and location of the lesions within the CNS, and to variations in the severity of disease activity. In endemic areas, neurocysticercosis is considered the “great imitator” as it may mimic almost any other neurologic disease (Del Brutto et al., 1988c). Seizures, focal neurologic signs, cognitive impairment, and intracranial hypertension, are the most common clinical manifestations of neurocysticercosis (Table 97.1).

Seizures Epileptic seizures are the most common clinical manifestation of neurocysticercosis and usually represent the primary manifestation of the disease in up to 70% of patients (Del Brutto et al., 1992). Neurocysticercosis is a leading cause of adult-onset epilepsy in areas where the disease is endemic and, as noted before, is partly responsible for the increased prevalence of epilepsy seen in developing countries (Medina et al., 2005). Seizures are more prevalent in patients with parenchymal neurocysticercosis than in those with subarachnoid or ventricular disease (Garcia and Del Brutto, 2005). While some series have shown that most patients with epilepsy due to neurocysticercosis have generalized seizures, it is most

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Table 97.1 Clinical manifestations of neurocysticercosis according to parasite location and disease activity Location/form of the disease Brain parenchyma Vesicular cysts Colloidal cysts Granulomas/calcifications Cysticercotic encephalitis Subarachnoid space Giant cysts in CSF cisterns Diffuse arachnoiditis Hydrocephalus Angiitis Ventricular system Ventricular cysts Ependymitis Spinal cord Arachnoiditis Parenchymal cysts Other forms of the disease Suprasellar cysticercosis Ophthalmic cysticercosis Muscle cysticercosis

Usual clinical manifestations

Seizures; may be asymptomatic Seizures; headache; vomiting; focal signs Seizures, may be recurrent Coma; seizures; intracranial hypertension Seizures; intracranial hypertension; focal signs; cognitive impairment Focal signs; intracranial hypertension Intracranial hypertension; cognitive impairment Acute stroke syndromes Focal signs; intracranial hypertension Seizures; intracranial hypertension Root pain; weakness; meningitis (rare) Motor and sensory signs below the level of the lesion Ophthalmologic and endocrinologic disturbances Visual loss; extraocular muscle paralysis Muscle pseudohypertrophy

likely that those patients actually presented with partial seizures with secondary generalization. The problem of neurocysticercosis and epileptogenesis has been a subject of debate. It has been suggested that seizures occur when the parasite begins to degenerate (White, 2000). However, large series of patients with neurocysticercosis-related epilepsy include patients who only have vesicular (viable) cysts at the time of diagnosis (Del Brutto et al., 1992). On the other end of the spectrum is the debate about the risk of seizures in patients with calcified parenchymal brain cysticerci (Nash et al., 2004). While calcifications have been usually considered inert lesions, recent data strongly suggest that calcified cisticerci are not clinically inactive, but may cause recurrent seizures when parasitic antigenic epitopes trapped in the calcium matrix are exposed to the host immune system due to a process of calcification remodeling (Nash et al., 2008; Mahanty and Garcia, 2010). In these cases, recurrent seizures may be the cause of hippocampal sclerosis, thus perpetuating the risk of seizures in these patients.

Focal neurologic signs A variety of focal neurologic signs related to the size, number, and location of the parasites have been described in patients with neurocysticercosis. Pyramidal tract signs predominate, but sensory deficits, language disturbances, involuntary movements, parkinsonian

rigidity, and signs of brainstem dysfunction may occur in these patients (Del Brutto et al., 1988c). Focal neurologic signs in neurocysticercosis usually follow a subacute or chronic course resembling that of a brain tumor, and are most often seen in patients with large subarachnoid cysts compressing the brain parenchyma (Fleury et al., 2011). Stroke syndromes, including transient ischemic attacks, cerebral infarcts, and intracranial hemorrhages – all causing focal neurologic deficits – have been described in patients with neurocysticercosis (Cantu and Barinagarrementeria, 1996). These infarcts are usually located in the posterior limb of the internal capsule, the corona radiata, or the brainstem, and produce typical lacunar syndromes such as pure motor hemiparesis and ataxic hemiparesis (Del Brutto, 2008).

Intracranial hypertension Some patients with neurocysticercosis present with increased intracranial pressure associated or not with seizures, focal neurologic signs, or dementia. The most common cause of this syndrome is acute or subacute hydrocephalus, which may be either related to cysticercotic arachnoiditis, granular ependymitis, or ventricular cysts (White, 2000; Fleury et al., 2011). Intracranial hypertension may be punctuated by episodes of sudden loss of consciousness related to movements of the head (Bruns syndrome) when the cause of hydrocephalus is a

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fourth ventricle cyst. Increased intracranial pressure also occurs in cysticercotic encephalitis, a severe form of neurocysticercosis that occurs as the result of a massive cysticerci infection of the brain parenchyma inducing an intense immune response from the host. This condition is more frequent among children and young women, and is characterized by clouding of consciousness, seizures, diminution of visual acuity, headache, vomiting, and papilledema (Rangel et al., 1987).

Psychiatric disturbances Patients with neurocysticercosis may present psychiatric manifestations ranging from poor performance on neuropsychological testing to a severe dementia (Forlenza et al., 1997). The latter may be found in 6–15% of cases. In the past, some of these patients were admitted to psychiatric hospitals for several years until the correct diagnosis was done at autopsy (Nieto, 1982). Psychotic episodes characterized by confusion, paranoid ideation, psychomotor agitation, and violent behavior have also been described in patients with parenchymal brain lesions. Conceivably, some of these episodes could represent attacks of psychomotor epilepsy or postictal psychosis.

Other clinical manifestations Spinal arachnoiditis is characterized by root pain and weakness of subacute onset, and cysts in the spinal cord parenchyma usually present with motor and sensory deficits that vary according to the level of the lesion (Venkataramana et al., 1989; Alsina et al., 2002). Widespread use of magnetic resonance imaging (MRI) has improved the detection of cysticercosis of the spinal cord. Indeed, the high frequency of spinal cysticerci among patients with intracranial subarachnoid NCC, which may coexist in 60% of cases, has recently been demonstrated (Callacondo et al., 2012). It is likely that this study will change the diagnostic approach to patients with intracranial subarachnoid NCC, since all of them will probably need MRI investigation of the spine to detect hidden lesions. The association of NCC and headache has been considered anecdotal in the past. However, a recent casecontrol study suggests a significant increased prevalence of NCC among patients with a “primary headache disorder” compared to subjects with other diseases of the CNS (Del Brutto and Del Brutto, 2012). Calcifications may experience periodic morphologic changes related to a mechanism of remodeling. This may expose parasitic antigenic material to the host, causing transient inflammatory changes in the brain parenchyma that may be the cause of transient and recurrent headache episodes mimicking a primary headache disorder in some patients.

Patients with cysticerci located in the sellar region present with ophthalmologic and endocrinologic disturbances (Del Brutto et al., 1988b). Intraocular cysticerci are most often located in the subretinal space and produce a progressive decrease of visual acuity or visual field defects. The cysts may induce vitritis, uveitis, and endophthalmitis; the latter is the most severe complication of ocular cysticercosis and may lead to phthisis bulbi (Madigubba et al., 2007). Massive cysticercal infection of striated muscles may produce generalized weakness associated with progressive muscle enlargement (Wadia et al., 1988).

DIAGNOSIS Laboratory findings Peripheral eosinophilia is the most common hematologic abnormality in patients with neurocysticercosis, and has been reported in up to 37% of cases (Loo and Braude, 1982). The frequency of positive stool examinations for Taenia solium eggs among patients with neurocysticercosis has varied from one series to another, and seems to be related to the severity of infection (Garcia and Del Brutto, 1999; Gilman et al., 2000). Recognition of Taenia eggs is not easy and many patients may escape detection when coproparasitologic studies are performed (Richards and Schantz, 1991). Specific coproantigen detection by ELISA and PCR will greatly improve the screening for Taenia solium carriers among healthy individuals from endemic areas (Mahanty and Garcia, 2010). Nonspecific abnormalities in the cytochemical composition of CSF have been reported in a number of patients with neurocysticercosis. These abnormalities directly correlate with the activity of the disease and with whether or not the parasites are located in the subarachnoid space. The most common finding is a moderate mononuclear pleocytosis, with cell counts rarely exceeding 300 per mm3. A moderate increase in CSF protein counts, usually in the range of 50–300 mg/dL, is common in these patients. CSF glucose levels are usually normal despite active meningeal disease (Del Brutto et al., 1988a). Hypoglycorrhachia, observed in a few patients, is associated with a poor prognosis (McCormick et al., 1982).

Neuroimaging CT and MRI provide objective evidence on the number and topography of lesions, their stage of involution, and the degree of the host’s inflammatory reaction against the parasites (Garcia and Del Brutto, 2003). In many cases, intracranial calcifications represent the only evidence of the disease. The sensitivity of conventional MRI for the detection of calcified lesions is poor, and thus CT appears as the best screening neuroimaging

NEUROCYSTICERCOSIS procedure for patients with suspected neurocysticercosis. There is recent evidence, however, that the use of susceptibility-weighted imaging may improve the identification of calcifications by MRI (Wu et al., 2009). MRI is the imaging modality of choice for the evaluation of patients with cystic lesions located in the ventricular system, the brainstem, and over the convexity of cerebral hemispheres.

PARENCHYMAL NEUROCYSTICERCOSIS CT and MRI findings in parenchymal neurocysticercosis depend on the stage of involution of the parasites (Fig. 97.4). Vesicular cysticerci appear on CT and MRI as small and rounded cysts that are well demarcated from the surrounding brain parenchyma. There is no edema and no contrast enhancement. Many of these lesions have in their interior an eccentric hyperdense nodule representing the scolex, giving them a pathognomonic “hole-with-dot” appearance. Colloidal cysticerci appear as ill-defined lesions surrounded by edema. Most of them show a ring pattern of enhancement after contrast medium administration. While the scolex is not usually visualized in colloidal cysticerci, the practice of diffusion-weighted images, may allow the recognition of the scolex, facilitating the diagnosis in selected cases (do Amaral et al., 2005) (Fig. 97.5). A particular neuroimaging pattern of parenchymal neurocysticercosis is observed in patients with cysticercotic encephalitis. In this severe form of the disease, both CT and MRI show diffuse brain edema and collapse of the ventricular system without midline shift. After contrast enhancement, multiple small ring-like or nodular lesions appear disseminated within the brain parenchyma (Rangel et al., 1987). Parenchymal brain cysticerci may also appear on CT or MRI as nodular lesions surrounded by edema after contrast administration. This pattern corresponds to the granular stage of cysticerci and is commonly referred to as “cysticercus granuloma” (Singh et al., 2010). On MRI, granular cysticerci are visualized as areas of signal void on both T1- and T2-weighted images surrounded by edema or gliosis with hyperintense rims around the area of signal void. Calcified (dead) cysticerci normally appear on CT as small hyperdense nodules without perilesional edema or abnormal enhancement after contrast medium administration.

SUBARACHNOID NEUROCYSTICERCOSIS The most common neuroimaging finding in patients with subarachnoid neurocysticercosis is hydrocephalus caused by inflammatory occlusion of Luschka and Magendie foramina. The fibrous arachnoiditis that is responsible for the development of hydrocephalus is seen on CT or MRI as areas of abnormal leptomeningeal

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enhancement at the base of the brain. Cystic subarachnoid lesions may be small when located within cortical sulci or may reach a large size if they are located in the Sylvian fissure or within the basal CSF cisterns (Fig. 97.6). Small cysts within cortical sulci usually follow the same stages of involution that were described for parenchymal brain cysts and may be found in the vesicular, colloidal, granular, or calcified stage. On the other hand, cystic lesions located within CSF cisterns usually have a multilobulated appearance, displace neighboring structures, and behave as mass occupying lesions (Fleury et al., 2011). Cerebrovascular complications of neurocysticercosis are well visualized with CT or MRI. While the neuroimaging appearance of cysticercosis-related infarcts is the same as cerebral infarcts from other causes, the association of subarachnoid cystic lesions (particularly at the suprasellar cistern) and abnormal enhancement of basal leptomeninges suggests the correct diagnosis (Del Brutto, 2008). Angiographic findings in subarachnoid neurocysticercosis include segmental narrowing or occlusion of the major intracranial arteries in patients with cysticercotic-related cerebral infarcts or even in patients lacking clinical or neuroimaging evidence of a cerebral infarct (Cantu and Barinagarrementeria, 1996). MRA is a valuable noninvasive imaging method to demonstrate segmental narrowing or occlusion of intracranial arteries in patients with subarachnoid neurocysticercosis.

VENTRICULAR NEUROCYSTICERCOSIS Ventricular cysticerci appear on CT as hypodense lesions that distort the ventricular system causing asymmetric obstructive hydrocephalus. Ventricular cysts are isodense with CSF; therefore, they only can be inferred on the basis of distortion on the shape of the ventricular cavities (Madrazo et al., 1983). In contrast, most ventricular cysts are readily visualized on MRI because the signal properties of the cystic fluid or the scolex differ from those of the CSF (Singh et al., 2003; do Amaral et al., 2005). Cyst mobility within the ventricular cavities in response to movement of the head, the “ventricular migration sign,” facilitates the diagnosis of ventricular cysticercosis in some cases (Rangel-Guerra et al., 1988).

SPINAL CORD NEUROCYSTICERCOSIS Using CT, anecdotal reports have described symmetric enlargement of the cord in a patient with intramedullary cysts and pseudoreticular formations within the spinal canal in a patient with leptomeningeal cysts. On MRI, intramedullary cysticerci appear as rounded or septated lesions that may have an eccentric hyperintense nodule representing the scolex (Garcia and Del Brutto, 2003). The periphery of the cyst usually shows abnormal

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Fig. 97.4. Imaging findings in parenchymal neurocysticercosis, including vesicular cysts (A), colloidal cysts (B), granular cysts (C), and calcifications (D).

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Fig. 97.5. Contrast-enhanced MRI (A) showing ring-enhancing lesions corresponding to colloidal cysts. Using diffusionweighted images (B), scolex are easily visualized.

mobile within the spinal subarachnoid space and may change their position during the examination according to movements of the patient on the table.

Immunologic diagnosis

Fig. 97.6. MRI showing abnormal enhancement of leptomeninges and racemose cysticerci at Sylvian fissures and basal CSF cisterns.

enhancement after contrast medium administration. The spinal cord is seen enlarged and if the scolex is not identified it is difficult to differentiate this condition from spinal tumors. Leptomeningeal cysts may be freely

Immunologic diagnostic tests are used to assess the prevalence of cysticercosis in populations and to exclude or confirm the diagnosis of neurocysticercosis in neurologic patients with inconclusive neuroimaging findings. The complement fixation test and the enzyme-linked immunosorbent assay (ELISA) are time-honored tests that have been used for the decades to diagnose cysticercosis (Richards and Schantz, 1991; White, 2000). However, both tests have been faced with problems inherent to poor sensitivity or specificity. False-negative results are related to local production of antibodies within the CNS without a parallel increase of antibodies in peripheral blood, or to immune tolerance to the parasite without production of anticysticercal antibodies, and false-positive results are due to previous contact with the adult T. solium or to cross-reactivity with other helminths (Garcia et al., 2005). The demonstration that antibodies to species-specific antigens of T. solium can be detected by enzyme-linked immunoelectrotransfer blot (EITB) assay stimulated investigators to develop highly purified antigens of cysticercus to be used in a new immunologic diagnostic test for cysticercosis (Tsang et al., 1989). The EITB has been

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extensively evaluated in different hospital-based and population-based studies (Garcia et al., 2005). While some reports suggested that serum EITB is from 94% to 98% sensitive and 100% specific for the diagnosis of human cysticercosis, results from other studies have been disappointing. One weakness of the test is the high number of false-negative results in patients with a single cerebral cyst; in such cases, the sensitivity of EITB falls significantly (Singh et al., 2010). In addition, patients with calcified lesions are less likely to test positive on EITB than those with active disease. Another weakness of the serum EITB is that it may be positive in patients who have been exposed to the adult parasite without developing cysticercosis. A recent preliminary study suggested that the use of conformation-sensitive immunoassay may detect almost 50% of patients with a single cysticercal granuloma who were negative with the EITB, thus improving the sensitivity of the test (Prabhakaran et al., 2007). Detection of circulating parasitic antigens using monoclonal antibodies is another immune diagnostic technique that has been used in some field studies (Garcia et al., 2000). However, detection of circulating antigens is possible only in patients with active disease. While the sensitivity of this test as a screening tool for the diagnosis of neurocysticercosis is poor, it may be of value to monitor the response to cysticidal drug therapy (Mahanty and Garcia, 2010).

Diagnostic criteria Despite the above mentioned advances in neuroimaging and immune diagnostic tests, the diagnosis of neurocysticercosis is a challenge in many patients. Clinical manifestations are nonspecific, neuroimaging findings are most often not pathognomonic, and serologic tests are faced with problems related to relatively poor specificity and sensitivity. A set of diagnostic criteria based on the objective evaluation of clinical, radiologic, immunologic, and epidemiologic data has been proposed to provide the physicians with elements to diagnose patients with suspected neurocysticercosis (Del Brutto et al., 2001). This set includes four categories of criteria – absolute, major, minor, and epidemiologic – stratified according to their individual diagnostic strength. Absolute criteria allow unequivocal diagnosis of neurocysticercosis, major criteria strongly suggest the diagnosis but cannot be used alone to confirm the disease, minor criteria are frequent but non-specific manifestations of the disease, and epidemiologic criteria refer to circumstantial evidence favoring the diagnosis of cysticercosis. Interpretation of these criteria result in two categories of diagnostic certainty – definitive and probable – according to the likelihood that neurocysticercosis is present in a given patient (Table 97.2).

Table 97.2 Diagnostic criteria and degrees of diagnostic certainty for neurocysticercosis Diagnostic Criteria Absolute: ● Histologic demonstration of the parasite from biopsy of a brain or spinal cord lesion ● Evidence of cystic lesions showing the scolex on neuroimaging studies ● Direct visualization of subretinal parasites by fundoscopic examination Major: ● Evidence of lesions highly suggestive of neurocysticercosis on neuroimaging studies ● Positive serum immunoblot for the detection of anticysticercal antibodies ● Resolution of intracranial cystic lesions after therapy with albendazole or praziquantel ● Spontaneous resolution of small single enhancing lesions MINOR: ● Evidence of lesions suggestive of neurocysticercosis on neuroimaging studies ● Presence of clinical manifestations suggestive of neurocysticercosis ● Positive CSF ELISA for detection of anticysticercal antibodies or cysticercal antigens ● Evidence of cysticercosis outside the central nervous system Epidemiologic: ● Individuals coming from or living in an area where cysticercosis is endemic ● History of frequent travel to disease-endemic areas ● Evidence of household a contact with T. solium infection Degrees of Diagnostic Certainty Definitive: ● Presence of one absolute criterion ● Presence of two major plus one minor or one epidemiologic criteria Probable: ● Presence of one major plus two minor criteria ● Presence of one major plus one minor and one epidemiologic criteria ● Presence of three minor plus one epidemiologic criteria (Modified from Del Brutto et al., 2001)

TREATMENT A single therapeutic approach is not useful in every patient with neurocysticercosis (Nash et al., 2006). Characterization of the disease in terms of viability of cysts, degree of the host’s immune response to the parasite, and location and number of lesions is important for rational therapy. Therapy usually includes a combination of symptomatic and cysticidal drugs. Surgery also has a role in the management of some patients (Garcia et al., 2002).

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Cysticidal drugs Praziquantel destroys 60–70% of parenchymal brain cysticerci. The initial regimen of praziquantel at doses of 50 mg/kg/day (given every 8 hours) for 15 days was arbitrarily chosen (Sotelo et al., 1984). Since then, recommended dosages of praziquantel have ranged from 10 to 100 mg/kg for periods of 3–21 days (Bittencourt et al., 1990). Plasma levels of praziquantel decline within less than 3 hours after its administration, and it seems that the cysticidal effect observed in such studies has been reached by exposing the parasites to intermittent peaks of the drug. It has also been suggested that if cysticerci are exposed to high concentrations of praziquantel maintained for up to 6 hours by giving three individual doses of 25–30 mg/kg at 2 hour intervals, this might be sufficient to destroy the parasites. While preliminary results with this new regimen were encouraging (Del Brutto et al., 1999), it seems that the single-day course of praziquantel only works for patients with a single parenchymal brain cyst (Pretell et al., 2001). Albendazole also has cysticidal properties. This drug was initially administered at doses of 15 mg/kg/day for 1 month (Escobedo et al., 1987). Further studies showed that the length of therapy could be shortened to 1 week without lessening the efficacy of the drug (Garcia et al., 1997), and even to 3 days if the patient has a single brain cyst (Bustos et al., 2006). Albendazole destroys 70–80% of parenchymal brain cysts, and has been superior to praziquantel in trials comparing the efficacy of these drugs (Sotelo et al., 1990; Takayanagui and Jardim, 1992). Another advantage of albendazole is that it also destroys subarachnoid and ventricular cysts due to its different mechanism of action (Del Brutto, 1997). In some of these cases, particularly in patients with large subarachnoid cysts, higher doses (up to 30 mg/kg/day) or more prolonged, or even repeated, courses of albendazole may be needed (Proan˜o et al., 2001; Gongora-Rivera et al., 2006; Fleury et al., 2011). Due to the benign nature of some forms of neurocysticercosis, the use of cysticidal drugs has been questioned, leading to confusion and incorrect decisions in the management of many patients. It has been claimed that cysticidal drugs only destroy the cysts without modifying the clinical course of the disease (Salinas et al., 1999). Nevertheless, more recent studies have shown that cysticidal drugs also produce clinical improvement in most patients. In a placebo-controlled trial, albendazole was effective for therapy of viable parenchymal brain cysticerci (Garcia et al., 2004). In this study, treated patients had better seizure control than the placebo group, as reflected by a 67% reduction in the number of seizures. In addition, the number of cystic lesions that resolved was significantly higher in patients receiving

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albendazole. Other controlled trials showed that the prognosis of patients with colloidal parenchymal brain cysts is better after therapy than when the disease is left untreated (Baranwal et al., 1998; Gogia et al., 2003; Kalra et al., 2003). Two recent meta-analyses of randomized trials have evaluated the effect of cysticidal drugs on neuroimaging and clinical outcomes of patients with neurocysticercosis (Del Brutto et al., 2006; Abba et al., 2010). According to these meta-analyses, cysticidal drug therapy results in better resolution of both colloidal and vesicular cysticerci, a lower risk of seizure recurrence in patients with colloidal cysticerci, and a reduction in the rate of generalized seizures in patients with vesicular cysticerci. Some patients should not be treated with albendazole or praziquantel. The use of these drugs may exacerbate the syndrome of intracranial hypertension observed in patients with cysticercotic encephalitis. In patients with both hydrocephalus and parenchymal brain cysts, cysticidal drugs may be used only after a ventricular shunt has been placed to avoid further increases of the intracranial pressure as a result of drug therapy. Cysticidal drugs must be used with caution in patients with giant subarachnoid cysticerci because the inflammatory reaction developed by the host in response to the acute destruction of the parasite within the subarachnoid space may occlude small leptomeningeal vessels surrounding the cyst. In such patients, concomitant steroid administration is mandatory to avoid the hazard of a cerebral infarct. In patients with ventricular cysts, the use of cysticidal drugs should be individualized. While albendazole successfully destroys many ventricular cysts, the inflammatory reaction may cause acute hydrocephalus if the cysts are located within the fourth ventricle or near the foramina of Monro. Finally, patients with calcifications alone should not receive cysticidal drugs since these lesions represent already dead parasites (Garcia et al., 2002).

Symptomatic therapy The administration of antiepileptic drugs usually results in adequate control of seizures in patients with calcified cysticerci. In contrast, there is some evidence that patients with viable intracranial cysts should first be treated with cysticidal drugs to achieve an adequate control of seizures with antiepileptic drugs (Del Brutto et al., 1992; Garcia et al., 2004). The optimal length of antiepileptic drug therapy in patients with neurocysticercosis has not been settled. A prospective study showed that up to 50% of patients with parenchymal brain cysticerci successfully treated with cysticidal drugs had relapses after withdrawal of antiepileptic drugs (Del Brutto, 1994). In this study, prognostic factors associated with

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seizure recurrence included the development of parenchymal brain calcifications and the presence of both recurrent seizures and multiple brain cysts before the institution of therapy. In patients with single enhancing lesions (colloidal cysts), the development of brain calcification after therapy is also the main determinant for seizure relapse after withdrawal of antiepileptic drugs; in such cases, long-term antiepileptic treatment may be needed (Singh et al., 2010). Corticosteroids represent the primary form of therapy of some forms of neurocysticercosis, including cysticercotic encephalitis, angiitis, and arachnoiditis causing hydrocephalus and progressive entrapment of cranial nerves. In patients with intracranial hypertension due to cysticercotic encephalitis, corticosteroids may be used in association with osmotic diuretics. Simultaneous administration of corticosteroids and cysticidal drugs has been recommended to ameliorate the secondary effects of headache and vomiting that may occur during therapy (Garcia et al., 2002). Such manifestations are related to the acute destruction of parasites within the brain, and are reliable indicators of drug efficacy. Absolute indications for corticosteroid administration during cysticidal drug therapy include the management of patients with giant subarachnoid cysticerci, ventricular cysts, spinal cysts, and multiple parenchymal brain cysts. In these cases, corticosteroids must be administered before, during, and even some days after the course of anticysticercal drugs to avoid the risk of cerebral infarcts, acute hydrocephalus, spinal cord swelling, and massive brain edema, respectively (Del Brutto, 1997; Garcia and Del Brutto, 1999; Garcia et al., 2005).

Surgery Patients with hydrocephalus require placement of a ventricular shunt. The main problem in these cases is the high prevalence of shunt dysfunction; indeed, it is common for these patients to have two or three shunts revisions during their lives. Their protracted course and their high mortality rates (up to 50% in 2 years) is directly related to the number of surgical interventions to change the shunt (Sotelo and Marin, 1987). Ventricular cysts may be removed by surgical excision or endoscopic aspiration (Rajshekhar, 2010). Cyst migration between the time of diagnosis and the surgical procedure is possible, and this phenomenon must be ruled out by CT or MRI immediately before surgery to avoid unnecessary craniotomies. In the absence of ependymitis, permanent shunt placing is not necessary after removal of a ventricular cyst. In contrast, shunt placement should follow or even precede the excision of ventricular cysts associated with ependymitis (Bergsneider et al., 2000).

CONTROL MEASURES Neurocysticercosis is common in areas where conditions favoring the transmission of T. solium are found, including deficient disposal of human feces, low levels of education, slaughtering of pigs without veterinary control, and presence of free roaming pigs around households (Garcia and Del Brutto, 2005). Neurocysticercosis is a potentially eradicable disease. To be effective, however, eradication programs must be directed to all the targets for control, particularly human carriers of the adult tapeworm, infected pigs, and eggs in the environment (Keilbach et al., 1989; Pawlowski, 2006). Since these targets represent interrelated steps in the life cycle of T. solium, inadequate coverage of one of them may result in a rebound in the prevalence of taeniosis/ cysticercosis after the program has been completed (Garcia et al., 2006).

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Gilman RH, Del Brutto OH, Garcı´a HH et al. (2000). Prevalence of taeniosis among patients with neurocysticercosis is related to severity of infection. Neurology 55: 1062. Gogia S, Talikdar B, Choudhury V et al. (2003). Neurocysticercosis in children: clinical findings and response to albendazole therapy in a randomized, double-blind, placebo-controlled trial in newly diagnosed cases. Trans R Soc Trop Med Hyg 97: 416–421. Gongora-Rivera F, Soto-Hernandez JL, Gonzalez-Esquivel D et al. (2006). Albendazole trial at 15 or 30 mg/kg/day for subarachnoid and intraventricular cysticercosis. Neurology 66: 436–438. Gonzalez AE, Lopez-Urbina T, Tsang B et al. (2006). Transmission dynamics of Taenia solium and potential for pig-to-pig transmission. Parasitol Int 55: S131–S135. Henneberg R (1912). Die tierischen Parasiten des Zentralnervensystems. I. Des Cysticercus cellulosae. In: M Lewandowsky (Ed.), Handbuch der Neurologie, vol 3. Spezielle Neurologie II. Verlag von Julius Springer, Berlin, pp. 643–709. Kalra V, Dua T, Kumar V (2003). Efficacy of albendazole and short-course dexamethasone treatment in children with 1 or 2 ring-enhancing lesions of neurocysticercosis: a randomized controlled trial. J Pediatr 143: 111–114. Keilbach NM, de Aluja AS, Sarti-Gutierrez E (1989). A programme to control taeniasis-cysticercosis (T. solium): experiences in a Mexican village. Acta Leiden 57: 181–189. K€ uchenmeister F (1855). Offenes sendschreiben an die k.k. Gessellschaft der Aertze zu Wein. Experimenteller Nachweis, dass Cysticercus cellulosae innerhab des menschlichen Darmkanales sich in Taenia solium umwandelt. Wiener Medizinische Wochenscriff 5: 1–4. Loo L, Braude A (1982). Cerebral cysticercosis in San Diego. A report of 23 cases and a review of the literature. Medicine 61: 341–359. Madigubba S, Vishwanath K, Reddy G et al. (2007). Changing trends in ocular cysticercosis over two decades: an analysis of 118 surgically excised cysts. Indian J Med Microbiol 25: 214–219. Madrazo I, Garcı´a-Renterı´a JA, Sandoval M et al. (1983). Intraventricular cysticercosis. Neurosurgery 12: 148–152. Mahanty S, Garcia HH (2010). Cysticercosis and neurocysticercosis as pathogens affecting the nervous system. Prog Neurobiol 91: 172–184. Mass-Sese, Vives-Pin˜eira I, Fernandez-Barreiro A et al. (2008). Estudio descriptivo de neurocisticercosis en un hospital terceario. Rev Neurol 46: 194–196. McCormick GF, Zee C-S, Heiden J (1982). Cysticercosis cerebri. Review of 127 cases. Arch Neurol 39: 534–539. Medina MT, Duron RM, Martinez L (2005). Prevalence, incidence, and etiology of epilepsies in rural Honduras: the Salama study. Epilepsia 46: 124–131. Montano SM, Villaran MV, Ylquimiche L et al. (2005). Neurocysticercosis. Association between seizures, serology, and brain CT in rural Peru. Neurology 65: 229–234.

Nash TE, Del Brutto OH, Butman JA et al. (2004). Calcified neurocysticercosis and epileptoenesis. Neurology 62: 1934–1938. Nash TE, Singh G, White AC et al. (2006). Treatment of neurocysticercosis: current status and future research needs. Neurology 67: 1120–1127. Nash TE, Pretell EJ, Lescano AG et al. (2008). Perilesional brain oedema and seizure activity in patients with calcified neurocysticercosis: a prospective cohort and nested casecontrol study. Lancet Neurol 7: 1099–1105. Ndimubanzi PC, Carabin H, Budke CM (2010). A systematic review of the frequency of neurocysticercosis with a focus on people with epilepsy. PLOS Nelected Tropical Diseases 4: e870. Nieto D (1982). Historical notes on cysticercosis. In: A Flisser, K Willms, JP Laclete et al. (Eds.), Cysticercosis: present state of knowledge and perspectives. Academic Press, New York, pp. 1–7. Pawlowski ZS (2006). Role of chemotherapy of taeniasis in prevention of neurocysticercosis. Parasitol Int 55: S105–S109. Pittella JEH (1997). Neurocysticercosis. Brain Pathol 7: 681–693. Prabhakaran V, Rajshekhar V, Murrell KD et al. (2007). Conformation-sensitive immunoassays improve the serodiagnosis of solitary cysticercus granuloma in Indian patients. Trans R Soc Trop Med Hyg 101: 570–577. Pretell EJ, Garcia HH, Gilman RH et al. (2001). Failure of oneday praziquantel treatment in patients with multiple neurocysticercosis lesions. Clin Neurol Neurosurg 103: 175–177. Proan˜o JV, Madrazo I, Avelar F et al. (2001). Medical treatment for neurocysticercosis characterized by giant subarachnoid cysts. N Engl J Med 345: 879–885. Rajshekhar V (2010). Surgical management of neurocysticercosis. Int J Surg 8: 100–104. Rangel R, Torres B, Del Bruto O et al. (1987). Cysticercotic encephalitis. A severe form in young females. Am J Trop Med Hyg 36: 387–392. Rangel-Guerra R, Herrera J, Elizondo G et al. (1988). Neurocysticercosis. Arch Neurol 45: 492. Richards F Jr, Schantz PM (1991). Laboratory diagnosis of cysticercosis. Clin Lab Med 11: 1011–1028. Robles C, Chavarrı´a M (1979). Presentacio´n de un caso clı´nico de cisticercosis cerebral tratado me´dicamente con un nuevo fa´rmaco: praziquantel. Salud Publica Mex 21: 603–617. Salinas R, Counsell C, Prasad K et al. (1999). Treating neurocysticercosis medically: a systematic review of randomized, controlled trials. Trop Med Int Health 4: 713–718. Serpa JA, Graviss EA, Kass JS et al. (2011). Neurocysticercosis in Houston, Texas: an update. Medicine (Baltimore) 90: 81–86. Singh S, Gibikote SV, Shyamkumar NK (2003). Isolated fourth ventricular cysticercus cysts: MR imaging in 4 cases with short literature review. Neurol India 51: 394–396. Singh G, Rajshekhar V, Murthy JM et al. (2010). A diagnostic and therapeutic scheme for a solitary cysticercus granuloma. Neurology 75: 2236–2245.

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Venkataramana NK, Jain VK, Das BS et al. (1989). Intramedullary cysticercosis. Clin Neurol Neurosurg 91: 337–341. Wadia N, Desai S, Bhatt M (1988). Disseminated cysticercosis. New observations, including CT scan findings and experience with treatment by praziquantel. Brain 111: 597–614. Weinberg M (1909). Recherche des anticorps spe´cifiques dans la distomatose et la cysticercose. C R Soc Biol (Paris) 66: 219–221. White AC Jr (2000). Neurocysticercosis: updates on epidemiology, pathogenesis, diagnosis, and management. Annu Rev Med 51: 187–206. Willms K (2008). Morphology and biochemistry of the pork tapeworm, Taenia solium. Curr Top Med Chem 8: 375–382. Wu Z, Mittal S, Kish K et al. (2009). Identification of calcification with MRI using susceptibility-weighted imaging: a case study. J Magn Reson Imaging 29: 177–182. Yoshino K (1933). Studies on the post-embryonal development of Taenia solium. Part III. On the development of Cysticercus cellulosae within the definite intermediate host. J Med Assoc Formosa 32: 166–169.

Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 98

Neurosyphilis 1

JOSEPH R. BERGER1* AND DAWSON DEAN2 Department of Neurology, University of Kentucky College of Medicine, Lexington, KY, USA 2

Department of Internal Medicine, Indiana University, Indianapolis, IN, USA

HISTORICAL NOTE AND NOMENCLATURE The origin of syphilis has perhaps best been addressed by medical interpretation of bones from archeological sites. Syphilis is one the treponemal diseases, like yaws, pinta and others, which may cause characteristic lesions of bone periosteum. As a result, studying ancient bone fragments can trace the path of these diseases over time. These studies (Rothschild and Rothschild, 1995; Rothschild et al., 1995) suggest that yaws originated in Africa approximately 1.5 million years ago. The disease spread over several continents, appearing in England and Ireland in the 13th century. Syphilis first appears in North America approximately 2000 years ago, presumably as a mutation of yaws. It is first seen in Europe at the end of the 15th century and is widely believed to have been carried from the New World by Columbus’ crew. Syphilis was first described as a clinical entity at the turn of the 15th century when a disease commonly referred to as the “Great Pox” or “Evil Pox” was recognized in Europe. The illness figured heavily in the wars that ravaged Europe at the time and, unlike the current disease, was associated with mortality rates as high as or higher than 25% in its early stages. Francisco Lopez de Villalobos published the first book on the illness in 1498. Physician and author Hieronymus Fracastor provided the name for the disease in his poem Syphilis sive Morbus Gallicus, published in 1530. Sexual transmission of the disease was identified shortly after its initial clinical recognition. Transmission of the disease to infants breast fed by affected wet nurses and vertical transmission were also commented on in the early literature. Over the years, syphilis became confused with gonorrhea, a situation rectified in the middle of the 18th century after the mistaken conclusions of

experiments performed by John Hunter, who selfinoculated urethral pus containing both Treponema pallidum and Neisseria gonorrhea. Signs of syphilis led to several advances in neurologic examination in the 19th century. In 1869, Douglas Argyll Robertson described patients who lost pupillary reaction to light but preserved accommodation, although he did not associate this with syphilis. As late as 1872, even Jean-Martin Charcot rejected the notion that tabes dorsalis was the consequence of syphilis (Schiller, 1995). However, by 1881, William Gowers and Wilhelm Erb (Schiller, 1995) had firmly established the link between syphilis and tabes dorsalis by epidemiologic studies. The causative organism of syphilis was not understood until the 20th century. In 1903 Metchnikoff and Roux demonstrated transmission of the disease to chimpanzees. Two years later, Schaudinn and Hoffmann identified the causative agent as an almost transparent, spiral-shaped organism that they labeled Spirochaeta pallida. The introduction of dark field microscopy by Landsteiner in 1906 greatly assisted studies of the organism, and observations of the pathogen in the meninges and brain were made in 1913. The first serologic tests for syphilis exploited a basic lipoidal antigen and were first reported by Wasserman, Neisser, and Bruck in 1906. Later, in 1949, Nelson and Mayer introduced a specific treponemal test, the Treponema pallidum immobilization test. The effective treatment of syphilis was also largely developed in the 20th century. Previously, and even at the beginning of the 20th century, the treatment was generally ineffective and largely confined to heavy metals, such as mercury, arsenic, and bismuth. Ehrlich developed Arsphenamine (commercially called Salvarsan) in 1911, which was a molecule containing arsenic that was effective against syphilis. Six years later, in 1917,

*Correspondence to: Joseph R. Berger, M.D., Department of Neurology, University of Kentucky College of Medicine, Lexington, Kentucky 40536-0284, USA. Tel: þ1-859-218-5039, E-mail: [email protected]

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J.R. BERGER AND D. DEAN

Wagner-Jauregg received the Nobel Prize for the introduction of malarial therapy. Malaria and other measures were used to induce high fever to treat syphilis. The modern treatment of syphilis began in 1943 with the introduction of penicillin by Mahoney.

EPIDEMIOLOGY Worldwide, it was estimated that by 1999, 11.6 million new cases of syphilitic infection occurred per year (WHO, 2001). The epidemiology of syphilis is complex, however, since epidemics in one country may coincide with a decline in others. Incidence of the disease is affected by public health policy as well as social, economic, and political factors. In 1999, there were approximately 107 000 new cases in North America and 136 000 new cases in Western Europe, but 3.8 million new cases in sub-Saharan Africa, 4 million cases in South Asia, and 2.9 million cases in Latin America (WHO, 2001). The combination of the ready availability of penicillin and the sensitivity of the organism to this antibiotic has led to a widely held perception that syphilis in contemporary times is rare. The annual incidence of syphilis in the US declined 36-fold from a peak of 72 cases per 100 000 in 1943 to 2.1 cases per 100 000 in 2000; however, it has increased by 114% to 4.5 cases per 100 000 in 2008 (Katz et al., 2010). Variations in incidence are noted over time, with local peaks approximately every 10 years. Moreover, in some areas of the country the incidence may be substantially higher than the national average. For instance, the incidence in Florida is three times the national average. In the 1970s, there was a clearly increased risk among gay and bisexual men; however, their adoption of safe sex techniques, with the advent of the AIDS era, resulted in a significant decline in the incidence of syphilis in this risk group, although this effect appears to be declining. In some populations, the disorder is quite rare. For instance, not one case of general paresis was observed among 560 demented individuals entered into the Rochester (Minnesota) Epidemiology Project over the 5 years from 1990 through 1994 (Knopman, 2006). The profile of a typical syphilis patient also varies over time. In the US, the epidemics that peaked respectively in 1982 and 2003 both involved many more men than women, while the 1990 peak affected approximately equal numbers of men and women. The age distribution has also varied; in 1992, 20–29-year-old men had the highest rates, while in 2003 it was highest for 35–39-year-olds. The current epidemics are concentrated among men who have sex with men (MSM). For example, in 2002, 93% of syphilis cases in San Francisco and 81% of cases in Los Angeles were MSM (CDC, 2004).

The male to female ratio of new cases has increased nationwide (Peterman et al., 2005). There are also variations in the incidence of different strains of syphilis, which has clinical importance because the various strains differ in their antibiotic resistance and neurologic effects. For example, one study sequenced genes of T. pallidum samples obtained from syphilis patients in San Francisco and found eight distinct subtypes, with the majority of cases caused by one particular subtype. Some subtypes are more resistant to azithromycin, so the popularity of a particular subtype in a community may determine which drug to use. A different study (Marra et al., 2010) found that only specific strains caused neurosyphilis. Neurosyphilis seems to occur with greater frequency in individuals coinfected with the human immunodeficiency virus (HIV) than in the HIV-seronegative population. Prevalence rates of CSF VDRL-reactive neurosyphilis have been reported to be between 1.0% and 2.0% for several large cohorts of HIV-seropositive individuals (Berger, 1991; Holtom et al., 1992; Brandon et al., 1993). This prevalence rate is substantially higher if only patients with serologic evidence of syphilis are included. In some HIV-infected populations, the prevalence rate of a reactive serum fluorescent treponemal antibody absorption test approaches 50% (Berger, 1991). In one study, 9.1% of HIV-infected patients undergoing lumbar puncture because of a reactive serology and having no history of recent treatment for syphilis had a reactive CSF VDRL (Holtom et al., 1992). Neurosyphilis may be responsible for HIV-related neurologic manifestations in a significant minority of some populations, and neurosyphilis needs to be considered in the differential diagnosis of any HIV-infected person presenting with neurologic disease (Berger, 1991). In a European study conducted between 1996 and 2006, overall HIV prevalence among MSM ranged between 5% and 18% for different countries, but 42% of MSM diagnosed with syphilis were HIV positive (Dougan et al., 2007). In the US in 2002, 61% of syphilis cases were HIV positive in one San Francisco study, and 58% of syphilis cases were HIV positive in a Los Angeles study the same year (CDC, 2004).

PATHOGENESIS Syphilis is caused by the bacterium Treponema pallidum, a long, slender, coil-shaped organism that measures 6–15 mm in length, but only 0.15 mm in width, a dimension below the resolution of light microscopy. The organism has regular spirals numbering 5 to 20 and is actively motile using a rotational screw-like activity, flexion, and back-and-forth motion. Electron microscopic studies reveal that the organism has an amorphous coat of

NEUROSYPHILIS 1463 mucopolysaccharides, an outer membrane, an electronmen and 5.0% of the women ultimately developed neudense peptidoglycan layer, and a cytoplasmic memrosyphilis (Clark and Danbolt, 1964). No satisfactory brane. Three flagella extending from each end of the explanation has yet been proposed to account for the organism are located between the outer membrane and lack of universal invasion of the central nervous system the electron-dense layer. These flagella twist around by T. pallidum, nor is there an explanation for failure of the body of the organism and provide the spiral shape clinically evident neurosyphilis to develop in the majority of the organism and its mode of locomotion. of individuals who manifest cerebrospinal fluid abnorT. pallidum belongs to one of five genera in the order malities indicative of CNS invasion. Spirochaetales. Three of these genera are pathogenic to Two processes account for pathology of neurosyphiman, including Treponema (syphilis), Leptospira lis: (1) invasion of the CNS by T. pallidum and (2) the (leptospirosis), and Borrelia (tick- and louse-borne associated immunologic response that is engendered relapsing fever). The organisms responsible for endemic by this invasion. In syphilitic meningitis, the earliest neusyphilis (T. pallidum), yaws (T. pertenue), and pinta rologic complication of syphilis, invasion of the menin(T. carateum) are morphologically identical and antigenges by the spirochete results in an infiltration of the ically similar. Extensive DNA homology has been meninges by lymphocytes and, to a much smaller degree, demonstrated between these organisms. plasma cells. This cellular infiltration may follow blood T. pallidum grows best in 3–5% oxygen, and 5% carvessels into the brainstem and spinal cord along the bon dioxide in histamine, but its cultivation in vitro is difVirchow–Robin spaces. Necrosis of the media and ficult. This and its exquisite fragility have rendered its proliferation of the intima of small meningeal vessels study difficult. Small mammals and primates have been accompanies T. pallidum invasion of the vessel walls. used as animal models. Treponemal disease in the rabbit Late stages of neurosyphilis can be divided into meninmost closely parallels that in man. The organism invades govascular and parenchymatous disease. The inflammainterstitial spaces and chiefly proliferates there, with a tion observed in the former parallels that observed with doubling time of 30–33 hours. It can, however, be found syphilitic meningitis. The classic lesion is an endarteritis intracellularly. Dissemination is hematogenous. obliterans of medium and large vessels first described by Shortly after infection, a spirochetemia results with Huebner in 1874. Fibroblastic thickening of the intima dissemination of T. pallidum to virtually any organ, and thinning of the media of small vessels is referred to including the central nervous system (CNS). Both as Nissl–Alzheimer arteritis. Even in the absence of clinihumoral and cellular immunity play a role in the ensuing cally apparent meningovascular disease, cerebral blood infection. Antibodies to T. pallidum are detectable flow abnormalities have been demonstrated by singlewithin 10–21 days of infection. While the humoral photon emission computed tomography (SPECT) in early response does not contain the infection, it may alter syphilis (Shi et al., 2003). A decline in cerebral blood flow the course of the disease. Cellular immunity appears following effective treatment of general paresis has been to be effective in controlling the infection as evidenced reported and was believed to reflect decreasing inflammaby immunity during rechallenge. The degree of protection (Kitabayashi et al., 2002). Syphilitic lesions of the brain tion is directly proportional to the extent of the response. and spinal cord occur as a secondary event. Gummas of Impairment of cellular immunity due to drugs, pregvarious sizes, from microscopic to mass-producing nancy, AIDS, etc. appears to result in a more aggressive lesions, may be observed. Pathologically, the gummas are syphilitic infection than otherwise anticipated. thick, tough, rubbery lesions of fibrous trabecula with Studies of cerebrospinal fluid abnormalities occurlymphocytic and plasma cell infiltration of the outer layers. ring in association with early (primary or secondary) Treponemes are seldom demonstrated in the gumma. syphilis have detected abnormalities in 16–48% of cases. Parenchymatous neurosyphilis is typified by tabes These results are suggestive of early invasion of the cendorsalis and general paresis. The pathology of tabes dortral nervous system by the organism. Several studies salis predominates in the dorsal roots and posterior colhave confirmed the presence of viable treponemes in umns of the lumbosacral and lower thoracic levels. the cerebrospinal fluid in these early stages of infection. Variable lymphocytic infiltration of the meninges Neurosyphilis is not believed to develop in the absence of accompanies these degenerative changes. The predomicerebrospinal fluid abnormalities. Merritt stated that “if nant findings are believed to result from irreversible the cerebrospinal fluid is normal 2 or more years after changes to the dorsal root fibers, but the exact pathogeninfection, it will always remain so, and parenchymatous esis of this disorder is not known. Typically, in general neurosyphilis will never develop.” The converse, howparesis, the brain is atrophic and the meninges thickened ever, is not true. The presence of cerebrospinal fluid on pathologic examination; however, the brain may abnormalities does not necessarily predict the developappear grossly normal in a minority of cases. The cerement of neurosyphilis. In the Oslo study, 9.4% of the bral cortex, striatum, and hypothalamus bear the brunt

1464 J.R. BERGER AND D. DEAN of the damage. The architecture of the cerebral cortex is because of serologic evidence of syphilis in the absence disrupted, and neuronal loss accompanies astrocytic and of neurologic sequelae. Examination of the cerebrospimicroglial proliferation. T. pallidum can be demonnal fluid reveals evidence of neurosyphilis; these patients strated in the cerebral cortex. Ependymal granulations are at risk for developing symptomatic disease. Among are commonly observed, and the meningeal inflammathe symptomatic disorders of neurosyphilis, the earliest tion is chiefly composed of plasma cells. manifestation is syphilitic meningitis which typically occurs within the first 12 months of infection and may CLINICAL MANIFESTATIONS accompany features of secondary syphilis. Although OF SYPHILIS the majority of patients with CSF abnormalities occurring in association with secondary syphilis are neurologInfection with T. pallidum is divided into several stages. ically asymptomatic, approximately 5% of all patients Primary syphilis is characterized by an ulcerated, painwith secondary syphilis will have an associated meningiless lesion with firm borders, referred to as a chancre. tis. Headaches, meningismus, cranial nerve palsies This lesion develops at the site of epidermal or mucous (chiefly, in descending order of frequency, VII, VIII, membrane inoculation and is accompanied by regional VI, and II), hearing loss, tinnitus, and vertigo may be adenopathy. This lesion occurs approximately 3 weeks observed in isolation or combination in upwards of after infection, although the time to development ranges 40% of patients with secondary syphilis. Impaired vision from 3 to 90 days. The latency to its appearance depends (Oette et al., 2005; Iwamoto et al., 2009) secondary to on the size of the inoculum. Although the lesion is a local chorioretinitis, retinitis, optic neuropathy, optic chiasmal manifestation, the spirochetes, even at this early stage, or optic tract disease is also reported. The symptoms of have disseminated systemically as evidenced by the abilsyphilitic meningitis include headache, photophobia, and ity to transmit syphilis by blood donation from incubata stiff neck. Encephalopathic features resulting from ing seronegative donors and the presence of detectable vascular compromise or increased intracranial pressure T. pallidum in the cerebrospinal fluid of a substantial may be observed. These include confusion, lethargy, seipercentage of infected persons. zures, aphasia, and hemiplegia. Intractable seizures Secondary syphilis develops within 2–8 weeks of the may, on rare occasions, be the initial manifestation of appearance of the chancre and is attributable to a bacterneurosyphilis (Phan et al., 1999). Acute sensorineural emic phase of the illness. Most striking is a macular, hearing loss and acute optic neuritis may occur in assomaculopapular, or pustular rash that often involves ciation with syphilitic meningitis or independently. the palms and soles; mucous patches; and alopecia. ConMeningovascular syphilis typically occurs 6–7 years stitutional signs, diffuse adenopathy, iridocyclitis, hepaafter the initial infection, but it may occur as early as titis, periostitis, and arthritis often accompany these skin 6 months after the primary infection. The nature of manifestations. A brisk immune response is observed, the neurologic features is dependent on the site of brain and immune complex deposition may lead to nephrotic or spinal cord affected. Many of the stroke eponyms syndrome. A symptomatic aseptic meningitis occurs in described at the turn of the 19th century were the conseup to 5% of patients with secondary syphilis. quence of meningovascular syphilis producing discrete Latent syphilis, a quiescent phase of syphilis that prelesions of the brainstem, lesions seldom seen as a consecedes the development of tertiary complications, is quence of atherosclerotic cerebrovascular disease. divided into early (within 2 years of infection) and late Syphilitic meningomyelitis is characterized by slowly (longer than 2 years) stages. An increased recurrence progressive weakness and paresthesia of the lower of secondary syphilitic manifestations is seen with the extremities. Eventually, bowel and bladder incontinence former. Tertiary syphilis is characterized chiefly by skin, and paraplegia supervene. Examination reveals a spastic osseous, cardiovascular, and neurologic complications. paraparesis or paraplegia with brisk lower extremity Clinically apparent neurologic complications of tertiary reflexes, loss of the superficial abdominal reflexes, syphilis affect less than 10% of untreated patients. Neuand impaired sensory perception, with vibratory and rosyphilis is simply the occurrence of neurologic compliposition sense being disproportionately affected. Syphications due to infection with T. pallidum. It may occur litic transverse myelitis may also be observed resulting in during early or late syphilis. The spectrum of neurosyan acute onset of lower extremity paraplegia and sensory philis is broad. loss. Occasionally, the manifestations of this syndrome are more variable with asymmetric findings noted, NEUROSYPHILIS including a Brown-Se´quard syndrome. An acute infarcThe most common form of neurosyphilis currently diagtion of the anterior spinal artery results in paraplegia and nosed is asymptomatic neurosyphilis. Individuals with loss of pain and temperature sensation below the level of this form of neurosyphilis come to medical attention the lesion with preservation of vibratory and position

NEUROSYPHILIS sense. The preceding spinal cord syndromes are manifestations of meningovascular syphilis. The quintessential spinal cord syndrome associated with parenchymatous neurosyphilis is tabes dorsalis. This disorder usually has a latency of 15–30 years following infection. The most distinctive and often heralding symptom is shooting or lightning-like pains that typically affect the legs and abdomen. On occasion, these pains have been mistaken for surgical emergencies. Touch of the affected areas may serve as a trigger for the pain. Pupillary abnormalities are observed in over 90% of patients; the hallmark abnormality is Argyll Robertson pupils: miotic, irregular pupils exhibiting light-near dissociation. The gait is ataxic, with an associated foot-stomping character due to an associated impaired position sense. The Romberg test, originally described in patients with tabes and at one time considered synonymous with tabes dorsalis (Pearce, 2005), is positive. The impaired sensory perception also leads to the development of Charcot joints, painless swelling of joints, chiefly the knees, due to repeated trauma, and to perforating ulcers of the toes and soles of the feet. The impaired sense of deep pain may be demonstrated by its absence on squeezing the testicle (Pitre sign), the ulnar nerve (Biernacki sign), or Achilles tendon (Abadie sign). Impotence and bladder dysfunction are expected. The lower extremity reflexes are absent. Optic atrophy and cranial nerve palsies are frequently observed. Tabes dorsalis has been mistakenly diagnosed as Miller Fisher syndrome as it may present as a constellation of ophthalmoplegia, ataxia, and areflexia (Stepper et al., 1998). Paraparesis may also be seen as a consequence of syphilitic aortic dissection (Kellett et al., 1997). The diverse spectrum of syphilitic spinal cord disease is presented in Table 98.1. General paresis is a manifestation of parenchymatous neurosyphilis and, like tabes dorsalis, usually develops after a long (15–30 year) hiatus from the time of infection. General paresis accounted for a substantial Table 98.1 Syphilis of the spinal cord ● Syphilitic meningomyelitis ● Syphilitic spinal pachymeningitis ● Spinal cord gumma ● Syphilitic hypertrophic pachymeningitis ● Spinal vascular syphilis ● Syphilitic poliomyelitis ● Tabes dorsalis ● Miscellaneous ● Syringomyelia ● Syphilitic aortic aneurysm ● Charcot vertebra with compression of the spinal cord (Modified from Berger, 1987.)

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percentage of psychiatric illness in the preantibiotic era and, in a study from South Africa, was found in 1.3% of all patients being admitted for acute psychiatric care (Roberts et al., 1992). In addition to a progressive dementia, these patients display a wide variety of psychiatric disturbances, including emotional lability, paranoia, illusions, delusions of grandeur, hallucinations, and inappropriate behavior. Tremors of the tongue, postural tremors of the extremities, hyperreflexia, hypomimetic facies, dysarthria, chorioretinitis, optic neuritis, and pupillary abnormalities, including Argyll Robertson pupils, are seen. Cranial MRI of patients with general paresis has demonstrated frontal and temporal atrophy, subcortical gliosis, and increased ferritin in the basal ganglia (Zifko et al., 1996). Gummas of the nervous system space-occupying lesions. Gummas are affecting the brain may result in progressive focal neurologic manifestations, seizures, or increased intracranial pressure. A linear dural enhancement on MRI similar to that observed with meningiomas may be found with cerebral gummas (Inoue et al., 1995). Gummas affecting the spinal cord result in progressive quadriparesis when located in the cervical area, or in progressive paraparesis when in the thoracic area. An atypical form of neurosyphilis referred to as “modified neurosyphilis” has been attributed to the use of antibiotics for conditions other than syphilis in patients with unrecognized syphilis. This illness is characterized by a negative cerebrospinal fluid VDRL test and clinical features that are outside the spectrum of classically described features of neurosyphilis; however, the contention that these manifestations are syphilitic in origin remains debatable. The natural history of neurosyphilis may be significantly altered by concomitant human immunodeficiency virus (HIV) infection (Johns et al., 1987; Katz and Berger, 1989; Katz et al., 1993). Syphilis with HIV infection appears to be not only more aggressive, but also more difficult to treat (Berry et al., 1987; Musher et al., 1990; Katz et al., 1993), emphasizing the importance of the host’s immune response in controlling this infection. The inability of the HIV-infected patient to establish delayed hypersensitivity to T. pallidum may prevent secondary syphilis from evolving to latency or may cause a spontaneous relapse from a latent state. This impairment of delayed hypersensitivity may account for a more rapid progression of neurosyphilis in HIV-infected individuals than would otherwise be expected. T. pallidum can be isolated from the cerebrospinal fluid of HIV-seropositive patients with primary, secondary, and latent syphilis following current US Centers for Disease Control and Prevention (CDC)recommended penicillin therapy (Lukehart et al., 1988). Despite the associated immunosuppression, serum

1466 J.R. BERGER AND D. DEAN nontreponemal titers at the time of presentation of neudark field microscopy from skin and mucous membrane rosyphilis in the HIV-infected individual are typically lesions, the diagnosis of syphilis is dependent on serohigh, averaging 1:128 (Flood et al., 1998). logic study. There are two categories of serologic study: In HIV infection, acute, symptomatic, syphilitic men(1) nontreponemal tests that are flocculation tests using ingitis during the course of secondary syphilis is not cardiolipin, lecithin, and cholesterol as antigen; (2) trepuncommon. A decrease in the latent period to the develonemal tests, which rely on specific treponemal cellular opment of some neurosyphilitic manifestations, such as components as antigens. Nontreponemal tests include meningovascular syphilis and general paresis, has been the VDRL, rapid plasma reagin, Wasserman, and suggested. The development of meningovascular syphilis Kolmer. The treponemal tests include the fluorescent within 4 months of primary infection despite the admintreponemal antibody absorption test, microhemagglutiistration of accepted penicillin regimens (Johns et al., nation assay, hemagglutination treponemal test for 1987), as well as the neurologic relapse of syphilis in syphilis, and the treponemal immobilization test. HIV-infected individuals after appropriate doses of benUnfortunately, no readily applicable “gold standard” zathine benzylpenicillin for secondary syphilis (Berry exists for the diagnosis of neurosyphilis. Culturing the et al., 1987), has been reported. Other unusual manifestaorganism from the cerebrospinal fluid is cumbersome tions of syphilis that have been reported in association and available in few laboratories. Furthermore, the frawith HIV infection include unexplained fever (Chung gility of T. pallidum may result in a low sensitivity of the et al., 1983), bilateral optic neuritis with blindness test. The presence of a reactive VDRL in the cerebrospi(Zambrano et al., 1987), Bell’s palsy, severe bilateral sennal fluid is specific, with rare reports of false-positives, sorineural hearing loss (Fernandez-Guerrero et al., 1988), but the test is not sufficiently sensitive to exclude the syphilitic meningomyelitis (Berger, 1992), syphilitic polydiagnosis of neurosyphilis on the basis of a negative radiculopathy (Lanska et al., 1988; Winston et al., 2005), study. The serum VDRL is positive in 72% of patients and syphilitic cerebral gumma presenting as a mass lesion with primary syphilis, nearly 100% of patients with sec(Berger et al., 1992). As with other disorders occurring ondary syphilis, 73% of patients with latent syphilis, and with HIV infection, an immune reconstitution inflamma77% of patients with tertiary syphilis. Therefore, as tory syndrome (IRIS) may be seen with syphilis, following many as one quarter of patients with neurosyphilis are a reduction in HIV viral load and return of CD4 lymphoanticipated to have a negative serum VDRL. In some cyte counts (Rushing et al., 2008). instances, the falsely negative VDRL is the consequence Certain ophthalmologic and otolaryngologic complicaof the “prozone phenomenon” in which high titers of tions of syphilis occurring in the absence of neurologic antibody impair the formation of the antigen-antibody disease may result in neurologic consultation. Although lattice that is needed to visualize a positive flocculation the characteristic ophthalmologic abnormality of syphilis test (Smith and Holman, 2004). This phenomenon has is the Argyll Robertson pupil, other conditions that can been reported in the presence of neurosyphilis (Lessig result from T. pallidum infection include interstitial kerand Tecoma, 2006). Its frequency of reactivity appears atitis, chorioretinitis, and optic atrophy. Syphilitic optic to vary with the clinical form of neurosyphilis, and its atrophy, which is commonly unilateral and may occur presence in asymptomatic neurosyphilis may be with or without an associated basilar meningitis, is notosubstantially lower than in symptomatic disease. The riously difficult to treat effectively. Progression is CSF VDRL test is too insensitive to be relied on to observed in as many as 50% of patients despite treatment. exclude the diagnosis of neurosyphilis. In one study, Otitic syphilis is associated with hearing loss, either acute in which cerebrospinal fluid was cultured in rabbit testior gradually progressive in nature, and may occur in assocles, T. pallidum was isolated from cerebrospinal fluid ciation with cochlear end organ damage (Darmstadt and of 12 (30%) of 40 patients with primary and secondary Harris, 1989). Vertigo may also be a feature of this illness. syphilis, but the CSF VDRL was positive in only four In a study of 85 patients with otosyphilis, hearing loss was (33%) of these 12 patients (Lukehart et al., 1988). Thereobserved in 90.6%, tinnitus in 72.9%, and vertigo in fore, measures other than a reactive CSF VDRL must 52.9%, whereas only 5.4% had positive CSF serology be relied on to establish the diagnosis of neurosyphilis. (Yimtae et al., 2007). Syphilitic eighth nerve dysfunction The frequency with which the CSF VDRL is negative is largely recognized as a late manifestation of congenital in the presence of neurosyphilis is not known, but has syphilis but is also observed in acquired illness. been estimated to exceed 25%. In many respects, neurosyphilis is a diagnosis established on clinical grounds. To date, no consensus has been reached regarding diagnosDIAGNOSIS tic criteria, and the physician should probably refrain With the exception of primary and secondary syphilis, in from rigid adherence to narrow guidelines in making which T. pallidum can be demonstrated by the use of the diagnosis.

NEUROSYPHILIS A cardinal requirement for the diagnosis of neurosyphilis is a reactive serum treponemal test. Neurosyphilis should be diagnosed in anyone with serologies reactive for a treponemal test occurring in association with a reactive CSF VDRL. A diagnosis of neurosyphilis should be considered in patients with serologic evidence of syphilis and one or more of the following abnormalities in their cerebrospinal fluid: a mononuclear pleocytosis, an elevated protein, increased immunoglobulin G, or the presence of oligoclonal bands. Undoubtedly, neurosyphilis is overdiagnosed using these criteria. The cerebrospinal fluid fluorescent treponemal antibody absorption test has been suggested as a sensitive screening test for the presence of neurosyphilis (Davis and Schmitt, 1989). However, as many as 32% of HIV-seronegative persons and 67% of HIV-seropositive hospitalized patients with serologic evidence of latent syphilis exhibited this abnormality, indicating its nonspecificity (Carey et al., 1995). Unlike the CSF VDRL, which requires gross blood contamination of the cerebrospinal fluid to be rendered falsely positive, small amounts of blood contamination of the cerebrospinal fluid may give false-positive tests with the fluorescent treponemal antibody absorption test. Furthermore, the fluorescent treponemal antibody absorption test is dependent on immunoglobulin G antibody that may cross the blood–brain barrier to result in a false-positive test for neurosyphilis. The cerebrospinal fluid fluorescent treponemal antibody-immunoglobulin G test has been suggested as an alternative to avoid the latter possibility. Other cerebrospinal fluid studies, not widely employed but believed to be diagnostically useful for neurosyphilis, are a treponemal pallidum hemagglutination test index greater than or equal to 100 (TPHA index ¼ CSF TPHA titers  CSF albumin [mg/dL  103]/ serum albumin [mg/dL]) and a TPHA-IgG index greater than or equal to 3 (THPA-IgG index ¼ CSF TPHA-IgG titer/total CSF IgG  TPHA-IgG titer/total serum IgG). Newer generation tests for syphilis and neurosyphilis, in particular those employing polymerase chain reaction (Hay et al., 1990; Burstain et al., 1991) and monoclonal antibodies (Whang et al., 1992), may solve this dilemma, but at the present time require further study before widespread adoption. An alternative approach that has been proposed for HIV-infected patients suspected of having neurosyphilis despite negative CSF VDRL is to couple the CSF fluorescent treponemal antibody test, which is 100% sensitive, with the percentage of CSF cells that are B lymphocytes (greater than 9% in fresh specimens) (Marra et al., 2004). Coinfection with HIV considerably complicates the interpretation of cerebrospinal fluid abnormalities as a mononuclear pleocytosis, increased protein, increased immunoglobulin G, and the presence of oligoclonal bands may all attend HIV infection in the absence of

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Table 98.2 Diagnosing neurosyphilis in the face of HIV infection Definite neurosyphilis: 1.Positive blood treponemal serology, e.g., FTA-ABS, MHA-TP, etc. 2. Positive CSF VDRL Probable neurosyphilis: 1.Positive blood treponemal serology 2. Negative CSF VDRL 3. CSF mononuclear pleocytosis ( > 20 cells/mm3) Or positive CSF protein ( > 60 mg/dL) Neurologic complications compatible with neurosyphilis, such as cranial nerve palsies, stroke, or evidence of ophthalmologic syphilis Possible neurosyphilis: 1.Positive blood treponemal serology 2. Negative CSF VDRL 3. CSF mononuclear pleocytosis ( > 20 cells/mm3) Or positive CSF protein ( > 60 mg/dL) No neurologic or ophthalmologic complications compatible with syphilis

neurosyphilis (Hollander, 1988). A schema has been proposed for diagnosing neurosyphilis in the face of HIV infection (Table 98.2). Controversy surrounds the issue of when to perform a lumbar puncture in the HIV-infected patient with serologic evidence of syphilis. A study from Spain of 112 HIV-infected persons with syphilis, in whom the diagnosis of neurosyphilis was predicated on the presence of a CSF WBC count of greater than 20 cells/cu mL, and/or reactive CSF VDRL, and/or a positive intrathecal T. pallidum antibody index, concluded that lumbar puncture could be restricted to those with neurologic manifestations or a serum rapid plasma reagin greater than 1:32 (Libois et al., 2007). Although not diagnostic of neurosyphilis, radiologic studies may be suggestive and are certainly helpful in excluding other pathologies. Radiologic manifestations of neurosyphilis include meningeal enhancement, CSF enhancement (Good and Jager, 2000), hydrocephalus, gummas, periostitis, generalized cerebral atrophy, and stroke. Gummas appear as avascular, dural-based masses with surrounding edema that on MRI are characteristically isointense with gray matter on T1-weighted image and hyperintense on T2-weighted image. Dense contrast enhancement and a dural tail may be observed (Soares-Fernandes et al., 2007). On rare occasions, the radiographic appearance of neurosyphilis may mimic the appearance of normal pressure hydrocephalus and herpes encephalitis (Fadil et al., 2006). Orbital periostitis typically involves the roof and supraorbital rim. These lesions may be hyperplastic, resulting in tender osteophytic nodules and exostoses (Harris et al., 1997). The

1468 J.R. BERGER AND D. DEAN periorbital inflammation can infiltrate the extraocular 2.4 million units of benzathine penicillin intramuscularly muscles and cranial nerves (Smith et al., 1990). MRI at weekly intervals for 3 weeks (Workowski and Berman, may also reveal multiple bilateral, discrete white matter 2010), but the recordable penicillin levels in the cerebrolesions involving deep periventricular and subcortical spinal fluid during treatment fail to reach treponemiciregions (Harris et al., 1997). Angiography of neurosyphidal levels (Polnikorn et al., 1980). The concentration of lis is nonspecific. Large vessels may exhibit segmental penicillin in the cerebrospinal fluid is typically unmeaconstriction or occlusion (Harris et al., 1997). Smaller surable, probably not exceeding 0.0005 mg/mL, which vessels, usually Sylvian branches of the middle cerebral is 1–2% of the serum levels. Furthermore, viable trepoartery, may display focal stenoses with or without adjanemes have been recovered from the cerebrospinal fluid cent dilatation (Harris et al., 1997). The sites of syphilitic of individuals at the completion of therapy (Tramont, brain lesions detected by MRI appear to correlate with 1976). As a result, the CDC also recommends a different psychiatric and cognitive symptoms (Russouw et al., regimen specifically for neurosyphilis. Patients with neu1997). Lesions in the temporal lobes, particularly the rosyphilis or syphilitic eye disease should be treated with mesial regions, on T2-weighted and fluid attenuated aqueous crystalline penicillin G, 18–24 million units per inversion recovery (FLAIR) magnetic resonance images day for 10–14 days. An alternate treatment is procaine have been described in patients with general paresis penicillin (procaine benzylpenicillin) 2.4 million units (Chen et al., 2005; Santos, 2005; Lessig and Tecoma, intramuscularly (IM) daily for 10–14 days plus probeni2006). The latter has led to the suggestion that neurosycid 500 mg orally four times a day for 10–14 days. philis must be excluded in any person suspected of havThe 2008 World Health Organization (WHO) guideing limbic encephalitis (Scheid et al., 2005). lines for treatment of syphilis in Europe (French et al., In a review of 35 patients with documented neurosy2009) also recommend different therapies specifically philis (three HIV-seronegative and 32 HIV-seropositive), for neurosyphilis. One recommended regimen for neuBrightbill and colleagues found that 31% had normal rosyphilis is benzylpenicillin 12–24 million units for brain imaging, 23% had cerebral infarction, and 20% 18–21 days, while another recommendation is a combinahad nonspecific cerebral white matter lesions. Cerebral tion of procaine penicillin 1.2–2.4 million units IM and gummas and extra-axial enhancement indicating meninprobenicid 500 mg for 10–17 days. The 2003 WHO gitis were each noted in two (6%) of 35 and arteritis was guidelines draw on recommendations from the CDC at demonstrated in two (50%) of four undergoing either that time, which recommended intravenous (IV) benzylmagnetic resonance angiography or conventional cerepenicillin for 10–14 days. bral angiography (Brightbill et al., 1995). Ideally, the treatment regimen for neurosyphilis should be 12–24 million units of crystalline aqueous penicillin administered intravenously daily (2–4 million units TREATMENT every 4 hours) for a period of 10–14 days. This regimen T. pallidum is highly sensitive to penicillin, as was demgenerally requires hospitalization, but a prolonged onstrated by Mahoney in 1943. T. pallidum has been hospitalization may be avoided in some reliable, wellshown to be capable of acquiring plasmids that produce motivated patients by placement of an indwelling cathepenicillinase, but in practice penicillin remains an effecter and home administration of penicillin after the first tive first-line treatment. Despite 50 years of experience, 24–48 hours of therapy. The penicillin should be adminhowever, the adequacy of currently recommended treatistered at no less than 4 hour intervals to maintain the ment regimens remains questionable due to an absence of penicillin levels consistently at or above treponemicidal controlled, randomized, prospective studies for the optivalues and to avoid the subtherapeutic troughs that occur mal dose and duration of therapy in neurosyphilis. For when it is administered at less frequent intervals. An example, there are different preparations of penicillin G alternative approach to the use of parenteral penicillin (benzylpenicillin) , which have different effectiveness, is the daily oral administration of amoxicillin (3.0 g) partly because they achieve different concentrations in and probenecid (0.5 g) administered twice daily for 15 various tissue compartments. This is particularly impordays (Faber et al., 1983). This regimen achieves treponetant for neurosyphilis, which requires a drug to reach thermicidal levels of amoxicillin in the cerebrospinal fluid apeutic levels in the CSF. The treponemicidal level of (Faber et al., 1983; Morrison et al., 1985). penicillin is 0.03 mg/mL, and when penicillin levels One complication to treatment is penicillin allergy, become subtherapeutic, spirochetes begin regenerating and there are separate recommendations for neurosyphiwithin 18–24 hours. lis patients who are allergic to penicillin. The CDC 2010 Neurosyphilis therefore requires different therapies guideline recommends ceftriaxone 2 g IV or IM daily for than typical syphilis. For example, the CDC has recom14 days for these patients. Ceftriaxone 2 g IV daily has mended treating primary and secondary syphilis with been demonstrated to be effective for neurosyphilis

NEUROSYPHILIS 1469 (Hook et al., 1986). Similarly, the 2008 WHO guidelines initially, particularly if accompanied by a Jarischfor treatment of syphilis in Europe (French et al., 2009) Herxheimer reaction. More important, the cerebrospinal recommends doxycycline 200 mg twice a day for 28 days fluid should be examined at the end of treatment to docfor neurosyphilis patients allergic to penicillin. Oral therument a fall in cell count, and it should then be examined apy with tetracycline yields low cerebrospinal fluid tetraat 6 month intervals for 2–3 years. The leukocyte count cycline concentrations and its efficacy has not been should return to normal within 1 year of treatment (usuproven, but doxycycline 200 mg twice daily for 21 days ally 6 months), and the protein level should return to norwas shown to be successful in an earlier trial (Yim et al., mal within 2 years. 1985). Finally, other sources have recommended 500 mg The disappearance of the CSF VDRL typically parallels of erythromycin four times daily for a period of 30 days. its resolution in the serum. Conversion of either the serum Erythromycin, however, does not diffuse readily into the VDRL or the rapid plasma reagin test to nonreactive should brain and cerebrospinal fluid, and its efficacy has not occur within 1 year after treatment of primary syphilis, been demonstrated in the treatment of neurosyphilis. within 2 years after treatment of secondary syphilis, and It has been associated with a high rate of treatment failwithin 5 years after treatment of latent syphilis. This delay ures and therefore cannot be recommended in the treatto reversion from a seropositive status reflects the duration ment of neurosyphilis (Goldmeier and Hay, 1993). HIV and severity of the illness. The long hiatus to its eventual coinfection is another complication to treatment, and clearing makes it less useful for purposes of determining the CDC guidelines recommend the same neurosyphilis the adequacy of treatment than the cerebrospinal fluid cell treatments for HIV-infected patients. However, all thercount or protein. However, the CSF VDRL titers should not apeutic regimens in individuals with established neuroincrease over time with effective therapy. The presence of syphilis and complicating HIV infection require persistently positive serum VDRL or rapid plasma reagin further study. For example, one study found a failure test suggests either persistent infection, reinfection, or a rate of 23% in HIV-infected patients with latent syphilis biological false-positive test. A significant negative correor asymptomatic neurosyphilis treated with ceftriaxone, lation between improvement in cognitive function and the typically administered as 1 g daily IV or IM over 10–14 CSF VDRL titers 1 year following treatment suggests that days (Dowell et al., 1992). the CSF VDRL titer is an indicator of continued T. pallidum Even when effective, neurosyphilis treatment may infection (Roberts and Emsley, 1995). If follow-up tests do cause known adverse reactions. For example, the not indicate progress, then retreatment may be necessary. Jarisch-Herxheimer reaction is a systemic reaction to For example, the CDC recommends retreatment if the CSF the rapid dissolution of treponemes occurring within cell count or protein count is not normal after 2 years. Alterseveral hours of the initiation of treatment. The disorder natively, the WHO (French et al., 2009) recommends presents with abrupt onset of fever and chills, headache, retreatment if there is not a fourfold decline in VDRL or tachycardia, flushing, myalgias, and mild hypotension. rapid plasma reagin. On rare occasion, neurologic deterioration, including In HIV-infected individuals, however, dependence on seizures, may occur during the Jarisch-Herxheimer reacthe cerebrospinal fluid for determining the adequacy of tion (Kojan et al., 2000). Although many authorities treatment of neurosyphilis often yields inaccurate advocate pretreatment with aspirin to ameliorate the results, due to the frequency with which cerebrospinal symptoms of this disorder, acute brain infarction during fluid abnormalities are detected with HIV infection the Jarisch-Herxheimer reaction has been observed in alone. Other than reversion of a positive CSF VDRL in patients with meningovascular syphilis. Instead, some those instances where it was initially present, a decline authorities recommend the administration of predniin a cerebrospinal fluid pleocytosis may be of greatest sone, 60 mg over the initial 24 hours, and the 2008 value in monitoring the success of therapy. Proper WHO guidelines for treatment of syphilis in Europe follow-up not only measures progress, but it also detects (French et al., 2009) recommends prednisolone relapses, which is particularly important in HIV-infected 20–60 mg daily for 3 days, starting the day before antipatients. In a study of 100 HIV-infected military persontreponemal treatment. nel with syphilis, four of seven persons with reactive Even with proper treatment, the neurologic deficits of cerebrospinal fluid VDRL relapsed following high-dose neurosyphilis may fail to improve, and some abnormalintravenous penicillin. Relapses were often observed ities, such as tabes dorsalis and optic atrophy, may more than 12 months after initial therapy (Malone worsen. Resolution of cerebrospinal fluid abnormalities et al., 1995). Other investigators, however, have found is the best measure of the adequacy of treatment. Examgood clinical and serologic responses to standard penicilination of the cerebrospinal fluid within several days of lin regimens in the HIV-infected population with syphilis beginning treatment may be confusing, however, (Bordon et al., 1999). The potential for relapse of neurobecause the cerebrospinal fluid leukocyte count may rise syphilis in HIV-infected patients suggests the potential

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need for secondary prophylaxis, as is employed in the management of some other CNS infections, such as toxoplasma encephalitis and cryptococcal meningitis. The CDC has recommended that the initial therapy of intravenous aqueous penicillin be followed in HIVinfected individuals by weekly intramuscular injections of 2.4 million units of benzathine penicillin for 3 weeks. However, in light of lack of treponemicidal levels of penicillin with the latter and evidence that high-dose penicillin regimens are not consistently effective in patients infected with HIV (Gordon et al., 1994), a more logical course may be the administration of a 30 day course of doxycycline 200 mg twice daily, following the completion of intravenous therapy. Although secondary prophylaxis is extensively employed, further studies are warranted before secondary prophylaxis (or some permutation of it) can be broadly recommended. HIVseropositive patients should be carefully monitored for relapse of neurosyphilis for 2 or more years following initial treatment. Finally, in all types of patients, neurosyphilis treatments may differ depending on the specific neurologic symptoms. For example, acute stroke due to meningovascular syphilis has benefited from tPA although the clinical experience is limited (Han et al., 2004). Otitic syphilis is relatively refractory to treatment regimens. Parenteral therapy is recommended for 6 weeks to 3 months with 12–24 million units of aqueous crystalline penicillin daily or oral therapy with 3.5 g of amoxicillin and 1.0 g of probenecid daily. Additionally, prednisone, 30–60 mg daily, is also recommended in combination with the antibiotic regimen. Similarly, treatment of progressive syphilitic optic neuritis may also include a trial of oral corticosteroids, e.g., prednisone, 60 mg daily for 2–4 weeks in addition to antibiotics. Finally, in patients with hydrocephalus complicating neurosyphilis, cerebrospinal fluid shunting has been recommended. However, resolution of syphilitic hydrocephalus following high-dose intravenous penicillin has also been reported (Cosottini et al., 1997).

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Katz KA, Pillay A, Ahrens K et al. (2010). Molecular epidemiology of syphilis – San Francisco, 2004–2007. Sex Transm Dis 37: 660–663. Kellett MW, Young GR, Fletcher NA (1997). Paraparesis due to syphilitic aortic dissection. Neurology 48: 221–223. Kitabayashi Y, Ueda H, Narumoto J et al. (2002). Cerebral blood flow changes in general paresis following penicillin treatment: a longitudinal single photon emission computed tomography study. Psychiatry Clin Neurosci 56: 65–70. Knopman DS (2006). Dementia and cerebrovascular disease. Mayo Clin Proc 81: 223–230. Kojan S, Van Ness PC, Diaz-Arrastia R (2000). Nonconvulsive status epilepticus resulting from JarischHerxheimer reaction in a patient with neurosyphilis. Clin Electroencephalogr 31: 138–140. Lanska MJ, Lanska DJ, Schmidley JW (1988). Syphilitic polyradiculopathy in an HIV-positive man. Neurology 38: 1297–1301. Lessig S, Tecoma E (2006). Perils of the prozone reaction: neurosyphilis presenting as an RPR-negative subacute dementia. Neurology 66 (5): 777. Libois A, De Wit S, Poll B et al. (2007). HIV and syphilis: when to perform a lumbar puncture. Sex Transm Dis 34: 141–144. Lukehart SA, Hook EW 3rd, Baker-Zander SA et al. (1988). Invasion of the central nervous system by Treponema pallidum: implications for diagnosis and treatment. Ann Intern Med 109: 855–862. Malone JL, Wallace MR, Hendrick BB et al. (1995). Syphilis and neurosyphilis in a human immunodeficiency virus type-1 seropositive population: evidence for frequent serologic relapse after therapy. Am J Med 99: 55–63. Marra CM, Tantalo LC, Maxwell CL et al. (2004). Alternative cerebrospinal fluid tests to diagnose neurosyphilis in HIVinfected individuals. Neurology 63: 85–88. Marra C, Sahi S, Tantalo L et al. (2010). Enhanced molecular typing of treponema pallidum: geographical distribution of strain types and association with neurosyphilis. J Infect Dis 202: 1380–1388. Morrison RE, Harrison SM, Tramont EC (1985). Oral amoxycillin, an alternative treatment for neurosyphilis. Genitourin Med 61: 359–362. Musher DM, Hamill RJ, Baughn RE (1990). Effect of human immunodeficiency virus (HIV) infection on the course of syphilis and on the response to treatment. Ann Intern Med 113: 872–881. Oette M, Hemker J, Feldt T et al. (2005). Acute syphilitic blindness in an HIV-positive patient. AIDS Patient Care STDS 19: 209–211. Pearce JM (2005). Romberg and his sign. Eur Neurol 53: 210–213. Peterman TA, Heffelfinger JD, Swint EB et al. (2005). The changing epidemiology of syphilis. Sex Transm Dis 32 (10 Suppl): S4–S10. Phan TG, Somerville ER, Chen S (1999). Intractable epilepsy as the initial manifestation of neurosyphilis. Epilepsia 40: 1309–1311. Polnikorn N, Witoonpanich R, Vorachit M et al. (1980). Penicillin concentrations in cerebrospinal fluid after different treatment regimens for syphilis. Br J Vener Dis 56: 363–367.

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Roberts MC, Emsley RA (1995). Cognitive change after treatment for neurosyphilis. Correlation with CSF laboratory measures. Gen Hosp Psychiatry 17: 305–309. Roberts MC, Emsley RA, Jordaan GP (1992). Screening for syphilis and neurosyphilis in acute psychiatric admissions. S Afr Med J 82: 16–18. Rothschild BM, Rothschild C (1995). Treponemal disease revisited: skeletal discriminators for yaws, bejel, and venereal syphilis. Clin Infect Dis 20: 1402–1408. Rothschild BM, Hershkovitz I, Rothschild C et al. (1995). Origin of yaws in the Pleistocene. Nature 378: 343–344. Rushing EJ, Liappis A, Smirniotopoulos JD et al. (2008). Immune reconstitution inflammatory syndrome of the brain: case illustrations of a challenging entity. J Neuropathol Exp Neurol 67: 819–827. Russouw HG, Roberts MC, Emsley RA et al. (1997). Psychiatric manifestations and magnetic resonance imaging in HIV-negative neurosyphilis. Biol Psychiatry 41: 467–473. Santos V (2005). Differential diagnosis of nesiotemporal lesions: case report and MRI findings. Neuroradiology 47: 664–667. Scheid R, Voltz R, Vetter T et al. (2005). Neurosyphilis and paraneoplastic limbic encephalitis: important differential diagnoses. J Neurol 252: 1129–1132. Schiller F (1995). Staggering gait in medical history. Ann Neurol 37: 127–135. Shi X, Wu J, Liu Z et al. (2003). Single photon emission CT perfusion imaging of cerebral blood flow of early syphilis patients. Chin Med J (Engl) 116: 1051–1054. Smith JL, Holman RP (2004). The prozone phenomenon with syphilis and HIV-1 co-infection. South Med J 97: 379–382. Smith JL, Byrne SF, Cambron CR (1990). Syphiloma/gumma of the optic nerve and human immunodeficiency virus seropositivity. J Clin Neuroophthalmol 10: 175–184. Soares-Fernandes JP, Ribeiro M, Mare´ R et al. (2007). Diffusion-weighted magnetic resonance imaging findings

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Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 99

Nervous system Lyme disease JOHN J. HALPERIN* Department of Neurosciences, Overlook Medical Center, Summit, NJ, USA

HISTORY The term Lyme disease describes the clinical disorder attributable to infection with any of the Borrelia burgdorferi group of spirochetes, disorders transmitted exclusively by bites of infected hard-shelled Ixodes ticks. The name derives from the Connecticut town where a cluster of cases of what appeared to be juvenile rheumatoid arthritis led first, in 1975, to the recognition of a syndrome named Lyme arthritis (Steere et al., 1977), then to the recognition that this was actually a multisystem disease (Reik et al., 1979), and ultimately to the identification of the causative spirochete, Borrelia burgdorferi (Burgdorfer et al., 1982; Benach et al., 1983; Steere et al., 1983b). As so often happens when our understanding of a disease evolves from a syndromic definition to the use of newly available biologic markers, subsequent clarification of the true spectrum of disorders caused by this infection led to the recognition that the disease had in fact been present for decades, under a variety of other labels. In 1910, Afzelius first described the characteristic skin lesion now known as erythema migrans (Afzelius, 1910) – a lesion first reported in the US literature in 1970 (Scrimenti, 1970). In 1922, two French physicians (Garin and Bujadoux, 1922) described a retired French Foreign Legionnaire who, 3 weeks after a tick bite, developed a large erythematous rash accompanied initially by high fever, sciatica, and a diffuse, extremely painful multifocal neuropathy. He had a cerebrospinal fluid (CSF) pleocytosis and a slightly positive Wasserman test, and improved following treatment with arsenic and mercury. Although the authors confused this disorder with tick bite paralysis, they did assert that it was due to infection with a tick-borne nonsyphilitic spirochete – a truly remarkably prescient conclusion. In 1941, the German neurologist Bannwarth described a series of patients with the same syndrome, and

included the term “rheumatism” in the title, providing the first sense that joint symptoms were part of the syndrome (Bannwarth, 1941). By the mid 1950s, this primarily neurologic syndrome was well recognized in Europe, and was being treated with penicillin (Hollstrom, 1951). Although Lyme arthritis was first reported in the mid 1970s, clinical folklore in eastern Long Island, New York (an area now known to be highly endemic for Lyme disease), relates that in the 1950s many individuals were being diagnosed with “Montauk knee,” a relapsing remitting, nontraumatic large joint oligoarthritis that in retrospect almost certainly was Lyme arthritis. Following the recognition of Lyme arthritis in Connecticut, groups from both Long Island and Connecticut simultaneously reported identifying B. burgdorferi as the causative organism (Benach et al., 1983; Steere et al., 1983b). At the same time, Steere’s neurologic colleagues Lou Reik (Reik et al., 1979) and Andrew Pachner (Steere et al., 1983c) helped define the classic neurologic triad of Lyme disease, which was entirely congruous with the disorder first characterized by Garin and Bujadoux. The identification of the organism in the early 1980s has allowed improved diagnostics, better characterization of the illness, better therapeutics, and the development of animal models, all of which has permitted significant advances in our understanding of the biology of this infectious disease.

CLINICAL FINDINGS It is commonplace to hear the assertion that the range of clinical manifestations of Lyme disease is vast; this is a considerable overstatement. Clinical disease begins following the inoculation of B. burgdorferi spirochetes – something that occurs solely with bites of infected hard-shelled Ixodes ticks. These ticks typically attach for several days during which time they inject their

*Correspondence to: John J. Halperin, M.D., Chair, Department of Neurosciences, Overlook Medical Center, Summit NJ 07078, USA. Tel: þ1-908-522-3501, E-mail: [email protected]

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saliva, containing, among other substances, local anesthetics and anticoagulants to permit prolonged feeding. Spirochetes reside in the tick gut; the ingested host’s blood triggers their proliferation and migration throughout the tick, eventually reaching the salivary glands from which they can be injected into the host. With US strains of ticks and B. burgdorferi this process requires at least 24–48 hours (Piesman and Dolan, 2002); in Europe this period is more variable. Once spirochetes enter the host’s skin, they multiply and migrate centrifugally. The resulting inflammatory response causes a slowly enlarging erythroderm, known originally as erythema chronicum migrans (ECM) but now just as erythema migrans (EM). This can become many centimeters in diameter. Central areas can lose their erythema by the time the advancing edge becomes red, resulting in a targetoid appearance (Fig. 99.1). The characteristics that differentiate EM from, for example, allergic reactions to tick saliva, are the large size (EM is typically more than 5 cm in diameter), relatively asymptomatic nature (EM is not typically pruritic or painful), and expansion and growth over many days to weeks (allergic reactions typically subside in a day or two). In some patients (about 25% in the US (Steere et al., 1983a), somewhat fewer in Europe), early hematogenous dissemination of spirochetes can lead to multifocal EM, with each satellite EM representing a new nidus of spirochetes, again proliferating and migrating centrifugally. Spirochete dissemination is often accompanied by typical symptoms of a bacteremia: fever, headache, malaise, diffuse aches and pains. Although these symptoms are often referred to as “flu-like,” importantly they generally do not include respiratory or gastrointestinal symptoms. The disseminating spirochetes have distinct organotropisms (Bacon et al., 2008), in particular the nervous system is symptomatically seeded in 10–15% of patients (polymerase chain reaction-based studies suggest that more may be seeded (Keller et al., 1992; Luft et al., 1992) but the infection is presumably

Fig. 99.1. Erythema migrans on the left thigh of a 5-year-old.

controlled by the host’s immune response in many). About 1–2% of infected patients will develop cardiac involvement, typically conduction block. This can be high grade and patients may require a temporary pacemaker. However, this is almost always reversible. Joint involvement, typically manifest somewhat later in infection, occurs in about one-third of US patients, but fewer than 10% in Europe. This can include nonspecific arthralgias but most typically is manifest as a large joint, relapsing oligoarthritis, with one large joint (knee, hip, etc.) at a time spontaneously becoming red and swollen, resolving over several weeks, with subsequent involvement of the same or a different joint months later. Nervous system involvement, termed neuroborreliosis, may take a number of different forms. Patients most commonly develop all or part of the triad first described by Garin and Bujadoux. Early seeding of the meninges can lead to a local inflammatory response with lymphocytic meningitis. Symptoms of this are highly variable, ranging from patients with an asymptomatic pleocytosis incidentally found to accompany a cranial neuritis, to others with an identical pleocytosis with severe headache, neck stiffness, photo- and phonosensitivity, typical of aseptic meningitis (occurring in isolation in approximately 2% of patients). In children, some with meningitis develop raised intracranial pressure, developing a syndrome clinically indistinguishable from pseudotumor cerebri (Jacobson and Frens, 1989; Belman et al., 1993; Zemel, 2000). Most reported patients have had a CSF pleocytosis at the time of presentation; a few have not. Regardless of whether the raised intracranial pressure is due to meningitis or another mechanism, affected children are at risk of visual loss and require monitoring and management identical to that of others with pseudotumor (in addition to being treated for the causative infection). More frequent manifestations include cranial neuritis in up to 8–10%, and radiculoneuritis, reported to occur in about 3% of confirmed cases (Bacon et al., 2007). Of patients with cranial neuritis, the facial nerve is involved in up to 80%, and may be bilateral (simultaneously or sequentially) in about 25% of these (Stiernstedt et al., 1988). Involvement of other cranial nerves is less common but primarily involves nerves to the extraocular muscles, the trigeminal, and the acousticovestibular. Lower cranial nerve involvement has only been reported anecdotally; optic neuritis probably occurs but is extremely rare (Sibony et al., 2005). Radiculoneuritis is probably the most frequently misdiagnosed disorder. As first described by Garin and Bujadoux, pain is severe and neuropathic in character, while objective sensory findings are mild. Motor deficits are common. Pain and motor deficits are classically dermatomal, and are said to preferentially affect the limb

NERVOUS SYSTEM LYME DISEASE that was the site of the tick bite (Rupprecht et al., 2008). Other mononeuropathies and plexopathies occur as well; in fact, detailed neurophysiologic studies (Halperin et al., 1990c), and the few available histopathologic studies (Halperin et al., 1987; Vallat et al., 1987), suggest that all these patients actually have various manifestations of a mononeuropathy multiplex. Some patients with untreated disease of significant duration (rarely seen any more) can develop what appears to be a lengthdependent “stocking and glove” type neuropathy. Neurophysiologic studies in these individuals suggest that this is actually a confluent mononeuropathy multiplex (Halperin et al., 1990c), similar to that seen in a variety of vasculopathies. Although a few case reports and small series suggest an association with demyelinating neuropathies (Muley and Parry, 2009), reported cases are so infrequent as to be possible chance associations. There is now one informative animal model of nervous system Lyme disease – the rhesus macaque monkey (Philipp et al., 1993; Pachner et al., 1995). Notably virtually all experimentally infected monkeys develop a mononeuropathy multiplex (England et al., 1997). Despite the availability of this model, our understanding of the pathophysiology of neuroborreliosis remains quite limited. Intact spirochetes, their antigens, or even their DNA have never been demonstrated in peripheral nerve of patients or of experimentally infected animals. Limited observations in the rhesus model suggest possible infection in dorsal root ganglia (Cadavid et al., 2000), an observation that might explain the severe pain, but not the frequent motor concomitants. Central nervous system (CNS) involvement is much less common. Symptomatic isolated meningitis occurs in only 1–2% of confirmed cases. Years ago, when many patients went months or years without accurate diagnosis and appropriate treatment, rare patients developed inflammation and presumably infection in the brain and spinal cord. The European literature suggests that patients with Garin–Bujadoux–Bannwarth syndrome, with prominent radicular symptoms, often have spinal cord involvement at the involved level (Hansen and Lebech, 1992). Very rarely, patients were identified with inflammation in the brain (Ackermann et al., 1988; Halperin et al., 1988; Hansen and Lebech, 1992). This appeared to affect white matter more than gray both clinically and radiographically. Seizures were very rare; spasticity, ataxia, and other white matter tract signs were more typical. This disorder has largely disappeared, presumably as a result of better disease diagnosis and early treatment. However, it remains a theoretical possibility that gives rise to a great deal of concern. This encephalomyelitis was presumably caused by direct brain infection by spirochetes. Patients usually had evidence of a targeted immune response against

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the causative spirochetes within the central nervous system (Henriksson et al., 1986; Ackermann et al., 1988; Halperin et al., 1989), accompanied by typical evidence of CNS inflammation (CSF pleocytosis, increased protein, increased overall IgG synthesis, and even oligoclonal bands). Magnetic resonance imaging (MRI) and positron emission tomography (PET) scans (Kalina et al., 2005) demonstrated contrast enhancing hypermetabolic areas (Fig. 99.2). The repeated observation that clinical, CSF, and imaging changes all resolve with antimicrobial therapy clearly indicates a necessary and sufficient role of active spirochetal infection in the maintenance of the process; yet, as in peripheral nerve, there has been little if any credible evidence of spirochetes in pathologic samples. This clinically rarely

Fig. 99.2. Imaging from a 28-year-old male with brainstem inflammation, strongly positive Lyme serology with intrathecal production of anti-B. burgdorferi antibodies, resolving after antimicrobial therapy (i.e., Lyme encephalomyelitis). (A) Fluid-attenuated inversion recovery MRI sequence. (B) PET scan. (Reproduced from Kalina et al., 2005, with permission; PET images courtesy of Ronald Van Heertum, M.D.)

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occurring disorder has not, to date, been identified in any animal model. One other early observation gave rise to tremendous subsequent controversy. In the 1980s, when there were still many patients whose active infection went undiagnosed and untreated for months or years, many infected individuals, symptomatic with arthritis or other manifestations of an ongoing inflammatory disorder, described difficulty with memory, mental focus, and cognitive processing (Halperin et al., 1988, 1990b; Logigian et al., 1990; Krupp et al., 1991). Early studies indicated that, although a very small number of such individuals had evidence of brain infection, the vast majority had a “toxic metabolic” encephalopathy, comparable to that seen in innumerable other systemic (extraneurologic) infections or inflammatory states (e.g., pneumonia, urinary tract infections, active rheumatoid arthritis, etc.). Some assumed that these symptoms had a high degree of specificity for Lyme disease, and in particular for nervous system involvement, and began diagnosing neuroborreliosis in individuals in whom there was no plausible evidence to support this assertion (Cameron et al., 2004). This incorrect attribution of these nonspecific symptoms to neuroborreliosis was then coupled with the not surprising observation that most of these individuals had negative Lyme blood tests and normal spinal fluid and failed to respond to conventional courses of antibiotics. Rejecting the simpler conclusion that the premise was incorrect, this then led to the assertion that testing was flawed and conventional treatment ineffective. This in turn resulted in the use – in patients without evidence of Lyme disease – of ever more prolonged and complex treatment regimens, all of which are illogical based on the biology of the organism, not to mention demonstrably unhelpful and often harmful. The mechanism of this encephalopathy remains unclear, as it does in other circumstances. In patients who develop it during infection there is evidence soluble neuroimmunomodulator molecules can diffuse across the blood–brain barrier, altering brain physiology without there being a brain infection or other potentially brain damaging process (Halperin and Heyes, 1992). The more challenging issue has been an entity labeled by some as “post Lyme disease syndrome” (Feder et al., 2007). As had been observed previously following other infections, there has been anecdotal evidence that some patients who receive usually curative courses of antibiotics will subsequently have – either persistent or newly developing – fatigue, malaise, and symptoms of cognitive slowing and memory difficulty. Although the mechanism of this disorder is unknown, several important observations bear on its pathophysiology. First, there is no biologically plausible evidence that this disorder responds in a meaningful fashion to additional

or prolonged antibiotic treatment. Second, this disorder appears to be extremely infrequent in that studies that attempted to study it have had tremendous difficulty recruiting sufficient numbers of patients (Krupp et al., 2003; Fallon et al., 2008). Third, in studies with control populations, it is not at all clear that these symptoms are any more common among individuals treated for Lyme disease than in controls (Skogman et al., 2008; Cerar et al., 2010). Finally, identical symptoms affect about one-third of the general population at any give time (Luo et al., 2005), significantly impacting quality of life in up to 2% (Luo et al., 2005), making it very challenging to determine if this syndrome is related to Lyme disease, or simply occurring in these individuals by chance. Disease manifestations are comparable in patients in the US and Europe, although the frequency of specific ones probably differs somewhat. Multifocal EM and arthritis are probably more common in US patients; painful radiculitis is said to be more common in Europe. All of these observations are subject to some ascertainment bias, given the historical perspective of this being considered a neurologic disease in Europe and a rheumatologic one in the US. Notably the responsible organisms do differ slightly. The broad group of spirochetes is now known as B. burgdorferi sensu lato with the sole strain found in the US referred to as B. burgdorferi sensu stricto. Although this strain is found in Europe, it is responsible for only a minority of European borreliosis. Most European infections are caused by B. garinii, which often causes neurologic disease, and B. afzelii, particularly likely to cause a number of cutaneous abnormalities. These strain differences could be responsible for somewhat different ranges of disease manifestations in the two geographically distinct populations, and could even cause differences in treatment responsiveness.

LABORATORY INVESTIGATIONS Laboratory support for the diagnosis of Lyme disease relies primarily on the demonstration of a serologic response to the causative organism. Unlike the related spirochete, Treponema pallidum, B. burgdorferi can be grown in culture. However, this is clinically impractical. The organism is very slow growing and requires special medium, BSK II, not typically available in clinical laboratories. Moreover sensitivity of culture is quite low in systemic disease – typically only about 10% in CSF in Lyme meningitis (Karlsson et al., 1990), even when enhanced by the use of polymerase chain reaction (PCR) (Keller et al., 1992), presumably because of the low number of organisms present in readily available fluids or tissues. The one exception to this is erythema

NERVOUS SYSTEM LYME DISEASE migrans, which, much like the syphilitic chancre, contains innumerable readily demonstrable spirochetes. However, EM is typically so characteristic that laboratory confirmation is unnecessary. Serologic testing for Lyme disease is much maligned but actually is both reliable and necessary to establish the diagnosis (CDC, 1995) in all but one circumstance, namely the first few weeks of disease (Nowakowski et al., 2001). As in all infections, it takes time – typically several weeks – for B cells to develop a measurable and specific antibody response. When patients present with erythema migrans, which typically develops within the first 30 days of infection, half or more may not yet have a measurable antibody titer (Aguero-Rosenfeld et al., 1996; Nowakowski et al., 2001). Occasionally patients can develop Lyme-related facial nerve palsy or meningitis before the antibody response is demonstrable (Halperin, 2003); in patients in whom this is a consideration, comparing acute and convalescent titers can be informative, just as with all other serologic testing. In the early years of serologic testing there was a concern that some patients might remain permanently seronegative (Dattwyler et al., 1988). These observations appear to have been based on shortcomings of early serologic techniques; this appears not to be an issue with current techniques. The current recommendation is to use a two-tier serologic technique (CDC, 1995), starting with an ELISA (enzyme linked immunosorbent assay) as a sensitive but somewhat nonspecific screening test, then proceeding to a Western blot in individuals with positive or borderline ELISAs (terms that are defined statistically). Western blots should generally not be performed in individuals in whom the ELISA is negative, as false-positives in this setting – in which low level background crossreactivity to B burgdorferi-specific epitopes can be misinterpreted as positivity – can be very misleading. Criteria for interpretation of Western blots have been developed based on statistical studies of large populations of patients with and without Lyme disease. Some epitopes that are relatively selective for B. burgdorferi are not included because these antibodies are so rarely present as to provide no discriminant value. Rather, specific combinations were identified (Table 99.1) that accurately predict which patients do or do not actually have infection. While some laboratories use their own criteria for interpretation, these have not been validated and cannot be relied upon for accurate diagnosis until or unless this is done. Western blots are usually performed for both IgM and IgG antibodies. As in all infections, the normal sequential antibody response is first, to produce comparatively nonspecific IgM antibodies, then within weeks refine the response switching to much more targeted

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Table 99.1 Western blot criteria for the serologic diagnosis of Lyme disease

Positive

IgM (2 of 3)

IgG (5 of 10)

24, 39, 41

18, 21, 28, 30, 39, 41, 45, 58, 66, 93

Only in first few weeks of disease (CDC, 1995.)

IgG antibodies. Because of this, IgM criteria are only useful in patients whose illness is of less than 3 to at most 6 weeks’ duration. Beyond this early window, IgM antibodies are far more likely to represent nonspecific crossreactivity and should not be considered diagnostic. When the central nervous system is involved, additional laboratory support for the diagnosis is available. As in any other bacterial CNS infection, there is almost always a CSF pleocytosis and elevated protein. As in neurosyphilis, CSF glucose is depressed minimally if at all. Also similar to neurosyphilis, B. burgdorferi stimulates a prominent B cell response in the CNS, often leading to an increased CSF IgG index or IgG synthesis rate, and even oligoclonal bands (the latter reported more often in Europe than the US). As in other CNS infections, this increased B cell response within the CNS can result in local synthesis of antibodies specific to B. burgdorferi. This can be assessed by measuring the proportion of CSF IgG that is specific to B. burgdorferi, comparing this to the proportion in the serum. This index of specific intrathecal antibody production – which can be performed by a capture assay, by appropriately diluting CSF and serum to match IgG concentrations and then performing conventional ELISAs, or by mathematical calculation – is highly specific but has a sensitivity that has been challenging to define (Henriksson et al., 1986; Halperin et al., 1989; Hansen et al., 1990; Steere et al., 1990). False-positives occur in just two settings: neurosyphilis and past neuroborreliosis. The first can generally be differentiated from neuroborreliosis by measuring reaginic antibodies such as the VDRL (Venereal Disease Research Laboratory), which is rarely if ever elevated in Lyme disease. The latter, which is not really a false-positive but rather an irrelevant one, can be more challenging. Longitudinal studies indicate that apparent intrathecal antibody production can persist up to a decade following successful treatment (Hansen and Lebech,

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1992; Hammers Berggren et al., 1993). This obviously makes this method unhelpful for judging treatment efficacy. However, as in other CNS infections, improvement and ultimately resolution of the CSF pleocytosis and protein elevation serve as reliable markers of disease resolution. Defining sensitivity is far more challenging due to the absence of an alternative “gold standard” marker of neuroborreliosis. Originally, European investigators required the demonstration of intrathecal synthesis of specific antibody to make the diagnosis, hence the sensitivity was, by definition, 100%. One small US study of patients with acute Lyme meningitis indicated a sensitivity of about 90% (Halperin et al., 1989). A subsequent US study with a more diverse group of patients, some of whom may not have had CNS infection, indicated sensitivity of about 50% (Steere et al., 1990). The issue remains unresolved. That notwithstanding, there is one subgroup of patients in whom sensitivity should be close to 100%. In individuals with active CNS inflammation (with or without parenchymal abnormalities on MRI scan), with increased overall IgG synthesis in the CSF and oligoclonal bands, if this inflammatory response is in response to a particular infection, logic would dictate that the bulk of the locally synthesized antibodies should be specific for the causative organism. Thus in those individuals with a multiple sclerosis (MS)like illness or otherwise prominent intrathecal IgG synthesis, measuring Lyme-specific intrathecal antibody production should be highly reliable. The one other obvious limitation is that if B. burgdorferi infection is limited to the peripheral nervous system, or does not affect the nervous system at all, there should be no expectation of abnormal antibody measures in the CSF.

NEUROIMAGING Neuroimaging is straightforward but, like so many other aspects of this disease, has been the subject of much debate that is only loosely rooted in reality. Central nervous system infection can, on very rare occasion, cause parenchymal inflammation of the brain or spinal cord. Like any other inflammatory CNS disease this can result in focal areas of increased T2 signal on MRI scans, with contrast enhancement and even bright signal on diffusion-weighted sequences (Halperin et al., 1989). The spirochete does appear to have an affinity for oligodendroglia (Garcia-Monco et al., 1989) so these abnormal areas are more likely to occur in white matter than gray. When active, these areas appear hypermetabolic on brain PET imaging (Kalina et al., 2005). Importantly, the presence of such abnormalities reflects the presence of an active infection and inflammatory

response within the CNS, and as such should almost invariably be accompanied by inflammatory CSF. Unfortunately, the prevalence of nonspecific white matter abnormalities on brain MRIs leads to frequent MRI reports suggesting the latter could be attributable to Lyme disease – a largely spurious suggestion. Most unfortunate has been the use of brain singlephoton emission computed tomography (SPECT) imaging. One carefully performed study used a sophisticated statistical analysis of quantitative brain SPECT scans in a well defined population of patients with Lyme disease and suggested that some might have areas of hypometabolism, of unclear etiology (Logigian et al., 1997). This has resulted in the use of qualitative SPECT, in which patchy metabolic changes are far too easy to infer incorrectly, to not only diagnose nervous system Lyme disease, but to serve as the primary basis for a diagnosis of Lyme disease in the absence of any other support for the diagnosis. This approach is both unfortunate and unsupported by any rigorous scientific evidence.

PATHOLOGYAND PATHOGENESIS Very few pathologic specimens have been studied. Peripheral nerve in both affected patients (Halperin et al., 1987; Vallat et al., 1987; Meier et al., 1989) and experimentally infected rhesus monkeys (England et al., 1997) typically demonstrates perivascular inflammatory infiltrates without vessel wall necrosis, with multifocal axonal changes, all suggestive of a mononeuropathy multiplex. Parenchymal brain involvement has not been demonstrated to date in any published animal studies. A few human biopsies have purported to show glial nodules or other nonspecific changes (Oksi et al., 1996; Bertrand et al., 1999). In neither human nor animal model material has there been compelling evidence of intact spirochetes, spirochetal antigens, or DNA. On the other hand, antimicrobial therapy is rapidly effective in reversing neuroborreliosis in virtually all instances. Thus the ongoing presence of viable spirochetes must be necessary. The prominent immune response appears to be out of proportion to the very small number of organisms demonstrable (a few in CSF and none in tissue); presumably this plays an important role in pathogenesis (Rupprecht et al., 2008, 2009). Yet the rapid resolution with antibiotics indicates that this immune response is not self-perpetuating and presumably not due to crossreacting epitopes (molecular mimicry). There is evidence that following entry of B. burgdorferi into the CNS, there is very rapid local production of CXCL13, a B cell attracting chemokine, presumably triggering local production of antibodies (Rupprecht et al., 2009). Other evidence points to local production of quinolinic acid within the CNS in response to infection (Halperin and Heyes,

NERVOUS SYSTEM LYME DISEASE 1992). This small molecule, produced in response to TNF-a and g-IFN can act at the NMDA receptor, presumably altering neuronal function or even being neurotoxic. The role of these or other mechanisms in the pathogenesis of this disease requires considerable additional clarification.

DIFFERENTIAL DIAGNOSIS As with any neurologic diagnosis, the clinical syndromes associated with neuroborreliosis suggest a range of possible disorders and are not diagnostic in and of themselves. If the three most distinctive manifestations of nervous system Lyme disease – lymphocytic meningitis, cranial neuritis, and radiculoneuritis – occur simultaneously in an individual with possible exposure in an endemic area, the diagnosis is highly probable. If, as usually occurs, only one or two elements are present, the diagnosis must be confirmed and other possibilities excluded. Lyme meningitis occurs in warm weather months and overlaps epidemiologically with enteroviral meningitis. Studies in children (Tuerlinckx et al., 2003, 2009; Shah et al., 2005) indicate that in Lyme meningitis symptoms evolve over days instead of hours (the latter more typical of enteroviral infection). Probably the best differentiator is if the patient develops a cranial neuropathy, something that occurs rarely, if ever, in viral meningitis. Although facial nerve palsies and other cranial neuropathies occur frequently in Lyme disease, a study in a highly endemic region indicated that even in the summer months, Lyme disease was responsible for no more than 25% of facial nerve palsies (Halperin et al., 1990a). The presence of multiple cranial neuropathies, particularly bilateral facial nerve palsies – or for that matter, a facial nerve palsy in a child – substantially increases the likelihood that the disorder is due to Lyme disease. Even in these circumstances though, other potential causes of cranial neuropathies need to be considered: in the appropriate context possibilities include bacterial meningitis, sarcoidosis, HIV infection, and even Guillain–Barre´ syndrome. Symptoms of Lyme radiculoneuropathy are generally indistinguishable from those of a mechanical radiculopathy. Clues that B. burgdorferi infection might be responsible include normal imaging studies of the responsible root, involvement of several myotomes clinically or by EMG, and presence of a CSF pleocytosis. In all instances B. burgdorferi antibodies should be evident in serum by two-tier testing, except that occasionally these disorders occur very early in infection, before the humoral response has developed sufficiently for antibody to be detectable. In such circumstances a follow-up sample in several weeks will typically be strongly positive. In all instances, possible exposure to Ixodes ticks in an area endemic for Lyme disease is

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essential as there are no other known means of transmission of infection. In patients with less characteristic presentations of neuroborreliosis, establishing the diagnosis can be more challenging. Again, plausible exposure in an appropriate geographic location at an appropriate time of year is a prerequisite. Patients suspected of having peripheral nervous system manifestations almost always have a mononeuropathy multiplex (Halperin et al., 1990c) demonstrable neurophysiologically. In such patients, confirmation of the infection with positive ELISA and Western blot, and exclusion of other common causes of vasculitis, generally is sufficient to establish the diagnosis. In the very rare patients with inflammatory parenchymal CNS disease, CSF examination is usually required. Although the overall sensitivity of measurement of intrathecal antibody production is still debated, in those patients with evidence of chronic CNS inflammation (i.e., increased IgG synthesis and/or oligoclonal bands in the CSF), if the immune stimulation is the result of a particular infection, the increased antibodies that are evident should be specific to the causative organism. In these patients, the diagnosis should only be considered definite if the production of specific anti-B. burgdorferi antibody is demonstrable in the CSF.

MANAGEMENT B. burgdorferi remains highly sensitive to commonly available antibiotics; no clinically relevant resistance has been demonstrated. Doxycycline, penicillin, and cefuroxime axetil (Table 99.2) remain the agents of choice for most disease (Wormser et al., 2006; Halperin et al., 2007). Severe disease can be treated with parenteral ceftriaxone, cefotaxime, or high-dose penicillin. Of these, ceftriaxone is usually the easiest to use, as its pharmacokinetics permit once a day dosing. When used either in higher than the conventional dose of 2 g/day, or for an extended period of time, it can lead to precipitates in the gall bladder; patients have required cholecystectomies. Optimal treatment of nervous system Lyme disease remains to be defined. No studies have specifically addressed parenchymal CNS disease so, by analogy to other CNS infections, this is conventionally treated parenterally. European studies have clearly shown that oral doxycycline is as effective as parenteral regimens in Lyme meningitis, cranial neuritis, and radiculitis (Halperin et al., 2007). Comparable studies have not been conducted in the US; given the difference in responsible strains of B. burgdorferi it is theoretically possible that parenteral treatment might be necessary. However, the organism differences are slight so this seems unlikely. It has long been debated whether CSF should be examined in patients thought to have Lyme disease-related

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Table 99.2 Nervous system Lyme disease: treatment recommendations{ Disorder

Adults

Children

Acute neuroborreliosis (meningitis, radiculitis, cranial neuritis)

Ceftriaxone{ 2 g/day IV; 2–4 weeks OR Cefotaxime 2 g q8/IV; 2–4 weeks OR Penicillin, 20–24 million units IV/day; 2–4 weeks OR Probably doxycycline* 100 mg PO b.i.d. to 4 times/day for 3–4 weeks Possible alternatives: Amoxicillin 500 mg PO t.i.d.; 21 days OR Cefuroxime axetil 500 mg PO b.i.d.; 21 days Ceftriaxone{ OR cefotaxime OR penicillin IV – as above Ceftriaxone{ OR cefotaxime IV – as above

50–75 mg/kg/day

Encephalomyelitis

Chronic or recurrent neuroborreliosis (e.g., treatment failure after 2 weeks of treatment)

150–200 mg/kg/day in 3–4 divided doses 300 000 units/kg/day

 8 years 1–2 mg/kg b.i.d.

50 mg/kg/day in three divided doses 30 mg/kg/day in 3–4 divided doses

(Reproduced from Halperin, 2010, by permission of the Journal of the Royal College of Physicians of Edinburgh.) *Doxycycline should not be used in pregnant women or children under the age of 8 years. { Ceftriaxone should not be used late in pregnancy. { Pediatric weight-based doses should never exceed the recommended adult dose. IV, intravenous; q, each; b.i.d., twice daily; PO, orally.

cranial neuropathies. This can certainly be helpful in assessing the extent of disease, and remains reasonable as long as the efficacy of oral doxycycline is unclear in US patients. However, if in fact these disorders are shown to be highly responsive to oral antibiotics, the information obtained from the lumbar puncture would become largely superfluous. Regardless of the regimen chosen, treatment should generally be for 2–4 weeks. While some advocate prolonged antibiotic treatment, particularly for individuals with chronic nonspecific symptoms that they attribute to Lyme disease, there are now multiple well performed trials that demonstrate that this not only provides no substantive or long-term benefit, but carries substantial risk of harm (Klempner et al., 2001; Krupp et al., 2003; Oksi et al., 2007; Fallon et al., 2008). Complications have been reported in up to 43% of patients (Krupp et al., 2003). In one study (Fallon et al., 2008) side-effects were sufficiently severe in 24% that these patients had to withdraw from the study, stop treatment, or be hospitalized. With rates such as this under the meticulously controlled circumstances of US National Institutes of Health (NIH)-funded clinical trials, one can only assume that standard clinical practice would carry even greater risk.

Finally, a potential role for corticosteroids has been debated in this disorder. There are studies suggesting that, used in conjunction with antibiotics, they can shorten the duration of radicular pain in Garin– Bujadoux–Bannwarth syndrome (Pfister et al., 1988). Given that steroids are now recommended to improve outcome in facial nerve palsy(Sullivan et al., 2007), it is not unreasonable to use them in conjunction with antibiotics in this setting as well. Early Lyme disease studies (before the infectious etiology was ascertained) using steroids in the absence of antibiotics clearly showed less favorable outcomes (Steere et al., 1983c). However, despite concerns based on anecdotal observations, most studies and guidelines suggest that using steroids adjunctively in combination with appropriate antibiotics does not worsen outcomes in any way.

CONCLUSION Lyme disease is a multisystem infectious disease caused by the tick-borne spirochete B. burgdorferi. The nervous system is involved in 10–15%, typically causing meningitis, cranial neuritis, radiculoneuritis, and mononeuropathy multiplex. Accurate diagnostic tools are readily available,

NERVOUS SYSTEM LYME DISEASE primarily based on measuring the antibody response in serum, CSF, or both. Standard antimicrobial regimens are well tolerated and highly effective. Prolonged antibiotic treatment adds no significant benefit but carries substantial risk.

REFERENCES Ackermann R, Rehse KB, Gollmer E et al. (1988). Chronic neurologic manifestations of erythema migrans borreliosis. Ann N Y Acad Sci 539: 16–23. Afzelius A (1910). Verhandlugen der dermatorischen Gesellshaft zu Stockholm. Arch Derm Syphiligr 101: 404. Aguero-Rosenfeld ME, Nowakowski J, Bittker S et al. (1996). Evolution of the serologic response to Borrelia burgdorferi in treated patients with culture-confirmed erythema migrans. J Clin Microbiol 34: 1–9. Bacon RM, Kugeler KJ, Griffith KS et al. (2007). Lyme disease – United States 2003–2005. MMWR Morb Mortal Wkly Rep 56: 573–576. Bacon RM, Kugeler KJ, Mead PS (2008). Surveillance for Lyme disease – United States 1992–2006. MMWR Morb Mortal Wkly Rep 57: 1–9. Bannwarth A (1941). Chronische lymphocytare meningitis entzundliche polyneuritis und rheumatismus. Arch Psychiatr Nervenkr 113: 284–376. Belman AL, Iyer M, Coyle PK et al. (1993). Neurologic manifestations in children with North American Lyme disease. Neurology 43: 2609–2614. Benach JL, Bosler EM, Hanrahan JP et al. (1983). Spirochetes isolated from the blood of two patients with Lyme disease. N Engl J Med 308: 740–742. Bertrand E, Szpak GM, Pilkowska E et al. (1999). Central nervous system infection caused by Borrelia burgdorferi. Clinico-pathological correlation of three post-mortem cases. Folia Neuropathol 37: 43–51. Burgdorfer W, Barbour AG, Hayes SF et al. (1982). Lyme disease: a tick borne spirochetosis? Science 216: 1317–1319. Cadavid D, O’Neill T, Schaefer H et al. (2000). Localization of Borrelia burgdorferi in the nervous system and other organs in a nonhuman primate model of Lyme disease. Lab Invest 80: 1043–1054. Cameron D, Gaito A, Harris NILADS Working Group (2004). Evidence-based guidelines for the management of Lyme disease. Expert Rev Anti Infect Ther 2: S1–S13. Centers for Disease Control and Prevention (CDC) (1995). Recommendations for test performance and interpretation from the Second National Conference on Serologic Diagnosis of Lyme Disease. MMWR Morb Mortal Wkly Rep 44: 590–591. Cerar D, Cerar T, Ruzic-Sabljic E et al. (2010). Subjective symptoms after treatment of early Lyme disease. Am J Med 123: 79–86. Dattwyler RJ, Volkman DJ, Luft BJ et al. (1988). Seronegative Lyme disease. Dissociation of specific T- and B-lymphocyte responses to Borrelia burgdorferi. N Engl J Med 319: 1441–1446.

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England JD, Bohm RP, Roberts ED et al. (1997). Mononeuropathy multiplex in rhesus monkeys with chronic Lyme disease. Ann Neurol 41: 375–384. Fallon BA, Keilp JG, Corbera KM et al. (2008). A randomized placebo-controlled trial of repeated IV antibiotic therapy for Lyme encephalopathy. Neurology 70: 992–1003. Feder HM Jr, Johnson BJ, O’Connell S et al. (2007). A critical appraisal of chronic Lyme disease. N Engl J Med 357: 1422–1430. Garcia-Monco JC, Fernandez-Villar B, Benach JL (1989). Adherence of the Lyme disease spirochete to glial cells and cells of glial origin. J Infect Dis 160: 497–506. Garin C, Bujadoux A (1922). Paralysie par les tiques. J Med Lyon 71: 765–767. Halperin JJ (2003). Facial nerve palsy associated with Lyme disease. Muscle Nerve 28: 516–517. Halperin JJ (2010). Nervous system Lyme disease. J R Coll Physicians Edinb 40: 248–255. Halperin JJ, Heyes MP (1992). Neuroactive kynurenines in Lyme borreliosis. Neurology 42: 43–50. Halperin JJ, Little BW, Coyle PK et al. (1987). Lyme disease – a treatable cause of peripheral neuropathy. Neurology 37: 1700–1706. Halperin JJ, Pass HL, Anand AK et al. (1988). Nervous system abnormalities in Lyme disease. Ann N Y Acad Sci 539: 24–34. Halperin JJ, Luft BJ, Anand AK et al. (1989). Lyme neuroborreliosis: central nervous system manifestations. Neurology 39: 753–759. Halperin JJ, Krupp LB, Golightly MG et al. (1990a). Lyme borreliosis-associated encephalopathy. Neurology 40: 1340–1343. Halperin JJ, Luft BJ, Volkman DJ et al. (1990b). Lyme neuroborreliosis – peripheral nervous system manifestations. Brain 113: 1207–1221. Halperin JJ, Golightly MLong Island Neuroborreliosis Collaborative Study Group (1990c). Lyme borreliosis in Bell’s palsy. Neurology 40: 342. Halperin JJ, Shapiro ED, Logigian EL et al. (2007). Practice parameter: treatment of nervous system Lyme disease. Neurology 69: 91–102. Hammers Berggren S, Hansen K, Lebech AM et al. (1993). Borrelia burgdorferi-specific intrathecal antibody production in neuroborreliosis: a follow-up study. Neurology 43: 169–175. Hansen K, Lebech AM (1992). The clinical and epidemiological profile of Lyme neuroborreliosis in Denmark 1985– 1990. A prospective study of 187 patients with Borrelia burgdorferi specific intrathecal antibody production. Brain 115: 399–423. Hansen K, Cruz M, Link H (1990). Oligoclonal Borrelia burgdorferi-specific IgG antibodies in cerebrospinal fluid in Lyme neuroborreliosis. J Infect Dis 161: 1194–1202. Henriksson A, Link H, Cruz M et al. (1986). Immunoglobulin abnormalities in cerebrospinal fluid and blood over the course of lymphocytic meningoradiculitis (Bannwarth’s syndrome). Ann Neurol 20: 337–345.

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Hollstrom E (1951). Successful treatment of erythema migrans Afzelius. Acta Derm Venereol 31: 235–243. Jacobson DM, Frens DB (1989). Pseudotumor cerebri syndrome associated with Lyme disease. Am J Ophthalmol 107: 81–82. Kalina P, Decker A, Kornel E et al. (2005). Lyme disease of the brainstem. Neuroradiology 47: 903–907. Karlsson M, Hovind HK, Svenungsson B et al. (1990). Cultivation and characterization of spirochetes from cerebrospinal fluid of patients with Lyme borreliosis. J Clin Microbiol 28: 473–479. Keller TL, Halperin JJ, Whitman M (1992). PCR detection of Borrelia burgdorferi DNA in cerebrospinal fluid of Lyme neuroborreliosis patients. Neurology 42: 32–42. Klempner MS, Hu LT, Evans J et al. (2001). Two controlled trials of antibiotic treatment in patients with persistent symptoms and a history of Lyme disease. N Engl J Med 345: 85–92. Krupp LB, Masur D, Schwartz J et al. (1991). Cognitive functioning in late Lyme borreliosis. Arch Neurol 48: 1125–1129. Krupp LB, Hyman LG, Grimson R et al. (2003). Study and treatment of post Lyme disease (STOP-LD): a randomized double masked clinical trial. Neurology 60: 1923–1930. Logigian EL, Kaplan RF, Steere AC (1990). Chronic neurologic manifestations of Lyme disease. N Engl J Med 323: 1438–1444. Logigian EL, Johnson KA, Kijewski MF et al. (1997). Reversible cerebral hypoperfusion in Lyme encephalopathy. Neurology 49: 1661–1670. Luft BJ, Steinman CR, Neimark HC et al. (1992). Invasion of the central nervous system by Borrelia burgdorferi in acute disseminated infection. JAMA 267: 1364–1367. Luo N, Johnson J, Shaw J et al. (2005). Self-reported health status of the general adult US population as assessed by the EQ-5D and Health Utilities Index. Med Care 43: 1078–1086. Meier C, Grahmann F, Engelhardt A et al. (1989). Peripheral nerve disorders in Lyme-borreliosis. Nerve biopsy studies from eight cases. Acta Neuropathol (Berl) 79: 271–278. Muley SA, Parry GJ (2009). Antibiotic responsive demyelinating neuropathy related to Lyme disease. Neurology 72: 1786–1787. Nowakowski J, Schwartz I, Liveris D et al. (2001). Laboratory diagnostic techniques for patients with early Lyme disease associated with erythema migrans: a comparison of different techniques. Clin Infect Dis 33: 2023–2027. Oksi J, Kalimo H, Marttila RJ et al. (1996). Inflammatory brain changes in Lyme borreliosis. A report on three patients and review of literature. Brain 119: 2143–2154. Oksi J, Nikoskelainen J, Hiekkanen H et al. (2007). Duration of antibiotic treatment in disseminated Lyme borreliosis: a double-blind randomized placebo-controlled multicenter clinical study. Eur J Clin Microbiol Infect Dis 26 (6): 571–581.

Pachner AR, Delaney E, O’Neill T et al. (1995). Inoculation of nonhuman primates with the N40 strain of Borrelia burgdorferi leads to a model of Lyme neuroborreliosis faithful to the human disease. Neurology 45: 165–172. Pfister HW, Einhaupl KM, Franz P et al. (1988). Corticosteroids for radicular pain in Bannwarth’s syndrome: a double blind randomized placebo controlled trial. Ann N Y Acad Sci 539: 485–487. Philipp MT, Aydintug MK, Bohm RJ et al. (1993). Early and early disseminated phases of Lyme disease in the rhesus monkey: a model for infection in humans. Infect Immun 61: 3047–3059. Piesman J, Dolan MC (2002). Protection against Lyme disease spirochete transmission provided by prompt removal of nymphal Ixodes scapularis (Acari: Ixodidae). J Med Entomol 39: 509–512. Reik L, Steere AC, Bartenhagen NH et al. (1979). Neurologic abnormalities of Lyme disease. Medicine 58: 281–294. Rupprecht TA, Koedel U, Fingerle V et al. (2008). The pathogenesis of Lyme neuroborreliosis: from infection to inflammation. Mol Med 14: 205–212. Rupprecht TA, Plate A, Adam M et al. (2009). The chemokine CXCL13 is a key regulator of B cell recruitment to the cerebrospinal fluid in acute Lyme neuroborreliosis. J Neuroinflammation 6: 42. Scrimenti RJ (1970). Erythema chronicum migrans. Arch Dermatol 102: 104–105. Shah SS, Zaoutis TE, Turnquist J et al. (2005). Early differentiation of Lyme from enteroviral meningitis. Pediatr Infect Dis J 24: 542–545. Sibony P, Halperin J, Coyle P et al. (2005). Reactive Lyme serology in patients with optic neuritis and papilledema. J Neuroophthal 25: 71–82. Skogman BH, Croner S, Nordwall M et al. (2008). Lyme neuroborreliosis in children: a prospective study of clinical features prognosis and outcome. Pediatr Infect Dis J 27: 1089–1094. Steere AC, Malawista SE, Hardin JA et al. (1977). Erythema chronicum migrans and Lyme arthritis. The enlarging clinical spectrum. Ann Intern Med 86: 685–698. Steere AC, Bartenhagen NH, Craft JE et al. (1983a). The early clinical manifestations of Lyme disease. Ann Intern Med 99: 76–82. Steere AC, Grodzicki RL, Kornblatt AN et al. (1983b). The spirochetal etiology of Lyme disease. N Engl J Med 308: 733–740. Steere AC, Pachner AR, Malawista SE (1983c). Neurologic abnormalities of Lyme disease: successful treatment with high-dose intravenous penicillin. Ann Intern Med 99: 767–772. Steere AC, Berardi VP, Weeks KE et al. (1990). Evaluation of the intrathecal antibody response to Borrelia burgdorferi as a diagnostic test for Lyme neuroborreliosis. J Infect Dis 161: 1203–1209. Stiernstedt G, Gustafsson R, Karlsson M et al. (1988). Clinical manifestations and diagnosis of neuroborreliosis. Ann N Y Acad Sci 539: 46–55.

NERVOUS SYSTEM LYME DISEASE Sullivan FM, Swan IR, Donnan PT et al. (2007). Early treatment with prednisolone or acyclovir in Bell’s palsy. N Engl J Med 357: 1598–1607. Tuerlinckx D, Bodart E, Garrino MG et al. (2003). Clinical data and cerebrospinal fluid findings in Lyme meningitis versus aseptic meningitis. Eur J Pediatr 162: 150–153. Tuerlinckx D, Bodart E, Jamart J et al. (2009). Prediction of Lyme meningitis based on a logistic regression model using clinical and cerebrospinal fluid analysis: a European study. Pediatr Infect Dis J 28: 394–397.

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Vallat JM, Hugon J, Lubeau M et al. (1987). Tick bite meningoradiculoneuritis. Neurology 37: 749–753. Wormser GP, Dattwyler RJ, Shapiro ED et al. (2006). The clinical assessment treatment and prevention of Lyme disease human granulocytic anaplasmosis and babesiosis: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 43: 1089–1134. Zemel L (2000). Lyme disease and pseudotumor. Mayo Clin Proc 75: 315.

Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 100

Tuberculosis JUAN CARLOS GARCIA-MONCO* Service of Neurology, Hospital de Galdacano, Galdacano, Vizcaya, Spain

INTRODUCTION

THE ETIOLOGIC AGENT

Tuberculosis remains an enormous burden worldwide, mainly due to its poor control in Southeast Asia, subSaharan Africa, and Eastern Europe, and because of the high rates of Mycobacterium tuberculosis and human immunodeficiency virus (HIV) coinfection in some African countries (Dye et al., 1999). The World Health Organization declared tuberculosis a global emergency in 1993. The AIDS epidemic, together with rising immigration and urban crowding, and the increase in drug-resistant M. tuberculosis strains have contributed significantly. Thirty percent of the global population is infected with M. tuberculosis, 15 million people around the globe are coinfected with HIV and M. tuberculosis, and 50 million are infected with multidrug-resistant tuberculosis (Kaufmann, 2005). In the US there was a resurgence of tuberculosis in the mid 1980s, after decades of declining rates of infection. The highest incidence was reached in 1992 and ever since the case rate has decreased steadily again. In 2000, 16 377 cases (5.8 cases per 100 000 population) were reported to the CDC, which represented a 45% decrease from the peak rate and was the lowest rate in US history. Despite this, the number of cases among foreign-born persons per 100 000 population continues to rise (7270 cases in 1992 and 7554 cases in 2000) with a case rate that remains seven times higher than that among people born in the US (CDC, 2002). In 2005, there were an estimated 8.8 million new cases of active tuberculosis reported annually, resulting in an estimated 1.6 million deaths per year(World Health Organization, 2007). Tuberculosis is currently the leading infectious cause of death and undoubtedly represents a global public health priority. Central nervous system (CNS) involvement occurs in 5–10% of extrapulmonary tuberculosis cases (Rieder et al., 1990).

Human tuberculosis is caused by mycobacteria belonging to the Mycobacterium tuberculosis complex, which consists of M. tuberculosis, M. bovis, and M. africanum. M. tuberculosis is the main agent in humans and the term tuberculosis should be reserved exclusively for infection caused by this organism. The other two species are implicated in very few human cases. M. bovis is transmitted by ingestion of unpasteurized milk and the distribution of M. africanum is largely restricted to central and west Africa. M. tuberculosis is an obligate aerobic, acid-fast bacillus of particularly slow growth (cell division time is about 22–24 hours, requires several weeks to grow on L€owenstein medium), which contributes to the chronic course of infection, and to the need for lengthy antibiotic therapy. Its cell wall is enriched with unusual lipids and glycolipids that conform a hydrophobic layer external to the cell wall that interferes with antibiotic penetration, thus explaining its difficult and lengthy therapy. Its genome was sequenced in 1998, is very rich in G þ C content (66%), and has many insertional sequences that could have a role in molecular diagnostics (Cole et al., 1998). Nontuberculous mycobacteria (NTM), or atypical mycobacteria, infect primarily patients with AIDS, and will not be discussed in this chapter. M. avium complex is responsible for most of these infections.

PATHOGENESIS OF CENTRAL NERVOUS SYSTEM TUBERCULOSIS Although mycobacteria are primarily soil or environmental organisms, M. tuberculosis has become so adapted to the human body that it has no natural reservoirs in nature other than infected/diseased persons. The principal mode of contagion of human tuberculosis is by inhalation of aerosolized droplet nuclei

*Correspondence to: Juan Carlos Garcia-Monco, M.D., Ph.D., F.A.A.N., Chief, Service of Neurology, Hospital de Galdacano, 48960 Galdacano, Vizcaya, Spain. Fax: þ34-94-400-133, E-mail: [email protected]

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Pathogenesis of CNS Tuberculosis Inhalation (1-10 organisms)

Dissemination Distant seeding Immunity develops (2-4 weeks)

Meningitis Tuberculomas, etc.

Reactivation

Fig. 100.1. Pathogenesis tuberculosis.

of

central

nervous

system

(Fig. 100.1). These nuclei contain few bacilli, and it is estimated that only 1–10 organisms are needed to cause infection (Canetti, 1965). Mycobacteria reach the alveoli where they multiply in alveolar spaces and interact with alveolar macrophages through different receptors. Once these innate immune cells are triggered, numerous cytokines and chemokines are released, the activation of a type 1 T helper cell-mediated immune response occurs, and, ultimately, a granuloma is formed. Within 2–4 weeks a silent hematogenous spread to distant extrapulmonary sites, particularly to regions that are highly oxygenated, such as the brain, where tubercles consisting of mononuclear cells surrounding a necrotic (caseous) center are formed. In fact, a magnetic resonance imaging (MRI) study disclosed the presence of CNS granulomas in patients with miliary tuberculosis that were neurologically asymptomatic (Gupta et al., 1997). The complex cellular immune response in tuberculosis, with a complex interplay of host immune factors and M. tuberculosis virulence factors, mediates largely the development of active disease, although the factors that influence the degree of immune protection are not completely understood. The period between contact and neurologic disease is shorter in children, which explains why they have, in contrast with adults, frequently abnormal chest X-rays and tuberculin test positivity. The inciting CNS tubercle has been called a Rich focus, which is thought to develop early in the infection during the spread phase (Rich and MacCordick, 1933) and to remain latent for months or many years until they reactivate for unclear reasons. The location of the expanding tubercle determines the type of CNS involvement. Tubercles rupturing into the subarachnoid space cause meningitis. Those tubercles deeper in the brain

or spinal cord parenchyma may expand resulting in tuberculomas or, more rarely, tuberculous abscesses. The cytokine tumor necrosis factor a seems critical in the neuropathogenesis of M. tuberculosis and plays an important role in granuloma formation and containment of mycobacterial infections (Rock et al., 2008). Pathologically, tuberculous meningitis is characterized by diffuse exudates that occupy the subarachnoid space, particularly in the base of the brain (oftentimes involving the cranial nerves) and choroid plexus. Arteries traversing the exudate become inflamed (vasculitis) and occluded leading to brain or spinal cord ischemic stroke. Communicating hydrocephalus results from blockage of the flow of the cerebrospinal fluid (CSF) secondary to the inflammatory exudate. Damage to the brain parenchyma adjacent to areas of exudate (“border-zone encephalitis”) can also occur. A leukoencephalopathy adjacent or distant to sites of prominent exudate has also been reported.

CLINICAL FINDINGS Tuberculous meningitis (TBM) is the most frequent and severe manifestation of CNS involvement in tuberculosis(Garcia-Monco, 1999). Tuberculoma and abscess formation as well as spinal cord involvement can also occur.

Tuberculous meningitis The clinical characteristics of patients with TBM in adults and children have been pooled in Tables 100.1 and 100.2. Typically, there is a prodromal period of 2–4 weeks before presentation during which nonspecific symptoms are present including fatigue, malaise, myalgia and fever. Chest X-ray abnormalities, a history of close contact with tuberculosis patients, and tuberculin test positivity are present more frequently in children, reflecting the shorter period between contact and development of meningitis. Hyponatremia is present in roughly half of the patients, in some cases constituting a true syndrome of inappropriate secretion of antidiuretic hormone (SIADH). The most prominent clinical features of tuberculous meningitis in adults are fever, headache, vomiting, mental status abnormalities, and meningismus. Cranial nerve palsies occur in approximately one-fourth of patients, involving mainly the sixth and, less frequently, the third, fourth, seventh and eighth cranial nerves. Hemiparesis, papilledema, and seizures occur in 10–15% of the patients. Funduscopic evidence of choroidal tubercles, an almost confirmatory finding of tuberculosis, is found in only a minority (less than 10%) of patients, most

TUBERCULOSIS

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Table 100.1 Tuberculous meningitis: associated features

Mean duration of illness prior to admission (range) Mean frequency of close contact with tuberculosis (range) Prior history of tuberculosis Abnormal chest X-ray (range) Positive tuberculin skin test (range) Patients with hyponatremia (plasma sodium level < 135 mEq/dL) (range) Mortality

Adults

Children

2 weeks (1 day–9 months) 28% (2–50%) 23% (5–45) 45% (25–55%) 51% (40–70%) 46% (25–75%) 27% (7–45%)

2 weeks (3 days–3 months) 56% (45–70%) NA 61% (35–75%) 72% (50–95%) 44% (25–65%) 19% (3–40%)

NA, not available or incomplete data. Based upon: Adults: (Barret-Connor, 1967; Hinman, 1967; Haas et al., 1977; Kennedy and Fallon, 1979; Klein et al., 1985; Clark et al., 1986; Kilpatrick et al., 1986; Ogawa et al., 1987; Berenguer et al., 1992; Davis et al., 1993; Kent et al., 1993; Verdon et al., 1996; Girgis et al., 1998; Hosoglu et al., 1998). Children: (Lincoln et al., 1960; Steiner and Portugaleza, 1973; Smith, 1975; Sumaya et al., 1975; Idriss et al., 1976; Delage and Dusseault, 1979; Cassleman et al., 1980; Naughten et al., 1981; Bhargava et al., 1982; Bullock and Welchman, 1982; Naheedy et al., 1983; Witrak and Ellis, 1985; Waecker and Connor, 1990; Yaramis et al., 1998).

Table 100.2 Signs and symptoms in patients with tuberculous meningitis Adults

Fever Headache Meningismus Abnormal mental status Hydrocephalus (CT scan) Vomiting Malaise–anorexia Cranial nerve palsies Papilledema Hemiparesis/hemiplegia Seizures

Children

Mean (%)

Range (%)

Mean (%)

72 67 67 59 52 43 41 24 15 12 11

55–85 45–85 55–90 30–80 40–65 30–70 45–65 20–40 5–30 5–20 7–10

76 34 62 42 85 58 52 29 9 24 25

Range (%) 45–95 20–40 25–75 25–75 75–100 30–70 30–70 10–45 9 5–40 10–55

Based upon: Adults: (Barret-Connor, 1967; Hinman, 1967; Steiner and Portugaleza, 1973; Sumaya et al., 1975; Haas et al., 1977; Kennedy and Fallon, 1979; Traub et al., 1984; Klein et al., 1985; Witrak and Ellis, 1985; Clark et al., 1986; Kilpatrick et al., 1986; Ogawa et al., 1987; Waecker and Connor, 1990; Berenguer et al., 1992; Davis et al., 1993; Kent et al., 1993; Verdon et al., 1996; Girgis et al., 1998; Hosoglu et al., 1998). Children: (Lincoln et al., 1960; Steiner and Portugaleza, 1973; Smith, 1975; Sumaya et al., 1975; Idriss et al., 1976; Delage and Dusseault, 1979; Cassleman et al., 1980; Naughten et al., 1981; Bhargava et al., 1982; Bullock and Welchman, 1982; Naheedy et al., 1983; Witrak and Ellis, 1985; Waecker and Connor, 1990; Yaramis et al., 1998).

frequently in association with miliary tuberculosis (Illingworth, 1950). Children also present with fever, meningismus, vomiting, and altered sensorium or behavioral changes. As compared to adults, a significantly lower percentage of children complain of headache, which in fact is absent under the age of 3 for obvious reasons. Hydrocephalus is

more frequent among children than among adults. Abdominal pain and constipation may also be present in children. The rest of the clinical manifestations do not differ very much between the pediatric and adult groups. The British Medical Research Council devised a staging system to assess the severity of patients with

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tuberculous meningitis which consists of three stages (Medical Research Council, 1948). In stage 1, patients are fully conscious and rational and do not have any neurologic signs. In stage 2, patients are confused but not comatose or have neurologic signs of localization such as hemiparesis or single cranial nerve palsy. In stage 3, patients are comatose or stuporous or have multiple cranial nerve palsies or complete hemiplegia or paraplegia.

CEREBROSPINAL FLUID FINDINGS The CSF shows a lymphocytic pleocytosis with an average cell count around 200 cells/mL, increased protein contents (around 200 mg/dL) and low glucose levels (Table 100.3). In 20–25% of non-HIV infected patients neutrophilic predominance is present, that usually shifts to lymphocytic predominance over the next 24–48 hours (Verdon et al., 1996). Occasionally neutrophils persist, resulting in the so-called “persistent neutrophilic meningitis,” a syndrome of varied etiology in which tuberculosis has to be carefully excluded (Pinto et al., 2009). This syndrome seems more frequent in HIVinfected patients, particularly when meningitis is caused by multidrug-resistant mycobacteria (SanchezPortocarrero et al., 1996). On the other hand, an initial mononuclear pleocytosis may briefly change in the direction of polynuclear predominance when therapy is initiated, and this may be

associated with clinical deterioration. This “therapeutic paradox” has been regarded by some authors as virtually pathognomonic of tuberculous meningitis (GarciaMonco et al., 2005) and manifests a few days after the start of antituberculous therapy by the patient’s rapid deterioration into coma or even death. This syndrome is thought to represent an uncommon hypersensitivity reaction to the massive release of tuberculoproteins into the subarachnoid space. Normal protein contents are seen in 5–15% of patients and normal glucose levels in less than one-third. CSF is acellular in up to 16% of HIV patients as compared to 3–6% in non-HIV infected patients. Acellular CSF samples may show pleocytosis if a spinal tap is repeated 24–48 hours later (Ogawa et al., 1987). Over time, CSF sugar levels seem to normalize first, followed by the cell count and the protein contents (Barret-Connor, 1967; Verdon et al., 1996). In a series, the most rapid return to normal of CSF glucose was 19 days and the slowest 11 weeks (Verdon et al., 1996).

DIAGNOSIS The diagnosis of TBM remains an important challenge to the clinician, since clinical presentation is nonspecific and microbiological confirmation is often difficult and late. From a clinical standpoint, the best predictors of TBM are a duration of symptoms greater than 6 days, a total cell count in the CSF < 1000/mL with lymphocytic

Table 100.3 Cerebrospinal fluid profile in patients with tuberculous meningitis

Mean cell count (range) Mean percentage of patients with neutrophilic pleocytosis (>50% neutrophils) (range) Percentage of CSFs with normal cell count Mean protein level in mg/dL (range) Percentage of CSFs with normal protein content Percentage of patients with depressed glucose levels ( < 45 mg/dL or 40% of serum glucose) Positive smear Positive culture

Adults

Children

223 cells/mL (0–4000) 27% (15–55)

200 cells/mL (5–950) 21% (15–30)

6% (5–15) 224 mg/dL (20–1000) 6% (0–15)

3% (1–5) 219 mg/dL (50–1300) 16% (10–30)

72% (50–85)

77% (65–85)

25% (5–85) 61% (40–85)

3% (0–6) 58% (35–85)

Based upon: Adults: (Barret-Connor, 1967; Hinman, 1967; Haas et al., 1977; Kennedy and Fallon, 1979; Klein et al., 1985; Clark et al., 1986; Kilpatrick et al., 1986; Ogawa et al., 1987; Berenguer et al., 1992; Davis et al., 1993; Kent et al., 1993; Verdon et al., 1996; Girgis et al., 1998; Hosoglu et al., 1998). Children: (Lincoln et al., 1960; Steiner and Portugaleza, 1973; Smith, 1975; Sumaya et al., 1975; Idriss et al., 1976; Delage and Dusseault, 1979; Cassleman et al., 1980; Naughten et al., 1981; Bhargava et al., 1982; Bullock and Welchman, 1982; Naheedy et al., 1983; Witrak and Ellis, 1985; Waecker and Connor, 1990; Yaramis et al., 1998).

TUBERCULOSIS predominance, and a peripheral blood white cell count < 15 000  103/mL (Thwaites et al., 2002; Moghtaderi et al., 2009). Acid-fast stains (Ziehl-Neelsen, Kinyoun, and auramine-rhodamine) of CSF samples are positive in 5–58% of patients. Up to 3–4 CSF samples of 6 mL each are recommended (Thwaites et al., 2009) if initial study comes negative. This is due to the fact that approximately 104 organisms are required for their reliable detection using acid-fast stains (Ziehl-Neelsen, Kinyoun, and auramine-rhodamine stains), a much higher load than that usually present in the CSF. Culture of CSF, when productive, takes 4–8 weeks for an unequivocal identification. The frequency of positive CSF cultures in clinically diagnosed patients with tuberculous meningitis has a wide range (25–85%), with an average of approximately 50%. Newer culture media, either radiometric – such as BACTEC – or nonradiometric systems, may give positive results in 7–10 days (Watterson and Drobniewski, 2000). Serologic assays for tuberculosis have been notoriously lacking in the laboratory arsenal for this infection (Orme, 1993) and are not in routine use at present. Determination in cerebrospinal fluid of adenosine deaminase (ADA) is useful for the diagnosis of tuberculous meningitis (Malan et al., 1984; Ribera et al., 1987; Pettersson et al., 1991; Mishra et al., 1996), although false-positives and negatives do occur in other infectious and neoplastic CNS disorders (Garcia-Monco and Berciano, 1988; Pettersson et al., 1991). ADA values may increase during the first 1–2 weeks of therapy and then progressively decrease (Ribera et al., 1987). A recent systematic search on the value of ADA in the CSF of TBM patients found that values within a range ( > 8 U/L, sensitivity < 59% and specificity > 96%) were useful in the diagnosis of TBM; lower values did not improve the diagnosis significantly (Tuon et al., 2010). The paucity of organisms in TBM, and the availability of a completely sequenced genome of M. tuberculosis provide reasons to be enthusiastic about the use of the polymerase chain reaction (PCR) as an important tool for the laboratory diagnosis of this disease. A recent meta-analysis concluded that the sensitivity of commercial PCR for the diagnosis of TBM was too low (56%, 95% CI 46–66) and perhaps not better than bacteriology (Pai et al., 2003).

NEUROIMAGING Enhancement of the basal cisterns either on contrast computed tomography (CT) scan or postgadolinium MRI is often striking (Fig. 100.2), corresponding to the thick exudate that is observed pathologically(Ozates et al., 2000). The interpeduncular fossa, the ambiens

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Fig. 100.2. Magnetic resonance image (T1-weighted sequence after gadolinium administration) of a patient with tuberculous meningitis. Coronal view showing the exudate involving the basal meninges and extending towards the middle cerebral artery. (Reproduced from Garcia-Monco, 1999.)

cistern, and the chiasmatic region are the sites of predilection. Meningeal enhancement seems more common in HIV-infected patients. In one study, meningeal enhancement was present in 23% of HIV-positive patients but only in 6% of HIV-negative individuals (Berenguer et al., 1992). Hydrocephalus is observed on CT scan and MRI, usually of the communicating type, although obstructive hydrocephalus may result from a focal parenchymal lesion and the associated mass effect. As mentioned before, hydrocephalus is more common in children.

COMPLICATIONS Ischemic brain infarctions occur in about 25–40% of patients during the course of tuberculous meningitis (Belorgey et al., 2006). Small and medium-sized arteries at the base of the brain are mainly involved by the inflammatory exudate with panarteritis and occlusion. In a series, one-fourth of patients developed unilateral choreoathetoid movements due to contralateral caudate nucleus infarction (Leiguarda et al., 1988). Other movements disorders such as myoclonus, tremor, or dystonia

1490 J.C. GARCIA-MONCO have also been described (Alarcon et al., 2000). Angiobut it is bacteriostatic in vivo, acting only against intragraphic findings in tuberculous meningitis includes evicellular bacteria). dence of hydrocephalus, narrowing of the arteries at the In areas where the incidence of drug resistance to M. base of the brain, and narrowed or occluded small and tuberculosis is lower than 4% (it is higher in Africa, Asia medium-sized arteries (Leiguarda et al., 1988). and parts of South America), an initial regimen with The development of a variable degree of hyponatrethree drugs (isoniazid, rifampicin and pyrazinamide, mia or true SIADH is frequent in TBM. all daily) for 2 months and two drugs (isoniazid and Syringomyelia can occur several years after the rifampicin, daily or twice a week) for 7–10 additional initial infection, although a few acute cases have been months is also acceptable (Small and Fujiwara, 2001). reported (Daif et al., 1997). Inflammatory edema and Liver enzymes should be monitored throughout therspinal cord ischemia appear to be the mechanisms apy; in the event of significant elevations of alanine amiimplicated in early cases, whereas chronic arachnoiditis notransferase ( > 5 times normal), isoniazid and underlies late cases. rifampicin are usually stopped and ethambutol and streptomycin started and continued until enzymes return to normal at which time isoniazid may be resumed with biweekly determinations. In most cases a combination of MANAGEMENT isoniazid, ethambutol, pyrazinamide, and streptomycin Guidelines for therapy of tuberculosis have been estabwill be well tolerated. During pregnancy, streptomycin lished by the American Thoracic Society, the US Centers (can cause congenital deafness) and pyrazinamide (not for Disease Control and Prevention (Bass et al., 1994), enough experience) should be avoided, and the preferred the Infectious Disease Society of America (Horsburgh regimen is isoniazid, ethambutol, and rifampicin. et al., 2000), and the British Infection Society Shorter regimens could suffice, although there have (Thwaites et al., 2009). been few controlled trials of treatment in patients with Unlike its pulmonary counterpart, from where it has extrapulmonary disease. Two studies reported that the often been extrapolated, the optimal therapy for TBM is 6 month therapeutic regimen resulted in a morbidity/ not the result of controlled studies and therefore is not so mortality ratio similar to that found in the longer course well established. Many patients will be empirically treatherapies (van Loenhout-Rooyackers et al., 2001). Cheted due to the diagnostic difficulties of TBM. Not infremotherapy with isoniazid and rifampicin for 9 months quently, the response to therapy constitutes a key to the has also proven successful in 95% of patients, equivalent diagnosis. Identification and early empiric treatment of to conventional therapy with two to three drugs for 18–24 patients at risk is critical to their outcome. TBM should months (Dutt et al., 1986). The authors claimed that their be suspected in patients with subacute meningitis and twice-weekly regimen has the additional advantages of moderate ( 11 (Verdon et al., 1996). Another study observed important neurologic sequelae 1 year after disease onset in 78.5% of patients that included cognitive impairment in 55%, motor deficit in 40%, optic atrophy in 37%, and other cranial nerve palsy in 23%. Focal motor deficit at admission was the most important predictor of neurologic deficits at 1 year, whereas Glasgow Coma Scale (GCS) score predicted the cognitive and motor sequelae (Kalita et al., 2007).

Parenchymal CNS disease: tuberculomas and abscesses Tuberculous granulomas (tuberculomas) are composed of a central zone of solid caseation necrosis with few bacilli surrounded by a capsule of collagenous tissue and mononuclear inflammatory cells (Dastur et al., 1968). They are most commonly supratentorial in adults (infratentorial in children), and are multiple in up to onethird of patients (Jinkins, 1991). The clinical course is subacute or chronic, and the commonest presentation includes headache, intracranial hypertension, seizures, and papilledema (Man et al., 2010). The tuberculin skin test is positive in up to 85% of patients and chest X-rays suggest pulmonary tuberculosis in 30–80% of patients. CSF findings are unremarkable, and microbiology is usually negative (Mayers et al., 1978). A recent retrospective review of 23 tuberculoma patients from highrisk countries found a laboratory-proven meningitis in 43.5% (Man et al., 2010). The diagnosis is made on the basis of neuroimaging findings, tuberculin test results, and response to

TUBERCULOSIS antituberculous therapy. Neuroimaging reveals that parenchymal disease most often involves the corticomedullary junction and periventricular regions, consistent with a hematogenous spread. On CT scan, tuberculomas appear as solid-enhancing, ring-enhancing or mixed lesions; on occasions, there is a central calcification surrounded by a hypodense area with peripheral ring enhancement (target sign) (Whiteman, 1997), a pattern highly suggestive of tuberculosis, although occasionally present in metastatic adenocarcinoma (Kong et al., 2006). On magnetic resonance imaging (MRI), tuberculomas appear as isointense to gray matter on T1weighted images and may have a slightly hyperintense rim (Gupta et al., 1990) (Fig. 100.3). Noncaseating lesions are bright on T2-weighted images with nodular enhancement. Caseating tuberculomas vary from isointense to hypointense on T2-weighted images, and also exhibit rim enhancement (Gupta et al., 1990). They demonstrate a variable degree of mass effect and perilesional edema, which are usually more prominent in the early stages (Gupta et al., 1990). Normal diffusion-weighted MRI with normal apparent diffusion coefficient (ADC) values have been described in tuberculomas (Basoglu et al., 2002). The differential diagnosis includes neoplasms and other granulomatous processes like sarcoidosis and parasitic diseases such as cysticercosis and

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toxoplasmosis. Magnetization transfer imaging analysis has proved helpful in differentiating tuberculomas and pyogenic abscess from brain tumors (Pui and Ahmad, 2002). With therapy, tuberculomas usually decrease in size to complete resolution within 3 months although it may take longer (even years), sometimes leaving a residual calcification (DeAngelis, 1981; Garcia-Monco et al., 1997). Medical therapy alone is indicated initially, and surgery is required in the presence of intolerably increased intracranial pressure or of medical failures. Mortality with current chemotherapeutic regimens is < 10%, while prior to the availability of antituberculous drugs, mortality after decompression and excision was 35–85% (Arseni, 1958). Some patients, however, develop intracranial tuberculomas, or present a paradoxical enlargement of pre-existing ones, during the first weeks or months of treatment for TBM (Afghani and Lieberman, 1994). Paradoxical deterioration in HIV-negative patients is frequently accompanied by an increase in peripheral blood lymphocyte count and an exaggerated tuberculin skin reaction (Cheng et al., 2002). Steroids seem to improve the general outcome, and dexamethasone is recommended for 4–8 weeks(Hejazi and Hassler, 1997). The review of the literature shows that surgery has been employed in approximately 60% of these patients (Cheng et al., 2002).

Fig. 100.3. Magnetic resoncance image of a patient with cerebellar tuberculoma. Gd-enhanced T1-weighted image (A) and ADC map sequence (B).

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When the caseous core of a tuberculoma liquefies, a tuberculous abscess will result. They are larger and much less frequent than tuberculomas, may be multiloculated, and often have greater mass effect and edema. In contrast to the solid caseation and few organisms seen in tuberculomas, the abscess is formed by pus, where many bacilli can be found (Tyson et al., 1978). Its wall is devoid of the granulomatous reaction that surrounds the tuberculoma, with its appearance resembling that of a typical pyogenic abscess. They have a more accelerated clinical course than tuberculomas, usually presenting acutely with fever, headache and neurologic focal signs, and are most commonly supratentorial (Kumar et al., 2002). On CT, abscesses are hypodense, with surrounding edema and mass effect, and peripheral enhancement, usually thin and uniform. On MRI, there is a central area of hyperintensity on T2-weighted images (Whiteman, 1997) (Fig. 100.4). This pattern is not specific and, thus, they are difficult to differentiate from toxoplasmic, fungal or pyogenic abscesses, or even from lymphoma in AIDS patients. Localized areas of cerebritis with gyriform enhancement are less frequently observed. Appropriate therapy includes antituberculous chemotherapy and surgical excision or aspiration where needed. Ofloxacin proved successful in a patient with

Fig. 100.4. Magnetic resonance image showing the presence of an occipital tuberculous abscess (T1-weighted sequence after gadolinium administration).

intracranial tuberculomas in whom first-line therapy failed (Sermet-Gaudelus et al., 1999).

Central nervous system tuberculosis in the HIV patient Coinfection with HIV and tuberculosis has important implications, since the prognosis of tuberculosis is poorer due to the immunosupression of these individuals. HIV testing is recommended for all patients with tuberculosis (Horsburgh et al., 2000). There is mounting evidence that the host immune response to M. tuberculosis enhances HIV replication and might accelerate the natural progression of HIV infection. The clinical features and CSF profiles of tuberculous meningitis are not modified by HIV infection (Berenguer et al., 1992; Thwaites et al., 2005). HIVinfected patients show a lower percentage of tuberculin test positivity (30% with initial infection as compared with 50% in the immunocompetent adult), reflecting their cell-mediated immune deficiency. Anergy develops with advanced stages of immunosuppression. Parechymal disease seems more common in patients with HIV coinfection (Berenguer et al., 1992), and has been reported in 15–44% of patients with CNS tuberculosis (Whiteman et al., 1995). When treating HIV-infected individuals, several facts should be considered. First, they usually have difficulty in controlling the infection due to the associated immune deficiencies. Second, rifamycins (rifampicin, rifabutin, and rifapentine) reduce the activity of protease inhibitors due to induction of cytochrome CYP450 (all protease inhibitors are metabolized by CYP450). For this reason, rifabutin – which has substantially less activity as an inducer of cytochrome enzymes – is used instead of rifampicin in these individuals, at a dose of 150 mg/day. Conversely, if protease inhibitors, particularly ritonavir or saquinavir, which are potent CYP450 inhibitors, are administered with rifabutin, blood concentrations of the latter increase markedly, and most likely rifabutin toxicity increases as well. Rifabutin is efficacious in nonresistant tuberculosis; its role in multiresistant cases is less clear (Wallace and Griffith, 2009). Third, HIV infected patients can have malabsorption of antituberculous drugs (Gordon et al., 1993) and are particularly prone to adverse drug reactions (Pozniak et al., 1992), which makes drug monitoring particularly important. Ideally, the management of tuberculosis among HIV-infected patients taking antiretroviral drugs should include directly observed therapy. It has to be taken into account that paradoxical reactions might occur during the course of tuberculosis treatment when antiretroviral therapy restores immune function (Rao et al., 1995).

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Fig. 100.5. Magnetic resonance image showing nodular thickening of the cauda equina roots in a patient with tuberculous meningitis and lumbosacral root involvement. Saggital (A) and axial (B) T1-weighted sequences after gadolinium administration.

Aside from classical regimens of long duration (see above), a 6 month (isoniazid, rifabutin, and pyrazinamide for 2 months and isoniazid and rifabutin for 4 additional months) as well as a 9 month schedule (isonazid, streptomycin, and pyrazinamide daily for 2 months and then 2—3 times/week for 7 months) are accepted regimens for HIV-infected patients (CDC, 1998). Paradoxical tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) is an important complication in HIV-infected tuberculosis patients who start combination antiretroviral treatment (ART). Neurologic manifestations occur in more than 10% of TB-IRIS cases, mainly meningitis and tuberculomas (Marais et al., 2010).

Spinal cord involvement Tuberculous myelitis or radiculomyelitis usually presents as an acute or subacute transverse myelitis with variable degree of radicular pain. Ischemic spinal cord infarction secondary to vasculitis may also occur (Kocen and Parsons, 1970). CSF analysis reveals an increased protein content with lymphocytic pleocytosis; low glucose levels are observed in up to one-third of patients (Dastur and Wadia, 1969). The thoracic cord

is most commonly affected, followed by the lumbar and the cervical regions. MRI shows contrast-enhancing tissue that surrounds the spinal cord and the roots and obliterates the subarachnoid space with focal or diffuse increased intramedullary signal on T2-weighted images and variable degrees of edema and mass effect. Postcontrast T1-weighted images reveal leptomeningeal enhancement (Fig. 100.5). The nerve roots may be clumped and show contrast enhancement depending on the degree of involvement (Gupta et al., 1994). Corticosteroids seem to improve the prognosis (de La Blanchardiere et al., 1996). Rarely, tuberculomas occur in the spinal cord, either as intramedullary lesions or located in the dural space (Lu, 2010), often requiring microsurgical resection and antituberculous chemotherapy. Infrequent cases of intramedullary tuberculous abscesses have been reported (Hanci et al., 1996). Tuberculous spondylitis most often involves the thoracolumbar region, with L1 being the most affected level and the cervical and sacral spine being only rarely involved (Whiteman, 1997). The infection initially predominates in the anterior part of the vertebral body, usually involving more than one vertebral level, and disseminates to affect the disk and eventually extends along the anterior or posterior longitudinal ligaments

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or through the end plate. Vertebral collapse may occur, resulting in kyphosis. In the lumbar region, tuberculous spondylitis may result in a calcified psoas abscess, a finding very suggestive of tuberculosis. Neuroimaging discloses bone destruction and fragmentation with involvement of the disk space and calcified paravertebral mass. MRI seems the method of choice, with an accuracy of 94% in vertebral osteomyelitis (Modic et al., 1985). It reveals hypointense T1-weighted areas in the vertebral bodies alternating with areas of hyperintense T2-weighted signal in the disk space and paravertebral soft tissue. Postgadolinium images show enhancement of infected bone and disk. Spondylitis can also complicate with an epidural abscess, resulting in different combinations of local and radicular pain, limb motor and sensory loss and sphincter disturbances. Eventually, complete spinal cord compression with paraplegia, the most dreaded complication, may supervene. Spinal cord disease is best treated with prolonged antituberculosis therapy and systemic steroids with the prognosis being better in those patients with recent onset disease and in whom prompt treatment is established. Surgery should be considered on an individualized basis depending on the extent and nature of the lesion and on the degree of neurologic deficit.

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TUBERCULOSIS Verdon R, Chevret S, Laissy JP (1996). Tuberculous meningitis in adults: review of 48 cases. [see comments], Clin Infect Dis 22: 982–988. Waecker NJ Jr, Connor JD (1990). Central nervous system tuberculosis in children: a review of 30 cases. Pediatr Infect Dis J 9: 539–943. Wallace RJ, Griffith DE (2009). Antimycobacterial agents. In: GI Mandell, JE Bennet, R Dolin (Eds.), Principles and Practice of Infectious Diseases. 7 th ed. ChurchillLivingstone, Philadelphia, pp. 533–548. Watterson SA, Drobniewski FA (2000). Modern laboratory diagnosis of mycobacterial infections. J Clin Pathol 53: 727–732. Whiteman ML (1997). Neuroimaging of central nervous system tuberculosis in HIV-infected patients. Neuroimaging Clin N Am 7: 199–214.

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Whiteman M, Espinoza L, Post MJ et al. (1995). Central nervous system tuberculosis in HIV-infected patients: clinical and radiographic findings. AJNR Am J Neuroradiol 16: 1319–1327. Witrak BJ, Ellis GT (1985). Intracranial tuberculosis: manifestations on computerized tomography. South Med J 78: 386–392. World Health Organization (2007). Global Tuberculosis Control: Surveillance Planning Financing. Who Report 2007 (http://www.who.int/tb/publications/global_report/ 2007/en/), WHO, Geneva. World Health Organization (2008). Guidelines for the Programmatic Management of Drug-resistant Tuberculosis. World Health Organization, Geneva. Yaramis A, Gurkan F, Elevli M et al. (1998). Central nervous system tuberculosis in children: a review of 214 cases. Pediatrics 102: e49.

Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 101

Rabies, tetanus, leprosy, and malaria J.M.K. MURTHY1*, FARAM D. DASTUR2, SATISH V. KHADILKAR3, AND DHANPAT K. KOCHAR4 1 Continental Institute of Neurosciences & Rehabilitation, Continental Hospitals, IT & Financial District, Gachibowli, Hyderabad, India 2

Department of Medicine, P.D. Hinduja National Hospital, Mumbai, India

3

Department of Neurology, Grant Medical College and Sir J.J. Group of Hospitals and Bombay Hospital Institute of Medical Sciences, Mumbai, India 4

Medical Research, Rajasthan University of Health Sciences, Jaipur, India

RABIES Introduction Rabies (rage or madness in Latin) is an ancient zoonotic disease, with man being the dead-end host, and is widely distributed across the globe. More than 55 000 people die of rabies each year, about 95% in Asia and Africa (WHO, 2008). Annually, more than 10 million people, mostly in Asia, receive postexposure vaccination against the disease. Postexposure rabies prophylaxis is estimated to prevent 330 304 deaths in Asia and Africa. It is estimated that rabies is responsible for 1.74 million disability adjusted life years (DALY) lost each year (Knobel et al., 2005). Globally, the major financial burden is the cost of prevention and control of rabies (Meltzer and Rupprecht, 1998). The causative viruses of rabies encephalitis belong to the Mononegavirales order, Rhabdoviridae family and Lyssavirus genus. The bullet-shaped, enveloped viruses are single-strand RNA viruses of negative polarity. Currently this genus comprises seven genotypes, type 1 of which represents the classic rabies virus. The RNA of this virus encodes five proteins: the neucleoprotein, the matrix protein, the glycoprotein, the phosphorylated protein, and a large polymerase protein. Various mammals serve as major hosts in different parts of the world, primarily in the Carnivora and Chiproptera (bats). Isolates of rabies virus from different animal species and locales differ in their antigenic and biologic properties, accounting for differences in virulence between isolates. Transmission to humans is through animal bites, most commonly from dogs. In addition to the domestic dog, a variety of

wild carnivores and bat species in the Americas and Europe may transmit rabies to humans. Children in the 5–15-year-old age group represent about 40% of people exposed to dog bites in rabies-endemic areas.

Clinical features Clinical features of human rabies can be divided into five stages: the incubation period; the prodrome; the acute neurologic phase; coma; and death (Hemachudha et al., 2002). The incubation period is the most variable, at 1–2 months with a range from less than 7 days to more than 6 years. The proximity of the site of virus entry to the central nervous system (CNS) increases the likelihood of a short incubation period. During the prodromal stage patients may experience local symptoms or neuropathic pain at the bite site. An intense and progressive local reaction, starting at the bite site and spreading to involve the whole limb, is a reliable indicator of rabies (Chopra et al., 1980; Hemachudha, 1989). Major clinical features in the acute neurologic phase are related to the virus-induced encephalomyeloradiculitis; classic rabies and nonclassic rabies. Classic rabies has two forms: encephalitic form and paralytic form (20%). Classic rabies is almost always associated with true rabies virus (genotype 1) and nonclassic rabies patterns can be found in patients exposed to bats (Hemachudha et al., 2002).

ENCEPHALITIC (FURIOUS) RABIES Fever is fairly a constant feature. The earliest feature of encephalitic rabies is hyperactivity, aggravated by stimuli

*Correspondence to: Dr. J.M.K. Murthy, M.D., D.M., F.A.M.S., F.A.A.N., Chief of Neurology, Institute of Neurological Sciences, CARE Hospital, Exhibition Road, Nampally, Hyderabad 500 001, India. E-mail: [email protected]

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such as thirst, fear, light, and noise. Within 24 hours, the three major cardinal signs of rabies follow: fluctuating consciousness with gradually deterioration to coma; phobic or inspiratory spasms; and signs of autonomic dysfunction. Phobic spasms, aerophobia, and hydrophobia can be incited by blowing or fanning air on the face or chest wall, by encouraging the patient to swallow, or by merely offering a drink (Hemachudha et al., 2002). The features of dysautonomia include hypersalivation, excessive sweating, piloerection, pupillary abnormalities, hemodynamic instability and cardiac arrhythmias, priapism, and rarely neurogenic pulmonary edema.

PARALYTIC (DUMB) RABIES Weakness generally starts in the bitten limb, and then progresses to all the limbs, and bulbar and respiratory muscles. Sphincter involvement is common. The major cardinal signs appear late and are not prominent. Excitation is less evident in paralytic rabies and phobic spasms occur in about 50% of patients. The clinical features that differentiate paralytic rabies from Guillain–Barre´ syndrome include persistent fever, intact sensory function, percussion myedema, absence of cranial nerve deficits at presentation, and pleocytosis in cerebrospinal fluid (CSF) (Chopra et al., 1980; Gadre et al., 2010).

NONCLASSIC RABIES This form of encephalitis is common with bat-related rabies and may not have any distinct characteristics. During the prodromal phase these patients in addition to neuropathic pain at the bite site may have radicular pain, objective sensory or motor deficits, and choreiform movements of the bitten limb. Convulsive and nonconvulsive seizures and hallucinations are frequent (Hemachudha et al., 2002).

Differential diagnosis Diagnosis of rabies based on clinical grounds alone is difficult and unreliable except when the major cardinal signs are present. The differential diagnosis includes other infective viral encephalitis. Patients with rabies may or may not have behavioral changes and phobic spasms. Behavioral changes can also be seen in patients with Japanese encephalitis and herpes simplex encephalitis. Flaccid paralysis can be seen in patients with West Nile virus encephalitis and poliomyelitis-like weakness can be the feature of Japanese encephalitis. In acute disseminated encephalomyelitis following vaccination, particularly neural vaccines (Semple vaccine), there will be signs and symptoms related to the widespread involvement of white matter of the cerebral hemispheres and spinal cord (Murthy, 1998).

Pathogenesis and pathology Rabies virus from the inoculation site passes to the spinal cord and brain via retrograde axoplasmic flow where it replicates. Rabies virus preferentially localizes in the brainstem, basal ganglia, and spinal cord. There is passive, centrifugal movement from the brain to other organs or glands such as salivary glands. The virus is widely disseminated throughout the body at the time of clinical onset. The hypothetical mechanisms in encephalitic rabies include production of proinflammatory molecules from rabies-infected neuronal processes in the brainstem, which in turn lead to functional modification of the limbic system and stimulation of the hypothalamo-pitutaryadrenal (HPA) axis. The p55 TNF-a receptors may be activated in encephalitic rabies and rabies virus antigen in the CNS is thus recognized. Subsequently recruitment of immune cells and intensification of limbic symptoms and HPA stimulation follow. Once V_8 T cells are stimulated by rabies virus nucleocapsid antigens, these cytokine cascades are reamplified, exaggerating the disturbance of the limbic and sympathetic nervous systems (Hemachudha et al., 2002). Pathologically the changes are those of polioencephalomyelitis occurring predominantly in the gray matter. Many neurons are infected by the virus, but the neuropathologic findings are quite mild, with inflammatory changes and few cells showing evidence of neuronal death. The characteristic pathologic feature of rabies is round or oval, discrete, sharply demarcated eosinophilic intracytoplasmic Negri inclusion bodies (Fig. 101.1) (Chopra et al., 1980; Gadre et al., 2010). However, these inclusions are not present in all cases. Immunohistochemistry using both monoclonal and polyclonal antibodies is a rapid, safe, and sensitive tool for the diagnosis of rabies. The amount of rabies viral antigen is much more abundant than could be expected from the histopathologic findings (Jogal et al., 2000; Gadre et al., 2010). Exactly why humans die of rabies is not understood. It is felt that rabies virus infection produces neuronal dysfunction rather than neuronal death. However, the fundamental cause of the dysfunction is not yet well understood (Jackson, 2005).

Diagnosis Clinical diagnosis of rabies is based on clinical history, symptoms, and major cardinal signs, supported by epizootologic information. Magnetic resonance imaging (MRI) is useful in suspecting human rabies in the appropriate clinical setting. Both the encephalitic and paralytic forms show extensive involvement of the gray matter

Fig. 101.1. Pathology of rabies. (A) Neuron with intracytoplasmic Negri body (H&E10); (B) immunoperoxidase stain showing Negri body, immunoperoxidase stain showing viral antigen in cytoplasm (C and D); in Purkinje cell (E), spread of antigen along dendritic process (F).

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including thalami, basal ganglia, midbrain, pons, and spinal cord (Sing and Soo, 1996; Pleasure and Fischbein, 2000; Awasthi et al., 2001; Desai et al., 2002; Laothamatas et al., 2003; Mani et al., 2003; Gadre et al., 2010) (Fig. 101.2). These lesions are hyperintense on T2 and FLAIR images and they reflect the pathologic studies of rabies that have shown maximal concentration of Negri bodies and antirabies antigen as revealed by immunohistochemistry (Jogal et al., 2000). Contrast enhancement with gadolinium is seen at the hypothalami, brainstem nuclei, spinal cord gray matter, and intradural cervical nerve roots only when the patients become comatose (Laothamatas et al., 2003). Definite diagnosis of rabies can only be obtained by laboratory investigations. Viral antigen may be detected by fluorescent antibody (FA) techniques on skin biopsy taken from the nuchal area of the neck with hair follicles containing peripheral nerves. The test is sensitive and is independent of the antibody status of the patient. FA testing on corneal impression is rarely reliable in most clinical settings. Rabies virus isolation can be performed using neuroblastoma cells or the intracranial inoculation of mice with patient saliva. The success rate depends upon the antibody status, positive in antibody-negative patients. The presence of neutralizing antibodies in the serum and CSF of unimmunized patients is diagnostic, but not highly sensitive. Detection of nucleic acid in saliva and other samples using polymerase chain reaction (PCR) is proving to be a rapid and reliable way of making the diagnosis (WHO, 1996; Smith et al., 2003; Solomon et al., 2005). Muhamuda et al. (2006) developed a more sensitive ELISA technique to detect immune complex to rabies N and G protein which was 100% specific and 76.6% sensitive. This may help in early antemortem diagnosis (Gadre et al., 2010).

Management Established rabies encephalitis is invariably fatal. In view of poor outcome, treatment of rabies encephalitis is purely symptomatic. Complications of the disease should be anticipated and appropriate treatments are instituted. Postexposure rabies prophylaxis should be initiated at presentation with rabies vaccine and human rabies immune globulin when rabies virus antibody status of the patient is unknown, especially since all previous survivors of rabies had received rabies vaccine. Several treatments have been tried, but without success. The expert group on the management of human rabies noted that a combination of specific therapies may be more effective. Specific treatments for consideration at the present time include: rabies vaccine, human rabies immunoglobulin (HRIG), ribavirin, IFN-a, and ketamine. Ketamine is a noncompetitive antagonist of N-methyl-D-aspartate (NMDA) receptor and has been demonstrated to inhibit the in vitro replication of rabies virus by inhibiting rabies virus genome transcription (Jackson et al., 2003). The expert group also suggested that in unusual circumstances, a decision may be made to use an aggressive approach to therapy for patients who present at an early stage of clinical disease. Willoughby et al. (2005) reported success in treating a patient with rabies related to a bite from bat with antiexcitatory agents (ketamine, midazolam, and phenobarbital) and antiviral agents (ketamine, amantadine, and ribavirin). However, such a treatment is very expensive and beyond the reach of the people in developing countries endemic to rabies. Probably this combination therapy should be reserved for only those patients who have confirmed cases of rabies, who remain conscious, and who already have rabies-neutralizing antibodies in serum and CSF (Hemachudha and Wilde, 2005).

Prevention Natural history Rabies in humans is a fatal disease. When the disease is not treated, death typically occurs within 5–7 days after onset of symptoms. Medical treatment may prolong survival up to 133 days (Emmons et al., 1973; Gode et al., 1976). To date there have been six patients with survival after rabies encephalitis; five of them received conventional care (Hattwick et al., 1972; Porras et al., 1976; Tillotson, 1977; Alvarez et al., 1994; Madhusudana et al., 2002) and one patient received antiexcitatory and antiviral agents (Willoughby et al., 2005). One of the patients who received conventional care had a satisfactory outcome (Hattwick et al., 1972). The patient who received the combination therapy also had favorable outcome (Hu et al., 2007).

The disease is preventable through eliminating the infection in the animal vectors and timely pre- and postexposure vaccination (WHO, 1992, 1997).

PRE-EXPOSURE TREATMENT Two types of vaccines to protect against rabies in humans exist: nerve tissue and cell culture vaccines. The nerve tissue vaccines cause more reactions and are less potent, but also less expensive. WHO recommends replacement of nerve tissue vaccines with the more efficacious safer vaccines developed through cell cultures. Rabies vaccination is indicated for persons at high risk of exposure to live rabies virus (laboratory staff, veterinarians, animal handlers, and wildlife officers). Toddlers and children in highly endemic areas

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Fig. 101.2. FLAIR MRI images of the brain showing symmetric hyperintensity of the thalami, caudate heads and lentiform nuclei (A), hipocampi (B), posterior portion of pons (C), and medulla (D).

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Table 101.1

Table 101.2

Vaccines and pre-exposure prophylaxis

Rabies postexposure prophylaxis

Human rabies vaccine

Category I: touching or feeding suspect animals, but skin is intact – no prophylaxis if history is reliable Category II: minor scratches without bleeding from contact, or licks on broken skin – vaccine alone Category III: one or more bites, scratches, licks on broken skin, or other contact that breaks the skin; or exposure to bats – immunoglobulin plus vaccine Rabies immunoglobulin (RIG): dose 20 IU/kg for human RIG or 40 IU/kg of equine RIG; as much as feasible should be infiltrated around the wound and any remainder should be injected at an intramuscular site distant from that of vaccine inoculation Vaccines: intramuscular schedules – (1) “Essen” regimen: one dose of the vaccine on days 0, 3, 7, 14, and 28 in deltoid region or, in small children into the anterolateral area of the thigh muscles; (2) 2-1-1 regimen: two doses on day 0 in the deltoid muscle, right and left arm, one dose in the deltoid muscle on day 7 and one on day 21 Vaccines: intradermal schedules – (1) 8-site intradermal method (8-0-4-0-1-1) for use with HDC and PCECV (both vaccines at 0.1 mL per intradermal site); (2) 2-site intradermal method (2-2-2-0-1-1 or 2-2-2-0-2) for use with PVRV and PCECV (0.1 mL per intradermal site for PVRV and 0.2 mL for PCEVC or 0.1 mL as an option) Previously vaccinated persons: vaccination schedule – one dose on days 0 and 3. The dose is either 1 standard intramuscular dose (which may be 1 mL or 0.5 mL depending on vaccine type) or one intradermal dose of 0.1 mL per site. However, full treatment should be given to persons: who received peri- or postexposure treatment with vaccines of unproven potency or who have not demonstrated an acceptable rabies neutralizing antibody titer

Human diploid cell vaccine (HDCV) – single dose: 1 mL; purified chick embryo cell vaccine (PCECV) – single dose: 1 mL; purified duck embryo vaccine (PDEV) – single dose: 1 mL; purified verocell vaccine (PVRV) – single dose: 0.5 mL Pre-exposure prophylaxis Regimen: three doses of vaccine fulfilling WHO requirements on days 0, 7, and 28; a dose is either 1 standard intramuscular dose (0.5 or 1 mL) or 0.1 mL intradermally (if antimalarial chemoprophylaxis is applied concurrently, intramuscular injections are preferable to intradermal) Monitoring and booster: (1) for persons working with live rabies in diagnostic laboratories, research laboratories, vaccine production laboratories, testing every 6 months and booster dose when the titer falls below 0.5 IU/mL; (2) for professionals at permanent risk of exposure to rabies, veterinarians, animal handlers, wildlife officers, etc., testing every year and booster when the titer falls below 0.5 IU/mL.

may be considered (Table 101.1). Pre-exposure vaccination does not eliminate the need for additional therapy after a rabies exposure; it simplifies management by eliminating the need for rabies immune globulin and decreasing the number of doses of vaccine needed.

POSTEXPOSURE TREATMENT Postexposure prophylaxis is highly effective and includes: wound care, infiltration of rabies immune globulin, and vaccine administration (Table 101.2). Attempts to identify, capture, or humanely sacrifice the animal involved should be undertaken immediately and the animal should be tested for the virus. Postexposure treatment is only stopped if the animal is a dog or cat and remains healthy after 10 days.

TETANUS

introduction of a vaccine in 1940s, tetanus is a preventable disease. The spores of the causative organism, Clostridium tetani, are widely distributed in the soil. When introduced into human tissues under anaerobic conditions spores germinate into bacilli and secrete a powerful exotoxin, 10–7 g of which is potentially fatal. The DNA for this toxin is contained in a plasmid.

Introduction Tetanus was known to the ancient Egyptians 3000 years ago, and was described in the medical writings of Hippocrates from Greece and Sushruta from India. The disease is now uncommon in developed countries; however, it remains endemic in developing countries and is an important cause of death worldwide. World Health Organization estimated 72,600 deaths in 2011 in children under 5 years (WHO, 2012). Since the

Clinical findings Clinical characteristics of tetanus can be best understood by the pathophysiology of the disease. Tetanus bacillus secretes two toxins: tetanospasmin and tetanolysin. Tetanolysin damages otherwise viable tissue surrounding the infection and optimizes the conditions for bacterial multiplication, and tetanospasmin causes the

RABIES, TETANUS, LEPROSY, AND MALARIA clinical syndrome of tetanus (Cook et al., 2001). This toxin binds to the membranes of local nerve terminals and if toxin load is high, some enters the bloodstream, from where it diffuses to bind to nerve terminals throughout the body. The toxin is then internalized and transported by retrograde axoplasmic flow to the cell body via motor, sensory, and autonomic axons. The toxin further moves to the brainstem by retrograde axonal transport and transsynaptic spread. The toxin exerts its effects on the spinal cord and brainstem through inhibitory neurons by inhibiting the release of inhibitory neuro-transmitters, glycine and g-aminobutyric acid (GABA). With the abolishing of central inhibition, both somatic and autonomic nervous systems become hyperactive (Farrar et al., 2000; Cook et al., 2001). The diagnosis of tetanus is clinical and does not require demonstration of C. tetani. Tetanus can be localized at the site of injury causing local rigidity and pain. Generalized tetanus is the most common form of the disease and the classic clinical triad includes: trismus, muscle rigidity, and reflex spasms. Marked muscle rigidity

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interferes with chest movements and impairs both cough and swallowing reflexes. Tetanic spasms are initially stimulus-sensitive, but later are spontaneous and may occur several hundred times a day. Laryngeal spasms are the most feared form of spasm and may cause immediate asphyxia. Generalized tetanic spasms cause simultaneous contraction of both agonist and antagonist groups of muscles and grimacing of the face (risus sardonicus) (Fig. 101.3A). The spasms chiefly affect the axial, trunk, and proximal muscle groups, sparing the distal muscles. In neonates, however, spasms may be clonic in nature (Fig. 101.3B) and when associated with fever can be mistaken for intracranial infection (Dastur, 1984). Tetanus characteristically occurs in four clinical situations: (1) a newborn child whose umbilical cord is cut with an unsterile instrument; (2) a child with otorrhea into whom spores may be introduced while indulging in ear probing with, e.g., a wire or matchstick; (3) a woman in whom unsterile handling of the genital tract allows organisms to gain access; (4) in injury,

Fig. 101.3. (A) Risus sardonicus. Contraction of facial muscles, retraction of the upper lip and angles of the mouth, narrowing of the palpebral fissures with wrinkling of the forehead (not seen here) give rise to the typical sneering appearance. (B) Opisthotonus in neonatal tetanus. Note clenched hands and flexed limbs.

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which is often trivial in civilian practice; this last situation accounts for more than half of the total cases of tetanus. A virulent form of tetanus can follow intramuscular injections with contaminated needles and also occurs in patients with peripheral vascular disease complicated by gangrene and tissue necrosis. The incubation period can be as short as 24 hours or as long as many months. Certain atypical forms of tetanus have been recognized: (1) cephalic tetanus: the paradoxical muscle paralysis seen in cephalic tetanus is due to the initial inactivation of cranial nerve motor neurons by the high local concentration of the toxin; (2) board-like rigidity of the local muscles seen in local tetanus in patients partially immunized is due to centripetal spread of the toxin and little access of the toxin to the bloodstream.

COMPLICATIONS Pulmonary infection is common in patients with tetanus. Aspiration of secretions results from impaired cough or swallowing. Poor movements of the thoracic cage and diaphragm cause collapse of small lung units. Autonomic disturbances usually start on day 4 and persist for 1–3 weeks and may include life-threatening cardiac arrhythmias or sudden cardiac or respiratory arrest. Vertebral fractures of the dorsal spine can occur during severe spasms. Myositis ossificans is occasionally found on recovery with calcium deposits in the ligaments around a joint, usually the knee and elbow. Surgical excision of the calcified material is the only remedy. Mortality in tetanus, some 10–40%, depends on the disease severity, the medical resources available, and the experience and expertise of care givers.

DIFFERENTIAL DIAGNOSIS Few conditions can be mistaken for classic tetanus. Inflammatory lesions inside the mouth can induce trismus. Generalized dystonic posturing can be due to antipsychotic medications. When the diagnosis is in doubt the patient should be asked to perform maneuvers involving muscle coordination such as walking along a straight line. This readily brings out the stiff musculature in patients with tetanus.

Natural history In tetanus maximal severity occurs by the end of the first week; this is followed by a plateau phase for 2 weeks, and then the disease abates over 4–6 weeks. Predicting the severity of the disease in a newly diagnosed case is difficult. The incubation period is unreliable since toxin production in the wound occurs only with the development of anaerobic conditions. The period of

onset is more reliable and is the time between the first symptoma and the first spasm and reflects the rate of toxin arrival in the central nervous system. The period of onset less than 48 hours is associated with poor prognosis. A more reliable prognostic factor, however, is the frequency and severity of witnessed tetanus spasms.

Management The treatment of tetanus remains empiric and the aims are: (1) to halt the toxin production in the wound; (2) to neutralize the released toxin; and (3) to provide support to the patient until the action of the toxin fixed to the nervous system is exhausted. Wound debridement is an essential step to eradicate tetanus spores. For tetanus bacilli, penicillin remains the standard therapy in most parts of the world, but penicillin is GABA antagonist and may be associated with convulsions; also could synergize the action of the toxin in blocking GABA release. Benzathine benzylpenicillin 2.4  106 units via the intramuscular route (IM) in a single dose provides bactericidal concentrations for 5 days by which time anaerobic conditions within a wound are usually eliminated. Metronidazole, 400 mg rectally every 6 hours or 500 mg every 6 hours intravenously (IV) for 7–10 days, is a safe alternative. Equine antitoxin (antitetanus serum (ATS) 10 000 units IV) can neutralize circulating toxin. Human tetanus immunoglobulin (TIG) in a dose of 1500 units IM is safer and has a half-life of 25 days. Meta-analysis of clinical trials has not found additional intrathecal antitoxin to be of clear benefit (Abrutyn and Berlin, 1991).

RESOURCE POOR SETTINGS Tetanus patients are anxious and should be kept in quiet surroundings in dim light, with minimum sensory stimulation, which is hard to achieve in the emergency department or hospital wards. Thus it is imperative to sedate the patient. Diazepam 5 mg IV is administered every 5 minutes until muscle relaxation is achieved, quiet breathing is restored, and cough and swallowing reflexes are effective. The next imperative is to control the airway. Bedside tracheostomy is often required and regular tracheal toilet is mandatory as secretions can be profuse. With the airway secure and the patient sedated, nasogastric feeds can be started, but aspirations following feeds are a constant hazard. Gastric bleeding from stress ulcers can occur. Caloric expenditure is high in tetanus. Intravenous alimentation is preferred whenever the patient’s condition is unstable. Benzodiazepines are useful drugs to control tetanic spasms and muscle rigidity and enteral diazepam is the preferred choice; large doses (up to 10–15 mg/kg/

RABIES, TETANUS, LEPROSY, AND MALARIA 24 h) are required in cases of severe tetanus. Such high doses of diazepam can be associated with unconsciousness and respiratory depression. Diazepam can alternatively be given by intravenous infusion (200–400 mg/ 24 h). The efficacy of diazepam is most convincingly demonstrable in neonatal tetanus, where mortality has been reduced from 80% to 40%. Magnesium sulphate intravenous infusion has been used to control spasms and autonomic dysfunction but it requires serum magnesium monitoring (Attygalle and Rodrigo, 2002). Sudden respiratory standstill is a feature of severe tetanus. Physical stimuli and intubation should be avoided for fear of provoking laryngeal spasms. High flow oxygen and diazepam 5 mg IV to reduce muscle rigidity forms the initial approach. In neonates high flow oxygen through a nasal catheter may reverse cyanosis and provide a noxious stimulus sufficient for the resumption of respiration.

INTENSIVE CARE UNIT In the 1950s, when it became possible to abolish the tetanic spasms with muscle relaxants and to support respiration with ventilator, the problem of tetanus appeared to have been solved. In fact there was little decline in the mortality in the early years thereafter and autonomic disturbances were recognized for the first time. Today expert intensive care therapy offers the best chances of survival but is extremely expensive and may not be affordable for the majority in developing countries (Udwadia, 1994). The patient is paralyzed with pancuronium 2–6 mg IV and is intubated and connected to a ventilator. Pancuronium is repeated whenever muscle rigidity reappears and the daily dose of pancuronium will be about 40–80 mg. Other neuromuscular blocking agents, vecuronium and atracurium, have also been used. Newer long-acting agents pipecuronium and rocuronium are expensive. As the patient is awake and will be apprehensive, sedation is required: diazepam, or morphine, or fentanyl are used(Cook et al., 2001).

AUTONOMIC DYSFUNCTION Autonomic disturbance is common and the features include sinus tachycardia, hypertension, high cardiac output state, and cardiac arrhythmias. Most of it responds to standard treatment, but hemodynamics at times can be dangerously labile and sudden bradycardia and hypotension can occur, rendering the drug treatment hazardous. If the episodes are recurrent and fail to respond to fluid resuscitation and inotropes, the prognosis can be grave, and sudden cardiac arrest is a risk. In tetanus myoglobinuria can be a complication of repeated spasms; however, oliguric renal failure is rare.

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A successful outcome with intensive care rests heavily on excellent nursing. Tracheal toilet is difficult when secretions may not declare themselves with the patient paralyzed. Regular physiotherapy, X-rays, and arterial blood gas estimations are necessary to monitor respiratory function and to diagnose complications such as atelectasis and pneumothorax, and to prevent infection. Hemodynamic monitoring requires both an arterial and a central venous catheter to be in place. The medical team must be alert for circulatory, respiratory, and metabolic emergencies for at least 1 month’s duration whilst toxin is active in the body. The threat of infection increases over time despite the disease having peaked. If the patient survives this ordeal, however, recovery from tetanus is complete.

Prophylaxis This consists of wound toilet and a booster dose of tetanus toxoid but ATS 1500 units or TIG 250 units should additionally be given to any previously unimmunized individuals.

Active immunization The present immunization schedule requires three doses of triple vaccine in the first year of life, with subsequent booster doses of tetanus toxoid at school entry and at 5–10 year intervals thereafter to maintain a protective antitoxin titer (>0.01 IU/mL). This schedule is followed well in childhood but irregularly thereafter. Many women are therefore unprotected without additional toxoid during pregnancy to prevent neonatal tetanus in their offspring (Roper et al., 2007).

LEPROSY Introduction Leprosy, a chronic mycobacterial infection of the skin and peripheral nervous system caused by Mycobacterium leprae, has affected humans for at least 4000 years. Leprosy probably had its origin in early inhabitants of East Africa and spread worldwide with human migration and trade (Monot et al., 2009). Globally, the annual detection of new cases continues to decline, but pockets with high endemicity still remain in some parts of the developing world. Rates of prevalence and new case detection are 1 case per 10 000 and per 100 000 population. Globally, the annual detection of new cases continued to decline, from 620 638 cases in 2002 to 249 007 in 2008. The global case detection declined by 3.54% during 2008 compared to 2007 (WHO, 2009). The disease manifests as a spectrum, embodied in the Ridley–Jopling classification based on clinical-bateriologic-pathologic features (Ridley and Jopling, 1966) (Table 101.3). For

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Table 101.3 Ridley–Jopling classification Disease

Manifestations

Indeterminate leprosy (I) Tuberculoid leprosy (TT)

The first type of skin lesions with hypopigmented spots Hypopigmented hypoesthetic patches with thickened nerves. Either go to BB stage or get cured. Low infective stage Small and numerous skin lesions Small irregular red lesions Plaques, macules, nodules seen Multiple skin lesions, madarosis, deformities. High infective stage

Borderline tuberculoid leprosy (BT) Borderline leprosy (BB) Borderline lepromatous leprosy (BL) Lepromatous leprosy (LL)

field-based work, however, the “operational classification” proposed by the World Health Organization (1982), based solely on the number of skin lesions as an index of bacteriologic status, is preferred. The heterogeneity of the two systems needs to be recognized and implemented by a harmonizing approach (Lockwood et al., 2007).

Neurology of leprosy The most common clinical pattern of peripheral nerve involvement is mononeuritis multiplex (MM) followed by symmetric polyneuropathy. While the tuberculoid form results in MM, the lepromatous form often produces generalized distal neuropathy. The nerves more commonly affected in leprosy include sural, posterior tibial, ulnar, peroneal, median, and superficial radial nerves (van Brakel, 2005). Other nerves affected by the disease include the greater auricular and facial nerves. Negative sensory phenomena such as anhidrosis, numbness (anesthesia in advanced disease) leading to painless injuries, are frequent. Positive phenomena such as paresthesias (pins and needles), pain (dysesthesias and allodynia), and hyperhidrosis are less common. Although abnormal sensation over a skin lesion is readily detectable, 30% of skin lesions are not associated with sensory changes and occur in patients with multibacillary disease, who are both infectious and at high risk of developing impaired nerve function (International Leprosy Association Technical Forum, 2002). Temperature is the first modality affected, followed by touch and pain. Leprous neuropathy produces a stereotyped picture, with preservation of position sense, noninvolvement of large girdle muscles, and retained muscle stretch reflexes. In a small number of patients, however, the neuropathy tends to be areflexic and pansensory, and is associated with deformities and disabilities (Khadilkar et al., 2008). Sensory and motor Tinel’s sign may be observed on tapping affected nerves. The motor

loss follows the area of the affected nerve. It can be very selective as leprosy tends to affect small nerve twigs as they become superficial, e.g., isolated orbicularis oculi weakness. Thickening of nerves is perhaps the most important clinical sign in leprosy. Tenderness of the thickened nerve and beaded nerve trunks, in the presence of other suggestive features, strongly favor the diagnosis of leprosy but ascertaining the presence of enlarged nerves can be difficult, and there is considerable variation between the examiners in detection rates (Chen et al., 2006). Rarely, leprosy can affect the proximal sensory segments. Involvement of dorsal root ganglia results in severe loss of the proprioceptive sensations resulting in pseudoathetoid movements. (Pandya and Bhakti, 1994). The spinal cord involvement in addition to the dorsal root ganglia has been recently reported (Khadilkar et al., 2007). Pure neuritic-type leprosy, limited to the peripheral nerves with no apparent dermatologic manifestations, is of particular clinical interest to the practicing neurologist. This form accounts for 4–8% of all cases of leprosy. The most frequently involved nerve in the pure neuritic type is the ulnar, followed by the posterior tibial nerve (Mahajan et al., 1996; Mendiratta, 2006). It is believed that the cutaneous component of this form is not detected clinically as the dermal inflammation is deep (Suneetha et al., 1998). As is the case with the other forms of leprosy, sensory symptoms are more frequent than motor symptoms. There is no correlation between the number and distribution of affected nerves and the type of immune response (Wilder-Smith, 2002). Acute and chronic immunologic phenomena known as leprosy reactions tend to cause considerable worsening of nerve function and are most frequent during the first 6 months of multidrug therapy, but may occur even after therapy is completed. Type 1 reactions (also called reversal reactions) are commonly seen in the BB form of leprosy (borderline leprosy) and occur when there is sudden increase in T cell reactivity to mycobacterial

RABIES, TETANUS, LEPROSY, AND MALARIA antigens. Such a reactivity increase mostly occurs in the context of an improved immune response associated with treatment, which moves the disease toward the tuberculoid response pattern. Type 2 reactions, also known as erythema nodosum leprosum, occur in patients with lepromatous disease, and result from widespread immune complex deposition and TNF-a overproduction. Frequent manifestations are skin nodules, neuritis, orchitis, lymphadenitis, arthritis, and iritis (Croft, 2000).

Pathophysiology of nerve damage M. leprae shows specific molecular affinity to Schwann cells via laminin 2 and a-dystroglycan receptors (Rambukkana, 2001). Early M. leprae-induced nerve damage is mediated via ErbB2 receptor tyrosine kinase signaling, which results in nerve demyelination (Tapios et al., 2006). The initial damage is in the small unmyelinated nerve fibers (Markendeya and Srinivas, 2004). This phenomenon might be associated with the fact that a greater number of Schwann cells surround small nerve fibers than large nerve fibers and the superficial sensory fibers of the extremities contain high numbers of small fibers (Wilder-Smith and van Brakel, 2008). Thus Ab and C fibers are also affected early, often subclinically (van Brakel et al., 2008).

Investigations and diagnosis The important signs which form the basis of a clinical diagnosis of leprosy include: anesthetic/hypoesthetic skin patches; a characteristic pattern of cutaneous sensory loss; enlarged, tender nerves; and acid-fast bacilli in slit skin smear (SSS), sensitivity 97%, positive predictive value 98% (Saunderson and Groenen, 2000). Any single sign, except a positive SSS, is inadequate as a diagnostic test. Clinical diagnosis of multibacillary (MB) leprosy employing two signs, namely the number of anesthetic patches and the presence of enlarged nerves, is generally regarded as adequate.

ELECTROPHYSIOLOGY Four sensory (sural, radial cutaneous, median, and ulnar) and four motor (median, ulnar, common peroneal, and posterior tibial) nerves are tested in patients with leprosy. The sural and ulnar are the most frequently and severely affected nerves. Early findings are lowamplitude or unrecordable sensory nerve action potentials and a drop in compound action potential (CMAP) amplitude and slowed motor conduction velocities in the across-elbow segment of the ulnar nerve. The sural nerve is particularly useful since it can be biopsied. Early in the disease, demyelinating features ensue, followed

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by secondary axonal damage. Impaired sudomotor function may be detected by absence of sympathetic skin response (SSR). Electrophysiologic studies are also useful to monitor for toxicity of therapy, particularly thalidomide-associated neuropathy and also dapsone neuropathy.

RADIOLOGY Magnetic resonance imaging (MRI), ultrasound (US), and computed tomography (CT) can be used to examine peripheral nerves in patients with leprosy (Slim et al., 2009) (Fig. 101.4 A–C). Martinoli et al. (2000) classified the patients with leprosy into three groups based on ultrasonographic and MRI findings: group I – normal-appearing nerves; group II – enlarged nerves with fascicular abnormalities; and group III – nerves with an absence of fascicular structure (Fig. 101.4B, C). The overall sensitivity of MRI to detect clinically recognized active type 1 reaction is 92% (Martinoli et al., 2000). High-frequency Doppler US has been used to study nerves in leprosy. The affected nerve is seen to have fusiform enlargement. The enlarged peripheral nerves seem to be assessed more accurately with US than with clinical examination (Jain et al., 2009). Color Doppler US shows increased vascularity in most patients with leprosy reactions (type 1 and 2). The overall sensitivity of Doppler US to detect clinically recognized active reversal reaction is 74% (Martinoli et al., 2000). Ultrasonography and MRI during type 2 reaction show lesser findings.

SEROLOGY Even though many serologic markers have been evaluated in leprosy, few have direct application. The most widely studied test is that for anti-PGL-1 (phenolic glycolipid-1) antibodies. PGL-I antibody testing has been reported to be helpful in the early detection of MB relapse and may have a role in detecting preclinical infection. Newer serologic tests based on recombinant technology may eventually be used in the field to trace the disease in contacts and in the general population (International Leprosy Association Technical Forum, 2002; Aseffa et al., 2005).

BIOPSY Material from a skin biopsy specimen can be used for a variety of purposes: slit skin smear, histopathologic examination, immunohistopathology, and “culture” of M. leprae in the mouse foot pad. Slit skin smears, when positive, directly demonstrate the presence of M. leprae, with a near 100% specificity. However, the sensitivity of

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Fig. 101.4. Demonstrates thickened peroneal nerve with MRI axial view of popliteal fossa (A) and ultrasound pictures of irregularly thickened peroneal nerve in a case of lepromatous leprosy in transverse section (diameter: 0.33  1.03 cm) (B), and longitudinal section marked with white arrows (C).

smears is low, 50% at best. Positive smears indicate the most infectious group of patients. Histopathologic examination shows the presence of granulomas and may show bacilli (Fig. 101.5A–C). In practice, most studies employ a combination of clinical and histopathologic abnormalities. Immunohistopathologic techniques offer increased sensitivity and specificity of the diagnosis of leprosy (Weng et al., 2001). Biopsy of a clinically involved cutaneous nerve may be more informative than routine biopsy of sural or radial cutaneous nerve. Nerve biopsy reveals macrophages and Schwann cells filled with bacilli and debris with numerous bacilli in LL (lepromatous leprosy) cases and caseating granulomas with few or undetectable bacilli in TT (tuberculoid leprosy) cases.

Treatment of leprosy Treatment approaches to leprosy include both antibacterial and anti-inflammatory therapy. Since 1982, leprosy has been treated with multidrug therapy (MDT) combining three drugs, in order to prevent antimicrobial resistance (Table 101.4). A single dose of the combination of rifampicin, ofloxacin and minocycline (ROM) for single lesion PB (paucibacillary) leprosy may be considered in the countries where the proportion of single lesion PB leprosy patients is large, as in India. Recently, uniform MDT (U-MDT) incorporating MDT of 6 months for both PB and MB leprosy has been proven to be equally effective for skin lesions. However, the long-term outcome is

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Fig. 101.5. Large number of solidly stained bacilli (viable) within a Schwann cell as seen under electron microscope (80 000 ) in sural nerve biopsy in a case of lepromatous leprosy (A). Epithelioid cells granulomas around adnexal structures in skin biopsy from a case of tuberculoid leprosy. Inset shows details of granuloma (stained with H&E mag 4 /40) (B). Dermis showing perivascular, periadnexal aggregates of foamy macrophages in skin biopsy from a case of lepromatous leprosy. Inset shows details of foamy macrophages (H&E 4 /40) and bacilli on Fite Farraco stain (C). (Figure courtesy of the Department of Pathology, Grant Medical College and FMR, Mumbai, India.)

Table 101.4 WHO-recommended multidrug leprosy regimens Type of leprosy

Drug treatment

Paucibacillary Multibacillary

Monthly supervised Rifampicin 600 mg Rifampicin 600 mg Clofazimine 300 mg

awaited (Kroger et al., 2008). The strategy “Final Push” advocated by WHO is expected to promote the elimination of leprosy. Prevention of new nerve damage in leprosy remains a challenge, with early detection being the key in preventing deformities (van Brakel, 2000).

Duration of treatment Daily, self-administered Dapsone 100 mg Clofazimine 50 mg Dapsone 100 mg

6 months 12 months

Anti-inflammatory treatment in leprosy has been more widely used in recent years. In 60–70% of patients with nerve involvement, corticosteroids have been shown to improve nerve function. However, the dosage and duration of prednisolone therapy is not yet

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standardized. The trend seems to be towards longer duration, higher dosage therapy (Richardus, 2003; Britton and Lockwood, 2004; van Veen, 2008). The WHO currently recommends a regimen of 12 weeks of prednisolone in tapering doses for ENL (erythema nodosum leprosum). For the two types of reactions, different protocols have been suggested (Lockwood and Kumar, 2004). Reports have cautiously recommended the use of thalidomide for the management of ENL, particularly in men and postmenopausal women (Bastuji-Garin, 2002; Walker, 2007). The effects of prophylactic use of steroids in newly diagnosed cases are under evaluation. The initial observations suggest short-term benefit (Smith et al., 2004). Other immunosuppressive agents such as azathioprine, ciclosporin, methotrexate, and pulse methylprednisolone are also under evaluation (Marlowe, 2004; Sena et al., 2006). Surgical decompression of nerves (neurolysis) that show functional impairment is sometimes performed as an additional form of treatment; however, the efficacy of this approach has not been conclusively demonstrated (van Veen, 2008). Future therapeutic research is expected to focus further on nerve function improvement. In this regard, systematic studies of steroid regimens with different duration and dosages, use of other immune suppressants and neurolysis surgery need to be evaluated.

MALARIA: NEUROLOGIC COMPLICATIONS Introduction Malaria is a protozoan disease cased by four species of the genus Plasmodium: P. falciparum, P. vivax, P. ovale, and P. malariae. Recently P. knowlesi has also been reported to cause human malaria in Southeast Asia (Mishra and Wiese, 2009). Cerebral malaria is mainly caused by P. falciparum and occasionally also by P. vivax monoinfection

(Kochar et al., 2009). Malaria is endemic in most countries, except the US, Canada, Europe, and Russia. Malaria accounts for 1.5–2.7 million deaths annually, mainly from cerebral malaria, other severe complications, and multiorgan dysfunction (WHO, 2000). Humans are infected by the bite of female Anopheles mosquito, inoculating the plasmodial sporozoite into the body which rapidly enters the hepatocyte and after multiplication releases around 30 000 merozoites into the bloodstream, which in turn invade the RBCs and multiply by 20-fold every 48 hours through the erythrocytic cycle. Some parasites develop into gametocytes, which are taken by the mosquito during a blood meal. At the end of the cycle in the mosquito numerous motile sporozoites are produced which spread the infection to another human during subsequent blood meal (Fig. 101.6) (Talman et al., 2004).

Neurologic manifestations CEREBRAL MALARIA For research purposes cerebral malaria is defined as “unarousable coma (GCS 10 or Blantyre scale 3) with presence of asexual parasites in blood and in which locally prevalent encephalitis and meningitis has been ruled out by appropriate tests.” However, every patient with malaria with altered mental state and abnormal behavior should be treated for cerebral malaria until proved otherwise. The onset of coma in patients with cerebral malaria may be either gradual or abrupt, with or without seizures (WHO, 2000). The clinical features of cerebral malaria include signs of diffuse symmetric encephalopathy, focal or generalized convulsions including convulsive status epilepticus (SE), and increased muscle tone. Muscle stretch reflexes are variable and plantar responses may be extensor. Neck stiffness and positive Kernig’s sign may be present.

Fig. 101.6. Life cycle of malarial parasite in human and mosquito.

RABIES, TETANUS, LEPROSY, AND MALARIA However, cerebrospinal fluid (CSF) examination is usually normal. Extrapyramidal signs, pout reflex, bruxism, and exaggerated tendon reflexes may be present. Cranial nerve involvement, nystagmus, dysconjugate eye deviation, and abnormal oculovestibular and oculocephalic reflexes may be present. In advanced stages, decerebrate and decorticate rigidity are frequently observed (Mishra and Newton, 2009). Examination of the ocular fundi may show retinal hemorrhages, exudates, and papilledema (Maude et al., 2009). Other associated severe manifestations of malaria which contribute to the onset and depth of coma include: hypoglycemia, hyperpyrexia, shock, renal failure, severe anemia, acute respiratory distress syndrome (ARDS) and pulmonary edema (WHO, 2000). The disease is often severe in children, nonimmune travelers, and pregnant women. The mortality in cerebral malaria is high in spite of adequate and meticulous treatment. Neurologic sequelae are common in a significant number of survivors and include: aphasia and other language disturbances, hemiplegia, cerebellar ataxia, cortical blindness, deafness, cranial and peripheral neuropathy, extrapyramidal features, impaired cognition, learning disabilities, and psychosis (Kochar et al., 2002). The sequelae may be transient or may persist for a longer period, especially in children. Studies from the African continent suggest an increase in the incidence of epilepsy (Ngoungou and Preux, 2008; Opoka et al., 2009), everyday memory (Kihara et al., 2009) and long-term cognitive impairment (Kihara et al., 2006) among the surviving children.

OTHER COMPLICATIONS Isolated case reports of peripheral and cranial neuropathy, asterixis, acute disseminated encephalomyelitis, and periodic paralysis complicating malaria have been reported. However, their association with malaria has not been well defined (Garg et al., 1999). Chakravarty et al. (2004) reported 12 patients with Guillain–Barre´ syndrome (GBS) following malarial illness; nine of them presented with distal symmetric sensory deficits and motor weakness was mild in seven patients. All the patients made complete recovery with no specific treatment over a period of 2–6 weeks. Cerebellar ataxia can be the manifestation in the acute febrile stage or as neurologic sequelae. Delayed cerebellar ataxia, a type of postmalaria neurologic syndrome, is a distinct entity reported from Sri Lanka and India and is supposed to be due to immune-mediated pathology (Kochar et al., 1999; Markley and Edmond, 2009).

Diagnosis The diagnosis of malaria is essentially clinical and is confirmed by the demonstration of presence of parasites in the peripheral smear or immunologic tests for parasite derived proteins (rapid diagnostic tests, RDTs).

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Fig. 101.7. Peripheral blood smear examination shows heavy parasitemia with ring stage of P. falciparum.

Microscopy of stained thick and thin peripheral blood smear (PBF) remains the gold standard for confirmation of malaria (Fig. 101.7). It is cost effective, fairly sensitive, and highly specific. It helps in knowing the exact species and quantification of parasites, and also in assessing response to antimalarial treatment. RDTs are based on the detection of circulating parasite antigen in whole blood. These tests are fairly sensitive and specific and can be done in the field situation. These tests are good to study the speices but not for quantification of parasites. Quantitative buffy coat (QBC) test using fluorescent dye and polymerized chain reaction (PCR) can also be used for the diagnosis. The sensitivity of PCR assay is very high and it can detect even one parasite per mL of blood.

NEUROIMAGING Significant hemorrhage or infarction with resultant edema can be detected in cerebral malaria by using conventional T1-weighted and T2-weighted imaging. Susceptibility-weighted imaging (SWI) sequences are more sensitive in the detection of small hemorrhages and the imaging findings correlate much more closely with the expected pathologic findings of diffuse petechial hemorrhages. The SWI sequences may play a significant role in accelerating the diagnosis (Nickerson et al., 2009). The underlying mechanisms responsible for coma in cerebral malaria are still unknown. Magnetic resonance imaging techniques may offer noninvasive means to study the anatomic substrates, metabolic, biochemical, and functional basis of the pathogenesis of cerebral malaria. Such an understanding may help in the development of neuroprotective agents in cerebral malaria.

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Pathogenesis The pathogenesis of malaria remains incompletely understood but the important observation includes mechanical blockade, sequestration of parasitized RBC, release of toxins, immunologic changes, and cytokine release. During the erythrocyte cycle, the parasite changes the RBC membrane characteristics such as its transport properties, exposing cryptic surface antigens and incorporating new parasite-derived protein. It becomes irregular in shape, rigid, and less deformable. The membrane protuberances appear on the RBC surface after 12–15 hours of P. falciparum invasion and these knobs extrude a high molecular weight antigenically variant strain-specific erythrocyte membrane protein (PfEMP1) which helps in its attachment to the receptors of the venular and capillary endothelium, cytoadherence. The important vascular ligands for cytoadherence are intracellular adhesion molecule 1 (ICAM-1) in the brain, chondroitin sulfate in the placenta, and CD36 in most other organs (Fig. 101.8). Plasmodium falciparum-infected RBCs also adhere to the uninfected RBCs to form rosettes and with other

infected RBCs to form agglutination. The combination of cytoadherence, rosetting, and agglutination results in sequestration of RBC in the capillaries and venules of the brain causing interference with microcirculation and tissue metabolism. It also helps the parasitized RBCs to escape the splenic processing and filtration. Various cytokines such as interferon g (IFN-g), IL4, IL2 and IL3, tumor necrosis factor a (TNF-a), interleukin 1 (IL1) and IL6 which are released from macrophages and mononuclear cells also play an important role in the pathogenesis. Inducible nitric oxide syntheses (INOS) and nitric oxide (NO) have an important role in the persistence of coma (Oleinikov et al., 2009). Histopathologic examination of the brain shows gross congestion and petechial hemorrhages in the white matter. Ring hemorrhages are a striking feature, consisting of central blocked vessel due to parasitized RBCs, surrounded by brain tissue, then by a ring of extravasated RBCs. Parasites are sometimes present at the periphery of hemorrhage. In older hemorrhages, there is necrosis and reaction of small glial cells, so-called malarial granuloma.

HA P Selectin E – Selectin

Modified Band – 3

PfEMP – 3

ICAM – 1 KAHRP CD – 36

PfEMP – 1

TSP VCAM – 1 CSA

Sequestrin

TM HA PECAM – 1

Endothelial Cell

CLAG RIFIN

Parasitized RBC

Fig. 101.8. Role of different ligands on parasitized RBC and endothelial cells in cytoadherence. Principal ligand on the knob of infected RBC is the variant antigen plasmodium falciparum erythrocyte membrane protein 1 (PfEMP-1), anchored beneath to the knob-associated histidine rich protein (KAHRP), and is stabilized by PfEMP-3. There is no direct role of rifin and CLAG gene products in adhesion but the latter is required for cytoadherence. Parasite modified band 3 (the major anion transporter) and Sequestrin contributes to adhesion. On the vascular endothelial side, the important molecules which facilitate the adhesion by binding to PfEMP1 is the. Intercellular adhesion molecule 1 (ICAM-1) in the brain and cellular differentiation antigen: CD-36 elsewhere. Chondroitin sulphate A (CSA) attached to thrombomodulin (TM) and hyaluronic acid (HA) are important for placental sequestration. Other adhesion molecules are vascular cell adhesion molecule 1 (VCAM1), E-selectin, platelet endothelial cell adhesion molecule-1 (PECAM-1), avb3 integrin, heparan sulphate (HS) and P-selectin.

RABIES, TETANUS, LEPROSY, AND MALARIA

Management Cerebral malaria is a medical emergency and should be treated urgently and preferably in the intensive care setting. The principles of management include: specific antimalarial drug treatment, care of the unconscious patient, symptomatic treatment, and treatment of associated complications. If parasitologic confirmation is likely to be delayed, specific antimalarial therapy should be started immediately even on the basis of clinical diagnosis. Irrespective of resistant status prevalent in the region, all patients should be treated with parenteral artemisinin derivatives or quinine; however, based on the evidence of many recent studies, IV artesunate should be preferred in adults. Artesunate should be administered in the dose of 2.4 mg/kg bodyweight IV on admission, at 12 hours and 24 hours, and then once a day for 7 days. Alternatively artemether or artether can be used parentally. Once the patient can tolerate oral therapy, he should receive complete dosage of artemisinin-based combination therapy (ACT) for 3 days. Alternatively, quinine is given as loading dose of 20 mg salt/kg to be diluted in glucose or glucose normal saline followed by 10 mg/kg bodyweight every 8 hours, and the infusion should take a minimum of 4 hours. Later on, treatment should be switched to oral therapy to complete the 7 days of treatment along with doxycycline (3 mg/kg once daily) or clindamycin (10 mg/kg twice daily), except for pregnant women and children less than 8 years of age for whom doxycycline is contraindicated. The loading dose of quinine is not given if the patient has taken oral quinine or mefloquine in the previous 24 hours. The dose of quinine is reduced to 5–7 mg/kg bodyweight if IV therapy is continued after 48 hours. The dose of artemisinin does not require any adjustment. The hyperpyrexia is treated by tepid sponging and paracetamol. Convulsions are treated by intravenous lorazepam followed by loading dose of phenytoin or fosphenytoin. Convulsive status should be treated as for the protocols. Hypoglycemia is very common in children and pregnant women and should be treated by IV 25% glucose. Blood transfusion is generally recommended if the hemoglobin level is < 5 g/100 mL (haematocrit < 15%). Other associated complications, such as acute kidney injury, hepatic failure, acute lung injury and acute respiratory distress syndrome, acidosis, electrolyte imbalance, coagulopathy, and shock, require early recognition and appropriate emergency management. A close monitoring of pregnant women is essential because of high incidence of pulmonary edema and hypoglycemia. Parenteral artesunate is preferred in the second and third trimesters, whereas quinine is the drug of choice in the first trimester. There is no evidence for the use of heparin, prostacyclin, desferrioxamine, pentoxifylline, low molecular

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weight dextran, urea, high-dose corticosteroids, acetylsalicylic acid, anti-tumour necrosis factor antibody, ciclosporin, dichloroacetate, adrenaline, and hyperimmune serum in the management, and their use should be avoided (WHO, 2010).

Malaria vaccine A malaria vaccine, deployed in combination with current malaria-control tools, could play an important role in future control and eventual elimination of malaria. The RTS,S vaccine, which targets the circumsporozoite protein, has been shown consistently to offer protection against Plasmodium falciparum malaria in children and infants in phase 2 trials. The first preliminary results of a phase 3 trial of RTS,S/AS01 malaria vaccine (full results are expected in 2014) shows reduction in clinical episodes of malaria and severe malaria by approximately half during the 12 months after vaccination in children 5–17 months of age. Despite the relatively high vaccine efficacy against severe malaria, there was no reduction in the rate of death from malaria or from any cause in this group (Agnandji et al., 2011).

Future research Future research areas include understanding of the pathogenesis, and identification of newer antimalarial and effective adjuvant molecules. There is growing evidence that erythropoietin has a neuroprotective role in cerebral malaria (Casals et al., 2009) Possible roles for other agents such as compounds preventing platelet aggregation, statins, immunomodulators, hyperbaric oxygen, or antiapoptosis agents have also been suggested. In the near future, MRI studies with novel contrast media may reveal pathologic changes in the brain which are not detected by conventional MRI. The application of time-of-flight magnetic resonance angiography (TOF-MRA), diffusionweighted (DWI) images, measurement of cerebral blood flow using arterial spin labeling (ASL) techniques, proton magnetic resonance spectroscopy (1H MRS) may be able to solve the questions related to the pathogenesis of cerebral malaria (Looareesuwan et al., 2009).

ACKNOWLEDGEMENTS Dr. J.M.K. Murthy wishes to sincerely thank Dr. C. Sundaram for providing the pathology of rabies and Dr. S. Sita Jayalaxmi for the MRI. Dr. S.V. Khadilkar wishes to sincerely thank Dr. Pramod Dhonde, Department of Neurology, Grant Medical College and Sir J.J. Group of Hospitals, and Dr. Vanaja Shetty, Foundation for Medical Research, Mumbai, for their help. Thanks are also due to Dr. S.S. Pandya for her input into the preparation of the manuscript.

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RABIES, TETANUS, LEPROSY, AND MALARIA Laothamatas J, Hemachudha T, Mitrabhakdi E et al. (2003). MR imaging in human rabies. AJNR Am J Neuroradiol 24: 1102–1109. Lockwood DN, Kumar B (2004). Treatment of leprosy. Br Med J 328: 1447–1448. Lockwood DN, Sarno EN, Smith WCS et al. (2007). Classifying leprosy patients – searching for the perfect solution? Lepr Rev 78: 317–320. Looareesuwan S, Laothamates J, Brown TR et al. (2009). Cerebral malaria. A new way forward with magnetic resonance imaging (MRI). Am J Trop Med Hyg 81: 545–547. Madhusudana SN, Nagaraja D, Uday M et al. (2002). Partial recovery from rabies in a six-year-old girl. Int J Infect Dis 6: 85–86. Mahajan PM, Jogaikar DG, Mehta JM et al. (1996). A study of pure neuritic leprosy: clinical experience. Indian J Lepr 68: 137–141. Mani J, Reddy BC, Borgohain R et al. (2003). Magnetic resonance imaging in rabies. Postgrad Med J 79: 352–354. Markendaya N, Srinivas CR (2004). Ninhydrin sweat test in leprosy. Indian J Lepr 76 (4): 299–304. Markley JD, Edmond MB (2009). Post- malaria neurological syndrome: a case report and review of the literature. J Travel Med 16: 424–430. Marlowe SN (2004). Clinical outcomes in a randomized controlled study comparing azathioprine and prednisolone versus prednisolone alone in the treatment of severe leprosy type 1 reactions in Nepal. Trans R Soc Trop Med Hyg 98: 602–609. Martinoli C, Derchi LE, Bertolotto M et al. (2000). US and MR imaging of peripheral nerves in leprosy. Skeletal Radiol 29: 142–150. Maude RJ, Dondrop AM, Sayeed AA et al. (2009). The eye in cerebral malaria: what can it teach us? Trans R Soc Trop Med Hyg 103 (7): 661–664. Meltzer MI, Rupprecht CE (1998). A review of the economics of the prevention and control of rabies: part 1, global impact and rabies in humans. Pharmacoeconomics 14: 365–383. Mendiratta V (2006). Primary neuritic leprosy: a reappraisal at a tertiary care hospital. Indian J Lepr 78: 261–267. Mishra SK, Newton RJCC (2009). Diagnosis and management of the neurological complications of falciparum malaria. Nat Rev Neurol 5: 189–198. Mishra SK, Wiese L (2009). Advances in the management of cerebral malaria in adults. Curr Opin Neurol 22: 302–307. Monot M, Honore N, Garnier T et al. (2009). Comparative genomic and phyleogeographic analysis of Mycobacterium leprae. Nat Genet 41: 1282–1289. Muhamuda K, Madhusudana SN, Ravi V et al. (2006). Presence of rabies specific immune complexes in cerebro-spinal fluid can help in ante-mortem diagnosis of human paralytic rabies. J Clin Virol 37: 162e7. Murthy JMK (1998). MRI in acute disseminated encephalomyelitis following Simple antirabies vaccine. Neuroradiology 40: 420–423. Ngoungou EB, Preux PM (2008). Cerebral malaria and epilepsy. Epilepsia 49 (Suppl. 6): 19–24.

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Nickerson JP, Tong KA, Raghavan R (2009). Imaging cerebral malaria with a susceptibility-weighted MR sequence. AJNR Am J Neuroradiol 30: E85–E86. Oleinikov AV, Amos E, Frye IT et al. (2009). High throughput functional assays of the variant antigen PfEMP1 reveal a single domain in the 3D7 Plasmodium falciparum genome that binds ICAM1 with high affinity and is targeted by naturally acquired neutralizing antibodies. PLoS Pathog 5: e1000386. Opoka RO, Bangirana P, Boivin MJ et al. (2009). Seizure activity and neurological sequelae in Ugandan children who have survived an episode of cerebral malaria. Afr Health Sci 9: 75–81. Pandya SS, Bhakti WS (1994). Severe pansensory neuropathy in Leprosy. Int J Lepr Other Mycobact Dis 62: 24–31. Pleasure SJ, Fischbein NJ (2000). Correlation of clinical and neuroimaging findings in a case of rabies encephalitis. Arch Neurol 57: 1765–1769. Porras C, Barboza JJ, Fuenzalida E et al. (1976). Recovery from rabies in man. Ann Intern Med 85: 44–48. Rambukkana A (2001). Molecular basis for the neural predilection of Mycobacterium leprae. Curr Opin Microbiol 4: 21–27. Richardus JH (2003). Treatment with corticosteroids of long standing nerve function impairement in leprosy: a randomized controlled trial (TRIPOD 3). Lepr Rev 74: 311–318. Ridley DS, Jopling WH (1966). Classification of leprosy according to immunity – a five group system. Int J Lepr 34: 255–273. Roper MH, Vandelaer JH, Gasse FI (2007). Maternal and neonatal tetanus. Lancet 370: 1947–1959. Saunderson P, Groenen G (2000). Which physical signs help most in the diagnosis of leprosy? A proposal based on experience in the AMFES project, ALERT, Ethiopia. Lepr Rev 71: 34–42. Sena CB, Salgado CG, Tavares CM et al. (2006). Cyclosporine A treatment of leprosy patients with chronic neuritis is associated with pain control and reduction in antibodies against nerve growth factor. Lepr Rev 77: 121–129. Sing TM, Soo MY (1996). Imaging findings in rabies. Australas Radiol 40: 338–341. Slim FJ, Faber WR, Mass M et al. (2009). The role of radiology in nerve function impairment and its musculoskeletal complications in leprosy. Lepr Rev 80: 373–387. Smith J, McElhinney L, Pearson G et al. (2003). Care report: rapid antemortem diagnosis of a human case of rabies imported into the UK from the Philippines. J Med Virol 69: 150–155. Smith WC, Anderson AM, Withington SG et al. (2004). Steroid prophylaxis for prevention of nerve function impairment in leprosy: randomised placebo controlled trial (TRIPOD 1). Br Med J 328: 1459. Solomon T, Martson D, Mallewa M et al. (2005). Paralytic rabies after a two week holiday in India. Br J Med 331: 501–503. Suneetha S, Arunthathi S, Chandi S et al. (1998). Histological studies in primary neuritic leprosy: changes in the apparently normal skin. Lepr Rev 69: 351–357.

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Talman AM, Domarle O, McKenzie FE et al. (2004). Gametocytogenesis: the puberty of plasmodium falciparum. Malar J 3: 24. Tapinos N, Ohnishi M, Rambukkana A (2006). ErbB2 receptor tyrosine kinase mediates early demyelination induced by leprosy bacilli. Nat Med 12: 961–966. Tillotson JR, Axelrod D, Lyman DO (1977). Rabies in a laboratory worker–New York. MMWR Morb Mortal Wkly Rep 26: 183–184. Udwadia FE (1994). Tetanus. Oxford University Press, Bombay. van Brakel WH (2000). Peripheral neuropathy in leprosy and its consequences. Lepr Rev 71 (Suppl): S146–S153. van Brakel WH (2005). The INFIR cohort study: investigating prediction, detection and pathogenesis of neuropathy and reactions in leprosy. Methods and baseline results of a cohort of multibacillary leprosy patients in north India. Lepr Rev 76: 14–34. van Brakel WH, Nicolls PO, Wilder Smith EP et al. (2008). Early diagnosis of neuropathy in leprosy– comparing diagnostic tests in a large prospective study (the INFIR cohort study). PLoS Negl Trop Dis 2: 1–12. van Veen NH, Nicholls PG, Smith WC et al. (2008). Corticosteroids for treating nerve damage in leprosy. A Cochrane review. Lepr Rev 79 (4): 361–371. Walker SL (2007). The role of thalidomide in the management of erythema nodosum leprosum. Lepr Rev 78: 197–215. Weng XM, Chen SY, Ran SP et al. (2001). Immunohistopathology in the diagnosis of early leprosy. Int J Lepr 68: 426–433. Wilder-Smith E (2002). Diagnosis of pure neuritic leprosy. Neurol J Southeast Asia 7: 61–66. Wilder-Smith EP, van Brakel WH (2008). Nerve damage in leprosy and its management. Nat Clin Pract Neurol 4 (12): 656–663.

Willoughby RE Jr, Tieves KS, Hoffman GM et al. (2005). Survival after treatment of rabies with induction of coma. N Engl J Med 352: 2508–2524. World Health Organization (1982). Chemotherapy of Leprosy for Control Programmes. Technical Report Series 675World Health Organization, Geneva. World Health Organization (1992). Expert Committee on Rabies. Eighth Report Technical Report Series 824World Health Organization, Geneva. World Health Organization (1996). In: F-X Meslin, MM Kaplan, H Koprowski (Eds.), Laboratory Techniques in Rabies. 4th edn. World Health Organization, Geneva. World Health Organization (1997). WHO recommendation on rabies post-exposure treatment and the correct technique of intradermal immunization. Geneva: WHO/EMC/ZOO/96.6, pp 1–24. http://www.who.int/emc-documents/rabies/ whoemczoo966.hmt. accessed March 8, 2010. World Health Organization (2000). Communicable diseases cluster. Severe falciparum malaria. Trans R Soc Trop Med Hyg 94 (Suppl 1): S1–S90. World Health Organization (2008). Fact Sheet. No 99; December 2008, http://www.int/mediacentre/factsheets/ fs099/en/accessed on 20-6-2010. World Health Organization (2009). Global leprosy situation. Wkly Epidemiol Rec 84 (33): 333–340. http://www.who. int/wer, accessed on June 24, 2010. World Health Organization (2010). Guidelines for the treatment of malaria. World Health Organization, Geneva. World Health Organization (2012). Tetanus Surveillance deaths in children under 5 Years. http://www.who.int/ immunization_monitoring/diseases/tetanus/en/index.html. accessed August 10, 2013.

Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 102

Tropical myelopathies GUSTAVO C. ROMA´N* Department of Neurology, Weill Cornell Medical College, Methodist Neurological Institute, Houston, TX, USA

INTRODUCTION The term tropical myelopathies addresses the multiple disorders of the spinal cord occurring in the tropics, i.e., the parts of the world situated between 23
270 latitude north and south of the Equator between the tropics of Cancer and Capricorn. This geographic definition includes most of Africa, Latin America, Asia, and Oceania. In addition to warm temperatures, days and nights of equal length, and abundant sunlight exposure, other environmental factors play a major role in determining the pattern of neurologic pathologies affecting the inhabitants of the tropics. According to Poser and Poser (2006), in tropical regions: highly influential environmental factors include extreme poverty, famine and malnutrition; lack of medical care and/or access to it; inadequacy or total lack of public health organization; war and political instability together with the population dislocations that ensue; gender and ethnic—cultural discrimination and infringement of civil rights, racial and religious persecution; climatic catastrophes such as tsunamis, earthquakes or typhoons; as well as tribal, cultural and family traditions. Many of these problems derive from what may well be the single-most important adverse environmental factor, overpopulation. It is a combination of these factors along with genetic profiles more than warmth and humidity that define tropical or developing countries. Many of what we now call tropical diseases were, at one time, widespread: leprosy, malaria, cholera and plague were well known in Western countries and temperate climates. In summary, the principal determinants of neurologic diseases in underdeveloped countries are lack of

education and poor socioeconomic conditions (Toro et al., 1983; Roma´n, 2005; Poser and Poser, 2006). The multiple causes of spinal cord injury in the tropics include etiologies also seen in temperate regions (Table 102.1). The recent introduction of brain and spinal cord imaging, in particular computed tomography (CT) and magnetic resonance imaging (MRI), in tropical countries has allowed a better definition of the magnitude of these pathologies. For instance, in Tanzania, Zellner et al. (2010) compared rural and urban spinal pathologies on CT/MRI of the spine demonstrating the preponderance of infectious extradural-extramedullary pathologies (tuberculosis and brucellosis) in the rural areas presenting with lumbar pain; in comparison, common pathologies were observed in the city of Dar es Salaam, including herniated discs and disc protrusions (81%) followed by spinal canal stenosis (7%), fractures of vertebrae (4.4%), and a lesser number of infections – in particular tuberculosis (Pott’s disease), as well as inflammatory lesions such as ankylosing spondylitis, and metastatic cancer. Overall, intradural-extramedullary lesions were rare (meningioma, neurofibroma). Intramedullary pathologies included syringomyelia, congenital anomalies, vascular malformation, myelitis, chronic myelopathy, and demyelinating diseases including multiple sclerosis (MS), granulomatous lesions (tuberculosis, sarcoidosis), ependymoma, astrocytoma, metastases, and spinal cord trauma. In large areas of the tropical world, including Africa and the Middle East, the Caribbean, Venezuela and Brazil, bilharziasis or schistosomiasis, a parasitic disease of the spinal cord, is a leading cause of intramedullary pathology. In the tropics, myelopathies are often accompanied by concurrent involvement of peripheral nerves, hence the term “tropical myeloneuropathies” used to describe this group of disorders (Roma´n, 1984;

*Correspondence to: Gustavo C. Roma´n, M.D., Professor of Neurology, Methodist Neurological Institute, 6560 Fannin Street, Suite 802, Houston, TX 77030, USA. Tel: þ1-713-441-1150, E-mail: [email protected]

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Table 102.1 Possible etiologies of myelopathies in the tropics Type of lesion Congenital Cerebral palsy, dysraphism, diastematomyelia, spina bifida Traumatic injury Fracture, cervical disc herniation, spondylosis, hematomyelia, syringomyelia. Cervical spondylosis is said to be rare in tropics Tumor Extradural or intradural; bony or epidural metastasis Vascular lesions Thrombosis of anterior spinal artery, arteriovenous malformations, dural arteriovenous fistula, vasculitis – lupus, Sj€ ogren’s disease, acute transverse myelitis secondary to nucleus pulposus embolism Multiple sclerosis (MS) Spinal forms of MS, Devic’s disease (optic neuritis and myelitis), postinfectious encephalomyelitis, acute transverse myelitis Inflammatory Sarcoidosis Infections Bacterial: Tuberculosis (Pott’s disease), epidural abscesses, tropical pyomyositis (Staph. aureus), arachnoiditis, syphilis, yaws, brucellosis, mycoplasma, leptospirosis, borreliosis (Lyme disease), listeria Fungal: Cryptococcus spp., aspergillosis, histoplasmosis, blastomycosis, mucormycosis, paracoccidioidomycosis Viral: Transverse myelitis from HSV-2 (genital), combined degeneration and opportunistic infections in patients with HIV infection, HTLV-I antibodies in patients with tropical spastic paraparesis (HAM/TSP), other chronic myelopathies and MS-like disease. Poliomyelitis due to motor neuron lesions in diseases caused by polioviruses and some echoviruses, arboviruses, West Nile virus, and acute hemorrhagic conjunctivitis Parasitic: Toxoplasma gondii, Schistosoma mansoni, Taenia solium Neurodegenerative disease Amyotrophic lateral sclerosis, Friedreich’s ataxia, hereditary spastic paraparesis Toxic Fluorosis Nutritional Vitamin B12 deficiency, copper toxicity Malnutrition may produce TAN, TSP, optic and hearing defects. Probably caused neurologic syndromes of POWs in the Far East during World War II Neurotoxicity Lathyrism: common cause of spastic paraplegia on the Indian subcontinent Cyanide: excessive cassava consumption, common in Nigeria and Tanzania, causes konzo and tropical ataxic neuropathy Clioquinol (Entero-vioform) caused subacute myelo-optico neuropathy (SMON) in Japan Organophosphates and pesticides: triorthocresylphosphate may cause tropical ataxic neuropathy Other problems: familial paraplegia, syringomyelia (Modified from Roma´n, 1989, p. 525.) HIV, human immunodeficiency virus; HTLV-I, HTLV-1, human T cell lymphotropic virus type 1; HSV, Herpes simplex virus; HAM/TSP, HTLV1-associated myelopathy/tropical spastic paresis; POWs, prisoners of war; TAN, tropical ataxic neuropathy; TSP, tropical spastic paraparesis.

Roma´n et al., 1985). In addition, endemic or epidemic clusters of myelopathies or myeloneuropathies occur with high prevalence almost exclusively in tropical regions. The latter are characterized by funicular lesions of the spinal cord accompanied by axonal, predominantly sensory peripheral neuropathy that may be due to nutritional or toxic causes and a number of other possible etiologies.

HISTORICAL ASPECTS The high prevalence of endemic myeloneuropathies in tropical and subtropical regions has been recognized for centuries (Table 102.2). However, reports from Africa, the Far East, and the West Indies remained unnoticed until World War II, when myeloneuropathies in prisoners of war detained in tropical camps made

TROPICAL MYELOPATHIES

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Table 102.2 Historical description of epidemic myelopathies and myeloneuropathies From Roman (1985) and Roman et al. (1985) Year

Place

Author

Clinical features

Probable etiology

50 BC 1671

Greece Germany

Palsy of legs Leg palsy

Lathyrism Lathyrism

1672 1826

Jamaica India

Dioscorides Georg, Duke of W€ urttemberg Ellwood Grierson

Palsies Burning feet

1888, 1897 1898 1917

Jamaica Cuba Jamaica

Strachan Ma´dan Scott

Multiple neuritis Optic neuropathy Ataxic myelopathy

1930 1930

Africa USA

Moore Several

1932

Africa

Stannus

1936–1939

Spain

1938

Congo

Garcı´a Jime´nez, Grande Covia´n Trolli

Optic neuropathy Jamaica ginger neuropathy Pellagra, painful neuropathy Neuromyelopathies

Lead from rum casks Vitamin/mineral deficiency Arsenic Malnutrition Post-conjunctivitis (viral?) Malnutrition TOCP

1942–1945

Far East

Cruickshank

1956 1962

Jamaica Senegal

Cruickshank Collomb et al.

1965 1968

South Africa Nigeria

Cosnett Osuntokun

Spastic paraplegia Sensorimotor neuropathy Spastic myelopathy Ataxic neuropathy

1969

South India

Mani et al.

Spastic paraplegia

1981 1982 1984

Colombia Seychelles Mozambique

Zaninovic et al. Kelly Cliff et al.

Spastic paraplegia Spastic paraplegia Spastic paraplegia

1987 1991–1993

Kagoshima, Japan Cuba

Osame PAHO

Spastic paraplegia Opticomyeloneuropathy

Spastic paraplegia, konzo WWII-POWs

Nicotinic acid deficiency Malnutrition, lathyrism Cyanide /cassava/ malnutrition Malnutrition/ malabsorption HTLV-1 Malnutrition HTLV-1 (?) Cyanide /cassava/ malnutrition HTLV1(?), lathyrism (?) HTLV-1 HTLV-1 Cyanide /cassava/ malnutrition HTLV-1 Malnutrition

WWII-POWs, World War II prisoners of war; HTLV-I, human T cell lymphotropic virus type 1; TOCP, tri-ortho-cresil-phosphate; PAHO, Pan American Health Organization.

neurologists aware of the relationships existing between tropical climate and the epidemic occurrence of these conditions in situations characterized by nutritional deprivation combined with tropical malabsorption caused by toxicogenic bacterial infections. Roma´n et al. (1985) and Bruyn and Poser (2000) have reviewed the history of the endemic and epidemic forms of tropical myelopathies. The earliest reports (1672) from Jamaica described epidemic outbreaks of strange palsies among settlers and African slaves (Roma´n, 1985); in 1888 and 1897, Henry Strachan reported 510 cases of “a form of multiple neuritis prevalent in the West Indies,” observed at the Kingston Public Hospital in Jamaica; in 1898, Domingo

Ma´dan in Cuba described epidemic cases of retrobulbar optic neuropathy that he considered identical to tobaccoalcohol amblyopia, “although none of these patients drank,” and were probably associated with malnutrition. In 1917, Henry Harold Scott reported an outbreak of 21 patients with neuropathy in Spanish Town, Jamaica. In 1956, Eric K. Cruickshank, working at the Medical School of the West Indies in Mona, Jamaica, described 100 patients with “a neuropathic syndrome of uncertain origin” characterized by spastic paraparesis with minimal sensory deficits (tropical spastic paraparesis). More recently (1991–1993), an epidemic of optic neuropathy of nutritional origin affected the island of Cuba (Roma´n

G.C. ROMA´N

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1994). The tropical myelopathies have been the subject of productive research, as demonstrated by the discovery of the role of human T-lymphotropic virus type 1 (HTLV-1), the first human retrovirus, in tropical spastic paraparesis.

CLINICAL ASPECTS The large number of conditions capable of producing involvement of the spinal cord in the tropics listed in Table 102.1 can be conveniently approached from the clinical viewpoint by separating them into acute and chronic. Acute myelopathies present with onset of symptoms within hours or days; chronic myelopathy cases evolve insidiously with slow progression over months and even years. Symptoms indicative of spinal cord involvement include loss of motor, sensory, and sphincter function. The motor involvement is usually bilateral and can produce leg weakness (paraparesis), or weakness of all four limbs (quadriparesis or tetraparesis); complete loss of movement is called respectively paraplegia and quadriplegia. Pain is also an important localizing sign of spine and root pathology; lesions affecting the cervical spinal cord and roots present with cervical, suboccipital, or interscapular pain radiating to the arms while chest pain or back pain is present with lesions of thoracic or lumbosacral spinal cord, respectively. Loss of sensation to pinprick and to the tuning fork vibratory stimulation demonstrates a sensory level that allows localization of the level of the spinal cord lesion. Finally, urinary and/or stool incontinence is an important sign of spinal cord damage. The combination of acute motor loss, sensory level, and sphincter incontinence is an emergency that should be treated with absolute priority to prevent long-term disability or death. In cases of trauma, appropriate immobilization of the neck and adequate transport of the patient is mandatory in order to prevent what has been called “the second injury.” Imaging of the spine and cord with CT/MRI or myelography should be obtained as soon as possible in order to rule out compression of the cord amenable to surgical decompressive treatment complemented with steroids (intravenous methylprednisolone). The management of acute spinal cord lesions has been reviewed recently (McDonald and Sadowsky, 2002; Fogelson and Krauss, 2008).

CAUSES OF ACUTE MYELOPATHY IN THE TROPICS Most of the etiologies of acute myelopathy listed in Table 102.1 are also seen in temperate regions of the world and will not be addressed here unless some peculiar features occur in the tropics.

Trauma Trauma is one of the leading causes of disability and death worldwide. In the tropics, lack of traffic regulations and poor emergency services result in enhanced mortality and morbidity. For instance, in Nigeria, Solagberu (2002) reported the characteristics of spinal cord lesions in 39 patients; most cases (36/39) were young males (mean age 37.7 years) and traffic accidents were the main cause of injury occurring while the subjects were riding in open lorries sitting on top of their goods; the second cause was falls from kolanut trees or palms. There was high mortality (10/39), mainly among the 70% of patients with cervical cord injuries. Also in Nigeria, Olasode and colleagues (2006) described similar findings; the poor condition of the roads and reckless driving were important causal factors of spinal cord injuries. In contrast, in the Fiji Islands, Maharaj (1996) also found a male preponderance of spinal cord lesions (male/female ratio 4:1); patients were quite young, between 16 and 30 years of age at the time of paralysis. The main causes of spinal cord injuries were falls (39%), followed by motor vehicle accidents (25%), sports (20%), shallow water dive (8%), and 4% each deep sea diving and others. Among nontraumatic causes, 53% were due to unknown causes, 32% infections, 9% neoplasms, and 6% others. Of the survivors, 31% had tetraplegia and 52% had complete lesions. The incidence of secondary complications such as pressure sores and urinary infections was also found to be high when compared with other studies.

Disc herniation and spondyloarthritis Disc herniation in the tropics has been considered to be less frequent than in temperate regions, accounted for in part by the alleged protection of the generalized habit of carrying heavy loads on the head. However, as mentioned above, imaging has shown that disc pathologies remain high in the list of lesions of the spine in tropical regions. Also, incorrect diagnosis may lead to surgery in cases of osteoarticular brucellosis that may mimic disc disease as documented in Iran by Janmohammandi and Roushan (2009), who retrospectively studied 232 patients with osteoarticular brucellosis causing polyarthritis, monoarthritis, spondylitis, and sacroilitis. Galukande et al. (2005), from Uganda, found in 204 patients with low-back pain that most cases, or 62%, had mechanical causes, 19% had nerve root compression due to prolapsed intervertebral discs, and 17% had serious spinal pathology due to tuberculosis, brucellosis, fractures, and degenerative changes. According to Richens and McGill (1995), the spondyloarthropathies occur with variable frequency in the

TROPICAL MYELOPATHIES tropics. Ankylosing spondylitis is rare in tropical Africa, due to low frequency of the HLA-B27 gene, but in contrast it is seen more often in the Melanesian populations of Papua New Guinea. In the tropics, cases of infectious and reactive arthritis are relatively common. With the spread of HIV infection in Africa an increasing prevalence of reactive arthritis has been observed. Common treatable causes of acute arthritis sometimes presenting with neurologic signs are chlamydia-triggered arthritis, disseminated gonococcal infection, tuberculosis, and brucellosis.

Vascular causes of acute myelopathy Vascular lesions are relatively rare causes of acute myelopathy; these lesions include spinal cord infarction, hematomyelia, and dural arteriovenous fistula. A condition that has been reported in the tropics and mimics acute transverse myelitis is spinal cord embolism of fibrocartilaginous material from the nucleus pulposus of intervertebral discs.

NUCLEUS PULPOSUS EMBOLISM Toro et al. (1994) reported a case from Colombia of a previously healthy 16-year-old girl living in a dairy farm who was milking a cow when she experienced acute onset of very severe low-back pain radiating into her thighs. About 15 minutes later she had become completely paraplegic. On examination she exhibited a flaccid paraplegia with areflexia of lower limbs, sensory level with loss of pinprick and vibration from L1 down, perineal anesthesia with urinary incontinence, and loss of rectal tone and arreflexia. The patient eventually died from complications and postmortem examination showed ischemic infarction of the lumbar spinal cord due to arterial and venous embolization with fibrocartiaginous material from nucleus pulposus embolism. Epidemiologic features. In an extensive review of the literature Toro et al. (1994) analyzed 32 cases reported from around the world; overall, there was a female preponderance with a women to men ratio of 2.2:1. Distribution by race and ethnicity included 27 white Caucasians, three blacks, and one case each from India and Latin America (Colombia). The age of onset ranged from 13 to 77 years with a median of 38.5 years and a bimodal distribution with two peaks of age incidence, the first one among young patients with a median age of 22 years, and a second peak among postmenopausal women at a median age of 60 years. Clinical picture. The typical clinical features included a sudden onset of severe, excruciating neck or back pain accompanied by muscle weakness. In cases of cervical disc embolism the pain was interscapular radiating to the neck, chest, and abdomen. Embolism from lumbar spine discs resulted in low-back pain radiating to the legs and abdomen. Cervical-medullary lesions were

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accompanied by respiratory failure. Motor manifestations included a flaccid paraplegia or quadriplegia with areflexia of deep tendon reflexes and cutaneous reflexes. Sensory examination revealed deficits consistent with anterior spinal artery occlusion, including loss of pinprick and temperature with preserved perception of vibration of the tuning fork. Differential diagnosis. The clinical picture resembles closely a transverse myelopathy, except for the severe pain. Cerebrospinal fluid (CSF) examination is usually normal. Imaging. MR images showed swelling of the cord and increased T2 signal intensity together with collapse of the intervertebral disc space, sometimes with nucleus pulposus herniation into the adjacent vertebral body end plate. Cord lesions may include increased T2 signal, minimal contrast-enhancing foci, and hemorrhagic necrosis of the cord as a late, terminal sign. Often, the vertebral body bone marrow shows evidence of infarction from the embolism. According to Tosi et al. (1996), in a patient with clinical symptoms suggestive of spinal cord embolism, the MRI finding of cord swelling associated with a collapsed disc space at the appropriate level is almost pathognomonic of nucleus pulposus embolism to the spinal cord (Fig. 102.1). Neuropathology. Neuropathological studies have shown that the most frequent level of involvement is the cervical spine (70%) extending sometimes from the medulla oblongata to upper thoracic levels, followed by the lumbar spine (22%) extending rarely from the lower thoracic cord the sacral segments. The territories involved are equally divided between arterial occlusion in the anterior spinal artery (50%) and venous embolism (50%). In some cases a typical transverse ischemic myelopathy occurs or, more rarely, a ramollissement en crayon (pencil-shaped infarction). Pathogenesis. The nucleus pulposus is a semifluid fibrocartilaginous cushion considered to be a remnant of the embryonic notochord. Close contact of the nucleus pulposus to vertebral body venous sinusoids is postulated to establish a communication between the nucleus pulposus and the venous system of the spine including Batson’s venous plexus. Increased intraosseus pressure within the vertebral body due to acute vertical disc herniation would inject nucleus pulposus material into veins, arteriovenous shunts, and arteries resulting in spinal cord ischemia and necrosis (Fig. 102.2). Treatment. The postulated treatment includes intravenous steroids and hyperbaric oxygen.

INFECTIOUS MYELOPATHIES Infection is one of the commonest causes of acute myelopathy in the tropics. The entire spectrum of infective agents capable of causing myelopathy (Table 102.1) is quite extensive (Berger and Sabet, 2002); therefore,

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Fig. 102.1. Nucleus pulposus embolism causing extensive ischemic myelopathy. T2-weighted MRI shows intramedullary longitudinal hyperintense signal from C6 down to the conus medullaris, intersomatic disc collapses and vertebral body infarctions (C5–7/T8–10). (Reproduced from Th€one et al., 2007.)

Fig. 102.2. Proposed physiopathological mechanism of nucleus pulposus embolization of the spinal cord. Increased disc pressure leads to extrusion of the nucleus pulposus into vertebral body sinusoidal veins. From the sinusoids fibrocartilaginous material is injected into vertebral veins in Batson’s plexus. Spinal arteriovenous communications allow entrance of the material into spinal arteries causing ischemia of the spinal cord. Spinal cord veins are also embolized, often leading to arterial and venous occlusions. (Reproduced from Toro et al., 1994.)

TROPICAL MYELOPATHIES 1527 the approach to etiologic diagnosis and management as aciclovir, valaciclovir, and famciclovir used in the treatshould be epidemiologic, considering first the most comment of shingles should be used to treat VZV myelitis as mon agents in the patient’s specific region of the world. early as possible (Berger and Sabet, 2002). The following etiologic agents will be briefly discussed: ● ● ●

● ●

viruses including herpes-group viruses, rabies, and enteroviruses retroviruses: HTLV-1, HTLV-2, and HIV bacterial infections including meningomyelitis and epidural abscess due to tuberculosis, brucellosis, Lyme borreliosis, mycoplasma and neurosyphilis fungal infections: Nocardia, Cryptococcus spp. parasites including nematode infections (angiostrongyliasis, gnathostomiasis, strongyloidiasis, toxocariasis); cestodes (cysticercosis, echinococcosis); and trematodes (paragonimiasis, schistosomiasis).

Viral myelopathies This topic has been extensively reviewed by Kincaid and Lipton (2006) and Berger and Sabet (2002). Except for endemic clusters of tropical spastic paraparesis due to HTLV-1, viral infections are uncommon causes of acute myelopathy.

POLIOMYELITIS Prior to universal vaccination the most common cause of acute viral myelitis presenting as an acute flaccid paralysis used to be poliomyelitis caused by polioviruses 1, 2, and 3. Cases of acute poliomyelitis may occur following the use of Sabin polio vaccine. The Australian National Polio Reference Laboratory identified 1325 isolates from acute poliomyelitis cases between 1995 and 2000; of these, 53% were confirmed as Sabin vaccine-like polioviruses, 41% were nonpolio enteroviruses, and 6% yielded no virus or viruses other than enteroviruses (Stambos et al., 2001). Other agents capable of causing of causing anterior horn cell necrosis with asymmetric acute flaccid paralysis include coxsackieviruses A and B; enterovirus-71, for instance during epidemics of viral conjunctivitis; and flaviviruses, including West Nile virus.

HERPESVIRUSES The herpesviruses, including varicella zoster (VZV), herpes simplex type 2 (HSV-2), and cytomegalovirus (CMV) are a common etiology of encephalitis but less often a cause of myelitis. VZV remains dormant in the dorsal root ganglia after causing varicella (chickenpox). Reactivation of the virus, due most often to immunosuppression, leads to viral multiplication and to herpes zoster (shingles), complicated in rare cases with a necrotizing myelopathy (Devinsky et al., 1991). Antiviral agents such

Chronic retroviral myelopathies HUMAN T CELL LYMPHOTROPIC VIRUS-1 The only human virus capable of chronically infecting the spinal cord without causing brain involvement is the human T cell lymphotropic virus type 1 (HTLV1), the causal agent of adult T cell leukemia/lymphoma and of tropical spastic paraparesis/HTLV-1 chronic myelitis (also called HTLV-1-associated myelopathy). Gessain and Mahieux (2012) have recently reviewed the epidemiologic, virologic, and clinical aspects of this infectious myelitis; Roma´n (2003) reviewed several proposed therapies. Virology. HTLV-1, the first human retrovirus, was discovered in 1980 in a patient with cutaneous lymphoma. HTLV-1 is classified in the Retroviridae family, Orthoretrovirinae subfamily and the Deltaretrovirus genus. HTLV-1 infects CD4þ lymphoid cells and has three major genes (gag, pol and env) encoding the structural and enzymatic proteins. Rare cases of tropical spastic paraparesis are caused by HTLV-2. The double infection with HTLV-1/HIV is not infrequent in areas with high prevalence of AIDS. Epidemiology. Cases of chronic HTLV-1 myelitis have been described in the Caribbean, particularly in Jamaica and Martinique, as well as in southern Japan, Colombia, Ecuador, Chile, Brazil, the Seychelles, Iran, and in some African countries. Tropical spastic paraparesis appears to be identical to a chronic myelitis described in the southern islands of Japan (HTLV-1associated myelopathy, or HAM). In most of Africa and southern India the etiology of tropical spastic paraparesis appears to be different, and remains unknown. An estimated 10–20 million people worldwide are infected with HTLV-1. Transmission of HTLV-1 occurs by three mechanisms: (1) mother to child by breastfeeding; (2) sexual contact mainly from infected male to female; (3) via transfusion of contaminated blood products. The lifetime risk of hematologic or neurologic involvement among HTLV-1 carriers is 0.25–3%. Clinical features. HTLV-1 myelitis occurs in adults with onset at 40–50 years of age; it is more common in women than in men. HTLV-1 myelitis causes a chronic spastic paraparesis syndrome with minor sensory signs; it appears to be quite uniform worldwide, with minor regional variations. Onset of the disease is gradual in more than 60% of cases with gait disturbance and urinary symptoms. In most patients, one leg is affected more than the other at onset. Progression usually is slow

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and indolent, sometimes reaching a plateau and remaining at that level for several years. All patients have weakness of the legs, back pain, leg numbness, and dysesthesias of the feet. Sphincter involvement and bladder dysfunction are manifested mainly by increased urinary frequency, urgency and incontinence; constipation and penile impotence also occur. The core of the syndrome on neurologic examination is defined by the presence of spastic paraparesis or paraplegia, increased knee reflexes, crossed adductor responses, ankle clonus, and extensor plantar responses indicative of bilateral pyramidal tract lesion affecting the lower limbs. Spasticity is moderate, predominating on the thigh adductors and to a lesser degree on the thigh extensors and gastrocnemius muscles. Motor weakness is proximal and affects mainly gluteus medius and iliopsoas muscles. Gait is typically slow and scissoring, with dragging and shuffling of the feet. The severe spasticity of lathyrism, with lurching gait on the ball of the foot and toes is not seen. Most patients ambulate with minimal support, but one-third are bedridden either as a result of rapid onset of the paraplegia or after long progression of the disease. Up to half the patients exhibit brisk reflexes in the upper limbs, and one-sixth have snout and brisk mandibular reflexes. There are minimal signs of involvement of the posterior columns but other sensory deficits, such as thoracic sensory level of loss of pain sensation, are not commonly present. Higher mental functions are normal. Examination of the cranial nerves is usually normal, except in Jamaica, where retrobulbar optic neuropathy and deafness occurred in 15% and 7%, respectively. Cerebellar signs, in particular intention tremor and dysmetria, have been observed in up to 20% of patients. Rare cases manifested as a spinocerebellar syndrome have been reported (Castillo et al., 2000). In addition to paresthesias in the feet, mild decrease of vibratory perception distally in the feet is found, usually without loss of proprioception. Ankle reflexes are absent in about 25%, and stocking-type loss of sensation in a pattern suggestive of peripheral neuropathy has been described in a third of patients. Laboratory findings. Peripheral blood may show atypical T lymphocytes with convoluted nuclei (“flower cells”). CSF shows a mild pleocytosis, sometimes with “flower cells,” mild increase in proteins, elevated IgG index, and oligoclonal bands due to local synthesis of anti-HTLV-1 antibodies. HTLV-1 antibodies are also present in the serum of the patients, but titers are typically higher in the CSF. Enzyme-linked immunoabsorbent assay (ELISA) is commonly used, but positive titers require confirmation with recombinant Western blot assay showing reactivity to gag (p19 or p24) and env (gp21 or gp46) gene products. Intrathecal immune

Fig. 102.3. T2-weighted sagittal MRI demonstrating atrophy of the spinal cord in a chronic case of HTLV-1 myelitis. (Reproduced from Howard et al., 2003.)

response against env gp21 synthetic peptides can be detected in the CSF by Western blot analysis. A high HTLV-1 proviral load is observed in the blood. Mild to moderate increase of proteins may be present in the CSF. Imaging. In the acute stage, MRI of the spinal cord may show localized spinal cord swelling of the lumbosacral segment, or high-intensity signal on T2-weighted images in the thoracic spinal cord, followed by atrophy, usually localized to the thoracic region (Fig. 102.3). Nonspecific hyperintense foci on T2-weighted signals may be found in the periventricular white matter of the brain. Neuropathology. On postmortem examination, HTLV-1 myelitis is characterized by chronic progressive myelin loss and funicular axonal degeneration in the white matter of the spinal cord, with chronic perivascular infiltrates. Optic nerve demyelination and foci of brain leukoencephalopathy may also be seen. It has been suggested that HTLV-1-infected CD4 þ T cells migrate to

TROPICAL MYELOPATHIES the central nervous system, and cytotoxic CD8þ T cells would produce cell-mediated cytotoxic demyelination. Differential diagnosis. Other causes of progressive myelopathy should be ruled out including spinal cord compression, tumors, bilharziasis, B12 deficiency, HIV infection, primary progressive multiple sclerosis, Lyme disease, and konzo, a form of spasticity prevalent in Africa and associated with excessive consumption of cassava and chronic cyanide intoxication. Treatment. Therapy remains symptomatic using medications to improve spasticity; transient improvement with corticosteroids has been documented. The combination therapy used in HIV infection (AZT þ 3TC) such as Combivir® (150 mg lamivudine plus 300 mg zidovudine: one tablet twice daily) could decrease HTLV-1 viral load and improve neurologic function. However, although no clinical experience with this therapy is available, Pot et al. (2006) reported near-complete radiologic and clinical recovery of a patient with HTLV-1 myelitis and Sj€ ogren syndrome treated with combined antiretroviral treatment (lamivudine and tenofovir) plus immunosuppressant therapy with prednisone and mycophenolate mofetil. Public health measures for HTLV-1/2. Public health programs for the control of HTLV-1/2 infection in endemic populations should be undertaken to prevent the high morbidity associated with these infections. These programs require several measures that can be implemented along with HIV control programs, as follows: 1. 2. 3. 4.

prenatal control of pregnant women to discourage breastfeeding among HTLV-1/2-positive women blood bank screening of all donors clean-needle programs for intravenous drug users safe-sex programs to encourage condom use.

HUMAN IMMUNODEFICIENCY VIRUS Myelopathy in patients infected with human immunodeficiency virus (HIV) occurs either during the acute phase of seroconversion or more commonly during the symptomatic phase of AIDS when infected patients may develop a vacuolar myelopathy resembling subacute combined degeneration from vitamin B12 deficiency; finally, infectious myelitis may occur in immunosuppressed patients as a result of infections with a potentially large number of infectious agents and as a result or other noninfectious conditions (Table 102.3). Vacuolar myelopathy According to Berger and Sabet (2002), vacuolar myelopathy is the most common form of spinal cord disease in HIV-infected individuals; however, it is under-recognized clinically since the symptoms of lower

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Table 102.3 Myelopathies associated with HIV infection Infectious Viral HIV Acute transient myelopathy occurring at the time of seroconversion Chronic progressive myelopathy (vacuolar) HTLV-1 Cytomegalovirus Herpes simplex Herpes zoster Bacterial Epidural abscess Mycobacterium tuberculosis Treponema pallidum Fungal Cryptococcus neoformans Other Parasites Toxoplasma gondii Noninfectious Multiple sclerosis-like illness Tumors Plasmacytoma Spinal cord astrocytoma Other Epidural hemorrhage secondary to thrombocytopenia Vascular injury secondary to vasculitis HIV, human immunodeficiency virus; HTLV-1, human T cell lymphotropic virus type 1 (Adapted from Berger and Sabet, 2002.)

extremity weakness and paresthesias are often attributed to general debility and concomitant peripheral neuropathy of the patient with AIDS. In some geographic areas, such as South Africa, Brazil, and the Caribbean, myelitis is seen in patients coinfected with HIV/HTLV-1. Herpes zoster virus (VZV) coinfection with HIV is also a common cause of myelopathy. Clinical manifestations. The vacuolar myelopathy of HIV presents with spastic paraparesis, but with more leg weakness than spasticity. Rarely, asymmetry of leg weakness, monoparesis or quadriparesis may be seen. Sensory gait ataxia is common and dysmetria may be present. Weakness may be slight on muscle strength testing but hyperreflexia of the lower extremities and extensor plantar responses are usually present. In patients with concomitant peripheral neuropathy deep tendinous reflexes may be diminished or absent, particularly at the ankles. Vibratory and position senses are disproportionately affected in comparison with pinprick, temperature, or light touch, suggesting dorsal column impairment. Presence of a superimposed peripheral neuropathy is frequent. Impotence and incontinence are commonly seen.

G.C. ROMA´N

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Neuropathology. On neuropathology examination there is loss of myelin and spongy degeneration involving mostly the lateral and posterior columns. There is microvacuolization of the white matter of the spinal cord with a honeycomb appearance resulting from intramyelin swelling, associated with lipid-laden macrophages, similar to that seen in subacute combined degeneration of the spinal cord from vitamin B12 deficiency. Axons are preserved except in areas of marked vacuolization. Microglial nodules may be seen in the gray matter of the cord along with central chromatolysis of anterior horn motor cells. The postulated cause is a defect in the vitamin B12-dependent transmethylation pathway; or a combination of immune-mediated injury to myelin and oligodendroglia with lack of repair mechanisms due to a deficiency of S-adenosylmethionine. Differential diagnosis. Concurrent infection with other viral, bacterial, fungal or even parasitic agents must be ruled out. Neurosyphilis is particularly common in patients with AIDS and myelopathy. The prevalence of vacuolar myelopathy is expected to decrease with better treatment of AIDS.

Bacterial myelopathies Mycoplasma pneumoniae and other agents may cause parainfectious myelopathies. Other bacterial conditions include scarlet fever, pertussis, whooping cough and pneumococcal pneumonia. A myelitis presenting as a Brown-Se´quard syndrome has been described with cat scratch disease due to Bartonella henselae (Berger and Sabet, 2002).

Fig. 102.4. Tuberculous spondylitis and epidural abscess at T4 on sagittal MRI of the spine on T2-weighted images. (Reproduced from Bale´riaux and Neugroschl, 2004.)

TUBERCULOSIS The most frequent form of involvement of the spinal cord in tuberculosis is Pott’s disease, or tuberculous paraplegia. The topic has been extensively reviewed by Gautam et al. (2005) in Nepal and by Turgut (2001) in Turkey. The neurosurgical experience in Turkey included 694 patients; most of the cases occurred in young adults with a mean age of 32 years, equally distributed between men and women. The presenting symptoms were leg weakness (69%), gibbus (46%), pain (21%), and palpable mass (10%). Tuberculosis is caused by Mycobacterium tuberculosis, a highly infectious agent that causes predominantly pulmonary tuberculosis; contagion is mediated by aerosols from cough and is favored by crowed living conditions particularly among socially disadvantaged groups, including the unemployed, the homeless sleeping in crowded shelters, and migrant populations with poor nutrition. Tuberculosis affecting the spine is seen in only 10% of subjects with tuberculosis and perhaps only 1% develop paraplegia and death. The lesion begins as tuberculous osteomyelitis of the vertebral body with erosion

and anterior collapse of the vertebral body (Figs 102.4 and 102.5), followed by formation of a gibbus and a cold abscess that eventually produces compression of the cord and neighboring nerve roots. Preservation of disc spaces is one of the hallmarks of spinal tuberculosis. The most common localization is in the thoracic region (56%), involving the vertebral body, followed by the lumbar region (23%), the thoracolumbar region (17%), and the cervical region (4%). Indications for surgical treatment include spine deformity, neurologic deficit, intractable pain and abscess enlargement despite medications. Anti-TB chemotherapy includes combinations of rifampicin, isoniazid, pyrazinamide, and either ethambutol or streptomycin administered for 2–6 months, followed by rifampin and either isoniazid or ethambutol for a total of 6–18 months. Decompressive surgery plus anti-TB chemotherapy remains the best mode of therapy for Pott’s disease. Neurologic involvement due to Pott’s disease can be relatively benign if urgent decompression is performed at the onset of leg weakness.

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Fig. 102.5. CT scan demonstrating destruction and fragmentation of the vertebral body and paravertebral soft tissue mass with paravertebral calcifications consistent with cold abscess in Potts’ disease. Reprinted with permission from JBR-BTR. (Reproduced from De Backer et al., 2005.)

BRUCELLOSIS Brucellosis is a systemic infectious disease, caused by Gram-negative bacilli belonging to the genus Brucella. This disease is a zoonosis transmitted to humans from infected animals such as goats, sheep, cows, and camels (B. melitensis, B. abortus, B. ovis). High-risk areas include the Middle East, the Arabian peninsula, the Mediterranean basin (Portugal, Spain, southern France, Italy, Greece, Turkey, North Africa), Mexico, Central and South America, Eastern Europe, Asia, Africa, and the Caribbean (Corbel, 1997). For instance, brucellosis is endemic in Turkey and during the last decade over 9000 cases/year were reported (incidence 14/100 000); screening of the general population for seropositivity (Wright test, positive at > 1/160) revealed a seroprevalence of 1.8% (G€ org€ ul€ u et al., 2006). Infection occurs in most cases by consumption of unpasteurized milk, cheese, or dairy products from infected animals. Infection from aspiration of bacteria in aerosols or from skin abrasion also occurs among veterinarians, laboratory workers, butchers, and hunters. The clinical manifestations include malaise, sweats, anorexia, headache, myalgia, and back pain usually with prolonged intermittent fever (Malta’s undulant fever); in addition, gastrointestinal, respiratory, arthritis, dermal, ocular, or neurologic manifestations may occur. Spondylitis is one of the most frequent and serious complications of the disease. Brucella lesions of the spine occur in up to 50% of cases.

Fig. 102.6. Brucellosis with formation of a cervical epidural abscess (black arrow) extending from C5 to C8. Sagittal MRI of cervical spine on T1-weighted images. (Reproduced from G€ org€ ul€ u et al., 2006.)

Lesions may affect all levels but most commonly involve the lumbar spine at the L4–5 level. Cervical involvement occurs in 6–10% of cases (Song et al., 2012). Spinal epidural abscess is relatively rare (G€org€ ul€ u et al., 2006). The lesion begins as spondylodiscitis with a progressive abscess that involves adjacent vertebral bodies, prevertebral soft tissues, and the epidural space causing compression of the spinal cord and nerve roots (Fig. 102.6). The diagnosis needs to be supported by laboratory tests including serum serology and blood culture during the acute phase. Isolation in blood or tissue is successful in 50–70% of cases. Treatment of spinal complications of brucellosis requires prompt surgical decompression and drainage of the abscess followed by antibiotic therapy. Treatment of acute brucellosis in adults requires a combination of rifampicin 600–900 mg and doxycycline 200 mg daily for a minimum of 6 weeks. A high relapse rate occurs with single antibiotics. Intramuscular streptomycin with oral tetracycline was recommended in the past due to fewer relapses. Complications of brucellosis, such as myelitis, meningoencephalitis, or endocarditis, require combination

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therapy with rifampicin, a tetracycline, and an aminoglycoside (Corbel, 1997). Resolution of brucellosis is indicated by seroconversion, negative blood cultures, improvement of clinical symptoms such as fever and CT/MRI imaging findings, as well as a decrease in inflammatory markers (ESR, CRP).

SPINAL EPIDURAL ABSCESS Infections of the spine may involve the vertebral body (spondylitis), the intervertebral disc (spondylodiscitis), the ligaments and paravertebral soft tissues, the epidural space (epidural abscess), the meninges and the subarachnoid space, and very rarely the spinal cord, causing infectious myelitis or spinal cord abscesses (Bale´riaux and Neugroschl, 2004). The clinical manifestations include pain and motor-sensory deficits in the appropriate dermatomal distribution. In patients with diabetes mellitus fever may be absent and one of the few indicators of the presence of the abscess is the increase in sedimentation rate and other inflammatory markers. Hematogenous dissemination from a primary source of invasive staphylococcal disease is the most common mechanism for the development of an epidural abscess. In children, the high vascularization of the disc explains the fact that discitis constitutes the primary spinal infectious lesion with secondary extension to the adjacent vertebral bodies. Iatrogenic infections following lumbar puncture, epidural anesthesia or surgical interventions remain common, as recently reported by Nwadinigwe and Anyaehie (2011) in Nigeria. According to Bale´riaux and Neugroschl (2004), the most common cause of spinal epidural abscesses is Staphylococcus aureus found in 55–80% of cases. Other causal organisms include Streptococcus, Pneumococcus, Enterococcus, Escherichia coli, Salmonella, Pseudomonas aeruginosa, and Klebsiella. Granulomatous infections are mainly due to Mycobacterium tuberculosis, Brucella spp., fungi, and parasites. CT is an excellent technique for the detection of bony erosions as well as for demonstrating infiltration of perivertebral regions; also, the MRI is critical for demonstration of lesions compressing spinal cord (Fig. 102.7) and nerve roots (Bale´riaux and Neugroschl, 2004). Lesions that fail to compromise the intervertebral disc or vertebral end plates include granulomatous osteomyelitis, metastasis, lymphoma, and, less likely, atypical presentation of pyogenic vertebral osteomyelitis (Song et al., 2012). The treatment includes surgical decompression, drainage of the abscess, and appropriate antibiotic treatment. Spinal epidural abscess due to Nocardia asteroides, a bacterial organism that grows readily in culture media used for fungus, usually

Fig. 102.7. Cervical epidural abscess in a patient with Staphylococcus aureus septicemia. Sagittal cervical MRI on T2weighted images demonstrating the posterior location of the abscess. (Reproduced from Bale´riaux and Neugroschl, 2004.)

responds to treatment with a triple antibiotic intravenous regimen consisting of trimethoprim/sulfamethoxazole, amikacin, and ceftriaxone (Harvey et al., 1998). Among the fungal organisms, Batra et al. (2011) recently reported in India a case of acute cauda equina syndrome due to Aspergillus fumigatus that improved after surgical treatment and oral itraconazole.

Spirochetal myelopathies The family Spirochaetaceae has three major genera: Treponema, Borrelia, and Leptospira; morphologically, these agents are spirochetes characterized by the corkscrew-like appearance and active motility with an axial filament. All three genera infect the nervous system producing meningoencephalitis, infectious myelitis, meningoradiculoneuritis and peripheral nerve inflammation (Estanislao and Pachner, 1999).

LYME DISEASE The spirochete Borrelia burgdorferi was identified as the cause of Lyme arthritis in 1983 (Burgdorfer et al., 1983; Burgdorfer, 1998); Lyme arthritis is manifested

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Fig. 102.8. Acute neuroborreliosis presenting as myelo-meningoradiculopathy. Gadolinium-enhanced sagittal MRI of the spine showing meningeal enhancement at cervical (A), thoracic (B) and lumbosacral (C) levels. (Reproduced from Chang et al., 2010.)

by a typical skin rash called erythema chronicum migrans, followed by dissemination of the spirochete to other organs with arthritis, myocarditis, cardiac arrhythmias (atrioventricular block), myalgias, and neurologic disease. History. In 1921, Afzelius described erythema chronicum migrans in Europe; Garin and Bujadoux (1922), in France, first reported cases of meningoradiculoneuritis and tick paralysis; in 1941, in Germany, Bannwarth described tick-borne chronic lymphocytic meningitis with polyneuritis and arthritis. Epidemiology: Lyme borreliosis is a zoonosis of deer transmitted to humans by infected ticks. B. burgdorferi has been identified in ticks in South America and cases of Lyme disease have been reported in Sa˜o Paulo, Brazil (Yoshinari et al., 1993), Colombia, and Bolivia. Cases have been reported also in North Africa, including Morocco, Algeria, Egypt, and Tunisia (Bouattour et al., 2004) as well as in South Africa (Fivaz and Petney, 1989) and Kenya, East Africa (Jowi and Gathua, 2005). Clinical features. Neurologic manifestations of neuroborreliosis include facial paralysis, lymphocytic meningitis, often with minimal symptoms. Meningeal inflammation indicates treponemal dissemination into the central nervous system and must be treated energetically with intravenous antibiotics. One of the most common manifestations of acute neuroborreliosis is meningoradiculopathy (Chang et al., 2010), manifested by burning back pain, spasms, and shooting pains in the limbs or the trunk indicating root invasion by Borrelia. Gadolinium enhancement of leptomeninges can be observed with MRI (Fig. 102.8). Chronic infection of the central nervous system may be manifested by cognitive and neuropsychiatric symptoms. Neuroborreliosis may be manifested by a myelopathy (Reik et al., 1979). Diagnosis. The diagnosis is based on a history of skin lesions (erythema migrans), lymphocytosis in the spinal fluid, and positive antibodies to B. burgdorferi by

enzyme-linked immunosorbent assay (ELISA) or immunofluorescence assay (IFA) confirmed by Western blot. CSF shows pleocytosis with preponderance of lymphocytes or monocytes, elevation of protein between 50 and 300 mg% with increased albumin and immunoglobulin concentrations; IgG, total protein, and the IgG/albumin ratio can be high or normal. Oligoclonal bands may be present with specific antibodies directed against B. burgdorferi. Treatment. Given the early treponemal invasion of the nervous system the recommended treatment is with intravenous cephalosporins or penicillin for 2–3 weeks using, for instance, penicillin G 20 million Units/day every 4 hours. Third-generation cephalosporins may be better alternatives to penicillin due to their long half-life, high serum levels for longer periods, good penetration of the blood–brain barrier and high CSF concentrations. Ceftriaxone administered intravenously or intramuscularly at 1–2 g twice a day for 14 days has resulted in clinically defined cure. Oral doxycycline 200 mg daily for 14 days is also cost-effective and adequate.

NEUROSYPHILIS The causative organism of neurosyphilis is Treponema pallidum; the clinical expression of syphilis can be divided into early manifestations (primary and secondary syphilis) and late (tertiary) neurosyphilis. Early infection of the nervous system occurs weeks to years after the primary infection and is characterized by involvement of the meninges and blood vessels; it includes asymptomatic neurosyphilis, acute syphilitic meningitis, and meningovascular syphilis. Late or tertiary syphilis causes parenchymal involvement of brain and spinal cord and is manifested by tabes dorsalis and general paresis. Epidemiology. Timmermans and Carr (2004) have reviewed the recent experience with neurosyphilis in

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the Western Cape province of South Africa on 161 patients: 82 presented with combinations of delirium and dementia and other neuropsychiatric conditions, and the remainder presented with stroke (24), spinal cord disease (15), and seizures (14). Age at presentation ranged from 36 to 43 years. Cerebrospinal fluid (CSF) Veneral Disease Research Laboratory (VDRL) test was positive in 73% of cases; the remaining cases had positive treponemal test in the CSF. Tabes dorsalis is the only form that declined in the antibiotic era. However, with the increase in HIV-positive population and AIDS the number of cases of neurosyphilis appears to have increased in population-based seroprevalence studies in Africa, particularly Tanzania (Mosha et al., 1993) and Uganda (Hudson et al., 1988). Syphilic myelopathy. Involvement of the spinal cord includes tabes dorsalis, meningomyelitis, and spinal vascular syphilis usually accompanying other forms of neurosyphilis. The spinal cord neuropathology includes meningovascular and parenchymatous lesions. Intraspinal gummas and compression of the cord by syphilitic hypertrophic pachymeningitis or by vertebral lesions resulting from syphilitic osteitis may also occur. Clinical symptoms. Tabes dorsalis presents with typical pain (lightning pains) characterized by bouts of severe jabbing and lancinating pain in the lower extremities. Tabes dorsalis has the longest latent period between primary infection and onset of symptoms, ranging from 3 to 47 years (average, 21 years). In comparison with asymptomatic and meningovascular neurosyphilis, the frequency of spinal and cerebral forms of tertiary syphilis has decreased in the antibiotic era. Also important is the increase of early neurosyphilis in HIV-positive patients that fail therapy for primary syphilis. Treatment of syphilis and neurosyphilis in the HIV-positive population indicates that there is often failure to eradicate T. pallidum or to clear completely the organism from sanctuary sites in the nervous system and the eye, increasing the risk of neurosyphilis. Syphilitic meningomyelitis presents with progressive paraparesis, usually asymmetric, with spasticity, global sensory involvement in the legs, brisk reflexes, ankle clonus and Babinski sign. Syphilitic meningomyelitis may occur concurrently with the skin rash of secondary syphilis (Strom and Schneck, 1991). Negative VDRL but positive fluorescent treponemal antibody absorbed (FTA-ABS) test could occur; CSF shows mild pleocytosis and elevated proteins; usually there is good response to antibiotic treatment (Fisher and Poser, 1977). Rarely, neurosyphilis may present as acute transverse myelitis (Lowenstein et al., 1987). Neuropathology. The main lesions in tabes dorsalis (Fig. 102.9) involve the posterior spinal roots and dorsal columns with demyelination, particularly of the

Fig. 102.9. Typical lesions of tabes dorsalis. Notice atrophy of dorsal columns on the myelin stain. (Reproduced from Toro et al., 1983.)

fasciculus gracilis, the root entry zone, and Lissauer’s tract, with astrocytosis, fibrosis and vascular damage. In syphilitic meningomyelitis pathological examination reveals thickened meninges, with chronic meningitis and vascular lesions (endarteritis) of medium and small vessel with plasma cell and lymphocytic perivascular cuffing. Diagnosis. Examination of the CSF is mandatory, with presence of pleocytosis with predominant lymphocytes or monocytes, increased protein, and a reactive CSF VDRL test; negative VDRL but reactive CSF FTA-ABS test is diagnostic of neurosyphilis. Treatment. For neurosyphilis the US Centers for Disease Control and Prevention (CDC) recommends highdose intravenous penicillin G sodium (3–4 million Units intravenously every 4 hours for 10–14 days) or a 10–14 day combination of intramuscular penicillin G procaine (2.4 million Units per day) with oral probenecid (500 mg by mouth every 6 hours) followed by intramuscular benzathine penicillin G, 2.4 million Units per week for 3 weeks. HIV-positive patients with reactive VDRL should have a lumbar puncture 6 months after treatment.

BORRELIOSIS Borrelia spp. are spirochetal organisms transmitted to humans by lice or ticks. According to Estanislao and Pachner (1999), relapsing fever is caused by several species of Borrelia. The epidemic form, called louse-borne relapsing fever, is caused by B. recurrentis transmitted by the human body louse Pediculus humanus; this infection is prevalent in East Africa. The endemic form is caused by several species of Borrelia transmitted by tick vectors. As the name indicates, these conditions present with intermittent, relapsing fever. Neurologic manifestations include a meningeal syndrome, facial palsy, and cranial nerve involvement, encephalitis, seizures, extreme somnolence, hemiplegia, aphasia, ataxia, extrapyramidal symptoms, and neuropsychiatric

TROPICAL MYELOPATHIES 1535 abnormalities. Involvement of the spinal cord as myelorsplenomegaly, and skin rash. In the late stage chronic adiculitis is rare (Estanislao and Pachner, 1999). inflammation of small and large intestine, liver, or urinary bladder with granuloma formation and portal hypertension occurs. Fungal myelopathies Neurologic involvement occurs mainly during the According to Berger and Sabet (2002), involvement of early postinfective stage and can affect the brain (meninthe spinal cord with fungal infection is rare. Compresgoencephalitis) or the spinal cord (myelitis and myelorsive myelopathy may result from vertebral osteomyelitis adiculitis). Schistosoma ectopic eggs reach the CNS but fungi such as Blastomyces, Coccidioides, Cryptothrough retrograde venous flow into the Batson venous coccus, and Aspergillus may invade the spinal epidural plexus formed by vertebral epidural valveless veins, space, producing granulomatous meningitis. Spinal cord which connect the veins of the spinal cord with the infeinfarction due to meningovascular inflammation may rior venae cava, deep iliac veins, and portal venous sysalso occur. tem. Embolic ova may also reach the brain localizing in the cortex, subcortical white matter, basal ganglia, and Parasitic myelopathies internal capsule. Neuropathology shows typical Schistosoma eggs with minimal or no histologic reaction in lepBILHARZIASIS (SCHISTOSOMIASIS) tomeninges, brain parenchyma, and choroid plexus. The most common cause of acute myelopathy in adults Granuloma lesions rarely develop in the brain but focal in the tropics is bilharziasis due to spinal cord involveor diffuse vasculitis may occur. In contrast, granulomament by Schistosoma haematobium in Africa and the tous reaction around the eggs is found in the conus Middle East, or by S. mansoni in the Caribbean, Venezumedullaris and in the spinal cord (T12 to L1 levels), causela, and Brazil. This parasitic disease is caused by treming radicular and cauda equina inflammation and atode blood flukes of the genus Schistosoma (Del Brutto edema. Vasculitis of the anterior spinal artery has been et al., 2002; Roma´n, 2011). Larval forms of the parasites suggested as the substrate for vascular forms. (cercariae) released from a freshwater intermediate snail Clinical features. Schistosomal encephalitis presents host, pierce and penetrate human skin or mucosal surwith seizures, focal findings, intracranial hypertension faces with invasion of the bloodstream, usually while or encephalitis. Cerebral bleeding and subarachnoid the human host swims in a pond or a river. In the body, hemorrhage may occur. The differential diagnosis of the larvae develop into schistosomula and adult schistoschistosomal encephalopathy should include cerebral somes, which live in the blood vessels. malaria, bacterial meningitis, and viral encephalitis. Epidemiology. According to the World Health OrgaSchistosomal myelopathy. S. mansoni and S. haemanization (WHO), schistosomiasis is a major health probtobium involve the spinal cord more frequently than the lem in the tropics with some 700 million people brain; about 2.6% of patients with chronic S. mansoni worldwide exposed to infested water because of agriculinfection develop myelitis. The conus medullaris is the tural, domestic, and recreational activities, with more most common site of involvement producing an intramethan 207 million people infected worldwide (85% in dullary granuloma characterized clinically by complete Africa); most live in poor communities without flaccid paraplegia with areflexia, urinary and rectal access to safe drinking water and adequate sanitation. incontinence, impotence, sensory disturbances and lumThe prevalence of cerebral and spinal schistosomiasis bosacral pain. Other neurologic syndromes include acute is unknown. transverse myelitis, spastic paraplegia, painful lumbosaMicrobiology. Schistosoma mansoni, Schistosoma cral radiculopathy with backache, and cauda equina haematobium and Schistosoma japonicum cause human syndrome. disease. Female Schistosoma worms living inside the Neuroimaging. Myelography may reveal partial or veins lay large numbers of eggs in the inferior mesencomplete spinal cord block with intramedullary cord teric (S. mansoni) and superior mesenteric (S. japoniswelling and thickening of the roots of the cauda equina. cum) veins, and in the venous plexuses of the urinary MRI in schistosomal myelitis demonstrates mild bladder (S. haematobium). The eggs of the parasite cause enlargement of the spinal cord, swelling of the conus delayed hypersensitivity host reaction that produces the medullaris, and areas of T2 hyperintensities with intrasigns and symptoms of the disease. medullary enhancement after gadolinium injection Pathogenesis. Skin penetration by cercariae produces (Fig. 102.10). initial fever and pruritus; 3–6 weeks later the female Diagnosis. Schistosomiasis of the spinal cord can be Schistosoma worms begin releasing eggs (early postindiagnosed based on clinical presentation (acute flaccid fective stage) resulting in Katayama syndrome with paraplegia, myeloradicular painful syndrome, and fever, lymphadenopathy, eosinophilia, diarrhea, cauda equina syndrome) plus epidemiologic data such

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Fig. 102.10. Spinal schistosomiasis. Coronal (A) and sagittal (B) T1-weighted MRI of the spine with gadolinium contrast showing enlargement of the conus medullaris, and patchy contrast enhancement (large arrow) punctuated by focal nodular enhancement (small arrows) at the lower cord and cauda equina roots from schistosomal granulomas. (Reproduced from Ferrari et al., 2008.)

as history of travel or exposure to Schistosoma by bathing or swimming in fresh water in endemic regions. Laboratory confirmation includes demonstration of Schistosoma antibodies in serum and/or CSF by means of an ELISA test. The diagnosis can be suggested by typical findings on MRI or CT scan, and by patient recovery with treatment. Neurosurgical biopsy with histopathologic study of spinal lesions confirms the diagnosis. Patients with schistosomal myelopathy rarely have clinical evidence of systemic schistosomiasis. CSF shows mild lymphocytic pleocytosis, elevation of proteins, presence of eosinophils, increased IgG index, and oligoclonal bands. Biopsy of rectal mucosa and examination of stools and urine may reveal Schistosoma eggs in about 25% of patients. Differential diagnosis. Tumors, bacterial and fungal infections, and other parasitic diseases such as paragonimiasis, echinococcosis, cysticercosis, and extradural dracunculiasis are other helminthic infections that may present with cerebral mass lesions or spinal cord disease

and peripheral eosinophilia should be considered in the differential diagnosis. Treatment. A combination of schistosomicidal drugs, steroids, and surgery is currently recommended (Lambertucci et al., 2007). Praziquantel results in parasitological cure in more than 70% of patients with schistosomal myelopathy. Doses between 40 and 60 mg/kg/day are used for 14 days, in combination with prednisone or dexamethasone. Oxamniquine and metriphonate are also schistomicidal. Surgical approach includes decompressive laminectomy in cases with severe compression or CSF block on myelography, mass exeresis, and liberation of roots in patients with acute myelitis that continue to deteriorate despite clinical treatment.

NEUROCYSTICERCOSIS Involvement of the spinal cord and roots by larvae of the pig tapeworm Taenia solium is relatively infrequent, even in endemic places. Human infection occurs from

TROPICAL MYELOPATHIES human-to-human transmission of fertilized T. solium eggs from a human carrier of intestinal taenia. Humans become intermediate hosts in the life cycle of T. solium by ingesting Taenia eggs due to fecal contamination of water or food. Failure of intestinal Taenia carriers to wash their hands after defecation is the most common source of infection. Ingested eggs hatch into oncospheres in the intestine, cross the intestinal wall, enter the bloodstream, and are carried into the tissues of the host where the cysticerci develop. Epidemiology. Cysticercosis is the most common helminthic disease of the nervous system and a frequent cause of neurologic disorders in tropical areas of Latin America, Africa, and Asia accounting for about 50 000 deaths per year; survivors are left with irreversible brain or spinal cord damage. Cysticercosis can be prevented with hand washing, clean water, and environmental sanitation. Cysticercosis is becoming increasingly prevalent in industrialized countries because of travel to diseaseendemic areas and migration of tapeworm carriers and people infected with the disease. According to Wallin and Kurtzke (2004), in the US a total of 1494 patients with neurocysticercosis (NCC) were reported between 1980 and 2004, making it one of the most important emergent diseases of the nervous system. In this series, the frequency of manifestations included seizures (66%), hydrocephalus (16%), and headaches (15%) due to parenchymal NCC brain lesions (91%), and the remainder had ventricular cysts (6%), subarachnoid cysts (2%), and spinal cysts (0.2%). Pathogenesis. Cysticerci are found in the brain parenchyma, the subarachnoid spaces, the ventricular system, the eye, the spinal cord, and intrathecal nerve roots. Although many cysticerci may fail to elicit a foreign-body reaction, inflammation around each cysticercus eventually develops, accompanied by edema, reactive gliosis, and formation of dense exudates in the subarachnoid space composed of collagen, lymphocytes, multinucleated giant cells, eosinophils, and hyalinized parasitic membranes. In the spine this causes myeloradiculitis with entrapment of nerve roots and blood vessels. Clinical manifestations. Cysticercosis is a pleomorphic disease but diagnostic criteria have been clearly established (Del Brutto et al., 1996, 1998, 2001). Involvement of the spinal cord is a very rare form of cysticercosis and intramedullary cysts are even less common. Patients may present with a clinical syndrome of cerebral neurocysticercosis associated with both cauda equina and Brown-Se´quard syndromes and CSF findings of eosinophilic meningitis (Torabi et al., 2004). Imaging. Leite et al. (1997) reviewed the imaging experience in 16 patients with spinal cord involvement demonstrated by surgery or laboratory tests in four medical

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centers (two in the US, one each in Brazil and Colombia). On MRI imaging isolated intradural-extramedullary involvement was seen in nine patients; isolated intramedullary involvement (n ¼ 3), combined intraduralextramedullary and intramedullary involvement (n ¼ 3), and syringomyelia caused by infection and associated with chronic spinal arachnoiditis (n ¼ 2). Lesions included cystic structures within the subarachnoid space (Fig. 102.11) or homogeneous sheet-like enhancement within the subarachnoid space (arachnoiditis) over the surface of the spinal cord. Evidence of intramedullary disease included focal cystic lesions or syringomyelia due to cavitation of the spinal cord. All patients had evidence of simultaneous intracranial cysticercosis as shown on cranial CT, MR imaging, or both. Imaging of parenchymal cerebral cysticercosis usually shows single or multiple cysts with the typical “hole-in-donut” appearance resulting from imaging of the scolex of the parasite. Characteristic findings of subarachnoid lesions include abnormal enhancement of the leptomeninges and cystic lesions. Multiple calcified lesions (“starry sky”) on CT are seen in cases with spontaneous resolution. Laboratory. CSF usually shows lymphocytic pleocytosis (up to 500 cells per mm3) often with increase of eosinophils (eosinophilic meningitis), increased protein (up to 2000 mg/dL), and normal glucose. Useful serologic tests are serum immunoblot and CSF-ELISA. Treatment. Therapy must be individualized according to the location of parasites and the degree of disease activity. Albendazole (15 mg/kg/day) for 8 days is advised for patients with viable subarachnoid or parenchymal cysts. Dexamethasone (16 mg/day) administration should begin prior to the start of albendazole therapy and should be prolonged for several days. According to Del Brutto and colleagues (2006), both albendazole and praziquantel, the two cysticidal drugs available for neurocysticercosis, are effective in achieving complete resolution of colloidal and vesicular cysticerci with a reduction of up to 67% in the frequency of seizures. For patients with hydrocephalus, shunt placement must be contemplated before the start of albendazole. There is no systematic analysis of results of treatment of spinal forms of cysticercosis.

MYELITIS PRESENTING WITH EOSINOPHILIC MENINGITIS In addition to bilharziasis and cysticercosis, other parasitic diseases may present with eosinophilic pleocytosis in the CSF or eosinophilic meningitis. The presence of eosinophils in the CSF can only be demonstrated with Giemsa or Wright stain and CSF eosinophilia is defined by more than 10 eosinophils per mL or more than 10% of the total CSF leukocyte count (Graeff-Teixeira

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Fig. 102.11. Spinal neurocysticercosis. Contrast-enhanced MRI of spine showing a well-defined intramedullary cystic lesion expanding the cord opposite D8 vertebral body, which is hypointense on T1 (saggital cuts (A), axial cuts (D)) and hyperintense on T2 (B). The cyst had two areas of altered signal inside, which were hyperintense on T1 and isointense on T2, representing scoleces. The cyst showed peripheral enhancement and perifocal edema (C). Follow-up MRI of the spine 2 months later showed no cysticercus (E). (Reproduced from Ahmad and Sharma, 2007.)

et al., 2009). Helminthic infections of the nervous system are the most common cause of CSF eosinophilia. Although benign aseptic meningitis is the most common clinical picture of eosinophilic meningitis caused by Angiostrongylus cantonensis, other, highly mobile and larger parasites such as Gnathostoma spinigerum and Baylisascaris procyonis usually cause meningoencephalitis and myelitis. Table 102.4 summarizes the geographic distribution of the most common causes of eosinophilic meningitis, including angiostrongyliasis, gnathostomiasis, schistosomiasis, toxocariasis, baylisascariasis, cysticercosis, paragonimiasis, and less frequently Table 102.4 Geographic distribution of nematode larvae causing eosinophilic meningitis and myelitis Geographic distribution Gnathostoma spinigerum Angiostrongylus cantonensis Angiostrongylus costaricensis Toxocara canis Baylisascaris procyonis

Southeast Asia Southeast Asia Central America Worldwide North America

(Reproduced from Schmutzhard, 2007, with permission from BMJ Publishing Group Ltd. Copyright © 2007.)

strongyloidiasis, trichinellosis, hydatidosis, coenurosis, and filariasis. Rarely, fungal infections (coccidioidomycosis), syphilis, lymphoma, illicit drugs, and CSF shunts may cause eosinophilic pleocytosis.

GNATHOSTOMIASIS Human infection by the nematode Gnathostoma spinigerum results from eating raw fish, snails, shrimp, snakes, frogs, or insufficiently cooked chicken or duck contaminated with larvae of this parasite. Once ingested, the highly motile larvae cross the intestinal wall and migrate to subcutaneous tissues, skeletal muscle, and internal organs, including the CNS. Dogs, cats, and pigs are definitive hosts (Fig. 102.12). Gnathostomiasis is endemic in tropical areas of Southeast Asia, particularly in Thailand, as well as in Central and South America. CNS involvement is rather common in Asia and rare in the Americas. Gnathostomiasis has been associated with transverse myelitis, meningitis, and subarachnoid or parenchymal brain hemorrhages. Intracranial hemorrhages occur in 15–30% of patients with cerebral involvement, and are the most severe complication of the disease. Autopsy shows that Gnathostoma larvae may form long hemorrhagic tracts extending from the basal ganglia to the lower brainstem. Neurologic forms of presentation

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Fig. 102.12. Sagittal MRI of spinal cord, T1-weighted images after intravenous gadolinium contrast demonstrating abnormal signal intensities at upper and lower thoracic levels (circled) in a patient with eosinophilic meningomyelitis from larvae migrans of the cat nematode Gnathostoma spinigerum. (Reproduced from Schmutzhard, 2007.)

include transverse myelitis, seizures, meningitis, subarachnoid hemorrhage, and focal neurologic deficits associated with parenchymal brain hemorrhages. In contrast with angiostrongyliasis, the CSF is usually bloody and xanthochromic, with eosinophilic pleocytosis (up to 3000 cells/mm3), mild increase in protein, and normal glucose. High blood eosinophilia is present. Neuroimaging may show unusually long or multiple parenchymal brain hemorrhages or evidence of multiple foci of myelitis. Diagnosis is confirmed by identification of the larvae in tissue samples. Nematode-specific serologic diagnostic tests are not commercially available. Eosinophilic meningomyelitis should be treated with a combination of antihelminthics and intravenous corticosteroids. Schmutzhard (2007) successfully used albendazole (400 mg twice per day for 4 weeks) in combination with intravenous dexamethasone (24 mg/ day, slowly tapering off) and obtained complete cure of a patient with myelitis from gnathostomiasis.

TOXOCARIASIS Ascaris lumbricoides is a common intestinal parasite of humans with worldwide distribution. The equivalent ascarids of cats and dogs are Toxocara catis and Toxocara canis, which cause visceral larva migrans in humans, but only T. canis is capable of invading the CNS. According to Vidal and colleagues (2003), the

clinical syndromes include ocular forms, eosinophilic meningitis (36%), myelitis (28%), and encephalitis (62%). CSF eosinophilic pleocytosis occurs in at least 74% of patients, along with modest elevation of proteins and normal or slightly reduced glucose. Elevation of eosinophils in peripheral blood is constant. MRI of the spine shows enhancing lesions; similar hyperintense micronodular lesions are present in the brain on T2-weighted MRI images; parenchymal or intraventricular hemorrhage may also occur. The usual treatment is albendazole (5 mg/kg to 15 mg/kg twice a day for 2–4 weeks) plus intravenous corticoids to control potential vasculitis.

BAYLISASCARIASIS Human infection with the large ascarid worm Baylisascaris procyonis, which infects raccoons (Procyon lotor), a native North American animal, cause a severe visceral larva migrans syndrome. Once ingested, the larvae migrate out of the intestine causing first cutaneous larva migrans with macular rash on the face and trunk, followed by ocular disease and concomitant neurologic disease manifested by an acute, severe, and rapidly progressive eosinophilic meningoencephalitis or meningomyelitis that is usually fatal if untreated. Antibodies can be detected in serum and CSF. MRI shows extensive enhancing white matter lesions. Surviving cases have been

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treated with albendazole (20 mg/kg/day to 40 mg/kg/day for 1–4 weeks) in addition to intravenous corticosteroids. Prophylactic treatment for at least 10 days with albendazole (20 mg/kg/day to 40 mg/kg/day) or thiabendazole (50 mg/kg/day) is recommended immediately after exposure to raccoon latrines or cages.

IMMUNE-INFLAMMATORY DISORDERS Acute transverse myelitis This is a rare disorder with an incidence of 1–8 new cases per million of population per year; 20% of all cases occur in patients younger than 18 years of age (Bigi et al., 2010). Acute transverse myelitis is the most common cause of spinal cord transection evolving over a period of hours or days, usually with minimal back pain. The diagnosis remains one of exclusion; as mentioned earlier, nucleus pulposus embolism must be considered in the differential diagnosis. Treatment with corticosteroids is recommended given that 20–40% of patients with acute transverse myelitis have evidence of preceding or concurrent viral infection, and that the myelitis is the result of a postinfectious demyelination rather than an acute infectious myelitis (Berger and Sabet, 2002). This condition often occurs after a viral infection or vaccination particularly after rabies vaccination and posthepatitis B vaccination. Also, human rabies may present as a viral transverse myelitis, usually following bat bites. Konzo, a form of acute-onset spastic paraplegia occurring in African children who survive on a diet of cassava, appears to be due to the combination of excessive cyanide consumption and poor dietary intake of sulphurcontaining amino acids (Tylleska¨r et al., 1992; Rosling and Tylleska¨r, 1996). Lyme borreliosis may present rarely as acute transverse myelitis (Bigi et al., 2010). In Taiwan, Lyme neuroborreliosis is often manifested as an acute myelopolyradiculitis, a feature that is different from Lyme disease in Europe and North America (Chang et al., 2010). Neurosyphilis can rarely present as acute transverse myelitis (Lowenstein et al., 1987).

Multiple sclerosis Multiple sclerosis is considered a rare disease in the tropics probably because sunlight exposure and increased synthesis of vitamin D have protective immunomodulatory effects against autoimmune diseases. Conditions such as systemic lupus erythematosus and Sj€ogren disease are exceptional in the tropics, except for cases associated with HTLV-1 infection. Kompoliti et al. (1996) and Nakamura et al. (2000) described cases of Sj€ ogren syndrome with HTLV-1 myelitis. A number of well-documented cases of multiple sclerosis have been reported from Africa and

Latin America. In cases from Colombia, a genetic association was found for the allele 202 belonging to the marker D6S276 and for the allele 114 belonging to the marker D6S265 at different loci, establishing an association among polymorphisms of genes located at 6p21.3-21.4 correlated with the TNF neighborhood (Palacio et al., 2002). Devic’s disease (neuromyelitis optica), characterized by the simultaneous occurrence of bilateral optic neuritis and transverse myelitis, was considered a form of multiple sclerosis observed more commonly in Asia (India, Japan) and the Caribbean. However, with the discovery that most cases of Devic’s disease are associated with serum anti-aquaporin-4 antibodies (NMO-IgG) this condition is now considered to be an autoimmune, antibodymediated disease directed against the main brain water channel, aquaporin-4 (AQP4).

NUTRITIONAL MYELONEUROPATHIES Recently, Gallo Diop et al. (2006) have revised for the World Health Organization the neurologic disorders associated with malnutrition. The prototypic nutritional myeloneuropathy is subacute combined degeneration due to cobalamin (vitamin B12) deficiency and will be reviewed here more extensively. Neurologic signs occur relatively late in situations of dietary restriction or when absorption of nutrients is impaired, such as in tropical malabsorption or following bariatric surgery. When the deficiency of essential nutrients is severe enough to injure the nervous system or when protective nutrients – such as sulfur-containing amino acids and antioxidant carotenoids such as lycopene – become unavailable the neuronal groups most sensitive to energy deficiency (dorsal root ganglia, large myelinated distal axons, bipolar retinal neurons, cochlear neurons) are the first to suffer damage and manifest symptoms earliest. Nutritional neuropathies may occur as epidemic outbreaks or as problems endemic to a particular geographic area. Although experimentally, selective deficiency of micronutrients, in particular B-group vitamins and vitamin E, have been associated with axonal neuropathies, in tropical regions specific vitamin deficits seldom occur, since most instances of human malnutrition are usually due to overall dietary deficiency. Tropical malabsorption, resulting from recurrent infections with toxicogenic E. coli and other bacteria, viral gastroenteritis, and intestinal parasites, plays a significant role by decreasing the availability of vitamins. Precipitating factors include pregnancy and lactation, infections such as malaria and diarrhea, as well as increased metabolic requirements for thiamine due to increased carbohydrate intake and intense physical activity under hot and humid weather conditions.

TROPICAL MYELOPATHIES A toxic-nutritional etiology often combines deficiencies of micronutrients with consumption of neurotoxins such as cyanide-producing tropical foodstuffs (cassava), alcohol abuse and tobacco smoking (alcohol-tobacco amblyopia).

Vitamin B12 (cobalamin) Myelopathy, peripheral neuropathy and optic neuropathy were recognized as common neurologic complications of pernicious anemia. History. In 1926, George Minot and William Murphy discovered that dietary consumption of liver was beneficial in pernicious anemia causing improvement of sensation in patients with spinal cord involvement. In 1929, Castle postulated that extrinsic and intrinsic factors were required to absorb the antipernicious anemia factor present in liver tissue. Vitamin B12 was eventually crystallized in 1948 and its coenzyme forms purified from liver extracts. In 1956, Dorothy Hodgkin elucidated the complex, three-dimensional structure of vitamin B12. Cobalamin. The coenzyme form is cobalamin, a complex organometallic corrin ring with a cobalt (Coþ) in the central position, similar to the one occupied by iron in the heme ring. Vitamin B12 is available as cyanocobalamin. Neither animals nor plants produce vitamin B12 and only microorganisms are capable of synthesizing this vitamin. Humans are totally dependent on the vitamin B12 available in animal tissues to fulfill the daily requirements (2–3 mg/day). Strict vegan and macrobiotic diets do not provide this essential nutrient and may result in increased homocysteine, macrocytic anemia, or signs of neurologic involvement. Vitamin B12 absorption. Cobalamin absorption is quite complex and involves at least five separate cobalamin-binding molecules, receptors and transporters. The process includes a salivary factor, release of cobalamin from dietary sources by peptic and acid digestion in the stomach; binding to haptocorrin in the stomach and then to the intrinsic factor (IF) produced by gastric parietal cells. The IF-cobalamin complex passes into distal ileum, where it binds to high-affinity IF receptors on ileal epithelial cells, to be absorbed in the distal small intestine. Cobalamin is then released for subsequent binding to transcobalaminII (TcII). The TcII-cobalamin complex is transported across the cell to be released into the circulation. All cells in the body have surface receptors for TcII-cobalamin complex. However, 90% of the cobalamin in plasma is protein-bound to transcobalamin-I and transcobalaminIII, probably as storage forms. Vitamin B12 deficiency. Cobalamin deficiency occurs from a large number of factors including absent dietary supply (vegans), antibodies against IF (pernicious

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anemia), gastrectomy, gastritis involving parietal cells in gastric fundus (Helicobacter pylori), malabsorption syndromes (tropical sprue), celiac disease, surgical resection or bypass of distal ileum, competition for vitamin B12 by bacterial proliferation in the intestine in the blind-loop syndrome, or by intestinal parasitism with the fish tapeworm Diphyllobotrium latum, and rare genetic enzyme deficiencies (methylmalonic aciduria). Inhalation of nitrous oxide in anesthesia or as a recreational drug produces cobalamin deficiency. The elderly are prone to vitamin B12 deficiency; about 10–15% of the elderly have cobalamin levels below 150 pmol/L, and almost half have serum elevations of sensitive markers such as homocysteine or methylmalonic acid (Wolters et al., 2004). Atrophic gastritis occurs in 20–50% of the elderly (Andre`s et al., 2004, 2008) and results in gastric achlorhydria and low pepsinogen secretion that prevent the release and absorption of cobalamin; alkalinization of the small intestine and bacterial overgrowth further decreases the bioavailability of cobalamin. Drugs such as metformin for diabetes, and use of antacids such as proton pump inhibitors or H2 receptor antagonists inhibit cobalamin absorption. Epidemiology. Pernicious anemia is common throughout the world, especially in persons of European or African descent (Rogers et al., 2003; Stabler and Allen, 2004). Dietary deficiency of vitamin B12 due to vegetarianism is increasing, particularly in Asia, North America, and Europe, causing hyperhomocysteinemia that raises the risk for vascular disease. Breast-fed infants of vitamin B12-deficient vegan mothers are at risk for severe developmental abnormalities, growth failure, anemia, lower academic performance, attentional deficits, and delinquent behavior. Dietary vitamin B12 deficiency is a severe problem on the Indian subcontinent, in Mexico, Central and South America, and in some African countries (Black, 2003; Stabler and Allen, 2004). Pathogenesis. Cobalamin-dependent enzymes catalyze two types of reactions: rearrangements such as the conversion of L-methylmalonyl coenzyme A (CoA) to succinyl CoA; and methylations, as in the synthesis of methionine. Deficiency of either vitamin B12 or folate inhibits purine and thymidylate syntheses, impairs DNA production, causes erythroblast apoptosis in hematopoietic tissues and leads to the megaloblastic anemia typical of pernicious anemia. Methionine is also important in the synthesis of S-adenosylmethionine (SAM), the major donor of methyl groups. The provision of activated methyl groups by SAM is the end result of the activated methyl cycle, important in the synthesis of norepinephrine and glutamate, as well as in myelin synthesis. Neurologic manifestations of vitamin B12 deficiency. Some effects of vitamin B12 deficiency appear to be

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oxidative in nature, partly mediated by increased homocysteine, as well as by abnormal production of cytokines (tumor necrosis factor-a, interleukin-6) and deficit of epidermal growth factor, a neurotrophic factor (Scalabrino et al., 2003). Signs of neurologic involvement in vitamin B12 deficiency may occur before the development of megaloblastic anemia; and rarely, with normal serum levels of vitamin B12 (Healton et al., 1991). A more sensitive indicator of neural damage is the presence of increased homocysteine, methlymalonic acid (MMA) and methyl-citric acid (Garcia et al., 2004). The spinal cord, brain, optic nerves, and peripheral nerves may be affected by vitamin B12 deficiency. Subacute combined degeneration. The typical lesion of the spinal cord in vitamin B12 deficiency is the degeneration of posterior and lateral columns causing subacute combined degeneration (SCD) manifested by a triad of sensory ataxia, spasticity and leg weakness (Healton et al., 1991). Symptoms begin with paresthesias, tingling, pins and needles sensations in the feet and then in the hands; Lhermitte’s sign may be present. These symptoms are constant and progress towards unsteadiness of gait due to pyramidal weakness and loss of proprioception and postural sense, with a positive Romberg sign caused by both damage to the posterior funiculi and the peripheral neuropathy. As the disease progresses, stiffness and weakness of the legs develop, with brisk knee reflexes, crossed adductor responses and Babinski sign. In a large series of patients with pernicious anemia, common symptoms included loss of cutaneous sensation, weakness, urinary or fecal incontinence, and orthostatic hypotension. About one in four patients had no evidence of anemia. The final stage in untreated cases is an ataxic paraplegia, with spasticity and contractures; flaccid paraplegia may occur in some patients, probably due to more severe peripheral nerve involvement. Response to treatment was inversely related to duration and severity of the neurologic symptoms and the anemia before the diagnosis. Neuropathology. The typical pathology involves the white matter in the spinal cord beginning with separation of myelin lamellae, vacuolization, and axonal damage with minimal gliosis, involving first the dorsal columns of the cervical and upper thoracic cord. Late lesions are scattered irregularly in posterior and lateral funiculi and disclose a typical honeycomb appearance. Visual symptoms due to involvement of the optic nerves were commonly seen in pernicious anemia. Clinically, there is loss of visual acuity and color vision and cecocentral scotomata, similar to those of other nutritional optic neuropathies. At autopsy, spongy degeneration of the optic nerves is usually found. In a model of dietary vitamin B12 deficiency in monkeys, neuropathologic examination revealed loss of ganglion

cells in the macula with early involvement of the maculopapillary bundles, extending to the retrobulbar portion of the optic nerves. CNS changes in the monkeys occurred after 33–45 months of deficiency, similar to the time required to produce vitamin B12 deficiency in humans. Sensory peripheral neuropathy also occurs in vitamin B12 deficiency, with a typical stocking-and-glove distribution, with loss of vibratory perception increasing the sensory symptoms due to dorsal column involvement. Unusual forms of presentation of vitamin B12 deficiency include cranial neuropathies with hoarseness from vocal cord paralysis, disturbances of taste and smell, tinnitus; nocturnal tabetic-type pains, upward or lateral gaze limitation, cerebellar dysfunction, and movement disorders occur in addition to the typical myelopathic manifestations. Cognitive and neuropsychiatric symptoms are frequently observed in patients with myelopathy from pernicious anemia; in some patients these were the presenting features (Garcia et al., 2004; Garcia and Zanibbi, 2004; Vogel et al., 2009). Diagnosis. The diagnosis of vitamin B12 deficiency from pernicious anemia is usually made in the presence of positive anti-IF antibodies, low levels of vitamin B12, and increased levels of homocysteine and MAM. Macrocytic anemia and neutrophil polysegmentation need not be present. Treatment. Neurologic complications of vitamin B12 deficiency are treated with intramuscular injections of 1000 mg of vitamin B12 daily for 5 days to replenish the stores, followed by monthly injections of 500–1000 mg indefinitely. Nasal spray and sublingual vitamin B12 are available. For preventive treatment, oral preparations of vitamin B12 appear to be adequate.

Toxic-nutritional myelopathies Two geographically well-defined conditions will be described: tropical ataxic myeloneuropathy in Nigeria and epidemic neuropathy in Cuba.

TROPICAL ATAXIC MYELONEUROPATHY This condition, also known as endemic ataxic polyneuropathy or tropical ataxic neuropathy (TAN) was first observed in an endemic area in southwestern Nigeria, in places where the diet depends almost exclusively on cassava (Osuntokun, 1968; Oluwole et al., 2000). In the 1960s, this toxic-nutritional myeloneuropathy used to reach estimated prevalences as high as 18–26 per 1000, with equal sex distribution. Onset was usually in the third and fourth decades. The chronic and slowly progressive syndrome is characterized by predominantly sensory polyneuropathy, posterior column involvement,

TROPICAL MYELOPATHIES optic atrophy, and sensorineural deafness. Symptoms include painful paresthesias in the legs, numbness, “burning feet,” and cramps. On examination there is impaired vibratory perception distally in the feet, and loss of knee and ankle reflexes. Two-thirds of the patients have incoordination of the legs and broad-based ataxic gait. Weakness and atrophy of distal leg muscles, mainly the peroneal-soleus muscles, may also occur. Other symptoms include blurring of vision with eventual bilateral optic atrophy (81%), and tinnitus followed by bilateral nerve deafness (36%). A few patients have pyramidal signs. About 40% of patients present skin and mucosal lesions suggestive of vitamin deficits. In other African countries such as Senegal, similar syndromes have been observed in malnourished populations, although not necessarily in association with high cassava intake. The frequency of visual loss (19%), deafness (13%), and mucocutaneous lesions (15%) is much lower in these patients than in those from Nigeria. Oluwole and colleagues (2000, 2002, 2003) conducted extensive studies on the role of chronic cyanide ingestion in ataxic neuropathy in Nigeria. Exposure to cyanide from cassava foods was proposed as the major causal factor. However, occurrence of ataxic polyneuropathy is rare in many parts of the tropics where cassava foods are the major source of calories. Consumption of cassava foods and exposure to cyanide from cassava foods were compared in the endemic and nonendemic areas. Efficiencies of the methods of processing cassava roots to gari and lafun, two common cassava foods in Nigeria, were compared, and changes in the level of cyanogenic compounds in gari during storage were studied. No association of occurrence of ataxic polyneuropathy and exposure to cyanide from cassava foods was demonstrated. In Nigeria, exposure to cyanide from cassava foods varies widely due largely to differences in the frequency of intake of cassava foods and the amount of cyanogenic compounds in cassava foods resulting from the method of processing cassava roots, the duration of storage of cassava, and the method of preparation of the meals. A reduction of exposure to cyanide from cassava foods was recommended. Other clinical syndromes associated with malnutrition and chronic cyanide intoxication included konzo, nerve deafness and tropical (nutritional) amblyopia. The latter is probably clinically identical to the retrobulbar neuropathy of pernicious anemia due to vitamin B12 deficiency. The common element in all the above conditions is the underlying deficit of micronutrients, in particular B-group vitamins, folic acid, and sulfur amino acids. Differential diagnosis should include methyl alcohol intoxication, a common cause of epidemic blindness in the tropics resulting from consumption of adulterated alcohol.

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Konzo This is the traditional name given in Kwango, Congo, to a form of epidemic spastic paraparesis described during times of drought and famine in cassava-staple areas (Rosling, 1986; Tylleska¨r et al., 1992; Tylleska¨r, 1994; Rosling and Tylleska¨r, 1996). Epidemics have occurred in rural areas of Mozambique, Tanzania, Zaire (Congo), and the Central African Republic. The disease predominates in children (63%) and lactating women, with prevalences ranging from 29 to 34 per 1000. Women and children eat raw and sun-dried, uncooked bitter cassava, whereas men normally eat well-cooked cassava. Traditional methods of cassava preparation in Africa such as soaking, fermentation and sun-drying leave substantial amounts of cyanogenic glycosides in the cassava meal. Signs of acute cyanide intoxication are present, followed by a clinical picture characterized by sudden onset of nonprogressive spastic paraparesis with flexion contractures of hamstrings and Achilles tendons developing later. Scissoring gait and toe walking are frequently present and patients require one or two sticks to walk. Increased tone in the lower limbs, hyperreflexia, ankle clonus, and Babinski signs are usually present. There is no sensory loss to light touch or pinprick. Impairment of rapid movements and hyperreflexia in the upper limbs are also present. About half the patients have optic neuropathy with decreased visual acuity, visual fields deficits with cecocentral scotomata and pallor of the temporal optic disc. Abnormal visual evoked potentials also occur. Pendular nystagmus and dysarthria may be found. There is minimal recovery with a nutritious diet and vitamin therapy.

CUBAN EPIDEMIC MYELONEUROPATHY A cluster of nutritional myeloneuropathies was observed in Cuba in 1993 (Roma´n, 1994). Epidemiology. This epidemic neuropathy affected 50 862 patients during 1991–1994 (CDC, 1994) with an incidence rate of 462 cases per 100 000. Most cases occurred between ages 25 and 64 years while children, adolescents, pregnant women and the elderly were rarely affected. The highest rates were found in the tobaccogrowing province of Pinar del Rı´o. Patients were farmers, with lower income and less education than healthy controls. Clinical manifestations. Clinical manifestations included retrobulbar optic neuropathy, sensorineural deafness, predominantly sensory and autonomic neuropathy, and dorsolateral myelopathy. Less often dysphonia, dysphagia, and spastic paraparesis were present. Mixed forms were frequent. Neurologic

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symptoms were preceded by weight loss, anorexia, chronic fatigue, lack of energy, irritability, sleep disturbances, and difficulties with concentration and memory. The most common form of spinal cord involvement was a dorsolateral myelopathy presenting with sensory symptoms along with complaints of leg weakness, increased urinary frequency, impotence in males, and difficulty walking. These cases often had brisk knee reflexes with crossed adductor responses contrasting with decreased ankle reflexes. Spasticity and Babinski signs were usually absent. Proximal motor weakness was present in one-third of these cases. Significant decrease in position sense in the feet, and a positive Romberg sign, were often present. Severe cases had sensory gait ataxia. The majority of cases had optic neuropathy characterized by blurred vision, photophobia, central and cecocentral scotomata, deficit of color vision for red and green, and loss of axons in the maculopapillary bundle with temporal disc pallor in advanced cases. One-third of the patients presented concomitant skin and mucous membrane lesions, evidence of peripheral nerve and spinal cord involvement and 20% had hearing loss. Symptoms of peripheral neuropathy included painful dysesthesias in soles and palms, mainly burning feet, numbness, cramps, and paresthesias. Nerves were sensitive to pressure. Motor involvement was minimal. Objective signs were often mild and included loss or decreased perception of vibration, light touch, and pinprick distally in the limbs in a stocking-glove pattern. Achilles tendon reflexes were decreased or absent. Motor nerve conduction velocities were normal and sensory nerve potential amplitudes were decreased only in severe cases. Some patients presented a sensation of body heat with excessive sweating, as well as coldness and hyperhidrosis of hands and feet. Sural nerve biopsies showed an axonal neuropathy with predominant loss of myelinated large caliber fibers (Borrajero et al., 1994). Patients with sensorineural deafness complained of high-pitch tinnitus and deafness. Pure tone audiometry demonstrated high frequency (4–8 kHz) hearing loss, bilateral and usually symmetrical. There were no associated vestibular symptoms. Etiology. Possible etiologies excluded were toxic (organophosphorus pesticides, chronic cyanide, trichloroethylene), genetic such as mitochondrial mutations of Leber’s hereditary optic neuropathy (Newman et al., 1994), and infectious causes (retroviruses such as HIV and HTLV-1/2, Coxsackie viruses). According to the Cuba Neuropathy Field Investigation Team (1995), factors associated with greater risk of optic neuropathy were the following: use of tobacco, in particular cigar smoking – those who smoked  4 cigars per day had the highest risk, lack of food for several days, eating lunch < 5 days per week, and eating breakfast < 1/week.

Protective factors included having relatives overseas (probably because with US dollars it was possible to buy supplementary food in the black market) and raising chickens at home (perhaps because of the nutritional value of eggs in terms of B-group vitamins and sulfurcontaining amino acids). High levels of lycopene (a nonvitamin A carotenoid antioxidant found in tomatoes, guavas, watermelons, and other red fruits) provided the strongest association with protection. Consumption of riboflavin, an antioxidant, was also protective. In summary, the etiology was basically nutritional with an added toxic component from tobacco use. Treatment and prevention. Marked improvement of vision was obtained with parenteral B-group vitamins and folic acid. Therefore, despite the absence of overt malnutrition in Cuba, a deficit of B-group vitamins, mainly cobalamin and thiamine, compounded by lack of essential sulfur-amino acids in the diet, was the cause of the outbreak. Cuba had eliminated childhood malnutrition and nutritional supplementation programs for children, pregnant women, and the elderly were maintained despite enormous difficulties resulting from political reasons. This explains the absence of cases in these groups so often affected by nutritional neuromyelopathies in the tropics.

TOXIC MYELONEUROPATHIES Cyanide A number of staple foods in the tropics contain large amounts of cyanogenic glycosides. These plants include cassava (Manihot esculenta, Crantz; yuca Spa., manioc Fr.), yam, sweet potato, corn, millet (Sorghum sp.), bamboo shoots, and beans such as Phaseolus vulgaris, particularly lima beans and the small black lima beans which grow wild in Puerto Rico and Central America. Tobacco smoke (Nicotiana tabacum) also contains considerable amounts of cyanide (150–300 mg per cigarette). Hydrolysis of plant glycosides releases cyanide as hydrocyanic acid. Intoxication occurs by rapid cyanide absorption through the gastrointestinal tract or the lungs. Detoxification is mainly to thiocyanate in a reaction mediated by a sulfur-transferase (rhodanase), which converts thiosulphate into thiocyanate (SCN) and sulfite. Thiocyanate is a goitrogenic agent that may be responsible for endemic cretinism in some tropical areas. The sulfur-containing essential amino acids (cystine, cysteine, and methionine) provide the sulfur for these detoxification reactions. Also important is vitamin B12 with conversion of hydroxocobalamin to cyanocobalamin. Cassava is a root-crop consumed in large quantities throughout the tropics and constitutes the major source of calories for some 300 million people. In Africa, cassava is the staple diet in western Nigeria, Congo, Tanzania, Senegal, Uganda, and Mozambique. In these

TROPICAL MYELOPATHIES countries, a number of neurologic disorders have been associated with high dietary intake of cyanogenic glycosides in association with depletion of sulfur-containing amino acids. However, it should be noted that these problems are not common in Latin America, even though the cassava consumption in countries such as Brazil is among the highest in the world.

Lathyrism Bruyn and Poser (2000) have extensively reviewed the history of lathyrism. Known since classic times, lathyrism is the cause of epidemic outbreaks of spastic paraparesis in the tropics. Lathyrism is caused by excessive dietary consumption of peas of the Lathyrus family, especially L. sativus (chickling pea). Lathyrism is still endemic in regions of India, Bangladesh, and Ethiopia and continues to be a public health problem (Ludolph et al., 1987). Previous outbreaks were described in Europe, North Africa, and parts of Asia, mainly in times of war, famine, or drought. The cause is b-N-oxalylamino-L-alanine (BOAA), a neurotoxic amino acid, considered the neurotoxin responsible for the spastic paraparesis of human lathyrism (Spencer et al., 1987). Lathyrism begins after weeks or months of consumption of the peas and usually occurs in a setting of protein-calorie malnutrition. Onset is acute, subacute, or insidious. Cramps in the calf muscles are an early sign followed by increased muscle tone, spasticity, brisk reflexes, and Babinski sign. Sensory loss is typically absent, although by clinical neurophysiology, slight damage to the dorsal columns is also present. The marked spasticity and hypertonia of the thigh extensor and adductor muscles and in the gastrocnemius muscles result in a typical gait on the balls of the feet with a lurching scissoring gait. Eventually there is permanent slight flexion of hips and knees, retraction of Achilles tendons, adductor crossing, and feet in plantar flexion; paraplegia in flexion is the eventual outcome. Neuropathological examination reveals obvious fiber loss in the pyramidal tracts, mainly in the lumbar cord, along with pallor of the fasciculi gracilis and axonal swelling in Goll’s nuclei. Lathyrism is irreversible and there is no specific treatment.

Fluorosis Endemic fluorosis is a condition described initially in some areas of India with high concentrations of fluorine in drinking water (Singh et al., 1963). The condition is characterized by excessive ossification of bones causing compressive myelopathy of the cervical cord and radicular compression. Surgical decompression is indicated (Misra et al., 1988). Public health measures have been implemented to prevent fluorosis.

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Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 103

Neurologic complications of vaccinations AUGUSTO A. MIRAVALLE1 AND TERI SCHREINER2* Department of Neurology, University of Colorado School of Medicine, Aurora, CO, USA

1

2

Department of Neurology, Children’s Hospital, Aurora, CO, USA

INTRODUCTION Disorders of the nervous system have been linked with vaccines since Pasteur’s rabies immunization in 1889 in which a neuroparalytic syndrome was associated with vaccination (Warrell, 1976). Since then, vaccines have been linked to encephalitis, Guillain–Barre´ syndrome (GBS), seizures, headaches, cranial neuropathies, and demyelinating disorders, to name a few. More recently, a proposed link between autism and vaccination has created a distrust of vaccinations, both in the US and elsewhere, that has limited vaccination efforts. In general, establishing causality is much more difficult than identifying an association. Within the US, there are governmental organizations established to detect potential associations, so that research may be targeted towards understanding these potential causal relationships. In 1990, the Vaccine Adverse Events Reporting System (VAERS) was established as a means of passive, postmarketing surveillance of adverse health events temporally related to vaccination. VAERS is operated jointly by the Centers for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA). Providers, healthcare workers and the public are encouraged to report to VAERS clinically significant adverse events following vaccination. However, causality cannot be determined solely by reports to VAERS. One of the major limitations to VAERS is the potential propensity towards underreporting; all data are compared against the number of vaccines distributed rather than the number of vaccines administered; and VAERS reports require only a preliminary diagnosis, which may not actually reflect the patient’s diagnosis. The Vaccine Safety Datalink (VSD) is collaborative endeavor between the CDC and eight managed-care organizations with a total of 9.5 million members.

VSD utilizes administrative data and electronic medical records to collect information on vaccinations and healthcare encounters to monitor vaccine safety. VSD has the capability to test and strengthen hypotheses generated through VAERS reports. VSD can quickly identify significant adverse events following immunization that may be worrisome enough to consider changing vaccine recommendations. VSD also conducts planned immunization safety studies as well as timely investigations of hypotheses that arise from review of medical literature, changes in immunization schedules, or the introduction of new vaccines. The Clinical Immunization Safety Assessment (CISA) Network is a project between six academic centers in the US which conduct research on adverse events that might be caused by vaccines. In assessing vaccine safety, it is important to know the background rates of disease in the population in order to identify legitimate safety concerns from events that are temporally associated, but not caused by vaccination. Causality is supported when an adverse event (AE) is reproduced (a positive re-challenge test) upon subsequent exposure to the same vaccine. The Code of Federal Regulations (Regulations) defines serious AEs as those that are reported as resulting in death, life-threatening adverse experience, hospitalization, prolongation of hospitalization, persistent or significant disability, congenital anomaly/birth defect, or any event that, based on appropriate medical judgment, may jeopardize the patient and may require medical or surgical intervention to prevent these outcomes. Various mechanisms have been proposed to explain the pathophysiology of neurologic adverse reactions following vaccinations. One potential scenario to explain the development of demyelination in postvaccinal encephalomyelitis is by activation of self-reactive

*Correspondence to: Teri Schreiner, M.D., Children’s Hospital, 13123 E. 16th Avenue, Aurora, Colorado 80045, USA. Tel: þ1-303266-1400, E-mail: [email protected]

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Table 103.1 Different types of vaccines with their mechanism of action Vaccine

Mechanism of action

Whole killed Influenza Pertussis Poliomyelitis Rabies Live attenuated viruses Influenza (nasal) Measles Mumps Poliomyelitis (oral) Rotavirus (RotaTeq) Rubella Varicella Yellow fever Conjugate vaccines Hib Meningococcal Pneumococcal conjugate Recombinant vaccines Hepatitis B

Vaccines made from whole killed organisms usually produce an antibody response that provides temporary immunity

Live attenuated virus vaccines are intended to trigger the immune system as the natural infection might yet without causing the disease. Once exposed to the antigen, the immune system produces immunity similar to that conferred by the natural disease. Similarly, denatured toxins can produce immune-mediated response immunity without the disease

These vaccines are created by linking weak, polysaccharide antigens to protein carriers. The combination facilitates a more robust immunologic response. This technique is often used with bacterial polysaccharides to prevent invasive bacterial disease These vaccines are developed by inserting genes for the antigen into a vector. Vectors are often viruses with a very low virulence. Recombinant vaccines have a low incidence of adverse events. Hepatitis B is the only recombinant vaccine currently in use in the US

lymphocytes by the vaccine. Autoreactive T cells can be found in blood, thymus, and secondary lymphoid tissues of healthy individuals, but through the action of suppressive cytokines, remain inactive. If a peptide or epitope present in the vaccine shares molecular similarities to self antigens within the host (i.e., myelin basic protein), an autoimmune phenomenon may occur. This mechanism is known as molecular mimicry. Another potential explanation for immune-mediated neurologic complications following vaccinations is by activation of autoreactive immune cells by cytokines released from host cells after virus-mediated cell death. All vaccines work by triggering the host’s immune system. However, the mechanism of action varies by the type of vaccine (Table 103.1). In this chapter we will review the most common neurologic adverse reactions reported after various vaccinations (Table 103.2).

VIRAL VACCINES Measles, mumps, and rubella Though individual vaccines for measles, mumps and rubella exist, the majority of children vaccinated against these diseases receive either the MMR vaccine or, more recently, the MMRV. MMR was first developed in the late 1960s. At the time that it was introduced, the annual incidence of measles infection was > 100 000 per year.

After the introduction of the vaccine, the incidence of measles infections dropped 100-fold. A second dose of the vaccine was recommended after an increase in number of annual cases in 1990. The second dose was introduced to produce immunity in a small portion of individuals who did not receive immunity from the first dose. More recently, the number of measles infections has been less than 100 per year. The most common neurologic complication of MMR is cerebellar ataxia. Onset usually occurs within 10 days of vaccination. Children less than 2 years old are more affected than other age groups. The overall incidence is less than one case per million vaccines. Each year in the US, nearly 10 million doses of the vaccine are distributed. CDC continues to recommend two doses of MMR vaccine for all children: dose 1 at ages 12–15 months, and dose 2 at ages 4–6 years. There appears to be an increased risk of febrile seizures 1–2 weeks after immunization with the MMR vaccine. A cohort study of almost 680 000 in the US showed a relative risk of febrile seizure following vaccination of 2.8 (Barlow et al., 2001). The same study showed no increased risk of nonfebrile seizures or neurodevelopmental disability following vaccination. The risk of febrile seizure 1–2 weeks after immunization was higher in children who receive the MMRV compared with children who receive separate injections of MMR and varicella vaccine (Marin et al., 2010). However, the

NEUROLOGIC COMPLICATIONS OF VACCINATIONS

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Table 103.2 Various neurological disorders reported to the Vaccine Adverse Event Reporting System (VAERS) Vaccine Viral vaccines MMR Varicella Smallpox Influenza Hepatitis B Poliomyelitis (OPV) Rabies (Semple) HPV JE YF Bacterial vaccines Meningococcal Pneumococcal Hib DtaP Anthrax Lyme

Various neurological complications reported to VAERS

Encephalitis, panencephalitis, aseptic meningitis, ADEM, cerebellar ataxia, parkinsonism, sensorineural hearing loss, seizures, mental retardation, autism, GBS Headaches, stroke, aseptic meningitis, encephalitis, cerebellar ataxia, gait disorders, sleep disorders, autism, developmental abnormalities, neuropathies Headaches, cranial neuropathies, strokes, aseptic meningitis, postvaccinial encephalitis, ADEM, transverse myelitis, multiple sclerosis, poliomyelitis-like syndrome, GBS MS, optic neuritis, CNS demyelinating disease, GBS MS, encephalitis, cerebellar ataxia, strokes, seizures, GBS, transverse myelitis, Bell’s palsy, myasthenia gravis, neuropathy VAPP, seizures, encephalitis Stroke, meningoencephalitis, ADEM, transverse myelitis, seizures, cranial and peripheral neuropathies, GBS, neuroparalytic disease Syncope, dizziness, headaches, GBS Encephalitis, seizures Encephalitis, ADEM, acute hemorrhagic fever, seizures, optic neuritis, cranial neuropathies, GBS, CIDP Encephalitis, meningitis, seizures, AHLE, stroke, demyelinating neuropathy, mononeuritis multiplex Encephalitis, meningitis, TIA, stroke, demyelinating neuropathy Seizures, encephalitis, meningitis, stroke, neuropathy Seizures, encephalitis, meningitis, neuropathy, GBS, CIDP Ulnar neuropathy, ON, GBS Aseptic meningitis, neuropathy, seizures

It is important to emphasize that a causal relationship was not evident in most cases, and some of the disorders listed may reflect an incidental association with the vaccination. MMR, measles-mumps-rubella; ADEM, acute disseminated encephalomyelitis; GBS, Guillain–Barre´ syndrome; MS, multiple sclerosis; CNS, central nervous system; TIAs, transient ischemic attacks; VAPP, vaccine associated paralytic poliomyelitis; HPV, human papilloma virus; JE, Japanese encephalitis; YFV, yellow fever; CIDP, chronic inflammatory polyneuropathy; AHLE, acute hemorrhagic leukoencephalitis; Hib, Haemophilus influenzae type B; DTaP, diphtheria-tetanus-pertussis (acellular); ON, optic neuritis.

overall occurrence of febrile seizure following MMR vaccination is rare: 4–5 cases per 10 000 vaccinations. In the late 1990s The Lancet published an article asserting that MMR vaccination was linked to ileocolonic lymphoid nodular hyperplasia. In the absence of reproducible evidence, this paper has since been retracted. However, the study proposed a mechanism by which nonpermeable peptide could be absorbed enterally. This has fueled an allegation that MMR vaccination can cause autism (Wakefield et al., 1998). This association has been investigated thoroughly, without revealing any scientific support to the hypothesis. Because signs of autism may appear around the same time children receive the MMR vaccine, some parents may worry that the vaccine causes autism. Vaccine safety experts, including experts at CDC and the American Academy of Pediatrics (AAP), agree that MMR vaccine is not responsible for recent increases in the number of children with autism. In 2004, a report by the Institute of

Medicine (IOM) concluded that there is no link between autism and MMR vaccine; unfortunately, there are still groups in the US attesting to the validity of this connection (Generation Rescue). Assertions that neuritis, deafness, and encephalitis occur more frequently among recipients of the mumps vaccine have not been proven.

Varicella vaccine In 1996, the US introduced a program of mass varicella vaccination for children aged 12–18 months (White et al., 1991). The vaccination campaign resulted in a fall in the annual incidence of varicella infection in the US. Some 95% of children immunized will seroconvert after one dose of the vaccine. This live attenuated vaccine is a routine vaccination for children in the US. The varicella vaccine is safe and effective for immunocompetent children, as well as selected immunocompromised children. Discretion is advised with children who are severely

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immunocompromised as the benefit of the vaccine may not outweigh the risk. Neurologic complications following varicella vaccination are extremely rare. Cerebrovascular disease, meningoencephalitis, and cerebellar ataxia have been reported, but no causal link has been identified (Zhou et al., 2003).

Smallpox vaccine Smallpox is an acute contagious disease caused by variola virus, a member of the orthopoxvirus family. Prior to vaccination against smallpox, it was one of the most devastating diseases known to humanity. Smallpox infection killed approximately 30% of those infected. Through history, it also killed Queen Mary II of England, Emperor Joseph I of Austria, King Luis I of Spain, Tsar Peter II of Russia, Queen Ulrika Elenora of Sweden, and King Louis XV of France. In addition to pockmarks, deep scars resulting from the infection, many victims of smallpox became blind. In 1798, Edward Jenner demonstrated that inoculation with cowpox could protect against smallpox. However, smallpox disease was not eradicated worldwide until 1978. Vaccination against smallpox had been discontinued for the general population in the US in 1971. Vaccination of healthcare workers was discontinued in 1976 and of US military personnel in 1990. Since that time, no new smallpox infections have been recognized. Vaccination was reinstated for US military personnel and selected healthcare workers in 2002 given the threat of bioterrorism. Neurologic complications of smallpox vaccination are rare, but severe. Postvaccinal encephalomyelitis, GBS, acute cranial neuropathies, poliomyelitis-like syndrome, and transverse myelitis are among the most commonly reported disorders (Zhou et al., 2003). Postvaccinal encephalitis, the most serious complication, was described in infants, presenting suddenly with encephalopathy and seizures. Recovery is often incomplete, leaving the patient with cerebral impairment and paralysis.

Influenza Influenza epidemics occur each winter and are a significant cause of morbidity and mortality. On average, more than 200 000 people in the US are hospitalized due to complications of influenza infection. Approximately 36 000 die as a result of influenza infection yearly. The elderly and the young are disproportionately affected. Influenza vaccines must be adjusted annually in response to antigenic drift – the process whereby point mutations arise during viral replication. Each influenza vaccine includes two A viruses and one B virus. The effectiveness of the vaccine depends on the vaccine developers’ ability to predict which strains will be circulating during the flu season. When the match of

predicted strains and actual season’s strains is close, the effectiveness of the vaccine is 70–90%. Two types of seasonal influenza vaccines are available: trivalent inactivated vaccine (TIV) and live attenuated influenza vaccine (LAIV). The US Food and Drug Administration (FDA) approved the first nasal live virus flu vaccine in 2003. As a live virus vaccine, the immune system is triggered in a manner similar to native infection. In addition to robust immune response from live virus response, other advantages include: ease of administration, subsequent mucosal and systemic immune responses, and long-term memory (Couch, 2004). An adjuvant is required for optimal response. LAIV is approved for use in healthy people 5–49 years old who are not pregnant. TIV is recommended for children 6 months to 23 months of age and adults older than 65 years. TIV is also recommended for people with chronic disease who are at increased risk of influenza infection. Several neurologic complications have been linked to the influenza vaccine. Facial palsy is one complication that was historically linked to the nasal influenza vaccine. Facial palsy is a common neurologic disorder with incidence of approximately 20 per 100 000. The etiology of facial palsy is not clear. Following the introduction of newly licensed intranasal influenza vaccine in Switzerland in October 2000, 46 cases of facial palsy were noted among people who received the vaccine. Following this report, the vaccine was removed from the market.

Influenza (trivalent inactivated vaccine) Perhaps the most notorious neurologic complication of trivalent inactivated vaccine (TIV) influenza vaccination occurred during the 1976–1977 influenza season. That year a vaccine against a swine-origin influenza virus was associated with a small, but statistically significant, increased risk of GBS. The incidence of GBS rose above the background rate of 10 cases per 1 million persons vaccinated (attributable risk: 1 per 100 000 vaccinees, a sevenfold increase in risk). The immunization campaign was discontinued prematurely after this increased incidence was identified. Further analysis identified a likely causal association between TIV and GBS for that seasonal vaccine only. The proposed mechanism was immune system response to Campylobacter jejuni antigens present in the vaccine. There is no evidence to support a proposed link between influenza vaccination and multiple sclerosis relapse (Miller et al., 1997). On the contrary, among patients with relapsing and remitting multiple sclerosis, more exacerbations are seen after influenza illness than after influenza vaccination. Annual influenza vaccination, preferably with inactivated vaccines, should be

NEUROLOGIC COMPLICATIONS OF VACCINATIONS offered to all patients with relapsing and remitting multiple sclerosis. Contraindications to influenza vaccinations include: fever, immune-suppression, or a history of GBS.

Influenza (H1N1) The FDA licensed the first 2009 influenza A (H1N1) monovalent vaccine in September 2009. Similar to yearly influenza vaccinations, the H1N1 vaccine was available both as a live, attenuated monovalent vaccine (LAMV) for intranasal administration and as a monovalent, inactivated, split-virus or subunit vaccine for injection (MIV). The H1N1 vaccine became available on October 5, 2010. Routine monitoring in the first months following vaccine release showed 82 adverse event reports per 1 million H1N1 vaccine doses, and 47 cases per 1 million seasonal influenza doses. Although the number of adverse event reports was greater than that of the seasonal influenza vaccine, there was no difference in the type or proportion of serious adverse events reported. By November 24, VAERS had received 10 reports of GBS, and two additional cases of possible GBS. Preliminary reports indicate that four of these 12 potential cases of GBS were confirmed by Brighton Collaboration criteria. No cases of GBS were reported in the VSD system during the same time period. VSD detected no increased incidence of demyelinating disease, peripheral nervous system disease, seizure, encephalomyelitis, facial palsy, other cranial nerve disorders, or ataxia during that time period (CDC-2009, 2009).

Hepatitis B vaccine Infection with hepatitis B virus may be subacute with nonspecific symptoms, clinically apparent with jaundice, or life-threatening with fulminant hepatitis. Vaccination against hepatitis B began with an inactivated plasmaderived vaccine in 1981. Shortly after, the first report of a demyelinating process after hepatitis B vaccination was reported. The patient suffered a case of transient inflammatory polyradiculoneuropathy (Shaw et al., 1988). A series of demyelinating disorders, including relapsing and remitting multiple sclerosis, optic neuritis, transverse myelitis, and GBS, were later described in patients with recent vaccination with hepatitis B. In 1986, a genetically engineered, recombinant vaccine was developed. Since then, few cases of cerebellar ataxia, demyelinating polyneuropathy, and other neurologic disorders have been reported. In 1988, a case of myasthenia gravis possibly triggered by the administration of hepatitis B vaccine was reported (Biron et al., 1988). However, a causal relationship was never established and this is likely to represent a temporal association only.

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Poliovirus vaccine Poliomyelitis is a viral infection spread by fecal–oral transmission. Polioviruses are enteroviruses, and consist of serotypes 1, 2 and 3. Most individuals (95%) have an asymptomatic infection. Between 1% and 5% may develop neurologic manifestations including aseptic meningitis, sometimes with paresthesias, and paralytic disease (Zhou et al., 2003). Paralytic disease is characterized clinically by rapid onset of asymmetric acute flaccid paralysis with areflexia of the involved limb. Since 1979, the only cases of paralytic polio have occurred as a result of vaccination. Two vaccines have been developed to prevent polio infection: the inactivated polio vaccine and oral polio vaccine. The inactivated polio vaccine, made of killed poliovirus, is administered subcutaneously or intramuscularly. Seroconversion occurs in almost all vaccines after three doses of the vaccine, with an excellent and long-lasting immune response to all three poliovirus types. However, the inactivated polio vaccine confers little immunity in the intestinal tract, increasing the risk of wild-type poliovirus circulation in the community. The oral polio vaccine, a live polio vaccine, is taken orally and thus resembles the fecal–oral route of transmission of the virus. By introducing the vaccine in this manner, the oral vaccine produces better local (mucosal) immunity. In addition to superior immunogenicity, the oral polio vaccine has a lower cost and an easier route of administration. The most serious disadvantage is the risk of vaccine-associated paralytic polio. The CDC estimate that there is one case of vaccine-associated paralytic poliomyelitis per 2.5 million doses of oral polio virus vaccine. The risk is highest after the first dose of the vaccine, resulting in one case per 790 000 doses administered (CDC-2006, 2006). Close contacts of vaccinees can also develop vaccine-associated paralytic poliomyelitis with an estimated incidence of 1 case per 6.4 million doses. In developing countries malnutrition, vaccine instability, vaccine formulation, inhibitory substances in the intestine or the presence of other gastrointestinal viruses may interfere with the replication of the attenuated polio vaccine viruses, and the account for a decrease in the effectiveness of the vaccine. The inactivated poliovirus vaccine is used for all routine polio vaccination in the US.

Rabies vaccine Infection with rabies virus characteristically produces an acute illness with rapidly progressive central nervous system manifestations, including anxiety, dysphagia, and seizures (Pickering et al., 2006). Illness almost invariably progresses to death. Worldwide, rabies causes

1554

A.A. MIRAVALLE AND T. SCHREINER

more than 50 000 deaths per year. There is no treatment once symptoms have begun. The high mortality associated with rabies infection significantly outweighs the risk of vaccination among exposed individuals. Pasteur developed the rabies virus vaccine in 1885 by using a suspension of dried spinal cord tissue infected with an attenuated rabies virus. Despite the development of newer and safer vaccines, an attenuated-virus vaccine similar to the one Pasteur developed is still widely used in many parts of the world. The Semple vaccine is a suspension of phenol or b-propiolactone killed virus in sheep brain. The incidence of neurologic complications with Semple vaccine is approximately one case per 220 vaccinees (Srivastava et al., 2004). Reported reactions include encephalomyelitis, transverse myelitis, acute polyradiculoneuropathy and peripheral neuropathy (Dutta and Dutta, 1994). Neurologic complications following Semple-type vaccine are attributed to myelin basic protein and some of the ganglioside and phospholipid constituents present in the vaccine. In 1997 the FDA licensed a new rabies vaccine for both pre-exposure and postexposure prophylactic use in humans. This purified child embryo cell culture vaccine has been shown to be safe and effective. Few minor neurologic adverse events have been reported. Given the lethality of the disease, there are no contraindications for postexposure vaccination (Schlenska, 1976).

Human papilloma virus In 2006, the FDA licensed the quadrivalent human papillomavirus recombinant vaccine. The vaccine is targeted against HPV types 6, 11, 16 and 18. Types 16 and 18 account for 70% of cervical cancer worldwide (Slade et al., 2009). HPV types 6 and 11 are common causes of genital warts. Shortly after the vaccine was approved for use, the Advisory Committee on Immunization Practices (ACIP) recommended routine vaccination for all girls aged 11– 12 years. Within the first 21 =2 years of distribution, VAERS received over 12 000 reports of adverse events, a rate of 53.9 reports per 100 000 doses of vaccine distributed. The most common adverse events reported were syncope, dizziness, and headache. Rare cases of transverse myelitis, GBS, and two cases of amytrophic lateral sclerosis, were reported (Slade et al., 2009). At this time, it does not appear that HPV vaccination was causally associated with any of these cases. Research is ongoing.

Japanese encephalitis Japanese encephalitis (JE) is a serious lifethreatening viral infection. It is the leading cause of viral encephalitis in Asia with a reported incidence of 50 000 cases per year (Nakayama and Onoda, 2007). Two types of killed JE virus vaccines are commercially available, an inactivated vaccine manufactured in Japan and Korea, and a killed

vaccine prepared in China. Also, a live attenuated vaccine has been developed in China with good efficacy. In December 1992, a JE virus inactivated vaccine was licensed for use in the US (JE-VAX). A new, live attenuated vaccine (ChimeriVax-JE) is in early clinical trials and appears to be well tolerated and immunogenic after a single dose. Encephalitis or generalized seizures have been reported after inactivated vaccines, with an estimated incidence of 1 case per 50 000 vaccinees (Marfin et al., 2005). JE immunizations are recommended for all persons living in endemic areas for JE virus, as well as for persons who are traveling to an endemic region during an endemic season. For travelers, the recommended schedule consists of three doses to be completed at least 10 days prior to exposure.

Yellow fever Yellow fever is an acute viral disease caused by a mosquito-borne flavivirus. It is endemic in at least 40 countries in Africa and South America. Yellow fever infection accounts for 200 000 cases worldwide and 30000 deaths per year (Marfin et al., 2005). The yellow fever vaccine is a live attenuated virus preparation that confers immunity within 1 week to 95% of vaccines. A single dose provides protection for 10 years, and may provide lifelong immunity. In the US vaccine type 17D204 is the only commercially available vaccine. Immunization is recommended for all people 9 months or older living in or traveling to endemic areas. Vaccine-associated neurotropic and viscerotropic diseases are rare, but well recognized adverse events (Pickering et al., 2006). The vaccine-associated neurotropic disease is the most common serious adverse event, especially among children. For this reason, children less than 4 months old are not recommended to receive the vaccine. In a series of 23 cases of encephalitis associated with yellow fever vaccines (strain 17D), 16 cases occurred in children younger than 9 months (McMahon et al., 2007). Analysis of these cases shows that vaccine-associated neurotropic disease can occur up to 30 days after vaccination. Clinically, neurologic adverse events can present as encephalitis, meningoencephalitis, myelitis, acute disseminated encephalomyelitis (Fig. 103.1) (Miravalle et al., 2009), retrobulbar optic neuritis, seizures, cranial neuropathies, GBS, and acute hemorrhagic fever among others.

BACTERIAL VACCINES Haemophilus influenzae type b (Hib), meningococcal, and pneumococcal vaccines Hib vaccination confers protection by induction of anticapsular antibodies and immunologic memory. Conjugate Hib vaccines were introduced during the 1990s with an immediate decline in the incidence of Hib. Rare cases

NEUROLOGIC COMPLICATIONS OF VACCINATIONS

1555

Fig. 103.1. (A) Magnetic resonance image (MRI) of the brain showing areas of high signal intensity on fluid attenuation inversion recovery (FLAIR) in the left middle cerebellar penduncle and right dorsal medulla oblongata. (B) T2-weighted magnetic resonance image (MRI) shows an extensive multilevel linear area of high signal intensity along the cervicothoracic spinal cord.

of GBS were documented following the administration of conjugated Hib, but there is inadequate evidence to accept or reject a causal relationship (Rosenstein and Feikin, 2004). The first vaccine to protect against meningococcal meningitis was developed in 1978. It was not until 2000 that the ACIP recommended that students in colleges and universities receive the vaccination. The ACIP later recommended that all children aged 11–12 years, students entering high school, and college students be vaccinated. Eighteen confirmed cases of GBS following meninogococcal conjugate immunization were published in 2005 (CDC-2005, 2005). A causal relationship has not been proven (CDC-2005, 2005). Few cases of seizures, aseptic meningitis, encephalitis and demyelinating polyneuropathy have been reported in association with pneumococcal conjugate and Pneumovax, but no causal relationship can be confirmed in any of those cases (Zhou et al., 2003).

Diphtheria-tetanus-pertussis vaccine Pertussis immunization originally consisted of inactivated whole cell Bordetella pertussis. This was first recommended as a vaccine in 1944 and combined with diphtheria and tetanus toxoids in 1947. Shortly after, Brody and Sorley documented the case of an infant who had episodes of generalized hypotonia and weakness followed by paralysis and decreased level of consciousness shortly after injection of pertussis vaccine (Brody and Sorley, 1947). Subsequently, various cases

of similar episodes were recognized as temporally associated with pertussis vaccination. Later, a large retrospective analysis suggested an estimated incidence of seizures of one in 1750 vaccinees (Berg, 1958). Whole cell pertussis contains an endotoxin, which is known to cause fever and localized injection site pain. A more serious condition consisting of seizures, irritability, obtundation, and hypotonia has been rarely reported and given credence by the Institute of Medicine (Bolukbasi and Ozmenoglu, 1999). This so-called hypotonic, hyporesponsive episode (HHE) has been reported in one in 1750 administrations of pertussis immunization (Stratton and Johnston, 1994). Subsequently, whole cell pertussis vaccine has been replaced by the acellular vaccine. The result has been a marked decrease in the incidence of reported severe neurologic reactions. Seizures, which rarely occur following this immunization, are now simply thought to represent febrile convulsions. Other complications of pertussis vaccine have been greatly reduced by the acellular pertussis antigen, but are still rarely reported. If the child does have an encephalopathic reaction with seizures and or alteration of the level of consciousness, no additional pertussis immunization should be given. In particular, caution should be exercised if seizures occur within 3 days of the immunization or if inconsolable crying occurs lasting more than 3 hours. If hypotonia and diminished responsiveness occur within 48 hours, or if a high fever occurs within 48 hours, further exposure to the attenuated pertussis antigen is contraindicated. Furthermore, the American Academy of Pediatrics recommends deferring pertussis

1556 A.A. MIRAVALLE AND T. SCHREINER immunization if the child has a history of significant Adjuvants developmental delay, and particularly if an early proVaccine adjuvants are sometimes added to improve gressive or degenerative disease is suspected. Other conimmune responses to vaccines, although addition of traindications include an active seizure disorder or an adjuvant can sometimes increase local side-effects, conditions known to predispose to epilepsy such as such as pain at the injection site. Thimerosal (thiomersal) tuberous sclerosis. However, static encephalopathies is a preservative that contains ethyl mercury and is used such as cerebral palsy and a family history of epilepsy in some vaccines and immunoglobulins. are not necessarily a contraindication. Neurologic The antrhrax vaccine (anthrax vaccine adsorbed, adverse events following tetanus toxoid have been AVA) is linked to few medically important adverse reported including acute and chronic demyelinating events. However, the Anthrax Vaccine Expert Commitpolyradiculoneuropathies. To date, no neurologic tee (AVEC) found that the aluminum-adjuvanted AVA adverse reactions have been attributed to diphtheria toxvaccine administered subcutaneously over the triceps oid (Zhou et al., 2003). could induce swelling sufficient to pinch the ulnar nerve and cause distal paresthesias (Sever et al., 2004).

Anthrax Anthrax is one of the oldest diseases of grazing animals. It is transmitted by spores from Bacillus anthracis. The spores are incredibly resilient, reportedly persisting in soil decades after host death. Currently, the only available anthrax vaccine available in the US is BioThrax, prepared from a cell-free culture filtrate. The anthrax vaccine, formerly known as Anthrax Vaccine Adsorbed (AVA), developed in 1970, was offered to individuals felt to be at risk of exposure. Only a minority of those who were offered the vaccine accepted the vaccine secondary to perceived threat of vaccination (Niu et al., 2009). The Anthrax Vaccine Expert Committee (AVEC) reviewed the data from VAERS between March 1988 and January 2007. Their evaluation reported few rare events associated with vaccination. Of the adverse events listed, few were neurologic. The neurologic adverse events included localized edema at the site of injection that caused ulnar nerve impingement resulting in paresthesias. Other neurologic sequelae: optic neuritis, GBS and facial palsy, were not felt to be causally linked. Among the 25 patients who died following AVA immunization (per VAERS reports), three died of amyotrophic lateral sclerosis (ALS). Two of these diagnoses occurred temporally, while the third occurred 7 years later. No causal link has been proposed. Likewise, 11 cases of multiple sclerosis were reported to VAERS. These cases are not thought to be linked to immunization.

Other bacterial vaccines Cognitive impairment, CIDP, multifocal motor neuropathy, and sensory axonal neuropathy have been described in patients receiving recombinant Lyme vaccine (Latov et al., 2004). Headaches, transverse myelitis, and seizures have been also reported following typhoid vaccination (Das and Jaykumar, 2007).

CONCLUSION Prevention of infectious diseases through immunization is one of the greatest public health accomplishments of the past century. In the last decades, new vaccines have become available to prevent various infectious diseases and improved vaccines have been developed. As a result, immunization strategies have changed the epidemiology of various diseases. Indeed, the epidemiology of disease has been markedly altered by the successes of the Haemophilus influenza type b, smallpox and polio vaccines. Prior to introduction of the conjugate vaccine, the incidence of Hib meningitis was between 10 000 and 20 000 per year in the US and Canada. Some 3% of those patients died from the infection. Of the survivors, 25% were left with neurologic disability as a result (Wenger, 1998). Polio has been eradicated from North America following vaccination programs. The World Health Organization reports only four countries with endemic polio (WHO). Likewise, vaccination against smallpox was so successful that vaccination ceased worldwide by 1986. Like all therapies, vaccination also carries certain risks. Even though vaccines are tested in clinical trials prior to introduction to the public, clinical studies are generally not large enough to detect the development of rare adverse effects. In recent years numerous controversies and allegations surrounding immunization safety have been reported with significant impact on public health policies and overall public trust. However, the risk of serious events caused by existing vaccines is very small. Neurologic adverse events following immunization may be caused by the active antigen in the vaccine or other constituents, such as adjuvants, or may merely be coincidental. In most cases, the absence of distinguishing clinicopathologic findings and the lack of biologically proven putative association between vaccinations and neurologic injury make it difficult to determine a coincidental or causative relationship. In addition, most of the

NEUROLOGIC COMPLICATIONS OF VACCINATIONS evidence incriminating vaccines as a cause of neurologic disorders has been based on case reports. In order to better determine the nature of this relationship, well controlled epidemiologic studies are necessary.

REFERENCES Barlow WE, Davis RL, Glasser JW et al. (2001). The risk of seizures after receipt of whole-cell pertussis or measles mumps and rubella vaccine. N Engl J Med 345: 656–661. Berg JM (1958). Neurological complications of pertussis immunization. Br Med J 2: 24–27. Biron P, Montpetit P, Infante-Rivard C et al. (1988). Myasthenia gravis after general anesthesia and hepatitis B vaccine. Arch Intern Med 148: 2685. Bolukbasi O, Ozmenoglu M (1999). Acute disseminated encephalomyelitis associated with tetanus vaccination. Eur Neurol 41: 231–232. Brody M, Sorley RG (1947). Neurologic complications following the administration of pertussis vaccine. N Y State J Med 47: 1016. CDC-2005 (2005). Guillain–Barre´ syndrome amoung recipients of Menactra meningococcal conjugate vaccine – United States June–July 2005. MMWR Morb Mortal Wkly Rep 54: 1023–1025. CDC-2006 (2006). Imported vaccine-associated paralytic poliomyelitis – United States 2005. MMWR Morb Mortal Wkly Rep 55: 97–99. CDC-2009 (2009). Safety of influenza A (H1N1). 2009 monovalent vaccines – United States October 1–November 24, 2009. MMWR Morb Mortal Wkly Rep 58: 1351–1356. Couch RB (2004). Nasal vaccination Escherichia coli enterotoxin and Bell’s palsy. N Engl J Med 350: 860–861. Das RN, Jaykumar J (2007). Acute transverse myelitis following typhoid vaccination. Ulster Med J 76: 39–40. Dutta JK, Dutta TK (1994). Rabies in endemic countries. BMJ 308: 488–489. Latov N, Wu AT, Chin RL et al. (2004). Neuropathy and cognitive impairment following vaccination with the OspA protein of Borrelia burgdorferi. J Peripher Nerv Syst 9: 165–167. Marfin AA, Eidex RS, Kozarsky PE et al. (2005). Yellow fever and Japanese encephalitis vaccines: indications and complications. Infect Dis Clin North Am 19: 151–168, ix. Marin M, Broder KR, Temte JL et al. (2010). Use of combination measles mumps rubella and varicella vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 59: 1–12. McMahon AW, Eidex RB, Marfin AA et al. (2007). Neurologic disease associated with 17D-204 yellow fever vaccination: a report of 15 cases. Vaccine 25: 1727–1734. Miller AE, Morgante LA, Buchwald LY et al. (1997). A multicenter randomized double-blind placebo-controlled trial of influenza immunization in multiple sclerosis. Neurology 48: 312–314. Miravalle AA, Biller J, Emanuel S et al. (2009). Acute disseminated encephalomyelitis: yellow fever vaccination. Arq Neuropsiquiatr 67: 710–711.

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Nakayama T, Onoda K (2007). Vaccine adverse events reported in post-marketing study of the Kitasato Institute from 1994 to 2004. Vaccine 25: 570–576. Niu MT, Ball R, Woo EJ et al. (2009). Adverse events after anthrax vaccination reported to the Vaccine Adverse Event Reporting System (VAERS) 1990–2007. Vaccine 27: 290–297. Pickering LK, Baker CJ et al. (Eds.), (2006). Red Book: 2006 Report of the Committee on Infections Diseases. American Academy of Pediatrics, Elk Grove Village IL. Regulations. Code of Federal Regulations. Post-marketing reporting of adverse experiences. Rosenstein NE, Feikin DR (2004). Vaccines against bacterial meningitis. In: WM Scheld, RJ Whitley, CM Marra (Eds.), Infections of the Central Nervous System. 3rd edn. Lippincott-Raven Philadelphia, pp. 899–920. Schlenska GK (1976). Neurological complications following rabies duck embryo vaccination. J Neurol 214: 71–74. Sever JL, Brenner AI, Gale AD et al. (2004). Safety of anthrax vaccine: an expanded review and evaluation of adverse events reported to the Vaccine Adverse Event Reporting System (VAERS). Pharmacoepidemiol Drug Saf 13: 825–840. Shaw FE Jr, Graham DJ, Guess HA et al. (1988). Postmarketing surveillance for neurologic adverse events reported after hepatitis B vaccination. Experience of the first three years. Am J Epidemiol 127: 337–352. Slade BA, Leidel L, Vellozzi C et al. (2009). Postlicensure safety surveillance for quadrivalent human papillomavirus recombinant vaccine. JAMA 302: 750–757. Srivastava AK, Sardana V, Prasad K et al. (2004). Diagnostic dilemma in flaccid paralysis following anti-rabies vaccine. Neurol India 52: 132–133. Stratton KR, H.C., Johnston RB (1994). DPT Vaccine and Chronic Nervous System Dysfunction: A New Analysis. National Academy Press, Washington DC. VAERS. http://vaershhsgov/index. Wakefield AJ, Murch SH, Anthony A et al. (1998). Ileallymphoid-nodular hyperplasia non-specific colitis and pervasive developmental disorder in children. Lancet 351: 637–641. Warrell D (1976). Rabies on the doorstep. Hot topics in infection and immunity in children II. Adv Exp Med Biol 586: 145–152. Wenger JD (1998). Epidemiology of Haemophilus influenzae type b disease and impact of Haemophilus influenzae type b conjugate vaccines in the United States and Canada. Pediatr Infect Dis J 17: S132–S136. White CJ, Kuter BJ, Hildebrand CS et al. (1991). Varicella vaccine (VARIVAX) in healthy children and adolescents: results from clinical trials 1987 to 1989. Pediatrics 87: 604–610. WHO http://wwwpolioeradicationorg/content/general/case countpdf. Zhou W, Pool V, Iskander JK et al. (2003). Surveillance for safety after immunization: Vaccine Adverse Event Reporting System (VAERS) – United States, 1991–2001. MMWR Surveill Summ 52: 1–24.

Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 104

Neurodermatology JEAN-PHILIPPE NEAU1*, GAE¨LLE GODENECHE1, STE´PHANE MATHIS1, AND GE´RARD GUILLET2 1 Department of Neurology, CHU La Miltrie, Poitiers, France 2

Department of Dermatology, CHU La Miltrie, Poitiers, France

Since the skin and the central and/or peripheral nervous system (Table 104.1) have a common source (the ectoderm), numerous genetic and acquired diseases (infectious, tumoral or autoimmune disorders) equally affect both. In order to avoid misleading classifications, we have chosen to divide neurodermatology into the relevant groupings encountered by the neurologist such as stroke, peripheral neuropathy, epilepsy, brain tumors. Several diseases have been described and tables corresponding to each grouping have been added.

NEUROCUTANEOUS DISORDERS ASSOCIATED WITH STROKE In many cases, stroke etiology research is facilitated by thorough examination of the skin, since vasculitis or vasculopathy, which is at times inherited, may affect not only cerebral vessels, but also the skin. Skin abnormalities differ from one another depending on family history, age of the patient, stroke subtype (cerebral infarct or hemorrhage) and stroke etiology (cervical dissection, aneurysms, cardiac myxoma or small artery disease).

Fabry disease Fabry disease (FD) is an X-linked inherited glycosphingolipid metabolism disorder due to deficient or absent lysosomal a-galactosidase A activity. It results in progressive accumulation of globotriaosylceramide in lysosomes of numerous tissues and cell types leading to progressive organ failure and premature death due to end-stage renal disease and cardiovascular or cerebrovascular complications. Fabry disease classically affects hemizygous males, and its annual incidence of 1 in 100 000 may be underestimated.

CLINICAL MANIFESTATIONS The first clinical symptoms begin in childhood, typically between the ages of 3 and 10 years, and generally a few years later in girls than in boys. With age, progressive damage to vital organ systems develops in both genders, leading to complications limiting life expectancy. Typical manifestations include cutaneous lesions (angiokeratoma), peripheral (neuropathic pain, sweating disturbances, and hearing impairment) and central neurologic complications (stroke), and disorders of the heart and kidneys. Cutaneous manifestations are characterized by angiokeratoma and clusters of small reddish-purple maculopapular skin lesions, which are typically found on the buttocks, groin, scrotum, umbilicus, and upper thighs with bilateral symmetry, but also at times on mucosal areas, such as the mouth or conjunctiva (Orteu et al., 2007). They do not blanch with pressure. They may be isolated and can occur in groups or in generalized formation. These skin lesions generally appear between 5 and 10 years of age and increase progressively in number and size with age. Absence of sweating (anhidrosis) or a decreased ability to sweat (hypohidrosis), resulting in accumulation of glycosphingolipid globotriaosylceramide (GB3) in the eccrine sweat glands and their blood vessels can lead to heat and exercise intolerance. Telangiectasia and subcutaneous edema have also been described in FD. Neurologic manifestations are likewise frequent and may reveal the disease. The neurologic manifestations of Fabry disease involve both the peripheral nervous system (PNS) and the central nervous system (CNS), with globotriaosylceramide accumulation found in Schwann cells and dorsal root ganglia together with deposits in CNS neurons. Neuropathic pain is a particularly early

*Correspondence to: Pr. Jean-Philippe Neau, Department of Neurology, CHU La Mile´trie, 86021, Poitiers Cedex 05, France. E-mail: [email protected]

Table 104.1 Neurocutaneous syndromes

Disease

Stroke

Neuropathy Seizures

Meningitis / Dementia/ mental Medullary pyramidal or retardation/ CNS gait disorders encephalopathy Tumors Ataxia infections

Behc¸et’s disease Carney’s complex Cerebrotendinous xanthomatosis Cholesterol emboli syndrome Cobb syndrome Degos disease

þ þ –

þ – þ

þ – þ

– – –

þ – –

þ – –

þ – þ (MR)

þ – þ

Erythema nodosum, genital and oral aphthous ulcers Lentigines, blue nevi, skin myxomas Tendon xanthomas (Achilles tendons)

þ

–

–

–

–

–

þ (E)

–

Purple toe, livedo reticularis

– þ

– þ

– –

– –

– –

– –

– –

þ þ

þ þ

–

–

–

–

þ –

–

–

þ

þ

–

–

–

–

þ (VD)

–

Metameric nevus flammeus, angiokeratomas Papulous aspect, erythematous rim, white “porcelainlike” atrophic center (trunk, lower limbs) Petechiae, Osler’s nodes, splinter hemorrhages Long scarring process with enlargement of scars, translucent skin Angiokeratoma (umbilicus, knees, buttocks, and scrotum) Mucocutaneous telangiectasia

Endocarditis Ehlers–Danlos syndrome Fabry disease Hereditary hemorrhagic telangiectasia Hypomelanosis of Ito

þ

–

–

–

–

þ (CA)

–

–

–

þ

þ

þ

þ

–

þ (MR)

–

Incontinentia pigmenti

þ

–

þ

–

þ

–

þ (MR)

þ

Leprosy

–

þ

–

–

–

–

–

–

Lyme disease Neurofibromatosis I

þ þ

þ þ

– þ

– þ

þ –

þ –

þ (E) þ (MR)

þ þ

Neurofibromatosis II Pangeria (Werner’s syndrome)

– þ

þ þ

þ –

þ –

– –

– –

– –

þ (ST) –

Main cutaneous manifestations

Hypochromic lesions in whorl, patches, and streaks with a midline cut-off Erythema, vesicles and pustules (extremities), verrucous lesions (distal extremities), linear hyperpigmentation (trunk and intertriginous sites), pallor and scarring (calves), linear hyperpigmentation (follows the Blaschko lines), alopecia of the vertex, woolly hair, nevi and nail dystrophy Hypopigmentation and hyperpigmentation, leonine facies, erythema nodosum leprosum, vitiligo Eyrthema migrans, acrodermatitis chronica atrophicans Cafe´ au lait patches, cutaneous, subcutaneous and plexiform neurofibromas Skin plaques, nodular subcutaneous schwannomas Scleroderma-like skin, graying hair and baldness, leg ulcers, progressive scalp alopecia, sparse body hair, telangiectasia, mottled pigmentation, loss of subcutaneous fat, subcutaneous calcification

POEMS

–

þ

–

–

–

–

–

–

Pseudoxanthoma elasticum

þ

–

–

–

–

–

–

–

Refsum syndrome Sneddon syndrome Sj€ ogren–Larsson syndrome Sturge–Weber syndrome Systemic lupus erythematosus

– þ –

þ – –

– – þ

– – –

þ – –

– – –

– þ (VD) þ

– – þ

Hyperpigmentation, thickening, verrucous angiomas, hirsutism, Raynaud’s phenomenon Pseudoxanthoma, multiple papules, peau d’orange skin, angioid streaks, subcutaneous calcification usually in blood vessels Ichthyosis Livedo racemosa, Raynaud’s phenomenon Generalized ichthyosis

þ SLE þ

–

þ

–

–

–

þ (MR)

–

Facial cutaneous angioma (port wine nevus)

þ

þ

–

–

–

þ (E, VD)

–

Photosensitivity, malar rash, telangiectasia, discoid lupus, patchy alopecia, mucosal ulcers, angioneurotic edema, Raynaud’s phenomenon, subcutaneous nodules, palpable purpura, gangrene Hypomelanotic macules (trunk and buttocks), bilateral facial angiomas, shagreen patches, molluscum fibrosum, forehead fibrous plaques, ungual fibromas (Koenen tumor) Photosensitivity, early onset skin cancer, atrophy, telangiectasia, actinic keratosis, angioma, keratoacanthomas Vesicles with oral lesions

Tuberous sclerosis complex

þ/ ICA

–

þ

þ

–

–

þ (MR)

–

Xeroderma pigmentosum

–

þ

–

–

þ

–

þ (MR)

þ

Zoster

þ

þ

þ

–

þ

þ

þ (E)

þ

VD, vascular dementia; CA, cerebral abscess; ICA, intracranial aneurysms; SLE, stroke-like episodes; ST, spinal tumors; MR, mental retardation; E, encephalopathy.

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symptom occurring in the first decades of life and consisting in recurrent episodes of severe pain in the extremities with agonizing burning pains in the palms and soles that may extend to the proximal extremities and other parts of the body (Hoffmann et al., 2007). These painful episodic crises are precipitated by fever, stress, exercise, fatigue, rapid changes in temperature, and may last from minutes to days. Chronic pain, characterized by burning and tingling paraesthesias, is less frequent. The pain may be due to destruction of the dorsal root ganglia by progressive deposition of GB3 leading to peripheral small fiber neuropathy. The early peripheral neuropathy is often followed by cerebrovascular complications in adulthood (Mehta et al., 2004). CNS involvement is mainly attributable to cerebrovasculopathy, with an increased incidence of stroke. Cerebrovascular involvement is the result of multifocal involvement of small blood vessels and leads to a wide variety of mild to severe signs and symptoms, including headache, transient ischemic attacks, ischemic strokes and, more rarely, vascular dementia. The prevalence of strokes in FD has been estimated at 6.9% in males (mean age: 39 years) and 4.3% in females (mean age: 46 years), which is much higher and of earlier occurrence than in the general population (Rolfs et al., 2005). Stroke in FD presents a high risk of recurrence, which has been evaluated at 76% for hemizygous patients with a mean delay of 6.4 years (Mitsias and Levine, 1996). A dilative arteriopathy of vertebrobasilar circulation and white matter lesions (single, multiple or confluent) on magnetic resonance imaging (MRI) have also been described (Burlina et al., 2008). On MRI, hyperintensity in the pulvinar on T1-weighted images appears to be a highly specific sign in FD, likely reflecting the presence of calcification (Burlina et al., 2008). Other nervous system symptoms include aseptic meningitis, hearing loss, vertigo and tinnitus. Ophthalmological manifestations are predominated by a characteristic lesion: cornea verticillata that can be observed by slit lamp microscopy since it is rarely of visual significance. It is observed in the majority of hemizygous males and is due to glycosphingolipid accumulation in the basal epithelial cells. Anterior and posterior cataracts, tortuosities of retinal blood vessels are also observed in affected patients (Germain, 2010). Cardiac involvement. Cardiac symptoms include left ventricular hypertrophy, arrhythmia, myocardial ischemia and infarction, mitral valve prolapse, severe mitral regurgitation, and congestive heart failure. They are reported in approximately 40–60% of patients with FD and usually observed in the second or third decade of life in hemizygous males. They are due to accumulation of GB3 in myocytes and fibrocytes in the cardiac valves and may necessitate implantation of a pacemaker (Sheppard, 2011).

Renal manifestations. Like most aspects of the disease, renal pathology often begins in childhood or early adulthood with microalbuminuria and microscopic hematuria and increases in severity with age. Further progression of renal impairment, indicated by a decrease in creatinine clearance and glomerular filtration rate, leads to chronic renal insufficiency and end-stage renal failure representing a major cause of premature death in FD patients. Renal lesions result from GB3 deposition in the glomerular endothelial, mesangial, interstitial cells and in podocytes. Other manifestations such as gastrointestinal distress and malabsorption (diarrhea, abdominal pain, nausea and vomiting) and pronounced obstructive airway disease have been described (Germain, 2010).

DIAGNOSIS AND COUNSELING In hemizygous males, FD can be ascertained by the demonstration of marked a-galactosidase A deficiency in plasma, leukocytes or fibroblasts. Elevated levels of GB3 in plasma, urinary sediment, and cells support the diagnosis. By measuring the activity of a-galactosidase A in male fetal cells, a prenatal diagnosis can be carried out.

TREATMENT There is increasing evidence that long-term enzyme therapy using recombinant human a-galactosidase A can halt disease progression, but its long-term outcome is still being investigated (Schiffman et al., 2001). Conventional management obviously remains important and consists in pain relief with analgesic drugs, nephroprotection (angiotensin converting enzyme inhibitors and angiotensin receptor blockers) and antiarrhythmic agents, while dialysis or renal transplantation are available for patients experiencing end-stage renal failure.

Cholesterol emboli syndrome Cholesterol emboli syndrome (CES) is a rare but serious complication of arteriosclerosis. It is associated with a high rate of morbidity and death. An annual incidence of 6.2 cases per million inhabitants has been reported in the Dutch population (Moolenaar and Lamers, 1996), but may actually be as high as 1.4% in selected patients (i.e., patients undergoing cardiac catheterization) (Fukumoto et al., 2003). Many organs can be involved, and the clinical manifestations are highly variable, depending on the flow distribution of cholesterol crystals (Varis et al., 2010).

CLINICAL PRESENTATION The cholesterol crystals originating in atherosclerotic plaques of large arteries lead to the occlusion of small

NEURODERMATOLOGY vessels. Key features include acute renal failure, cutaneous lesions such as livedo reticularis, toe necrosis and neurologic manifestations such as strokes or encephalopathy (Andreux et al., 2007). A typical cutaneous presentation is a blue or a purple toe due to cholesterol crystals that are carried to the lower extremities. Other cutaneous signs include livedo reticularis, cyanosis, ulceration, and even gangrene (Fig.104.1A). Neurologic symptoms are due to cholesterol emboli, which occlude small arteries with their diameter of 17–585 mm and lead to multiple small infarctions and encephalopathy. In the largest reported series of cholesterol emboli to the brain (29 autopsy-proved cases), encephalopathy, mostly severe, was the predominant finding on examination in 75% of patients and focal neurologic deficits were found in 42% of patients, isolated in one of three patients and associated with encephalopathy in the others. CT scan or MRI was normal in 35% of patients and demonstrated multiple cerebral infarctions or border zone infarction distribution in the other cases (Ezzeddine et al., 2000). Other symptoms include gastrointestinal manifestations (nausea, abdominal pain or discomfort, and melena

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due to ischemia or infarction of the alimentary tract), and acute or end-stage renal failure due to renal artery occlusion. Angioplasty, cardiac catheterization, vascular surgery and any invasive vascular procedure such as angiography, long-term anticoagulant therapy or fibrinolytic therapy are potential triggers for CES. However, the syndrome may also appear spontaneously without any clearly established predisposing etiological factor.

DIAGNOSIS Diagnosis is essentially based on clinical presentation. There are no specific laboratory tests for cholesterol microembolization syndrome. On laboratory testing, azotemia, proteinuria, normocytic anemia, a certain degree of eosinophilia and an increase in the sedimentation rate are often found. However, a biopsy of the affected organ or the involved skin may be carried out and typically shows cholesterol crystals in the lumen of arteries, where they appear as elongated, biconvex, needle-shaped transparent clefts, associated with varying degrees of inflammatory cell infiltration including

Fig. 104.1. (A) Cutaneous cholesterol emboli. In atheromatous patients, cholesterol emboli may induce purple toe, reticulated purpura or multiple infarctive lesions on tip-toe leading to ulceration and even gangrene. (B) Cutaneous cholesterol emboli: eye fundus with Hollenhorst plaques appearing as a bright, glistening, refractile plaque, usually at the bifurcation of a retinal arteriole.

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eosinophilic infiltration around the occluded vessels. Eye fundus study is of utmost importance for the diagnosis, since retinal cholesterol emboli (Hollenhorst plaques) are present in 16% of cases (Fig. 104.1B) with microhemorrhages occurring at times. A Hollenhorst plaque appears as a bright, glistening, refractile plaque, usually at the bifurcation of a retinal arteriole.

TREATMENT Since there exists no specific and curative treatment for CES, prevention remains particularly crucial. Various therapies have been used to treat CES, such as steroid treatment, antiplatelet agents, statins, and heparin; but they have been found to have little or no effect (Varis et al., 2010).

Carney complex When a cardiac myxoma is discovered, a Carney complex (CC) should be sought, especially if other members of the family were also carriers of a myxoma. CC, first described in 1985 (Carney et al., 1985) is a dominantly inherited syndrome characterized by spotty skin pigmentation, endocrine overactivity, and myxomas due to PRKAR1A mutations (Veugelers et al., 2004). Cutaneous manifestations include lentigines and blue naevi. Lentiginosis (Fig. 104.2) is observed in most patients and appears as small (2–10 mm) brown to black macules typically located around the upper and lower lips, on the eyelids, ears and the genital area. Multiple blue nevi and junctional or compound nevi as well as cutaneous myxomas may be observed. The skin myxomas present as nonpigmented subcutaneous nodules. The most common endocrine gland manifestations are acromegaly, thyroid, and testicular tumors, and adrenocorticotropic

Fig. 104.2. Carney complex. Pigmentary abnormalities such as cutaneous lentigines, located on the upper and lower lips.

hormone-independent Cushing’s syndrome due to primary pigmented nodular adrenocortical disease. Myxomas can be observed in the heart, skin and breast (Bertherat, 2006). Cardiac myxomas can develop in any cardiac chamber and may be multiple. Systemic embolizations, especially CNS embolization, are observed in up to 45% of left atrial myxomas. The most common manifestation is acute cerebral ischemia secondary to vessel occlusion by myxomatous material or thrombus, although intracerebral or subarachnoid hemorrhages are not rare (Neau et al., 1993). Delayed neurologic complications are much less common and may result from cardiac tumor recurrence with embolization, progressive vascular stenosis, parenchymal metastasis, or cerebral aneurysm formations with subsequent risk of rupture. These cerebral aneurysms may develop many years after definitive treatment of the cardiac tumor (Blanc et al., 2008). Genetic analysis should be proposed in all CC index cases. Patients with CC or with a genetic predisposition to CC should undergo regular screening for manifestations of the disease. Clinical workup for all manifestations of CC should be performed at least once a year in all patients and should start in infancy with a long-term follow-up since myxoma recurrence is far from rare. Cardiac myxomas require surgical removal. Bilateral adrenalectomy is the most common treatment for Cushing’s syndrome (Bertherat, 2006).

Antiphospholipid syndrome and Sneddon disease Sneddon’s syndrome is characterized by a combination of ischemic cerebrovascular episodes and widespread livedo (Sneddon, 1965). Sneddon’s syndrome is most common in young women between 20 and 40 years of age and may be associated with other manifestations such as systemic hypertension, acrocyanosis, Raynaud’s phenomenon, secondary headaches, venous thrombosis, valvulopathy (mitral insufficiency), spontaneous abortion history, seizures, renal involvement, and vascular dementia. Livedo is the key point of the diagnosis and often precedes the cerebrovascular manifestations. Livedo racemosa is characterized by a striking violaceous netlike patterning of the skin similar to the familiar livedo reticularis, from which it differs by its location (more generalized and widespread, noninfiltrated, found not only on the limbs, but also on the trunk, arms, face and/or buttocks), its shape (irregular, broken, circular segments), and its biopsy results (Miyakis et al., 2006). Cerebrovascular events, usually occurring before the age of 45 years, consist of ischemic strokes or transient ischemic attacks, which mainly affect medium-sized arteries and are observed particularly in the territory of the middle and posterior cerebral arteries.

NEURODERMATOLOGY Intracerebral, subarachnoid or intraventricular hemorrhages have also been reported. Recurrent cerebral damage can lead to vascular dementia. The diagnosis can be reinforced by the positivity of antiphospholipid antibodies, which can be found at a highly variable frequency in up to 80% of patients with Sneddon’s syndrome (Fetoni et al., 2000). Management of Sneddon syndrome remains controversial (Aladdin et al., 2008). In fact, nifedipine may reduce livedo reticularis and acrocyanosis, but it in no way helps to prevent cerebrovascular complications, which are the most severe. Various antiplatelet and immunomodulatory agents, including steroids and azathioprine, have been ineffective in both antiphospholipid syndromes and Sneddon syndrome. Anticoagulation using warfarin sodium (International Normalized Ratio (INR): 3–4) is now recommended and warranted by the frequent presence of asymptomatic cardiac valvulopathy and an abundance of cerebral microemboli (Maamar et al., 2007).

Degos disease (malignant atrophic papulosis or Kohlmeier–Degos disease) Degos disease is a rare vasculopathy of unknown origin, characterized by vascular lesions of the skin, gastrointestinal tract, and CNS (Fernandez-Perez et al., 2005). Cutaneous lesions (papulous aspect, erythematous rim, and white “porcelain-like” atrophic centre, localized over the trunk and the lower limbs) are asymptomatic or mildly itchy. They are often the first signs of the disease and are followed by a variable, progressive involvement of visceral organs. The heart, eyes, gastrointestinal tract (intestinal hemorrhage and perforation), lungs, and kidneys are also involved. The onset of a systemic diffusion of the disease leads to death in several months or years. Despite use of the term “malignant” in its name, there have been several reports of cases with only cutaneous manifestations and a favorable prognosis (Amato et al., 2005). The neurologic manifestations of Degos disease are frequent (20–60% of cases) and include multiple cerebral infarcts, subdural hematomas, venous sinus thrombosis, polyradiculoneuropathy, and less frequently, myelopathy and myopathy (Subbiah et al., 1996). There is no known successful therapy for malignant atrophic papulosis. Inconsistent responses have been obtained with blood viscosity-reducing agents, antiaggregant therapy and/or plasma exchange (FernandezPerez et al., 2005).

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Ehlers–Danlos syndromes, essentially type IV, osteogenesis imperfecta, and autosomal dominant polykystic kidney disease are collagenopathies, while pseudoxanthoma elasticum (PXE) and Marfan syndrome are elastinopathies, some of which are characterized by cutaneous and vascular manifestations that can lead to cervical artery dissections and cerebral aneurysms due to the fragility of the arterial wall.

EHLERS–DANLOS SYNDROME (EDS) TYPE IV Ehlers–Danlos syndrome type IV is the vascular type of Ehlers–Danlos syndrome. The prevalence for all forms of EDS varies from 1/10 000 to 1/25 000 and EDS type IV represents approximately 5–10% of EDS cases. It is an autosomal inherited connective tissue disorder caused by mutations in the COL3A1 gene coding for type III procollagen. The disease is defined in most patients by characteristic facial aspects (acrogeria with an emaciated face featuring prominent cheekbones and sunken cheeks), abnormally thin, pale, and translucent skin with highly visible subcutaneous vessels on the trunk, shoulders and lower back, ecchymoses, hematomas and extensive easy bruising, and severe arterial, digestive (high risk of recurrent colonic perforations) and uterine (rupture aggravated by pregnancy) complications. However, in EDS type IV, there is often no hyperelasticity of the skin (Fig. 104.3), whereas an abnormally long scarring process with secondary enlargement of scars is typical of the disease. The vascular complications essentially affect arteries of large and medium diameter. Dissections of the vertebral arteries and the carotids in their extra- and intracranial segments (carotid-cavernous fistulae) are typical of EDS type IV

Connective tissue diseases Based on the two major constituents of the connective tissue (collagen and elastin), connective tissue disorders can be divided into “collagenopathies” and “elastinopathies.”

Fig. 104.3. Ehlers–Danlos type IV syndrome. Type IV is characterized by minimal joint hypermobility and major bruising and thin scarring translucent skin that may be hyperexpandable.

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(North et al., 1995; Schievink et al., 1998; Chuman et al., 2002; Schievink, 2004). Diagnosis is based on clinical signs, noninvasive imaging, and identification of a mutation of the COL3A1 gene (Germain, 2007). There are major diagnosis criteria (arterial, digestive or uterine fragility or rupture; thin, translucent skin; extensive bruising, and characteristic facial appearance) and minor diagnosis criteria (positive family history, sudden death of a close relative; acrogeria, hypermobility of small joints, tendon and muscle rupture, talipes equinovarus, early onset varicose veins, and spontaneous pneumothorax or hemothorax). Given the absence of any specific treatment for EDS type IV, medical intervention should be focused on symptomatic treatment and prophylactic measures. However, celiprolol, a b1-adrenoceptor antagonist with a b2-adrenoceptor agonist action, might be the treatment of choice to prevent arterial dissections and ruptures (Ong et al., 2010). Invasive imaging techniques are contraindicated. A conservative approach is usually recommended when caring for a vascular complication in a patient suffering from EDS type IV. Surgery may, however, be required urgently to treat potentially fatal complications. Examination of the skin for cutaneous manifestations of EDS type IV should be performed in the event of cervical artery dissection, especially if dissection or aneurysm rupture has been found in the family (Martin et al., 2006).

PSEUDOXANTHOMA ELASTICUM (PXE) OR GRo¨NBLAD–STRANDBERG SYNDROME Pseudoxanthoma elasticum (PXE) is a recessive inherited systemic disease of connective tissue affecting primarily the skin, retina, and cardiovascular system. The prevalence of PXE is 1/25 000, but is probably underestimated. PXE is characterized pathologically by elastic fiber mineralization and fragmentation. It has recently been associated with mutations in the ABCC6 gene found in about 80% of patients (Chassaing et al., 2005). Clinically, there is a high heterogeneity in age of onset and the extent and severity of organ system involvement.

CLINICAL MANIFESTATIONS Cutaneous manifestations. The primary skin lesion is a yellowish papule 1–5 mm in diameter that tends to gradually coalesce to form plaques with a cobblestone appearance (Fig. 104.4). They are located on the neck and in flexural areas. Cervical lesions often initially develop between the ages of 8 and 12 years. Flexural involvement tends to start in the teenage years in the axillae, but also in the antecubital and popliteal fossae and the groin. In the area of maximum papular coalescence, the skin loses its elasticity and typical redundant skin

Fig. 104.4. Pseudoxanthoma elasticum. Small asymptomatic xanthoma-like papules are distributed in the axillae. The skin then loses its elasticity and typical redundant skin folds develop in the neck. (Figure courtesy of Dr. Bruno Sassolas, CHU de la Cavale Blanche, Brest, France.)

folds develop. A skin biopsy specimen is mandatory for the diagnosis of PXE. Eye involvement. The characteristic signs in the eye of PXE are angioid streaks, which are irregular, reddishbrown, or gray lines that radiate from the optic disc. They are present in at least 85% of patients with PXE and begin between the ages of 15 and 25 years. Retinal hemorrhages, neovascularization, and scarring may occur and can lead to loss of central vision in as many as an estimated 50–70% of cases. However, the first ocular sign is often a yellowish mottled hyperpigmentation of the retina (“peau d’orange” or orange peel appearance), which may precede angioid streaks by up to 10 years. Vascular manifestations. Two types of clinical manifestations may result from arterial involvement, namely occlusive disease and bleeding. Occlusive arterial disease may be responsible for limb arteritis, coronary artery disease, digestive angina, and cerebrovascular disease. Absence of peripheral pulses and intermittent claudication in the lower limbs are frequent. Angina pectoris or silent coronary insufficiency may be present, but myocardial infarction is rare. Cerebral infarction and confluent periventricular white matter lesions in patients with PXE are due to small vessel disease (Pavlovic et al., 2005), but association between intracranial aneurysms and PXE was ruled out (Van Den Berg et al., 2000), even though intracerebral hemorrhage has been described (Bock and Schwegler, 2008).

DIAGNOSIS AND MANAGEMENT A diagnosis of PXE in young individuals with vascular manifestations should be suggested in the absence of vascular risk factors. About 10% of PXE patients experience

NEURODERMATOLOGY Table 104.2 Criteria for diagnosis of pseudoxanthoma elasticum (PXE) Major criteria

Characteristic skin signs (yellow cobblestone lesions in flexural areas) Characteristic ophthalmologic features (angioid streaks, orange peel appearance, maculopathy) Characteristic histologic features of lesional skin (elastic tissue and calcium or von Kossa stains) Minor criteria Characteristic histologic features of nonlesional skin (elastic tissue and calcium or von Kossa stains) Family history of PXE in first-degree relatives Category I patients fulfill all three major criteria and definitely have PXE. In children, however, ocular changes are not required to establish the diagnosis as they often do not develop until early adulthood. Category II patients do not have typical skin lesions but do have either angioid streaks with at least one major criterion, or two minor criteria

bleeding complications, especially gastrointestinal hemorrhage, due to the fragility of calcified submucosal vessels. Recently, criteria for the diagnosis of PXE have been suggested (Laube and Moss, 2005) (Table 104.2). PXE management is essentially based on symptomatology alone with support and corrective measures (diet, lifestyle exercise) and yearly eye and cardiovascular assessment (Laube and Moss, 2005).

Zoster Zoster of trigeminal distribution (Fig. 104.5) may be followed by homolateral cerebral infarct. The mean time of onset of neurologic disease is 7 weeks after the development of zoster, but intervals of up to 6 months have been

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recorded (Gilden et al., 2000). Herpes zoster ophthalmicus (HZO) may represent a marker of increased risk of stroke development during the 1 year follow-up period since stroke developed in 8.1% of patients with HZO and 1.7% of patients in the comparison cohort during the same follow-up period (Lin et al., 2010). Lesions of the arterial wall are homolateral to the facial rash with multinucleated giant cells, varicella zoster virus antigen, Cowdry A inclusions, and herpes virus particles on microscopical examination (Gilden et al., 2000). Vascular lesions consist of focal constriction and segmental narrowing primarily in middle (M1 segment) and anterior (A2 segment) cerebral arteries, internal carotid arteries and more rarely the central retinal artery (Kuroiwa and Furukawa, 1981) or posterior circulation with brainstem infarction after rash behind the ear or on the neck (Ortiz et al., 2008) and thalamic infarct after rash on the tongue. Most patients are older than 60 years of age. Patients should receive aciclovir intravenously (10–15 mg per kilogram of bodyweight, three times daily for 7–10 days) associated with a short course of a steroid (60–80 mg of prednisone daily for 3–5 days). (Gilden et al., 2000). Other neurocutaneous vascular syndromes such as hereditary hemorrhagic telangiectasia or Rendu–Osler disease, Sturge–Weber (intracranial leptomeningeal angioma, facial port-wine nevi, epilepsy, and glaucoma), blue rubber bled nevus or Bean syndromes (Tomerelli et al., 2010) are exceptionally complicated by stroke and subarachnoid hemorrhages due to cerebral aneurysm rupture. More rarely, other diseases can associate cutaneous manifestations and cerebrovascular disorders: endocarditis, sarcoidosis (Hodge et al., 2007), neurofibromatosis type 1 (Cre´ange et al., 1999), Werner syndrome (Renard et al., 2009), Lyme disease (Topakian et al., 2008) or systemic diseases such as Behc¸et disease which may be revealed by cerebral venous thrombosis (Borhani Haghighi et al., 2005; Al-Araji and Kidd, 2009), systemic scleroderma (He´ron et al., 1998; Lucivero et al., 2004), Takayasu’s arteritis, systemic lupus erythematosus, or periarteritis nodosa.

NEUROCUTANEOUS DISORDERS ASSOCIATED WITH CUTANEOUS ANGIOMA

Fig. 104.5. Right herpes zoster ophthalmicus.

Several diseases associate cutaneous angioma or telangiectasias and cerebral or medullar vascular malformations. In cases of cutaneous angioma, neurologic manifestations should be searched for and neurologic investigations carried out. The most frequent neurologic diseases associated with angiokeratomas or cutaneous angioma or telangiectasia are Fabry disease (as previously described), Sturge–Weber disease, and hereditary hemorrhagic telangiectasia (HHT) or Osler–Weber–Rendu syndrome.

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Sturge–Weber syndrome Sturge–Weber syndrome (SWS), or encephalotrigeminal angiomatosis, is a rare, sporadic congenital neurocutaneous syndrome characterized by unilateral facial cutaneous vascular malformation in association with ipsilateral leptomeningeal angiomatosis. Prevalence is approximately one per 50 000 live births. The common clinical manifestations of SWS include progressive seizures, unilateral cutaneous vascular nevus following the ophthalmic divisions of the trigeminal nerve, ipsilateral glaucoma, contralateral hemiparesis, hemiatrophy, hemianopia and mental retardation.

CLINICAL MANIFESTIONS Clinical manifestations begin typically at birth with facial cutaneous vascular malformation. Facial cutaneous angioma is a port-wine nevus, usually affecting the upper face ipsilateral to the angiomatosis (Fig. 104.6A). However, most children with a facial cutaneous vascular malformation do not have SWS, but the likelihood of SWS increases when the cutaneous malformation is unilateral or bilateral and includes the ophthalmic division of the trigeminal nerve and, more precisely, the upper or lower eyelids. In rare cases, patients with SWS lack

a facial cutaneous vascular malformation but present neurologic or ophthalmic components. Neurologic manifestations include epilepsy, mental retardation, and attention-deficit hyperactivity disorder, migraine, and stroke-like episodes (Di Rocco and Tamburrini, 2006). Between 75% and 90% of children with SWS have epilepsy that worsens with age. Most seizures are focal and typically occur contralateral to the neurocutaneous abnormality. Infantile spasms and generalized seizure are likewise observed. Seizures are often precipitated by fever or infections. Other neurologic complications secondary to leptomeninges angioma include vascular headaches that affect 30–45% of patients with SWS, stroke-like episodes, contralateral hemiparesis, hemiatrophy, and hemianopia. Transient focal deficits (stroke-like episodes) are a unique feature in SWS. The most common manifestations are transient episodes of hemiparesis or visual field defects not directly associated with epilepsy and lasting for some hours to several days. Approximately half of the children with intracranial angiomatosis will have developmental delay or frank mental retardation, or both, whereas others may suffer from learning disabilities, attention disorders, or behavioral disturbances (attention-deficit hyperactivity disorder).

Fig. 104.6. Sturge–Weber syndrome. Left port-wine stain in the distribution of the first branch of the trigeminal nerve (A) is associated with homolateral leptomeningeal angiomatosis (B) in a 16-year-old girl.

NEURODERMATOLOGY Ophthalmologic manifestations. When the facial cutaneous vascular malformation involves the eyelid, vascular abnormalities of ocular circulation may occur. Glaucoma is the most common ophthalmic complication of SWS, occurring in 30–70% of patients in infancy or later in childhood or early adulthood.

RADIOLOGIC FEATURES While MRI is best suited for structural imaging, CT remains superior to MRI when demonstrating microcalcifications or classic gyriform calcification, which usually involves the occipital and parietal lobes underlying the leptomeningeal angiomatosis (Fig. 104.6B). About 90% of the children with SWS have intracranial calcifications. Gadoliniumenhanced T1-weighted spin-echo MRI is best suited for evaluation of the vascular malformation and enlargement of the choroid plexus. T2-weighted MRI demonstrates atrophy ipsilateral to the leptomeningeal angiomatosis, gliosis, and white matter lesions (Di Rocco and Tamburrini, 2006). In addition, functional neuroimaging studies with positron emission tomography (PET) and single-photon emission computed tomography (SPECT) may demonstrate the hypoperfusion and cortical hypometabolism underlying the leptomeningeal angiomatosis and may detect latent angiomas (Griffiths et al., 1997).

TREATMENT Consistent and thorough monitoring for development of glaucoma, seizures, headache, and stroke-like episodes is required in patients with SWS. For facial cutaneous vascular malformations, laser therapy should begin soon after diagnosis for optimal results. b-Antagonist eye drops, adrenergic eye drops, and carbonic anhydrase inhibitors are the treatments of choice for glaucoma, whereas trabeculectomy is a surgical option if drops fail. For seizures, children are initially placed on carbamazepine, with phenobarbital and phenytoin as second-line therapies. If control is not achieved, valproate or topiramate may be added to the carbamazepine, the ultimate goal being to achieve monotherapy seizure control with valproate or topiramate (Thomas-Sohl et al., 2004). Epilepsy surgery (lobectomy or hemispherectomy) is required for children with frequent, debilitating, and recurrent seizures (Schropp et al., 2006). A delay in surgical treatment may result in further cognitive deterioration. Recommended treatments for headaches are ibuprofen or triptan for abortive migraine management and propanolol for preventive migraine management. Prophylactic aspirin (3–5 mg/kg/day) is recommended for prevention of transient focal deficits (hemiparesis or visual field defects) (Thomas-Sohl et al., 2004).

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Hereditary hemorrhagic telangiectasia Neurologic presentations of hereditary hemorrhagic telangiectasia (HHT) are various and can be vascular (ischemic or hemorrhagic strokes), epileptic (vascular malformations) or infectious (cerebral abscess, meningitis), affecting either the brain or the spinal cord. HHT, or Osler– Weber–Rendu syndrome, is an autosomal dominant vascular disorder with multiple systemic manifestations. It affects approximately 1 in 5000–8000 people and is characterized by skin and mucosal telangiectasias and arteriovenous malformations (AVMs) that can lead to severe bleeding and various neurologic complications. HHT gene mutations lead to the development of abnormal vascular structures, which range from dilated microvessels to large AVMs. Several mutations in two genes involved in vascular development and repair, endoglin on chromosome 9 (HHT type 1) and activin receptor-like kinase-1 on chromosome 12 (HHT type 2), are associated with HHT. Recently, the gene MADH4 has been linked to HHT in association with juvenile polyposis and a new locus on chromosome 5.

CLINICAL MANIFESTATIONS Clinical symptoms vary according to genotype, since mutations in HHT subtype 1 are associated with a higher frequency of pulmonary AVMs and mutations in HHT subtype 2 are likely associated with a higher frequency of hepatic lesions. Mucocutaneous telangiectasias. Telangiectasias of the skin and mucosa are common among patients with HHT and are usually located on the face, lips, tongue, oral mucosa, gums, conjunctiva, trunk, arms, and fingers (Fig. 104.7). They tend to occur at a young age and to progress as the patient ages (Grand’Maison, 2009). Bleeding from these sites is usually mild and

Fig. 104.7. Osler–Rendu syndrome. Mucocutaneous telangiectasias predominate on lower lip and tongue.

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easily contained. Laser ablation can be used as needed. However, nasal and gastrointestinal telangiectasias can lead to severe bleeding requiring transfusions and specific treatments. Spontaneous and recurrent epistaxis secondary to nasal telangiectasias occurs in more than 90% of patients with HHT and represents the most common clinical manifestation. Nasal bleeding, which usually appears early in childhood, can be mild with no treatment required. Medical treatments, laser therapy, surgery or embolization may be useful in case of severity or recurrence of bleeding causing anemia. Gastrointestinal telangiectasias are found in the large and small intestine in 15–30% of patients with HHT and represent frequent causes of acute or chronic gastrointestinal bleeding (rarely occurring before the age of 30 years) and anemia. Medical treatments and laser therapy may also be effective. Arteriovenous malformations. AVMs develop most commonly in the lungs, liver, and CNS. Pulmonary AVMs occur in 5–30% of patients aged 30 or more years with HHT. They can be asymptomatic or present with bleeding (hemoptysis), hypoxemia (dyspnea, cyanosis, and polycythemia) related to a right-to-left shunt, strokes and brain abscess. They can easily be detected using chest radiographs, echocardiography to identify the presence of a right-to-left shunt, chest CT scan or pulmonary angiography. Appropriate investigation and treatment are crucial to avoidance of neurologic complications. Embolization remains the treatment of choice, but surgery is an option for patients who are not candidates for embolization. Up to 70% of patients with HHT will develop hepatic AVMs, which are often silent or may lead to high-output congestive heart failure, portal hypertension and, rarely, liver failure with or without encephalopathy. Neurologic manifestations. Vascular or infectious manifestations occur in 10–15% of patients. They tend to occur later in life, but may be an initial manifestation of HHT. They are due to medullary or cerebral vascular malformations (aneurysms, arteriovenous malformations, telangiectasias, dural arteriovenous fistula) or to pulmonary AVMs that can lead to paradoxical or gas embolism (Cohen et al., 2006). Strokes in HHT patients may be ischemic (cerebral or medullar) or hemorrhagic (subarachnoid, intracerebral, or subdural hemorrhages) (Espinosa et al., 2008). Hemorrhagic strokes are due to the rupture of different types of cerebral vascular malformations, and treatment includes microsurgery, radiation therapy or embolization of these malformations (Maher et al., 2001). Transient ischemic attacks or ischemic strokes are associated with distal emboli from a cerebral aneurysm or with paroxysmal or gas emboli from the pulmonary AVM (Cottin et al., 2007). Finally, brain abscesses from septic emboli occur in 5–9% of HHT

patients with pulmonary AVMs. They are due to streptococcus and are often multiple and recurrent.

DIAGNOSIS AND GENETIC TESTING The diagnosis of HHT is now based on the Curacao criteria, published in 2000 (Shovlin et al., 2000). A definite diagnosis of HHT is made in the presence of at least three separate manifestations: ● ● ● ●

spontaneous recurrent nosebleeds mucocutaneous telangiectasia (multiple at characteristic sites: fingertip pulps, lips, oral mucosa or tongue) visceral involvement (gastrointestinal, pulmonary, hepatic, cerebral or spinal AVM) family history: a first-degree relative affected according to these criteria.

Genetic testing for endoglin, ALK1/ACVRLI and Smad4 is available and can both confirm the diagnosis for the family, and confirm or refute HHT in family members. For patients with definite clinical HHT, molecular testing is not required to confirm their diagnosis. Mutations are not found in about 20% of HHT families, and failure to detect a causative HHT mutation in a family does not rule out HHT (Govani and Shovlin, 2009). Recently, international guidelines for the diagnosis and management of HHT were published (Faughnan et al., 2011).

Cobb syndrome Cobb syndrome, or cutaneomeningospinal angiomatosis (CMA), first described in 1895 and reported by Cobb in 1915, is a rare, nonfamilial condition associating cutaneous vascular lesions (Fig. 104.8) with arteriovenous malformations involving the spinal cord in the same metamere as the cutaneous lesion (Shim et al., 1996). Clinical manifestations can occur at any age, but are

Fig. 104.8. Cobb syndrome.

NEURODERMATOLOGY most common during late childhood. The most widespread dermatologic manifestations include nevus flammeus and angiokeratomas. Neurologic manifestations vary from monoparesis to sudden-onset spastic quadriplegia due to blood steal syndrome involving cord ischemia, cord compression by spinal arteriovenous malformation, or venous hypertension. Current treatment options include combinations of embolization, neurosurgical intervention, corticosteroid therapy, and radiotherapy (Clark et al., 2008). Other cutaneous lesions are exceptionnally associated with central or medullary vascular malformations. Cerebral cavernous malformations (CCM) are vascular lesions characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. Although often asymptomatic (0.5% of the general population), CCMs may be revealed by seizures, cerebral hemorrhages and focal neurologic deficits. Mutations in the CCM1, CCM2 and CCM3 genes have been identified in familial CCM. In rare instances, the association of congenital hyperkeratotic cutaneous capillary-venous malformations on the limbs, buttocks and forearms with CCM1 has been reported (Labauge et al., 1999; Toll et al., 2009). Klippel–Trenaunay–Weber syndrome is a sporadic or rarely autosomal dominant inheritance syndrome. It consists of a triad of venous varices, cutaneous vascular nevi (port-wine stains, hemangiomas, or lymphangiomas), and limb hypertrophy and may include spinal cord arteriovenous malformations (Rohany et al., 2007) or cerebral and medullary cavernomas (Boutarbouch et al., 2010).

NEUROCUTANEOUS DISORDERS ASSOCIATED WITH PERIPHERAL NEUROPATHY In many cases, the etiology of a neuropathy is difficult to determine, and research may be facilitated through careful examination of the skin. Different types of neuropathy (mononeuropathy, mononeuritis multiplex, peripheral neuropathy, meningoradiculitis, and polyradiculoneuropathy) may be associated with skin disorders and due to infectious diseases (AIDS, leprosy, herpes zoster, Lyme disease), plasma cell disorders (POEMS syndrome), autoimmune diseases (sarcoidosis, systemic scleroderma, systemic lupus erythematosus, periarteritis nodosa), genetic diseases (xeroderma pigmentosum, Fabry disease, Refsum disease, cerebrotendinous xanthoma, neurofibromatosis type 1 and 2, Ito melanosis, pangeria, Chediak–Higashi disease).

Leprosy A chronic granulomatous disease affecting the skin and nerves, leprosy is caused by Mycobacterium (M.) leprae.

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Worldwide, leprosy continues to be a significant public health problem, but its prevalence values fell dramatically from 620 638 cases in 2002 to 213 036 in 2009 (Rodrigues and Lockwood, 2011). This decrease could be attributed partly to the reduction of the duration of treatment from 24 months to 12 months and by operational factors such as integration of leprosy services into primary healthcare services in some countries (Rodrigues and Lockwood, 2011). Thus, 249 000 were reported in 2008, of which 94% were in the 17 countries that had reported detecting more than 1000 new cases in that year (Anon., 2008). However, this disease is prevalent in India (70% of all leprosy cases worldwide) and Africa (Mozambique, Madagascar, Angola, Central African Republic, Democratic Republic of Congo, and United Republic of Tanzania), but is also found in other Asian countries (Nepal for instance) and on other continents (Brazil). At the end of 2003, these nine countries accounted for 84% of the global prevalence and 88% of the new cases detected (Bennett et al., 2008). Drug treatment is effective in killing bacilli, but does not prevent nerve damage since immunologic reactions continue to occur, leading to disability and deformity due to neuropathy. When untreated, on the other hand, the disease is progressive and results in permanent damage (Agrawal et al., 2005).

CLINICAL MANIFESTATIONS The clinical features of the disease are determined by host response to M. leprae. Patients present with skin lesions, numbness or weakness caused by peripheral nerve involvement, or more rarely, a painless burn or ulcer in an anesthetized hand or foot (Britton and Lockwood, 2004). Leprosy can be classified according to the number of skin lesions present and the number of bacilli found on slit-skin smear examination. Paucibacillary disease (indeterminate, tuberculoid tuberculoid and borderline tuberculoid forms) is defined as fewer than six skin lesions with no bacilli on slit-skin smear testing. Multibacillary disease (borderline borderline, borderline lepromatous and lepromatous leprosy forms) is characterized by six or more lesions with or without positive skin smear results. However, there can be discrepancies in nerve and skin biopsies, showing paucibacillary involvement in one and multibacillary disease in the other (Nilsen et al., 1989). Skin manifestations and neurologic involvement depend on the stage of disease and the immunologic status of the patient. Cutaneous manifestations (Fig. 104.9A, B, C) (Lockwood and Kumar, 2004). Macules or plaques are the commonest lesions and papules and nodules are seen more rarely. Inspection of the whole body with adequate lighting is of the utmost importance because otherwise

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Fig. 104.9. Leprosy. (A) Hypochromic anesthetic flat macules feature indeterminate early leprosy (see in the middle a scar on painless burnt skin). (B) Peripheral nerve thickening. (C) Diffuse infiltration of skin with a pattern of leonine facies featuring lepromatous leprosy (multibacillar leprosy) with extensive bacillary diffusion.

NEURODERMATOLOGY lesions might be missed, particularly on the buttocks in borderline disease. Early skin lesions may be rather poorly defined hypopigmented or erythematous macules. Intermediate leprosy is diagnosed when there is a single lesion or only a few macules, with well or illdefined margins and a smooth or mildly scaly surface. Sensations are variably impaired and a thickened nerve supplying the lesion may be clinically palpable. Tuberculoid tuberculoid leprosy is characterized by a welldefined uniformly circular or oval erythematous/ hypopigmented plaque with maximal induration of the margins sloping towards the centre. The surface is bald, dry and scaly, and completely anesthesthetic. These lesions usually number from one to three in a patient. A thickened nerve in the vicinity is usually palpable. Borderline tuberculoid leprosy is characterized by hypopigmented and/or erythematous macules or plaques with well-defined irregular margins. The surface of the lesions is also bald, dry, and scaly with variable sensory loss. The number of lesions in a patient may vary from three to 10. Cutaneous nerves within the area of skin lesion may be thickened, tender, or both. Mid-borderline leprosy combines lesions of borderline tuberculoid (BT) and borderline lepromatous disease. The number of BT-type lesions tends to equal the number of lepromatous-type lesions. Nerves are affected bilaterally and symmetrically and may be thickened, tender, or both. There is variable/ partial sensory loss over different types of lesions, but the loss tends to be coterminous with the clinically apparent skin involvement. Borderline lepromatous leprosy has some features in common with mid-borderline leprosy. The lesions have variable sensory loss, tend to vary in number from countable to uncountable, and are bilaterally distributed with a tendency towards symmetry. Symmetrical involvement of the nerves in the form of thickening and/or tenderness along with sensory loss not limited to clinically apparent skin lesions are features that contribute to the diagnosis. Lepromatous leprosy is a generalized disease with multisystem involvement, sparing only the CNS. Cutaneous lesions are multiple, bilateral, symmetrical, infiltrated, and hypopigmented, shiny with ill-defined margins and merge imperceptibly with surrounding skin. Lepromatous leprosy characteristically involves the eyebrows, nose, and lips, and entails a flattening of the bridge of the nose resulting in classical “leonine facies” (Fig. 104.9C). Nerve involvement results in progressive bilateral symmetrical cutaneous sensory loss. The nerve trunks tend to be bilaterally and symmetrically thickened. Nail changes and hair loss may also be observed in leprosy. Neurologic manifestations. Leprosy should be considered as a possible cause of peripheral neuropathy or neuropathic ulcers in patients of Indian or African origin. Nerve involvement in leprosy affects sensory,

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motor, and autonomic function of peripheral nerves. Sensory loss is the earliest and the most frequent neurologic presentation, but predominantly motor loss can also occur. Granulomatous inflammation of peripheral nerves causes palpable enlargement, which may or may not be painful, and causes sensory and motor loss in the distribution of the affected nerve. Enlarged nerves can also be damaged because of entrapment within fibro-osseous tunnels. Patients with neuritic leprosy will have signs and symptoms of sensory impairment, paresthesia, nerve enlargement, nerve pain, and muscle weakness, without skin manifestations. Mononeuritis or mononeuritis multiplex are the most common presentations. In a few cases distal symmetric neuropathy with temperature and pain anesthesia is not accompanied by muscle weakness. The extent and distribution of nerve involvement is variable and leprosy most commonly affects the posterior tibial nerve, causing anesthesia on the soles of the feet followed by the ulnar, median, lateral popliteal, facial, greater auricular, radial, and radial cutaneous nerves. Small dermal nerves can also be affected, leading to reduced sensation, loss of sweating, and a glove and stocking hypohidrosis. Lesions of nerves with impaired sensation lead to trauma and secondary infection and finally to disability and deformity. Ocular manifestations. Blindness affects 5.3% of individuals with leprosy (Ffytche, 1998). It is due to optic nerve damage and to direct bacillary invasion of the skin or eye itself with inability to close the eyes normally (due to damage to the facial nerve), corneal ulceration (damage to the ophthalmic branch of the trigeminal nerve), acute or chronic iridocyclitis, and secondary cataract. Other manifestations. Infiltration of nasal structures leading to a saddle deformity due to septal perforation and destruction of the anterior nasal spine, testicular atrophy and amyloid and renal disease may also be observed.

DIAGNOSIS Diagnosis is clinical, by the finding of a cardinal sign of leprosy, and is supported by acid-fast bacilli in slit-skin smears or typical histology on skin biopsy (Lockwood and Kumar, 2004). Skin biopsy reviewed by an experienced histopathologist is invaluable when classifying the patient and excluding other diagnoses. This diagnosis is difficult to evoke outside areas where leprosis is endemic, but should be considered as a possible cause of peripheral neuropathy or neuropathic ulcers in patients of Indian or African origin.

TREATMENT First-line antimicrobial therapy with rifampicine, clofazimine, and dapsone is safe and effective in treating

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M. leprae infection. Patients with high bacterial loads need treatment with multidrug therapy for at least 24 months. Clinical improvement is rapid and toxicity is uncommon. However, multidrug therapy does not stop the inflammatory impairment of nerve function. Patients with motor or sensory loss of less than 6 months’ duration should receive a 6 month course of oral corticosteroids. However, steroids do not help if nerve impairment has lasted for more than 6 months, and a recent Cochrane review failed to find evidence of significant long-term benefit due to prednisolone in improving nerve function, even in patients with impairments of less than 6 months’ duration. Unfortunately, there is no specific vaccine against leprosy, but several trials have shown BCG to be protective. Preventing disability is crucial since nerve damage produces anesthesia, dryness and muscle weakness, which lead to misuse of the affected limb and resultant ulceration, infection and, ultimately, severe deformity (Rodrigues and Lockwood, 2011).

Lyme disease Lyme disease is a chronic inflammatory disease caused by the spirochete Borrelia burgdorferi and is transmitted by a tick bite (Ixodes dammini). Borrelia burgdorferi affects the skin, the heart, the nervous system, and the joints. Most cases arise during the summer.

CLINICAL MANIFESTATIONS The frequency of the individual clinical manifestations is highly variable. The disease is classified as early or late in terms of three stages. The first stage (stage I), is characterized by erythema migrans (EM), which is the most common (>80%) manifestation of early Borrelia infection. EM is usually observed 1–2 weeks after the tick bite, most often at the site of the tick bite (lower extremities, back, groin, or axilla). It begins as an erythematous macule or papule that spreads centrifugally by as many as 3 cm per day and may develop central clearing, reaching 10–16 cm at presentation (Fig. 104.10). Associated signs and symptoms may include fatigue, fever, headache, pain and pruritus at the site of the tick bite, or regional lymphadenopathy. EM usually resolves spontaneously in a few days or weeks (Bhate and Schwartz, 2011a). The second stage (stage II) occurs from a few weeks to 6 months after the tick bite and particularly affects the neurologic and cardiac systems. Lymphomonocytic meningitis, radiculitis (inflammation of the spinal nerve roots), cranial nerve deficits (most commonly a uni- or bilateral peripheral facial palsy), radicular pain, and paresis are the main neurologic features (Bagger-Sj€ oba¨ck et al., 2005). The typical cardiac manifestation is an atrioventricular block of variable severity, which usually resolves within several weeks and more rarely ST- and

Fig. 104.10. Erythema chronicum migrans of Lyme disease. Expanding erythematous annular plaque with a small central red papule or scar at the site of the tick bite (the right shoulder) allows the diagnosis of early Lyme disease. (Figure courtesy of Dr. Particia Schoenlaub, Hoˆpital des Arme´es, Brest, France.)

T-wave changes indicating a myocarditis (Nau et al., 2009). Stage III occurs from 6 months to several years after the tick bite and its typical manifestations are acrodermatitis chronica atrophicans (ACA), chronic arthritis, and central nervous complications. ACA is essentially located on the extensor surfaces of the limbs and consists of parchment-like thinning of the skin with prominent venous markings and, sometimes, altered pigmentation of the skin. ACA can be associated with pain, pruritus, and hyperesthesia or paresthesias (Bhate and Schwartz, 2011a). Progressive chronic meningoencephalitis affects fewer than 5% of all patients with neuroborreliosis. It consists of spastic quadri- or paraparesis; cranial nerve deficits, bladder dysfunction, sensory disturbances, ataxia, or altered personality and dysarthria (Ackermann et al., 1985). Cerebral vasculitis can lead to stroke (Topakian et al., 2008) and is an obliterating vasculitis with thickening of the vascular intima and adventitia and perivascular lymphocytic infiltrates. Rare cases of extrapyramidal motor disease have also been described (Kohlhepp et al., 1989). Chronic mono- or asymmetrical oligoarthritis can arise months to years after the tick bite in untreated Lyme disease, most commonly affecting the knee and elbow joints. This form of arthritis is a not very painful, and is often associated with a voluminous effusion but only mild signs of inflammation. Each episodic attack lasts for several days to weeks. Untreated adults may develop a persistent arthritis resembling septic arthritis, crystalline-induced arthritis, or reactive arthritis.

DIAGNOSIS Only in highly specialized laboratories can Borrelia burgdorferi be cultured from body fluids. Serologic

NEURODERMATOLOGY 1577 examination should be performed immediately whenever unilateral erythema followed within 12–24 hours by an infection with Borrelia burgdorferi is suspected on grouped vesicles which become confluent after 2–4 clinical data (Bhate and Schwartz, 2011b). If the findings days. On the third day, the vesicles may cloud and then are negative or ambiguous and clinical suspicion usually dry out over approximately 7–12 days. In immuremains, then the serologic examination should be nologically healthy patients, duration of the rash until repeated 3 weeks later. Antibodies against Borrelia are disappearance of the crusts is generally 2–3 weeks found in fewer than 50% of patients with erythema (Gross et al., 2003). Zoster may occur in any dermatome, migrans. In contrast, when neurologic manifestations but the most frequent are zoster thoracicus (50–56%) are present, Borrelia-specific IgM or IgG antibodies and zoster in the vicinity of the head such as the innervaare found in the serum of more than 90% of patients. tion areas of the trigeminal nerve and other cranial In neuroborreliosis, CSF protein concentration is often nerves (VII and VIII) (20%) and, more rarely, in cervical, elevated to 1 g/L or higher, usually associated with pleolumbal and sacral segments (Gross et al., 2003). cytosis (leukocyte concentration below 1000/mL with Neurologic manifestations. Pain is the most frequent lymphocyte predominance) and intrathecally formed neurologic manifestation and may occur before, during specific antibodies against Borrelia. or after the dermatomal rash stage (zoster-associated pain) or appear 4 weeks after a pain-free interval or persist for more than 4 weeks after the cutaneous symptoms TREATMENT (postherpetic neuralgia or PHN) (Dworkin et al., 1997). Lyme disease usually has a good prognosis. Antibiotic PHN affects approximately 10–20% of zoster patients treatment shortens the clinical course and prevents comof all ages. Its incidence is age-dependent: the risk of plications and rare chronic infections. The choice of antiPHN is low (2%) in patients younger than 50 years of biotic, its mode of administration, and the duration of age, 20% in those older than 50 years, and 35% over treatment depend on the stage of the disease, the clinical the age of 80 years, and increases in patients with ophmanifestations, and the age of the patient. In randomthalmologic localization. Neurologic complications ized studies involving patients with stage II neuroborreinclude peripheral manifestations (motor neuropathies liosis, intravenous penicillin 6  106 U three to four and paralysis, Guillain–Barre´ syndrome, and disorder times a day (evidence level A), cefotaxime 2 g three of cranial nerves) and central manifestations (zoster times a day (evidence level A), intravenous ceftriaxone meningitis, large and small vessel encephalitis, granulo2 g a day for 14 days (evidence level A), which is the stanmatous arteritis, and myelitis) (Gilden et al., 2000). As dard treatment because it needs to be given only once regards peripheral neurologic manifestations, the facial daily, and oral doxycycline 100 mg two or three times nerve is often injured, leading to a peripheral facial nerve a day for 2 weeks (evidence level B), were found to be palsy accompanied by an erythematous vesicular rash on effective (Nau et al., 2009; Bhate and Schwartz, 2011b). the ear (zoster oticus) or in the mouth (Ramsay Hunt syndrome). Compared with Bell’s palsy (facial paralysis Zona without rash), patients with Ramsay Hunt syndrome often have more severe paralysis at the onset and are less Varicella zoster virus is an exclusively human herpes likely to recover completely. Studies suggest that treatvirus that causes chickenpox (varicella), becomes latent ment with prednisone and aciclovir may improve the outin cranial -nerve and dorsal -root ganglia, and frequently come (Uri et al., 2003), although a prospective reactivates decades later to produce shingles (zoster) and randomized treatment trial remains to be undertaken. postherpetic neuralgia (Gilden et al., 2000). Following or Zoster may also be accompanied by ophthalmoplegia accompanying the typical vesicular rash, central (myeli(most commonly affecting the third cranial nerve), optic tis, large -vessel granulomatous arteritis, and small neuritis, or both. Palsies of the lower cranial nerve occur vessel encephalitis) or peripheral (Ramsay Hunt less frequently. These cranial neuropathies often occur syndrome, preherpetic and postherpetic neuralgia) neuweeks after acute zoster has developed. Cervical zoster rologic manifestations can occur. is occasionally associated with arm weakness, which is at times accompanied by diaphragmatic paralysis. LumboCLINICAL MANIFESTATIONS sacral zoster may be accompanied by leg weakness as Cutaneous manifestations. In 80% of the patients well as bladder and bowel dysfunction. Guillain–Barre´ affected by zoster, the skin manifestation is preceded syndrome is rare and follows a rash outbreak after a by a prodromal stage lasting approximately 3–5 days latent period ranging from 2 weeks to 2 months (tiredness, weariness, mild temperature, pain or pares(Cresswell et al., 2010). Large-vessel encephalitis is thesias). The characteristic zoster rash usually affects characterized by cerebral infarction that develops weeks a single dermatome. It begins with a painful, asymmetric, or months after zoster of contralateral trigeminal

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distribution (as described elsewhere). Small vessel encephalitis is the most common complication of zoster that involves the CNS (mainly on account of an increase in the number of patients with AIDS or immunosuppression due to transplantation or cancer). Clinical symptoms are subacute and comprise headache, fever, vomiting, mental changes, seizures, and focal deficit, commonly leading to death. Ischemic and/or hemorrhagic infarcts of cortical and subcortical gray and white matter clearly appear on brain MRI. CSF exploration usually shows mild mononuclear pleocytosis, a normal or elevated level of protein, and a normal level of glucose (Gilden et al., 2000). Diagnosis may be particularly difficult in patients without rash or when the clinician is unaware of a history of zoster rash. An empirical treatment with aciclovir (15–30 mg per kilogram per day) for 10 days (or longer in severely immunocompromised patients) is recommended (Gilden et al., 2000). Myelitis may complicate acute varicella or zoster, usually 1–2 weeks after the development of rash, and associates paraparesis with sensory-level and sphincter impairment. The CSF is either normal or shows mild pleocytosis with a normal protein level or a mild elevation, and T2weighted MRI reveals hyperintense lesions, sometimes with focal swelling of the spinal cord. In immunocompromised patients, myelopathy is often more insidious and progressive (Gilden et al., 2000). Ventriculitis and meningitis may also be encountered (Gilden et al., 2000).

DIAGNOSIS The diagnosis of peripheral and CNS manifestations due to varicella zoster can be confirmed by PCR analysis and antibody testing of CSF. Analysis of serum for antibodies is of no value, because antibodies to varicella zoster virus persist in serum in nearly all adults (Vafai et al., 1988).

POEMS syndrome POEMS syndrome or Crow–Fukase syndrome is a rare multisystemic paraneoplastic disorder secondary to plasma cell dyscrasia. POEMS syndrome is characterized by peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasmaproliferative disorder, skin changes and other systemic features (papilledema, extravascular volume overload with peripheral edema, pleural effusions, and ascites, sclerotic bone lesions, thrombocytosis). The pathogenesis of POEMS is not fully understood, but overproduction of vascular endothelial growth factor (VEGF) is likely to be responsible for most of the characteristic symptoms. Clinical features. Peak incidence of the POEMS syndrome occurs is the 5th and 6th decades of life. Peripheral neuropathy is quite common and consists of early sensory symptoms with tingling, pins and needles, and

coldness that always starts in the feet. Sensory loss usually affects touch pressure, vibratory sense and joint position, and less frequently involves temperature discrimination and nociception. Motor symptoms follow and usually overshadow the sensory symptoms, and both are distal, symmetric, and progressive, usually leading to disability. Absence of the deep tendon reflexes is frequently observed. Patients do not usually present with autonomic symptoms or cranial nerve involvement except for papilledema, which is frequent (Kelly et al., 1983). Nerve conduction studies and electromyelography show a polyneuropathy with prominent demyelination as well as features of axonal degeneration. Biopsy of the sural nerve usually shows both axonal degeneration and demyelination. The most common cutaneous lesion is hyperpigmentation, which can be diffuse or localized and is unrelated to adrenal insufficiency. Other skin manifestations associated with POEMS are characterized by thickening, hypertrichosis, clubbing, skin angiomas, acrocyanosis, flushing, and white nails. Other symptoms may include testicular atrophy, gynecomastia, edema of the lower extremities, ascites and pleural effusion in approximately one-third of patients, organomegaly (hepatomegaly in almost half of patients, and more rarely splenomegaly and lymphadenopathy), arterial and/or venous thromboses such as end artery borderzone infarctions (Kang et al., 2003). Laboratory studies and diagnosis. Thrombocytosis and elevated levels of VEGF are common. The size of the M protein on electrophoresis is small and it is usually in the form of IgG or IgA and almost always of the l type. Bone marrow usually contains < 5% plasma cells, and when clonal cells are found, they are almost always monoclonal l. Protein levels in the CSF are elevated in nearly all patients. The classic pattern of the bone lesions in POEMS is sclerotic or mixed sclerotic and lytic. Osteosclerotic lesions occur in approximately 95% of patients, and are solitary or multiple. Exclusively lytic lesions are very rare. Hypogonadism, thyroid, glucose metabolism, and adrenal abnormalities are frequent and often associated. The diagnosis is based on revised criteria and can be ascertained if at least one other major criterion and one minor criterion (except for diabetes mellitus and thyroid abnormalities) is fulfilled (Dispenzieri, 2007) (Table 104.3).

TREATMENT Because of its rarity, there are no randomized controlled trials in patients with POEMS. Radiation therapy, alkylator-based therapies, and corticosteroids should be considered. Single or multiple osteosclerotic lesions in a limited area should be treated with radiation. Plasmapheresis and intravenous immunoglobulin do not

NEURODERMATOLOGY Table 104.3 Criteria for the diagnosis of POEMS syndrome Major criteria

Minor criteria

Polyneuropathy Monoclonal plasma cell-proliferative disorder (almost always l) Sclerotic bone lesions Castleman disease Vascular endothelial growth factor elevation Organomegaly (splenomegaly, hepatomegaly, or lymphadenopathy) Extravascular volume overload (edema, pleural effusion, or ascites) Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic) Skin changes Papilledema Thrombocytosis/polycythemia

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Other neurologic symptoms, usually observed in the third decade, include an increased sensitivity and tendency to weep and to be frightened, choreoathetoid-type involuntary movements, sensorineural deafness and corticospinal involvement slowly progressing to spastic tetraplegia and difficulty swallowing. Brain MRI demonstrates brain atrophy and white matter T2hyperintensities (Anttinen et al., 2008). In nearly 80% of XP patients, ocular abnormalities include photophobia, ectropion, conjunctival injection, keratitis, and tumors (Webb, 2008). Diagnosis and treatment: The diagnosis of XP is established by skin biopsy for fibroblast culture to measure unscheduled DNA synthesis. Treatment includes protection from ultraviolet light and skin cancer surveillance every 3 months, an annual ophthalmologic review, and a neurologic assessment every 6 months in the event of neurologic disorders (Webb, 2008).

Refsum disease usually produce clinical benefit. High-dose chemotherapy with peripheral blood transplant is promising (Dispenzieri, 2007).

Xeroderma pigmentosum Xeroderma pigmentosum (XP) is a rare autosomal recessive genodermatosis with a worldwide incidence of 1:250 000 live births. XP associates cutaneous, ocular and neurologic symptoms. Patients have a genetic inability to repair DNA damage that has been induced by ultraviolet light. XP patients have been assigned into eight complementation groups (XP-A to XP-G, and XP variant form) (Anttinen et al., 2008). Clinical manifestations begin at age 1–2 years with cutaneous manifestations (XP-C group) associating photosensitivity and burning after minimal sun exposure. Later cutaneous manifestations include increasing dryness of skin, freckling, telangiectasia, and an increased incidence of skin cancer on sun-exposed sites (Kraemer et al., 1987). Neurologic abnormalities occur in about 20–30% of the patients (commonly in groups XP-A, D, and G). The XP patients have normal early development until the age of 2 years. The first neurologic symptom, which is mild cognitive impairment, appears before the age of 8 years. The next symptoms (between the ages of 4 and 16 years) are cerebellar, predominantly presenting as dysarthria followed by gait disturbances with ataxia of the legs and milder ataxia of the upper limbs. Later (second decade to third decade), progressive difficulties in walking are explained by concurrent neuropathy with areflexia and moderate to marked axonal sensory motor neuropathy on electromyography (EMG).

Refsum disease (also named hereditary motor and sensory neuropathy IV: HMSN IV), is an autosomal recessive disorder characterized by defective peroxisomal a oxidation of the fatty acids leading to impairment of the metabolism of branched chain fatty acids such as phytanic acid that accumulate in the blood and other tissues. Clinical manifestations: The onset of symptoms typically occurs in late childhood or adolescence, but may take place as late as the fifth decade. The disease usually follows a progressive course, but acute and subacute presentations have been described. The three main clinical features are chronic demyelinating polyneuropathy with occasional marked nerve hypertrophy, cerebellar ataxia, and retinitis pigmentosa. Other clinical manifestations of the disease include pes cavus, syndactyly and a characteristic shortening of the fourth toe, sensorineural deafness, anosmia, cranial nerve involvement, and cardiac manifestations (conduction abnormalities and a cardiomyopathy). Ophthalmogical manifestations may include nyctalopia and visual failure secondary to retinitis pigmentosa, constriction of the visual fields, miosis, and cataracts. They often precede the neurologic symptoms. The skin is also affected, with ichthyosis and rough scaly thickening over the extremities (Wills et al., 2001). Diagnosis and treatment. Nerve conduction studies are abnormal, with slowing of conduction velocities. CSF protein levels are usually elevated. The electroretinogram may be abnormal. Nerve biopsies from affected patients have shown “onion bulb” formation, and targetoid inclusions have been described in Schwann cells. Plasma levels of phytanic acid measured by gas chromatography-mass spectroscopy are consistently elevated.

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Plasmapheresis or apheresis and dietary restriction of phytanic acid intake constitute two different strategies for treatment of RD (Baldwin et al., 2010).

CUTANEOUS DISORDERS ASSOCIATED WITH BRAIN OR PERIPHERAL NERVE TUMORS Melanoma brain metastasis Malignant melanoma is the third most common cause of brain metastasis behind lung and breast cancer. Of all primary neoplasms, melanoma has the highest propensity to metastasize to the brain in adults. The incidence of brain metastasis in patients with melanoma is 9.6%, and it typically occurs relatively late, with a median interval of 2.2–3.8 years after its diagnosis (Barnholtz-Sloan et al., 2004). Nearly 37% of patients with stage IV melanoma eventually develop clinically apparent brain metastasis, and the prevalence of brain metastasis in autopsy series is 55—75% of patients who died of melanoma (Sampson et al., 1998; Barnholtz-Sloan et al., 2004). Suspicious primary cutaneous lesions (Fig. 104.11) are characterized by asymmetry, border

Fig. 104.11. Facial malignant melanoma. Assymetry, border irregularity, color changes (i.e., blue, red, black, white), diameter over 6 mm and enlargement at times represent clinical criteria for an overly late diagnosis.

irregularities, color heterogeneity, dynamics (dynamics in colors, elevation or size) (the ABCD rule) (Dummer et al., 2009) and many primary melanomas have a diameter of < 5 mm (Bono et al., 2006). Risk factors associated with melanoma brain metastasis include male gender, mucosal or head and neck primaries, thick or ulcerated neoplasms, acral lentiginous or nodal lesions, and stage IV disease (Sloan et al., 2009). Clinical presentation of brain metastases is not characteristic, with headaches or other symptoms due to increased intracranial pressure, mass effect, impaired cerebrospinal fluid drainage, focal deficits (e.g., weakness, numbness, imbalance, visual loss, behavioral changes related to particular brain regions), cranial nerves affected by the mass, or seizures. However, the onset of symptoms may be sudden, since melanotic tumors are frequently hemorrhagal. More than three-quarters of brain metastases are supratentorial; while 15% are infratentorial or leptomeningeal, and 5% affect the brainstem. Melanoma metastases typically enhance on CT scan and on MRI with gadolinium and are frequently associated with hemorrhage and edema. CT of the brain can detect most metastases  10 mm in the supratentorial region and most hemorrhagic lesions, but MRI is obviously more sensitive, particularly for smaller lesions, lesions in the posterior fossa, and leptomeningeal disease. Current management strategies appear unsatisfactory (McWilliams et al., 2003), and brain metastases contribute to death in nearly 95% of patients, with a median survival of less than 1 year despite treatment (Barth et al., 1995; Sloan et al., 2009), although patients with a single brain metastasis and an absence of extracranial metastasis have a better prognosis (Sampson et al., 1998). Chemotherapy, immunotherapy, and biochemotherapy, whole brain radiotherapy (WBRT), open conventional surgery, and stereotactic radiosurgery (SRS) have proven effective in the treatment of melanoma brain metastasis (Sloan et al., 2009). However, there is no level I evidence that specifically guides treatment of patients with melanoma brain metastasis. For patients with a good performance status (Karnofsky score  70) and stable extracranial disease, therapeutic intervention is usually indicated. Surgery or stereotactic radiotherapy (SR) remains the standard of care for patients with single and/or small brain metastasis without mass effect. Surgery continues to be the standard of care in patients suffering from mass effect, especially in cases of a solitary metastasis. SR is most likely to be the treatment of choice for patients with 2–5 brain metastases if mass effect is not problematic. Palliative whole brain radiotherapy continues to be the treatment of choice for poorly functioning patients as well as those with multiple brain metastases or leptomeningeal symptoms. Several chemotherapeutic agents (fotemustine, temozolomide)

NEURODERMATOLOGY have been tested alone and in combination with radiotherapy in patients with melanoma brain metastasis, though none have been shown to be significantly more effective than darcabazine (Sloan et al., 2009).

Neurofibromatosis type 1 or Von Recklinghausen’s neurofibromatosis Neurofibromatosis type 1 (NF1), first described by Von Recklinghausen in 1882 with regard to benign peripheral nerve tumors, is an inherited autosomal dominant neurocutaneous disorder in which any organ system including the skin, skeleton, and central and peripheral nervous system can be affected (Reynolds et al., 2003). NF1 has a birth incidence of one in 2500 to one in 3000 and a minimum prevalence of one in 4000–5000 and represents 95% of neurofibromatosis. NF1 has almost 100% penetrance, but there may exist considerable variation in clinical manifestations within a family and 50% of cases are sporadic (Evans et al., 2010). The NF1 gene, isolated in 1990, is located on chromosome 17q11  2 and encodes a protein, so-called neurofibromin, which has a role in tumor suppression. Clinical symptoms. “Cafe´ au lait” (white coffee) patches and neurofibromas, of which there exist three clinically and histologically different types (cutaneous, subcutaneous and plexiform neurofibromas), are the most conspicuous clinical features of NF1. Cutaneous manifestations (Fig. 104.12A, B) are more pronounced in NF1 than in neurofibromatosis type 2 (NF2) and essentially represented by caf au lait spots (Fig. 104.12A), which are very frequent and arise in 99% of patients with NF1 by the age of 5 years, but may also be seen in newborn babies with NF1. Their number and size increase during infancy and adolescence. They may be the only sign observed in young children, even without a family

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history of NF1. They are not pathognomonic of NF1, since they may be observed in other dermatologic pathologies and about 10% of the general population has one to two caf au lait patches. Cutaneous angiomas, hypopigmented macules, and xanthogranulomas, appearing during childhood as orange papules, are less frequent. Cutaneous neurofibromas are observed in 99% of patients, usually appearing in early adulthood (Fig. 104.12B). They increase in size and number during pregnancy. Excision is the usual treatment, but laser treatment may be helpful for small lesions, albeit they do not undergo malignant change. Subcutaneous neurofibromas are peripheral nerve tumors that frequently cause pain, neurologic symptoms and deficit. Finally, plexiform neurofibromas, usually congenital, are present in 30–60% of patients with NF1 and are difficult to remove. These tumors represent the major cause of morbidity and death since they are responsible for neurologic deficits, disfigurement and mechanical complications. In about 2–16% of patients, subcutaneous and plexiform neurofibromas transform into malignant peripheral nerve sheath tumors. Ophthalmologic manifestations are represented by Lisch nodules and optic nerve gliomas. Lisch nodules are benign multiple melanotic hamartomas of the iris that are visualized on slitlamp examination and encountered in 10% of the patients before the age of 6 years and in almost all patients with NF1 after adolescence. Optic nerve gliomas are the most frequent cerebral tumors and are observed in 15% of NF1 children. They produce symptoms in only 5% of cases (impaired visual acuity and colour vision) and are detectable with MRI. These pilocytic astrocytomas are particularly slowly growing gliomas. There is still debate about when to treat them, but decline in visual acuity associated with tumor progression on MRI constitute the main deciding factors. Children with diagnosed

Fig. 104.12. Neurofibromatosis type 1. Along with six or more cafe´ au lait spots (A), the diagnosis is supported by other cutaneous signs such as numerous axillary freckles, and dermal or subcutaneous pedunculated neurofibromas or schwannomas (B).

1582 J.-P. NEAU ET AL. optic pathway gliomas should consequently undergo visit, including for children a developmental assessment, regular MRI and visual assessment. However, gliomas examination of the skin, long bones and spine, monitorcan develop in any other part of the CNS (cerebellum ing of blood pressure and the heart for congenital heart and brainstem). They have a more aggressive course disease, visual assessment and measurement of height, and are associated with a worse prognosis. Cognitive disweight, head circumference, and checks for delayed or ability is the most common neurologic symptom in chilprecocious puberty (Ferner, 2010). dren with NF1 and is characterized by an intelligence quotient in the low-average range with specific learning Neurofibromatosis type 2 difficulties (occurring in at least 60% of children), including visual spatial difficulties, impaired attention, Neurofibromatosis type 2 (NF2), first described by inability to interpret nonverbal cues, reduced working Wishart in 1822, was formerly known as bilateral acousmemory, speech and language deficits, and disorder tic or central neurofibromatosis. NF2 is essentially charof executive function (Hyman et al., 2005). Other neuroacterized by a bilateral vestibular schwannoma. NF2 is an logic manifestations that may be associated with NF1 autosomal-dominant multiple neoplasia syndrome that include axonal symmetrical neurofibromatous neuroparesults from mutations in the NF2 tumor suppressor gene located on chromosome 22q11-2. The gene protein thy with mild distal sensory and motor symptoms merlin acts as a tumor suppressor, controlling prolifer(affecting at least 1% of NF1 adults), Chiari 1 malformation and aqueduct stenosis (1.5% of NF1 patients), epiation of Schwann and leptomeningeal cells by interaclepsy (6% of NF1 patients) starting between childhood tion with multiple intercellular signaling pathways and middle age and due to several underlying causes, (Ferner, 2010). NF2 has a birth incidence of about one and headache (Cre´ange et al., 1999). NF1 vasculopathy in 25 000 and nearly 100% penetrance by 60 years of is rare and affects arterial and venous blood vessels of age. NF2 should be distinguished from NF1. all sizes. A variety of vascular lesions have been noted Clinical symptoms. Cutaneous manifestations are not conspicuous in NF2 and are less pronounced than in NF1. in patients with NF1, including moyamoya disease, However, they may constitute the presenting features of occlusion, cerebral aneurysm, pseudoaneurysm, ectasia, stenosis, fistula, and rupture (Rosser et al., 2005). the disease. Although 70% of patients have skin tumors Orthopedic problems frequently arise in patients with including skin plaques, subcutaneous tumors and intraNF1 from inherent abnormalities in the maintenance of dermal tumors, the majority of NF2 patients have fewer bone structure and reduction in bone mineral density. than 10 lesions. Skin plaques, present in nearly half of the They include an increased risk of developing osteoporoNF2 patients, are well-circumscribed, slightly raised, sis and osteopenia, pseudoarthrosis mostly involving the roughened areas less than 2 cm with usually slight hyperpigmentation and hypertrichosis (Ferner, 2010). Nodular tibia (3–4% of NF1 patients), and scoliosis (10% of NF1 subcutaneous schwannomas, also reported in nearly half patients). Other manifestations that arise more frequently in NF1 patients include pheochromocytoma the NF2 patients, are often painful and sensitive to pres(0.1–5.7% of patients), mesenchymal gastrointestinal sure. They can be palpated or seen as fusiform or stromal tumors, and hypertension (6% of NF1 patients). nodular swellings developing along peripheral nerves. Diagnosis. The diagnosis criteria and the name of NF1 Intradermal tumors are less frequent and appear as epiwere proposee in 1988 at the National Institutes of Health cutaneous, well-demarcated, soft lesions with violaConsensus Development Conference. Two or more of ceous colouring. Finally, cafe´ au lait patches are reported in 40% of NF2 patients, but are less numerous the following criteria are required for the diagnosis of than in NF1, appearing as flat, hyperpigmented areas of NF1: (1) six or more cafe´ au lait macules (>0.5 cm in children or > 1.5 cm in adults); (2) two or more cutaneous or skin (Mautner et al., 1997). Ocular manifestations are subcutaneous neurofibromas or one plexiform neurofialso frequent since cataracts are present in about broma; (3) axillary or groin freckling; (4) optic pathway three-quarters of the patients and present as posterior glioma; (5) two or more Lisch nodules; (6) bony dysplasubcapsular lens opacities that do not usually require sia; and finally (7) a first-degree relative with NF1 removal since they interfere with vision in only (NIH, 1988). 10–25% of NF2 patients and as cortical wedge opacities (peripheral cortical cataracts). There exist no Lisch nodCurrent laboratory techniques can detect the causaules. Other manifestations include orbital meningiomas, tive NF1 mutation in 95% of cases but the phenotype cannot be predicted from the type of mutation. Prenatal retinal hamartomas that can impair vision, and epiretinal mutation testing is available. There is a one in two chance membrane (translucent, semitranslucent, or whitish gray of transmitting NF1 to an offspring and the risk of havmembranes with prominent whitish edges) affecting the ing a severely affected child is 1 in 12 (Ferner, 2007). Surmacula. Neurologic tumors are the most striking feaveillance is of the utmost importance with an annual tures of NF2. NF2 is characterized by vestibular

NEURODERMATOLOGY schwannomas occurring in 95% of patients, presenting with progressive unilateral or bilateral sensorineural deafness, but also tinnitus, impaired balance, and sometimes with signs of raised intracranial pressure and brainstem compression. Hearing loss and tinnitus are the presenting symptoms in 60% of adults and up to 30% of children. Up to 51% of patients demonstrate nonvestibular cranial nerve schwannomas (cranial nerves III, V, and VII). In addition, schwannomas of the spinal nerve root are frequent (Fig. 104.13), multiple, and account for almost 90% of extramedullary spinal tumors. Intramedullary schwannomas have also been reported in NF2 patients. Finally, they only rarely undergo malignant change (Ferner, 2010). Meningiomas are the second most common tumor related to NF2 and are frequently multiple, developing at a younger age than do sporadic meningiomas, presenting with all major histologic subtypes (fibroblastic, meningothelial, psammomatous, or transitional). In addition, up to 20% of the children presenting with meningiomas will suffer one day from NF2. Intracranial meningiomas are present in 45–58% of patients and intradural extramedullary spinal meningiomas are present in about 20% of NF2 patients. Ependymomas account for more than 75% of the intramedullary spinal cord tumors associated with NF2.They are present in 18–53% of patients, but cause clinical symptoms in fewer than 20%. These three types of tumors are frequently encountered in the same NF2 patient. However, intramedullary astrocytomas of the spinal cord (diffuse and pilocytic) can be found in NF2

Fig. 104.13. Neurofibromatosis type 2. Typical appearance of a left L2 neurofibroma (arrow) that can be demonstrated with lumbar MRI (Coronal view of gadolinium-enhanced T1-weighted MRI.)

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patients. Epilepsy, accounting for 10% of NF2 patients, is not exclusively related to any one of the tumors. Cortical dysplasia has been reported in NF2 patients. Finally, peripheral neuropathy developing during the lifetime of NF2 patients is very frequent. It can be attributed to tumors within or compressing a nerve, but are also frequently found in up to 66% of NF2 patients without being associated with tumors (Sperfeld et al., 2002). Histopathologic study has demonstrated myelinated and unmyelinated fiber loss and abnormal Schwann cell proliferation with or without a bulb-like, onion appearance. Treatment of these peripheral neuropathies, which are not related to tumors, is essentially based on symptom management (medical treatment of neuropathic pain). Vascular dysplasia and cerebral aneurysms are very rare (Ryan et al., 2005). Diagnosis. The diagnosis of NF2 is based on the Manchester diagnostic criteria (Evans et al., 2005). Bilateral vestibular schwanomas is sufficient for NF2 diagnosis. In other cases additional findings are necessary for NF2 diagnosis. Thus, the NF2 diagnosis can be established in case of a unilateral vestibular schwannoma plus multiple meningiomas or a first-degree relative with NF2. It can also be made if two of the following findings are present: schwannoma, glioma, meningioma, neurofibroma, posterior subcapsular lens opacity plus a unilateral vestibular schwannoma or a first-degree relative with NF2 (Evans et al., 2005; Ferner, 2010). NF2 gene mutation testing is useful for diagnosis in all patients because there exists a phenotype–genotype correlation. Prenatal testing is also available (Ferner, 2010). Radiology. Brain and spinal cord MRI is the keystone of the NF2 diagnosis. Vestibular schwannomas vividly enhance and are best observed by high resolution contrast-enhanced, T1-weighted MRI. Meningiomas homogeneously enhance and are also best observed with contrast-enhanced T1-weighted MRI. Spinal cord ependymomas are isointense or slightly hyperintense on nonenhanced T1-weighted MRI and enhance homogeneously after contrast administration. Spinal ependymomas are hyperintense on T2-weighted MRI with a hemosiderin cap at the upper and lower poles of the tumor. Ophthalmologic and skin examination, and audiology with auditory brainstem evoked potentials are obviously also recommended. In at-risk individuals, vision assessment and examination of the skin and nervous system should be undertaken annually from birth with brain MRI performed every 2 years from age 12 until 20 years and every 3–5 years until age 40 years and spinal MRI every 3 years. Once vestibular schwannomas are detected, brain MRI is required at least annually with concomitant speech and pure tone audiometry (Evans et al., 2005).

1584 J.-P. NEAU ET AL. Treatment of NF2 tumors. For vestibular schwannoto abnormal cellular growth, proliferation, and protein mas, complete surgical resection is curative, but the synthesis. timing of treatment is still under debate due to the risks of this surgery and the tumor’s natural history, CLINICAL SYMPTOMS which is unforeseeable. Early surgical management of small vestibular schwannomas can usually preserve Cutaneous manifestations. Hypomelanotic macules are hearing and normal function of the facial nerves in the most common dermatologic manifestations, being present in 90–98% of patients, particularly on the trunk 30–65% and 75–92% of NF2 patients, respectively and buttocks, and can be optimally observed under (Asthagiri et al., 2009). Thus, conventional management strategies are typically conservative and recommend Wood’s lamp (ultraviolet light). Bilateral facial angiofisurgical resection of tumors 2–3 cm in size only if bromas are observed in about 80% in children older than serviceable hearing is lost or rapid growth identified. 5 years of age and generally appear in children of 3–4 Fractionated stereotactic radiotherapy may be useful, years of age. They take on a butterfly pattern over the but remains under evaluation although its toxicity is malar eminences and nasal labial folds of the face minimal (Chan et al., 2005). In addition, a recent study (Fig. 104.14A, B). Shagreen patches are present in 54% of children with tuberous sclerosis who are older than noted improved hearing in some patients and reduction 5 years of age, and usually become evident by 10 years. in tumor size with bevacizumab, which is a vascular endothelial growth factor inhibitor (Plotkin et al., They are generally located on the lumbosacral flank, but 2009). An auditory brainstem implant might be an option can also be scattered across the trunk or thighs. Mollusin hearing rehabilitation. Most meningiomas of the cum fibrosum pendulum is common on the neck, groins, cerebral hemispheres and spine can be fully and safely axillae, and near the flexory surfaces of limbs, especially resected. At times, adjuvant stereotactic radiosurgery in adults. Forehead fibrous plaques (36% of patients with for local control of residual tumor can be performed. TS) are yellow-brown or flesh-coloured patches of raised skin of variable size and shape, with a diameter ranging Spinal cord ependymomas frequently remain quiescent from a few millimetres to several centimetres. Ungual and asymptomatic for many years, and surgery is needed when they become symptomatic. Resection fibromas (Koenen tumors), are close to nail beds and remains the treatment for symptomatic intramedullary more common on toes than on fingers (Fig.104.14C). astrocytomas with adjunctive radiotherapy in the event Neurologic manifestations. About 85% of children and of residual diffuse astrocytomas. Symptomatic schwanadolescents with TSC have CNS complications, including nomas of peripheral nerves are mainly treated by surgiepilepsy, brain lesions, cognitive impairment, behavioral cal resection. problems, and autism (Curatolo et al., 2008). Brain lesions include cortical tubers, subependymal nodules, subepenNEUROCUTANEOUS DISORDERS dymal giant-cell tumors, and white matter abnormalities. ASSOCIATED WITH EPILEPSY Cortical tubers are developmental abnormalities of the cerebral cortex characterized histologically by a loss of Numerous neurocutaneous disorders are associated with the normal six-layered structure of the cortex and by dysepilepsy, which can be due to brain tumors (NF1, NF2, morphic neurons, large astrocytes, and a unique type of tuberous sclerosis complex), cortical dysplasia and cell known as a giant cell (Crino et al., 2006). They are vartubers (tuberous sclerosis complex) or other complex iable in size and multiple in number, and can easily be pathophysiology (cerebrotendinous xanthomatosis). detected by MRI even as early as 26 weeks of gestation. Epilepsy is almost always accompanied by other neuroSubependymal nodules are seen in the subependymal wall logic symptoms (mental retardation, cognitive disorders, of the lateral ventricules, can protrude into the ventricular gait disturbances, and pyramidal and extrapyramidal cavity, and are usually asymptomatic. Transformation of symptoms). a subependymal nodule into a subependymal giant cell tumor is usually slow growing, essentially during the first Tuberous sclerosis complex two decades of life. They typically arise near the foramen The tuberous sclerosis complex (TSC) is an autosomal of Monro, develop in 5–20% of patients with TSC and can dominant disorder with a prevalence approaching 1 in lead to sudden death from acute hydrocephalus. Neuro6000 live births. It is characterized by benign tumors surgical resection is the standard treatment; however, (hamartomas) in multiple organ systems, including the the deep-seatedness of these tumors can render resection brain, skin, kidney, lung, heart, and retina. Mutations difficult, and it carries a major risk of perioperative and are found in over 85% of patients (TSC1: hamartin or postoperative complications. A potential alternative to TSC2: tuberin). When either TSC1 or TSC2 is deficient, neurosurgical resection is the use of everolimus, which mTOR complex 1 is constitutively upregulated, leading induces a marked reduction in tumor volume and seizure

NEURODERMATOLOGY

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Fig. 104.14. Tuberous sclerosis. Facial cutaneous angiofibromas (so-called Pringle adenomas) develop in 65–90% between 2 and 6 years of age (A, B) prior to periungual fibromas of the toes (Koenen tumors) (C).

frequency (Krueger et al., 2010). Epilepsy occurs in more than 70–80% of patients with TSC, and all listed subtypes of seizure have been reported. A pronouncedly high number of tubers is associated with the development of infantile spasms and intractable epilepsy. Seizures usually begin during the first year of life and, in most patients, over the first few months. Focal seizures precede, coexist with, or evolve into infantile spasms and are often refractory to treatment, even polytherapy with antiepileptic drugs. Infantile spasms occur in 20–30% of children with TSC and are often associated with a poor neurologic prognosis and profound mental retardation. The risk and degree of intellectual impairment correlates with prompt seizure control. Vigabatrin may be beneficial to some of these extremely young children, since it can stop spasms in up to 95% of infants. However, patients with medically refractory epilepsy may require a surgical evaluation, which often means resection of a tuber. Neurocognitive manifestations and psychopathologic features are highly variable in severity, ranging from severe autism to normal life. About 30% of individuals with TSC are profoundly impaired and more than 50% of them have average intelligence, but with specific cognitive deficits of memory, attention, or executive skills (Joinson et al., 2003). Finally,

intracranial aneurysms, especially those involving the internal carotid artery, have also been observed in TSC (Curatolo et al., 2008). Other manifestations. Dental pits are seen in 90% of patients with TSC. Cardiac manifestations include cardiac rhabdomyomas. They are rarely symptomatic, usually 3–25 mm in diameter, and located within the ventricles, more often within the walls than the septum. These tumors, which are the main feature of the disease in the fetus and newborn baby, usually recede over time, with complete regression in childhood. Renal complications are represented by multiple and bilateral angiomyolipomas (70–90% of adult patients) with spontaneous bleeding. Surgical resection or tumor embolization for lesions more than 3–4 cm in diameter should be discussed in the event of complication or progression of tumor size. Patients with TSC may also exhibit renal cysts and renal cell carcinomas (2–3% of patients). Retinal hamartomas, with different morphologic types, are present in about 40–50% of people with TSC (Rowley et al., 2001). Other manifestions include hepatic multiple, bilateral angiomyolipomas and pulmonary lymphangiomyomatosis, which is progressive, affects women almost exclusively, and is extremely difficult to treat.

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DIAGNOSIS AND GENETIC TESTING Diagnosis of TSC can be ascertained by criteria when two major features, or one major and two minor ones, can be demonstrated (Roach et al., 1998) (Table 104.4). An antenatal diagnosis can also be made, based on fetal ultrasound and MRI showing cardiac and brain lesions. Finally, genetic testing for TSC1 and TSC2 mutations is available and prenatal or preimplantation genetic testing is presently becoming more widely available. Extensive studies of the TSC1 and TSC2 genes in patients with TSC have revealed a wide spectrum of mutations. However, among patients meeting the clinical criteria for a diagnosis of TSC, 15–20% of patients, usually with milder clinical disease, have no identifiable mutations (Crino et al., 2006).

Cerebrotendinous xanthomatosis First described by Bogaert et al., in 1937, cerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive disease due to defective activity of the mitochondrial enzyme sterol 27-hydroxylase. CTX is more common than previously recognized, with prevalence estimated at 1 per 50 000 (Lorincz et al., 2005), and has been reported in many countries worldwide. In 1991, the sterol 27-hydroxylase gene (CYP27A1) was localized on the

Table 104.4 Diagnostic criteria for tuberous sclerosis Major features ● Facial angiofibromas or forehead plaque, pits in dental enamel ● Nontraumatic ungual or periungual fibroma ● Hypomelanotic macules ( 3) ● Shagreen patch (connective tissue nevus) migration lines ● Multiple retinal nodular hamartomas ● Cortical tuber ● Subependymal nodule ● Subependymal giant-cell astrocytoma ● Single or multiple cardiac rhabdomyoma ● Lymphangiomyomatosis and/or renal angiomyolipoma Minor features ● Multiple, randomly distributed ● Hamartomatous rectal polyps ● Bone cysts ● Cerebral white matter radial ● Gingival fibromas ● Nonrenal hamartoma ● Retinal achromic patch ● Confetti-like skin lesions ● Multiple renal cysts (Roach et al., 1998)

long arm of chromosome 2 (Cali et al., 1991). Since 1991, more than 50 different mutations of the CYP27A1 gene have been reported (Berginer et al., 2009); almost all of them lead to the absence or inactive form of sterol 27-hydroxylase. Because of this mitochondrial enzyme deficiency, large amounts of cholestanol and cholesterol are produced. Cholestanol easily crosses biologic membranes and the blood–brain barrier and accumulates in many tissues, especially eye lenses, brain, peripheral nerves, and muscle tendons, thereby explaining the different clinical symptoms (Kuriyama et al., 1991). Clinical symptoms. The onset of symptoms and signs in patients with CTX usually occurs in childhood, with cognitive disorders, diarrhea, and seizures. The combination of bilateral cataracts and diarrhea in childhood is virtually pathognomonic for the disease (Moghadasian et al., 2002; Berginer et al., 2009). Chronic diarrhea from infancy may be the earliest clinical manifestation. In approximately 75% of affected individuals, cataracts are the first finding, often appearing in the first decade of life. Tendon xanthomas usually appear in the second or third decade. They occur in the Achilles tendons (Fig. 104.15), the extensor tendons of the elbow and hand, the patellar tendon, and the neck tendons, but have also been reported in the lung, bones, and CNS. Neuropsychiatric manifestations such as behavioral changes, hallucinations, agitation, aggression, depression, suicidal thoughts, catatonia, and psychotic symptoms may be prominent and usually appear at early stages (Lee et al., 2002). Some individuals show mental impairment from early infancy, whereas the majority have normal or only slightly subnormal intellectual function until puberty. Dementia with slow deterioration in intellectual abilities occurs in the 20s in more than 50% of individuals. Neurologic symptoms usually begin in the second decade of life and include ataxia, pyramidal and extrapyramidal signs, peripheral sensory-motor neuropathy, epilepsy, and dementia (Berginer et al., 2009). Pyramidal signs and/or cerebellar signs become evident between the ages of 20 and 30 years. Other clinical manifestations include osteoporosis, bone fractures (Federico et al., 1993), premature arteriosclerosis (myocardial infarction, atherosclerotic aneurysms in coronary arteries), and lung disease (mild pulmonary insufficiency) (Potkin et al., 1988; Segev et al., 1995). Radiology. MRI usually demonstrates nonspecific supratentorial atrophy and deep white matter changes. More typical hyperintense lesions may be seen on T2weighted images in the dentate nucleus (in more than three-quarters of patients), globus pallidus, substantia nigra, and inferior olive and extend into adjacent white

NEURODERMATOLOGY

Fig. 104.15. Cerebrotendinous xanthomatosis: skin colored or yellowish smooth subcutaneous non-tender nodule on extensor tendon of heel.

matter as the disease progresses. Hypointensity was occasionally found on T2-weighted images in the dentate nucleus pertaining to deposition of hemosiderin and calcifications. CT has demonstrated fewer lesions with low attenuation, except for calcifications. Spinal cord MR imaging has revealed increased signal intensity in the lateral and dorsal columns on T2-weighted images (Barkhoff et al., 2000). MRI has shown intermediate signal intensity on T1- and T2-weighted images in Achilles tendon xanthomas, but there has been no indication to perform this exam to detect xanthomas (Barkhoff et al., 2000). Lipid peaks may be detected in the depth of the cerebellar hemisphere using MR spectroscopy with a decrease in NAA concentration attributed to neuroaxonal damage (Embiruc¸u et al., 2010). Diagnosis and testing. CTX is diagnosed by clinical findings and biochemical testing. The biochemical abnormalities that distinguish CTX from other conditions with xanthomas (familial hypercholesterolemia and sitosterolemia) include: high plasma and tissue cholestanol concentration, normal to þ low plasma cholesterol concentration; decreased chenodeoxycholic acid; increased concentration of bile alcohols and their glyconjugates; and increased concentration of cholestanol and

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apolipoprotein B in CSF. Pretreatment cholestanol levels were elevated 4–6 times in patients with CTX (Berginer et al., 2009). Molecular genetic testing of CYP27A1 is clinically available. Treatment. Early recognition and diagnosis of CTX before neurologic deterioration are crucial since cholic and chenodeoxycholic acid (CDCA) replacement therapy can prevent CTX-induced brain damage, which leads to severe neurologic dysfunction and death. Long-term treatment with CDCA normalizes plasma and CSF cholestanol concentration, and improves neurophysiologic findings. In 1984, Berginer et al.,. demonstrated that 1 year of CDCA oral supplementation treatment at 750 mg/day was sufficient to produce a significant improvement in neurologic symptoms, normalization of electroencephalographic (EEG) readings, and reduction in serum cholestanol in CTX patients (Berginer et al., 1984). Early administration of CDCA therapy is mandatory, even for asymptomatic or minimally affected patients (Berginer et al., 2009). Inhibitors of HMG CoA reductase alone or in combination with CDCA have previously been used, but no additional benefits have been observed when compared with CDCA alone (Berginer et al., 2009). Symptomatic treatment is also useful. Cataract extraction is typically required in at least one eye by the age of 50 years. Epilepsy, parkinsonism and spasticity are treated symptomatically.

Incontinentia pigmenti or Bloch–Sulzberger syndrome Incontinentia pigmenti (IP) or Bloch–Sulzberberger syndrome is an uncommon hereditary X-linked dominant genodermatosis that can affect markedly variable abnormalities of the skin, eyes, hair, nails, teeth and the CNS (Berlin et al., 2002). IP is caused by mutations in the NEMO (NF-kB essential modulator) gene (Smahi et al., 2000). The vast majority of individuals with IP are female patients, since the deletion of NEMO exons 4–10 that underlies most cases is prenatally lethal in the hemizygous (XY) state. However, IP can occur in male patients in the context of mosaicism or in association with Klinefelter syndrome (XXY) (Fusco et al., 2007). Clinical symptoms. Cutaneous findings are the most common manifestation of IP and usually constitute the presenting signs. The skin lesions may occur in four classically successive, but at times overlapping diagnostic stages: erythema, then vesicles and pustules prevailing on the extremities during the first few months of life (stage 1); verrucous lesions favoring the distal extremities in patients 1–6 months of age and at times adolescents (stage 2); linear hyperpigmentation predominating on the trunk (Figs 104.16 and 104.17) and intertriginous sites from 3 months of age through

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Fig. 104.16. Incontinentia pigmenti.

Fig. 104.17. Incontinentia pigmenti. The early characteristic pigmented lines and swirls resemble Chinese characters.

adolescence (stage 3), and pallor and scarring affecting the calves in adolescents and adults (stage 4). A linear hyperpigmentation that follows the Blaschko lines leads to IP. Other dermatologic features include alopecia of the vertex, woolly hair, nevi and nail dystrophy. Dental abnormalities are the most common noncutaneous manifestation of IP, occurring in more than 80% of all patients, with nearly 65% presenting with major anomalies persisting for life in contrast to the skin abnormalities: partial anodontia, or absence of teeth (43% of patients), pegged and conical teeth (30%), late dentition (18%). Additional dental findings may include anomalous crowns with supplementary cusps in the posterior teeth and supernumerary teeth, poor enamel quality with hypomineralization leading to increased incidence of dental caries (Berlin et al., 2002). Nearly 19% of the patients with IP experience serious or vision-threatening ophthalmologic abnormalities (Berlin et al., 2002). They

are divided into retinal (retinal detachment, visual loss) and nonretinal (strabismus, cataract, pigmentation of the conjunctiva). The incidence of strabismus and microphthalmia is significantly higher in IP than in the general population (Hadj-Rabia et al., 2003). CNS deficits represent the most serious threat to the normal life span of patients with IP (Berlin et al., 2002). Overall prevalence of neurologic impairments is estimated at one-third of IP cases (Hadj-Rabia et al., 2003). Neurologic manifestations include infantile spasms and seizure disorders in 13%, spastic paralysis in more than 11%, motor retardation in 7.5%, and microcephalus in almost 5% of cases (Carney, 1976). Patients with early seizures are frequently found to have poor cognitive development. Cerebellar ataxia, congenital hearing loss, muscle paresis, strokes and aseptic encephalomyelitis were also infrequently reported (Berlin et al., 2002). Radiology. Neuroradiologic abnormalities are nonspecific and their frequency is unknown: microcephaly, cerebral atrophy, hypoplasia of corpus callosum, periventricular white matter damage, ischemic strokes, hydrocephalus, porencephalic cysts, and neuronal heterotopias have been described (Mirowski and Caldemeyer, 2000). Diagnosis. Diagnosis is based on clinical status and histologic findings of the skin, which differ in each phase of progression of the disease (Pereira et al., 2010). Treatment. The management of the skin and systemic abnormalities in IP is essentially based on symptomatology alone, with support and corrective measures to be used whenever possible. Dental care, ophthalmologic and neurologic follow-up are of the utmost importance.

Hypomelanosis of Ito Hypomelanosis of Ito (HI), which is perhaps the fourth most common neurocutaneous syndrome, is characterized by cutaneous and neurologic manifestations. Cutaneous manifestations include hypochromic unilateral or bilateral lesions in whorls, patches, and streaks, with a midline cutoff. Neurologic involvement is noted in more than three-quarters of the patients, most often with seizures and mental retardation, and ataxia, neuropathy, distal spinal muscular atrophy, torticollis, deafness, and spina bifida occulta. Hemimegalencephaly on either side of skin lesions, hemihypertrophy frequently ipsilateral to hypomelanotic lesions, arm and leg length discrepancy, and scoliosis have also been noted. Neuroimaging may reveal hypoplastic corpus callosum, heterotopias, ipsilateral pachygyria, absence of the anterior limb of the sylvian fissure, periventricular white matter changes, vascular malformations, medulloblastoma, and choroid plexus papilloma (Shobha et al., 2006).

NEURODERMATOLOGY 1589 neurologic symptoms appear. Cognitive development Sj€ ogren–Larsson syndrome is slow with mild to moderate mental retardation. Most Sj€ ogren–Larsson syndrome (SLS) is an autosomal recespatients have mild to moderate mental retardation, sive condition characterized by a triad of ichthyosis, the severity of which tends to coincide with the degree mental deficiency, and spastic diplegia or tetraplegia, of spasticity. Cognitive impairment is often present which was first described in 1957 (Sj€ ogren and but sporadic cases present with normal intelligence. In Larsson, 1957). In addition, a characteristic retinopathy a study of the Swedish Sj€ogren–Larsson syndrome pophas been noted. This disease is due to mutations in the ulation, two-thirds of the patients had IQs lower than 50. ALDH3A2 gene on chromosome 17p11.2 that encodes No progression of the neurologic findings or mental fatty aldehyde dehydrogenase (FALDH). This enzyme retardation occurs after puberty. Other neurologic signs catalyzes the oxidation of long-chain aldehyde to fatty such as pseudobulbar dysarthria, delayed speech, and acids. More than 70 mutations have been identified in oral-facial motor abnormalities are usually found, but SLS patients (Rizzo and Carney, 2005). SLS occurs in severe dysphagia is rarely encountered. Seizures occur all races and over 300 cases worldwide have been in approximately 40% of patients during infancy (Van reported. Very high prevalence of SLS has been observed Domburg et al., 1999), and there is no peripheral and spiin northeastern Sweden with an incidence of 8.3:100 000 nal sensory conduction disorder, either clinically or by births (Jagell et al., 1981). Due to deficiency of this somatosensory evoked potentials of the median and enzyme, there is an accumulation of aldehyde-modified sural, or posterior tibial nerve (Van Domburg et al., lipids or fatty alcohol that probably disrupts the barrier 1999). Finally, there exists no correlation between the function of the skin and white matter of the brain. severity of neurologic symptoms and the ichthyosis. PhoClinical symptoms. The diagnosis of SLS is invariably tophobia, macular dystrophy and decreased visual acuity delayed, similarly to other rare multisystem diseases. are the other most striking ophthalmologic features. Diagnosis of SLS is strongly suggested when neurologic One-third of the patients exhibit a distinctive and perand cutaneous symptoms are recognized simultaneously haps pathognomonic presence of glistening white dots (Ganemo et al., 2009). While other symptoms are lacksurrounding the macular region of the retina, which first ing, the cutaneous symptoms of scaling hyperkeratosis appears after several years of age (Willemsen et al., are usually present at birth with erythema. Most patients 2000). The nature of the crystalline deposits in the retina were born preterm (Willemsen et al., 2001a). In rare remains unclear, but may represent accumulations of cases, the newborn can be surrounded by the colloid long-chain fatty alcohols or fatty aldehydes membrane and the ectropion. At first the skin becomes (Willemsen et al., 2000). Most patients with SLS have dry, rough, desquamative with a brownish yellow colour short stature, due in part to leg contractures and due to a defect in keratinization. The ichthyosis is generdecreased leg growth rather than general growth delay. alized in distribution, and typically affects the flexures, Kyphoscoliosis is not uncommon, particularly in trunk, abdomen, back, extremities, nape of the neck, and severely spastic patients. dorsal areas of the hands and feet. The palms and soles Diagnosis and testing. The diagnosis of SLS is made are less severely affected, while the face is usually by noting the presence of the classic triad along with spared. Pruritus, contrasting with other ichthyotic skin alteration of the eye fundus and is confirmed by demondisorders that are usually nonitching, is persistent and stration of the deficiency of FALDH in cultures of fibrogenerates lichenification and excoriations. Palmoplantar blasts or leukocytes. keratoderma may exist. Diminished sweating occurs in a Radiology. MRI demonstrated retardation of myeliminority of patients. At the beginning, minor neurologic nation and a mild persistent myelin deficit with an signs are usually missed. Later, when neurologic signs increased signal intensity in the periventricular white appear, neurologists may fail to recognize the coexismatter on T2-weighted images. Abnormalities on MRI tence of cutaneous disease, especially if it is mild or imaging usually and gradually emerged during the first being treated with moisturizing lotions. An abnormal years of life and then stabilized. The patterns are strikgait, with pyramidal signs in the first 2 years of life, indiingly similar among patients with SLS, but their severity cates nervous system involvement. Spasticity may be varies (Willemsen et al., 2004). A correlation between the apparent before age 3 years and is more severe in the degree of MRI abnormality and the neurologic features lower limbs than in other parts of the body, leading to could not be demonstrated (Moghaddam et al., 2009). wheelchair dependency. Many patients never gain the Proton MR spectroscopy of white matter have demonability to walk, and those that do manage to walk often strated a prominent and narrow resonance at 1.3 ppm, require leg braces or other assisting devices. However, where protons of methylene groups resonate, normal hyperreflexia may be the only sign (Willemsen et al., levels of N-acetylaspartate, and elevated levels of crea2001a). Development is progressively delayed after the tine, choline, and myoinositol. This peak could represent

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accumulation of lipids due to the FALDH deficiency. Proton MR spectroscopy of gray matter is normal (Willemsen et al., 2004). Treatment. There is no specific treatment for SLS. However, favorable effects on pruritus were found with sileuton for 3 months. This treatment inhibits the synthesis of leukotriene B4 (its degradation is one of the defective metabolic routes in SLS). However, neurologic, neuroradiologic, and neuropsychological disturbances have not been found to change significantly (Willemsen et al., 2001b).

CONCLUSIONS Careful examination of the skin, hair, and nails by the neurologist is of the utmost importance, with frequent referral to a dermatologist when unusual abnormalities of the skin are discovered or when greater expertise is required (Hurko and Provost, 1999).

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Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 105

Neurology of pregnancy H. STEVEN BLOCK AND JOSE´ BILLER* Department of Neurology, Loyola University Chicago, Stritch School of Medicine, Maywood, IL, USA

Pregnancy presents a unique set of physiologic conditions, upon which certain diseases are seen either in a specific manner or with increased frequency. This chapter will not attempt to reduplicate the entire field of neurology, but will focus predominately upon clinical features that are unique to pregnancy. Whenever possible, mechanisms of disease will be described to facilitate a deeper understanding of contributory role of pregnancy.

STROKE DURING PREGNANCY AND THE PUERPERIUM Stroke during and shortly after pregnancy may be caused by a unique set of physiologic conditions that are distinct from stroke occurring in the young nonpregnant adult. It is beyond the scope of this section to discuss all causes of stroke in young patients. The following will describe stroke syndromes unique to pregnancy, along with a detailed description of underlying mechanisms that may produce stroke in this context. Stroke during pregnancy can be divided into three main groups: ischemic stroke (IS), hemorrhagic stroke (HS), and from cerebral venous thrombosis (CVT). Some strokes may demonstrate both ischemic and hemorrhagic features.

Epidemiology Ischemic and hemorrhagic stroke most commonly occurs in the third trimester and up to 6 weeks postpartum. The estimated incidence excluding subarachnoid hemorrhage (SAH) is 8.1–34.2 cases per 100 000 pregnancies. Third trimester IS relative risk in one study was not found to be elevated. However, in another study one fifth of all strokes occurred in the third trimester. Postpartum IS relative risk was 8.7. HS adjusted relative

risk was 2.5 during pregnancy, rising to 28.3 in the first 6 weeks postpartum (Kittner et al., 1996; Skidmore et al., 2001; James et al., 2005; Roger et al., 2012).

Underlying mechanisms producing stroke syndromes unique to pregnancy Several stroke syndromes are unique to pregnancy. They occur through multiple factors which have a common final action upon vascular endothelium, hemodynamic and clotting function.

THE ROLE OF VASCULAR ENDOTHELIUM Vascular endothelial dysfunction has a central role in many cerebrovascular disorders of pregnancy. A continuous monolayer lining blood vessels, vascular endothelium creates a surface area of more than 1000 m2 in the adult, and serves multiple roles in hemostasis, fibrinolysis, and vascular reactivity with maintenance of blood pressure (Sagripanti and Carpi, 2000).

THE ROLE OF CLOTTING FUNCTION AND FIBRINOLYSIS Pregnancy produces a relative hypercoagulable state for several reasons. Firstly, in the placental architecture, blood flows through intravillous spaces and exchanges molecules across the trophoblastic lining, which creates the potential for hemorrhage. Placental trophoblast cells express procoagulant factors (Lanir et al., 2003). A second function is to prevent hemorrhage when the placenta separates at term. During normal pregnancy, fibrinogen concentrations increase, protein S decreases by 60% of control values by the 10th week of pregnancy, protein C activity falls in conjunction with a rise in natural fibrinolytic activity (t-PA and type I plasminogen activator activity, the latter increasing by 31st week of gestation).

*Correspondence to: Jose´ Biller, M.D., F.A.C.P., F.A.A.N., F.A.H.A., Department of Neurology, Loyola University Chicago, Stritch School of Medicine, 2160 S. First Avenue, Building 105, Room 2700, Maywood, IL 60153 USA. Tel: þ1-708216-2438, E-mail: [email protected]

1596 H.S. BLOCK AND J. BILLER Shortening of the prothrombin time (PT) begins in the Vascular endothelial dysfunction 20th week of pregnancy, likely due to increased factor syndromes of pregnancy VII levels. Procoagulants including fibrinogen begin to Several important cerebrovascular syndromes of pregincrease at the 30th week and remain stable until nancy have common features which appear to represent delivery. Prothrombin fragments 1 þ 2 increase throughexpression along a spectrum of maternal vascular endotheout pregnancy and fall in the puerperium. Factors VII lial dysfunction. The commonality of clinical and laboraand VIII increase and factor X remains stable or tory features seen in pre-eclampsia, eclampsia, reversible increases. The activated partial thromboplastin time cerebral vasoconstriction syndrome (RCVS), postpartum (aPTT) and factor X, factor XI and factor XII cerebral angiopathy and reversible encephalopathy synlevels remain unchanged. D-dimer gradually increases drome suggest a final common action affecting vascular during pregnancy, consistent with fibrinolytic activity. endothelium. While these conditions are likely multifactoIn summary, while there is both an increase in procoagurial, we propose classification under the heading vascular lation factors and fibrinolysis, the relative imbalance endothelial dysfunction syndromes of pregnancy (VESOP) favoring the former supports a net hypercoagulable state to foster a greater understanding from a mechanistic in pregnancy (Comeglio et al., 1996; Cerneca et al., 1997). rather than purely syndromic basis. While the biophysiology has not been completely defined, a brief overview of the physiologic changes that occur during pre-eclampsia THE ROLE OF IMMUNITY will create a framework for understanding the aforementioned unique pregnancy-related syndromes. An embryo is semi-allogenic, necessitating adjustments in maternal immunity. The immune system interacts with the aforementioned placental coagulation factors. PRE-ECLAMPSIA AND ECLAMPSIA Derangements in this delicate immune balance can produce hemostatic abnormalities and contribute to A multitude of cerebrovascular and systemic vascular pre-eclampsia, miscarriage, recurrent spontaneous sequelae of pregnancy occur as a manifestation of abortion and intrauterine growth retardation (Li and pre-eclampsia and eclampsia. Understanding common Huang, 2009). mechanisms leading to the development of pre-

THE ROLE OF VASCULAR HEMOSTASIS The kidney-based renin–angiotensin system (RAS) is well known for its effects upon arteriolar vasoconstriction and fluid and electrolyte homeostasis necessary to maintain blood pressure. Additionally, the renin– angiotensin system is also found in the uteroplacental unit, serving a role in the placentation of normal pregnancy. Derangements of pregnancy can upset the delicate equilibrium of RAS signaling, which has been implicated as contributory to the development of preeclampsia, with its associated edema and hypertensive component (Irani and Xia, 2008).

Maternal physiologic changes during pregnancy To meet the physiologic needs of the developing fetus, cardiac output, heart rate and stroke index increase, with decreased systemic vascular resistance, pulmonary vascular resistance and mean arterial blood pressure. There is increased regional blood flow in the uterus, kidneys, extremities, skin, and breasts with essentially unchanged blood flow in the brain and liver (Roach et al., 2010).

eclampsia creates a framework for understanding the mechanisms producing these vascular complications, including those that occur long after the completion of pregnancy. Pre-eclampsia is characterized by the new onset of arterial hypertension  140/90 mmHg measured on two separate occasions and proteinuria  300 mg/24 hours after 20 weeks of pregnancy. Edema and excessive third trimester weight gain (>2 pounds/week) can occur, but are not necessary for the diagnosis. Pre-eclampsia occurs in 5–8% pregnancies and accounts for 50 000 annual deaths worldwide. Risk factors for pre-eclampsia include obesity, prior pre-eclampsia or eclampsia, insulin resistance, hyperlipidemia, hypertension, renal disease, and thrombophilia. Neurologic symptoms include headache, confusion, visual disturbances, and IS or HS. Systemic manifestations may also include renal failure, pulmonary edema, epigastric or right upper quadrant pain, hemolysis, elevated liver enzymes and low platelets (HELLP syndrome). Pre-eclampsia-induced HELLP is associated with activation of blood coagulation resulting in macroscopic fibrin deposits in various organs in severe cases. Such peripartum hemostatic emergencies may occur in 1–5% of patients with disseminated intravascular coagulation (DIC), producing abruptio placenta and retained dead fetus syndrome (Levi, 2009). Fetal growth restriction may occur.

NEUROLOGY OF PREGNANCY 1597 Eclampsia is defined after a seizure occurs in a prematernal decidual arterial layers to remodel into a eclamptic patient in the absence of other provocation large-caliber, high-capacitance vascular bed which (ACOG Practice Bulletin, 2002). The cornerstone of allows for a steep rise in the oxygen tension gradient. treatment includes magnesium sulfate. While magneWhen cytotrophoblasts cannot gain access to a supply sium sulfate has been demonstrated to generally be more of richly oxygenated maternal arterial blood there is efficacious in preventing recurrent seizures than phenytimpairment in the ability to differentiate into fully invaoin and diazepam (Duley, 1995), seizures that do not sive cells (Zhou et al., 1997; Genbacev et al., 1997). initially respond to magnesium sulfate may necessitate the addition of a benzodiazepine such as diazepam or The role of humoral factors in pre-eclampsia lorazepam. Long-term anticonvulsant management Circulating soluble fms-like tyrosine kinase-1 (sFlt-1) is a following delivery is generally not needed. Hydralazine circulating antiangiogenic protein made by placenta. or labetalol can be used for hypertension not controlled Vascular endothelial growth factor (VEGF) triggers by magnesium sulfate. Delivery often is curative. Howangiogenesis. Pre-eclampsia occurs when the relative ever, delayed postpartum eclampsia occurs in 10–45% of functional activity sFlt-1 exceeds that of VEGF. Renal women with eclampsia between 2 and 48 days following capillary endothelium is very sensitive to VEGF, needed delivery, and may be associated with other conditions to maintain normal fenestration of glomerular endothesuch as postpartum angiopathy (aka reversible cerebral lial cells. This may explain why pre-eclampsia-induced vasoconstrictor syndrome, see below). renal dysfunction characterized by proteinuria and Pre-eclampsia begins in the placenta and affects the hypertension (in part) is an important and early marker maternal multiorgan vascular endothelium (Powe of the disease. A second soluble factor, endoglin (Eng), et al., 2011). In 1988, Rogers first proposed that multioris highly expressed in vascular endothelial cells and syngan dysfunction occurring in pre-eclampsia was due to cytiotrophoblasts, which amplifies the antiangiogenic endothelial dysfunction (Rogers et al., 1988). The followeffect of sFlt-1. Endothelium-derived nitrous oxide ing year, additional information suggested that poorly (NO) produces vascular relaxation and contributes to perfused placental tissue triggered a dysfunctional casregulation of systemic blood pressure, vascular permecade of systemic factors producing such endothelial ability, and angiogenesis. The combination of sFlt-1 injury causing vasoactive, coagulation and intravascular and Eng has an effect upon endothelial nitric oxide synfluid redistribution (Roberts et al., 1989). Subsequently, thetase and is the cause of abnormalities of vascular tone the origins of eclampsia can be traced to two major facobserved in pre-eclampsia as well as inducing multiortors: abnormal development of the placenta that subsegan dysfunction which produces hemolysis, elevated quently produces an imbalance of humoral factors liver enzymes, and low platelets (HELLP syndrome), which affect vascular endothelial function, most notably which can predispose to maternal hemorrhage. Like angiogenic versus antiangiogenic peptides. sFlt-1, Eng begins to rise 6–10 weeks before the clinical symptoms of pre-eclampsia, and falls following compleThe role of the placenta in pre-eclampsia tion of pregnancy. Multiple small studies have confirmed measurable disproportionally high circulating The placenta is necessary to develop pre-eclampsia; a antiangiogenic factors in pre-eclamptic patients, as early fetus is not. Maternal hypertension and/or proteinuria as the first and second trimester (Koga et al., 2003; occurring before 20 weeks gestation can occur in a molar Levine et al., 2004, 2006; Rana et al., 2007; Singhal pregnancy. This is caused by either an extra set of pateret al., 2009). If these findings are confirmed by largenal chromosomes producing a fertilized egg and a growscale studies, such ELISA-based screening of all ing mass of cysts rather than a viable fetus (complete pregnant patients may one day be used to predict molar pregnancy) versus malformed nonviable embryo patients at risk for pre-eclampsia and eclampsia long and some normal placenta (incomplete molar pregbefore the appearance of clinical symptoms. nancy) (Mutter and Karumanchi, 2008). Removal of the placenta generally cures pre-eclampsia. Under norThe long-term effects of pre-eclampsia and mal circumstances, differentiation of epithelial stem eclampsia on maternal health in later life cells (cytotrophoblasts) and their invasion into the uterine arterioles occurs at approximately the end of the first Women who have pre-eclampsia have an increased risk trimester. The uterine spiral arteriolar vascular bed is of future cardiovascular disease. Pre-eclampsia is assocomposed of small, low-flow, high-resistance vessels ciated with asymptomatic global left ventricular dysand is relatively hypoxic. This induces production of vasfunction and abnormal geometry during the acute cular endothelial growth factor, allowing the cytotrophophase of the disorder. One year postpartum, asymptomblasts embedded in the smooth muscle and endothelial atic left ventricular moderate-severe dysfunction and

1598 H.S. BLOCK AND J. BILLER hypertrophy were significantly higher in preterm pressure elevation values > 150–160/105–110 mmHg eclampsia (56%) compared to term pre-eclampsia are commonly considered by various consensus reports (14%) or matched controls (8%). There was also a signifto be the initial threshold to initiate antihypertensive icant risk of developing hypertension within 2 years treatment (JNC 7, 2004). However, Martin and col(Melchiorre et al., 2011). Bellamy and colleagues perleagues found that only 12.5% of patients experiencing formed a meta-analysis of studies published between pre-eclamptic-mediated stroke (mostly hemorrhage) 1960 and 2006 encompassing almost 3.5 million women. exhibited diastolic blood pressures at or above Almost 200 000 were affected by pre-eclampsia and 110 mmHg before experiencing a stroke, but all patients almost 30 000 were affected by cardiovascular disease experienced stroke when the systolic blood pressure was and cancer. Women who experienced pre-eclampsia greater than 155 mmHg. They recommended initiation had an absolute risk of cardiovascular events: 17.8% of antihypertensive therapy to prevent pre-eclampsiaby the age of 59 and 30.7% by the age of 69 in comparmediated cerebral hemorrhage if the systolic blood presison to women who did not experience pre-eclampsia sure exceeded 155–160 mmHg even without diastolic (8.3% and 14.2% respectively). More specifically, followhypertension (Martin et al., 2005). These observations ing pre-eclampsia the increased risk of future hypertendeserve evaluation in a larger prospective series. sion was 3.7, ischemic heart disease 2.16, stroke 1.81, Ischemic strokes and venous thromboembolism 1.79. Breast cancer risk was not found to be significantly increased. All-cause CARDIOGENIC EMBOLISM mortality risk was 1.49 (Bellamy et al., 2007). Similarly, Brown et al. found that women who experienced preAs in the nonpregnant patient, cardiogenic embolization eclampsia were 60% more likely to have a may occur from a multitude of disorders including carnonpregnancy-related ischemic stroke (Brown et al., diac valvular disease, atrial fibrillation, left ventricular 2006). Staff, Dechend and Redman have hypothesized thrombi, paradoxical embolization via intracardiac shunt, congenital heart disease, infective and noninfecthat oxidative stress of the placenta presents an inflammative endocarditis, etc. Availability of antibiotic therapy tory burden to the mother even in normal pregnancies. Pre-eclampsia further stresses the uteroplacental circulahas reduced but not completely eliminated the incidence tion to the point of decompensation based upon the histoof rheumatic heart disease. Similarly, advances in carlogic finding of acute atherosis (defined as subendothelial diac surgery have allowed women with congenital heart lipid-filled foam cells, fibrinoid necrosis, and leukocyte defects to survive into childbearing age. Transthoracic infiltration resembling early atherosclerosis) in placental echocardiography has demonstrated attenuated cardiospiral arteries of women suffering from pre-eclampsia. vascular adaptation with reduced systolic function and progressive diastolic function during pregnancy which While not seen in all women with pre-eclampsia or unique persists for 6 months after pregnancy, placing them at to pre-eclampsia, its presence may suggest that there may be a subset of women that have an augmented risk for risk for adverse cardiovascular outcomes (Cornette future atherosclerosis (Staff et al., 2013). et al., 2012). Following the observation of decreased incidence of Peripartum cardiomyopathy (PPCM) produces heart breast cancer and other solid tumors in women with a hisfailure with left ventricular systolic dysfunction, occurtory of pre-eclampsia, it has been hypothesized that there ring with an estimated incidence of 18–333 cases per may be chronic residual antiangiogenic balance that may 100 000 live births. Mortality may be as high as 20%. PPCM typically occurs in the last month of pregnancy confer partial protection from growth and metastases of or within 5 months of delivery. No clear etiology has been certain vascular solid tumors (Cohn et al., 2001; Vatten et al., 2002; Aagaard-Tillery et al., 2006). proven, but there may be an association with preOf note, a mutation in the gene that encodes Eng is eclampsia mediated through cleavage of the prolactin responsible for causing hereditary hemorrhagic molecule. It is a diagnosis of exclusion after other causes telangiectasia type I (Osler–Weber–Rendu syndrome), of heart failure have been ruled out. It may recur with which produces abnormal multiorgan vasculogenesis subsequent pregnancies. In conjunction with the hyperthat can produce cerebral hemorrhage in pregnancy coagulable nature of pregnancy, reduced left ventricular ejection fraction (LVEF) < 35% increases the risk for left (Venkatesha et al., 2006). ventricular thrombus, at which point therapeutic anticoagulation should be considered. While many patients Pre-eclampsia, hypertension, and stroke-risk spontaneously recover cardiac function, women with mitigation LVEF 25% are at greater risk for nonrecovery and may need cardiac transplantation (Reuwer et al., 2010; Hypertension in pre-eclampsia can precipitate cerebral Blauwet and Cooper, 2011). hemorrhage. While not studied prospectively, blood

NEUROLOGY OF PREGNANCY

REVERSIBLE CEREBRAL VASOCONSTRICTION SYNDROME A unique syndrome of intracranial arterial vasospasm may occur during pregnancy, pre-eclampsia or postpartum (aka: postpartum angiopathy, PPA, Call–Fleming syndrome) (Call et al., 1988). Reversible cerebral vasoconstriction syndrome (RCVS) is often heralded by thunderclap headache followed by focal neurologic signs, visual disturbances, and occasionally one or more seizures. Aneurysmal SAH, arterial dissection and primary angiitis of the central nervous system (PACNS) need to be rapidly sought and excluded. Cerebral infarction may occur, often in a watershed distribution. Cortical SAH involving one or several sulci has a

1599

radiographic appearance distinct from aneurysmal SAH (Fig. 105.1). Concurrent impairment of vascular endothelial cell function may cause disruption of the blood–brain barrier with vasogenic edema (posterior reversible encephalopathy syndrome, PRES). Cerebroispinal fluid (CSF) is generally normal or may only show mild elevation of protein and white cells. Initial cerebral arteriography may be normal, but within 1 week demonstrates multifocal arterial segmental constriction, often in a widespread distribution. The hallmark of RCVS is the radiographic resolution of the intracranial vasconstriction, generally in less than 12 weeks (Calabrese et al., 2007). While outcome is generally

Fig. 105.1. A 27-year-old right-handed woman, G1, P1 with history of gestational diabetes and pre-eclampsia had acute onset of “marching” left face and left hand numbness associated with slurred speech and nonpostural posterior head pain following delivery. Examination showed a blood pressure of 160/101 mmHg and bilateral pitting edema of her legs. Neurologic examination was unremarkable. Unenhanced CT (A) showed a focal cortical right frontal SAH (arrow). MRI (B, C, D, E) showed areas of abnormal signal intensities on the right posterior frontal and anterior parietal regions. MRA (F, G, H) demonstrated diffuse, bilateral areas of arterial narrowing and dilation more pronounced on the right middle cerebral artery (MCA) (oval and circles). CTA (I) corroborated areas of intracranial arterial narrowing (oval). Post-treatment CTA (J) showed resolution of the diffuse intracranial vasoconstriction. Final diagnosis was RCVS (postpartum angiopathy) in a pre-eclamptic patient.

1600 H.S. BLOCK AND J. BILLER favorable, fatalities have been reported (Singhal et al., elucidated. Clinical symptoms as described below can 2009; Fugate et al., 2012a). occur either with or without the detection of currently Two-thirds of the cases of PPA begin in the first week recognized biomarkers; conversely, biomarker positivity following delivery after a normal pregnancy or one comcan occur in the absence of symptomatology. The plicated by proteinuria and HELLP, suggesting an overlap American Heart Association (AHA) published proposed with eclampsia. Patients with PPA may have a more severe criteria for the evaluation of novel biomarkers of cardiomanifestations and a potentially worse outcome. Up to vascular risk (Hlatky et al., 2009). Among other attri40% may experience a cerebral hemorrhage. In so far butes, the biomarker should be able to correlate with as the initial CTA, MRA, or cerebral arteriogram may specific clinical symptoms, distinguish between subjects be negative, a high index of suspicion and a repeat study with and without a specific outcome, provide predictive are recommended (Ducross, 2012; Fugate et al., 2012a, b). information over standard risk markers, predict future Hemorrhage may occur in one-third of patients, most events which would predict out, or influence managecommonly in a cortical sulcus, and less commonly in the ment, etc. De Groot and Urbanus methodically detail brain parenchyma or subdural space. In contrast to vasothe current limitations in the predictive power of the spasm near an aneurysmal SAH, cases of RCVS-induced aforementioned three biomarkers, which are limited in cortical SAH have more widespread vasospasm. their ability to predict the risk of recurrence with a high RCVS is a syndrome of various conditions with simdegree of confidence. A more complete understanding ilar outward expression, but without a definitive underof the clinical manifestations to characterize APS is standing of the underlying cause. One proposed needed as well as new assays to provide tailored theramechanism involves sudden alteration of cerebrovascupies and prognostic value (deGroot and Urbanus, lar tone. Constriction or dilation of peripheral cortical 2012). The following highlights the literature thus far. pain-sensitive small distal arteries triggers the thunderGeoepidemiology of APS has been elegantly reviewed clap headache. Subsequently, abnormal vessel reactivity (Biggioggero and Meroni, 2010). To briefly summarize, spreads more centrally within the brain to involve primary APS occurs in the absence of underlying automedium- and large-sized arteries responsible for ischeimmune disease. Secondary APS most commonly occurs mic events (Ducross et al., 2007; Werring, 2010). with systemic lupus erythematosus (SLE), other autoimTriggers of RCVS include exposure to medications that mune disorders, inflammatory diseases, neoplasia, affect vascular reactivity including sympathomimetic, infections, and medications. It can also be found in serotonergic, dopaminergic agonists, illicit drugs, etc. No asymptomatic patients. Between 30% and 40% of cause can be found in approximately one half of cases. patients with aPL have a history of thrombosis of which Various treatments to mitigate vasospasm have been 30% is arterial, most predominantly in the cerebral circutried, including magnesium sulfate, calcium channel lation producing stroke or TIA, and involves the coroblockers, intracranial angioplasty, etc. However, there nary arteries to a lesser degree. Deep venous has been no proven treatment that influences outcome. thrombosis (DVT) occurs in up to 30% of patients. In Initial seizures generally do not produce epilepsy, and addition to fetal loss, aPL is associated with predo not require a long-term antiepileptic therapy. eclampsia, eclampsia, intrauterine growth retardation, HELLP syndrome, oligohydramnios, uteroplacental insufficiency, and premature birth due to pregnancyANTIPHOSPHOLIPID SYNDROME induced hypertension. Antiphospholipid syndrome (APS) is an autoimmune How to interpret the antibody positivity. A single posdisorder which can produce arterial or venous thromboitive test may not be associated with thrombosis. aPL and sis, recurrent miscarriages, stroke and a myriad of other b-2 glycoprotein 1 antibody positivity has a modest assosymptoms described below. The hallmark of the condiciation with thrombosis and a low recurrence rate. Curtion is antiphospholipid antibodies (aPL), of which anticrently, triple antibody positivity has the highest ardiolipin antibodies (aCL), b-2 glycoprotein 1 and a correlation with clinical symptoms of APS. b-2 Glycolupus anticoagulant (LA) have been observed most comprotein 1 antibodies are more specific and related to monly associated with various clinical syndromes. Antithrombosis, especially if the titer is high (Devreese, bodies to other phospholipids currently play an uncertain 2012). All three antibodies need to be drawn. To omit role in APS. aCL or anti-b-2 glycoprotein 1 antibody testing would Diagnosis and treatment of patients with suspected lead to the failure to diagnose APS and 9.5% and APS should be approached with caution. Twenty-six 29.4% of patients respectively (Gardiner et al., 2013). years after the first clinical description of APS was pubAntiphospholipid effect upon the hemostatic mechalished (Hughes et al., 1986) the potential mechanisms nism is complex, and not completely elucidated. There is producing various clinical symptoms have not been fully protein C resistance, inhibition of protein S,

NEUROLOGY OF PREGNANCY antithrombin and tissue factor pathway inhibition, impairment of fibrinolysis by inhibiting tPA, interacting with the antiplasmin and activating factor XI. Activated complement C3a and C5a activate monocytes and macrophages and trigger inflammatory process. Following cell death, small detached membrane microparticles rich in phospholipids may lead to thrombin formation and thrombosis. The mechanism has not been established for antiphospholipid cognitive dysfunction and demyelination. Criteria manifestations of APS. Stroke and TIA occur in younger patients, more frequently women. Twenty percent of patients under 45 years have APS, and antiphospholipid antibodies are found in 6.8% of stroke patients. Sneddon syndrome is a progressive noninflammatory arteriopathy with cerebrovascular disease and livedo reticularis (aka: livedo racemosa), affecting small- and medium-sized arteries in the skin and brain. Antiphospholipid antibodies are found in 41%. Pregnancy loss may occur early or late. While the definition of APS includes fetal loss as described above, the literature supporting APS-induced early fetal loss demonstrates conflicting and inconsistent findings, and deserves further study. Clark and colleagues (2012) outlined biologic false positives and inconsistencies in reported study methodology over the past 25 years. Antiphospholipid antibodies in recurrent pregnancy loss without SLE varied depending upon the antiphospholipid antibody measured. The association of anticardiolipin IgG and IgM appeared variable dependent upon the titer and gestational age. Prospective human data on the relationship of antiphospholipid antibodies and recurrent pregnancy loss are lacking and the mechanism for uteroplacental insufficiency is not completely understood. Furthermore, up to 30% of pregnancies end before the first trimester, mostly due to chromosomal abnormalities. The current criteria for the diagnosis of APS do not include fetal chromosomal assessment, only ultrasound or direct examination of the fetus. Hence, it is difficult to ascribe the early fetal loss in the presence of an antiphospholipid antibody solely upon the latter. In late fetal loss, lupus anticoagulant positivity was a strong predictor but b-2 glycoprotein 1 antibodies and high anticardiolipin antibody titers were not. They further note that inconsistent with the current classification criteria for APS, there was not a consistent correlation between the presence of antiphospholipid antibodies and the clinical manifestations of the syndrome. A majority of women with early recurrent pregnancy loss, DVT and stroke are negative for antiphospholipid antibodies. Additionally, women with uneventful pregnancies were found to have antiphospholipid antibodies. They reference the recommendations from the 13th International Congress on Antiphospholipid Antibodies

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(2010) to treat aPLs as a risk factor marker rather than a diagnostic focus. Given the inconsistent presence of aCLs, they also recommend redefinition of the criteria for early fetal loss (distinct from late fetal loss and early delivery with placental infarction). Non-criteria manifestations associated with APS. Multiple sclerosis (MS)-like syndrome may resemble MS both clinically and radiographically, with the presence of white matter lesions. However, white matter hyperintensities on long TR-weighted pulse sequences perpendicular to the lateral ventricles (Dawson’s fingers) are more common in MS. This may produce sensory or motor dysfunction, optic neuritis, or transverse myelitis. MS, primary APS and neuropsychiatric SLE with or without APS are all multisystem autoimmune diseases with similar relapsing-remitting courses, affecting the same population of patients and may produce multifocal white matter lesions on MRI. Seizures may be caused by SLE or APS associated with SLE. They are likely due to hypercoagulable-induced cortical infarction. Chronic intermittent headaches may be migraine-like in character. Proximal stabbing headaches have been described in various autoimmune disorders (Rampello et al., 2011). Chorea is rare with SLE and/or APS, but strongly associated with aPL. Precipitating factors include estrogen-containing oral contraceptives, pregnancy and the early postpartum period. Cognitive dysfunction is poorly understood. Poor memory, difficulty with concentration and attention may be related to cerebral ischemia. Livedo reticularis and Raynaud’s phenomenon represent cutaneous manifestations. Mitral and aortic valve disease, including valvular vegetations, thickening and dysfunction to be present. Platelet counts less than 100,000/mm3 may produce bleeding complications. Catastrophic APS is a rare, rapidly evolving and lifethreatening variant, occurring in approximately 1% of patients with APS, associated with high levels of aPL. The condition is manifest as a multiorgan thrombotic microangiopathy and exists along a continuum with other similar conditions including thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), and HELLP syndrome, and has an associated higher incidence of DIC-related hemolysis. Diagnosis may be difficult to establish in view of similarities from false positive aPL from infection or anticoagulation (positive lupus anticoagulant test), other microangiopathic thrombotic states as described above and heparin-induced thrombocytopenia. Manifestations include pulmonary emboli, intra-alveolar hemorrhage, renal microangiopathy with infarction producing acute renal failure, livedo reticularis, purpura, skin ulcerations, liver failure, stroke, encephalopathy, seizures, headache, silent brain infarctions, and CVT. Given its

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infrequent occurrence, a registry was established in 2000 (Cervera, 2012). From the first 280 patients, 72% were women, with a mean age of 37 years, 46% suffered from primary APS, 40% SLE, 5% lupus-like disease and 9% other autoimmune disease. In almost half of patients with catastrophic APS, this was their first presentation. It is most commonly triggered by infection, surgery, oral anticoagulation withdrawal, medications, obstetric complications, and neoplasia and SLE flares. Diagnostic criteria were initially published in 2003 (Asherson et al., 2003) and updated in 2010 (Erkan et al., 2010). Criteria include involvement of three or more organs, symptom onset in less than 1 week, biopsy confirmation of small vessel occlusions and laboratory confirmation of the presence of a LA and/or anticardiolipin antibody. Treatment consists of corticosteroids, anticoagulant therapy, plasma exchange (PLEX) and/or intravenous immunoglobulin (IVIG). Seronegative APS may produce clinical features of APS, with persistently negative testing for LA, ACL and anti-b-2 glycoprotein. Rodriguez-Garcia compared the clinical manifestations of SLE-seronegative APS (SN-APS) with seropositive APS. There was no significant difference in the occurrence of DVTs, pulmonary emboli, transient ischemic attacks, early spontaneous abortions, stillbirths, prematurity and pre-eclampsia. Additionally, both groups developed recurrence of arterial and venous vascular events following withdrawal of anticoagulation. They question whether other antibodies directed against other phospholipids (prothrombin, and phosphatidyl ethanolamine, annexin V, and vimentin/ Cardiolite and complex) might have a contributory influence, and suggest it deserves further study (RodriguezGarcia et al., 2012). Treatment of CNS manifestations of APS. Risk stratification for recurrent thrombosis can be estimated based upon the clinical presentation (arterial versus venous, etc.), involved antibodies, and underlying risk factors. Les and associates have outlined the intensity and duration of anticoagulation therapy in APS (Les et al., 2012). In severe cases, combined anticoagulation and immunosuppression/immunomodulation may be needed. Underlying triggers including infection need to be sought and treated. In mild disease low-dose aspirin and hypertension control may be adequate. In SLE and secondary APS, consider low-dose steroids, hydroxychloroquine or chloroquine. In difficult cases of thrombosis and nonthrombotic CNS-APS, high-dose oral or intravenous corticosteroids, Cytoxan, plasma exchange and/or or IVIG may be needed. Insofar as anticoagulation is a nonselective therapy, not effective in all patients and carries a risk of bleeding, investigation into targeted immunomodulatory therapies is ongoing, assessing the efficacy of hydrochloroquine, statins, B cell suppression

such as rituximab, certain antiplatelet agents, anticytokine therapies, etc. (Comarmond and Cacoub, 2013). Anticoagulant considerations in pregnancy. Various conditions may require anticoagulant therapy, including both primary and secondary hypercoagulable states, atrial fibrillation, CVT, cardiac valvular disease and prosthetic mechanical heart valves (especially in the mitral position), mural thrombi, APS, DVT, etc. Vitamin K antagonists (VKA) such as warfarin are teratogenic between 6 and 12 weeks of pregnancy, producing intellectual disability, facial and limb deformities. Several malformations have been associated with VKA exposure at any time during pregnancy, including agenesis of the corpus callosum, Dandy–Walker malformations, midline cerebellar atrophy, and optic atrophy. Current anticoagulant guidelines from the American College of Chest Physicians (Bates et al., 2012) are based upon observational studies and deserve further investigation. Various recommendations are based upon the underlying condition. In general, unfractionated (UFH) or low molecular weight heparin (LWMH) may be used throughout pregnancy as they do not cross the placenta. VKA should be avoided in the first trimester, but may be considered in the second trimester, followed by conversion back to a heparin product, which should be discontinued at least 24 hours before anticipated delivery or cesarean section. VKA can be initiated after delivery, and is not present in breast milk. UFH poses a risk for heparin-induced thrombocytopenia and osteoporosis. LMWH does not carry these risks. The optimal dosage of LMWH has not been established. Measurement of trough and peak anti-Xa levels may guide dosing (Goland and Elkayam, 2012; McClintock, 2013). Direct thrombin inhibitors and factor Xa inhibitors have not been adequately studied in human pregnancy and should be avoided. Table 105.1 illustrates FDA categories in drug safety in pregnancy.

Hemorrhagic strokes SUBARACHNOID HEMORRHAGE Subarachnoid hemorrhage (SAH) may occur during pregnancy from a variety of conditions. In addition to intracranial aneurysmal rupture, a variety of nonaneurysmal conditions can also produce SAH. These include trauma, CVT, pre-eclampsia and eclampsia, hypertension of pregnancy, and inherited and acquired thrombophilias. Intracerebral hemorrhages with subarachnoid extension may be caused by various conditions such as hypertensive hemorrhage, hemorrhagic infarction, occult cerebrovascular malformation, Moyamoya disease, RCVS (postpartum angiopathy). Infective endocarditis and metastatic choriocarcinoma may produce infective (mycotic), or oncotic aneurysms.

NEUROLOGY OF PREGNANCY Table 105.1 US Food and Drug Administration categories for the use of medications in pregnancy FDA pregnancy category A

B

C

D

X

Description Controlled studies on animals and humans have shown no risk in the first trimester, and possible fetal harm is remote Either animal studies have not demonstrated a fetal risk but there are no controlled studies in pregnant women, or animal studies have shown an adverse effect that was not confirmed in controlled studies in women in the first trimester No controlled studies in humans have been performed, and animal studies have shown adverse events, or studies in humans and animals or not available; give if potential benefit outweighs the risk Positive evidence of fetal risk is available, but the benefits may outweigh the risk if life-threatening or serious disease Studies and animals or humans show fetal abnormalities; drug contraindicated

Radiographically, acute SAH is generally detected by either unenhanced cerebral CT or MRI FLAIR imaging. However, it should be kept in mind that other conditions can mimic the radiographic appearance of SAH, including meningitis, leptomeningeal metastases, leptomeningeal melanosis, status epilepticus, supplemental oxygen administration, intravenous anesthetic agents, prior administration of radiographic contrast agents and artifacts (Cuvinciuc et al., 2010). In the general population, SAH from ruptured intracranial aneurysms accounts for approximately 5% of all strokes. The overall incidence of SAH for women varies geographically, typically ranging between 7 and 13 per 100 000 person-years. However, the incidence in Japan and Finland is substantially greater (22.7 and 19.7 per 100 000 person-years, respectively) and increases with age (de Rooij et al., 2007). The true incidence may even be greater due to pre-hospital death. In addition to the modifiable risk factors of SAH which include excessive alcohol consumption, hypertension, and smoking (Feigin et al., 2005), a possible contribution of hormonal factors in aneurysmal SAH has been suggested, but a clear mechanism has not been strongly established. This is based upon the observation that

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women have a greater incidence of SAH than men (1.24, range 1.09–1.42), which begins at age 55 (de Rooij et al., 2007). Noncontraceptive hormonal replacement therapy used at any time in life has been associated with a lower incidence of SAH (Mhurchu et al., 2001; Feigin et al., 2005; Algra et al., 2012). The risk of SAH in a woman that has taken oral contraceptives is unclear. Some studies have demonstrated little or no increased incidence of SAH, while other meta-analyses have suggested otherwise (Johnston et al., 1998; Mhurchu et al., 2001; Algra et al., 2012). The risks of SAH are lower in older women with a first pregnancy (Mhurchu et al., 2001), and greater with earlier age of menarche (1000 U) and GPT, proteinuria, myoglobinuria Eventually, rhabdomyolysis, disseminated intravascular coagulation, acute renal failure Also seen in Parkinson’s disease, after withdrawal of dopaminergic drugs, dehydration, infections and “wearing off” (Ikebe et al., 2003) Generally begins after weeks/months of DRBD Common parkinsonism features, but symmetric “Rabbit” syndrome Appears mostly after months/years, or on discontinuation or dose reduction of DRBD Several clinical syndromes: Classic: oral-lingual: tongue pressing or rolling (“bonbon” sign), protruding (“fly-catcher’s” sign), chewing, cheek blowing Stereotypic: pelvic: “copulatory” rocking respiratory: panting, puffing, gasping, wheezing vocal: moaning, humming finger: “piano playing” chorea Withdrawal-emergent syndrome: transient chorea after sudden removal of DRBD Tardive akathisia: worsens with DRBD removal Tardive dystonia: face, neck, trunk, often painful Other: myoclonus, tremor, tics, orogenital pain

Discontinuation of DRBD Biperiden 2–8 mg/day Benztropine 1–2 mg IV Diphenhydramine 10–50 mg IV Diazepam 5–10 mg IV Discontinuation of DRBD Change to other neuroleptics Propranolol 40–120 mg/day Biperiden 2–8 mg/day Trihexyphenidyl 2–10 mg/day Consider related conditions: catatonia (Vesperini et al., 2010), serotonin syndrome (Carbone, 2000) Discontinuation of DRBD Oral dantrolene sodium 200–400 mg/day Bromocriptine 10–30 mg/day Dopaminergics resumption if due to its withdrawal Alkalinize urine to prevent myoglobinuria

Neuroleptic-induced parkinsonism Tardive dyskinesia

DRBD, dopamine receptor-blocking drug; CK, creatine kinase; GTP, glutamic-pyruvic transaminase; IV, intravenous.

Discontinuation of DRBD or dopamine-depleting (reserpine, tetrabenazine) drug Anticholinergics Discontinuation of DRBD Initial worsening, thenceforth slow improvement through months, may persist Avoid anticholinergics

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Sedatives and hypnotics Barbiturates and benzodiazepines may cause varying and well known dose-dependent degrees of sedation: slowed thinking, cognitive impairment, somnolence or drowsiness, incoordination, ataxia, hypotonia, dysarthria, nystagmus, delirium, coma. Benzodiazepine dependence may occur with therapeutic doses, through the appearance of withdrawal symptoms upon abrupt discontinuation (anxiety, tremor, eventually seizures) that may be controlled by progressive dose tapering (O’Brien, 2005). Carbamazepine as an adjunctive therapy has shown some benefit in reducing benzodiazepine withdrawal severity, significantly improving drug-free outcome (Denis et al., 2006). Benzodiazepines may specifically cause anterograde amnesia, especially for events occurring near the time of their peak plasma concentrations (Buffett-Jerrott and Stewart, 2002). Paradoxical aggressive reactions (physical aggression, rape, impulsive decision making, violence, and autoaggressiveness) may also occur (Saı¨as and Gallarda, 2008).

NEUROLOGIC ADVERSE EFFECTS OF PSYCHOSTIMULANTS AND RELATED DRUGS The clinical effects of psychostimulants include increased alertness, wakefulness, activity and drive, enhanced attention, concentration, and memory, and mood improvement. Adverse effects include insomnia, restlessness, agitation, tremor, irritability and aggression, anxiety or panic, malaise, dizziness, nausea or vomiting, abdominal pain, headache, anorexia and weight loss. Associated adrenergic effects include mydriasis, dry mouth, hypertension, tachycardia, hyperthermia and hyperhydrosis. Most psychostimulants act by inhibiting the reuptake of selective neurotransmitters, such as epinephrine, norepinephrine, dopamine, and serotonin. The most commonly used drugs with psychostimulant-like effect today include atomoxetine, methylphenidate, bupropion, and modafinil. Atomoxetine, introduced as “the first nonstimulant for the management of ADHD,” is thought to enhance noradrenergic function via selective inhibition of the presynaptic norepinephrine transporter (Corman et al., 2004). Pemoline, introduced in the 1980s to treat attention deficity hyperactivity disorder (ADHD), has been discontinued in the US and several other countries because of liver toxicity, and overwhelmingly replaced by methylphenidate, and, increasingly, atomoxetine for that indication (Garnock-Jones and Keating, 2009). Bupropion is mainly a norepinephrine reuptake inhibitor which has shown

benefit for smoking cessation. Modafinil increases monoamine release and hypothalamic histamine levels. Exacerbation of the tics in Tourette’s syndrome has been linked to the use of psychostimulants indicated for the frequent coexistence of ADHD. However, whereas individual patients may eventually undergo an increase in tics, group data have not shown a significant adverse effect. Psychostimulants, used with caution, are therefore not considered today contraindicated in persons with tics and ADHD (Erenberg, 2005). Reported adverse effects of psychostimulants also include chorea (Weiner et al., 1978), growth retardation (Correll and Carlson, 2006), and hypomania (Masand et al., 1995). However, mania and other possible psychiatric effects, such as “behavioral rebound,” withdrawal risk, and psychosis are presently controversial. Concerns have been raised whether to continue or withdraw psychostimulants in adult patients treated for ADHD since childhood, and showing other psychiatric symtpoms (Ashton et al., 2006). On the other hand, the belief that stimulants are contraindicated in mania has been challenged. ADHD and mania share symptoms or pathogenetic mechanisms. Patients with features of both ADHD and psychosis (“ADHD psychosis”) do benefit from treatment with psychostimulants, possibly by improvement of frontal lobe dysfunction (Opler et al., 2001). Psychostimulants have a low risk and might thus even be a treatment option for mania (Hegerl et al., 2010). Other specific neurologic adverse efects of psychostimulants appear in Table 107.9. Recreationally used or abused psychostimulants, such as amfetamines (dextramfetamine, methamfetamine, MDMA or “ecstasy”, MDEA or “eve”), sympathomimetics (phenylpropanolamine, ephedrine), and cocaine may cause movement disorders, seizures, ischemic and hemorrhagic stroke, and severe withdrawal symptoms, other than the general neuropsychiatric and cardiovascular effects mentioned above.

NEUROLOGIC ADVERSE EFFECTS OF ANTIBACTERIAL, ANTIVIRAL, ANTIFUNGAL, ANTIPARASITIC DRUGS, AND VACCINES Antibacterial agents (antibiotics) About 80% of the adverse effects of antibacterial agents are the result of allergic reactions. Neurologic complications, mostly ototoxicty and seizures, are much less frequent. Serious neurologic complications are generally related to inadequate dose management in patients with renal failure. Imipenem and cefepime are the antibacterial agents with the highest neurotoxic risk.

IATROGENIC NEUROLOGY Table 107.9

Antiparasitic agents

Other neurologic adverse effects of most commonly used psychostimulants and related drugs Drug

Adverse effects

Methylphenidate

Stuttering (Burd and Kerbeshian, 1991) Paroxysmal kinesigenic dystonia (Gay and Ryan, 1994) Cerebral arteritis Priapism (Schwartz and Rushton, 2004) Akathisia (Almeida et al., 2006) Rabbit syndrome (Mendhekar and Duggal, 2006) Orofacial and extremity dyskinesia (Bala´zs et al., 2007) Enuresis (Ghanizadeh, 2008) Bruxism (Mendhekar and Andrade, 2008) Excessive talking (Ghanizadeh, 2009) Complex visual hallucinations (Halevy and Shuper, 2009) Acute urinary retention (Desarkar and Sinha, 2006) Suicidal ideation (Bangs et al., 2008) Bruxism worsening (Mendhekar and Lohia, 2009) Priapism (Levenson, 1995) Rhabdomyolysis (David and Esquenazi, 1999) Tactile hallucinations (Charuvastra and Yaeger, 2006) Acute dystonia (Wang et al., 2007) Neck and shoulder pain (Sansone and Sansone, 2009) Seizures (Starr et al., 2009) Serotonin syndrome (Thorpe et al., 2010) Cataplexy worsening (Poza, 2003) Hyperkinetic nondystonic movement disorder (Luborzewski et al., 2006) Visual and cenesthetic hallucinations (Oulis et al., 2008)

Atomoxetine

Bupropion

Modafinil

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The neurologic adverse effects of the most frequently used antibacterial agents are shown in Table 107.10.

Antiviral agents The neurologic adverse effects of the most frequently used antiviral agents are shown in Table 107.11.

Systemic antifungal agents The most frequently encountered adverse effects of systemic antifungal agents are shown in Table 107.12.

The salient neurologic adverse effects of the most frequently used antiparasitic agents are shown in Table 107.13.

Vaccines The reported neurologic adverse effects of the most frequently used vaccines are shown in Table 107.14, but it must be pointed out that no clear causal association could be confirmed for some of the adverse effects shown.

NEUROLOGIC ADVERSE EFFECTS OF ANTINEOPLASTIC AND IMMUNOMODULATORY DRUGS Antineoplastic drugs The most prevalent neurologic complication of chemotherapy is peripheral neuropathy. Encephalopathy is also relatively frequent, especially after repeated intrathecal administration. The most common adverse effects of antineoplastic agents are shown in Table 107.15.

Immunomodulatory drugs Common adverse effects of immunomodulatory agents are shown in Table 107.16.

NEUROLOGIC ADVERSE EFFECTS OF ANTI-INFLAMMATORY, ANALGESIC, AND ANTIALLERGIC DRUGS Anti-inflammtory and analgesic drugs CORTICOSTEROIDS Corticosteroids or glucocorticoids commonly used as anti-inflammatory agents have a central stimulating effect and may cause well-known behavioral changes, such as insomnia, hyperactivity, logorrea, hallucinations, agressiveness, mania, and delirium (“steroid psychosis”). Longer treatment with corticosteroids can induce dose-dependent depression and memory decline, often during the first few weeks of therapy, with changes in the temporal lobe detected by structural, functional, and spectroscopic imaging. Lithium and phenytoin may prevent the mood symptoms, whereas lamotrigine and memantine can partially reverse the memory changes. Both alterations may also revert with dose reduction or discontinuation. The symptoms and treatment response have been likened to those of bipolar disorder (Brown, 2009).

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Table 107.10 Neurologic adverse effects of the most frequently used antibacterial drugs Group

Adverse effects

Penicillins

Seizures (Meropol et al., 2008) Penicillin psychosis (Hoigne’s syndrome) (Rao, 1999) Aseptic meningitis (Prieto-Gonza´lez et al., 2011) Delirium (Tong et al., 2004) Benign intracranial hypertension (Schmitt and Krivit, 1969) Seizures (Chow et al., 2005) Delirium (Chow et al., 2003) Encephalopathy (Roncon-Albuquerque et al., 2009) Dysgeusia (Noel et al., 2008) Agitation and confusion (Slaker and Danielson, 1991) Elevated creatine phosphokinase (Talbot et al., 2007) Vestibular toxicity (Sennesael et al., 1982) Psychosis, aphasia, and dizziness (Mitropoulos et al., 2007) Headache (Dauner et al., 2010) Aseptic meningitis (Nakajima et al., 2007) Hearing loss (Schmutzhard et al., 1995) Seizures (Schranz, 1998) Headache (Bazan et al., 2009) Stroke-like symptoms and delirium (Duquaine et al., 2011) Hearing loss (Schmutzhard et al., 1995) Vertigo (Duque et al., 1991) Insomnia (Matthews and Lancaster, 2009) Encephalopathy (Ferna´ndez-Torre et al., 2004) Paresthesiae (Gotuzzo et al., 1994) Hearing loss (Pedrajas et al., 1993) Hearing loss (Moore et al., 1984) Vestibular toxicity (Darlington and Smith, 2003) Neuromuscular blockade (Snavely and Hodges, 1984) Musical hallucinations (Tanriverdi et al., 2001) Psychosis (Kane and Byrd, 1975) Polyneuropathy/encephalopathy (Bischoff et al., 1977) Aseptic meningitis (Granowitz and Brown, 2008) Optic neuritis (Bucy, 1937) Confusion (Lehr, 1957) Psychosis Multiple peripheral neuropathy (Blankenhorn, 1938) Seizures (Meropol et al., 2008) Vertigo (Granowitz and Brown, 2008) Pseudotumor cerebri (Tabibian and Gutie´rrez, 2009) Headache (Doan et al., 2006) Vestibular dysfunction (Fanning et al., 1977) Visual disturbances (Aagaard and Hansen, 2010) Neuromuscular blockade (Bezzi and Gessa, 1961) Hearing loss (Ress and Gross, 2000) Headache and dizziness (Hopkins, 1991) Dysgeusia (Snyman et al., 2009) Hallucinations and seizures (Schiff et al., 2010) Psychosis, anxiety, confusion, and restlessness (Aagaard and Hansen, 2010) Headache and dizziness (Nguyen and Chung, 2005) Dysgeusia (Kasbekar and Acharya, 2005)

Cephalosporins

Carbapenems

Monobactams Aminoglycosides

Sulfonamides

Tetracyclines

Macrolides

Ketolides

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Table 107.10 Continued Group

Adverse effects

Glycopeptides

Hearing loss (Farber and Moellering, 1983) Headache and dizziness (Noel et al., 2008) Dysgeusia (Leonard and Rybak, 2008) Seizures (Aagaard and Hansen, 2010) Elevated creatine phosphokinase (Canto´n et al., 2010) Headache, drowsiness, and dizziness (Radner, 1973) Headache, insomnia, and seizures (Owens and Ambrose, 2005) Dysgeusia and seizures (Noel, 2009) Seizures (Walton et al., 1997) Dysgeusia (Geddes, 1999) Peripheral neuropathy (Lode, 2010) Psychosis and anxiety (Stahlmann and Lode, 2003) Delirium (Slobodin et al., 2009) Dizziness (Anzueto et al., 2002) Neuromuscular blockade (Tang and Schroeder, 1968), Headache, insomnia, and dizziness (Fung et al., 2001)

Lipopeptides Rifamycins Fluoroquinolones

Lincosamides Oxazolidinone Other agents Metronidazole

Chloramphenicol

Polymyxin

Isoniazid

Trimethoprim

Cerebellar dysfunction (Kusumi et al., 1980) Peripheral neuropathy (Coxon and Pallis, 1976) Seizures (Frytak et al., 1978) Optic neuritis (Lasky et al., 1957) Peripheral neuropathy (Wallenstein and Snyder, 1952) Ophthalmoplegia (Hill and Armstrong, 1950) Neuromuscular blockade (Fogdall and Miller, 1974) Hearing loss, visual disturbances, paresthesiae, vertigo, confusion, hallucinations, seizures, and ataxia (Falagas and Kasiakou, 2006) Seizures (Sullivan et al., 1998) Optic neuritis (Kass et al., 1957) Peripheral neuropathy (Goldman and Braman, 1972) Encephalopathy (Adams and White, 1965) Aseptic meningitis (Granowitz and Brown, 2008)

By an uncertain mechanism, corticosteroids may induce exacerbation of myasthenia gravis symptoms, especially at initiation of therapy, in up to 50% of patients. Predictors of exacerbation appear to be old age, predominant bulbar symptoms, and clinical severity of the disease, rather than a high initial dose (Bae et al., 2006). Proximal progressive lower limb girdle myopathy is a frequent complication of prolonged steroid therapy. It may extend to upper limbs, and occasionally present as an acute quadriplegic myopathy after high intravenous doses (Hirano et al., 1992). Other rarer reported adverse effects of steroids are optic neuropathy with fluprednisolone (Teus et al., 1991) and pseudotumor cerebri on steroid withdrawal (Lessell, 1992).

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS Non-selective COX inhibitors Aspirin has antiplatelet effects that have been dealt with earlier in this chapter. Its most common side-effect is gastrointestinal bleeding linked to inhibition of anticyclooxygenase-1 (COX-1). Aspirin administered in children with high fever may cause Reye syndrome believed to be due to impaired oxidation on the long chain hydroxyacyl-CoA dehydrogenase enzyme (Glasgow, 2006). However, the cause– effect relationship between aspirin and Reye syndrome has recently been put into question (Schr€or, 2007). Reye syndrome has also been linked to the use of phenothiazines and antiemetics (Casteels-Van Daele et al., 2000).

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Table 107.11 Neurologic adverse effects of the most frequently used antiviral drugs Drug Nonretroviral agents: Anti-herpesviridae agents

Anti-influenza agents*

Antihepatitis agents*{{ Other nonretroviral agents Retroviral agents: Nucleoside reverse transcriptase inhibitors

Non-nucleoside reverse transcriptase inhibitors

Fusion inhibitors CCR5 antagonists

Adverse effects

Delirium (Revankar et al., 1995) Encephalopathy (Onuigbo et al., 2009) Seizures (Fan-Harvard et al., 2009) Aseptic meningitis (Olin and Gugliotta, 2003) Psychosis (Yang et al., 2007) Headache, insomnia, peripheral neuropathy, and paresthesia (Curran and Noble, 2001) Depression (Sirota et al., 1988) Confusion and ataxia (Martinez-Diaz and Hsia, 2011) Headache (Dutkowski et al., 2010) Dizziness (Choo et al., 2011) Insomnia and hallucinations (Jefferson et al., 2006) Depression (Chung and Joung, 2010) Myopathy (Tak et al., 2010) Tetany secondary to hypocalcemia or hypomagnesemia (Muller et al., 2007) Psychosis (Quarantini et al., 2006) Psychosis (Maxwell et al., 1988) Depression (Foster et al., 2004) Migraine and mood changes (Colebunders et al., 2002) Sleep disturbances and peripheral neuropathy (Sharma et al., 2008) Seizures (D’Silva et al., 1995) Psychosis (Wise et al., 2002) Cognitive impairment (Prime and French, 2001) Insomnia, vivid dreams, and night terrors (Cespedes and Aberg, 2006) Mania (Shah and Balderson, 2003) Delirium and behavioral changes (de la Garza et al., 2001) Depression Insomnia, peripheral neuropathy, and headache (Fung and Guo, 2004) Dizziness and insomnia (Lieberman-Blum et al., 2008)

*Adverse effects of interferons and amantadine have been addressed in other sections. { Adverse effects of lamivudine are included in the NRTI group. { Ribavirin is included in the group of other nonretroviral agents.

Acute aspirin/salicylate intoxication, accidental or voluntary, presents as hyperpnea, sweating, tinnitus, deafness, encephalopathy (confusion, stupor, seizures) and metabolic acidosis, and can be confirmed by measuring plasma salicylate concentrations. Gastric emptying, forced alkaline diuresis, and eventually hemodialysis are accepted therapeutic interventions (Pearlman and Gambhir, 2009). Consensus management guidelines have been published (Chyka et al., 2007). Aspirin and salicylates are ototoxic, causing usually reversible tinnitus, high frequency hearing loss, and alterations of perceived sounds. Salicylates act as competitive inhibitors of Cl-anions at the anion-binding site of prestin, the motor protein of the outer hair cell. Regular use of aspirin, non-steroidal antiinflammatory

drugs (NSAIDs), and acetaminophen/paracetamol may cause hearing loss (Curhan et al., 2010). Aseptic ibuprofen-induced meningitis, often recurrent, may occur with therapeutic doses, especially in patients with an autoimmune connective tissue disorder. It presents as an acute meningeal or meningoencephalopathic syndrome, sometimes with focal neurologic signs (Agus et al., 1990). The cerebrospinal fluid shows elevated neutrophils and protein, and, unlike acute bacterial meningitis, normal glucose. Symptoms abate on discontinuation. Screening for autoimmune disease has been recommended in previously healthy patients with ibuprofen-related meningoencephalitis (Rodrı´guez et al., 2006). Diclofenac is a NSAID inhibiting COX-1, COX-2, and prostaglandin synthesis. Nonselective COX inhibitors

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Table 107.12

Selective COX-2 inhibitors

Neurologic adverse effects of most frequently used antifungal drugs

Selective COX-2 inhibitors, especially rofecoxib, have been associated with an increased risk of thromboembolic vascular events, possibly stroke, either through prothrombotic effects or blood pressure destabilization (Farkouh and Greenberg, 2009). Other COX-2 inhibitors include celecoxib, parecoxib, valdecoxib, etoricoxib, and lumiracoxib.

Drug

Adverse effects

Polyenes

Benign intracranial hypertension (Heudier et al., 1992) Seizures (Aruna et al., 2000) Delirium and depression (Weddington, 1982) Headache and dizziness (Bodhe et al., 2002) Visual loss (Li and Lai, 1989) Recurrent hemiparesis (Devuyst et al., 1995) Myelopathy (Carnevale et al., 1980) Leukoencephalopathy (Liu et al., 1995) Anxiety, confusion, and insomnia Visual disturbances (Herbrecht et al., 2002) Hallucinations (Cleveland and Campbell, 1995) Vertigo (Costa et al, 1994) Headache and dizziness (Tucker et al., 1990) Sexual dysfunction (Terrell, 1999) Cerebellar syndrome (Cubo Delgado et al., 1997) Headache (Mayr et al., 2011) Dizziness (Menichetti, 2009) Insomnia (Hiemenz et al., 2005) Sexual dysfunction (Hull and Vismer, 1992)

Triazoles

Pyrimidine analogs Echinocandins

Allylamines

may have an increased risk of cardiovascular thromboembolic adverse effects, and diclofenac-related stroke has been reported (Kornowski et al., 1995). Other neurologic or neurologically related adverse effects induced by diclofenac include myoclonus/myoclonic encephalopathy (Sa´nchez Valiente, 1995), corneal disorders either with oral or topical use of the drug (Zanini et al., 2006), and, in association with mefenamic acid, another NSAID, pediatric posterior reversible leukoencephalopathy (Yokobori et al., 2006). Naproxen, a nonselective COX inhibitor, has been reported to cause hearing loss, sometimes irreversible (Chapman, 1982). Both naproxen and phenylbutazone, another NSAID now in scant use because of agranulocytosis risk, in combination with misoprostol, a prostaglandin E1 analog preventing the development of NSAID-induced gastric ulcers, have been reported to cause ataxia and other neurosensory effects (Huq, 1990).

OPIATES AND OPIOIDS Both opiates and opioids have narcotic and analgesic effects. Opioids, predominantly, are as a rule used today for the treatment of chronic pain, mostly related to cancer, but also to selected cases of headache, neuralgias, facial, radicular, rheumatic, and low back pain. Drowsiness, somnolence, stupor, shallow respiration, pinpoint pupils, bradycardia, and hypothermia are classic narcotic effects of opioids. Opioid withdrawal symptoms, also well known, include agitation, sweating, shivering, piloerection, abdominal pain, vomiting and diarrhea. Naloxone may reverse the narcotic symptoms as well as precipitate withdrawal. Sedation and cognitive changes can occur on initiation of therapy with opioids (Swegle and Logemann, 2006). Cognitive changes have been reported in patients on long-term therapy (Larsen et al., 1999), but psychological measures and pain severity seem to be more predictive of cognitive decrements than specific opioids or daily dose (Brown et al., 2006). Opioid-induced dose-related myoclonus may appear with various agents, including methadone (Ito and Liao, 2008). It occurs particularly in the perioperative setting, in patients on chronic opioid therapy, and with coexisting dehydration or renal disease (Mercadante, 1998). Prolonged opioid treatment may result in opioidinduced hyperalgesia, with worsening pain despite accelerating opioid doses, and abnormal pain sensitivity and symptoms such as allodynia (Mitra, 2008). Intrathecal use of opioids may increase the likelihood of adverse events (Ruan, 2007).

FLUPIRTINE Flupirtine, an aminopyridine, is a centrally acting nonopioid, non-NSAID, nonsteroidal analgesic, a selective neuronal potassium channel opener and NMDA receptor antagonist, used in Europe for treating fibromyalgia and other types of back pain. It is not commercialized in the U.S.A. Reported cases of flupirtine-induced neurologic toxicity include “paradoxical cerebral cortical

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Table 107.13 Neurologic adverse effects of most frequently used antiparasitic drugs Drug

Adverse effects

Benzimidazoles

Vertigo (Knopp et al., 2010) Headache and dysgeusia (Can˜ete et al., 2006) Encephalopathy (Blum et al., 2001) Dizziness (Keystone and Murdoch, 1979) Blurred vision, optic neuritis, and seizures (Bagheri et al., 2004) Post-ivermectin Loa loa encephalopathy (Kamgno et al., 2008) Myalgia, dizziness, and headache (Bussaratid et al., 2005) Optic neuritis (Bagheri et al., 2004) Neuromuscular blockade (Ojewole, 1984) Headache and myalgia (Pani et al., 2005) Sleepiness, headache, and dizziness (Bagheri et al., 2004) Seizures (Hewagama et al., 2010) Vertigo and headache (Yangco et al., 1987) Psychosis (Zaki et al., 2009) Ototoxicity (Bortoli and Santiago, 2007) Seizures (Marquardt and Albertson, 2001) Cinchonism (Wolf et al., 1992) Dizziness, sleep disturbances, anxiety, and psychosis (Toovey, 2009) Fatigue and dysgeusia (Fung and Doan, 2005) Headache and dysgeusia (Kapoor et al., 1999)

Avermectins

Other anthelmintics

Antimalarials

Agents for other parasitic infections

hyperexcitability” entailing an increased risk of seizures (Hoffmann et al., 2004), and, more specifically, a clinical syndrome of headache, blurred vision, confusion, ataxia, syncope, and, characteristically, green urine (Hufschmidt et al., 2009).

OTHER ANTI-INFLAMMATORY AND ANALGESIC DRUGS Acute colchicine poisoning causes abdominal pain, vomiting, metabolic acidosis, pancytopenia, lifethreatening cardiac arrythmias, hypotension, respiratory distress, and hypocalcemia. Rhabdomyolysis, peripheral neuropathy, and ascending paralysis may occur a few days after exposure (Maxwell et al., 2002). Longer use of colchicine may induce axonal peripheral neuropathy and associated vacuolar myopathy with elevated CK levels (colchicine myoneuropathy), especially in patients with altered renal function, that may resolve on discontinuation of the drug (Kuncl et al., 1987). Gold salts can cause peripheral neuropathy, sometimes with segmental demyelination and axonal degeneration, a Guillain–Barre´-type syndrome, cranial nerve palsies, encephalopathy showing white matter lesions on contrast CT, and associated myokimia or generalized muscle fasciculations. Both symptoms and lesions revert on withdrawal (Schlumpf et al., 1983; Fam et al., 1984; Perry and Jacobsen, 1984).

ANTIMIGRAINE AGENTS Ergotamine Long-term use of ergotamine may cause the so called “ergotism,” characterized by headache and an intensive generalized, even gangrenous, vasoconstriction of small and large blood vessels. Angiography may show arterial narrowing, tapering, or segmented stenosis in different vascular territories (Ruano-Caldero´n and Zermen˜oPohls, 2005). Ergot vasospasm and ischemia may involve the cerebral arteries, producing various ischemic syndromes with neurologic and neuropsychiatric manifestations. Convulsive ergotism, with generalized tonic-clonic seizures, may be due to ischemia or other unclear mechanisms. Neurologic adverse effects of ergotamine toxicity are summarized in Table 107.17. Patients taking ergotamine, ergotamine derivatives and other vasoconstrictive medications may undergo a specific reversible cerebral vasoconstriction (“Call– Fleming”) syndrome. Patients present with sudden, severe, and recurrent (“thunderclap”) headache, and may have seizures, focal motor signs, bilateral paramedian hyperintense diffuse lesions on MRI with a nonvascular distribution, and characteristic (“string of beads”) vasospasm on angiography, mostly resolving spontaneously or on withdrawal of the medication. Localized cortical subarachnoid hemorrhages and later cerebral ischemic events may occur (Ducros, 2010).

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Table 107.14 Reported neurologic adverse effects of vaccines included in recommended immunization schedules Drug

Adverse effects

Hepatitis B

Guillain–Barre´ syndrome and optic neuritis (Shaw et al., 1998) Multiple sclerosis (Herroelen et al., 1991) Ototoxicity (DeJonckere and de Surge`res, 2001) Cerebellar ataxia (Deisenhammer et al., 1994) Transverse myelitis (Tartaglino et al., 1995) Irritability (Cheuvart et al., 2009) Guillain–Barre´ syndrome (Pollard and Selby, 1978) Encephalomyelitis (Schwarz et al., 1988) Transverse myelitis (Whittle and Robertson, 1977) Optic neuritis and myelitis (Topaloglu et al., 1992) Peripheral neuropathy (Baust et al., 1979) Febrile and afebrile seizures (Barlow et al., 2001) Seizures (Kulenkampff et al., 1974) Hypotonic/hyporesponsive episodes (DuVernoy and Braun, 2000) Guillain–Barre´ syndrome (Gervaix et al., 1993) Giant cell arteritis (Perez et al., 2000) Seizures, encephalopathy, ataxia, insomnia, meningitis, and hypotonic/hyporesponsive episodes (Wise et al., 2004) Paralytic poliomyelitis (Nathanson and Kew, 2010) Guillain–Barre´ syndrome (Kinnunen et al., 1989) Encephalitis (Landrigan and Witte, 1973) Subacute sclerosing panencephalitis (Modlin et al., 1977) Febrile and afebrile seizures (Griffin et al., 1991) Cranial neuropathy (Chan et al., 1980) Optic neuritis (Kazarian and Gager, 1978) Peripheral neuropathy (Schaffner et al., 1974) Aseptic meningitis (Fujinaga et al., 1991) Transverse myelitis and optic neuritis (Kline et al., 1982) Encephalitis (Gilden et al., 2000) Behavioral changes and delirium (George and Benonis, 2003) Encephalitis (Goulleret et al., 2010) Herpes zoster ophthalmicus and encephalitis (Chouliaras et al., 2010) Headache (Mick, 2010) Meningitis and Guillain–Barre´ syndrome (De Wals et al., 2009)

Rotavirus DT and DTP

Haemophilus influenzae type b4 Pneumococcal Poliovirus Measles, mumps, and rubella

Varicella Hepatitis A Zoster

Meningococcal

Triptans The most salient potential complication of triptans is coronary spasm and acute myocadial infarction. Concerns have been raised about the risk of serotonin syndrome when triptans are used in association with selective serotonin reuptake inhibitors (SSRIs), usually indicated for affective disorders, and the FDA in the US has suggested that fatal serotonin syndrome (SS) is possible in that case. However, the evidence for this risk is uncertain and such a concern has recently been put into question (Gillman, 2010). Rare reported neurologic side-effects of triptans have included triptan-induced daily headache (G€ obel et al., 1996), axial dystonia (Oterino and Pascual,

1998), postpartum cerebral angiopathy in association with dihydroergotamine (Granier et al., 1999) and acute pathologic laughter (Barbanti et al., 2008).

Antiallergic drugs: antihistamines (H1-receptor antagonists) Diphenhydramine poisoning may induce a central anticholinergic syndrome with clouding of consciousness, optical/acoustic hallucinatory psychosis, fever, and dry skin and mouth (Lang et al., 1995). The most common neurologic symptoms for fatal cases of diphenhydramine intoxication have been seizures and/or sympathetic pupil responses (Nine and Rund, 2006). Other rarer toxic

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Table 107.15 Common neurologic adverse effects of antineoplastic agents Group

Adverse effects

Alkylating agents

Seizures (Salloum et al., 1997) Blurred vision (Kende et al., 1979) Confusion (Tashima, 1975) Retinal hemorrhages and diplopia (Burns, 1992) Visual loss (Shapiro et al., 1992) Myoclonus (Wyllie et al., 1997) Hallucinations (Walsh et al., 1984) Encephalopathy (Nicolao and Giometto, 2003) Peripheral neuropathy (Patel et al., 1997) Headache (Middleton et al., 2000) Seizures (Tfayli et al., 1999) Visual disturbances (Ostrow et al., 1978) Encephalopathy (Lyass et al., 1998) Peripheral neuropathy (Roelofs et al., 1984) Cranial neuropathy (Bokemeyer et al., 1998) Muscle cramps (Siegal and Haim, 1990) Stroke (Doll et al., 1986) Hearing loss (Extra et al., 1998) Paraparesis and quadriparesis (Cheson et al., 1994) Cerebellar dysfunction (Herzig et al., 1987) Aseptic meningitis (Nelson and Frank, 1981) Locked-in syndrome (Kleinschmidt-DeMasters and Yeh, 1992) Encephalopathy (Hwang et al., 1985) Myeloencephalopathy (Resar et al., 1993) Leukoencephalopathy (Lien et al., 1991) Posterior reversible encephalopathy (Russell et al., 2001) Peripheral neuropathy (Dormann et al., 1998) Stroke-like syndrome (Yim et al., 1991) Encephalopathy (Nieto et al., 1999) Coma (Whittaker et al., 1973) Cortical blindness (Byrd et al., 1981) Hallucinations (Ghosh et al., 1994) Lethargy (Brown et al., 2000) Transient dysarthria (Baz et al., 2001) Peripheral neuropathy (Hilkens et al., 1996) Cranial neuropathy (Delaney, 1982) Autonomic disturbances (Carmichael et al., 1970) Optic neuropathy (Capri et al., 1994) Myalgias (McGuire et al., 1989) Stroke (Kukla et al., 1982) Myeloencephalopathy (Arico et al., 1990) Encephalopathy (Pisoni et al., 2001) TIA (Schachter and Freeman, 1982) Stroke (Doll and Yarbro, 1992) Encephalopathy (Pirzada et al., 2000) Multifocal inflammatory leukoencephalopathy (Hook et al., 1992) Subacute leucoencephalopathy (Kuzuhara et al., 1987) Wernicke–Korsakoff-like syndrome (Heier et al., 1986) Cerebellar dysfunction (Riehl and Brown, 1964) Optic neuropathy (Adams et al., 1984) Focal dystonia (Brashear and Siemers, 1997) Acute parkinsonian syndrome (Bergevin et al., 1975) Stroke (Doll and Yarbro, 1992)

Platinum-based agents

Antimetabolites

Plant alkaloids

Antitumor antibiotics

Fluorinated pyrimidines

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Table 107.15 Continued Group

Adverse effects

Tyrosine kinase inhibitors Bortezomib

Headache (Giampaglia et al., 2010) Peripheral neuropathy (Richardson et al., 2006) Stroke (Guo et al., 2010) Encephalopathy (Leonard and Kay, 1986) Ischemic and hemorrhagic stroke (Feinberg and Swenson, 1988) Headache and idiopathic intracranial hypertension (Bigby and Stern, 1988) Cerebellar dysfunction (Bernstein and Leventhal-Rochon, 1996) Depression and suicide (Jacobs et al., 2001) Myalgias/rhabdomyolysis (Trauner and Ruben, 1999) Stroke (Royer et al., 2002) Peripheral neuropathy (La Rocca et al., 1990) Disorientation, visual and hearing loss (Hussain et al., 2000) Stroke (Laterra et al., 2004) Somnolence (Singhal et al., 1999) Peripheral neuropathy (Molloy et al., 2001) Seizures (Fine et al., 2000) Stroke (Ortin et al., 2006)

L-Asparaginase Retinoids

Suramin

Lenalidomide/thalidomide

Table 107.16 Common neurologic adverse effects of immunomodulatory agents Group

Adverse effects

Interferons

Encephalopathy and parkinsonism (Meyers et al., 1991a) Confusion, lethargy, and dizziness (Weiss, 1998) Depression and suicide (Jonasch and Haluska, 2001) Paranoid psychosis (Schafer and Schwaiger, 2003) Cognitive impairment (Valentine et al., 1998) Hearing loss (Kanda et al., 1994) Oculomotor nerve paralysis (Bauherz et al., 1990) Peripheral neuropathy (Bernsen et al., 1988) Spastic diplegia (Barlow et al., 1998) Seizures and vegetative state (Meyers et al., 1991b) Encephalopathy (Siegel and Puri, 1991) Acute fatal leukoencephalopathy (Vecht et al., 1990) Transient visual loss (Bernard et al., 1990) Peripheral neuropathy (Loh et al., 1992) Cerebellar dysfunction (Meyers and Yung, 1993). Transient dysarthria (Baz et al., 2001) Multifocal inflammatory leukoencephalopathy (Kimmel et al., 1995) Insomnia, headache and dizziness (Parkinson et al., 1977) Progressive multifocal leukoencephalopathy (Carson et al., 2009) Hemorrhagic stroke (Ranpura et al., 2010) Hypophysitis (Blansfield et al., 2005) Uveitis (Weber et al., 2008) Cerebral aspergillosis (Amadori et al., 2010)

Interleukins

Levamisole

Monoclonal antibodies

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Table 107.17 Neurologic adverse effects of ergotamine toxicity Drug

Adverse effects

Ergotamine tartrate

Coma (Hudgson and Hart, 1964) Peroneal nerve palsy (Merhoff and Porter, 1974) Transient monocular blindness (Merhoff and Porter, 1974) Headache (Wainscott et al., 1974) Homonymous hemianopia, hemiplegia, uninhibited behavior (Senter et al., 1976) Neuropsychiatric symptoms (Fl€ ugel et al., 1977) Paraplegia (Lenger, 1984) Bilateral focal cortical atrophy/ infarcts (Fincham et al., 1985) Carotid artery territory infarct (Berlit et al., 1986) Bilateral ischemic optic neuropathy (Sommer et al., 1998) Dystonia and reflex sympathetic dystrophy (Merello et al., 1991)

effects observed have been rhabdomyolysis (Emadian et al., 1996) and opsoclonus (Irioka et al., 2009). Cetirizine has been reported to cause sedation and mental performance changes (Spangler and Brunton, 2006), oculogyric crises (Fraunfelder and Fraunfelder, 2004), and dystonia (Esen et al., 2008). Cyproheptadine may cause anticholergic delirium (Scott et al., 2007). Choreoathetosis has also been observed (Samie and Ashton, 1989).

NEUROLOGIC ADVERSE EFFECTS OF HORMONES, HORMONE-RELATED AND METABOLISM DRUGS Hormones and hormone-related drugs Estrogens given in contraceptive doses may have prothrombotic effects and increase stroke risk, both ischemic and hemorrhagic, whether in higher (more than 50 mg per pill) or lower doses (Collaborative Group, 1973; Stadel, 1981). Smoking and migraine increase this risk (Tzourio et al., 1995). Progestogens increase the hazard of venous thromboembolism and may contribute to stroke risk (Jick et al., 1995). There has been a long-standing controversy about the benefit of hormone replacement therapy in postmenopausal women, through possible vascular and cognition protective effects. However, an excess risk of stroke, cognitive decline and dementia was observed with

combined estrogen/progestogen replacement therapy in large randomized studies (Shumaker et al., 2003; Wassertheil-Smoller et al., 2003), and the US Preventive Services Task Force has discouraged or not recommended its use (Humphrey et al., 2002). Oral contraceptives are also known to cause chorea (Nausieda et al., 1979). Agents that inhibit or block natural endogenous hormones and have neurologic side-effects are listed in Table 107.18. Sildenafil may cause headache and eventually cluster headache (de L Figuerola et al., 2006). Visual adverse effects have been described in some patients, such as increased brightness of lights, blue-tinged or blurry vision (Laties and Sharlip, 2006). They are usually transient, appear after higher doses, and are attributed to associated inhibition of the retinal PDE6. Serious ophthalmic side-effects may occur, generally after longer exposure to the drug: branch retinal artery occlusion (Tripathi and O’Donnell, 2000), central serous chorioretinopathy (Allibhai et al., 2004), anterior and posterior ischemic optic neuropathy (Pomeranz and Bhavsar, 2005; Su et al., 2008), acute angle-closure glaucoma (Ramasamy et al., 2007), optic atrophy (Sowka et al., 2007), and stepwise decline in visual field (Pepin and Pitha-Rowe, 2008). Priapism (Sur and Kane, 2000), tonic-clonic seizures (Gilad et al., 2002), vestibular dysfunction (Hamzavi et al., 2002), and amnesia and aggressive behavior (Milman and Arnold, 2002) have also been reported. Intracerebral hemorrhage (McGee et al., 2005), sudden sensorineural hearing loss (Snodgrass et al., 2010) and epileptic seizures (Koussa et al., 2006) have been linked to vardenafil, and transient global amnesia to tadalafil (Schiefer and Sparing, 2005), both sildenafil-related drugs.

Metabolism drugs Long-term ingestion of allopurinol may rarely cause axonal peripheral neuropathy, receding after discontinuation (Azulay et al., 1993). Oral glucose lowering drugs include sulfonylureas and biguanides. Their most frequent side-effect is hypoglycemia. Hypoglycemic encephalopathy can develop insidiously and result in disabling residual neurologic deficits if not recognized in time (Turkington, 1977). Chlorpropamide can cause optic neuropathy (Wymore and Carter, 1982). Biguanides may induce lactic acidosis and encephalopathy, but encephalopathy without lactic acidosis has also been reported (Jung et al., 2009). Vitamins may be neurotoxic (Snodgrass, 1992). Pseudotumor cerebri (benign intracranial hypertension) linked to vitamin A (Drouet and Valance, 1998) and pyridoxine-generated peripheral neuropathy (Scott

IATROGENIC NEUROLOGY

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Table 107.18 Neurologic adverse effects of most commonly used antihormonal drugs Group

Drug

Adverse effects

Antithyroid agents

Methimazole

Prolactin blocking agents

Bromocriptine Cabergoline

Anti-osteoporotic agents (diphosphonates) Antiandrogens and antigonadotrophin-releasing agents Antiestrogens

186Re-HEDP

Optic neuritis (Sponzilli et al., 1979) Cerebral vasculitis (Tripodi et al., 2008) Postpartum cerebral angiopathy (Chartier et al., 1997) Puerperal seizures (von Werder, 1996) Cerebrospinal fluid leakage (Netea-Maier et al., 2006) SUNCT syndrome (Jime´nez Caballero, 2007) Pathological gambling and hypersexuality (Falhammar and Yarker, 2009) Chiasmal herniation and secondary deterioration of visual field (Raverot et al., 2009) Priapism (De La Pen˜a Zarzuelo et al., 2010) Transient cranial neuropathy (de Klerk et al., 1996)

Leuprolide

Atypical absence seizures (Akaboshi and Takeshita, 2000)

Tamoxifen

Retinopathy (Nayfield and Gorin, 1996) Cerebral venous sinus thrombosis (Bushnell and Goldstein, 2004)

et al., 2008) are well-established neurologic adverse effects of vitamins. The initiation of vitamin B12 treatment for cyanocobalamin deficiency has been reported to eventually induce seizures (Benbir et al., 2007) and involuntary movements (tremor, myoclonus) (Ozdemir et al., 2010). Vitamin D has also been related to pseudotumor cerebri (Alpan et al., 1991). Prolonged vitamin D administration may result in muscle calcinosis due to hypercalcemia (Chiricone et al., 2003). Drug-induced hypercalcemia is caused by increased bone resorption (vitamin D and vitamin A intoxication), increased gastrointestinal absorption (vitamin D intoxication, excessive calcium intake) or increased renal tubule reabsorption (thiazide diuretics) of calcium (Sato, 2006). The administration of high levels of vitamin E is contraindicated in subjects who are receiving vitamin K antagonists as anticoagulant therapy (Machlin, 1989).

NEUROLOGIC ADVERSE EFFECTS OF RESPIRATORY TRACT DRUGS Bronchodilators with b-stimulating adrenergic effect may cause classic adrenergic reactions. Tremor may sometimes be intense and disabling (Ozog and Lerner, 1989). Posterior reversible encephalopathy has been observed in relation to pseudoephedrine (Ebbo et al., 2010). Theophylline may induce seizures and nonconvulsive status epilepticus (Paloucek and Rodvold, 1988; Krieger and Takeyasu, 1999).

Dextromethorphan, alone or in association, has been observed to cause distonic reaction (Warden et al., 1997), agitated psychosis, and ataxia (Roberge et al., 1999; Price and Lebel, 2000).

NEUROLOGIC ADVERSE EFFECTS OF GENITOURINARY AND DIGESTIVE TRACT DRUGS Smooth muscle spasmolytic drugs with anticholinergic antimuscarinic action all entail a risk of anticholinergic delirium: sudden confusion, distractibility, dysarthria, logorrhea, dry mouth, restlessness, tremor, and visual hallucinations (Lipowski, 1990). Agents stimulating uterine contractility to induce labor have been associated with postpartum cerebral angiopathy and hypertensive encephalopathy (Garre´ et al., 1978; Chartier et al., 1997; Sato et al., 2004). Antiemetic and gastroprokinetic drugs may cause extrapiramidal side-effects. Related antiemetic agents with an indirect parasympathomimetic effect may also induce extrapyramidal toxicity. The neurologic adverse effects of antiemetics appear in Table 107.19. Gastric H2-receptor inhibitors have been associated with some neurologic side-effects, including confusion (Sonnenblick and Yinnon, 1986), extrapyramidal and cerebellar syndrome with encephalopathy (Handler et al., 1982), and hemiballism (Elzinga-Huttenga et al., 2006). Gastric protonic pump inhibitors have been associated with central fever with severe myalgia (Grattagliano

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Table 107.19 Neurologic adverse effects of most commonly used antiemetic drugs Drug

Adverse effects

Metoclopramide

Myoclonus (Hyser and Drake, 1983) Parkinsonism, tardive dyskinesia, tardive dystonia, akathisia (Miller and Jankovic, 1989) Acute dyskinesia (Andrejak et al., 1990) Dystonic reaction (Guala et al., 1992) Oculogyric crisis (Lou and Abou-Zeid, 2006) Oculogyric crisis (Shafrir et al., 1985) Acute dyskinesia (Andrejak et al., 1990) Acute dystonia (Yamada et al., 2010) Syncope associated with QT prolongation (Gray, 1998) Akathisia, abnormal movements (Elzinga-Huttenga et al., 2006) Transient dyskinesia (Martı´nez-Martı´n, 1993) Parkinsonism, tardive dyskinesia (Sempere et al., 1994) Acute dystonic reaction (Sprung et al., 2003) Oromandibular/limb dystonia, oculogyric crisis, multifocal encephalopathy (Ritter et al., 2003)

Domperidone Droperidol Cisapride Clebopride Ondansetron

et al., 2005), myopathy (Clark and Strandell, 2006), and panic attacks and confusion (Polimeni et al., 2007).

CONCLUSION Almost every drug can produce neurologic adverse effects. The compelling evidence of the frequency of iatrogenic pharmacologic disease is large enough to warrant its consideration as a differential diagnosis when assessing the neurologically ill patient.

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Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 108

Neuromuscular complications in intensive care patients ZOHAR ARGOV1* AND NICOLA LATRONICO2 Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

1 2

Department of Anesthesia Intensive Care and Postoperative Care, Division of Neuroanaesthesia and Neurocritical Care, University of Brescia, Spedali Civili, Brescia, Italy

INTRODUCTION AND DEFINITIONS Severe weakness due to polyneuropathy or myopathy was recognized as a direct complication of intensive care unit (ICU) hospitalization in the 1980s, but seemed a rare complication in critically ill patients (Bolton, 2010). Since then it has become clear that ICU-acquired weakness (ICUAW) is a common feature amongst such patients, especially when their ICU hospitalization time is long (Latronico and Bolton, 2011). The improvement in the ability to treat critically ill patients for lengthy periods in ICU and their increased survival has resulted in many patients developing severe limb and respiratory muscle weakness leading to increased risk of permanent morbidity, mortality and to prolonged and costly hospitalization. Weakness in an intensive care patient may be due to a pre-existing disorder, which was either the cause of the hospitalization or a known condition in a patient that required ICU treatment due to other medical or surgical emergencies. Such conditions will not be dealt with in this chapter, which is devoted to a newly appearing weakness while in ICU (hence the term ICUAW) (De Jonghe et al., 2002; Ali et al., 2008; Stevens et al., 2009). Such new paralysis may infrequently be due to a previously undiagnosed condition that was unmasked by the ICU conditions but usually it is the result of complications of the actual stay in the ICU. Most of the conditions lead to generalized weakness, which will be the main topic of this chapter; however, some complications result only in focal weakness. The newly acquired generalized weakness of intensive care is usually due to either a neuropathic disorder

or a myopathy, or to a combination of both, but disorders of the neuromuscular junction may also lead to a similar clinical picture. Disorders of the central nervous system, especially of the spinal cord, may also develop in the ICU patient and lead to generalized paralysis, but these rarely pose a diagnostic difficulty and will be discussed only in terms of the differential diagnosis of such severe weakness in critically ill patients. Various terms have been given to the different ICUAW conditions and we will use the terms CIP for the critical illness polyneuropathy, CIM for the critical illness myopathies and CINM for the mixed or undifferentiated neuromyopathies of intensive care patients.

INTENSIVE CARE UNIT-ACQUIRED GENERALIZED WEAKNESS Clinical presentation The typical presentation is that of severe flaccid weakness that symmetrically affects the four limbs but spares the ocular, bulbar, and usually the facial muscles (Bolton, 2005). In some patients facial weakness can be seen but ophthalmoplegia (especially ptosis) is so uncommon that it should raise a completely different list of potential diagnoses. Recently a Medical Research Council (MRC) combined muscle power score of less than 48/60 was suggested as a diagnostic criterion (De Jonghe et al., 2002). This score depends much on patient’s cooperation and may ignore the less severe forms of ICUAW, but is an independent predictor of morbidity and mortality (Ali et al., 2008). Muscle weakness is associated with marked and early atrophy, more

*Correspondence to: Zohar Argov, M.D., Department of Neurology, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel. Tel: þ972-2-677-6938, E-mail: [email protected]

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than can be expected from the disuse atrophy of immobilization in such patients (Latronico and Bolton, 2011). Skeletal muscle weakness is frequently associated with weakness of respiratory muscles (resulting in difficulty to wean the patient from a respirator or in a need for reintubation). In many cases the condition is recognized only when a patient who was unconscious or under anesthetic or neuromuscular blocking agents regains his consciousness, the medications are stopped, but movement of the limbs is weak and respiratory effort is inefficient (Bolton et al., 1984). In fact in many instances failure to wean from a ventilator once sedation is over is the initial cause for neurologic consultation (Zochodne et al., 1987). Deep tendon reflexes are reduced or unobtainable (especially if the cause is neuropathic or the degree of weakness is severe). Sensory impairment is not as severe as the weakness and is detected only in peripheral neuropathic causes. Reduced sensation to pin prick, vibration, and temperature is usually found in the legs. It should be noted that sensory examination is at times difficult in an ICU patient with clouded sensorium. Pain and autonomic dysfunction are rare. While usually the condition appears after prolonged period in the ICU with several complications such as sepsis, systemic inflammatory response syndrome, and multiorgan failure (Latronico et al., 1996), it may be observed after relatively short ICU course and progress rapidly (Tennila et al., 2000; Khan et al., 2006; Latronico et al., 2007). The above clinical presentation is typical to most of the specific conditions to be described below.

Incidence Exact incidence of ICUAW is unknown due to wide variation in the patient population, the risk factors, the diagnostic criteria used, and the timing of evaluation (Latronico et al., 2005a; Stevens et al., 2007). The incidence varies from 25% in patients with ICUAW defined clinically by the MRC score (De Jonghe et al., 2002; Ali et al., 2008) to 33% in those who have no evidence of multiorgan failure on ICU admission (Latronico et al., 2007). It may be higher (up to 77%) with longer (>1 week) ICU stay (Coakley et al., 1998; Van den Berghe et al., 2005; Hermans et al., 2007; Nanas et al., 2008). High incidence was recorded in patients with acute respiratory distress syndrome (up to 60%) (Bercker et al., 2005; Hough et al., 2009), multiple organ failure or systemic inflammatory response syndrome (up to 80%) (Witt et al., 1991; Garnacho-Montero et al., 2001; Bednarik et al., 2003; Bednarik et al., 2005) and in almost all patients with septic shock (Tennila et al., 2000) or severe sepsis plus coma (Latronico et al., 1996).

Critical illness polyneuropathy Critical illness polyneuropathy (CIP) is an axonal sensorimotor polyneuropathy affecting the limb (usually more distally) and respiratory muscles (Zochodne et al., 1987). Limb involvement is symmetric, but is more prominent in the lower extremities. Early clinical diagnosis is difficult either because CIP is often preceded by encephalopathy (Bolton et al., 1993), usually attributed to sepsis (Pandharipande et al., 2007), or because of ongoing sedation (Latronico and Bolton, 2011). Brain imaging and cerebrospinal fluid examination are often nondiagnostic and electroencephalogram (EEG) may confirm the presence of diffuse encephalopathy. During recovery from the encephalopathy, weaning from mechanical ventilation or apparent weakness of limb movements will be the first evidence of this complication. Deep tendon reflexes are usually lost at the early stage of the disorder. If the patient is alert, distal loss to pain, temperature, and vibration is diagnostic for the neuropathic source of the problem as most other causes of ICUAW do not affect the sensory system (Latronico and Bolton, 2011).

Critical illness myopathy Critical illness myopathy (CIM) is a primary acquired myopathy in the ICU with distinctive electrophysiologic and morphologic features (Latronico and Candiani, 1998; Lacomis et al., 2000). The clinical features are usually indistinguishable from CIP apart from the lack of sensory involvement. It is reported that very few patients have ocular muscle involvement in CIM (Sitwell et al., 1991; Gorson, 2005). It was also reported to occur in pediatric patients (Kaplan et al., 1986). Evidence of a relationship between corticosteroids and CIM is conflicting. Historically, CIM was first described in asthmatic, mechanically ventilated patient treated with high-dose steroids in combination with neuromuscular blocking agents (NMBA), antibiotics, and other drugs (MacFarlane and Rosenthal, 1977). However, as in CIP, CIM evolves mainly in patients who also had severe sepsis and multiple organ failure (Latronico et al., 1996; Latronico et al., 2005a). Because the weakness becomes apparent when these medications (especially the steroids and neuromuscular blockers) are stopped, the assumption was that CIM is a drug-induced condition. However, CIM was described in patients who received only one of these agents, or had very low doses of them for short periods, and even when none was administered. Steroid administration in conjunction with intensive insulin treatment and strict blood glucose control might even exert a protective effect on muscle, possibly because its beneficial anti-inflammatory effect is not counteracted by hyperglycemia and insulin resistance

NEUROMUSCULAR COMPLICATIONS IN INTENSIVE CARE PATIENTS (Hermans et al., 2007). In a recent series based on 208 limb and abdominal muscle biopsies taken from ICU patients, the duration of corticosteroid treatment was associated with loss of myofibrillar (mainly myosin) filaments. Taken together these results suggest that high-dose corticosteroids in critically ill patients should be used cautiously and only when strictly indicated (Derde et al., 2012). Pathologically there seem to be three types of this myopathy: thick filament (myosin) loss myopathy, necrotic, and type 2 fiber atrophy (see Pathophysiology) (Latronico and Bolton, 2011). Only the first two can be associated with a clear rise in serum creatine phosphokinase (CPK) levels; however, normal CPK levels do not exclude CIM (Stevens et al., 2009). It is not clear if these are three distinct disorders or represent histopathologic variations of a single condition. Clinically and electrophysiologically they are indistinguishable from each other (Latronico, 2003). Differential diagnosis requires muscle biopsy (see Muscle and nerve biopsy).

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a major risk factor since ICUAW was regarded in the past as drug-induced disorder (Op de Coul et al., 1985; Hirano et al., 1992). Later it became clear that both CIP and CIM may develop without the use of these drugs (Latronico et al., 1996; Deconinck et al., 1998; Hoke et al., 1999). Still, in patients with acute respiratory distress syndrome, treatment with steroids was the main determinant of impaired ability to exercise at 3 months after hospitalization, but no longer thereafter (Herridge et al., 2003, 2011). Immobility has been suggested as a risk factor for muscle weakness during critical illness. Repeated daily passive and early mobilization prevents muscle atrophy and improves functional independence of patients (Griffiths et al., 1995; Burtin et al., 2009; Schweickert et al., 2009). Diaphragmatic weakness and atrophy develop rapidly after initiation of mechanical ventilation, and are significantly correlated with the duration of such respiratory support (De Jonghe et al., 2002; Jaber et al., 2011).

Critical illness neuromyopathy Critical illness neuromyopathy (CINM) is a very severe form of ICUAW (Latronico et al., 1996). The patient cannot be weaned from the ventilator for a long time and limbs are severely weak or totally paralyzed. However, it is now recognized that combined CIP and CIM often occur in many ICU patients and could possibly manifest a less severe form. It is claimed that the combined form may be the commonest manifestation of neuromuscular weakness in the ICU (Latronico et al., 1996; Bednarik et al., 2003; Lefaucheur et al., 2006; Koch et al., 2011). The prognosis for recovery in these patients with the less severe form of CINM is relatively good but in general neuropathy accompanying CIM protracts ICU discharge (Koch et al., 2011).

Risk factors for critical illness polyneuropathy and myopathy Several studies have consistently identified sepsis, systemic inflammatory response syndrome, and multiple organ failure as risk factors for ICUAW (Stevens et al., 2007) but the following factors have been identified as independent risk factors in a few prospective studies (Hermans et al., 2009): severity of illness, duration of multiple organ dysfunction, duration of vasopressor and catecholamine support, duration of ICU stay, hyperglycemia, female gender, renal failure, hyperosmolality, parenteral nutrition, low serum albumin, and encephalopathy. Aminoglycoside antibiotics have been identified as risk factors in some studies, but not in others (Hermans et al., 2009). The use of neuromuscular blocking agents, especially in combination with steroids, was thought to be

Pathophysiology of critical illness polyneuropathy and myopathy Pathophysiology of CIP and CIM is still poorly understood; however, several microcirculatory, cellular and metabolic events concur to cause the axonal and muscle damage and dysfunction during critical illness (Latronico and Bolton, 2011). These events are potentially reversible (Latronico et al., 1993; Latronico, 2009; Novak et al., 2009), and common to other organ dysfunction, as CIP and CIM do not develop as isolated syndromes, but rather in association with other organ or system dysfunction and failure, such as respiratory, circulatory, renal, hepatic, coagulation, and the central nervous system. There is no direct evidence that peripheral nerve microcirculation is impaired. However, E-selectin expression is present in the vascular endothelium of both epineurial and endoneurial vessels of patients with CIP (Fenzi et al., 2003). E-selectin is not expressed in normal conditions; its activation may increase microvascular nerve permeability, facilitating the passage of neurotoxic factors into the endoneurium and formation of endoneural edema. Axonal degeneration can thus be the consequence of altered endoneurial microenvironment and impaired nerve nutrition (Bolton, 2005). In the rat, an acquired sodium channelopathy with nerve hypoexcitability or inexcitability may cause nerve dysfunction and hence muscle weakness before or possibly even in the absence of axonal degeneration (Novak et al., 2009). Critically ill patients with CIP do have nerve membrane depolarization that is related to endoneurial hyperkalemia and/or hypoxia (Z’Graggen et al., 2006).

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In the muscle, microcirculatory alterations are prominent, particularly in patients with sepsis, in whom the density of perfused capillaries is reduced (De Backer et al., 2002, 2010). Matching of perfusion to metabolic needs is altered, and tissue perfusion and oxygenation are, therefore, compromised. Muscle ATP concentration is reduced suggesting that bioenergetic failure is an important pathophysiologic mechanism (Brealey et al., 2002). Muscle wasting in sepsis is prominent, resulting from increased calpain- and ubiquitin-proteasomemediated muscle protein degradation (Callahan and Supinski, 2009). Since many of the degraded proteins are myofibrillar, this process directly alters the muscle ability to contract (Latronico and Candiani, 1998). Thick myosin filaments are selectively lost, while Z-discs and actin filaments are relatively preserved (Helliwell et al., 1998). The selective loss of myosin causes generalized muscle weakness by reducing the number of motor proteins interacting with the thick filament. Skeletal muscle immobility causes muscle atrophy beginning within hours of bed rest or deep sedation, further enhancing muscle weakness (Kortebein et al., 2007). Acquired sodium channelopathy causing muscle electrical membrane inexcitability is a relevant event also for muscle weakness in ICU patients (Rich et al., 1998; Rich and Pinter, 2003), providing a unifying hypothesis of CIP and CIM as different manifestations of a single disorder (Khan et al., 2008).

(Wilson et al., 1974; Van Wilgenburg, 1979), and are better avoided if prolonged administration of these agents is needed, as in patients with acute respiratory distress syndrome (ARDS) (Papazian et al., 2010). In fact, evidence is now accumulating that the prognosis of ARDS is improved with early administration of neuromuscular blockers. Despite the older notion that NMBA are a major risk factor for the development of ICUAW, this improvement in ARDS prognosis has not been associated with marked increase in resulting weakness. While NMBA may still be contributing to the pathophysiology of ICUAW their early and skilled use should not be avoided.

Unmasking of myasthenia gravis Numerous drugs used in the ICU can interfere with neuromuscular junction transmission and lead to marked weakness (Argov and Mastaglia, 1979). This generalized myasthenic-like weakness involves not only the limb muscles but also the ocular and bulbar musculature. For an unclear reason acute drug induced myasthenia has a predilection for early involvement of the respiratory muscles. The clinical set up at which such NMJ blockade appears may have several circumstances: 1.

Prolonged neuromuscular junction block Prolonged neuromuscular junction (NMJ) block is defined as weakness due to persisting impairment of the synaptic transmission after treatment with neuromuscular blocking agents is terminated. Slowed elimination of competitive, nondepolarizing blockers leading to accumulation of the drugs, due to hepatic or renal pathology, is the main cause of this condition (Segredo et al., 1992). Muscle weakness commonly lasts few hours, but cases of up 42 days duration are documented (Partridge et al., 1990). Most reports that attributed weakness to prolonged neuromuscular block have not included detailed electrophysiologic studies or muscle biopsy to exclude other disorders, and serial assessment of neuromuscular transmission was not routinely performed (Gorson, 2005). Therefore, it is uncertain if prolonged (more than few hours) weakness was really caused by prolonged neuromuscular block or by a superimposed CIP or CIM. Virtually all patients recover completely and a more protracted recovery probably reflects either CIM or CIP, erroneously attributed to prolonged neuromuscular block. High-dose steroids may potentiate the effects of neuromuscular blocking agents with their potential pre- and postsynaptic effect

2.

3.

aggravation of the neuromuscular blocking agents that were administered during surgery. This usually appears as inability to wean off the respiratorassisted ventilation during surgery. This is not similar to the prolonged NMJ block of ICU and usually resolves quickly deterioration of a patient with a disease of the neuromuscular junction (myasthenia or myasthenic syndromes) treated for other conditions or for his basic disease in the ICU unmasking of a previously unknown NMJ defect by the drug. This is a very rare situation but has been described.

The ICU drugs which should be used with extra caution are listed in Table 108.1.

Rhabdomyolysis Rhabdomyolysis in the ICU is rare among the neuromuscular complications. It may occur as a complication of metabolic defect (known or unmasked) but may also be a complication of drug therapy, as in the combined use of ciclosporin and statins after heart transplantation. But special attention should be given to the unusual syndrome of pediatric rhabdomyolysis during ICU treatment for status asthmaticus (Mehta et al., 2006). This is an unusual syndrome of progressive rise of CPK values to extreme levels (>50 000 IU/L) associated at

NEUROMUSCULAR COMPLICATIONS IN INTENSIVE CARE PATIENTS Table 108.1 Drugs which can aggravate neuromuscular junction transmission in the intensive care unit patient Antibiotics Aminoglycosides, polymixin B, clindamycin Drugs with local anesthetic-like action Lidocaine, procainamide, quinidine, phenytoin Calcium channel blockers Magnesium Used for in obstetrics and tetanus treatment b-Blockers Especially propranolol Diuretics (via loss of electrolytes)

times with renal failure. There is no good description of their muscle status but the patients were probably weak with some electromyographic (EMG) evidence of myopathy. Interestingly, patients were under assisted ventilation already prior to the development of the condition which usually started after few days in the ICU and reached a maximum by the second week of hospitalization. These patients received numerous medications but it is hard to attribute the condition to one of them. This form of rhabdomyolysis occurred despite high doses of steroids, which usually reduce CPK levels in a nonspecific way. It must be differentiated from the more common form of CIM in the pediatric population, since it poses extra risk to the kidneys (Banwell et al., 2003). This is especially important as many ICU patients may have a mild to moderate rise in serum CPK during the early phase of the hospitalization (Douglass et al., 1992; De Jonghe et al., 2002), but this finding must be followed to exclude delayed or continuous rise. The borderline between rhabdomyolyis and the acute necrotizing myopathy of intensive care remains to be defined (Ramsay et al., 1993; Zochodne et al., 1994). It should also be noted that elevation of CPK levels may occur in the ICU because of other reasons such as muscle trauma (postcrush syndrome), muscle ischemia (especially in compartment syndrome), and pyomyositis. Another rare cause of marked increase in CPK with rhabdomyolysis is the propofol syndrome. Propofol is a potent hypnotic drug with rapid onset of action, short duration of effect, ability to reduce intracranial pressure and cerebral oxygen consumption, and anticonvulsant properties. As such, propofol is commonly used in the ICU as continuous intravenous infusion for patient sedation. However, high-dose propofol (5 mg/kg/hour) administered for prolonged periods (>48 hours) is associated with a rare and often fatal condition known as propofol infusion syndrome, which is characterized by metabolic acidosis, cardiac and kidney failure, rhabdomyolysis, hyperlipidemia, myoglobinuria, and fatty liver

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enlargement (Parke et al., 1992). Uncoupling of the mitochondrial respiratory chain and impaired utilization of fatty acids by mitochondria are key pathophysiologic events explaining this condition (Vasile et al., 2003). Overall, the occurrence of propofol infusion syndrome is low (1.1% of critically ill patients receiving it) (Roberts et al., 2009), but isolated components of the syndrome are frequently observed, particularly in patients with severe head trauma or acute inflammatory syndrome (Vasile et al., 2003). In patients with severe sepsis and multiple organ failure, propofol-related rhabdomyolysis may overlap with acute necrotizing myopathy (Latronico and Bolton, 2011). Prompt recognition of the propofol-induced syndrome is important to reduce the risk of propofol-associated mortality and morbidity, as immediate interruption of propofol administration can abort the syndrome.

Differential diagnosis of intensive care unit-acquired weakness The most important task of the neurologist called to evaluate an ICU patient with generalized weakness is to set a differential diagnosis plan so as not to miss treatable conditions, to understand better the nature of the condition and its prognosis, and to plan further patient care. The list of the main differential diagnoses of ICUAW appears in Table 108.2. First to be excluded are central nervous system disorders that may develop during the patient’s stay in the ICU. Brain pathology is usually associated with disturbed consciousness of such patients. An ICU patient may develop brainstem stroke, which manifests with respiratory failure and quadriplegia. This is more common of course in the elderly patient. Central pontine myelinolysis is a rare but well recorded complication of metabolic derangements during intensive care. Usually it is described in relation to hyponatremia but may occur in other situations and was recorded after liver transplantation without such biochemical abnormalities. In the awake patient with weakness affecting only the lower limbs one should look for spinal cord conditions; however, quadriplegia may also result from various acute myelopathies. Sensory level and marked difference between lower limb weakness and upper limb power should alert the clinician to this possibility. Compression from an ICU-acquired event (e.g., epidural abscess), inflammatory (postinfection acute transverse myelitis) and even vascular diseases (e.g., anterior spinal artery thrombosis due to coagulation disorders) should be evaluated with proper imaging and other diagnostic techniques. Metabolic impairments such as hypokalemia, hypermagnesemia, and hyophosphatemia should always be sought in the ICU weak patient with reduced reflexes

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Table 108.2 Differential diagnosis of ICU-acquired weakness (ICUAW) Brain disorders Brainstem infarcts Brainstem encephalitis Central pontine myelinolysis Spinal cord and anterior horn disorders Anterior spinal artery infarct Acute transverse myelitis (immune-mediated) Infective myelitis (West Nile, polio, cytomegalovirus, HIV) Postinfective myelitis (zoster, West Nile) Acute spinal cord compression (epidural abscess, metastasis) Hopkins syndrome Neuropathies Critical illness polyneuropathy Guillain–Barre´ syndrome and postinfective and paraneoplastic radiculitis Toxic neuropathy Porphyria Phrenic neuropathy (idiopathic) Infective radiculitis (cytomegalovirus) Lymphomatous and carcinomatous infiltration Vasculitic neuropathy Neuromuscular junction diseases Myasthenia gravis and myasthenic syndromes Prolonged neuromuscular blockade Hypermagnesemia Myopathies Critical illness myopathy Drug-induced rhabdomyolysis Myositis and pyomyositis Toxic myopathies Metabolic myopathies, unmasked (carnitine palmityl transferase (CPT), mitochondrial) Compartment syndrome Propofol syndrome Unmasking of subclinical myopathy Cachexia and disuse General medical conditions Electrolyte disturbances (hyponateremia, hypokalemia, hypophosphatemia) Paraneoplastic disorders of peripheral and central nervous system

and no sensory deficiency. High CPK levels will clearly point toward a myopathic condition. The most important next test in the evaluation of the weak ICU patient is the electrophysiologic evaluation, mainly the nerve stimulation studies, which not only help in determining the neuropathic basis of the patient’s weakness but may point toward possible other causes. If a patient has a neuropathy it should be determined whether it is an axonal or a demyelinating type. The latter is not typical for the ICU-acquired conditions and suggests other diagnoses. Guillain–Barre´ syndrome (GBS)

may occur after an infection that was acquired in the ICU or led to the ICU hospitalization. A well-recognized example of this situation is West Nile virus infection. West Nile fever may first lead to encephalitis and reduced consciousness but once this phase is established paralysis maybe found and several postviral GBS cases have been recently recorded after an epidemic of this viral disease (Nash et al., 2001; Jeha et al., 2003). There are some reports of surgery (Aranason and Soliven, 1993) or epidural anesthesia (Steiner et al., 1985) triggering GBS. Porphyria, with resulting GBS-like neuropathy, can also be precipitated by severe disease or medications used in the ICU. Other causes of neuropathy may be related to drug therapy although this is rare (unless chemotherapy for oncologic conditions was used). Myopathy in the ICU may be the result of toxic reactions to medication (e.g., to statin therapy with a combination of other drugs, such as ciclosporin to prevent rejection, that are also metabolized by the P450 system). Myositis may develop in an ICU patient with other autoimmune disorders (e.g., systemic lupus erythematosus). Compression muscle damage is now very rare in ICU patients due to aggressive position changes and better care of the immobilized patient. However, compartment syndrome, especially of the anterior portion of the calf, can still occur as a result of edema or compression by medical devices used to prevent venous stasis. Weakness is usually limited but the rise in CPK levels may be very high due to severe muscle necrosis. Early recognition (not trivial in the comatose patient) is of high importance to prevent permanent muscle damage. Many drugs used in the ICU have neuromuscular blocking properties, which may lead to weakness in the patient due to impaired transmission at the neuromuscular synapse (e.g., aminoglycosides, b-blockers). Such medications may show more blocking when electrolyte disturbances are present too or rarely may unmask a myasthenic condition (Argov and Mastaglia, 1979). In general, the ICU hospitalization may unmask other neuromuscular disorders such as metabolic myopathies. Fever may precipitate myoglobinuria in a patient with carnitine palmityl transferase deficiency. Any serious disease may lead to a first ever lactic acidosis crisis in a patient with mitochondrial cytopathy (especially in children, e.g., Leigh’s disease). Acute infection may lead to respiratory failure in subclinical myopathies such as acid maltase deficiency (Rosenow and Engel, 1978).

Diagnostic methods in intensive care unit-acquired weakness NERVE STIMULATION STUDIES Determining the conduction features of both motor and sensory nerves is a very important diagnostic test in

NEUROMUSCULAR COMPLICATIONS IN INTENSIVE CARE PATIENTS ICUAW. However, these studies are hard to perform in the ICU environment with electrical interference from other equipment and patients who are not easy to handle (although these tests can be done without patients’ cooperation). Simplified electrophysiologic evaluation of the peroneal nerve shows promise as a rapid, highly sensitive diagnostic test for CIP (Latronico et al., 2007). Abnormal findings in nerve stimulation studies may be an early feature in the ICU patient and may appear as early as 72 hours after the onset of the ICU hospitalization (Khan et al., 2006). Changes can even be of sudden onset within 24 hours after a normal electrophysiology evaluation (Latronico et al., 2007). Nerve conduction studies in CIP will show a reduction in amplitude of both compound muscle action potentials (CMAP) and sensory nerve action potentials with normal or only mildly reduced nerve conduction velocity (Bolton et al., 1986). CMAP duration is not significantly prolonged. Distal motor latencies are usually prolonged resulting in a general conclusion of “axonal” neuropathy. In CIM, nerve stimulation tests are also informative: there is a reduction in the amplitude of CMAPs and an increase in their duration. The prolongation of CMAP is an important diagnostic sign of CIM (Bolton, 2000; Allen et al., 2008; Goodman et al., 2009). Such a change is not observed in the axonal neuropathy of CIP but may result from other ICU related disorders leading to demyelinating neuropathies (Latronico and Bolton, 2011). The latter, however, are usually associated with marked slowing of motor conduction. Normal sensory potentials are the rule in pure CIM (Lacomis et al., 2000). Attention has been drawn to a unique feature of CIM: reduced muscle excitability on direct stimulation (Rich et al., 1996, 1997, 1998; Trojaborg et al., 2001; Lefaucheur et al., 2006). Normally the CMAP should be of the same amplitude whether the nerve or the muscle is stimulated and recording is made from the same site. If the nerve is affected then the muscle response to direct stimulation will be bigger than that evoked by nerve stimulation. In reduced muscle membrane excitability the nerve stimulation should yield a higher CMAP. It is now suggested that if the ratio of the CMAP amplitude after nerve stimulation to the muscle response upon direct stimulation is bigger than 0.5, CIM should be considered as the cause of ICUAW (Trojaborg et al., 2001). The technique used for this test requires skilled personnel. Repetitive nerve stimulation at 3 Hz (preferably at distal and proximal sites) in a search for possible decrement of CMAP amplitude is an important part of the evaluation of the severely weak ICU patient. It is especially indicated when routine conduction studies do not give a clear diagnosis of neuropathy or suspected myopathy and may be the only clue to the existence of

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a neuromuscular junction transmission defect. It is also of high importance when ocular or bulbar muscles are affected. In prolonged neuromuscular block, repetitive nerve stimulation demonstrates the characteristic decremental CMAP amplitude response. If, however, neuromuscular block is complete the CMAP may be absent, simulating CIP or CIM. The presence of normal sensory potentials and serial measurements is helpful in clarifying the diagnosis.

EMG Fibrillation potentials and positive sharp waves are seen in both CIP and CIM, representing either the acute denervation or the necrotizing myopthic changes. The presence of spontaneous activity in myopathy is thought to be the result of functional disconnection of the muscle fiber from its nerve end plate (Zochodne et al., 1994; Hund, 1999). Motor unit potentials are hard to quantify in the ICU because the patient’s cooperation may not be full. Thus, EMG is not helpful in distinguishing between CIM and CIP (Latronico et al., 2009). Spontaneous activity tends to disappear during recovery with an increase in motor unit amplitudes and recruitment.

MUSCLE AND NERVE BIOPSY Muscle biopsy is currently an important research tool for understanding ICUAW but its importance as a diagnostic test remains to be determined. It is now suggested that there are three types of muscle pathology associated with the CIM syndrome. However, it is not clear whether these are part of a spectrum of muscle pathology under ICU conditions or represent a different disease process (Latronico and Bolton, 2011). The first and least specific is type 2 fiber atrophy (Gutmann et al., 1996), which probably results from the disuse and undernutrition of the patient (and possibly also from an additional neuropathic component). Necrotizing myopathy, with fibers undergoing active necrosis and regeneration, is frequently demonstrated in muscle biopsies, especially in those with marked elevation of CPK levels (Ramsay et al., 1993; Zochodne et al., 1994). Inflammatory cell infiltration is uncommon (Bolton et al., 1984; Latronico et al., 1996). If present, other diagnoses should be considered. The most typical histologic finding for CIM is thick filament (myosin) loss (Sher et al., 1979; Danon and Carpenter, 1991; Helliwell et al., 1998). It is expressed in loss of central stain in ATPase stain (“doughnut appearance”) of fibers with classic loss of striated muscle structure on electron microscopy (mainly disappearance of the A band) (Hirano et al., 1992). Immunohistologic studies (Showalter and Engel, 1997; Matsumoto et al., 2000) and molecular evaluation (Larsson et al., 2000)

1680 Z. ARGOV AND N. LATRONICO have shown that the loss of thick filaments is due to selecmajority of patients, usually in 3–6 months (although tive myosin loss. Loss of myosin filaments can be easily CIM can also lead to incomplete recovery). In the CRIMdemonstrated by electrophoretic separation of myofibrilYNE study (Guarneri et al., 2008), patients with CIM lar proteins and measurement of myosin/actin ratio, recovered within 6 months, whereas those with CIP which is greatly reduced in this type of CIM (Stibler had a slower recovery, or did not recover at all. Mortality et al., 2003). This histologic picture is practically only may be also increased in patients with CIP (Leijten et al., recorded in CIM (although it was described in other rare 1995; Garnacho-Montero et al., 2001). conditions that are not relevant to the ICU), thus it is To date, there is no specific therapy for CIP or CIM thought to be a good marker of the disease. (Hermans et al., 2009). Nutritional, antioxidant, hormonal In CIP muscle histology will give evidence of acute therapy and immunoglobulins have all failed to show condenervation with atrophy of both type 1 and type 2 fibers. sistent benefit. Daily sessions of electrical muscle stimuDuring recovery muscle biopsy can demonstrate group lation is feasible in the ICU (Routsi et al., 2010), but its atrophy, but is rarely performed at this stage. efficacy in reducing muscle weakness still awaits convincNerve biopsy is rarely indicated in ICU patients unless ing evidence (Ali, 2010; Poulsen et al., 2011). Intensive another diagnosis is suspected for the evolving neuropinsulin therapy (IIT) titrated to maintain normal blood athy (e.g., vasculitis). It may show signs of axonal neuglucose level throughout the ICU stay has been shown ropathy if performed late in CIP (Latronico et al., 1996). in randomized controlled trials to reduce the incidence of electrophysiologically proven CIP (using denervation OTHER LABORATORY TESTS IN INTENSIVE CARE potentials as the sole diagnostic criterion) both in surgical UNIT-ACQUIRED WEAKNESS (Van den Berghe et al., 2005) and medical ICU patients (Hermans et al., 2007). The risk of CIP was almost halved Serial measurement of CPK can be of value to follow in (risk ratio 0.65; 95% confidence interval 0.55–0.77) when ICUAW. High values (>5 times the upper limit of normal blood glucose could be maintained tightly normal during range) clearly indicate a necrotic myopathy and point the ICU stay (Hermans et al., 2009). IIT also reduced the toward one of the forms of CIM or to another condition. duration of mechanical ventilation, whereas no data are Milder increases in levels are not of diagnostic value. available on the effects of IIT on limb muscle strength About 75% of asthma patients receiving assisted ventilaand function (Stevens et al., 2009). Severe hypoglycemia tion had high CK values already 4 days after the admission is a frequent complication of IIT aiming at normoglyce(Douglass et al., 1992). CPK levels may mildly increase in mia that has been associated with slightly but significantly patients on mechanical ventilation of more than a week increased mortality (Finfer et al., 2009). Thus, this treateven without ICUAW (De Jonghe et al., 2002). ment is no longer recommended (Qaseem et al., 2011). Measurements of serum electrolytes (in particular Future studies should establish the optimal blood glucose magnesium, potassium, and phosphate) is of major level to prevent or treat CIP. importance in the differential diagnosis. Prolonged immobility may exacerbate CIP or CIM. Respiratory muscle strength can be tested by measurPassive limb muscle stretching may reduce muscle atroing the maximal inspiratory and expiratory pressures phy (Griffiths et al., 1995), and active exercises with physand vital capacity. Low values are correlated with limb ical and occupational therapy may increase functional muscle weakness, and are associated with delayed extuindependence (Schweickert et al., 2009). Recent research bation, prolonged ventilation (De Jonghe et al., 2007) emphasizes the cardinal importance of early mobilization and unplanned ICU readmission (Latronico et al., 1999). in facilitating the recovery of ICU patients and reducing their weakness. The evidence for this therapeutic Outcome and prognosis approach has recently been reviewed (Lipshutz and CIP and CIM are responsible for prolonged and at times Gropper, 2013). Therefore, it seems reasonable that stratsevere disability after critical illness. There is strong eviegies to mobilize patients are implemented early on in the dence that both conditions (or a combined one) may ICU. At the least, sedation protocols that minimize doscause persistent weakness for months or even years after ages as much as possible should be considered, as they resolution of the critical illness (Leijten et al., 1995; may decrease the duration of mechanical ventilation, Zifko, 2000; Fletcher et al., 2003; Guarneri et al., impaired consciousness, delirium, and ICU and hospital 2008; Intiso et al., 2011). As a consequence, 28% of stay (Kress et al., 2000; Girard et al., 2008; Strom et al., patients with CIP, CIM, or both may not recover inde2010). A coordinated approach to daily awakening and pendent walking or persistent spontaneous ventilation spontaneous breathing trial, delirium assessment and (Latronico et al., 2005b). early exercise in critically ill, mechanically ventilated CIP is the main contributor to permanent disability, patients may reduce the burden of both delirium and while CIM is associated with complete recovery in the muscle weakness (Vasilevskis et al., 2010).

NEUROMUSCULAR COMPLICATIONS IN INTENSIVE CARE PATIENTS

INTENSIVE CARE UNIT-ACQUIRED FOCAL WEAKNESS Focal amyotrophy Polio-like disease was described in several patients recovering from West Nile virus infection. Unlike the more general GBS-like disease, this condition shows segmental, often asymmetric weakness with marked atrophy (Leis et al., 2002, 2003; Li et al., 2003). It is usually noticed when the patient is at the recovery phase from a more severe disease but can certainly be detected in the ICU if the hospitalization is prolonged. A very rarely reported condition is acute postasthmatic amyotrophic syndrome or Hopkins’ syndrome (Hopkins, 1974; Liedholm et al., 1994). It was mainly reported after a severe asthmatic bout in children, although some adults developed a similar condition. This manifests with acute flaccid monoparesis (or even paraparesis) with neurogenic EMG and muscle histology. The cause of this condition is unknown but suspected to be immunogenic based on “inflammatory” CSF and response in intravenous immunoglobulin (IVIG) treatment (Cohen et al., 1998).

Pressure palsy ICU patients may develop nerve palsy due to prolonged pressure. This could be positional or induced by a medical device. Intermittent pneumatic compression device has been associated with peroneal palsy (Lachmann et al., 1992). The typical sites for pressure palsies are the peroneal nerve around the fibular head causing foot drop; the ulnar nerve at the elbow leading to sensory impairment on the 4–5 digits and at times to small hand muscle weakness; and the peroneal nerve leading to secondary damage in anterior compartment syndrome induced in the ICU. Meticulous care in changing position should prevent many such complications.

Phrenic neuropathy This is not necessarily an ICU-related complication but may be revealed when investigating the patient with inability to wean from a respirator. Diaphragmatic paralysis can result from many different etiologies; some of them may bring the patient to the ICU (trauma, compression and surgical-related damage) and not be the result of it (Qureshi, 2009). But some of the reported causes may appear during the ICU stay (e.g., postinflammatory isolated phrenic nerve damage). It is believed that few people have idiopathic isolated diaphragmatic paresis, which goes unnoticed during regular living conditions but may be emerging in the ICU. However, there have been several reports of patients that developed this focal nerve lesion

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during their ICU hospitalization and it is thought to represent a localized form of ICU neuropathy. Transient phrenic nerve paralysis has been recorded in pediatric and adult patients recovering from status asthmaticus, which can be unilateral or bilateral (Rohatgi et al., 1980; Hillerdal, 1983; Santuz et al., 2004). This rare complication is often transient but will prolong the need for assisted ventilation. A method to follow the development of diaphragmatic weakness in ICU by using magnetic stimulation of the phrenic nerve in the neck has been suggested (Watson et al., 2001) but is not a common procedure.

Needle damage ICU patients are usually given intavenous (IV) medications but in some instances the intramuscular (IM) route is sought. Very rarely this can lead to mechanical damage to a peripheral nerve close to the injection site, usually the sciatic nerve during IM injection in the gluteal area (Small, 2004). The damage to the nerve can result from several mechanisms: direct physical injury to the nerve with a section of fibers, compression by the injected volume of the drug, and toxic effect of the injected substance. Microsurgery in the pediatric group was suggested (Senes et al., 2009), but no controlled studies are available to assess this approach. Venipuncture is also not fully safe and there are series reports of nerve damage in the proximity of this procedure (Berry and Wallis, 1977; Horowitz, 1994; Sander et al., 1998). Arterial puncture in the elbow region or the wrist can also result in nerve lesion (Watson, 1995).

SUMMARY ICUAW can be caused by many disorders of various etiologies. The more frequent disorders, CIP, CIM, or the combined condition, are of major importance to the modern management of ICU patients and pose a challenge to all physicians and researchers dealing with these conditions as they have a major impact on the course, survival, and sequelae of ICU stay. While some pathophysiologic mechanisms have already been elucidated, the full understanding of the spectrum of causes of generalized ICU-associated weakness remains to be identified. Controlled therapeutic interventional studies are highly required to prevent or rehabilitate ICUAW.

REFERENCES Ali NA (2010). Have we found the prevention for intensive care unit-acquired paresis? Crit Care 14: 160. Ali NA, O’Brien JM Jr, Hoffmann SP et al. (2008). Acquired weakness handgrip strength and mortality in critically ill patients. Am J Respir Crit Care Med 178: 261–268. Allen DC, Arunachalam R, Mills KR (2008). Critical illness myopathy: further evidence from muscle-fiber excitability

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Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 109

Posterior reversible encephalopathy syndrome C. LAMY*, C. OPPENHEIM, AND J.L. MAS Department of Neurology, Universit Paris Descartes, Hoˆpital Sainte-Anne, Paris, France

INTRODUCTION A reversible syndrome of headache, altered mental status, seizures and visual loss, associated with posterior white matter changes on neuroimaging, termed reversible posterior leukoencephalopathy syndrome, was first described by Hinchey and colleagues in 1995 (Hinchey et al., 1996). Seven of the 15 reported patients of this series were receiving immunosuppressive therapy (ciclosporin or tacrolimus) after transplantation or as treatment for aplastic anemia, one was receiving interferon-a for melanoma, three had eclampsia, and four had hypertensive encephalopathy. Most of patients had an abrupt increase in blood pressure, but three of 15 were normotensive. There has been some controversy about what should be the proper term for this syndrome and whether it truly represents a leukoencephalopathy. Because MRI has shown that lesions can occur in both gray and white matter, a new name, posterior reversible encephalopathy syndrome (PRES), has been coined (Casey et al., 2000). Since the initial account, this syndrome has been subsequently described in an increasing number of medical conditions or new medications. Most are chemotherapeutic agents, immunosuppressive or cytotoxic treatments, or autoimmune diseases (Hinchey, 2008; Lee et al., 2008; Fugate et al., 2010). The diagnosis has important therapeutic and prognostic implications because the reversibility of the clinical and radiologic abnormalities is contingent on the prompt control of blood pressure and/or discontinuing the offending drug. In contrast, when unrecognized, conversion to irreversible cytotoxic edema may occur.

CLINICAL FEATURES The classic clinical manifestations of PRES include severe headache, nausea and vomiting, alterations in consciousness, seizures and visual disturbances

(Hinchey et al., 1996; Bartynski, 2008a; Lee et al., 2008). Alterations in consciousness range in severity from mild somnolence to frank confusion, stupor, or coma in extreme cases (Keswani and Wityk, 2002). Temporary restlessness and agitation may alternate with lethargy. Memory and the ability to concentrate may be impaired, although severe amnesia is unusual. Seizures were reported in more than 70% of cases in two recent series of 113 and 36 patients with PRES respectively (Lee et al., 2008; Fugate et al., 2010). Seizures can be generalized tonic-clonic or partial (Bakshi et al., 1998; Lee et al., 2008; Fugate et al., 2010). Patients may have multiple seizures or status epilepticus (Wartenberg et al., 2004; Lee et al., 2008). Patients often report blurred vision. Hemianopia, visual neglect, visual hallucinations (Tallaksen et al., 1998), and frank cortical blindness may occur. Papilledema may be present with flame-shaped retinal hemorrhages and exudates (Dinsdale, 1982), but a normal ocular fundus examination does not exclude a diagnosis of PRES. The tendon reflexes are often brisk, and some patients have weakness and incoordination. Occasionally, focal neurologic signs may be noted. Paraparesis and signs of brainstem or cerebellar dysfunction have been reported (Cruz-Flores et al., 2004; Milia et al., 2008). The electroencephalogram may show focal sharp waves, slowing or normal findings (Lee et al., 2008). Examination of the cerebrospinal fluid in 18 patients with PRES has revealed a mean protein level of 92 mg/dL (range 10–455 mg/dL) and a mean white blood cell count of 1.6/mL (range, 0–5/mL (Lee et al., 2008). The clinical presentation of PRES is often nonspecific (Lee et al., 2008). The onset is usually subacute, with symptoms developing over 24–48 hours. The frequency of the main presenting symptoms is shown in Table 109.1. The differential diagnosis includes various neurologic conditions, such as stroke, venous thrombosis,

*Correspondence to: Dr. Catherine Lamy, Service de Neurologie, Hoˆpital Sainte-Anne, 1, rue Cabanis 75674, Paris Cedex 14, France. Tel: þ33-1-45-65-86-34, E-mail: [email protected]

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Table 109.1

Table 109.3

Frequency of the main presenting clinical symptoms of PRES from two series totaling 158 cases*

Main neuroimaging features of PRES

Seizures (75–87%) Status epilepticus (3–17%) Generalized tonic-clonic seizures (54–64%) Partial seizures (3–28%) Encephalopathy (28–92%) Visual disturbances (20–39%) Headache (26–53%) *(Lee et al., 2008; Fugate et al., 2010)

Table 109.2 Main differential neuroradiological diagnosis of PRES Ischemic stroke (watershed or posterior cerebral artery territory) Cerebral venous thrombosis Vasculitis Postictal reversible edema MELAS Acute disseminated encephalomyelitis Infectious encephalitis Progressive multifocal leukoencephalopathy Hypoxic brain damage Creutzfeldt–Jakob disease

encephalitis, all of which can mimic PRES (Table 109.2). Transient elevations of blood pressure can be observed in those conditions as in PRES. In cases with sudden onset of neurologic deficits, the clinical presentation may be indistinguishable from bilateral posterior cerebral artery territory infarct (Hinchey et al., 1996). Initially described in adults, PRES has been subsequently described in children (Pavlakis et al., 1999; Gumus et al., 2010). Recurrent PRES have been occasionally reported (Wong et al., 2003; Lee et al., 2008).

NEURORADIOLOGIC FEATURES (Table 109.3)

Conventional imaging The most characteristic imaging pattern is the presence of edema involving the posterior white matter of both cerebral hemispheres, especially the parieto-occipital regions (Fig. 109.1), in a relatively symmetric pattern (Schwartz et al., 1995; Hinchey et al., 1996; Bartynski, 2008a; Lee et al., 2008). The calcarine and paramedian occipital-lobe structures are usually spared, which could help to distinguish PRES from bilateral infarction in the posterior cerebral artery territory (Hinchey et al., 1996).

Parieto-occipital lesions involving subcortical white matter Cortical lesions frequently associated Bilateral and relatively symmetric pattern Predominant watershed distribution Frequently associated with frontal and temporal lobes lesions Occasionally, isolated or predominant posterior fossa lesions Hyperintensities on T2-weighted and FLAIR sequences Contrast enhancement, petechial hemorrhage or hematoma can be observed Lesions can be iso-, hypo-, or hyperintense lesions on DWI Interpretation of DWI alone may underestimate the extent of lesions Increased ADC values favor reversibility after appropriate therapy Decreased ADC values favor irreversibility and true infarction Pseudonormal ADC values may indicate mixed cytotoxic and vasogenic edema ADC, apparent diffusion coefficient; FLAIR, fluid attenuated inversion recovery; DWI, diffusion-weighted imaging.

Other regions of the brain are also frequently affected. In a series of 136 patients with PRES, evaluated with CT (n ¼ 22) or MRI (n ¼ 114), edema was consistently present in the parietal or occipital regions (98%), but other locations were common including the frontal lobes (Fig. 109.2) (68%), inferior temporal lobes (40%), and cerebellar hemispheres (30%) (Bartynski and Boardman, 2007). Involvement of the basal ganglia (14%), brainstem (Fig. 109.3) (13%), and deep white matter (18%) including the splenium (10%) was not rare. A tendency of the milder cases to have a greater involvement of gray than white matter have been observed (Casey et al., 2000). Lesion confluence may develop as the extent of the edema increases. The basic pattern of PRES resembles the brain watershed zones, with the cortex and subcortical and deep white matter involved to varying degrees (Bartynski, 2008a). Three hemispheric pattern variants with similar frequency have been proposed: holohemipsheric, superior frontal sulcal and primary parieto-occipital (Bartynski and Boardman, 2007). Isolated or predominant posterior fossa lesions are less often reported (Casey and Truwit, 2000; Se`ze et al., 2000; Cruz-Flores et al., 2004). In some rare cases, the posterior fossa lesions are severe enough to cause hydrocephalus (Wang et al., 1999; Lin et al., 2006; Keyserling and Provenzale, 2007). Spinal cord involvement has been reported (Milia et al., 2008). Signal enhancement (Fig. 109.4), asymmetric and unilateral lesions have been reported (Bartynski and Boardman, 2007; Lee et al., 2008; Fugate et al., 2010), sometimes making the diagnosis of PRES challenging (McKinney et al., 2007).

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Fig. 109.1. (A) MRI showing bilateral high signal in the occipital regions on axial FLAIR sequences. (B) MRI showing normal signal in the same regions on diffusion-weighted sequences. (Reproduced from Lamy and Mas, 2011.)

Fig. 109.2. MRI showing bilateral cortical and subcortical edema on axial FLAIR sequences.

Fig. 109.3. Hypertensive encephalopathy in a 65-year-old man. MRI showing extensive increased signal in the brainstem on axial FLAIR sequences. (Reproduced from Lamy and Mas, 2011.)

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Fig. 109.4. Postgadolinium T1-weighted MR sequences showing slight cortical enhancement (arrow).

The abnormalities are often apparent on CT scan but are best depicted by MR imaging (Schwartz et al., 1995; Hinchey et al., 1996; Bartynski, 2008a; Lee et al., 2008). The most commonly observed abnormalities on MR imaging are punctate or confluent areas of increased foci on proton density and T2-weighted images. FLAIR sequences improve the ability to detect subtle peripheral lesions and have shown cortical lesions to be more common than previously thought (Casey et al., 2000). Gradient-echo imaging may reveal petechial hemorrhages. Mild or large hematoma and subarachnoid hemorrhage have also been described (Schwartz et al., 1992; Weingarten et al., 1994; McKinney et al., 2007). In most patients, imaging abnormalities are regressive after appropriate therapy, suggesting transient edema rather than true infarction (Hinchey et al., 1996). Follow-up MR studies may be key in the diagnosis because initial differentiation between a reversible and permanent parenchymal lesion is not possible on the basis of conventional MR imaging or CT scan. The ideal timing of repeated brain imaging to document recovery is unclear. In the series of Lee et al. (2008), the earliest neuroimaging resolution occurred in 5 days. Resolution of PRES neuroimaging abnormalities probably occurs in the range of several days to weeks.

Other magnetic resonance imaging sequences In the majority of cases, diffusion-weighted MR sequences show increased apparent diffusion coefficient (ADC) in

the involved brain regions consistent with vasogenic edema. These areas with increased ADC values may be hyper-, hypo- or isointense on diffusion-weighted imaging (DWI), depending on the amount of the “T2 shine-through” effect. Interpretation of DW images alone, without the benefit of quantitative diffusion information, may underestimate the extent of lesions (Schaefer et al., 1997; Schwartz et al., 1998; Coley et al., 1999; Engelter et al., 2000; Friese et al., 2000; Provenzale et al., 2001; Lamy et al., 2004). ADC values provide prognostic information. Lesions with high ADC values are most often reversible, whereas those with decreased ADC values usually progress to true infarction (Fig. 109.5) (Schaefer et al., 1997; Ay et al., 1998; Schwartz et al., 1998; Coley et al., 1999; Engelter et al., 2000; Friese et al., 2000; Provenzale et al., 2001; Covarrubias et al., 2002; Lamy et al., 2004) and may be associated with an adverse outcome (Koch et al., 2001; Covarrubias et al., 2002). Interestingly, in some cases, ADC values can be paradoxically normal in areas of high T2 or DWI signal (Covarrubias et al., 2002). These so-called pseudonormalized ADC values may result from intravoxel averaging of both cytotoxic and vasogenic edema in the cortex affected by PRES. The extent of T2-weighted and DWI signal changes and ADC values seems to correlate well with patient outcome (Covarrubias et al., 2002) and can help guide more aggressive treatment in more severely affected patients. Diffusion-tensor imaging in 12 patients with PRES revealed that the increases in ADCs were accompanied by anisotropy loss in posterior regions, compared to normal-appearing anterior regions. These changes, which were confined to zones of normally low anisotropy (cortical and subcortical areas), and their reversibility suggests the presence of vasogenic edema, because the interstitial water accumulation is expected to increase the mean diffusitivity and reduce the directionality of diffusion along white matter tract (Mukherjee and McKinstry, 2001). Both single-photon emission computed tomography (SPECT) (Schwartz et al., 1992) and MR perfusion imaging (Jones et al., 1997) have shown preserved or increased perfusion to edematous portions of the brain in patients with hypertensive encephalopathy. These data support the hypothesis that the condition begins with hyperperfusion, resulting in failure of autoregulation, and breakthrough accumulation of vasogenic edema. Further perfusion-weighted imaging is needed to clarify the precise evolution of lesions in PRES. A few cases of PRES examined with proton magnetic resonance spectroscopy imaging have been reported (Sengar et al., 1997; Russell et al., 2001; Eichler et al., 2002). Widespread metabolic abnormalities, consisting of increased choline and creatinine

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Fig. 109.5. (A) MRI showing cortical high signal in the frontal region on axial diffusion-weighted sequences with decreased ADC values. (B) Control MRI 2 weeks later showing the persistence of a cortical high signal on FLAIR sequences. (C) MRI showing bilateral high signal in the external capsules and basal ganglia on axial FLAIR sequences. (D) MR angiography showing bilateral narrowings and dilatations (arrows) in the branches of the middle cerebral artery (MCA).

levels and mildly decreased N-acetylaspartate, occurred in regions with both normal and abnormal MRI appearances. These findings suggest a diffuse metabolic defect in PRES, possibly consistent with microglial activation and neuronal dysfunction. In

one case, all metabolite levels had returned to normal by 2 months (Eichler et al., 2002). However, abnormal metabolite ratio may persist (Sengar et al., 1997). Perfusion MRI studies designed to identify asymptomatic patients who are taking immunosuppressants and who

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may be at risk for PRES have failed to detect subclinical lesions in these patients (Sheth et al., 1999).

Catheter or magnetic resonance angiography Diffuse vasoconstriction, focal vasoconstriction, vasodilatation, and even string-of-beads appearance, consistent with vasospasm, have occasionally been demonstrated at catheter or MR angiography (MRA) in patients with eclampsia and pre-eclampsia (Will et al., 1987; Lewis et al., 1988; Trommer et al., 1988; Tsukimori et al., 2008; Bartynski and Boardman, 2008). More recently, PRES was associated with vasospasm in patients with porphyric encephalopathy (Black et al., 1995), hypercalcemia (Kaplan, 1998), intravenous immunoglobulin treatment (Voltz et al., 1996), intrathecal chemotherapy (Henderson et al., 2003), ciclosporin treatment (Lin et al., 2003) or transfusion (Ito et al., 1997; Boughammoura et al., 2003; Heo et al., 2003). Followup MRA may demonstrate reversibility of vasculopathy. In a series of 47 patients with PRES, reversible vasculopathy was present in eight of nine patients on catheter angiography and in 30 of 43 patients on MRA (Bartynski and Boardman, 2008). These findings suggest that vasospasm is a more common finding in PRES than previously thought. Mild or medium-sized arterial narrowing might escape detection with MRA. Timing of vascular imaging might explain that vasospasm escapes detection, since vasoconstriction is not always present at the onset of symptoms, can begin abruptly, fluctuate or resolve within days (Singhal, 2004). These imaging features are closed to those of reversible cerebral vasoconstriction syndrome (RCVS), which has been associated with various conditions such as the postpartum or exposure to various vasoactive substances (Ducros et al., 2007). Clinical features such as abrupt onset, severe headaches, confusion, seizures, and visual deficits are common in patients with RCVS and PRES. The topographic features of ischemic strokes that occasionally complicate PRES are similar to those of strokes associated with RCVS (Singhal, 2004). Finally, brain lesions consistent with PRES have been described in six (9%) of 67 consecutive patients with RCVS (Ducros et al., 2007). These data indicate that large and medium-sized cerebral vasoconstrictions can occur in patients with PRES, and that vasogenic edema can occur in patients with RCVS. In patients with RCVS, PRES is an early feature occurring mainly during the first week, while ischemic events, including transient ischemic attack and cerebral infarction, occur significantly later, mainly during the second week. This pattern suggests that the underlying vasospastic disorder of RCVS starts distally and progresses toward mediumsized and large arteries (Ducros et al., 2007).

The overlap in the clinical and imaging features of RCVS and PRES suggests that a clinical and pathophysiologic continuum could exist between the two conditions. But further studies are needed to fully understand their interrelationships.

CAUSES Since its initial description, PRES has been linked to an increasing number of medical conditions or medications (Table 109.4). The correlation between clinical features, location of imaging abnormalities, and causes has not been elucidated (Hinchey, 2008). For example, whether Table 109.4 Causes and contributing factors of PRES Hypertensive encephalopathy Acute or chronic renal diseases Vasculitis systemic lupus erythematosus polyarteritis nodosa Wegener’s Endocrine disorders pheochromocytoma primary aldosteronism Porphyria Thermal injury Scorpion envenomation Cocaine or amphetamines abusers Over-the-counter stimulants phenylpropanolamine hydrochloride ephedrine pseudoephedrine caffeine Eclampsia Carotid dissection Hyperperfusion syndrome Thrombotic thrombocytopenic purpura Hemolytic and uremic syndrome Guillain–Barre´ syndrome Triple-H therapy

Immunosuppressive drugs Ciclosporin A Tacrolimus Sirolimus Vincristine Cisplatin Cytarabine L-asparaginase Gemcitabine Bortezomib Bevacizumab Intrathecal chemotherapy Combination chemotherapy Other drugs Interferon-a TNF-antagonist Immunotherapy with interleukin Antiretroviral therapy in HIV-infected patients Erythropoietin Granulocyte stimulating factor Intravenous immunoglobulin Other conditions or associations Reversible cerebral vasoconstriction syndrome Infection/sepsis/shock Blood transfusion Tumor lysis syndrome Cholesterol embolism syndrome Hypomagnesemia Hypercalcemia Hypocholesterolemia

POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME 1693 predominant cerebellar or brainstem involvement is 1990); cocaine or amfetamine abuse (Grewal and Miller, more frequent in hypertensive encephalopathy than in 1991); interactions with monoamine oxidase inhibitors other causes of PRES remains to be determined (Cruz(tyramine), triple-H therapy for symptomatic subarachFlores et al., 2004; Lee et al., 2008). noid hemorrhage-related vasospasm (Wartenberg and Parra, 2006) and use of over-the-counter stimulants (Moawad et al., 2006) (phenylpropanolamine hydrochloHypertension ride, ephedrine, pseudoephedrine, caffeine). One of the main causes of PRES is acute, sustained rise in blood pressure from any cause, sufficient to exceed the upper limit of cerebral blood flow autoregulation Pre-eclampsia/eclampsia (see Pathophysiology). This hypertensive encephalopaThe association of PRES with pre-eclampsia/eclampsia thy may occur at any age but is most common in the secis well established (Hinchey et al., 1996; Schaefer ond to fourth decades of life (Dinsdale, 1982). et al., 1997; Schwartz et al., 2000; Koch et al., 2001; It is estimated that about 1% of patients with hypertenBartynski, 2008a). Pre-eclampsia usually occurs during sion will, at some point, develop a hypertensive crisis the third trimester of pregnancy. Postpartum eclampsia (defined as a systolic BP of 180 mmHg or greater or a diais rare and occurs mainly within 48 hours after delivery, stolic BP of 110 mmHg or greater). Hypertensive crisis but delayed eclampsia (occurring within several weeks can be further classified as a hypertensive urgency or after delivery) has been reported (Matthys et al., hypertensive emergency depending on end-organ involve2004). In one case, delayed eclampsia was associated ment including cardiovascular, renal, and neurologic with retained placental fragments (Delefosse et al., injury (i.e., hypertensive encephalopathy). Hypertensive 2003). PRES has also been reported after resection emergencies represent approximately 25% of hypertenand chemotherapy for hydatidiform mole (Malow sive crises and require immediate BP reduction (not necet al., 1990). essarily to normal levels) to prevent or limit target organ Pre-eclampsia is usually diagnosed in the presence of damage (Varon, 2009; Papadopoulos et al., 2010). hypertension and proteinuria. Hypertension is defined as Antihypertensive treatment has markedly reduced a blood pressure of at least 140 mmHg (systolic) or at the incidence of hypertensive encephalopathy in individleast 90 mmHg (diastolic) on at least two occasions uals with known hypertension. However, abrupt elevaand at least 4–6 hours apart after the 20th week of gestions of blood pressure (characteristically above 220/ tation in women known to be normotensive beforehand. 110 mmHg) in patients with chronic hypertension who Proteinuria is defined as excretion of 300 mg or more of are receiving either no treatment or insufficient treatprotein every 24 hours (Sibai et al., 2005). Pre-eclampsia ment, or in patients whose treatment has been discontinoccurs in 2–7% of healthy nulliparous women. The ued may cause hypertensive encephalopathy. Acute or underlying pathogenetic mechanisms are much debated. chronic renal diseases (acute glomerulonephritis Current hypotheses include placental dysfunction, (Hinchey et al., 1996; Lee et al., 2008), renovascular disinflammatory disease, genetic predisposition, and ease (Weingarten et al., 1994), renal infarction immune maladaptation (Sibai et al., 2005). (Christophe et al., 1993), renal failure (Sharer et al., The classic clinical presentation of eclampsia consists 1993)) are some of the most common causes of hypertenof epileptic seizures or coma manifesting during the sive encephalopathy (Vaughan and Delanty, 2000). third trimester or early puerperium in women who Whether the greater tendency toward development of already have the pre-eclamptic symptom triad of edema, hypertensive encephalopathy in patients with renal proteinuria, and hypertension. However, hypertension hypertension than in those with essential hypertension or proteinuria may be absent in 10–15% of women is related to increased circulating permeability factors who develop HELLP syndrome (hemolysis, elevated or to endothelial damage remains to be determined. liver enzymes, or low platelet counts) and in 38% of Other clinical situations associated with hypertensive those who develop eclampsia (Sibai et al., 2005). It has encephalopathy (Varon, 2009; Papadopoulos et al., 2010) been reported that a substantial subset of women diaginclude autoimmune disorders (Fugate et al., 2010); endonosed with late postpartum eclampsia had not been idencrine disorders (pheochromocytoma (Se`ze et al., 2000), tified as pre-eclamptic before seizure onset. It remained primary aldosteronism, Cushing’s syndrome, reninunclear whether this represented a true variant of the secreting tumors), porphyria (Kupferschmidt et al., clinical presentation of eclampsia or merely reflected 1995); thermal injury (Popp et al., 1980), head injuries decreased caretaker attention towards pre-eclamptic and central nervous system (CNS) trauma, autonomic signs in the postpartum period (Veltkamp et al., 2000; hyperactivity (Guillain–Barre´ syndrome) (Elahi et al., Matthys et al., 2004). 2004), scorpion envenomation (Sofer and Gueron,

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A recent systematic study and meta-analysis has shown that women who have had pre-eclampsia have an increased risk of cardiovascular disease, including an almost fourfold increased risk of hypertension and an approximately twofold increased risk of fatal and nonfatal ischemic heart disease, stroke, and venous thromboembolism in later life (Bellamy et al., 2007). The mechanism underlying this association remains to be defined. Whether these longterm observations are due to persistent and subtle endothelial damage as result of pre-eclampsia remains unknown (Steinberg et al., 2009).

Other conditions An increasing number of medical conditions associated with PRES have been reported. Although most patients with these conditions had moderate to severe hypertension, blood pressure levels were usually lower than those typically encountered with pure hypertensive encephalopathy. Hypertension may therefore be the sole cause leading to PRES or may act as a contributory factor.

CYTOTOXIC AND IMMUNOSUPPRESSIVE DRUGS PRES is most frequently observed after high-dose multidrug cancer therapy. A variety of immunosuppressive drugs have been associated with PRES in the setting of cancer chemotherapy (cisplatin (Ito et al., 1997), cytarabine (Vaughn et al., 2008), vincristine (Hurwitz et al., 1988), gemcitabine (Rajasekhar and George, 2007; Russell et al., 2001), tiazofurin, bortezomib (Kelly et al., 2008), antiangiogenic therapies such as bevacizumab (Allen et al., 2006; Glusker et al., 2006), sorafenib (Vaughn et al., 2008) or sunitinib (Cumurciuc et al., 2008), or transplantation (ciclosporin, tacrolimus, sirolimus (Bodkin and Eidelman, 2007)). PRES is a well-recognized complication of allogeneic bone marrow or stem cell transplantation for hematologic malignancies (Schwartz et al., 1995; Hinchey et al., 1996; Wong et al., 2003). PRES seems to occur most frequently in the first month after allogeneic bone marrow transplantation, with the remainder during the subsequent year after transplantation (Bartynski, 2008a). PRES is also described after solid organ transplantation (Besenski et al., 2005; Bartynski et al., 2008; Wu et al., 2010). The reported incidence after solid organ transplantation varies between 0.4% and 6% (Bartynski et al., 2008; Wu et al., 2010) and seems to be lower than that reported after allogeneic bone marrow transplantation (5–8%), with several important factors potentially accounting for the differences. In allogeneic bone marrow transplantation, conditioning regimens (marrow ablative chemotherapy, total body irradiation) are used to eliminate host marrow, which may induce endothelial or tissue injury with production of

inflammatory cytokines. Graft-versus-host disease is likely a more systemic and aggressive immunoreactive process than organ rejection, and the dose of immunosuppression (ciclosporin, tacrolimus) is typically greater in patients undergoing allo- bone marrow transplantation than in those undergoing solid organ transplantation. Although blood levels of ciclosporin and tacrolimus tend not to correlate with PRES, medication withdrawal often results in alleviation of toxicity (Wong et al., 2003; Bartynski et al., 2008). PRES seems to occur earlier after liver transplantation (within 2 months) than after kidney transplantation, whereas hypertension was found to be more common after renal transplantation than after heart, lung, or liver transplantation (Singh et al., 2000). Transplant rejection and infection often accompany PRES in solid organ transplantation (Bartynski et al., 2008).

AUTOIMMUNE DISEASES PRES has been identified in patients with various autoimmune diseases (Fugate et al., 2010), including systemic lupus erythematosus (Primavera et al., 2001), polyarteritis nodosa (Vora et al., 1992), systemic sclerosis, Wegener’s granulomatosis, rheumatoid arthritis, thrombotic thrombocytopenic purpura, and ulcerative colitis (Fugate et al., 2010). Many patients received immunosuppressive drugs for disease control or had some degree of hypertension.

INFECTION, SEPSIS AND SHOCK PRES may be associated with infection and sepsis, particularly in relation to Gram-positive infections (Bartynski et al., 2006; Fugate et al., 2010). A systemic inflammatory response with evidence of multiple organ dysfunction syndrome may develop, including coagulation disorders, renal or liver dysfunction, and cardiovascular instability (Bartynski et al., 2006).

METABOLIC ABNORMALITIES Hyponatremia, hypomagnesemia, hypercalcemia, renal or hepatic dysfunction may also be contributing factors (Hinchey et al., 1996; Bartynski, 2008a; Lee et al., 2008). Urinary magnesium wasting, due to glomerular or tubular dysfunction, occurs in patients with eclampsia, and in those treated by ciclosporin and tacrolimus. In some cases, symptoms resolved with adequate magnesium replacement (Thompson et al., 1984). Hypomagnesemia could promote vasoconstriction but the precise mechanism by which it contributes to PRES is unclear. Close serum magnesium level monitoring has been recommended in patients receiving tacrolimus or ciclosporin in order to prevent neurotoxicity.

POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME 1695 (Taylor et al., 2000), blood transfusion (Ito, 1997), and HYPERPERFUSION SYNDROME contrast media exposure (Sticherling et al., 1998). Cerebral hyperperfusion (HS) (or reperfusion) syndrome is a rare but well-described complication following carotid PATHOPHYSIOLOGY endarterectomy or stenting (Karapanayiotides et al., 2005; van Mook et al., 2005; Adhiyaman and The pathophysiology of PRES remains controversial. Alexander, 2007). Most studies report incidences of HS Two main theories have been advanced to explain the of 0–3% after carotid endarterectomy. Clinical signs pathogenesis of PRES. The earlier theory postulated that are ipsilateral, throbbing, unilateral headache with nausea PRES results from intense cerebral autoregulatory vasoor vomiting, seizures, and neurologic deficits. It can constriction in response to acute hypertension. Vasocondevelop at any time from immediately after surgery to striction results in decreased cerebral blood flow, up to a month later, but most patients develop symptoms ischemia, and subsequent edema involving mainly the within the first few days (mean 5 days). If not treated border-zone arterial regions (Dinsdale, 1982; Bartynski, properly it can result in severe brain edema, intracerebral 2008b). The direct observation of alternating constriction or subarachnoid hemorrhage, and death. Hyperperfusion and dilatation during episodes of acute rise in blood pressyndrome is more common in patients with an increase in sure in hypertensive rat’s pial vessels seemed to confirm cerebral perfusion of more than 100% compared to the this hypothesis (Dinsdale, 1982). value before carotid endarterectomy and is rare in The brain is protected from extremes of blood prespatients with an increase in cerebral perfusion less than sure by an autoregulation system that ensures constant 100% (van Mook et al., 2005). perfusion over a wide range of systemic pressures. The most important risk factors for hyperperfusion Under normal circumstances, brain vessels possess syndrome are contralateral carotid occlusion or recent intrinsic vascular tone. In response to systemic hypotencontralateral carotid endarterectomy (Adhiyaman and sion, cerebral arterioles dilate to maintain adequate perAlexander, 2007), diminished cerebrovascular reserve, fusion, whereas vessels constrict in response to high postoperative hypertension, and hyperperfusion lasting pressure (Strandgaard and Paulson, 1984; Schwartz more than several hours after carotid endarterectomy et al., 1992). The autoregulatory vessel caliber changes (van Mook et al., 2005). The associated edema is reversare most likely mediated by an interplay between myoible and has a vasogenic MRI pattern similar to that in genic and metabolic mechanisms. The endothelium plays PRES. The pathogenesis involves impaired autoregulaa central role in blood pressure homeostasis by secreting tion as a result of endothelial dysfunction mediated by relaxing factors such as nitric oxide and vasoconstriction generation of free oxygen radicals. Hyperperfusion synfactors (thromboxane A2 and endothelin). In normotendrome is usually homolateral to carotid endarterectomy sive individuals, cerebral blood flow remains unchanged but involvement of the contralateral hemisphere has between mean blood pressures of approximately been reported, confirming that carotid endarterectomy 60 mmHg and 150 mmHg (Vaughan and Delanty, influences cerebral hemodynamics bilaterally 2000; Slama and Modeliar, 2006; Bartynski, 2008b). (Karapanayiotides et al., 2005). This syndrome can be At pressures above the upper limit of autoregulation, prevented by early identification of hyperperfusion hypertensive encephalopathy may occur. Conversely, and control of blood pressure (Karapanayiotides et al., when cerebral perfusion pressure decreases below the 2005; van Mook et al., 2005; Adhiyaman and lower limit of autoregulation, cerebral blood flow Alexander, 2007). decreases and cerebral ischemia occurs. There may be differences between individuals in the degree of hypertension that can give rise to autoregulatory dysfunction MISCELLANEOUS CONDITIONS leading to encephalopathy as well as differences within a Many other drugs or conditions (Table 109.4) may single person over time depending on comorbid factors. occasionally cause PRES (Hinchey et al., 1996; Bartynski, The degree of hypertension required to induce PRES 2008a; Lee et al., 2008; Fugate et al., 2010), such as treatdepends on the baseline pressure (Strandgaard and ment with erythropoietin (Delanty et al., 1997), granulocyte Paulson, 1984). Rapidly developing, fluctuating, or interstimulating factor (Leniger et al., 2000), intravenous mittent hypertension carries a particular risk of PRES. immunoglobulin (Mathy et al., 1998), myeloproliferaLong-standing hypertension causes a shift of the ceretive disorders, carotid dissection (Burrus et al., 2010), bral blood/flow curve to the right presumably due to human immunodeficiency virus (HIV) infection (Giner structural changes (vascular hypertrophy and inward et al., 2002), cholesterol emboli syndrome (Andreux remodeling) and diminished responsiveness of resiset al., 2007), thrombotic thrombocytopenic purpura tance vessels. Therefore, sudden elevations to relatively (Bakshi et al., 1998), hemolytic and uremic syndrome higher blood pressure levels are required to produce

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PRES in a patient with chronic hypertension, as compared to a normotensive person (Strandgaard and Paulson, 1984). Previously normotensive individuals can show signs of encephalopathy at blood pressures as low as low as 160 mmHg systolic, 100 mmHg diastolic (160/100 mmHg) (Vaughan and Delanty, 2000). Children and young adults may have the curve shift to the left, leaving them more at risk for the development of PRES (Dinsdale, 1982). The second theory implicates forced vasodilatation of cerebral vessels (autoregulation breakthrough) rather than vasoconstriction as the major component of PRES, resulting in extravasation of fluid into the interstitium, termed vasogenic edema. In fact, patterns of cerebral blood flow with acute hypertension may be complex with both low and high flow areas coexisting in adjacent cortical regions. The concept of breakthrough of autoregulation has been initially characterized as a passive phenomenon. Later evidence suggests that breakthrough of autoregulation may be an active process initiated by calcium-dependant potassium channels. This process generates reactive oxygen species and an active increase in permeability of the blood–brain barrier, as well as an increase in vesicular transport, rather than disruption of tight junctions (Heistad, 2001). Eclampsia has been considered as a form of hypertensive encephalopathy on the basis of similarities in clinical, radiologic, and pathologic features (Richards et al., 1988; Digre et al., 1993; Manfredi et al., 1997; Engelter et al., 2000; Schwartz et al., 2000). The fluid accumulation often observed during pregnancy may accentuate the tendency for brain edema to develop. Recent experimental data suggest that pregnancy may predispose the brain to cerebral edema through increased hydraulic conductivity (Euser and Cipolla, 2007). However, several findings suggest that eclampsia is more than hypertensive encephalopathy (Mas and Lamy, 1998; Schwartz et al., 2000). There is not always a good correlation between symptoms and signs of eclampsia and blood pressure levels and blood pressure is reported as only minimally elevated in 23% of patients (Schwartz et al., 2000). Pre-eclampsia/eclampsia is a multisystem disorder, characterized by abnormal vascular response to placentation that is associated with increased systemic vascular resistance, enhanced platelet aggregation, activation of the coagulation system and endothelial-cell dysfunction (Sibai et al., 2005). Production of placental antiangiogenic factors has been shown to be upregulated in pre-eclampsia (Wang et al., 2009). These placental antiangiogenic factors are released into the maternal circulation; their actions disrupt the maternal endothelium and result in hypertension, proteinuria, and the other systemic manifestations of pre-eclampsia/ eclampsia (Wang et al., 2009). Generalized endothelial

dysfunction may lead to: (1) increased sensitivity to normally circulating pressor agents and impaired synthesis of vasoactive compounds which may result in vasospasm and reduced organ perfusion; (2) platelet activation with transitory platelet rich microvascular occlusion; (3) activation of the coagulation cascade; (4) loss of fluid from the intravascular compartment (Roberts and Redman, 1993). Immunosuppressive and cytotoxic drugs can damage the blood–brain barrier by various means: direct toxic effects on the vascular endothelium, endothelial dysfunction secondary to the vascular endothelial growth factor inhibition, vasoconstriction caused by release of endothelin, increases in thromboxane and prostacyclin causing microthrombi (Hinchey et al., 1996; Bartynski, 2008a). The additional role of seizures has been suggested . Seizures can result in elevations of blood pressure, regional hyperperfusion breakdown of the blood–brain barrier and vasogenic edema. Failure of the autoregulatory capabilities of the cerebral vessels, itself resulting from various mechanisms including hypertension and endothelial dysfunction, may represent a common pathophysiologic mechanism leading to this syndrome. A complex underlying systemic process is present in most patients with PRES, irrespective of the underlying cause. T cell activation and inflammatory cytokine production are common. Cytokines upregulate endothelial surface antigens, and increase leukocyte adherence leading to microcirculatory dysfunction (Bartynski, 2008b). Endothelial activation and injury likely result in vasculopathy with altered intrinsic vascular tone (Tallaksen et al., 1998). Ultimately, loss of endothelial fibrinolytic activity, activation of coagulation and platelets, and degranulation on damaged endothelium may promote further inflammation, thrombosis, and vasoconstriction (Vaughan and Delanty, 2000). The preferential distribution of white matter lesions in posterior brain regions in PRES is recognized but not fully understood, although regional heterogeneity of the sympathetic innervation has been suggested (Beausang-Linder and Bill, 1981). In contrast to the anterior cerebral circulation which is richly innervated by sympathetic nerves from the superior cervical ganglion, the vertebrobasilar vessels are relatively devoid of sympathetic innervation (Bill and Linder, 1976). It is possible that sympathetically mediated vasoconstriction protects the anterior circulation from overperfusion in acute hypertension (Beausang-Linder and Bill, 1981).

PATHOLOGIC FEATURES The neuropathologic findings in patients who died from hypertensive encephalopathy or eclampsia (Chester et al., 1978a; Richards et al., 1988) consist of varying

POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME degrees of vascular alterations (fibrinoid necrosis of arterioles, thrombosis of arterioles and capillaries), and of parenchymal lesions (microinfarcts, petechial hemorrhages, cerebral edema). Ring hemorrhages around a thrombosed precapillary compose the classic microscopic lesion. If hypertensive encephalopathy develops in a patient with long-standing hypertension, a variety of additional hypertensive cerebrovascular changes may be found, including medial atrophy, hyperplasia, hyalinization and microaneurysms. The lesions are most often multiple and bilateral, most prominent in the deep white matter and at the gray–white junction in the watershed and posterior areas; the brainstem is usually severely affected (Chester et al., 1978b). They may also be present in the basal ganglia, diencephalon, and cerebral cortex. Their extent and severity vary but are generally correlated with the severity of neurologic manifestations and blood pressure, especially during the terminal stage. Brain swelling, occasionally sufficient to cause herniation of cerebellar tonsils through the foramen magnum, has been documented. The vascular changes are not confined to the brain but may also affect the eyes (retinal hemorrhages, papilledema), kidneys (fibrinoid arteriolar lesions of glomeruli), and other organs (Chester et al., 1978b). These findings, however, may not be representative of those of surviving patients instead representing the extreme of a spectrum of abnormalities. A brain biopsy performed in a patient with hypertensive encephalopathy demonstrated white matter edema with no evidence of vessel wall damage or infarction, consistent with MRI findings of vasogenic edema. The patient made a full neurologic recovery and follow-up MRI revealed complete resolution of lesions (Schiff and Lopes, 2005).

TREATMENT Failure to recognize the syndrome and correct the underlying cause as well as the associated metabolic abnormalities may result in irreversible brain injury. Treatment with antiepileptic medications is the standard of care for seizures associated with PRES but long-term antiepileptic therapy is not usually necessary (Lee et al., 2008).

Hypertensive encephalopathy Hypertensive encephalopathy requires immediate blood pressure reduction (not necessarily to normal ranges) to prevent or limit target organ damage. As there have been no large clinical trials, treatment of hypertensive encephalopathy is dictated by consensus (Vaughan and Delanty, 2000). Most experts recommend that mean arterial blood pressure should not be lowered by more than 20%

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during the first hour with a target diastolic blood pressure of 100–110 mmHg (Slama and Modeliar, 2006). If possible, patients should be admitted to an intensive care unit and the blood pressure lowered under constant monitoring. Intravenous administration of antihypertensive drugs is generally preferred. Excessive falls in pressure must be avoided, particularly in elderly patients and in those with pre-existing hypertension, because they may precipitate renal, cerebral, or coronary ischemia. Although not evidence-based, the use of anticonvulsants in patients with hypertensive encephalopathy who are having seizures is reasonable (Vaughan and Delanty, 2000; Slama and Modeliar, 2006). Suitable agents in the management of hypertensive encephalopathy must satisfy a number of criteria: be usable by intravenous injection, have rapid onset of action, and be easily titrated with a short half-life allowing more flexible use. The drugs proposed include nicardipine, urapidil, labetalol,and sodium nitroprusside (Vaughan and Delanty, 2000; Slama and Modeliar, 2006; Varon, 2009). There is insufficient randomized control trials evidence to determine which drug or drug class is most effective in reducing mortality and morbidity (Perez and Musini, 2008). Oral therapy should be instituted before parenteral agents are discontinued. The management of hypertensive encephalopathy also includes early recognition and withdrawal of exacerbating factors such as immunosuppressive drugs (Hinchey et al., 1996).

Pre-eclampsia/eclampsia The only successful treatment for pre-eclampsia is delivery. No definitive preventive strategies have been identified. Magnesium sulfate is indicated to prevent further seizures in women with eclampsia. Magnesium has cerebral vasodilatory effects, alters the expression of endothelin-1 receptors, and reduces the permeability of the blood–brain barrier. These actions are relevant, since regional vasoconstriction, altered cerebral autoregulation with cerebral hyperperfusion, endothelial dysfunction, and breakdown of the blood–brain barrier are central to the pathophysiology of vasogenic edema in patients with eclampsia. The role of prophylactic magnesium sulphate in pre-eclampsia is less clear. There is also long-standing experience with several suitable antihypertensive drugs. The parenteral antihypertensive drugs most commonly used during pregnancy are labetalol, nicardipine, hydralazine, or urapidil (Sibai et al., 2005; Slama and Modeliar, 2006; McCoy and Baldwin, 2009). Angiotensin-converting enzyme inhibitors and angiotensin-receptor antagonists are contraindicated in pregnancy because of fetal side-effects.

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PRES associated with immunosuppressive drugs Treatment consists of prompt control of blood pressure and/or discontinuing the offending drug or decreasing the dose. The potential of magnesium supplementation in treating or preventing seizures remains unknown.

CONCLUSION PRES is not a single disease entity but an increasingly recognized clinicoradiologic syndrome associated with a multitude of clinical disorders, including hypertensive encephalopathy and immunosuppressive treatments. Because neuroimaging findings are often characteristic, they may be the first clue to the diagnosis. MRI with diffusion-weighted sequences is not only a powerful means for diagnosing PRES but also provides prognostic information that can guide therapeutic decisions. The pathogenesis is incompletely understood, although it seems to be related to the breakthrough of cerebral blood flow autoregulation and endothelial dysfunction. Early recognition of this disease is crucial because prompt and appropriate treatment can lead to fewer irreversible cases.

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Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 110

Neuro-Behc¸et syndrome SABAHATTIN SAIP1, GULSEN AKMAN-DEMIR2, AND AKSEL SIVA1* Department of Neurology, Cerrahpasa School of Medicine, Istanbul University, Istanbul, Turkey

1

2

Department of Neurology, School of Medicine, Istanbul Bilim University, Istanbul, Turkey

INTRODUCTION Behc¸et’s disease, originally described in 1937 by Hulusi Behc¸et as a distinct disease with orogenital ulceration and uveitis (Behc¸et, 1937), known as the “triple-symptom complex,” is an idiopathic chronic relapsing multisystem vascular-inflammatory disease of unknown origin. The disease affects many organs and systems, causing mucocutaneous lesions, uveitis sometimes resulting in blindness, nervous system involvement, major vessel disease that may be fatal, musculoskeletal problems, gastrointestinal involvement, and others. Because of this multisystem involvement and the wide range of clinical manifestations and presentations, many prefer to call Behc¸et’s a syndrome (BS) rather than a disease (Yazici, 2003).

EPIDEMIOLOGY The epidemiology of the disease shows a geographical variation, seen more commonly along the Silk Route that extends from the Mediterranean region to Japan. This is coupled by a similar variation in HLA-B51 association, which is strongly associated with the disease in high prevalence areas such as Middle and Far East (Yazici et al., 2010). Interestingly, BS also shows a geographical variation in disease expression, with severe eye involvement and inflammatory bowel disease being more common in the Far East than in the Mediterranean basin, and the pathergy reaction being less frequent in in patients from northern Europe and the US than the Mediterranean region and Japan (Yazici et al., 2010). The prevalence rate of BS has been reported to be less than 1/105 in northern and central Europe, and to range between 2.5 and 6.4/105 in the north-western Mediterranean region; it increases considerably in the eastern

Mediterranean region, and has rates up to 20/105 in Japan, China, and Korea (Sakane et al., 1999). Most of these rates come from hospital-based series, with the exception of the higher rates coming from Turkey, which are from population-based studies. In these field surveys carried out in Turkey, the prevalence of BS was found to be between 20 and 421 per 100 000 adults (Yazici et al., 2010). The prevalence in Turkish immigrants living in Germany is lower (21–77/105) than that reported in Turkey, but is much higher than the native German population (0.6/105), which may point to the greater significance of genetic compared with environmental factors in the etiology of the disease (Zouboulis et al., 1997; Yazici et al., 2010). The reported prevalence rates for the US range between 1 and 5.2/105. The usual onset of BS is in the third or fourth decade; however, although rare, onset in children has also been reported (Kim et al., 1994). The gender distribution is almost equal. However, the reported increased tendency to affect men more than women may be explained by the higher incidence of systemic complications and more severe disease in men, possibly bringing them to earlier medical attention.

DIAGNOSIS AND SYSTEMIC MANIFESTATIONS OF BEHC° ET SYNDROME Currently the most widely used diagnostic criteria are those of the International Study Group’s classification, according to which a definitive diagnosis requires recurrent oral ulcerations plus two of the following: recurrent genital ulcerations, skin lesions, eye lesions and a positive pathergy test (International Study Group for Behc¸et’s disease, 1990, 1992) (Table 110.1).

*Correspondence to: Aksel Siva, M.D., Chair and Professor of Neurology, Istanbul University, Cerrahpasa School of Medicine, Department of Neurology, Cerrahpasa 34093-Istanbul, Turkey. Tel (mobile): þ90-532-615-8781, Fax: þ90-212-5290886/ þ90-212-240-2106, E-mail: [email protected]; [email protected]

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Table 110.1 Criteria for diagnosis of Behc¸et disease* Finding

Definition

Recurrent oral ulceration

Minor aphthous, major aphthous, or herpetiform ulcers observed by the physician or reliably described by the patient, which recurred at least three times over a 12 month period Recurrent genital ulceration Aphthous ulceration or scarring observed by the physician or reliably described by the patient Eye lesions Anterior or posterior uveitis or cells in the vitreous body on slit-lamp examination; or retinal vasculitis detected by an ophthalmologist Skin lesions Erythema nodosum, pseudofolliculitis, papulopustular lesions or acneiform nodules not related to glucocorticoid treatment or adolescence Positive pathergy test Test interpreted as positive by the physician at 24–48 hours For a clinical definite diagnosis of BS the patient must have recurrent oral ulceration plus at least two of the other findings in the absence of any other clinical explanations *(International Study Group for Behc¸et’s Disease, 1990.)

Oral aphthae The presence of recurrent oral ulcers is required for the diagnosis of Behc¸et syndrome. It is unusual to see cases without oral ulcers and almost all our patients with neuro-Behc¸et syndrome (NBS) had a history of oral ulcers by the time that they had developed their neurologic symptoms. However, 1–3% of patients can have several of the other features of the syndrome without ever having aphthae. Aphthae are frequently the first manifestation of the syndrome and it is not uncommon for some patients to have only oral ulcers for many years before other signs appear. The majority of oral ulcers in Behc¸et syndrome are indistinguishable from those seen in recurrent oral ulceration, but they tend to be multiple and occur more frequently. These ulcers are small, round, or oval, with a sharp, erythematous border, and painful. They appear in the gingiva, tongue, palate, and buccal and labial mucosal membranes, and usually heal without scars. Large (major) ulcers are less frequent and herpetiform ulcers are rare.

Genital ulceration External genital ulcers, which have the next highest sensitivity for the diagnosis of BS, are deeper, painful, have irregular margins, and leave scars, producing an objective sign even in the absence of active lesions. They usually occur on the scrotum in men and on the labiae in women.

Skin lesions Skin lesions of different kinds are seen in up to 80% of patients with BS. These are folliculitis, papulopustular

lesions, and acneiform lesions, which occur more commonly in men, and erythema nodosum, which are more common in women. These lesions all represent various forms of vasculitis. The other forms of skin lesions are leukocytoclastic vasculitis, necrotizing arteritis of the small and medium arteries, superficial thrombophlebitis, and unclassifiable papules and pustules.

Eye involvement This is one of the most serious manifestations and a leading cause of morbidity in BS. The overall prevalence is about 50%, but it is more common and more severe in men and young patients, generally occurring within 3 years of disease onset (Yazici et al., 2010). Eye disease is bilateral in 90% of the patients and consists of a chronic relapsing posterior and anterior uveitis, and acute panuveitis, with blurred vision, decreased visual acuity, photophobia, pain in the eye and conjunctival hyperemia being the common ocular symptoms. Intense inflammation (hypopyon) is seen in 20% of patients with eye disease, and as rule is almost always associated with severe retinal disease and indicates a grave prognosis associated with blindness. Optic nerve involvement can occur, but is rare.

The pathergy phenomenon The pathergy phenomenon is one of the diagnostic tests that is almost specific to Behc¸et syndrome (Yazici et al., 2010). This is a nonspecific hypersensitivity or hyperirritability reaction of the skin. It has a sensitivity that varies largely between different ethnic and geographical groups (range: 20–80%). It is produced by inserting an

NEURO-BEHC¸ET SYNDROME 20 gauge needle into the dermis of the forearm of the patients. The reaction is considered positive if a papule or pustule is formed at the site of the puncture within 24–48 hours. Erythema alone is considered negative.

Musculoskletal involvement A nonerosive, nonmigrating monoarthritis or oligoarthritis, involving the large joints, especially knees, ankles and wrists, either in the form of arthritis or arthralgia, is reported in about 50% of patients. Another musculoskletal manifestation associated with Behc¸et syndrome is aseptic necrosis of the bone. This is possibly related to vasculitis and not necessarily to steroid use (Sakane et al., 1999).

Gastrointestinal involvement Constipation, diarrhea, abdominal pain, or vomiting are common gastrointestinal symptoms but their frequency varies in different geographic populations (Sakane et al., 1997; Yazici et al., 2010). These symptoms are seen relatively frequently in Japan, but not in Turkey and other Mediterranean countries. Due to their common occurrence, oral ulcers are considered separately from the remaining gastrointestinal tract, of which any part, especially the distal ileum and caecum, may also have ulcers. It can be difficult to distinguish inflammatory bowel disease from BS histologically. The rarity of rectal involvement and fistulas in BS can be helpful in differential diagnosis (Yazici et al., 2010).

Cardiovascular involvement Major vessel involvement is another serious cause of morbidity and mortality in BS. BS is one of the few vasculitides that can involve both the venous and arterial sides of the circulatory system. Arterial disease is less common (occurring in < 5% of cases), but it is of high importance as it may manifest itself in the form of arterial aneurysms or occlusions, or as pulmonary artery aneurysms, with the risk of fatal hemoptysis and death. Deep vein thrombosis and thrombophlebitis are among other large vessel complications, and all are expected to be seen in 25–30% of the cases, while a possibly higher proportion do have small vessel involvement, mostly affecting postcapillary venules (Koc¸ et al., 1992). In BS there is also a tendency to develop venous thrombosis after venepuncture. Although rare, myocardial ischemia associated with coronary vasculitis or with inflammation such as endocarditis, myocarditis, and pericarditis may all occur, resulting in ventricular dysfunction and intracardiac thrombi. Cases with ventricular aneurysms have also been documented. Currently available data show

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that the prevalence of atherosclerosis is not increased in BS patients (Yazici et al., 2010).

Other systems Other systems reported to be involved through the course of the disease are pulmonary, urinary, and the central nervous system. Unlike many other systemic vasculitides, glomerulonephritis is uncommon. Amyloidosis of the AA type is seen sporadically (Yazici et al., 2010).

Laboratory investigations There are no laboratory findings specific for BS. Moderate anemia of chronic disease and leukocytosis can be seen in some patients. Erythrocyte sedimentation rate is only mildly elevated, as is C-reactive protein. None of these correlates with disease activity. Autoantibodies are absent, whereas complement levels may be high (Sakane et al., 1999; Yazici et al., 2007). However, HLA testing can support the diagnosis in populations where the disease is associated with HLA B51 phenotype and may help in the differential diagnosis.

PATHOLOGYAND PATHOGENESIS OF BEHC° ET SYNDROME The core histopathologic phenomenon seems to be a vasculitic involvement in some cases and a low-grade, chronic, nonspecific inflammation in others (Sakane et al., 1999; Demirkesen et al., 2010). The vessel wall changes and perivascular mononuclear cell infiltration consistent with vasculitis involving both arterial and venous systems have been shown in histopathologic studies. However, vascular involvement in BS is predominantly venous in contrast to what is seen in most other systemic vasculitides (Direskenli and SaruhanDireskeneli, 2010). Other than vasculitis, involved tissues may show various types of histopathologic lesions varying with the age of the lesion at the time of examination; a nonspecific inflammatory reaction with neutrophilic predominance in early lesions is expected, whereas in older lesions lymphocytes become more predominant (Mendoza-Pinto et al., 2010). Interestingly, usually a clear-cut vasculitic process cannot be demonstrated in the central nervous system (CNS) and studies on pathology of the CNS involvement indicate that NBS may not be a cerebral vasculitis, but rather a perivasculitis (Hadfield et al., 1997; Arai et al., 2006; Hirohata, 2008; Demirkesen et al., 2010). Despite broadened clinical understanding of this disease, the etiopathogenesis of BS still remains obscured and speculative, but clinical and laboratory data suggest that there is dysfunction of both innate and adaptive

1706 S. SAIP ET AL. immune systems, resulting in an exaggerated response autoimmune and autoinflammatory disorders. On the to viral or bacterial insults; however, along with immuother hand, IL-23 is a potent stimulator of Th17 cell pronological factors, genetic causes and fibrinolytic defects liferation leading to an increased secretion of IL-1, IL-6, have been implicated as well (Direskeneli and SaruhanIL-17, and TNF-a; while IL1-2 induces IFN-g secretion Direskeneli, 2010). As there is no evidence for a direct and Th1 cell proliferation. These data should be further infectious cause in BS, antigenic cross-reactivity suggesverified by various functional experiments (Gul, 2011). tive of an autoimmune origin for Behc¸et syndrome has Both innate and adaptive immune systems are actialso been speculated (Sakane et al., 1999). However, the vated in BS, with the predominant changes being consisautoimmune theory in BS is challenged too, based on sevtent with a proinflammatory and Th1 type cytokine eral facts such as male predominance, lack of concurrent profile (Direskeneli and Saruhan-Direskeneli, 2010). autoimmune diseases, lack of any specific antigen or antiMany studies have shown an activation of Th1 type cytobody, and lack of any relationship with HLA-class II antikines, but also some Th2 cytokines and neutrophil hypergens (Yazici et al., 2010). More recent data have carried activity. Recently, it was shown that polymorphonuclear this ongoing debate further and raised the possibility that leukocytes (PMNs) from BS patients do not exhibit the hyperreactivity seen in BS is an autoinflammatory hyperchemotaxis per se, but they show an exagerated phenomenon, rather than an autoimmune phenomenon chemotaxis in response to BS plasma; similarly normal (Gul, 2005; Direskeneli and Saruhan-Direskeneli, 2010). neutrophils also show exagerated chemotaxis when Autoinflammatory diseases indicate a relatively rare exposed to BS plasma. Increased IL-8, tumor necrosis group of heritable disorders that are characterized by factor (TNF) a, and IL-1 production from lymphomonoseemingly unprovoked episodes of inflammation and relnuclear and endothelial cells are other findings in BS. ative lack of an obvious autoimmune pathology (i.e., pathInteractions of HLA-B51 and killer immunoglobulin-like ogenic high titer autoantibodies, or antigen-specific receptors (KIR) on inflammatory cells seems to be T cells). These disorders arise from various genetic disorimportant in the generation of nonspecific inflammatory ders which result in a chronic low-grade inflammatory response in BS (Gul et al., 2002). In the CSF of neuro-BS activity with overlapping recurrent inflammatory attacks. patients a neutrophil chemoattractant chemokine Genetic susceptibility plays a critical role in the pathoCXCL8 is found to be elevated, as well as mononuclear genesis of BS. Up to now, HLA-B51 association is the chemoattractant chemokines CCL2 and CXCL10. In strongest genetic susceptibility factor ever shown (Gul active parenchymal neuro-BS IL-12 and IL-17 were not and Ohno, 2012). However, the exact role played by different, but IL-10 was significantly elevated. When HLA-B51 is still unknown. Although the disease is not neuro-BS was compared to MS and infectious disorders, transmitted through Mendelian patterns, there is familial it more closely resembled the infectious side of the aggregation in BS, indicating a complex genetic inheriinflammatory spectrum (Saruhan-Direskeneli et al., tance. However, in multiplex families, the contribution 2003). Treatment success with agents such as TNF-a of HLA B locus is less than 20% (Gul et al., 2001). TNF inhibitors and interleukin-1 b regulating antibody sugand MICA (MHC class I related gene-A) genes are located gest that Th17 cells play an important role in the near HLA-B51; and MICA was suggested to be the link pathogenesis of BS (Gul et al., 2012). with HLA-B51 and BS (Mizuki et al., 1997). As for TNF, Interestingly, CNS parenchymal inflammation and a meta-analysis of studies involving TNF polymorphisms cerebral vein thrombosis, the two different forms of revealed that there were some polymorphisms associated NBS, rarely occur together in the same individual with BS in some ethnic groups (Touma et al., 2010). (Akman-Demir et al., 1999; Siva et al., 2001). This clinical In a recent genome-wide association study in BS the observation was further confirmed by laboratory studies. most significant association was found with the MHC An antibody response to the 65 kD heat shock protein and region in chromosome 6, mostly due to HLA-B51; while a-B crystallin in the CSF of parenchymal NBS as comassociations were with CPLX1 (a regulator of exocytosis pared to the sinus thrombosis group was shown (Tas¸c¸i during vesicle membrane fusion), and interleukin (IL) et al., 1998) and also increased CSF IL-6 levels were found 10, and IL23R, IL12RB2 (Remmers et al., 2010). Morein parenchymal NBS (Hirohata et al., 1997), whereas, there over, IL-10 production was found to be diminished in was no such increases in BS patients with sinus thrombosis BS in the same study. Another genome-wide association (Akman-Demir et al., 2008a). study from Japan also showed association with IL10 and Although thrombotic events are believed to play a sigIL23R, IL12RB2 (Mizuki et al., 2010). IL-10 is a potent nificant role in a subset of BS patients, no specific defect suppressor of many proinflammatory cytokines such in the coagulation system so far has been demonstrated as IL-1, IL-6, IL-12, TNF-b, and IFN-g. It also reduces (Direskeneli and Saruhan-Direskeneli, 2010). Present T cell and NK cell activation by macrophages. IL10 data are suggestive that both coagulation and fibrinoreceptor mutations have been indicated in various lytic pathways are activated even when there is no

NEURO-BEHC¸ET SYNDROME thrombosis (Direskeneli and Saruhan-Direskeneli, 2010). Thrombosis in BS is thought to be due to immunemediated endothelial dysfunction, which increases in the presence of multiple other risk factors that are common in BS (Gul, 2005; Mendoza-Pinto et al., 2010). In summary, despite a large and increasing number of studies on its cause, the etiopathogenesis of BS remains obscure; probably there is more than one pathogenetic mechanism responsible for heterogeneous disease presentations (Yazici et al., 2012). It is generally accepted as a multifactorial disease with a strong genetic background, in which the wide spectrum of disease manifestations is considered to be triggered in genetically susceptible individuals by various environmental factors (Gul, 2005).

NERVOUS SYSTEM INVOLVEMENT IN BEHC° ET SYNDROME: “NEURO-BEHC° ET SYNDROME” Neuro-Behc¸et syndrome (NBS) is defined as the occurrence of neurologic symptoms in a patient with BS that is not better explained by any other well-known systemic or neurologic disease. The prevalence of NBS in BS is between 3% and 9% in nonselected large series (Akman-Demir et al., 1999; Kidd et al., 1999; Siva et al., 2001; Al-Araji and Kidd, 2009; Davatchi et al., 2010). Although rates up to 59% have been reported, most of these high rates come from hospital-based selected series from countries where BS is relatively rare and more severe cases are likely to be admitted and diagnosed. In another longitudinal study from our center, however, when the frequency of neurologic involvement was evaluated prospectively, the frequency became 13.0% among the males and 5.6% among the females after two decades of follow-up (Kural-Seyahi et al., 2003). In a Japanese autopsy series of patients with Behc¸et syndrome, 20% showed pathologic evidence for neurologic involvement (Lakhanpal et al., 1985). A neurologic onset of BS is unlikely, mainly for the parenchymal form. Many of the patients who will be diagnosed as having BS after developing neurologic problems will turn out to have had recurrent oral ulcers, as well as one or several of the other systemic manifestations of the disease, months to years prior to the neuro-onset. In our series from the two large Behc¸et centers in Istanbul the mean age of onset of BS was found to be 25.8  7.8 and 26.7  8.0 years, and for NBS 31.5  8.9 and 32.0  8.7 years, respectively (Akman-Demir et al., 1999; Siva et al., 2001). In most other reported series the age of onset for BS in patients who developed neurologic involvement ranged between 25 and 33 years of age, and neurologic involvement occurred 3–5 years later (Kidd et al., 1999; Al-Araji and Kidd, 2009), consistent with our cohort. Despite the gender difference being

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insignificant in BS, neurologic involvement occurs more commonly in men, with a male to female ratio of up to 4:1 (Siva and Saip, 2009). Such a significant male predominance has also been noted for other severe vascular complications of BS (Kural-Seyahi et al., 2003). However, once NBS develops the severity does not show a gender difference. BS is rare in the pediatric population and in a recent review of our data, BS patients who presented at or before 16 years of age with any neurologic involvement consisted of only 3.6% of our whole NBS cohort of 728 cases (Uluduz et al., 2011). Despite the fact that neurologic involvement is not common in Behc¸et syndrome (BS), when it occurs it presents with numerous and different neurologic problems that are related either directly or indirectly to the disease (Siva and Saip, 2009) (Table 110.2). Cerebral venous sinus thrombosis (CVT), central nervous system (CNS) parenchymal involvement secondary to vascular inflammation, the neuro-psycho-Behc¸et variant, in which an organic Table 110.2 The neurologic spectrum of Behc¸et syndrome* Primary neurologic involvement (neurologic involvement directly related to BS) ● ● ● ● ● ●

Cerebral venous sinus thrombosis (extra-axial NBS) Central nervous system involvement (intra-axial NBS) Neuro-psycho-Behc¸et syndrome Headache (migraine-like, nonstructural) Peripheral nervous system involvement Subclinical NBS

Secondary neurologic involvement (neurologic involvement indirectly related to BS) ● Neurologic complications secondary to systemic

involvement of BS (i.e., cerebral emboli from cardiac complications of BS, increased intracranial pressure secondary to superior vena cava syndrome) ● Neurologic complications related to BS treatments (i.e., CNS neurotoxicity with ciclosporin; peripheral neuropathy secondary to thalidomide or colchicine) ● Tension type headache and other somatoform neurologic symptoms related to psychogenic factors of having a chronic disease Coincidental – unrelated (non-BS) neurologic involvement ● Primary headaches and any other coincidental neurologic

problem *(Modified from Siva and Saip, 2009.) BS, Behc¸et syndrome; NBS: neuro-Behc¸et syndrome; CNS: central nervous system.

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psychotic syndrome is prominent, are considered direct effects. As all of them demonstrate neurologic manifestations which are considered to be signs and symptoms due to nervous system involvement in BS, they will be reviewed here as “neuro-Behc¸et syndrome” (NBS). Peripheral nervous system involvement is extremely rare, though neurophysiologic and histopathologic studies may demonstrate nonspecific findings in some patients without related symptoms. Neurologic complications of various BS treatments, neurologic complications secondary to systemic involvement of the disease, tension type headache, and depression are among indirect neuropsychiatric consequences of the disease. The suggested diagnostic criteria for NBS in a patient who fulfills the international diagnostic criteria for Behc¸et’s disease is the occurrence of neurologic symptoms not otherwise explained by any other known systemic or neurologic disease or treatment, and in whom objective abnormalities are detected either on neurologic examination, and/or with neuroimaging studies (MRI disclosing findings suggestive of NBS) and/or abnormal cerebrospinal fluid findings consistent with NBS (Siva and Saip, 2009) (Table 110.3). The two major forms of neurologic involvement in BS are central nervous system (CNS) parenchymal involvement and cerebral venous sinus thrombosis (CVST). Neurologic manifestations are clinically related commonly to brainstem and/or corticospinal tract syndromes in the former, and to increased intracranial pressure in the latter form. There is a tendency to designate only CNS parenchymal involvement as NBS, and include cerebral venous sinus thrombosis within the spectrum of so-called vasculo-Behc¸et (Serdaroglu et al., 1989; Table 110.3 Suggested diagnostic criteria for neuro-Behc¸et syndrome* A. Fulfilling the International Diagnostic Criteria for Behc¸et’s disease B. Onset of neurologic symptoms not otherwise explained by any other known systemic or neurologic disease or treatment C. Presence of at least one of the following: 1. Objective abnormalities on neurologic examination (clinical evidence) 2. Abnormal neuroimaging findings suggestive of NBS (imaging evidence) 3. Abnormal cerebrospinal fluid findings suggestive of NBS (laboratory evidence) 4. Abnormal neurophysiologic (electromyography or evoked potentials) studies consistent with the current neurologic symptoms (neurophysiologic evidence) *(Modified from Siva and Saip, 2009.)

Wechsler et al., 1992). However, as both have significant neurologic consequences and are neurologic diseases they will be identified as “intra-axial NBS” and “extraaxial NBS,” respectively, in this review. Clinical and neuroimaging evidence also confirm this subclassification of NBS. CNS-NBS or intra-axial NBS is due to small vessel disease and causes the focal or multifocal CNS involvement manifested in the majority of patients. The second form, CVST or extra-axial NBS, which is due to large vessel disease presenting with thrombosis of the major cerebral venous sinuses, has limited symptoms, a better neurologic prognosis and generally an uncomplicated outcome (Siva and Saip, 2009). These two types of involvement very rarely occur in the same individual, and presumably have a different pathogenesis. Many of the CNS-NBS patients with small vessel inflammation have a relapsing remitting course initially, with some ultimately developing a secondary progressive course later, and a few will have a progressive CNS dysfunction from the onset. In our series of patients with neurologic manifestations related to BS, the rates of intra-axial NBS and CVST were 75.6%, and 12.2% respectively, with the remainder having other, or indefinite diagnoses (Siva et al., 2001).

Extra-axial neuro-Behc¸et syndrome Cerebral venous sinus thrombosis is seen in 10–20% of BS patients in whom neurologic involvement occurs (Siva and Saip, 2009; Essaadouni et al., 2010). Thrombosis of the venous sinuses may cause increased intracranial pressure with severe headache, mental changes, and motor ocular cranial nerve palsies, but in some patients the only manifestation may be a moderate headache. It is well known that the clinical manifestations resulting from thrombosis of the intracranial venous system vary according to the site and rate of venous occlusion and its extent. Our experience suggests that the CVST in BS evolves relatively slowly, as in none of our patients have we observed a fulminating syndrome of violent headache, convulsions, paralysis and coma; CVST due to BS seems to have a different course when compared to those with other etiologies (Yesilot et al., 2009). But acute onset cases have been reported in whom seizures and focal neurologic signs occurred besides headache (Wechsler et al., 1992). Papilledema and sixth nerve paresis are the most common signs reported, and hemiparesis may develop in some (Wechsler et al., 1992; Akman-Demir et al., 1999; Kidd et al., 1999; Siva et al., 2001; Saadoun et al., 2009; Aguiar de Sousa et al., 2011). There is a tendency for CVST to occur earlier in the disease course compared to the parenchymal type of CNS disease and this difference is significant in male

NEURO-BEHC¸ET SYNDROME 1709 patients (Tunc et al., 2004). In the pediatric age group of the disease will be described. Many patients may never affected with BS, the neurologic involvement is mostly have consulted a physician because of the mild nature of in the form of CVST (Uluduz et al., 2011). Any of the their systemic symptoms, or diagnosis may be missed sinuses may be affected, but the superior sagittal sinus because a full-blown picture of the disease has not been is the most commonly thrombosed, with a substantial reported. As mentioned above, it is uncommon to see number of these patients also disclosing lateral sinus NBS cases without oral ulcers. The MRI findings of the thrombosis. Intracranial hypertension without any disease are almost pathognomonic, and this will further demonstrable neuroimaging abnormality has been support the diagnosis (Koc¸er et al., 1999). However, it reported, with some of these patients developing neuroshould be kept in mind that parenchymal NBS (intra-axial imaging findings consistent with CVST in further NBS) does not always present with corticospinal tract and attacks later (Akman-Demir et al., 1996). brainstem signs and symptoms. Cognitive-behavioral Parenchymal CNS involvement in BS patients with changes, emotional lability, a self-limited or progressive CVST is unlikely. The extension of the clot into the ceremyelopathy, urinary sphincter dysfunction, and to a lesser bral veins causing focal venous hemorrhagic infarction is extent other CNS manifestations, such as extrapyramidal uncommon, and also the occurrence of CVST with prisigns and seizures, have been reported (Bussone et al., mary CNS involvement (coexistence of intra- and extra1982; Bogdanova et al., 1998; Cetinel et al., 1998; axial NBS) is extremely rare (Saadoun et al., 2009; Siva Akman-Demir et al., 1999; Oktem-Tanor et al., 1999; and Saip, 2009; Yesilot et al., 2009; Aguiar de Sousa Aykutlu et al., 2002; Karandreas et al., 2007; Yesilot et al., 2011). We have also observed that CVST in BS is et al., 2009). There are also a few cases reported with isostrongly associated with systemic major vessel disease, lated optic neuritis or recurrent peripheral facial paresis and tends to occur earlier in the disease course compared (Kansu et al., 1989; Hatzitolios et al., 2008), but optic neuwith the parenchymal-CNS type of neurologic involveritis is extremely rare in BS, and most visual symptoms in ment (Tunc et al., 2004), confirming some other studies BS are due to ocular involvement. (Wechsler et al., 1992; Houman et al., 2002). We believe Isolated progressive ataxia with cerebellar atrophy that these observations also support the notion that the on MRI have been reported in a few patients with BS two major forms of neurologic disease (intra- and and it was suggested that this form of presentation extra-axial involvement) in BS might have different pathmay be a novel manifestation of NBS (Gardner and ogenic mechanisms. It is also well established that neuroSchmahmann, 2008; Taskapilioglu et al., 2009). Howlogic disease in the form of CVST has a better neurologic ever, since the relationship between the neurologic preprognosis than CNS-parenchymal involvement (Siva and sentation and BS was not clear in those cases and Saip, 2009; Yesilot et al., 2009; Aguiar de Sousa et al., comorbidity could not be ruled out, further observation 2011). However, considering the fact that patients with is needed before such a conclusion may be reached. major vessel disease have a higher rate of morbidity Aseptic meningitis was reported previously to be a and mortality, a diagnosis of CVST in a patient with BS relatively frequent form of neurologic involvement in may not always be associated with a favorable outcome. patients with BS, which was based on normal CT scans used as the primary imaging modality (Serdaroglu et al., 1989). Our experience has been otherwise Intra-axial neuro-Behc¸et syndrome (Akman-Demir et al., 1999; Siva et al., 2001), and we susThe most common form of presentation of intra-axial pect that in some patients, parenchymal disease was misNBS is the onset of a subacute brainstem syndrome that classified as aseptic meningitis due to lack of sensitive includes ophthalmoparesis and other cranial nerve findimaging data. Similarly, in another study of 50 patients ings, dysarthria as well as unilateral or bilateral corticospfrom the UK (Kidd et al., 1999), four cases were reported inal tract signs with or without weakness and ataxia. The to have meningitis symptoms, while two of these patients presentation may include all or some of these symptoms had parenchymal lesions and two had normal MRI. and signs, and during the acute stage a mild confusion There was no discussion of meningeal enhancement may also be seen. The patient most commonly is a young and the CSF findings were within the same range as with man, and if he is also of Mediterranean (or Middle patients who had brainstem parenchymal involvement. Eastern, or oriental) origin the probability of “NBS” In support of this, we have always observed inflammashould be included in the differential diagnosis. Such a tory findings in CSF together with parenchymal disease patient (or, if a reliable history cannot be obtained from in MRI. Taken together, we conclude that pure aseptic the patient, family member/s) needs to be interviewed meningitis is very rare within the clinical spectrum of for the presence of systemic findings of BS. In the case neurologic involvement in BS. of BS, it is very likely that a past or present history of oral Japanese authors have a tendency to classify NBS into aphthous ulcers and some other systemic manifestations acute and chronic progressive forms. They define acute

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NBS manifested by an acute CNS syndrome, which responds well to corticosteroids and is usually selflimiting with some continuing to have further attacks, whereas chronic progressive NBS is characterized by slowly progressive neurobehavioral changes and ataxia, along with persistent marked elevation of CSF IL-6 (Hirohata et al., 1997; Ideguchi et al., 2010). However, these are terms consistent with the course of neurologic disease, rather than implying two different types of neurologic involvement. Most large series and recent review articles on neurologic involvement in BS, as already mentioned, have clearly shown that the involvement and the course of CNS parenchymal involvement may indeed be limited to a single attack, or may show relapses with a subgroup showing secondary progression, and finally, in some it may be (primarily) progressive from onset, hence being chronic progressive NBS (Al-Araji and Kidd, 2009; Siva and Saip, 2009).

Arterial neuro-Behc¸et syndrome Arterial involvement resulting in CNS vascular disease is rare, consistent with the systemic arterial involvement which is also infrequent in BS. Observations in cases with bilateral internal carotid artery occlusion, vertebral artery thrombosis, vertebral artery dissection, intracranial aneurysms and intracranial arteritis with their corresponding neurologic consequences (Al-Araji and Kidd, 2009; Siva and Saip, 2009) suggested that arterial involvement may be a subgroup of NBS (Siva et al., 2004). Intracranial hemorrhages may occur but are extremely rare, with most arising within parenchymal lesions (Kocer et al., 1999; Kikuchi et al., 2002). It is noteworthy that the arterial involvement affects mostly large arteries located at the extracerebral sites of the craniocervical arterial tree, suggesting that an extraaxial arterial pattern of NBS may exist, as well as an intra-axial arterial NBS pattern related to intracranial arteritis and intra-axial small arterial occlusions (Siva and Saip, 2009). An analogy with the patterns of venous involvement seen in NBS may be made, but whether this subdivision has any pathognomonic or other meaning, currently is not known.

Neuro-psycho-Behc¸et syndrome Some patients with BS develop a neurobehavioral syndrome which consists of euphoria, loss of insight/disinhibition, indifference to their disease, psychomotor agitation or retardation, with paranoid attitudes and obsessive concerns. We have observed the development of these psychiatric symptoms either at the onset of other neurologic symptoms of NBS, or independently. They were not associated with glucocorticosteroid or any other therapy. We have named this syndrome

“neuro-psycho-Behc¸et syndrome” (Siva et al., 1986). A similar personality change was observed by others as well (Oktem-Tanor et al., 1999).

Cognitive changes observed in patients with Behc¸et syndrome In a prospective neuropsychological study of 12 patients with neuro-Behc¸et disease (NBS), memory impairment was the major finding (Oktem-Tanor et al., 1999). The most severely affected memory process was delayed recall, being impaired in all of the patients in the verbal and/or visual modalities. An impairment in the process of acquisition and storage, attention deficit, and deficits of executive functions of frontal system were other cognitive functions involved. Neuropsychological status deteriorated insidiously, regardless of the neurologic attacks during the follow-up period in most of the patients, and the presence of cognitive decline was not directly related to detectable lesions on neuroimaging at early stages of the disease. However, an enlargement of the third ventricle and atrophy of the posterior fossa structures were observed in the late stages of the disease, which was correlated with memory loss. When NBS patients were compared with patients with multiple sclerosis, another disorder associated with “subcortical dementia,” NBS patients showed significantly worse performance in frontal executive functions and behavioral tests (Gunduz et al., 2012). In a recent work, 53% of NBS patients and 40% of BS patients were found to have impairment in at least one neuropsychological measure, with attention and shortterm retention capacities particularly being affected (Cavaco et al., 2009). The results were suggestive that cognitive abilities may be affected in the absence of overt neurologic symptoms in BS.

Headache in Behc¸et syndrome Headache is the most common neurologic symptom seen in patients with BS and may be due to different causes (Table 110.4). It can occur as the presenting symptom Table 110.4 Differential diagnosis of “headache” in patients with Behc¸et syndrome* ● Headache due to cerebral venous sinus thrombosis ● Headache due to central nervous system parenchymal

involvement ● Headache in association with ocular inflammation ● The nonstructural headache of Behc¸et syndrome ● Coexisting primary headaches (i.e., migraine; tension type

headache) *(Modified from Siva and Saip, 2009.)

NEURO-BEHC¸ET SYNDROME 1711 of NBS either due to CNS involvement or CVST. It can also electrophysiological findings consistent with mononeurbe seen in association with ocular inflammation (Siva et al., itis multiplex, a peripheral neuropathy prominent in the 2004; Saip et al., 2005). In several studies on headache in lower extremities, and polyradiculoneuritis, a sensoriBS, the most common type of headache was reported to be motor axonal neuropathy and an axonal sensory neuropmigraine (Monastero et al., 2003; Aykutlu et al., 2006; athy with recurrent episodes of myositis (Namer et al., Kidd, 2006; Haghighi et al., 2008). However, when BS 1987; Takeuchi et al., 1989; Atasoy et al., 2007). Isolated patients with headache are studied in detail, it will be found muscle involvement with focal or generalized myositis that some report a bilateral, frontal, moderate paroxysmal has been reported but these are extremely rare migraine-like pain, which is not true idiopathic migraine, (Serdaroglu, 1998; Sarui et al., 2002). since it generally starts after the onset of BS and comElectroneuromyographic studies disclosed demyelinmonly accompanies the exacerbations of systemic findation, chronic denervation, and even myogenic involveings of the disease, such as oral ulcerations or skin ment in the reported cases (Namer et al., 1987; Takeuchi lesions, though this is not always the rule (Saip et al., et al., 1989; Serdaroglu, 1998). However, electroneuro2005). It may be explained by a vascular headache trigmyographic studies may disclose a subclinical neuropagered by the immunomediated disease activity in suscepthy in patients who do not report symptoms suggestive tible individuals and may be seen in 3–18% of BS patients of neuropathy (Takeuchi et al., 1989; Akbulut et al., (Saip et al., 2005; Haghighi et al., 2008). This type of head2007; Atasoy et al., 2007). Besides, it should be kept in ache is not specific for migraine and similar headaches mind that the neuropathy may develop secondary to a have been described in some other systemic inflammatory various drugs used in the treatment of BS, such as disorders such as systemic lupus erythematosus thalidomide or colchicine, or may be coincidental. (Mitsikostas et al., 2004). According to the 2004 International Headache Society classification (Headache Subclinical neuro-Behc¸et syndrome Classification Subcommittee of the International The incidental finding of neurologic signs in patients Headache Society, 2004), this type of headache will be conwith BS without neurologic symptoms was reported in sistent with the subdigit (7.3.3), “headache attributed to other noninfectious inflammatory diseases” of “headache some series, with a minority of these patients developing attributed to nonvascular intracranial disorders (7)” and mild neurologic attacks later (Akman-Demir et al., 1999; neurologically it may not have any significant impact in Al-Araji et al., 2003). In another study looking at silent most patients. However, a substantial number of patients neurologic involvement in BS, the authors also conwith BS may report a severe headache of recent onset withcluded that this group of patients represent a milder out any neurologic deficit and not consistent with any form of the disease, since the mortality and disability rate was found to be significantly low when they were coexisting primary headache or ocular inflammatory pain. followed prospectively (Yesilot et al., 2006). Cognitive These patients require further evaluation and follow-up even if they do not have neurologic signs, as such a sympdysfunction that can be shown only by appropriate testtom may indicate the early onset of NBS (Siva et al., 2001; ing is also suggestive of silent neurologic involvement Aykutlu et al., 2006; Kale et al., 2009). Finally coexisting (Cavaco et al., 2009). primary headaches such as migraine and tension type Subclinical CNS involvement was also detected by headache in patients with BS also are seen. MRI, brain perfusion MRI and in SPECT studies (Watanabe et al., 1995; Avci et al., 1998; Shimojo et al., 1998; Tunc et al., 2006; Alkan et al., 2012), but these Peripheral nervous system involvement reports are limited in the number of patients studied, in Behc¸et syndrome the findings being unspecific, and that no follow-up Peripheral nervous system (PNS) involvement with clininformation is available, and so whether such findings ical manifestations is extremely rare in BS, an observahave any significance remains unclear. tion that was reported almost universally (Akman-Demir Brainstem auditory and somatosensory evoked et al., 1999; Siva et al., 2001; Ben Taarit et al., 2002; Alpotentials, and transcranial magnetic stimulation were Araji and Kidd, 2009; Siva and Saip, 2009; Essaadouni studied in patients with intra-axial (CNS) NBS in several et al., 2010; Shahien and Bowirrat, 2010). However, in studies and showed a wide range of abnormality, mainly a small series of patients with BS in a Caribbean popudue to the involvement the basal parts of the brainstem lation from the French West Indies two of the seven and corticospinal tracts. The demonstration of subclinicases were reported to have PNS involvement cal involvement by detection of abnormal responses in (Lannuzel et al., 2002). The limited number of BS examined areas without corresponding clinical symppatients, including the Caribbean cases, who have been toms and signs in some of these patients is noteworthy reported with PNS involvement had clinical and in providing information for the extent of the CNS

1712 S. SAIP ET AL. involvement. In another study subclinical involvement with diencephalic and brainstem lesions. A frequent was investigated by using P300 in Behc¸et’s patients withfinding is the resolution or the decrease in the size of out neurologic manifestations (Kececi and Akyol, the lesions, when follow-up imaging studies are available 2001).). The findings suggested that the P300 measures (Koc¸er et al.,1999; Akman-Demir et al., 2003; Siva and and motor response time may reflect subclinical neuroSaip, 2009). Such studies may also disclose the appearlogic involvement in BS. ance of new “silent” lesions without corresponding clinElectroneuromyographic studies, as already menical symptoms and signs. In a recent limited series of tioned, have also shown a subclinical neuropathy in some patients with intra-axial NBS, who were followed by patients who do not report symptoms suggestive of neuMRI over a mean 29.2 months with either a relapsing ropathy, and also silent muscle involvement was reported remitting or progressive CNS disease, a significant in patients without overt muscle involvement who were increase in the number of lesions and MRI burden based studied with electron microscopy (Serdaroglu, 1998). on the volume of lesions particularly in the relapsing Autonomic nervous system involvement was also reported cases and evolution of black holes and brainstem atrophy in asymptomatic patients with BS (Karatas et al., 2002). particularly in patients with progressive course were The detection of abnormalities on neurophysiologic observed (Borhani Haghighi et al., 2011). These findings studies, as well as by neuroimaging in asymptomatic observed on serial MRIs of NBS patients are suggestive patients, further suggests that the subgroup of patients of an ongoing pathologic process. Similarly, in an earlier with subclinical CNS and PNS involvement may not be so study in patients with a progressive course after an initial uncommon. However, the clinical and prognostic value attack the development of isolated brainstem atrophy of detecting abnormalities in such diagnostic studies in and third ventricle enlargement was reported (Akmanthis subgroup of patients with BS currently is not clear. Demir et al., 2003). Recently, diffusion MRI and proton magnetic resonance spectroscopy findings were reported in a number Secondary neurologic involvement of patients with acute intra-axial-NBS (Kang et al., 2001; Neurologic complications secondary to systemic Hiwatashi et al., 2003; Sener, 2003). The authors coninvolvement of Behc¸et disease, such as cerebral emboli cluded that their findings were suggestive of vasogenic from cardiac complications of Behc¸et disease or edema rather than true infarction of the lesions seen durincreased intracranial pressure secondary to superior ing the acute phase of the disease. These observations vena cava syndrome, are indirect neurologic problems further confirm the inflammatory nature of CNS lesions seen in Behc¸et disease. CNS neurotoxicity with ciclosin NBS. porin and peripheral neuropathy secondary to thalidoThere are also a number of reports of NBS cases mide or colchicine use are among other neurologic where MRI images showed mass lesions that mimicked complications related to Behc¸et disease treatments. brain tumors, some necessitating histological diagnosis (Park et al., 2002; Matsuo et al., 2005; Schmolck, DIAGNOSTIC STUDIES IN 2005; Heo et al., 2008). Despite the fact that the inflamNEURO-BEHC° ET SYNDROME matory nature of these lesions could not be confirmed in all cases, they are likely to be acute inflammatory edemNeuroimaging atous lesions that following intravenous methylprednisCranial magnetic resonance imaging (MRI) is both more olone (IVMP) show significant resolution. In a recent specific and more sensitive than computed tomography series of NBS patients with pseudotumoural NBS based (CT) in showing the reversible inflammatory parenchyon personal and collected cases from the literature, the mal lesions of intra-axial NBS. Lesions are generally authors reported that such patients who present with located within the brainstem, occasionally extending to large tumefactive lesions on their MRIs are more likely the diencephalon, and less often, within the periventricuto have severe initial and longterm disability when comlar and subcortical white matter (Koc¸er et al., 1999). pared with patients with what they have named as “clas(Figs 110.1 and 110.2) sical NBD” (Noel et al., 2012). However, initial treatment The most commonly affected region is the mesodienresponses were not different than expected and the cephalic junction, followed by the pontobulbar region unclear definition of tumefactive lesions, the retrospec(Koc¸er et al., 1999; Akman-Demir et al., 1999). Most tive nature, and well known heterogeneity of the NBS as patients who do have mesodiencephalic junction lesions well as of the included cases necessitates confirmation also show an upward extension involving the dienceof these results. phalic structures and basal ganglia and/or a downward We have studied lesion characteristics in parenchymal extension. Hemispheric lesions are not common and NBS using susceptibility-weighted imaging (SWI) when they are present they are almost always associated (Albayram et al., 2011). The proportion of lesion

NEURO-BEHC¸ET SYNDROME detection in SWI was significantly larger than that with conventional T2*GE. Most of the lesions in intra-axial NBS were found to be hemorrhagic with SWI, supporting the proposed venous theory in pathology. Additionally, in the lesion neighborhood, prominent venous

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structures, as well as the occlusion of venous and collateral venous structures, were also revealed with SWI. In a recent study, brain perfusion MRI (pMRI) was reported to disclose more brain abnormalities than conventional MRI in patients with BS who have both neurologic

Fig. 110.1. (A, B, C) A 30-year-old male patient with known Behc¸et syndrome presenting with a subacute brainstem syndrome and right hemiparesis. Axial T2-weighted MR images showing an inflammatory pontine lesion involving lower part of the midbrain and extending upwards bilaterally. The lesion is nonhomogenous and suggestive of an inflammatory nature. (D) Coronal T2 images of the same patient showing the pontine–midbrain lesion extending upwards on both sides. Continued

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Fig. 101.1—cont’d the lesion.

S. SAIP ET AL.

(E) Gadolinium enhancement within

involvement and also in patients without overt clinical neurologic symptoms and signs (Alkan et al., 2012). The authors concluded that detection of signs of hypoperfusion in different brain regions by pMRI indicated that that subclinical vascular and neuronal dysfunction in BS is more widespread than clinically expected. Spinal cord involvement is not common, but can be seen. In reported cases, the major site to be involved was the cervical spinal cord with the myelitis-like inflammatory lesions continuing more than two segments, and extending to the brainstem in some (Kocer et al., 1999; Green and Mitchell, 2000). Single or multiple cervical and/or dorsal lesions on spinal MRIs, lesions smaller than the length of one vertebral body, resolution of these lesions, spinal cord atrophy, and gadolinium enhancement have all been reported in earlier studies and also in a recent larger series (Yesilot et al., 2007). Recently we have observed a young man who had three successive attacks of myelitis. He had a longitudinally extensive cord lesion with gadolinium. He initially responded clinically to steroid therapy, with less improvement on his

Fig. 110.2. (A, B) Axial T2-weighted MR images of a neuro-Behcet patient. An inflammatory lesion in the left mesodiencephalic region extending to both deep hemispheric structures, more prominent on the left is seen.

NEURO-BEHC¸ET SYNDROME imaging studies. The third attack in which there was further spinal cord involvement with heterogenous gadolinium enhancement left him almost paraplegic despite treatment. His NMO-IGg was negative, but this case seems to be consistent with the so-called NMO spectrum, a recurrent longitudinally extensive myelitis associated with systemic vascular inflammatory disease. We have observed two patients with optic neuropathy, with one showing an enhancing isolated optic nerve lesion. So far no antiaquaporin antibodies have been reported either in these optico/spinal cases or in other NBS patients. MR venography, which includes both the intra- and extracranial venous system, is the preferred study to diagnose or confirm CVST in BS, but most of the time T1- and T2-weighted MR-images also disclose the venous sinus thrombosis. With the exception of two cases, we have not observed hemorrhagic venous infarcts or other parenchymal CNS lesions on MRI in our patients with CVST/extra-axial NBS (Siva et al., 2001; Yesilot et al., 2009), and others also reported a similar observation or a low rate of such changes in their patients (Saadoun et al., 2009). This finding, together with the clinical findings already mentioned above, suggests that the cerebral venous sinus thrombosis in BS may not be acute and complete in a significant number of cases. Cerebral or spinal arteriography may serve to demonstrate vasculitis, dissection, or aneurysms, and have also been used to monitor treatment effects in patients with vasculitic involvement (Krespi et al., 2001). However, the probability of detecting a significant finding in the cerebral arteriography is low, as in most cases with CNS parenchymal disease the vascular involvement is most prominent in the postcapillary venules. Therefore it is our impression that cerebral arteriography is not a priority in NBS, as well as in cases with extracerebral vascular involvement. It should be kept in mind that not only a neutrophilic infiltration with arterial injury may occur at the site of arteriographic puncture in patients with BS, but that there may be more unfortunate consequences related to this procedure. Indeed, fatal rebleeding during the arterial injection of the contrast medium was reported in a Behc¸et’s patient with basilar artery aneurysm (Aktas et al., 2008). Since patients with BS have vascular inflammatory changes that may increase the rebleeding tendency of the aneurysm, the authors suggested that once an intracranial aneurysm is suspected or detected by noninvasive studies, further investigation of the aneurysm may be done by multislice computed tomography, which is known to be a sensitive diagnostic tool.

SPECT studies in Behc¸et syndrome SPECT studies disclosed areas of hypoperfusion localized in the deep basal ganglia and in the frontal and

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temporal lobes in a group of BS patients with neuropsychiatric manifestations (Huang et al., 2002; Nobili et al., 2002). MRI was normal in some of them and these nonspecific SPECT findings, which were consistent with multiple hypoperfusion areas that correlated with decreased metabolic demand, were interpreted as indicative of early functional changes in the brains of this patient population.

Cerebrospinal fluid If performed during the acute stage, cerebrospinal fluid (CSF) studies usually show inflammatory changes in most cases of NBS with parenchymal involvement (Akman-Demir et al., 1999; Kidd et al., 1999). An increased number of cells, up to 100 and sometimes more per mm3, and modestly elevated protein levels are expected in most intra-axial-NBS patients. When lumbar puncture is performed in the acute stage the increased cells are likely to show a neutrophilic predominance, but this is not the rule, and a lymphocytic prominence may also be seen. However, in later stages as cells decrease the lymphocytosis is almost always the prominent cell type. Oligoclonal bands can be detected, but this will be an infrequent finding and is seen in less than 20% of NBS cases (Akman-Demir et al., 1999; Siva et al., 2001). Elevated concentrations of IL-6 in the CSF of patients with both acute and chronic progressive NBS in relation to disease activity have also been reported (Hirohata et al., 1997; Akman-Demir et al., 2008a). CSF in patients with CSVT will be under increased pressure, but the cellular and chemical composition is usually normal (Siva et al., 2001).

DIFFERENTIAL DIAGNOSIS Differential diagnosis of intra-axial (parenchymal) neuro-Behc¸et syndrome The major diseases to be included in the differential diagnosis of parenchymal NBS are shown in Table 110.5. Patients with NBS are young and frequently present with an acute or subacute brainstem syndrome or hemiparesis, as well as with other various neurologic manifestations. Hence, the possibility of BS is often included in the differential diagnosis of multiple sclerosis and in the stroke of the young adult, especially in the absence of its known systemic symptoms and signs. Multiple sclerosis is more common in women, whereas NBS is seen frequently in men. Onset age is about the same but optic neuritis, sensory symptoms and spinal cord involvement, which are common in MS, are rarely seen in NBS (Table 110.6). However, sometimes the clinical presentation of NBS may be confused with MS, but the neuroimaging-MRI findings are

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Table 110.5 The differential diagnosis of intra-axial (CNS) neuro-Behc¸et syndrome* ● ● ● ● ● ● ● ● ● ● ● ● ● ●

Multiple sclerosis Stroke in young adults Primary CNS vasculitis Secondary CNS vasculitis Neurosarcoidosis CNS tuberculosis Brainstem glioma Primary CNS lymphoma Vogt–Koyanagi–Harada syndrome Reiter syndrome Eales’ disease Cogan’s syndrome Susac syndrome Neuro-Sweet syndrome

*(Modified from Siva and Saip, 2009.) CNS, central nervous system.

clearly different. The pattern of brainstem involvement in NBS, which commonly extends to involve basal ganglia and diencephalic structures are not expected to be seen in MS. Furthermore, periventricular, corpus callosum, and ovoid lesions suggestive of MS are unlikely to be seen in NBS, and when hemispheric white matter lesions are present in NBS they are more likely to be hemispheric or subcortical than periventricular, and these are almost always associated with the brainstemdiencephalic lesions (Kocer et al., 1999). Brainstem lesions in MS are usually small even in the acute stage, and prominent brainstem and cerebellar atrophy without cerebral volume loss that is seen in the chronic phase of

NBS is unusual in MS (Miller et al., 1987; Morrissey et al., 1993). When one considers spinal cord involvement, this rarely extends more than a few vertebral segments in MS, contrary to the more extensive lesions that were observed in the few cases of NBS (Siva and Saip, 2009). The CSF also reveals different patterns, with a more prominent pleocytosis and low rate of positivity for oligoclonal bands in NBS. An acute stroke-like onset is not common in NBS, and MRI lesions compatible with classic arterial territories are also not expected. The absence of systemic symptoms and signs will serve to differentiate the primary CNS vasculitic disorders from NBS, and the difference in the systemic symptoms and signs from the secondary CNS vasculitides, as well as the MRI findings. In primary CNS vasculitis cerebral angiography was reported to be abnormal in up to 90% of patients and MRI had shown multiple infarcts that mostly involved cortical areas as well (Salvarani et al., 2007), both unusual for NBS. Sarcoidosis can also be confused with BS, due to uveitis, arthritis, and CNS involvement, but the absence of oral and genital ulcers, and the presence of peripheral lymphadenopathy, and bilateral hilar lymph nodes on chest X-ray, as well as pathologic examination of the noncaseating granulomatous lesions of sarcoidosis help in the differential diagnosis. In some patients with sarcoidosis, however, involvement of the nervous system may be the presenting and only manifestation of the disease (Patel et al., 2007). Cranial neuropathies with the seventh nerve are the most commonly involved; seizures, diabetes insipidus and other symptoms related to chronic meningitis and hydrocephalus as well as sarcoid

Table 110.6 The differential diagnosis of multiple sclerosis and intra-axial (CNS) neuro-Behc¸et syndrome*

Gender Symptoms at onset Common Uncommon MRI PV and SC lesions BS lesions Spinal cord lesions CSF Inflammatory changes OCB (þ)

Multiple sclerosis

CNS neuro-Behc¸et syndrome

Female > Male

Male > Female

ON; sensory; spinal cord; BS including INO; motor; cerebellar Headache

Headache; motor; cerebellar; BS excluding INO

(þþþ) small, discrete, extension () (þþ)

() large, diffuse, extension (þ) ()

() > 90%

(þþ) < 20%

ON; sensory; spinal cord;INO

*(Modified from Siva et al., 2004.) CNS, central nervous system; MRI, magnetic resonance imaging; CSF, cerebrospinal fluid; OCB, oligoclonal bands; ON, optic neuritis; BS, brainstem; INO, internuclear ophtalmoplegia; PV, periventricular; SC, subcortical.

NEURO-BEHC¸ET SYNDROME neuropathies and myopathies are among the nervous system manifestations of sarcoidosis (Park, 2008). These are not common in NBS, and MRI findings are unlikely to be confused between the two diseases. Tuberculosis may resemble BS because of its multisystem involvement and for its potential to affect the nervous system. However, hilar lymphadenopathy and pulmonary cavities are not seen in BS, whereas its mucocutaneous manifestations are unusual for tuberculosis. Furthermore CSF and MRI findings are different and microscopic and pathologic examination, as well as culture and PCR analysis of body fluids or tissue specimens, will help to identify the disease as tuberculosis. Brainstem glioma and primary CNS lymphoma may be included in the differential diagnosis of NBS in patients presenting with localized brainstem findings and whose initial MRI may disclose a large brainstem lesion, but the presence of systemic findings and the resolution of the MRI lesion following high-dose steroids will solve the problem at once. Due to their ophthalmologic and some other systemic manifestations, rare diseases such as Vogt–Koyanagi– Harada syndrome; Reiter syndrome; Eales’ disease; Cogan’s syndrome; and Susac syndrome are other considerations in the differential diagnosis of BS. All may present with nervous system manifestations and therefore are included in the differential diagnosis of NBS too. However, a complete ophthalmologic examination will reveal the true nature of eye involvement in each of these syndromes, which have differences from the eye involvement seen in BS. The Vogt–Koyanagi–Harada syndrome (VKH) is a bilateral, diffuse granulomatous uveitis associated with poliosis, vitiligo, alopecia, and central nervous system and auditory signs (Goodwin, 2010). Symptoms of meningeal irritation and occasional encephalopathy are most common in the prodromal phase of the illness and a CSF pleocytosis has been noted to be even more common than symptomatic meningitis, but it rarely causes significant focal neurologic disease. This inflammatory syndrome, which occurs more commonly among heavily pigmented populations such as Asians, Hispanics, Native Americans, and Indians is probably the result of an autoimmune mechanism, influenced by genetic factors, and appears to be directed against melanocytes. Ocular inflammation, arthritis, and urethritis are seen in Reiter syndrome, but conjunctivitis is more common than uveitis in this disease, and genital lesions are painless. Eales’ disease, a syndrome of retinal perivasculitis and recurrent intraocular hemorrhages, is infrequently associated with neurologic abnormalities (Atabay et al., 1992). Cogan’s syndrome (CS) is an idiopathic inflammatory disease in which the major symptoms are ocular and cochleovestibular. The eye inflammation consists of

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interstitial keratitis and uveitis, and inner ear inflammation will cause symptoms clinically indistinguishable from Me´nie`re’s disease. Almost three-quarters of the patients develop systemic manifestations, and a vasculitis involving large vessels, similar to Takayasu’s arteritis, or involving medium vessels, resembling periarteritis nodosa, may develop in 10–15% of the patients (Ramachandran et al., 2010). Nervous system involvement is not common, but when present the neurologic manifestations are wide and include headache, psychosis, stroke, cerebral sinus thrombosis, seizures, encephalopathy, myelopathy, cranial neuropathies, mononeuropathies, and polyneuropathy. Susac syndrome is an autoimmune endotheliopathy causing small infarcts in the retina, the cochlea, and the brain, resulting in the clinical triad of retinopathy, hearing loss, and encephalopathy (Susac et al., 2007). Gastrointestinal symptoms in BS may mimic Crohn’s disease or chronic ulcerative colitis. Eye disease is rare and genital ulcers are absent in inflammatory bowel diseases. The diagnosis can be confirmed by intestinal biopsy. Whipple disease may be briefly mentioned here as a disease with gastrointestinal and various nervous system symptoms which may resemble BS too. “Neuro-Sweet disease”(NSD) is the rare CNS involvement that is seen with Sweet disease (SD), which is an idiopathic multisystem inflammatory disorder characterized by peculiar erythematous skin lesions and fever that resembles BS. It may be difficult to differentiate it from BS, but the ocular signs seen in Sweet disease are episcleritis and conjunctivitis versus the uveitis in BS, and HLA-Cw1 and B54 association has been reported for SD compared with the high frequency of HLA-B51 in BS (Hisanaga et al., 2005; Hisanaga, 2007). In NSD any region of the CNS can be involved without site predilection, resulting in a variety of neurologic symptoms. The neurologic events may be recurrent but the prognosis is benign, as the disease is not a true vasculitis.

Differential diagnosis of extra-axial neuro-Behc¸et syndrome (CVST) In patients who present with symptoms of intracranial hypertension, and in whom neuroimaging reveals thrombosis in one or more of the cerebral venous sinuses, BS needs to be included in the differential diagnosis. The presence of its systemic findings is the only clue to the association of CVST with BS, and their absence will exclude this possibility. As already mentioned, hemorrhagic venous infarcts or other parenchymal lesions on MRI is not expected in patients with extra-axial NBS, and lumbar puncture will reveal elevated pressure, but otherwise a normal CSF.

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PROGNOSIS Neurologic involvement in BS is a remarkable cause of morbidity and approximately 50% of the NBS patients are moderately to severely disabled after 10 years of disease. We rated the neurologic disability of our patients with BS by using the Expended Disability Status Scale of Kurtzke (EDSS), which was originally devised for multiple sclerosis-associated disability. Taking into consideration that the visual disability is most commonly due to uveitis in BS, the visual function was eliminated from the original scale. By 10 years after the onset of neurologic symptoms and signs, 78.2% of our patients developed at least mild (EDSS  3), and 45.1% moderate to severe neurologic disability (EDSS  6) (Siva et al., 2001). An EDSS score of 3 represents full ambulation despite neurologic moderate disability on neurologic examination, and a score of 6 represents patients requiring assistance in walking such as one-sided support to walk for 100 meters, and during other activities of daily life. However, when patients were evaluated separately, all with CVST had EDSS scores of either 1 or 2 (minimal disability). Despite the fact that neurologic outcome is good in NBS patients with CVST, due to increased prevalence of systemic large vessel disease, the overall morbidity and mortality is significant in this group of patients (Tunc et al., 2004). Onset with cerebellar symptoms and a progressive course were unfavorable factors, while onset with headache, a diagnosis of CVST, and disease course limited to a single episode were favorable (Siva et al., 2001). An elevated protein level and pleocytosis in the CSF were also reported to be associated with a poorer prognosis (Akman-Demir et al., 1999). In studies with large cohorts of NBS, the mortality rates were reported to range between 5.5% and 11% (Akman-Demir et al., 1999; Siva et al., 2001), whereas in studies with BS in general, the mortality rate due to all causes went up to 9.8% when patients were followed for up to two decades, with the mortality rate due to neurologic involvement remaining around 12% of these patients (Kural-Seyahi et al., 2003; Saadoun et al., 2010). The patients who died were predominantly male and had a significantly higher frequency of vascular (mainly arterial) involvement and more severe disease requiring a higher frequency of corticosteroid and immunosuppressant use.

TREATMENT Neurologic involvement in BS is heterogeneous and it is difficult to predict its course and prognosis, and response to treatment. Therefore, it is not possible to reach a conclusion on the efficacy of any treatment

unless properly designed, double masked, placebo controlled studies are carried out for each type. However, this is difficult to accomplish, as even in large centers the yearly numbers of new neuro-cases are very limited. Most studies which report some kind of efficacy with various treatments in BS with neurologic involvement have not included uniform cases, have not followed their patients for long periods, and did not have controls. So, currently we have no evidence for the efficacy of any treatment for any form of NBS and empirical impressions and expert opinion statements are the guidelines for management (Hatemi et al., 2008; Akman-Demir et al., 2011). As in many chronic relapsing inflammatory disorders, the treatment options in NBS consist of relapse treatment, long term attack-preventing treatment, and symptomatic treatment. Moreover, management of the two major clinical forms of neurologic involvement of BS, i.e., parenchymal CNS involvement and dural venous sinus thrombosis, differ slightly as well.

Intra-axial neuro-Behc¸et syndrome: acute episodes Glucocorticoids are used to treat acute CNS involvement in BS, but their effects are short-lived and they do not prevent further attacks or progression. Acute attacks of intra-axial neuro-Behc¸et syndrome are treated with high-dose intravenous methylprednisolone (IVMP 1 g/day) for up to 10 days or by oral prednisolone (1 mg/kg for up to 4 weeks, or until improvement is observed). Both forms of treatment should be followed with an oral tapering dose of glucocorticoids over 2–3 months in order to prevent early relapses (AkmanDemir et al., 2011). There is no apparent difference between the two regimens, but our impression is that the high-dose IVMP regimen is associated with earlier improvement. Our current practice is to give IVMP, 1 g/day for 7–10 days, followed by the oral regimen in patients with clinical and imaging evidence of CNS involvement.

Intra-axial neuro-Behc¸et syndrome: long-term treatments After the attack treatment, long-term maintenance treatment with immunosuppressive agents should be considered in patients with parenchymal CNS involvement, since this form may follow a relapsing or secondary progressive course, and may result in significant physical and cognitive deficits leading to neurologic disability. The choice of treatment can partly be guided by the clinical controlled trials for the systemic findings of BS. There are a number of randomized controlled studies for systemic manifestations of BS. Colchicine was found to be effective in mucocutaneous symptoms,

NEURO-BEHC¸ET SYNDROME thalidomide was found to be effective in erythema nodosum-like skin lesions; azathioprine, ciclosporin, and more recently interferon-a and anti-TNF agents were shown to be effective in BS uveitis, and cyclophosphamide was shown to be effective in major vascular involvement (Akman-Demir et al., 2011). However, none of these agents, including chlorambucil and methotrexate, which was reported to show some efficacy in open trials, have been shown beneficial in NBS in a properly designed study. Furthermore, ciclosporin was reported to cause neurotoxicity or to accelerate the development of CNS symptoms and therefore its use in NB is not recommended (Kotake et al., 1999; Mitsui et al., 2005; Kotter et al., 2006; Akman-Demir et al., 2008b). A common clinical practice is to add an immunosuppresant drug such as azathioprine or monthly pulse cyclophosphamide to glucocorticoids in patients who present with a neurologic episode or who are diagnosed to have progressive NBS; however, the efficacy of such a combination has not been demonstrated. In a recent analysis based on a comparative retrospective-prospective observation on 351 consecutive patients with NBS, it was suggested that azathioprine may have a role in controlling the disease activity to a certain extent in NBS regardless of disease duration (Kurtuncu et al., 2008). Therefore, it seems that currently azathiopirine, although not evidence based, may be considered as a first-line preventive therapy in patients with NBS who experience relapses, together with initial high-dose steroid treatment followed by low-dose steroid maintenance therapy or on monthly pulses of IVMP for the first 6 months of treatment. In patients who cannot tolerate azathioprine, mycophenolate mofetil may be an option (Shugaiv et al., 2011); however, there is also no class 1 evidence regarding the potential effect of this drug in preventing CNS involvement or new neurologic attacks. The severity of the initial neurologic event, as well as the systemic manifestations of BS, influence treatment decisions, which should be made together with the patient’s treating rheumatologist. A growing number of case reports in recent years have suggested that anti-TNF agents may be an effective alternative in NBD (Pipitone et al., 2008; Akman-Demir et al., 2011). A recent multicenter observational study has supported these case reports and also suggested that infliximab may be somewhat effective in controlling relapses and progression in NBD if first-line immunotherapies fail (Al-Araji et al., 2010). However, the occurrence of neuro-relapses after stopping infliximab, formation of neutralizing antibodies, and the probability of increased CNS autoimmunity with monoclonal antiTNF-a antibody treatment should also be kept in mind. A panel of experts recently reviewed anti-TNF therapy in the management of BS and recommended that

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infliximab or etanercept could be used as an add-on therapy in BS that also includes CNS involvement for selected patients who are refractory or intolerant to traditional immunosuppressive regimens (Sfikakis et al., 2007). Tocilizumab, a humanized monoclonal antibody that inhibits IL-6 signaling, was suggested as a therapeutic alternative in severe NBS cases who are either refractory or develop side-effects to anti-TNF treatment and so far has been reported to be effective in two cases (Shapiro et al., 2012; Urbaniak et al., 2012). The use of interferon-a or b agents in NBS is more theoretical as the experience is limited to only a few case reports, and they may only be considered as an option for second-line treatment in patients who cannot receive anti-TNF-b antibody treatment (Akman-Demir et al., 2011). In theory, intravenous immunoglobulin (IVIg) would be expected to have a possible regulatory effect in the reported immunologic abnormalities of BS and its CNS involvement. However, in our limited experience with a few cases with progressive CNS involvement, we have not observed any significant improvement. Data on the use of plasma exchange in NBS are also limited and unclear. Cerebral aneurysms are rare in BS, but when small unruptured aneurysms are detected, medical therapy with steroids with or without cytotoxic agents may be tried. As an alternative to surgery, endovascular treatment is another option in the management of BSassociated intracranial aneurysms and this form of treatment is suggested for ruptured, peripherally located, fusiform-shaped dissecting pseudoaneurysms and posterior circulation aneurysms (Kizilkilic et al., 2003; Berard et al., 2010). Pretreatment with low-dose glucocorticoids can be recommended to prevent the so-called “vascular pathergy reaction,” as the puncture of arteries and veins in BS could be complicated by thrombosis and pseudoaneurysm formation.

Cerebral venous sinus thrombosis (CVST)/ extra-axial-neuro-Behc¸et syndrome CVST in BS is also treated with steroids since the clot formation in the veins is accepted to be caused by a low-grade endothelial inflammation rather than hypercoagulability. The addition of anticoagulation, including short-term fractionated heparin, to glucocorticoids is controversial, as these patients have a higher probability of harboring pulmonary or other aneurysms which may be associated with an increased risk of bleeding (Hatemi et al., 2008; Akman-Demir et al., 2011). Therefore the use of anticoagulation should be considered only after such possibilities are ruled out and in selected cases. However, it is noteworthy that in a recent systematic review and meta-analysis no evidence of increased bleeding was

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found in cases with CVST who were treated with anticoagulants (Aguiar de Sousa et al., 2011). Patients with CVST should be evaluated frequently, with detailed neuro-ophthalmic examination. Naturally, such an evaluation can only be carried out in the absence of ocular involvement due to BS. When the patients continue to report headache and visual symptoms, CSF analysis needs to be repeated at week 4 or earlier to measure the opening pressure: If this is found to be elevated, the oral glucocorticoid treatment should be continued until the patient improves and stabilizes in terms of clinical symptomatology, CSF pressure, and on neuroophthalmic examination. Recurrence of CVST, although uncommon, is possible after the initial episode (Yesilot et al., 2009); if recurrences happen, long-term treatment with azathioprine may be added.

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Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 111

Reversible cerebral vasoconstriction syndrome ANNE DUCROS* Department of Neurology, Hoˆpital Gui de Chauliac, Montpellier, France

HISTORY AND TERMINOLOGY Reversible cerebral vasoconstriction syndrome is a clinical-radiologic syndrome characterized by severe headaches with or without additional neurologic symptoms, and multifocal constriction of cerebral arteries, which resolves spontaneously in 1–3 months (Headache Classification Subcommittee of the International Headache Society, 2004; Calabrese et al., 2007). The most common clinical feature is recurrent thunderclap headache – a sudden excruciating headache that peaks in less than 1 minute – over 1–2 weeks (Chen et al., 2006a; Ducros et al., 2007). The major complications are ischemic or hemorrhagic parenchymal strokes (9–39%) (Singhal et al., 2002, 2011; Ducros et al., 2007, 2010; Chen et al., 2010). Reversible cerebral vasoconstriction syndrome (RCVS) is the name proposed in 2007 by Calabrese et al. to regroup all similar cases reported over the years under many different appellations (Table 111.1) (Calabrese et al., 2007). These various eponyms each reflected the associated clinical setting or the presumed pathophysiology, for example, migrainous “vasospasm” or “angiitis” (Serdaru et al., 1984; Jackson et al., 1993), thunderclap headache with reversible vasospasm (Day and Raskin, 1986; Slivka and Philbrook, 1995; Dodick et al., 1999), postpartum cerebral angiopathy, angiitis, or vasospasm (Bogousslavsky et al., 1989; Barinagarrementeria et al., 1992; Yasuda et al., 1993), drug-induced cerebral arteritis or angiopathy (Raroque et al., 1993; Ryu and Chien, 1995; Ryu and Lin, 1995), Call or Call–Fleming syndrome(Call et al., 1988), central nervous system (CNS) pseudovasculitis (Razavi et al., 1999), and benign angiopathy of the central nervous system (Rousseaux et al., 1983; Geraud and Fabre, 1984; Calabrese et al., 1993). Indeed, RCVS has long been viewed completely differently by the various concerned specialists, most likely due to its broad clinical and radiologic spectrum, ranging from purely

cephalalgic forms to catastrophic forms with multiple strokes causing permanent sequelae, and even death (Dodick et al., 1999; Singhal et al., 2002; Singhal, 2004a; Williams et al., 2007). Cerebral vasopasm was historically thought to be the major cause of stroke, until pathologic studies from the 1950s onwards demonstrated that cerebral infarcts were mainly caused by obstructive arterial lesions such as carotid atherosclerosis, lipohyalinosis. and cardioembolism. Thereafter, “vasospasm” was forgotten by stroke specialists except for those dealing with aneurysmal subarachnoid hemorrhage. Fisher first described the phenomenon of reversible segmental cerebral vasoconstriction in the early 1970s, in a paper reporting cases of postpartum women with transient neurologic dysfunction associated with reversible cerebral arterial irregularities (Fisher, 1971). Five other similar cases were reported in France (Millikan, 1975; Rascol et al., 1979) and the entity became known as “postpartum angiopathy.” Over the next decade, similar cases were documented in association with such diverse conditions as pregnancy (Bogousslavsky et al., 1989), migraine (Jackson et al., 1993), vasoconstrictive drugs and medications (Raroque et al., 1993), neurosurgical procedures (Suwanwela and Suwanwela, 1972), hypercalcemia (Yarnell and Caplan, 1986), and even unruptured saccular aneurysms (Day and Raskin, 1986). In the early 1980s, two small series of patients were reported in the French literature (Rousseaux et al., 1983; Michel et al., 1985). In the English litterature, the first large series of 19 patients was published in 1998 (Call et al., 1988) and some authors still refer to this syndrome as “Call’s or Call–Fleming syndrome” (Dodick, 2003; Nowak et al., 2003). Meanwhile, patients with RCVS were being misinterpreted as having primary angiitis of the central nervous system (PACNS), an inflammatory condition affecting

*Correspondence to: Anne Ducros, Urgences Ce´phale´es, Hoˆpital Lariboisie`re, 2 rue Ambroise Pare´, 75475 Paris, Cedex 10, France. Tel: þ33-1-49-95-65-37, Fax: þ33-1-49-95-24-81, E-mail: [email protected]

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Table 111.1 Various names used to describe the reversible cerebral vasoconstriction syndrome Isolated benign cerebral vasculitis or angiopathy Call or Call–Fleming syndrome Central nervous system pseudovasculitis Benign angiopathy of the central nervous system (BACNS) Postpartum angiopathy Postpartum angiitis Migrainous vasospasm Migraine angiitis Idiopathic thunderclap headache with reversible vasospam Drug-induced cerebral arteritis or angiopathy Fatal vasospasm in migrainous infarction

brain arteries, because of overlapping angiographic as well as clinical features such as headache, seizures, and stroke (Snyder and McClelland, 1978; Bettoni et al., 1984). Calabrese and colleagues recognized that these patients did not exhibit the typical severe and progressive course of PACNS; instead, their angiographic abnormalities reversed promptly and clinical resolution occurred within weeks, even without immunosuppressive therapy (Calabrese et al., 1993). They suspected a transient or mild form of PACNS, and the term “benign angiopathy of the central nervous system” (BACNS) was proposed. Calabrese’s group subsequently analyzed the clinical characteristics and longterm outcomes of BACNS, and concluded that it is consistent with RCVS (Hajj-Ali et al., 2002; Hajj-Ali and Calabrese, 2009). Some years later, patients with the pure cephalalgic form of RCVS were considered as having a variety of primary headaches – i.e., headaches spontaneously produced by the activation of cerebral/cranial pain circuits without an underlying lesion (Slivka and Philbrook, 1995; Dodick et al., 1999; Dodick, 2002; Liao et al., 2003; Lu et al., 2004; Chen et al., 2006a). Indeed, many patients with RCVS have isolated recurrent thunderclap headaches over 1–2 weeks and a benign course. An entity called “primary thunderclap headaches” was even introduced in the second version of the International Classification of Headache Disorders (Headache Classification Subcommittee of the International Headache Society, 2004). During the last 5–10 years, RCVS has been increasingly recognized as a distinct syndrome due to a transient and reversible disturbance of arterial tone regulation, without inflammation of the arteries, mainly characterized by severe headaches, which are secondary and symptomatic of the underlying vascular abnormality. The recent proposal and adoption of the broad term RCVS has encouraged retrospective and prospective studies that have helped to characterize RCVS (Ducros

et al., 2007, 2010; Chen et al., 2008, 2010; Singhal et al., 2011). The now routine use of relatively noninvasive angiographic techniques such as computed tomography angiography (CTA) and magnetic resonance angiography (MRA), combined with the widespread use of illicit drugs, and serotonergic and sympathomimetic medications, makes it likely that stroke neurologists and other specialists will encounter an increasing number of patients with this syndrome. However, the debate about RCVS is not extinguished. Indeed, recent studies confirmed the “historical” observation (Rousseaux et al., 1983) that hemorrhagic manifestations, such as cortical subarachnoid hemorrhage, intracerebral and subdural hematoma, were as least as frequent as ischemic infarcts in RCVS (Nighoghossian et al., 1998; Roh and Park, 1998; Ursell et al., 1998; Veyrac et al., 2001; Geocadin et al., 2002; Edlow et al., 2007; Moskowitz et al., 2007; Moustafa et al., 2008; Santos et al., 2009; Wong et al., 2009; Ducros et al., 2010) but some are still reluctant to attribute an intracranial hemorrhage to RCVS and rather consider the arterial narrowings as a consequence of hemorrhage.

ASSOCIATED CONDITIONS RCVS may be spontaneous (so-called idiopathic RCVS). In the remaining 25–60% of cases, RCVS occurs in peculiar settings or with associated conditions (secondary RCVS), mostly after exposure to vasoactive substances and/or in the postpartum state (Table 111.2) (Hajj-Ali et al., 2002; Calabrese et al., 2007; Ducros et al., 2007; Williams et al., 2007; Singhal et al., 2011). The incriminated substances include various medications such as selective serotonin reuptake inhibitors (Singhal et al., 2002; Noskin et al., 2006) and all a-sympathomimetics (Singhal, 2004a), often used as over-the-counter nasal decongestants (Ryu and Lin, 1995; Cantu et al., 2003), some diet pills and herbal medications (Worrall et al., 2005; Ichiki et al., 2008), and most illicit drugs (Martin et al., 1995), including cannabis (Alvaro et al., 2002; Koopman et al., 2008), which is the most frequent cause in France (Ducros et al., 2007) (Table 111.2). In some patients, RCVS occurs only after a few days of exposure, while in others, the syndrome occurs after several months of either regular or irregular exposure to one or several of these substances, at normal or excessive doses. Acute alcoholic intoxication may be an additional precipitating factor (Ducros et al., 2007). Postpartum RCVS starts in two-thirds of cases during the first week after delivery, usually after a normal pregnancy (Singhal, 2004b; Singhal and Bernstein, 2005; Williams et al., 2007). In 50–70% of the cases, it is associated with the intake of vasoconstrictors, mostly

REVERSIBLE CEREBRAL VASOCONSTRICTION SYNDROME Table 111.2 Causes of reversible cerebral vasoconstriction syndrome and associated conditions Postpartum With or without exposure to vasoactive substances, eclampsia/pre-eclampsia Exposure to vasoactive substances Cannabis, cocaine, ecstasy, amphetamines, LSD, binge drinking Selective serotonin reuptake inhibitor antidepressants (SSRIs) Nasal decongestants – phenylpropanolamine, pseudoephedrine, ephedrine Acute migraine medications – ergotamine tartrate, triptans Methergine Bromocriptine, lisuride Isometheptine Nicotine patches Ginseng Catecholamine-secreting tumors Pheochromocytoma, bronchial carcinoid tumor, glomus tumors Exposure to immunosuppressants or blood products Tacrolimus (FK-506), cyclophosphamide, erythropoietin, intravenous immunoglobulin, red blood cell transfusion, interferon-a Miscellaneous Hypercalcemia, porphyria, head trauma, subdural spinal hematoma, carotid endarterectomy, neurosurgical procedures, CSF hypotension Extra- or intracranial large artery disorders Cervical dissection, unruptured intracranial aneurysm, dysplasia

ergots – bromocriptine – used to treat postpartum hemorrhage or to inhibit lactation (Williams et al., 2007). Myriads of other causes have been reported, such as catecholamine-secreting tumors (Razavi et al., 1999), head trauma (Wilkins and Odom, 1970; Suwanwela and Suwanwela, 1972; Lee et al., 1997), neurosurgical procedures (Khodadad, 1973; Hyde-Rowan et al., 1983), carotid endarterectomy (Lopez-Valdes et al., 1997; Rosenbloom and Singhal, 2007), cerebrospinal fluid (CSF) hypotension (Schievink et al., 2007) and autonomic dysreflexia (Edvardsson and Persson, 2010) (Table 111.2). RCVS may also be associated with other extra- or intracranial arterial lesions such as cervical artery dissection (Singhal, 2004b; Ducros et al., 2007; Field et al., 2010; Mawet et al., 2013) especially in women with postpartum RCVS (Arnold et al., 2008), unruptured intracranial aneurysm (Day and Raskin, 1986; Ducros et al., 2007), and arterial dysplasia (Ducros et al., 2007). The mechanism of the link between these arterial abnormalities and the vasospastic process of RCVS is unknown.

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Overlap with the posterior reversible encephalopathy syndrome RCVS has also been reported in association with a neurotoxic state called the “posterior reversible encephalopathy syndrome” or PRES. This syndrome has similar clinical features to severe RCVS with acute headache, confusion, seizures, cortical blindness (Hinchey et al., 1996; Lee et al., 2008), but a characteristic MR imaging pattern with bilateral symmetric hemispheric boundary zones of high signal on FLAIR sequences affecting the cortex, and subcortical and deep white matter to varying degrees (Bartynski and Boardman, 2008). The vasogenic edema is usually totally reversible in a few days. However, infarction or cytotoxic edema may occur in areas of severe hypoperfusion (Chen et al., 2006b; Bartynski and Boardman, 2008). PRES is recognized as a complication of many conditions including pre-eclampsia/eclampsia, immunosuppression after transplantation, autoimmune disease, high-dose chemotherapy and septic shock (Bartynski et al., 2006; Bartynski et al., 2008; Lee et al., 2008). Like RCVS, the exact pathophysiology of PRES is unknown and two hypotheses are debated (Bartynski, 2008b). In the most popular one, severe arterial hypertension leads to a failure of cerebral autoregulation with subsequent hyperperfusion and vasogenic edema. In the emerging second hypothesis, T cell and/or endothelial cell activation may trigger cerebral vasoconstriction leading to hypoperfusion with subsequent brain ischemia and vasogenic edema. Whatever the pathophysiology, recent studies have shown that first, a reversible cerebral vasoconstriction is a frequent if not a constant feature of PRES; second, 20–30% of PRES cases are normotensive; and third, normotensive cases have vasogenic edema that is more extensive than hypertensive cases which suggests that hypertension may be a reaction to the increase in cerebral blood flow in some cases (Dodick et al., 2003; Chen et al., 2006b; Bartynski, 2008a, b). Besides the association of RCVS and PRES in the setting of severe conditions, it is important to appreciate that 10% of RCVS cases are associated with PRES regardless of the cause: idiopathic, secondary to a vasoactive substance or to the postpartum state, or associated with arterial dissection (Singhal, 2004b; Ducros et al., 2007).

CLINICAL FINDINGS Demographics RCVS has been reported in patients aged from 10 to 70 years (Kirton et al., 2006; Ducros et al., 2007; Liu et al., 2010). The mean age of onset is around 45 years with a female over male preponderance ranging from

1728 A. DUCROS 2 to 10:1 (Hajj-Ali et al., 2002; Ducros et al., 2007; one trigger factor: sexual activity with orgasmic or preorChen et al., 2010). gasmic headaches, straining, sudden emotion, exertion, The exact incidence is unknown. Cases have been coughing, sneezing, urinating without effort, bathing or documented from numerous countries from the five showering, and sudden bending down (Chen et al., continents (Barinagarrementeria et al., 1992; Modi and 2006a, 2010; Calabrese et al., 2007; Ducros et al., 2007, Modi, 2000; Ichiki et al., 2008; Bouchard et al., 2009; 2010). In some patients, all thunderclap headaches are Elstner et al., 2009; Garcin et al., 2009; Saini et al., triggered by one or several of these factors, while in other 2009; Field et al., 2010) and RCVS appears to affect indipatients, some thunderclap headaches occur at rest and viduals of all races. However, RCVS is probably still others after a trigger. Some patients have a single thunderunderdiagnosed, particularly the pure cephalalgic clap headache, but in most cases thunderclap headaches forms. Only three groups have published series including recur over the ensuing 1–3 weeks, with an average of four more than 10 patients. An American group published a recurrences (Ducros et al., 2007). retrospective series of 16 patients hospitalized for susSome patients describe acute headache attacks awakpected CNS angiitis, of whom 10 had a repeat angiograing them from sleep, a situation that does not allow them phy to assess reversibility of vasoconstriction (Hajj-Ali to be sure of the thunderclap onset. Rarely, the headache et al., 2002). This series was thereafter increased to 139 is more progressive and moderate. In the presence of latpatients retrospectively recruited from a stroke unit and eral or posterior neck pain, it is important to carefully an internal medicine department (Singhal et al., 2011). look for carotid or vertebral artery dissection (Ducros A Taiwanese group extensively studied RCVS first in a et al., 2007; Arnold et al., 2008; Mawet et al., 2013). prospective series of 56 patients with recurrent thunderclap headaches of whom 22 had proven initial vasoconFocal deficits and seizures striction (Chen et al., 2006a), then in a series of 77 patients with proven RCVS who were mainly recruited The frequency of other neurologic signs and symptoms depends on how the patients are recruited into the studies, through a headache centre for thunderclap headache is higher in retrospective in-patient series, and varies from (Chen et al., 2008, 2010). A French group (to which the author belongs) studied a prospective series of 67 cases, 9% to 63% for focal deficits, and for seizures from 0% to seen in a single institution between 2004 and 2007, who 21% (Hajj-Ali et al., 2002; Calabrese et al., 2007; Ducros all had an initial demonstration of the vasoconstriction et al., 2007, 2010; Chen et al., 2010; Singhal et al., 2011). and repeat angiography showing its resolution (Ducros Indeed, the presence of such features systematically leads et al., 2007). This series was subsequently completed to extensive investigations, whereas isolated headaches reaching 89 patients (Ducros et al., 2010), than patients are often misinterpreted as “benign” and not thoroughly explored (even though for a thunderclap headache a nor(Mawet et al., 2013). mal CT scan should be followed by a lumbar puncture to look for blood in the CSF followed often by imaging of the Headache cervical and cerebral arteries and the intracranial veins). Headache is often the only symptom, as in 75% of the Whereas generalized tonic-clonic seizures are reported French series (Ducros et al., 2007). The onset is typically in up to 20% of patients at the time of presentation, recurdramatic with a thunderclap headache, a “worst-ever” rent seizures are rare. Some transient focal deficits have a headache that reaches its peak intensity in less than sudden onset, such as transient ischemic attacks (TIAs), 1 minute, often within seconds. Multiple thunderclap while others begin progressively and successively over a headaches recurring every day or so over 1–4 weeks few minutes, with positive visual and/or sensory sympare almost pathognomonic (Chen et al., 2006a, 2008; toms, mimicking migraine aura (Ducros et al., 2007). Ducros et al., 2007). Persistent focal deficits reveal a stroke (cerebral infarcThe headache is typically bilateral, with a posterior tion or intracerebral hematoma) (Hajj-Ali et al., 2002; onset followed by a diffuse pain, with a severe to very Ducros et al., 2010; Singhal et al., 2011). Visual deficits severe intensity, sometimes excruciating, with agitation, are common, including scotoma, blurring, hemianopia, shouting and yelling, often associated with nausea, vomitand cortical blindness (full or partial Balint syndrome). ing, photophobia and phonophobia. Migraineurs clearly Hemiplegia, tremor, ataxia, and aphasia have also been identify the thunderclap headaches as different from their reported. Impairment of consciousness is infrequent usual headaches (Ducros et al., 2007). Severe pain usually and usually mild. Less than 5% develop progressive ceresubsides within 1–3 hours (but ranges from a few minutes bral arterial vasoconstriction culminating in multiple to several days) and 50–75% of patients describe a permamassive strokes, brain edema, severe morbidity, or death nent mild baseline headache between two thunderclap (Hyde-Rowan et al., 1983; Geraghty et al., 1991; Marshall exacerbations. About 80% of patients report at least et al., 2007; Williams et al., 2007; Singhal et al., 2011).

REVERSIBLE CEREBRAL VASOCONSTRICTION SYNDROME

General examination The general physical examination is usually normal, except in complex conditions combining RCVS and PRES in the setting of eclampsia, septic shock, immunosuppression, and so forth. About 25–30% of the patients have blood pressure surges (Ducros et al., 2007) during the thunderclap headaches, whether from the pain, the disease itself, or the associated condition (e.g., eclampsia), and some patients also have a facial flush.

Diagnosis criteria A RCVS must be suspected in all patients with thunderclap headache, with or without other neurologic symptoms, after the exclusion of all other causes (Tables 111.3 and 111.4) (Schwedt et al., 2006). With the actual diagnosis criteria, it is impossible to diagnose RCVS in the absence of headache. However, RCVS without headache or with very minimal headache does probably exist. We had a young woman with multiple infarcts and minimal headache, smoking cannabis, with a characteristic MRA and transcranial Doppler (TCD), and a control MRA and TCD showing normalization at 2 months, and no other cause to better explain her illness. She is well now. Another middle-aged woman was seen in our institution with cortical subarachnoid hemorrhage (cSAH) and multiple cerebral hematomas, but minimal headaches. She had a huge diffuse segmental vasoconstriction on transfemoral angiography, which Table 111.3 Diagnostic criteria for RCVS adapted from the International Headache Society diagnosis criteria for “acute reversible cerebral angiopathy”* and the criteria proposed in 2007 by Calabrese et al.{ Acute and severe headache (often thunderclap headache) with or without focal neurological deficits or seizures Monophasic course without new symptoms more than 1 month after clinical onset Segmental vasoconstriction of cerebral arteries demonstrated by angiography (MRA, CTA, or catheter) Exclusion of subarachnoid hemorrhage due to a ruptured aneurysm Normal or near normal CSF (protein < 1 g/L, white cells < 15 per mm3, normal glucose) Complete or marked normalization of arteries demonstrated by a repeat angiogram (MRA, CTA or catheter) performed at 12 weeks of clinical onset, although they may be normal earlier *(Headache Classification Subcommittee of the International Headache Society, 2004) { (Calabrese et al., 2007)

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had completely resolved on the control angiogram at 2.5 months (A. Ducros, unpublished observation).

NATURAL HISTORY One of the main characteristics of RCVS is the temporal pattern of the different clinical features and the associated arterial abnormalities (Table 111.5) (Ducros et al., 2007). The first symptom is usually a thunderclap headache that recurs during the first week, with the last attack at a mean of 7–8 days after onset. Mild baseline headache may then persist in about three-quarters of the patients, and finally all significant headaches have gone by about 3 weeks (Ducros et al., 2007; Chen et al., 2008, 2010). Any intracranial hemorrhages and PRES are early complications during the first week, while ischemic complications (TIA and infarction) occur later, at the end of the second week, sometimes when the headaches have improved or even resolved (Chen et al., 2006a, 2008, 2010; Ducros et al., 2007, 2010). RCVS has a monophasic course, generally without new symptoms after 1 month. In most patients, headaches and angiographic abnormalities completely resolve within days to weeks. The long-term prognosis is determined by the occurrence of stroke and seems to be more severe in hemorrhagic forms of RCVS in the French series (Ducros et al., 2010) and in ischemic forms of RCVS in the US series (Singhal et al., 2011), but overall, less than 10% of patients are left with residual deficits (Calabrese et al., 2007; Ducros et al., 2007; Chen et al., 2010). Progressive vasoconstriction resulting in progressive symptoms or death can occur in rare cases (Buckle et al., 1964; Hyde-Rowan et al., 1983; Geraghty et al., 1991; Marshall et al., 2007; Williams et al., 2007; Singhal et al., 2009). It should be noted that “reversibility” in the appellation RCVS refers to the dynamic and reversible nature of vasoconstriction; clinical deficits from brain damage might persist and the vasoconstriction (particularly if severe and prolonged) may not fully reverse in some rare patients. During the months following the acute phase, onethird of the patients report persistent headaches with either chronic tension-type headache or exacerbation of pre-existing migraine headaches, often associated with fatigue or depression. Some patients develop a kind of post-traumatic stress-like syndrome, and live in the fear of a recurrence of thunderclap headaches. Some patients who had orgasmic thunderclap headaches as the main clinical feature of RCVS may have eventual milder sexual headaches at one time or another during follow-up, without evidence of recurrence of visible vasoconstriction (A. Ducros, unpublished observation). Whereas these milder sexual headaches have the same underlying mechanisms as thunderclap headaches

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A. DUCROS

Table 111.4 Investigation of a thunderclap headache Causes of thunderclap headaches that may be detected by this investigation

Investigation

Indications

Noncontrast CT brain scan (with visualization of sinuses if clinical symptoms suggest acute sinusitis)

All thunderclap headaches as first investigation

CSF analysis

All CT normal thunderclap headache

ESR and CRP

Age > 60 years

EKG

Thunderclap headache triggered by exertion

Complete MRI (diffusion, FLAIR, gradient-echo, sagittal T1, T1 with gadolinium, cervical FAT/SAT) þ MRA þ MRV

All thunderclap headache after normal CT and normal or near normal CSF Fewer sequences if cervical and transcranial Doppler shows abnormalities suggesting dissection or an increase in intracranial flow velocities suggesting RCVS

Catheter angiography

Gold standard for subarachnoid hemorrhage In the absence of SAH, to be performed only in case of increasing headaches, occurrence/increase of focal deficits, unexplained after CT scan, CSF analysis and complete MRI/MRA/ MRV

during RCVS or are “true” primary sexual headaches is an unresolved issue. Recurrence of an “episode” of RCVS is possible (Ursell et al., 1998), but without long-term follow-up studies, the rate is unknown. In our French series of 67 patients followed for a mean of 3.2 years (range 26–62 months), we have so far not observed any angiographically proven recurrence. However, 3 years after a severe RCVS complicated by an occipital hemorrhage, one patient had a recurrence of multiple thunderclap

Subarachnoid hemorrhage (90% within the first 24 hours) Intracerebral hematoma Intraventricular hemorrhage Subdural hematoma (rare cause of thunderclap headache) Some infarcts particularly in the cerebellum Hydrocephalus Tumors Acute sinusitis Subarachnoid hemorrhage Meningitis Giant cell arteritis (very rare cause of thunderclap headache) Cardiac cephalalgia due to myocardial ischemia (very rare cause of thunderclap headache) Intracranial venous thrombosis Dissection of cervical arteries (extra- or intracranial, carotid or vertebral) Pituitary apoplexy RCVS Unruptured but symptomatic aneurysm Acute infarct from less than 3 hours not visualized on CT scan CSF hypotension Better visualization of all abnormalities previously seen on CT scan Ruptured aneurysm in 85% of patients with subarachnoid hemorrhage Intracranial venous thrombosis Dissection (cervical, intracranial) RCVS Differential diagnosis of cerebral arteritis Unruptured but symptomatic aneurysm (Painfull palsy of the third cranial nerve)

headaches over 1 week, after smoking cannabis. He did not seek medical advice and it was thus impossible to make a firm diagnosis. In another patient not included in our first case series, who had a proven RCVS, multiple sexual thunderclap headaches recurred 6 months later, 2 days after the intake of an SSRI. He did not seek medical attention but remembered our recommendation, stopped the antidepressant, and no more thunderclap headaches occurred. In 2008, we had a woman with a first episode of RCVS characterized by multiple

REVERSIBLE CEREBRAL VASOCONSTRICTION SYNDROME Table 111.5 Mean delay from headache onset to the other features of reversible cerebral vasoconstriction syndrome Delay from headache onset to:

Mean  SD (days)

Range (days)

Diagnosis of cerebral hematoma In patients with a focal deficit In patients without focal deficit Diagnosis of subarachnoid hemorrhage Diagnosis of subdural hemorrhage First seizure Posterior reversible encephalopathy syndrome Last recurrent thunderclap headache Transient neurologic deficit Diagnosis of cerebral infarction

2.2 2.5 1.1  1.7 4  2.9

0–8 0–4 3–8

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Mild cerebrospinal fluid (CSF) abnormalities are found in more than half the patients with an excess of white blood cells (5–35/mm3), and red blood cells with or without visible subarachnoid blood on MRI, and increased protein levels up to 1 g/L (Calabrese et al., 2007; Ducros et al., 2007; Singhal et al., 2011). If the lymphocytic reaction exceeds 10 cells per mm3, it is better to repeat the lumbar puncture after a few weeks to make sure it is normal and exclude chronic meningitis.

NEUROIMAGING INVESTIGATIONS 4.6  4.3

0–20

5.5  3.5

3–8

4  1.4 4  1.5

2–5 1–6

7.4  5.6

0–28

11.6  4.9

0–23

9  6.2

2–16

(Adapted from Ducros et al., 2007, 2010.)

thunderclap headaches triggered by strong exertion, with a cortical subarachnoid hemorrhage, and a fully reversible “string and beads” aspect on cerebral angiographies. One year after, she had a proven recurrence of RCVS with multiple thunderclap headaches, again triggered by strong exertion and a reversible diffuse segmental vasoconstriction (A. Ducros, unpublished observation).

LABORATORY INVESTIGATIONS Blood counts, erythrocyte sedimentation rate, serum electrolytes, and liver and renal function tests are usually normal. In patients with oropharyngeal infections who took nasal decongestants, blood tests may show a moderate and transient inflammatory response. Rheumatoid factor, antinuclear and antinuclear cytoplasmic antibody tests, Lyme titer, and urine vanillylmandelic acid and 5hydroxyindoleacetic acid levels, are useful to rule out vasculitis and evaluate for vasoactive tumors (e.g., pheochromocytoma, carcinoid) that have been associated with RCVS (Singhal, 2004a). Serum and urine toxicology screens, in addition to a careful medication history, are important to uncover exposure to vasoactive drugs and medications (cannabis, cocaine, amfetamines, ecstasy).

Brain computed tomography and magnetic resonance imaging Patients with RCVS typically present to the emergency department for evaluation of thunderclap headaches, and appropriately undergo urgent brain and vascular imaging to rule out secondary causes. Between 30% and 70% of patients ultimately diagnosed with RCVS show no parenchymal lesion on the initial head CT or brain MRI, despite having widespread vasoconstriction on concomitant cerebral angiography (Calabrese et al., 2007; Ducros et al., 2007; Ducros et al., 2010; Singhal et al., 2011). This wide range in the frequency of abnormal brain imaging findings reflects the wide clinical spectrum of RCVS. In the French patients with purely cephalalgic RCVS, MRI showed a cortical subarachnoid hemorrhage (cSAH) in 20% and features of PRES in 10%; and in patients that presented with a persistent focal deficit, MRI showed an infarct or hematoma in 100% (Ducros et al., 2010). If abnormal, brain imaging might show a variety of lesions on initial or on follow-up studies, including cortical surface (nonaneurysmal) subarachnoid hemorrhage, intracerebral hemorrhage, subdural hemorrhage, reversible brain edema (PRES), and ischemic stroke (Singhal, 2004a; Calabrese et al., 2007; Chen et al., 2010; Ducros et al., 2010; Singhal et al., 2011). Any combination of lesions can be present and different types of lesions may successively appear. Hemorrhagic complications and brain edema are usually diagnosed during the first week after clinical onset while ischemic events occur later during the second week after headache onset. Cortical subarachnoid hemorrhage (20–30% in the French series) is usually mild, unilateral or bilateral, visible as high signal on FLAIR in a few sulci near the convexity (Fig. 111.1) (Ursell et al., 1998; Hajj-Ali et al., 2002; Singhal, 2004b; Spitzer et al., 2005; Moustafa et al., 2008; Ducros et al., 2010; Singhal et al., 2011). Convexity subarachnoid hemorrhages account for about 7% of all spontaneous subarachnoid hemorrhages, and RCVS was suggested to be the most frequent cause of cortical subarachnoid hemorrhage in patients 60 years or younger whereas amyloid angiopathy was the most frequent cause in patients over 60 (Kumar et al., 2010). Focal

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A. DUCROS

Fig. 111.1. Cortical subarachnoid hemorrhage in reversible cerebral vasoconstriction syndrome. (A) CT brain scan showing a small right frontal hemorrhage. (B) In another patient with a normal CT scan, MRI (FLAIR) shows bilateral cortical subarachnoid hemorrhage with high signal in several sulci. (Reproduced from Ducros and Bousser, 2009.)

intracerebral hemorrhage (12% in the French series) may be single or multiple, cortical or deep, of variable volume (Fig. 111.2) (Rousseaux et al., 1983; Roh and Park, 1998; Geocadin et al., 2002; Doss-Esper et al., 2005; Moskowitz et al., 2007; Santos et al., 2009; Singhal et al., 2009; Ducros et al., 2010; Singhal et al., 2011). Subdural hemorrhage has also been reported. (Santos et al., 2009; Ducros et al., 2010). It appears that hemorrhages are more common in women, and in patients with a history of migraine. Interestingly, some patients with negative initial imaging go on to develop an intracranial hemorrhage after their second or third headache exacerbation, reflecting the dynamic nature of RCVS (Ducros et al., 2010). Cerebral infarction is reported as the most frequent complication in retrospective or inpatient series, affecting 39% of the cases in the series from the USA, but is found in only 6–8% in the French and Taiwanese large prospective series (Fig. 111.3) (Calabrese et al., 2007; Chen et al., 2010; Ducros et al., 2010; Singhal et al., 2011). Infarcts are often bilateral and symmetric, and located in arterial “watershed” regions of the cerebral hemispheres. Cerebellar infarcts are also possible. Smaller infarcts are typically located in the corticalsubcortical junction, and larger infarcts are often wedge-shaped. Perfusion-weighted imaging may show areas of hypoperfusion. The presence of reversible brain edema with symmetric high signal on fluid-attenuated inversion recovery (FLAIR), in a distribution similar to the posterior reversible leukoencephalopathy syndrome, suggests an overlapping pathophysiology between these syndromes (Fig. 111.4) (Singhal, 2004b). FLAIR images may show dot or linear hyperintensities within sulcal spaces, which are distinct from subarachnoid hemorrhage and reflect

slow flow within dilated surface vessels (Iancu-Gontard et al., 2003). Finally, cervical FAT/SAT sequences are very useful to search for any associated cervical artery dissection (Ducros et al., 2007; Mawet et al., 2013).

Cerebral angiography The diagnosis of RCVS can only be considered after documenting the presence of cerebral vasoconstriction with transfemoral, CT, or MR angiography. The angiography shows segmental narrowing and dilatation (string of beads) of one or more cerebral arteries (Fig. 111.5) (Slivka and Philbrook, 1995; Calabrese et al., 2007). Caliber irregularities may affect the anterior as well as the posterior circulation, and are mostly bilateral and diffuse, and large arteries such as the basilar or the carotid siphon may also be involved (Dodick et al., 1999). The narrowings are not fixed, and a repeat angiogram after a few days may show the resolution of some with new zones of constriction often involving more proximal vessels. Noninvasive angiography (MRA or CTA) was only 75% sensitive in the French series compared with the gold standard of catheter angiography which is by definition 100% sensitive (because it defines the syndrome), although nowadays rarely necessary (Ducros et al., 2007). The first angiogram, whatever its type, may be normal if performed early, within the 4–5 days of onset of symptoms; therefore if the first MRA or CTA is normal, a second angiogram a few days later may be diagnostic (Fig. 111.6) (Ducros et al., 2010). If another condition or another lesion is very unlikely, and if the initial MRA/CTA is definitely normal, and if there is no cSAH and no stroke on MRI, we do not systematically perform a catheter angiography. But depending on the clinical state of the patient, we may repeat TCD with

REVERSIBLE CEREBRAL VASOCONSTRICTION SYNDROME

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Fig. 111.2. Intracerebral hemorrhage in reversible cerebral vasoconstriction syndrome which may be single (A, C, D) or multiple (B), lobar (A, B, D) or deep (C), isolated or associated with cortical subarachnoid hemorrhage arrow please (B, right frontal cortical subarachnoid hemorrhage) or with an acute subdural hemorrhage (D, occipital subdural blood). (Reproduced from Ducros and Bousser, 2009.)

or without repeat MRA/CTA, or we simply follow up. Of course, in these patients, no definite diagnosis is possible (Ducros and Bousser, 2009). RCVS may be associated with single or multiple unruptured cerebral aneurysms (6% in our French series, which is not that much more frequent than in the general middle-aged population, but these patients had no red blood cells in the CSF and no extravasation of contrast on catheter angiography) (Day and Raskin, 1986; Ducros et al., 2007). RCVS might also be associated with vertebral or carotid dissection, more frequently in females, particularly postpartum (Singhal, 2004b; Ducros et al., 2007; Arnold et al., 2008; Field et al., 2010; Mawet et al., 2013).

Ultrasound Cervical ultrasound examination is usually normal except in the rare cases associating RCVS with cervical

arterial dissection. Transcranial Doppler, on the other hand, is very useful for monitoring the temporal evolution of cerebral vasoconstriction. Maximal mean flow velocities in the middle cerebral arteries may be normal during the first few days, then begin to increase and reach a peak ( 95%), showing an inflammatory reaction, while it is normal (40–80%) or shows only mild abnormalities in RCVS. Catheter angiography is frequently normal in PACNS, while it is by definition always abnormal in RCVS. Some aspects are suggestive of PACNS and are not observed in RCVS: irregular, eccentric, and asymmetric arterial stenoses or multiple occlusions. In the rare case of persistent uncertainty it may be best to wait a few days; RCVS should stabilize and improve quickly with regression of the vasoconstriction, while arterial irregularities in PACNS do not improve so fast. Heavy immunosuppressive treatments should be reserved for patients with biopsy-proven vasculitis. However, the anxiety awaiting the reversibility affects even the most experienced clinical teams. Intra-arterial nimodipine could serve as a differential diagnosis test because in RCVS it has been shown in a few cases to immediately normalize the arterial abnormalities (Elstner et al., 2009), whereas in PACNS it is not expected to change the lesions.

Migraine Migraine is another consideration because a prior history of migraine is frequently elicited (16–22%) by patients with a proven RCVS (Chen et al., 2006a; Ducros et al., 2007), although this frequency is not that much higher than the prevalence of migraine in the general

REVERSIBLE CEREBRAL VASOCONSTRICTION SYNDROME population. In patients with a history of migraine, attribution of any severe headache and even of stroke to migraine is a common problem, frequently leading to inappropriate treatment with antimigraine agents such as sumatriptan, which in the case of RCVS can exacerbate vasoconstriction and stroke (Meschia et al., 1998; Singhal et al., 2002). Headaches in RCVS are secondary headaches, symptomatic of the vascular disorder, that have nothing to do with migraine, which is a primary headache without any underlying causal lesion. Migraine sufferers who had a RCVS recognized the thunderclap headaches as totally different from their usual migraine attacks (Ducros et al., 2007). However, when entering the emergency room, they often complained of the “worst ever migraine attack,” which may be misleading.

Primary thunderclap headaches and headaches associated with exertion or sexual activity If imaging is negative and the patient does not prove to have vasoconstriction, primary headache disorders such as primary thunderclap headache, primary exertional headache, or orgasmic headache are usually considered (Wang and Fuh, 2010). However, a diagnosis of primary headache can be accepted only after the exclusion of all causes of secondary headaches. As presented above, sensitivity of MR or CT angiography is incomplete in RCVS and the highest load of arterial abnormalities as assessed by MRA is found only 3 weeks after headache (Chen et al., 2010). Moreover, in one study, 39% of patients presenting with thunderclap headache and normal brain MRI proved to have vasoconstriction on MRA, and those with and without vasoconstriction had similar clinical features, suggesting that RCVS and “primary thunderclap headache” belong to the same spectrum of disorders (Chen et al., 2006a). Furthermore, a recent prospective series of 30 patients complaining of headache associated with sexual activity showed that 60% had MRA features consistent with RCVS, suggesting that RCVS with thunderclap headaches triggered by sexual activity and “primary sexual headaches” also belong to the same spectrum of disorders (Yeh et al., 2010).

ETIOLOGY AND PATHOPHYSIOLOGY The cause of the prolonged but reversible arterial abnormalities with segmental vasoconstriction and vasodilatation is not known. Altered cerebral arterial tone due to abnormal vascular receptor activity or sensitivity appears critical; this may result from either a spontaneous or evoked central vascular discharge, or a variety of exogenous or endogenous factors including vasoconstrictive drugs and medications, female reproductive hormones, hypercalcemia, and others (Table 111.2). The anatomic basis to explain both the vasoconstriction

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and the headache may be the dense innervation of cerebral blood vessels with sensory afferents from the first division of the trigeminal nerve and dorsal root of C2. At the molecular level it is reasonable to postulate a role for the numerous immunologic and biochemical factors known to be involved in vasospasm associated with aneurysmal subarachnoid hemorrhage (catecholamines, endothelin-1, serotonin, nitric oxide, prostaglandins). The association of RCVS with serotonin-enhancing medications and tumors suggests that serotonin might play a pivotal role in this still mysterious condition. We previously hypothesized that arterial abnormalities first involve small distal arteries and then progresses towards medium and large-sized vessels, which could explain the high rate of normal early angiograms (up to 33%) in RCVS (Ducros et al., 2007). The finding that up to 17% of patients with hemorrhagic RCVS initially presented with isolated headaches and normal brain imaging, and only subsequently developed cSAH, intracerebral hemorrhage (ICH) and/or subdural hematoma (SDH) after a few days of recurrent severe headaches, suggests that the abnormal vascular process starts before hemorrhage (Ducros et al., 2010). Moreover, up to 17% of the patients with a cSAH due to RCVS also have a PRES. The co-occurrence of PRES, a transient vasogenic cerebral edema related to small-vessel dysfunction with acute disruption of blood–brain barrier, and cSAH suggests that the abnormal process initially affects very small cortical arteries. Serial MRA and TCD studies in a large cohort of RCVS cases showed that vasoconstriction affecting first segments of large arteries was maximal 18–22 days after headache onset, similar to the timing of headache resolution (Chen et al., 2008, 2010). Moreover, marked vasoconstriction could persist weeks after headache resolution, suggesting that vasoconstriction is not directly causing headache. Segmental vasodilatation could play an important role at the initial stage of RCVS, triggering thunderclap headaches by abrupt stretching of vessel walls, and causing hemorrhages by small vessel rupture or reperfusion injuries, whereas small vessel segmental constriction remains asymptomatic (no or rare small vessel infarction in RCVS). In a second stage, vasoconstriction of second and first segments of major cerebral arteries becomes the major problem causing mainly watershed infarction (Ducros et al., 2010).

MANAGEMENT In the absence of controlled trials, management is guided by observational data and expert opinion. For patients presenting with thunderclap headache but who have not undergone vascular imaging, empiric therapy is not justified. However, once cerebral vasoconstriction has been documented, treatment can be considered. It is

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important to note that RCVS is usually self-limited, with clinical and angiographic resolution occurring spontaneously within a few weeks. Therefore simple observation alone is reasonable in patients, especially those who show no signs of clinical progression. Calcium channel blockers such as nimodipine and verapamil (Nowak et al., 2003), and magnesium sulphate (Singhal, 2004b) have been administered in an effort to relieve the vasoconstriction. Data from two prospective case series suggest that nimodipine does not affect the time course of cerebral vasoconstriction (Chen et al., 2006a; Ducros et al., 2007; Ducros et al., 2010). However, nimodipine might relieve the number and intensity of headaches. Nimodipine may be given intravenously for a few days, in the same doses as is used in aneurysmal subarachnoid hemorrhage (1–2 mg/kg/hour with monitoring of blood pressure). More often, nimodipine is given orally, the dose varying from 60 mg every 4–8 hours for 4–12 weeks. Thunderclap headaches seem to stop within 48–72 hours, but TIAs or even infarction have been reported in patients treated for several days (Lu et al., 2004; Ducros et al., 2007). Some patients might have an increase in their background headaches on nimodipine, and rarely a thunderclap headache triggered by a nimodipine tablet. Finally, nimodipine should be avoided in patients with low blood pressure and in patients with an associated dissection with hemodynamic compromise. Short courses of glucocorticoids do not seem to prevent clinical deterioration (Singhal et al., 2011), and are even suspected to worsen sometimes the clinical course. Thus, they should be avoided. Direct intra-arterial administration of milrinone, nimodipine and prostacyclin, and balloon angioplasty, have been used with variable success (Song et al., 2004, Bouchard et al., 2009, Elstner et al., 2009, Grande et al., 2010). These interventions carry a high risk of reperfusion injury and should be reserved for patients exhibiting clear signs of clinical progression (Singhal et al., 2009). Unfortunately, there are no known clinical or imaging features that reliably predict disease progression. Symptomatic treatment includes analgesics (headache is extreme and frequently warrants round-the-clock opioid analgesic use), antiepileptic drugs for any seizures, monitoring blood pressure, hospitalization in intensive care units in severe cases, and rest for all other patients for a few days to a few weeks according to the severity of their headaches. Benzodiazepines can be used to relieve anxiety, which is common and could be an aggravating factor. Patients should be counseled to avoid sexual activity, physical exertion, the Valsalva maneuver, and other known triggers of recurrent headaches for 1 or 2 weeks. Finally, it is crucial to search for all possible vasoactive substances (repeated questioning

is sometimes necessary), eliminate all these substances immediately them and, and firmly suggest to the patient that he or she should avoid these kinds of drugs and medications in the future. Usual stroke preventive medications such as antiplatelets, anticoagulants, cholesterol-lowering agents, and others are probably not indicated.

CONCLUSIONS AND FUTURE DIRECTIONS RCVS is probably more frequent than previously thought and affects patients of both genders, with a female preponderance. It is attributed to a transient disturbance in the control of cerebral vascular tone leading to multifocal arterial constriction and dilatation. Some cases are spontaneous while others (60%) are secondary, mostly to exposure to vasoactive substances and to the postpartum state. It has a characteristic course; the onset is sudden followed by a monophasic course, generally without new events after 1 month. The main pattern is of recurrent thunderclap headaches. Cortical subarachnoid hemorrhage, intracerebral hemorrhage, seizures, and PRES are early complications, occurring mainly within the first week. Ischemic events, including TIAs and cerebral infarction, occur later than any hemorrhagic strokes, mainly during the second week. Recent results indicate that intracranial hemorrhages affect up to onethird of all RCVS cases, are far more frequent than ischemic events, and are more frequent in women and in migraineurs. RCVS should be considered as a differential diagnosis in patients with any type of spontaneous intracranial hemorrhage, and especially with localized cortical SAH. The diagnosis of RCVS may be difficult when initial brain and vascular imaging are normal, requiring repeated investigations. The definitive diagnosis is made when a later angiogram shows a resolution or at least a marked improvement of the arterial abnormalities after about 12 weeks. Nimodipine is the proposed treatment but does not seem to prevent infarctions; randomized trials are needed. Relapses do occur but are rare. Studies of cerebral blood flow at the acute stage and of cerebrovascular reactivity at a distance from RCVS could help to understand the mechanisms underlying this poorly understood syndrome.

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Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 112

Complications of neuroimaging 1

JORDAN D. ROSENBLUM1*, OLGA PASTERNAK1, AND MYROSIA T. MITCHELL2 Department of Radiology, Loyola University Chicago, Stritch School of Medicine, Chicago, IL, USA 2

Department of Radiology, Advocate Christ Hospital, Oak Lawn, IL, USA

INTRODUCTION The widespread availability of computed tomography (CT) and magnetic resonance imaging (MRI) has introduced a new era in noninvasive neuroimaging. In the past, the diagnosis of intracranial vascular abnormalities and mass lesions required invasive techniques including direct puncture carotid angiography and air cisternography. Patients suspected of having intracranial pathology can now be evaluated rapidly, safely, and noninvasively. Magnetic resonance angiography (MRA) and CT angiography (CTA) have revolutionized the practice of routine cerebral angiography and have supplanted the direct puncture transfemoral techniques pioneered by Seldinger (1953) for most diagnostic indications. The increased use of CT and MR imaging has eliminated the risks associated with invasive neuroimaging, but has also introduced potential new risks. Imaging guided techniques including vertebroplasty, kyphoplasty, myelography, and biopsies are also associated with complications that must be kept in mind when ordering these procedures.

CONVENTIONAL CATHETER ANGIOGRAPHY Conventional angiography is still superior to CT or MR angiography in both spatial and temporal resolution, though the gap is closing rapidly. It remains the gold standard against which competing technologies are measured. The main indications for conventional catheter angiography include ruptured aneurysm with subarachnoid hemorrhage, intraparenchymal hemorrhage with no lesion seen by CT or MR, evaluation for small unruptured aneurysm, arteriovenous malformation (AVM) assessment, and diagnosis of vascultitis. Angiography

also has a specific role in the diagnosis and endovascular treatment of atherosclerotic disease of the carotid arteries and the endovascular management of intracranial stenosis, aneurysm, or other vascular abnormalities. The most significant complication of catheter angiography is that of permanent neurologic deficit. This may be due embolic events from catheter induced thrombosis (Figs. 112.1, 112.2), but can also be caused by vasospasm and by vessel thrombosis. In a frequently quoted study of 5000 patients who underwent conventional angiography, Mani et al. reported a risk of neurologic complication of 3.9% at training institutions and 0.9% at nontraining institutions, with a risk of permanent deficit of 0.1% (Mani and Eisenberg, 1978). Several more recent studies have reported much lower complication rates. These may be attributable to technological advances including smaller, softer catheters, newer wires, use of nonionic contrast, and newer imaging systems that allow shorter examinations, lower contrast dose, and lower radiation dose. In a study of 19 829 patients undergoing conventional angiography at the Mayo Clinic between 1981 and 2003, 522 patients (2.6%) suffered a neurologic complication, with 27 permanent neurologic deficits (0.14%) (Kaufmann et al., 2007). A 2007 study of 2924 patients, reported no permanent neurologic deficits (Dawkins et al., 2007). A 2006 study of 241 pediatric cases (Burger et al., 2006) and a 2009 study of 333 adult patients (Al-Ameri et al., 2009) also reported no permanent neurologic deficits. Transient neurologic deficits occur more frequently. These are commonly defined as any new neurologic symptom occurring either during or immediately following a cerebral angiography procedure that resolves within 30–60 minutes after the procedure, with no abnormalities on follow-up imaging. Reported transient neurologic deficits include not only focal cortical

*Correspondence to: Jordan Rosenblum, M.D., Professor of Radiology, Chief, Section of Neuroradiology, Loyola University Chicago. 2160 S. 1st Avenue, Maywood, IL 60153, USA. Tel: þ1-708-216-8302, Fax: þ1-708-216-0899, E-mail: jrosenblum @lumc.edu

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Fig. 112.1. AP cerebral angiogram demonstrates occlusion of the left middle cerebral artery following previously normal injection of the same vessel. Presumed catheter-related thrombus with distal embolization.

Fig. 112.2. AP angiogram of the left vertebral origin demonstrates a serpiginous filling defect just distal to the catheter tip, not present on initial arch study and compatible with thrombus. This may serve as a nidus for thrombus propagation and distal embolization.

deficits, but also less well understood symptoms including transient cortical blindness, transient global amnesia, cranial nerve deficits, transverse myelopathy, seizures, and pituitary apoplexy. Most of these atypical symptoms have been attributed to the use of ionic contrast material, as there have been no reports of such idiosyncratic reactions since 1981 when the use of nonionic contrast material became widespread. Other rare complications reported include headache, transient memory loss/disorientation (Dawkins et al., 2007), and transient vertigo (Ringer et al., 2008). Imaging in the setting of acute subarachnoid hemorrhage and imaging in patients with atherosclerotic cerebrovascular disease are risk factors associated with increased neurologic morbidity. Other risk factors include hypertension, coronary artery disease, peripheral vascular disease, hyperlipidemia, diabetes, and advanced age (Kaufmann et al., 2007; Al-Ameri et al., 2009). Increased duration of the angiographic procedure and operator expertise are also factors in complication rates. A long-term study by Kaufmann et al. noted that the rate of neurologic complications decreased significantly over the 24 year course of the study (Kaufmann et al., 2007). In fact, the complication rate was 34% less likely to occur with each successive 5 year time increment, with a 3.8% neurologic complication rate in the first one-third of the study period that decreased to 0.57% in the last one-third of the study period. The authors hypothesized that the improvement may have been a function of increased operator skill, improved equipment, or some combination of both. In contrast to findings of Mani and Eisenberg (1978), Kaufmann et al. noted that the participation of a trainee in the angiographic examination was protective, with neurologic complications 29% less likely to occur. While neurologic deficits may be the most devastating, the most common complications resulting from catheter angiography are related to the procedure access site, most often a puncture-site hematoma. In 19 826 angiography procedures, Kaufmann et al. reported 828 puncture site hematomas (4.2%), with five (0.03%) requiring surgical management (Kaufmann et al., 2007). Dawkins et al. reported 12 puncture-site hematomas in 2924 procedures (0.41%) (Dawkins et al., 2007). In their study of 3636 procedures, Fifi et al. reported four significant puncture site complications (0.11%), consisting of two femoral occlusions requiring thrombectomy, a femoral artery pseudoaneurysm, and a femoral abscess (Fifi et al., 2009). Interestingly, they related these complications to use of closure devices. They also reported five asymptomatic iatrogenic dissections (0.14%). Other potential complications of catheter angiography include vessel dissection, catheter-induced spasm and contrast-related complications including

COMPLICATIONS OF NEUROIMAGING 1745 allergic reactions and contrast-induced nephropathy necessary to induce cataracts may be as low as which are described more fully below. 200 mGy (Klein et al., 1993). Physicians working with ionizing radiation are at greatest risk, but patients receiving multiple head CT scans and neurointerventional proCOMPLICATIONS RELATED TO cedures also can receive enough radiation to the eyes to COMPUTED TOMOGRAPHY SCANS be at risk. Patients receiving a temporal bone CT or an The speed and ease of obtaining CT scans, as well as the orbit CT can receive 0.05 Sv–0.08 Sv, depending on additions of CT angiography and more recently CT perthe CT scanner (Tan et al., 2009). In a study of 95 fusion to the diagnostic applications of CT, have made patients undergoing stroke evaluation, the average dose CT an essential element in the diagnosis of a wide specto the head was 0.15 Sv for a noncontrast CT scan of the trum of disease processes; however, CT also poses risks head and 0.59 Sv for a CT perfusion scan. The entire to patients. The main risks are radiation dose, allergic stroke series, including the pre- and postcontrast head reactions to iodinated contrast, and contrast-induced CT with perfusion averaged a dose of 0.93 Sv nephropathy (CIN). (Mnyusiwalla et al., 2009). While these doses are below CT radiation doses are currently a topic of considerthe dose for cataract induction, they are over 250 times able interest, as many newer exam techniques may subthe background radiation dose in the US. Hospitalized ject the patient to significantly higher doses of radiation. patients are frequently scanned multiple times and the Though the actual risk from this radiation is still a much total dose may exceed the threshold doses during a single debated topic, it seems clear that reducing the currently hospitalization. The use of eye shields can decrease the applied dose, particularly in pediatric patients, must be a radiation exposure to the eyes and decrease the risk high priority. for cataract induction. Radiation dose should be kept in mind whenever orderThe most commonly reported adverse events related ing an imaging study utilizing radiation. The annual averto intravenously administered contrast material are allerage per capita effective radiation dose, excluding gic reactions. Cochran et al. reviewed 90 473 intravenous smoking, in the US is 0.0036 Sv (360 mrem). Approxiiodinated contrast agent administrations from 1985 to mately 80% is from naturally occurring sources, but 1999 (Cochran et al., 2001). They defined allergic reac20% is from diagnostic X-ray procedures (Bushberg tions as sneezing/nasal congestion, hives, itching, rash et al., 2002). While the carcinogenic effects of high-dose and swelling, laryngeal edema, bronchospasm, and anaradiation exposure have been exhaustively researched, the phylaxis. Nausea, vomiting, and arm pain were classified effects of low-dose radiation exposure are still unclear. as nonallergic adverse events. With ionic contrast media, Risks of cataract formation and cancer are largely based their reported incidence of adverse events was 11–12%, on data of Japanese atomic bomb survivors, as well as with 96% of these in the allergic category. With nonionic subsequent laboratory studies using animal models. contrast media, the incidence of adverse events was Cancer is the most common late effect of radiation in 0.2%, with 92% in the allergic category. patients, with a latency period for cancer induction of Contrast-induced nephropathy (CIN) is another imporapproximately 12–20 years. Since there is no threshold tant and clinically significant complication of radiodose below which radiation exposure will not cause cangraphic imaging and interventional procedures. CIN cer, there is an assumption that small doses of ionizing refers to a reduction in renal function as a result of conradiation from diagnostic X-rays may induce some cantrast media administration. It is a nonoliguric impairment cers (Berrington de Gonzalez and Darby, 2004). The lifein renal function defined by an increase in serum creatitime risk from a single small dose of ionizing radiation is nine of more than 25% or 0.5 mg/dL that peaks within 2–4 higher in women, mostly attributable to breast cancer days after the administration of contrast material, and because of the sensitivity of breast tissue to often resolves within 1–2 weeks (Morcos et al., 1999). It radiation.(Boice et al., 1979). In addition, the younger is thought to be caused by both toxic effects on the tubular the patient is during radiation exposure, the greater their cells of the kidney and direct hemodynamic effects on the risk for developing secondary cancers. There is evidence kidney leading to reduced renal perfusion (Thomsen and for a small lifetime increase in cancer if chronic radiation Morcos, 2003). The incidence of CIN in elderly adults exposure is above 0.2 Sv (Aspelin et al., 2003). The goal with a decreased creatinine clearance of < 60 mL/min is then is to find an optimal compromise between the necesestimated to be approximately 3–4% (Aspelin, 2003; sary imaging study and the radiation dose to the patient. Woo Park et al., 2007). The induction of cataracts is a known effect of ionizIdentifying the high-risk patient is critical to avoiding ing radiation, with a threshold dose of 5 Sv (5 Gy) for CIN. The patients at greatest risk are those with a chronic exposure and 2 Sv (2 Gy) for acute exposure combination of pre-existing renal insufficiency and (Huda, 2010). There is evidence to suggest the dose diabetes (Parfrey et al., 1989). Other risk factors include

1746 J.D. ROSENBLUM ET AL. dehydration, congestive heart failure, hypotension, hismagnetic field. The alignment tends to persist even after tory of “kidney disease” as an adult (including tumor the magnetic field is removed. These materials are used and renal transplant), family history of renal failure, in some medical implants and also in implantable elecparaproteinemia symdromes, collagen vascular disease, tronic devices. Due to the strong magnetic field in the advanced age, and certain medications including MR magnet, ferromagnetic objects are attracted by metformin, nonsteroidal anti-inflammatory drugs and the scanner. External ferromagnetic support devices nephrotoxic antibiotics (ACR Manual on Contrast such as IV poles or ventilators can become projectiles Media, version 5.0). and must be replaced with nonferromagnetic substitutes Metformin is an oral antihyperglycemic agent that if the patient requires them during the scan. Internal fercan be used alone or as a combination drug. Its most sigromagnetic devices or implants can also move in the scannificant adverse event is metformin-associated lactic aciner. This is not a problem if the implant is immobile, as dosis, which is estimated to occur at a rate of 0–0.034 with a well endothelialized intravascular stent; however, cases per 1000 patient-years. This has a mortality rate it can become an absolute contraindictation if the implant in reported cases of about 50%, though in almost all is mobile and in a critical location as is the case with aneureported cases a patient-associated contraindication rysm clips or recently placed carotid stents. Electronic for metformin (e.g., cardiovascular or renal disease) devices may become dislodged or may malfunction, espewas overlooked (ACR Manual). Given that metformin cially at the points of highest force of the magnet, such as is excreted unchanged by the kidneys, any factor that the entrance edges and inside the bore (Gotte et al., 2010). decreases metformin excretion is a risk factor for lactic The magnetic field can also induce electric currents or acidosis. For this reason, current ACR recommendations cause heat generation in metallic elements and wires. are that metformin be discontinued at the time of an For these reasons, the US Food and Drug examination or procedure using intravascular contrast Administration (FDA) has issued a black box warning medium, withheld for 48 hours after contrast adminisconcerning the life-threatening risks of implantable tration, and reinstated only after renal function has been devices such as pacemakers, implantable cardioversion re-evaluated and found to be normal (ACR Manual). If devices, and deep brain stimulators (FDA, 1997). the creatinine level does not return to baseline, metforPotential risks specific to cardiac implantable devices min should be held longer until it does (Thompson, 2010). include heating of the leads of the device, induction of Large doses of contrast media, either as a single dose ventricular tachycardia, pacing disturbances, and loss or as a cumulative dose from multiple administrations in of communication with the external programmer. The 72 hours, increase a patient’s risk of developing CIN. Peorisks specific to deep brain stimulators include excessive ple who are hydrated and have normal renal function are heating, induced electrical currents, and disturbances of unlikely to suffer acute renal injury if they receive less normal device operation. MR imaging can be performed than 4 mL/kg of contrast media. Patients who have renal in patients with these devices when the benefits outweigh impairment require adequate hydration before contrast the risks, but should be attempted only in a carefully conadministration (Thompson, 2010). In addition, intratrolled setting, preferably a hospital setting, under direct arterial administration of contrast carries a higher risk physician supervision, and with trained personnel in of CIN than intravenous administration. While most cases attendance to respond to any device malfunction or of CIN resolve over 1–2 weeks, it is important to identify other critical issues (Chhabra et al., 2010). the high-risk patients, hydrate them appropriately, and Nephrogenic systemic fibrosis (NSF) is a serious and monitor for nephropathy after diagnostic procedures. potentially fatal fibrosing condition that affects the skin and multiple organs. The first report of NSF was published in 1997 and described a skin disorder resembling COMPLICATIONS RELATED TO scleromyxedema with an atypical cutaneous distribuMAGNETIC RESONANCE IMAGING tion. The syndrome was thought to have a predilection EXAMINATIONS for patients undergoing dialysis (Cowper et al., 2000). MRI presents different risks to the patient: those associDocumented cases of NSF in patients with end-stage ated with the magnetic field and those associated with renal disease undergoing MRI examinations with gadolinium contrast agents. Magnetic field risks include gadolinium-based contrast agents were first reported movement of ferromagnetic external objects or in 2006 (Marckmann et al., 2006), prompting the FDA implants, malfunction of implanted electronic devices, to issue a cautionary advisory in December 2006. By and heat generation or current inductions in patients 2007, the FDA required a black box warning from all with implanted wires. Gadolinium contrast risks include manufacturers of gadolinium-based contrast agents allergic reactions and neurogenic systemic fibrosis. concerning the risks of NSF from these agents. Ferromagnetic materials have unpaired electrons that The clinical features of NSF may begin several days to align readily with each other in response to an external several months after exposure to gadolinium-based

COMPLICATIONS OF NEUROIMAGING 1747 contrast agents (with a median of 25 days) and include of all spinal tumors; however, 40% are acquired and skin swelling, skin induration, erythematous or fleshare thought to arise from iatrogenic epidermal cell colored papules with peau d’orange appearance, and implantation in the subarachnoid space such as followskin thickening with woody texture that is primarily ing lumbar puncture. located on the distal lower extremities but may be on Other rare complications of myelography include the lower thighs, lower abdomen, or upper extremities. infection, hematoma, nerve root injury and, with cervical Skeletal muscle, myocardium, lungs, kidneys, testes, puncture, the risk of cord injury by direct manipulation and dura mater may be involved as well (Juluru et al., or by inadvertent parenchymal injection within the cord. 2009). Patients at greatest risk for developing NSF include those with acute or chronic renal failure, patients VERTEBROPLASTY with vasculopathy and venous thrombosis or coagulopathy, and patients with vascular injury. High doses of Percutaneous vertebroplasty and balloon kyphoplasty, gadolinium-based contrast agents increase the risk of also known as vertebral augmentation procedures, developing NSF. New MR imaging protocols have were first described to treat painful vertebral destrucimproved the sensitivity of noncontrast examinations tion caused by hemangiomas, but have since become widely utilized for osteoporotic and tumor-related verin the diagnosis of many pathologic conditions. If a tebral fractures (Krueger et al., 2009). Since 1987, these contrast-enhanced examination is needed in a high-risk patient, consideration should be given to low-dose procedures have generally been considered safe and techniques. effective methods of managing pain from vertebral fractures. Nevertheless, several complications are associated with these procedures including cement extravaMYELOGRAPHYAND LUMBAR sation, pulmonary cement embolization, adjacent level PUNCTURE fractures, nerve root irritation, and arterial The most common complication of myelography is spiembolization. nal headache. A spinal headache generally begins within The most frequent complication reported in the liter3 days of the procedure and lasts 3–5 days. It is positional ature is cement extravasation, either into the adjacent in nature and is aggravated by sitting, standing, coughdisc space, into the paraspinal soft tissue, or into the spiing, or straining and relieved by lying supine. The pronal canal. Cement extravasation is generally asymptomposed mechanism for the postmyelography headache atic if confined to the paraspinal tissues. is continuous leakage of the CSF from the dural puncIn a meta-analysis of the literature and medical datature site (Peterman, 1996). There are conflicting reports bases, Krueger et al. found that transvertebral cement in the literature on the correlation of needle size to postleakage into surrounding tissues and cement leakage myelograpahy headaches. After the introduction of 22G into paravertebral veins were common complications. and 24G needles in 1956, the incidence was estimated to However, in the majority of the cases the cement leakage be 11% (Turnbull and Shepherd, 2003). Studies by (Jones did not cause significant problems and was often et al., 1994; Prager et al., 1996) reported a lower incidence detected incidentally during radiographic follow-up of spinal headache when a pencil point needle was used studies. Teng et al. also noted that although epidural compared to a beveled needle (Jones et al., 1994; Prager leaks occur commonly, most are subclinical and are et al., 1996). Treatment is supportive. Bed rest and/or detected incidentally on postprocedure CT examination maintaining a supine position has not been proven to (Teng et al., 2006). In cases where there were neurologic be beneficial. In the rare instances when a spinal headsymptoms, the proposed mechanism of injury after ache persists over 1 week, an epidural blood patch may intraspinal cement leak was either mass effect from be used to treat the persistent leaks. the cement or thermal injury to the spinal cord and nerve Arachnoiditis was at one time a significant complicaroots. Injury can also occur by inadvertent penetration of tion of myelography, but is now a rare complication due the spinal cord by the needle (Fig. 112.3). The most devto the use of nonionic water-soluble contrast agents (Ho, astating complication of vertebroplasty or kyphoplasty 1975). This decreased incidence is attributed to rapid is epidural cement leakage that causes spinal cord comabsorption of water-soluble contrast agents compared pression or cord injury with clinical symptoms of motor to the slower absorption of ionic contrast agents and weakness or bowel/bladder incontinence. older oil-based agents. With current contrast agents, conContrast intravasation into draining veins may lead trast absorption begins almost as soon as the contrast is to pulmonary cement embolization (PCE). In their review administered (Sage, 1983). of 214 published case reports, Krueger et al. found 95 Iatrogenic epidermoid spinal tumors are an uncomreported complications after vertebroplasty or kyphomon complication of myelography. Epidermoid spinal plasty, 34 of which were PCE. The most common symptumors are rare tumors that account for less than 1% tom of PCE was dyspnea that resolved after a short

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Fig. 112.3. (A) Axial T2-weighed image through the lower thoracic spine demonstrates heterogeneously increased signal within the cord following vertebroplasty procedure. Note the increased signal in the right lamina. (B) Axial CT scan though the same level clearly demonstrates a defect in the right lamina. The needle trajectory was medial to the pedicle and penetrated the thoracic cord with intramedullary hematoma and edema.

period of time. In four of the reported cases, PCE resulted in patient death. Venmans et al. conducted a retrospective review of 532 osteoporotic compression fractures treated with vertebral augmentation procedures in 299 patients and found only 11 cases of PCE (2.1%) (Venmans et al., 2008). They defined a PCE as a venous polymethylmethacrylate “cement” migration toward the lungs that is visible on fluoroscopy. If migration occurred, a chest CT was done to detect the location, number, and distribution of the methacrylate particles. Layton et al. (2007) reported 1000 compression fractures (552 patients) treated with vertebroplasty, with only one PCE and no longterm sequelae. They reported complications including rib fractures, new-onset radiculopathy, and one case of central spinal canal compromise from vertebroplasty cement displacing tumor into the canal, requiring surgical decompression. The complications of invasive neuroimaging techniques including angiography and myleography have been well described for many years. Newer modalities, including CT angiography and MR angiography, bring with them new risks to the patients that are less well described. While a single head CT radiation dose is well within the standards that have traditionally been considered safe, multiple examinations, especially repeat examinations such as a stroke work-up, may approach threshold doses for radiation effects such as cataract

induction. Interventional procedures utilizing prolonged fluoroscopy times may subject patients to significant radiation doses during therapeutic procedures. Numerous reports of local radiation injury including epilation and radiation burns are present in the literature (Koenig et al., 2001). Transient erythema may be seen with skin doses as low as 2 Gy. Epilation may be seen with doses of 3–6 Gy. In a report of 103 neuroembolization procedures from 6 institutions, Suzuki et al. (2008) reported an average maximum entrance skin dose of 1.9 Gy with a range of 0.4– 5.6 Gy. Epilation was observed in 6 of the patients. Clearly advances in neuroimaging have also led to significant new risks that must be factored into a decision to utilize imaging modalities.

REFERENCES ACR Manual on Contrast Media, Version 5.0. Available at: http://www.acr.org/secondarymainmenucategories/ quality_safety/contrast_manual.aspx. Al-Ameri H, Thomas M, Yoon A et al. (2009). Complication rate of diagnostic cerebral angiography performed by interventional cardiologists. Available at:www.interscience. wiley.com. Assessed January 29, 2009. Aspelin P, Aubry P, Fransson SG et al. (2003). Nephrotoxic effects in high-risk patients undergoing angiography. N Engl J Med 348: 491–499.

COMPLICATIONS OF NEUROIMAGING Berrington de Gonzalez A, Darby S (2004). Risk of cancer from diagnostic X-rays: estimates for the UK and 14 other countries. Lancet 363: 345–351. Boice JD Jr, Land CE, Shore RE et al. (1979). Risk of breast cancer following low-dose radiation exposure. Radiology 131: 589–597. Burger I, Murphy K, Jordan L et al. (2006). Safety of cerebral digital subtraction angiography in children, complication rate analysis in 241 consecutive diagnostic angiograms. Stroke 37: 2535–2539. Bushberg J, Seibert J, Leidholdt E et al. (2002). The Essential Physics of Medical Imaging. 2nd edn. Lippincott Williams and Wilkins, pp. 739–741. Chhabra V, Sung E, Mewes K et al. (2010). Safety of magnetic resonance imaging of deep brain stimulator systems: a serial imaging and clinical restrospective study. J Neurosurg 112: 497–502. Cochran S, Bomyea K, Sayre J (2001). Trends in adverse events after IV administration of contrast media. Am J Roentgenol 176: 1385–1388. Cowper SE, Robin HS, Steinberg SM et al. (2000). Scleromyxoedema-like cutaneous diseases in renal dialysis patients. Lancet 356: 1000–1001. Dawkins A, Evans A, Wattam J et al. (2007). Complications of cerebral angiography: a prospective analysis of 2,924 consecutive procedures. Interv Neuroradiol 49: 753–759. Fifi J, Meyers P, Lavine S et al. (2009). Complications of modern diagnostic cerebral angiography in an academic medical center. J Vasc Interv Radiol 20: 442–447. Food and Drug Administration, United States (1997). A Primer on Medical Device Interactions with Magnetic Resonance Imaging Systems. Available at: http://www.fda.gov. Food and Drug Administration, United States (2006). Public Health Advisory: update on magnetic resonance imaging (MRI) contrast agents containing gadolinium and nephrogenic fibrosing dermopathy – 12/22/2006. Available at: http://www.fda.gov/cder/drug/advisory/ gadolinium_agnets_20061222.htm. Gotte M, Russel I, Roest G et al. (2010). Magnetic resonance imaging, pacemakers and implantable cardioverterdefibrillators: current situation and clinical pespective. Neth Heart J 18: 31–37. Ho P (1975). The hazards of myelography. Radiology 115: 237–239. Huda W (2001). Review of Radiologic Physics. 3rd edn. Lippincott and Wilkins, Philadelphia, pp. 106–107. Jones MJ et al. (1994). Technical note: the influence of using an atraumatic needle on the incidence of post-myelographic headache. Br J Radiol 67: 396–398. Juluru K, Vogel-Claussen J, Macura K et al. (2009). Quality initiatives, MR imaging in patients at risk for developing nephrogenic systemic fibrosis: protocols, practices, and imaging techniques to maximize patient safety. Radiographics 29: 9–22. Kaufmann T, Huston III, Mandrekar J et al. (2007). Complications of diagnostic cerebral angiography: evaluation of 9,826 consecutive patients. Radiology 243: 812–819.

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Klein BE, Klein R, Lingon KL et al. (1993). Diagnostic X-ray exposure and lens opacities: the Beaver Dam Eye Study. Am J Public Health 83: 588–590. Koenig T, Wolff D, Mettler F et al. (2001). Skin injuries from fluroscopically guided procedures: part 1, characteristics of radiation injury. Am J Radiol 177: 3–11. Krueger A, Bliemel C, Zettl R (2009). Management of pulmonary cement embolism and percutaneous vertebroplasty and kyphoplasty: a systematic review of the literature. Eur Spine J 18: 1257–1265. Layton KF, Thielen KR, Koch CA et al. (2007). Vertebroplasty, first 1000 levels of a single center: evaluation of the outcomes and complications. AJNR Am J Neuroradiol 26: 683–689. Mani R, Eisenberg R (1978). Complications of catheter cerebral angiography, analysis of 5,000 procedures. Am J Roentgenol 131: 871–874. Marckmann P, Skov L, Rossen K et al. (2006). Nephrogenic systemic fibrosis: suspected causative role of gadodiamide used for contrast-enhanced magnetic resonance imaging. J Am Soc Nephrol 17: 2359–2362. Mnyusiwalla A, Aviv R, Symons S (2009). Radiation dose from multidetector row CT imaging for acute stroke. Neuroradiology 51: 635–640. Morcos S, Thomsen H, Webb Amembers of the ESUR (1999). Contrast-media-induced nephrotoxicity: a consensus report. Eur Radiol 9: 1602–1613. Parfrey PS, Griffiths SM, Barrett BJ et al. (1989). Contrast material-induced renal failure in patients with diabetes mellitus, renal insufficiency, or both. A prospective controlled study. N Engl J Med 320: 143–149. Peterman SB (1996). Postmyelography headache: a review. Radiology 200: 765–770. Prager JM, Roychowdhury S, Gorey MT et al. (1996). Spinal headaches after myelograms: comparison of needle types. AJR 167: 1289–1292. Ringer A, Lanzino G, Veznedaroglu E et al. (2008). Does angiographic surveillance pose a risk in the management of coiled intracranial aneurysms? A multicenter study of 2,243 patients. Neurosurgery 63: 845–849. Sage MR (1983). Kinetics of water soluble contrast media in the central nervous system. AJNR Am J Neuroradiol 14: 815–842. Seldinger SI (1953). Catheter replacement of the needle in percutaneous arteriography: a new technique. Acta Radiol 39: 368–376. Suzuki S, Furui S, Matsumaru Y et al. (2008). Patient skin dose during neuroembolization by multiple-point measurement using a radiosensitive indicator. AJNR Am J Neuroradiol 29: 1076–1081. Tan J, Tan K, Lee J et al. (2009). Comparison of eye lens dose on neuroimaging protocols between 16- and 64-section multidetector CT: achieving the lowest possible dose. AJNR Am J Neuroradiol 30: 373–377. Teng M, Cheng H, Ho D et al. (2006). Intraspinal leakage of bone cement after vertebroplasty: a report of 3 cases. AJNR Am J Neuroradiol 27: 224–229. Thompson K (2010). Safe use of radiographic contrast material. Australian Prescriber 33: 19–22.

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Thomsen H, Morcos S (2003). Contrast media and the kidney: European Society of Urogenital Radiology (EUSR) Guidelines. Br J Radiol 76: 513–518. Turnbull D, Shepherd D (2003). Post-dural puncture headache: pathogenesis, prevention, and treatment. Br J Anaesth 91: 718–729. Venmans A, Lohne PNM, Rooij WJ et al. (2008). Frequency and outcome of pulmonary polymethylmethacrylate

embolism during percutaneous vertebroplasty. AJNR Am J Neuroradiol 29: 1983–1985. Woo Park K, Koo B, Kim H et al. (2007). The incidence and predictors of contrast-induced nephropathy in adequately hydrated elderly patients with impaired renal function. Nephrol Dial Transplant 22: 1794–1795.

Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 113

Neurotraumatology EDWARD C. PERRY III, HAZEM M. AHMED*, AND THOMAS C. ORIGITANO Department of Neurological Surgery, Loyola University Medical Center, Maywood, IL, USA

INTRODUCTION Traumatic events levy a heavy physical, emotional, and economic cost on those who suffer them. Damage can occur to many different organ systems, but none seems as mystifying as neurologic injury. A lung contusion improves, a large laceration or broken bone heals, but brain and spine injury can be lifelong and irreparable. The nervous system does not have the regenerative capabilities of the rest of the body. Yet some patients with severe brain injury can come out of a coma after days or even weeks of treatment and return to a surprising level of function. It has taken many years to develop effective treatments to improve patient outcome, but even these tremendous efforts often yield a mortal or severely morbid result. The primary injury cannot be undone, but the goal of modern medical and surgical management is to prevent secondary neurologic decline. This chapter deals with the treatment of neurotrauma from a neurosurgeon’s perspective as we, along with neurologists, confront the immediate and long-term effects of this clinical problem.

HISTORY The human race has been at war before and since recorded history. Blunt and penetrating trauma to the head produced either death or debilitating morbidity. As the graves of some of the ancient battlegrounds have been unearthed, people have found holes drilled in the skulls near signs of fracture. A skull with 9 cm healed perforations was found in France dating to over 7000 BC (Walker, 1997). This may have been the earliest neurosurgery performed, a form of trepanation (or drill hole) to relieve blood on the brain. Egypt, Greece, and ancient Mesopotamia is where the earliest known practice of medicine began, and the earliest document reporting brain and spine injury management was the Edwin

Smith Papyrus, written about 1650–1550 BC by an Egyptian physician (Sanchez and Burridge, 2007; van Middendorp et al., 2010). Trepanation has been reported through history as both a medical and spiritual form of treatment for head trauma and evil humors (Oakley et al., 1959). The Andean culture was particularly fascinated with this practice. Based on the healing around the primitive craniotomies of skulls discovered in Peru, the mortality from the procedure itself was less than 30% (Verano, 1997). The foundation of neurotraumatology was developed during the major world wars. Modern evidence-driven management really began with the use in intracranial pressure monitoring devices in the 1950s (Marshall, 2000).

TRAUMATIC BRAIN INJURY Epidemiology Nearly 1.5 million people per year visit US emergency rooms with traumatic brain injury(TBI)-related problems. Some 294 500 are admitted for care, and 52 350 will die from their head injury. Primary etiologies are listed in Table 113.1. Overall, this represents an increase of 14.4%, 19.5%, and 3.5% respectively from 2002 to 2006 (CDC, 2007). There has been an associated 3.8% increase in the US population during that time, so the incidence of death from TBI may actually be decreasing. However, it is likely the actual overall incidence of injury is higher, as many mild injuries go unreported when people do not seek medical care. Head trauma occurs in 4.5% of all traumatic injuries, but accounts for 30.5% of deaths. Of those affected, 70% are male, with a peak incidence between 15 and 25 years old, although falls (as a causative mechanism) are most common among children (0–4 years) and the elderly (>75 years). Alcohol is a major factor in traumatic brain injury, and it is believed that stricter drink driving laws have led to a reduced death

*Correspondence to: Edward C. Perry III, MD, Spine Nevada Minimally Invasive Spine Institute, 9990 Double R Blvd, Suite 200, Reno, NV, 89521, USA. Tel: þ1-775-348-8800, E-mail: [email protected]

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Table 113.1 2002–2006 TBI average yearly statistics (CDC) Mechanism

ER visits

Admission

Death

Falls Struck by/against Motor vehicle accidents Assault Other Unknown

523 043 271 713 218 936 148 471 108 467 94 165

62 334 7791 56 864 15 341 27 536 105 282

9718 378 16 402 5813 19 252 0

(CDC, 2007) TBI, traumatic brain injury; CDC, US Centers for Disease Control and Prevention; ER, emergency department.

rate in motor vehicle brain injury. Also, recent Cochrane Database reviews have concluded that the use of helmets has definitively reduced head injury-related deaths in moving vehicle accidents (Thompson et al., 2000; Liu et al., 2008). Firearms are a greater cause of head injury admission and death in the US than in other countries. Many of those admitted for head injury will undergo surgical evacuation of a mass occupying lesion, and about 35% will suffer long-term morbidity.

Pathophysiology TBI can be divided into two main mechanisms: point-ofimpact focal injury and diffuse brain injury. These mechanisms occur in the context of two time points that respectively contribute to the clinical outcome: primary (occurring at the time of injury) and secondary (occurring in delayed fashion). Examples of focal injury during the primary insult are cerebral contusions and lacerations, intracerebral hematomas, skull fractures, penetrating gunshot wounds, extra-axial hemorrhages and vascular injury. Contusions are due to direct penetrating or concussive forces on parenchyma (Gennarelli et al., 1982), as well as gliding forces where a brain moving within the skull contacts irregularly shaped bony surfaces such as at the skull base (Holburn, 1945). Coup (or ipsilateral) contusions occur just below impact or fracture site when a stationary head absorbs direct impact. They can also occur on the opposite (or contrecoup) side of the brain as the translating brain tissue decelerates against the opposite side of the skull. Cerebellar tonsils and mesial temporal gyri can undergo herniation contusion against the tentorium. Lacerations of brain occur as a result of significant shearing forces to the parenchyma, and therefore usually represent a severe injury. Intracerebral hematomas (ICH) primarily occur in frontal and temporal lobes due to venous rupture, but can develop over the 24 hours after trauma from contusion injury (Snoek et al., 1979). There is a

subset of hematomas that develop in delayed fashion, and are seen in patients who suddenly deteriorate between 1 and 3 days after trauma due to softening of contused and necrotic cerebrum (Gudeman et al., 1979). Delayed intracerebral hematomas have a mortality of 50—75% (Cohen and Gudeman, 1996). Fractures of the cranium include linear, comminuted, or depressed types. Linear fractures represent the vast majority of pediatric and adult fractures and are for the most part clinically insignificant. In comminuted fractures, the energy dissipates by fragmenting bone, and often occurs where the bone is particularly thin. The depressed skull fracture is of special concern because it can damage underlying brain and may require debridement and elevation, particularly if an overlying scalp laceration leaves dura or cerebrum exposed to the open environment. In addition, vascular damage can occur if it impinges upon an artery or a venous sinus. Penetrating gunshot wounds represent a particularly violent insult to the brain, and are associated with significant intracranial pressure (ICP) elevations due to rapid edema formation. The bullet may traverse vital intracranial vessels. Outcome is particularly poor (with mortality of comatose patients approaching 95%) if the bullet crosses the midline or violates the ventricular system (Benzel et al., 1991). Infections and cerebral spinal fluid (CSF) leaks are considerations that impact future management. Extra-axial hemorrhages include epidural hematomas (EDH) and subdural hematomas (SDH). An EDH typically results from fracture and underlying meningeal vessel injury (most commonly the middle meningeal artery), and are lenticular shaped due to cranial suture constriction of the clot. SDH are crescent shaped compared to EDH since they are confined only by dural folds such as the falx or tentorium. The presence of a SDH is generally indicative of a more serious diffuse brain injury due to the force necessary to tear a low-tension vein. All extra-axial hematomas go through a process of product breakdown, liquefaction, and at least partial absorption, but can become chronic fluid collections that exert mass effect and require later surgical evacuation. Direct vascular injury during TBI can take many forms, including traumatic arterial dissection or pseudoaneurysm formation from directed force to the arterial wall, and carotid-cavernous fistula formation (CCF). CCF occurs when direct or concussive vascular injury induces communication between the carotid artery within the cavernous sinus and the rich venous sinus channels that surround the artery. CCFs cause pulsatile proptosis and visual acuity loss (Debrun et al., 1981). Sinus thrombosis can occur in the major draining sinuses from traumatic injury to these outflow tracts.

NEUROTRAUMATOLOGY 1753 In significant head trauma that results in rotational with outcome (Wu et al., 2004). Cerebral oxygenation forces as well as translational acceleration/deceleration, can be dramatically reduced as all of the above factors acute axonal shear can occur. Sometimes this leads to are summated. Hypoxic episodes significantly increase immediate coma from which the patient never recovers. mortality, and early intubation is advocated (Stochetti If the patient survives, these rotational forces cause difet al., 1996; Winchel and Hoyt, 1997). Newer parenchymal fuse axonal injury (DAI). DAI pathophysiology seems microcirculation monitoring techniques have identified to be related to structural neuronal and vascular changes, 15 mmHg/PtO2 as the minimum oxygen pressure to prevent infarction (Rose et al., 2006), although these with shear forces causing cytoskeletal disruption and loss apparatus have not been fully integrated into current pracof axoplasmic flow. This entity was first described by tice. Most importantly, cerebral infarction has been Strich (1955) and its pathology elucidated by Adams shown to more than double the mortality after TBI et al. (1982). It is characterized by varying states of altered (Tawil et al., 2008). mental status and macroscopic foci of hemorrhage in the Edema patterns in TBI vary depending on the pathoareas of brain most susceptible to rotational shear forces, physiology of both the primary and secondary insults. such as the corpus callosum, dorsolateral rostral brainAround contusions, primary injury leads to vasogenic stem, and pontine tegmental tracts. Microscopic changes edema via arteriolar dysregulation and increased vascuin axonal structure occur diffusely, such as axonal disconlar permeability (Klatzo, 1979). In acute SDH, dysregunect and wallerian degeneration, retraction bulbs, myelin lation and the rapid rate of swelling from hemorrhage breakdown, and gliosis. Often notably absent is hypoxic lead to venous congestion and edema throughout the ischemic changes and only mild brain edema. damaged hemisphere. Later, the injury leads to breakIn primarily damaged areas, secondary insults occur down of blood–brain barrier and additional vasogenic due to changes in cerebrovascular homeostasis. Noredema (Adams et al., 1980). Cytotoxic edema occurs mally regulated cerebral blood flow (CBF) becomes from excitotoxin-induced cell death. Diffuse brain swellderanged and reduced (Bouma and Muizelaar, 1992), ing is more often present in children and is also likely due leading to a switch to anaerobic metabolism (Werner to dysregulated vasodilatation, congestion, and edema and Engelhard, 2007; Andriessen et al., 2010). Mem(Bruce et al., 1981), and this can be dramatic and rapid brane permeability changes lead to edema formation, due to the baseline fullness of the pediatric brain within and loss of ion channel regulation leads to the release the skull. of glutamate (Choi, 1987; Rothman and Olney, 1987; The Lund concept of pathophysiology-based manageBullock et al., 1998). This initiates the neurotoxicity casment of TBI was developed in 1992 (Asgeirsson et al., cade and cell apoptosis. Early hypoperfusion after TBI is 1994; Grande, 2006). Maintenance of cerebral perfusion followed by reactive hyperperfusion due to the impaired (CPP-guided management) and regulation of brain volvasoreactivity. Normal cerebral blood flow (CBF) is conume (ICP-guided management) are the two underlying stant over a range of cerebral perfusion pressures (CPP) goals. The injured brain loses its ability to control overall from 60 to 140 mmHg when autoregulation is functionvolume when the blood–brain barrier is damaged. The ing. In TBI, CBF can be significantly elevated even when resultant edema reduces perfusion due to local hydroCPP is < 60 mmHg. Hyperperfusion elevates the cerestatic pressure increases, particularly around contusions. bral blood volume and causes increasing intracranial The brain lacks a lymphatic system to deal with the fluid pressure from the uncoupling of blood flow and metaboverload, and catabolic breakdown of injured brain furolism (Lassen, 1996; Kelly et al., 1997). The autoregulather increases interstitial osmotic pressures; ICP rises as tion curve is significantly disrupted after TBI a result. Hypothermia, a tool used in some TBI treatment (Enevoldsen and Jensen, 1978; Hlatky et al., 2002), and protocols, has been found to be detrimental to perfusion it is difficult to predict the length of perturbation or cordue to the resultant sympathetic outflow and vasoconrelate it to severity of injury (Werner and Engelhard, striction from systemic stress. The Lund concept also 2007). In addition, hypoxic ischemic injury can occur identifies a collapsible subdural venous outflow system when there is relative hypotension after trauma. It occurs that protects the intracranial compartment from sysin areas of the brain that may have dual end artery vastemic fluctuations, and recommends arterial blood prescular supply but not true anastomoses, such as the antesure control and use of albumin (to normalize volume rior and middle cerebral artery interface. Other status and oncotic pressure simultaneously) to reduce secondary insults include post-traumatic vasospasm, overall brain edema. which is a poor prognostic indicator for outcome as it Elevated ICP results from several factors. Posthas significantly more symptomatic consequences than traumatic cerebral edema that is primarily cytotoxic aneurysmal subarachnoid hemorrhage (Oertel et al., from primary and secondary insults increases ICP. 2005). There is also a reduction in the effective metabolic Post-traumatic hydrocephalus raises ICP, and can be rate of the brain after injury that correlates directly

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either due to subarachnoid hemorrhage (communicating) or interventricular hemorrhage (noncommunicating/ obstructive). Mass effect from hemorrhages can cause elevated ICP due to the fixed space in the cranial vault or blockage of ventricular outflow. Frequent use of ICP monitoring in TBI is advocated because of the relatively low risk of the procedure for the value of the information obtained (Brain Trauma Foundation, 2000). The ICP waveform obtained provides significant information about the environment and compliance of the brain after injury. A recent meta-analysis examining the prognostic role of elevated ICP found that raised but reducible ICP has a three- to fourfold increase in mortality, while refractory ICP (especially values over 40 mmHg) was unequivocally associated with poor outcome (Treggiari et al., 2007). The increased blood volume after TBI can manifest itself on the ICP monitor as plateau waves, manifested by a dramatic increase in ICP up to 50 mmHg with a fall in CPP over 5–10 minutes (Lundberg, 1960). These waves actually highlight the complex feedback loops of compensatory vasodilatation and constriction, suggest preserved cerebral autoregulation, and do not adversely affect outcome (Czosnyka et al., 1999).

Clinical evaluation A comatose state is often present after TBI. Coma occurs by bilateral cortical injury, bilateral thalamic injury, or upper brainstem damage within the reticular activating system. The severity of coma after TBI has been quantitated by different scales that take into account level of consciousness and neurologic activity on admission. The Glasgow Coma Scale (GCS) is the most widely used system (Teasdale and Jennett, 1974), and is listed in Table 113.2. It ranges from a score of 3 (worst) to 15 (best), rating the level of eye opening, verbal, and motor responses. The best score is given regardless of exam symmetry. The verbal portion of the score is modified when patients arrive intubated, automatically making the maximum verbal score a 1 T, with the “T” indicating an intubated status. The relationship of GCS score and TBI severity is listed in Table 113.3. Many studies have shown the correlation between initial GCS score and outcome, and GCS < 6 carries a rate of mortality or vegetative state of 80% (Choi et al., 1988). Neurosurgeons use a GCS score < 8 to determine the need for ICP monitoring. The scale also predicts an increased need for surgical intervention when a drop of two or more points occurs after admission, highlighting the need for frequent neurologic exams in these patients (Servadei et al., 1998). The GCS calculation for a child differs from the adult scoring with consolability and

Table 113.2 Glasgow Coma Scale score Adult

Pediatric

Eye Opening (E)

Score

Eye Opening

Spontaneous To speech To pain None

4 3 2 1

Spontaneous To speech To pain None

Verbal response (V)

Crying/interaction

Oriented Confused Inappropriate

5 4 3

Incomprehensible None (intubated)

2 1 (1T)

Smiles/interacts Consolable/inappropriate Sometimes consolable/ moans Inconsolable/restless None (intubated

Motor response (M)

Motor response

Follows commands Localizes to pain Withdraws to pain Flexor posturing Extensor posturing None

Follows commands Localizes to pain Withdraws to pain Flexor posturing Extensor posturing None

Table 113.3 TBI classification and GCS score TBI classification

GCS score

Severe Moderate Mild

3–8 9–12 13–15

TBI, traumatic brain injury; GCS, Glasgow Coma Scale.

level of interaction replacing verbal scoring (Hahn et al., 1988). The interpretation of the GCS score can be affected by some clinical parameters. Sedation given in transport from the scene of the accident or intoxication of drugs or alcohol can depress consciousness, so sedation should be held to obtain the best exam and toxicology levels should be checked on admission. A cervical spinal cord injury can cause loss of motor responses and therefore lower the GCS, although consciousness may be maintained. There are other scales to grade TBI. Developed as a tool for retrospective research, the Mayo grading system classifies TBI into three categories focusing on positive

NEUROTRAUMATOLOGY indicators of TBI that would be less likely to be affected by confounding conditions such as sedation or systemic shock: symptomatic (possible), mild, and moderatesevere (Malec et al., 2007). The Swedish reaction scale is based on findings in acute cerebral disorders including TBI (Stalhammar et al., 1988), but does lack some specificity for identifying moderate TBI, as does the GCS scale (Johnstone et al., 1993). There are many clinical signs of TBI that the assessor can use to determine the extent of injury. The relative asymmetry of the motor and pupil examination is particularly helpful for determining if extra-axial hemorrhages exist. Note that unilateral orbital injury may cause traumatic dilation of one pupil. Patients with significant basofrontal contusions may exhibit varying degrees of an agitated or abulic exam. A symmetric but nonparticipatory motor exam in an incomprehensible patient with no eye opening is often a marker of diffuse head injury and DAI. Depressed level of consciousness, asymmetry and progressive dilatation of the pupils with contralateral hemiparesis often indicate impending transtentorial herniation from a mass lesion that may require emergent surgical intervention. Of particular concern is the patient that talks and then deteriorates, often more notable in patients with initial GCS score under 13, age over 50, and with significant CT findings, again highlighting the need for frequent neurologic checks (Marshall et al., 1983b). Other herniation syndromes include tonsillar herniation through the foramen magnum that can initially present with neck stiffness and head tilt. If there is enough compression of the brainstem, respiratory arrest can occur so these patients must be watched diligently. Subfalcine herniation

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can be seen radiographically with unilateral frontal massoccupying lesions, but rarely produces any clinical effect.

Imaging The use of appropriate and timely radiographic imaging supplements the clinical exam. Computed tomography (CT) of the head is the gold standard for acute trauma, as it is quickly obtained and provides significant information. Acute hemorrhage on CT is hyperdense and the mass effect on parenchyma can be evaluated. Fractures are seen well on bony windows. Fine cuts on the CT can be utilized to evaluate trauma to intricate temporal bone and skull base structures and guide management. Linear nondisplaced fractures are treated conservatively, but if they overlie important vascular structures they should alert the clinician to possible arterial and venous injury. Examples of these include temporal bone fractures near the middle meningeal artery, and occipital bone fractures over the dural sinuses, both of which can cause EDH (Fig. 113.1). Skull base fractures are often indicative of significant head injury because of the force necessary to fracture thick bone such as the petrous temporal bone. Cranial nerves can be involved if these fractures involve neural foramina or bony casings, such as the facial nerve within the temporal bone. Coronal and 3D reconstructions of source images are useful for depressed skull fractures and operative decision making. Pneumocephalus (intracranial air outside of the sinuses or mastoid air cells) can be seen on bony windows, suggests a mastoid or sinus fracture, and alerts the clinician to look for active or future CSF leak. Loss of a clear

Fig. 113.1. Diffuse brain injury with effacement of basal cisterns, loss of sulcal gyral pattern, as well as a thin subdural hematoma after being hit by a high-speed vehicle. This patient succumbed to his injuries despite decompressive hemicraniectomy.

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sulcal–gyral pattern and effacement of cisterns indicate brain edema, as seen in Figure 113.2. Effacement of ventricles or enlargement of ventricles suggest elevations in ICP from brain edema and hydrocephalus respectively. Contusions have a mixed hyper- and hypodense appearance on CT, as immediate concussive injury is interspersed with necrotic areas that can form hemorrhages over 1–2 days (Fig. 113.3). Significant midline axial shift

Fig. 113.2. Bilateral epidural hematoma with associated skull fracture after nonaccidental trauma. This very young patient had a respiratory arrest soon after admission.

Fig. 113.3. Basofrontal contusion with mild subfalcine mass effect after a fall down concrete stairs. This patient recovered from his injuries with mild cognitive deficits and aphasia.

can be seen with edema or mass occupying lesions, and is more predictive of a poorer outcome than sagittal or vertical displacement. There are considerations about relative cancer risk from frequent CT scans and its use in pregnant patients. It is common practice in local emergency rooms to obtain a head CT in any patient with reported recent head trauma or fall, but criteria have been proposed to delineate when imaging is warranted and to address unnecessary utilization. The New Orleans criteria (Haydel et al., 2000) were developed to help decide which patients with minor head trauma, normal GCS scores, and normal neurologic exams warranted surveillance CT scans. An increasing number of seven symptoms patients had improved the sensitivity for positive radiographic findings toward 100%: headache, vomiting, age over 60, drug or alcohol intoxication, shortterm memory problems, supraclavicular trauma, and seizure. The Canadian CT Head Rule for minor head trauma derived five high-risk factors to predict the likelihood of positive findings: failure to reach a GCS of 15 within 2 hours of injury, open skull fracture, signs of basilar skull fracture such as periorbital ecchymosis, two or more vomiting episodes, or age over 65 (Stiell et al., 2001). These two methods were compared recently, and the Canadian Rule was found to be more specific for predicting neurosurgical intervention (Stiell et al., 2005). In general, CT imaging should be obtained in any patient that has any of the following: loss of consciousness of more than 5 minutes, worsening mental status, seizure, focal deficit, amnesia lasting more than 24 hours, penetrating skull injury, clinical evidence of basal or depressed skull fracture, and significant aggression or confusion. As already mentioned, there are distinct CT changes that should alert the physician to the severity of TBI, and the possible need for surgical intervention. The Marshall criteria in Table 113.4 outlined early predictors of poor outcome (Marshall et al., 1991, 1992). The criteria have been modified over the years to include several findings that predict a poor outcome in serious TBI. These include obliteration of basal cisterns, significant midline shift, large mass effect-inducing hemorrhages, and significant interventricular blood (Maas et al., 2005). The classification also predicted the severity of TBI, with abnormal CT findings in only 2.5–8% in mild (GCS 13–15) TBI, while 68–94% of severe (GCS < 9) TBI patients have at least one of the findings listed above. Absent basal cisterns may be the most predictive, with a mortality of over 75% (Toutant et al., 1984). A recent study of contusions showed an initial size > 14 mL and presence of a subdural hematoma (correlating to severity of injury) predicted radiographic progression, and up to 20% may require surgical intervention for mass effect (Alahmadi et al., 2010).

NEUROTRAUMATOLOGY Table 113.4 Marshall CT classification of TBI Category

Definition

Diffuse injury I Diffuse injury II

No visible pathology on CT scan Cisterns are present with midline shift < 5 mm and/or lesion densities present No high or mixed-density lesion > 25 mL, may include bone fragments and foreign bodies Cisterns compressed or absent with midline shift 0–5 mm No high or mixed-density lesions > 25 mL Midline shift > 5 mm No high or mixed-density lesions > 25 mL Any lesions surgically evacuated

Diffuse injury III

Diffuse injury IV

Evacuated mass lesion Non-evacuated mass lesion

High or mixed-density lesion > 25 mL, not surgically evacuated

CT, computed tomography; TBI, traumatic brain injury,

There are modalities within the spectrum of tomographic imaging that provide other useful information. Involvement of the carotid canal in a skull base fracture warrants a CT angiogram (CTA), as carotid dissection occurs in 40% of patients with petrous carotid canal fracture (York et al., 2005). CTA is more effective for identifying wall abnormalities (such as traumatic pseudoaneurysm or dissection) and less invasive than a formal angiogram. CT perfusion imaging allows measurement of CBF and may have some benefit as a supplement to CPP obtained from monitoring, since CPP and CBF autoregulation is altered in TBI (Wintermark et al., 2004). CT perfusion also helps determine the volume of ischemic versus infarcted tissue to guide therapy and provide prognosis. CT spectroscopy (SPECT) can also reveal abnormalities in CBF. A negative post-TBI SPECT has been shown to have some utility in predicting a good long-term outcome (Jacobs et al., 1996). Other imaging modalities have been used. Magnetic resonance imaging (MRI) is another option in TBI, and is considered to be superior 2–3 days after injury (Lee and Newberg, 2005). It is more sensitive than CT for neuronal damage and stroke, brainstem injury (which CT cannot detect due to skull base beam artifact), as well as smaller multifocal hemorrhages seen in DAI. Hypoxic ischemic injury is easily identified on diffusionweighted MR sequences. MRI can be helpful to date subdural hematomas, as the changes that occur in

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T1- and T2-weighted sequences reflect the location and type of hemoglobin in the clot over time (Atlas and Thulborn, 2002). MRI is also more sensitive than CT for picking up small SDHs as is seen in child abuse (Gentry et al., 1988) and for detection of traumatic subarachnoid hemorrhage, especially gradient echo and FLAIR sequences (Wiesmann et al., 2002). It does not use the ionizing radiation of CT, so it is considered safer in children and pregnant patients. Despite its utilities, no relationship has been established between MRI appearance of the brain after traumatic injury and neurologic outcome (Levin et al., 1989). MR arteriography and venography can identify vascular injury, including sinus thrombosis. MR spectroscopy can reveal a reduced N-acetylaspartate/creatinine ratio indicating neuronal loss, but its utility in predicting outcome in TBI remains unclear. Position emission tomography (PET) scans can identify disturbances in autoregulation by changes in local metabolism, but the technology is not universally available and resolution of anatomic areas is not as sharp as MRI or CT. Electroencephalography (EEG) is useful for identifying subclinical seizure activity exhibited by some TBI patients, and plays a role in brain death determination. The future modalities which may enter the diagnosis and management of TBI include functional MRI and tractography, which may provide prognostic information for patients on the function they can expect to be affected after their injury and to track the progress of recovery.

Management The crucial parameter in the treatment of TBI is avoidance of cerebral ischemia by maintaining CPP. CPP is generally defined as mean arterial blood pressure (MAP) minus ICP. CBF is relatively constant when the CPP is between 60 and 140 mmHg in the normally autoregulated brain. Therefore, despite the derangement of autoregulation in TBI, the goal of CPP management is generally > 60–70 mmHg, and has been shown to improve neurologic outcome (Changaris et al., 1987; Rosner and Daughton, 1990). The medical algorithm for management of severe brain injury and any resultant elevated ICPs is generally based on Brain Trauma Foundation guidelines published in 1996 in collaboration with the American Association of Neurological Surgeons (Bullock et al., 1996). These guidelines were developed by the leading experts in the field, and have been shown to reduce hospital days and charges and improve outcome score measures (Fakhry et al., 2004).

ACUTE MEDICAL MANAGEMENT OF TRAUMATIC BRAIN INJURY

The following principles represent our general guidelines for management of head trauma patients. First

1758 E.C. PERRY III ET AL. are appropriate volume administration, resuscitation studies that show no early or late post-traumatic seizure and maintenance of blood pressure including placement prevention benefit (Young et al., 1983a, b). Furthermore, of an arterial line. One episode of inadequate mainteno evidence exists that prevention of early seizures has nance of systolic blood pressure over 90 mmHg has a any effect on TBI outcome. 150% increase in mortality (Chesnut et al., 1993), and Administration of broad-spectrum antibiotics for outcome seems to be improved as systolic blood pressure open depressed skull fractures is a consideration. There (SBP) is maintained up to 135 mmHg (Butcher et al., are limited studies supporting prophylactic antibiotics 2007). This must be balanced against over-resuscitation for open depressed skull fractures. The incidence of that can contribute to brain edema. Hypertonic saline has meningitis is not affected, but the rate of infectionbeen advocated in the trauma literature as an alternate related complications is improved with antibiotics volume expander to treat hypotension in severe head (Demetriades et al., 1992). trauma, and it has some osmotic effects to reduce cereNutritional support using enteral or parenteral forbral edema (Vassar et al., 1993). It can be used in hypomulas should be instituted soon after injury. The brain volemic patients when mannitol would exacerbate that trauma foundation has a guideline recommendation state. Hypertonic saline does not have the renal sidefor replacing 140% of resting metabolism expenditure effects of mannitol, but it requires central line placein nonparalyzed patients and 100% of resting metaboment. Dextrose solutions are not recommended, as lism expenditure in paralyzed patients, with at least hyperglycemia worsens outcome after TBI. 15% of calories as protein (Bullock et al., 1996). Maintaining oxygenation is also paramount to a good clinical outcome. Hypoxia defined as PaO2 < 60 mmHg MEDICAL MANAGEMENT OF ELEVATED exacerbates ischemic brain injury and predicts poor outINTRACRANIAL PRESSURE come. Laboratory evaluation should be undertaken, including hemoglobin, platelet count, coagulation proTreatment for elevated ICP traditionally starts when ICP is > 20, based on the only randomized controlled trial on files, chemistry panel including sodium, blood alcohol this subject (Eisenberg et al., 1988) and other studies level and urine toxicology. Timely completion of appropriate cranial imaging based on previously mentioned (Marmarou et al., 1991). Control of ICP is the most sigcriteria helps guide crucial clinical decision making. nificant way to improve outcome in TBI. Several steps The patient should be admitted to the intensive care unit assist in successful treatment. Taking into consideration for frequent neurologic examinations and monitoring. appropriate spine injury precautions should they need to Evaluation of secondary injuries and general medical be applied, the head can be positioned upright and eleconditions that may be risk factors for future surgical vated to maximize venous return and reduce ICPs. Vasopressors should be used as needed to augment MAP and intervention should be performed. thereby improve CPP. Sedation can be used in the acute ICP monitor or external ventricular drain (EVD) placement is one of the cornerstones of management setting to reduce metabolic demands on the brain and due to the relationship of ICP to CPP. An ICP monitor resultant elevations in ICP. In the first 1–2 days propofol should be placed in any patient with a GCS < 8 and an is preferred because of its short time of action, facilitating abnormal CT scan, or in patients with normal CT, frequent neurologic exams. Propofol infusion syndrome GCS < 8, and any two of the following: age > 40, unilatis characterized by metabolic acidosis, cardiomyopathy, eral extensor posturing or systolic blood pressure and renal failure (Vasile et al., 2003). To avoid this, sedation is switched to fentanyl and Versed (midazolam) for 8 and without focal deficits may be treated conservatively. Second, any IPH with no neurologic compromise, controlled ICP, and without CT mass effect may be closely observed. These guidelines are derived from class III evidence that includes case series, case reports, comparative studies with historical controls, or expert opinion.

PEDIATRIC MEDICAL MANAGEMENT OF ELEVATED INTRACRANIAL PRESSURE

The pediatric guidelines were published in 2003 (Adleson et al., 2003), and share similar basic principles with the adult counterpart. CPP goals are > 70 mmHg, and treatment should begin when ICP is > 20 mmHg. There are some differences. First-line therapy for ICP control is external ventricular drainage, with the addition of lumbar drainage considered if no mass-occupying lesion exists and basal cisterns are open. Second-line therapy is hyperosmolar treatment, mannitol, or hypertonic saline. Third-line therapy includes hyperventilation, barbiturate coma, and decompressive craniectomy. MAP goals are > 80 mmHg for children age 5–12 years old, >75 mmHg for age 2–5 years old, and > 65 mmHg for < 2 years old.

TREATMENT OF PERSISTENT ELEVATIONS IN INTRACRANIAL PRESSURE

In addition to barbiturate coma mentioned earlier, surgery can be considered for intractable intracranial

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hypertension. Decompressive craniectomy has been recently reviewed in the Cochrane Database (Sahuquillo and Arikan, 2006). Current data consist of all nonrandomized studies except one randomized trial in the pediatric population (Taylor et al., 2001). That study of 27 patients showed some reduction in mortality and unfavorable outcome, defined as severe disability, vegetative state, and death. There are two randomized trials ongoing that may lead to further conclusions, the Rescue ICP in Europe and DECRA study in Australia.

SURGICAL GUIDELINES FOR TRAUMATIC BRAIN INJURY Several surgical procedures exist with the goals of removing mass effect within the cranial vault, reducing the effects of elevated intracranial pressure, or repairing overlying bony fractures. Craniotomy for evacuation of supra- and infratentorial hematomas remains the most common procedure performed. The surgery involves removal of an overlying bone flap and decompression of the brain (and by opening the dura as well in the case of SDH and IPH). If the brain is soft and pulsatile at the end of the case, the dura is loosely closed and the bone flap secured back into place before skin closure. Decompressive craniectomy is often utilized when the brain exhibits more diffuse hemispheric swelling. This is sometimes a salvage procedure in severe TBI when all other attempts at ICP control have failed. If there is a unilateral predominance to the edema, the majority of the cranial vault on that side is removed and left off. Bilateral craniectomy can be performed when the cerebral edema is symmetric (Whitfield et al., 2001), but this increases the morbidity of the procedure significantly. There is much debate in the literature as to whether this therapy should be considered very early after TBI. The procedure necessitates that the bone flap or a custom-fitted prosthetic substitute be reimplanted at a later date. This reconstructive procedure should be undertaken within 2 months to prevent scarring of the exposed dura to the overlying galea, which makes the cranioplasty more difficult. Open depressed skull fracture repair and removal of foreign objects represent a special subset of TBI. Communication between the intracranial compartment and the penetrating object that caused the scalp laceration and cranial fracture is considered contaminated, and warrants careful elevation, debridement, and closure to prevent CSF leak. Included in this treatment spectrum is frontal sinus fracture repair. The flora present in the paranasal sinuses can cause meningitis if contacting the cerebrum via a lacerated dural covering. These are often treated surgically with a bicoronal craniotomy, obliteration of the frontal sinuses, followed by dural repair and sinus outlet occlusion. No communication between the

inhaled air and the intracranial compartment should exist after surgery, as this puts the patient at risk for persistent CSF leak. Other procedures exist for certain post-TBI surgical problems. Optic nerve decompression for orbital fracture is usually done in conjunction with ophthalmologists to save visual acuity or decompress trapped extraocular muscles. Placement of a ventriculoperitoneal shunt after TBI may be necessary. A subset of patients who develop post-traumatic hydrocephalus will become dependent on their external ventricular drain. Internalization of the drain is done via cranial and abdominal incisions, with a tunneled subcutaneous catheter linking the two to allow drainage of CSF into the peritoneal space. These patients have a 10% infection rate of the implanted devices, and must be watched for signs and symptoms of failure for the remainder of their life. Endovascular obliteration of traumatic carotid-cavernous fistula may be performed. Vision loss, painful proptosis, and an orbital bruit signify a communication from the high-flow carotid artery into the draining sinuses. A detachable balloon can be deployed with endovascular tools to occlude the fistula and potentially save vision. There are general operative indications for traumatic intracranial hemorrhages based on clinical and radiographic parameters, again taken from the TBI surgical guidelines (Bullock et al., 2006a, b, c). EDHs are considered surgical emergencies for GCS < 9 with anisocoria, or if the EDH volume is > 30 cm3 regardless of GCS. SDHs are considered surgical if > 1 cm or midline shift (MLS) > 5 mm regardless of GCS, or if < 1 cm with MLS < 5 mm with GCS < 9 when the GCS has decreased by 2 or more during transport, the patient has asymmetric pupils, or has an ICP > 20. An IPH is considered surgical when there is a mass lesion with coinciding neurologic deficit and refractory ICP, or if the IPH volume is > 50 cm3. Depressed skull fractures sometimes require surgical interventions. In general, criteria for elevation of depressed fragments include: >1 cm depression (roughly the thickness of the skull), cosmetic deformity such as frontal bone fracture, neurologic deficit that can be correlated to underlying damaged brain, a CSF leak, or an open fracture with visible brain parenchyma or dura. These guidelines are again based on class III evidence. As one can imagine, the feasibility of a randomized controlled trial comparing outcome in operative versus conservative management in acute hemorrhage such as EDH is low.

Outcomes Outcomes after TBI are reported most frequently using the Glasgow Outcome Scale (GOS) (Jennett and Bond, 1975). In broad terms, the GOS score is considered

NEUROTRAUMATOLOGY 1761 favorable for 4 (moderate disability with some indepenThe cervicothoracic and thoracolumbar junctions are dence) or 5 (good recovery), and not favorable for 1 particularly sensitive to mechanical loads due to the (death), 2 (vegetative state), or 3 (severe disability requirabrupt change in the way stress is distributed at those ing daily care). When the major head injury trial levels. The ribcage makes the thoracic spine relatively (Edwards et al., 2005) and databases (Maas et al., fixed. Each segment has a curve to it that provides bio2007) were looked at collectively, several factors have mechanical stability: cervical lordosis, thoracic kyphosis, been associated with a poor outcome in head trauma. and again lordosis in the lumbar region. The cervicothorThese include age over 40, loss of pupil reactivity, posacic and thoracolumbar junction are relatively flat and turing on motor exam, and Marshall CT criteria III or this increases stress at those points. Parts of the cord more, particularly compressed cisterns and traumatic parenchyma that have a rich blood supply (such as the subarachnoid hemorrhage (Steyerberg et al., 2008). conus medullaris) suffer less perfusion-related secondOther factors that contribute to poor outcome are persisary injury than vascular watershed areas like the upper tently elevated ICP, hypotension, hypoxia, and anemia thoracic spine. (Miller et al., 2004). Patients who required surgery for a mass-occupying hemorrhage do worse overall. In mild Pathophysiology TBI, clinical factors of younger age, higher alcohol toxAs with TBI, SCI occurs due to primary and secondary icity and presence of facial fractures have been shown to be more predictive of outcome than CT appearance insults. Primary traumatic forces on the bony and liga(Jacobs et al., 2010). mentous integrity of the spinal column can cause fracture or disruption, and these forces are transmitted to SPINAL CORD INJURY the neural tissue within. Bony fractures can compress the spinal cord directly, especially when there is abnorEpidemiology mal angulation due to the fracture. Distraction and shear Approximately 10 000 patients each year suffer a spinal forces result in gross tearing of long tracts. Rupture of cord injury (SCI) (Nobunaga et al., 1999). Infrastructure vessels can cause an EDH or SDH that can have comsuch as the National Spinal Cord Injury Database and pressive effects. Penetrating trauma causes direct injury hospitals that participate in the Model Spinal Cord Injury to the tissue. Intrinsic damage can occur as well. TranSystems have been instrumental in centralizing and stansient loss of function as is seen in spinal cord concussion dardizing epidemiologic and outcome data to aid practiis its mildest form, and by definition resolves within 72 tioners in defining treatment standards for this difficult hours (Zwimpfer and Bernstein, 1990). Intraparenchyto treat spectrum of neurologic disorder. Some trends mal contusion and hemorrhage can be noted on MRI. have emerged in SCI over the past decade when comEven with extreme trauma, it is rare to have complete pared to previous data. Although motor vehicle accitranssections of the cord. Animal studies have verified dents still account for over 50% of injuries, the that viable axons in varying states of continuity are preaverage age of patients suffering SCI has risen to 37 sent below the level of injury when there is some preser(National SCI Statistical Center, 2005), and falls have vation of function (Fehlings and Tator, 1995; Kwon et al., become the fastest growing mechanism of injury, espe2004). It is the preservation of the intact axons and mincially in those over 60 (Jackson et al., 2004). Another imizing secondary injury that is the goal of therapeutics trend has been the increase in cervical cord injury (versus (Tator and Fehlings, 1991; Amar and Levy, 1999). thoracolumbar) and incomplete tetraplegia. This is likely The primary injury can cause gross instability of the due to advanced age of patients with cervical spondylospinal column. This has been defined by several criteria. sis who have trauma and suffer intrinsic cord damage The spine is divided into three bony columns: anterior from hyperflexion or extension. Pediatric spinal columns (comprised of the vertebral body), middle (the pedicles, have increased ligamentous laxity, which creates inherfacets and pars interarticularis), and posterior (the lament instability and a predisposition to distraction injuries. ina and spinous process). Fracture of more than one colAdults as a whole have fairly rigid spinal columns with umn increases instability, and fracture of all three poor bone quality, and suffer traumatic bony damage columns is considered grossly unstable. Classification and neurologic injury from fracture impingement. Spisystems to link injury to outcome have been developed nal cord injury without radiographic abnormality for both the subaxial cervical spine (C3–7) (Dvorak (SCIWORA) is therefore more common in younger et al., 2007) and the thoracolumbar spine (Vaccaro patients (Pang and Wilberger, 1982) due to this ligamenet al., 2005) by the Spine Injury Study Group. The three tous laxity, particularly in those under 8 years old. main criteria are mechanism, integrity of the discoligaOther factors contributing to SCI include segmental mentous complex, and extent of neurologic deficit. differences in spine biomechanics and vascular supply. Mechanism of injury is an important consideration in

1762 E.C. PERRY III ET AL. determining stability. Fractures that involve rotation and that is a reactive process to primary insult. Arachnoiditis translation of the spine are generally considered highly causes clumping or scarring of the lumbar roots to the unstable. The White and Panjabi criteria contain several periphery of the thecal sac. Patients can get variable pain radiographic measures of cervical spine instability, syndromes from the tethering. Neuropathic pain is the including: >3.5 mm listhesis of a vertebral body on broad term used to describe this type of traumatic another, angulation of > 11 , or sagittal plane sequelae. As a result of the neurologic trauma and axorotation > 20 on dynamic imaging (White and Panjabi, nal damage, abnormal signals occur at rest and in 1990). Although only one or maybe two columns are response to simulation, including burning dysesthesias, involved, compression fractures of the lumbar spine hyperalgesia, and allodynia to light touch. These can are considered increasingly unstable when: there is more be very distressing to patients and troubling for practithan 50% of height loss, there is more than 40 of tioners to treat. kyphotic angulation, more than three levels are consecutively involved with fracture, or there is progressive Clinical evaluation kyphosis (Greenberg, 2001). The mechanisms of SCI secondary insults have some SCI should be presumed until proven otherwise in any polytrauma patient with significant mechanism of injury, similarities to TBI, including microvasculature disrupespecially one with hypotension and bradycardia that may tion and loss of local autoregulation (Senter and Venes, 1979; Tator and Fehlings, 1991). This makes the be a sign of spinal cord disruption and shock. Some clintraumatized cord especially sensitive to hypotension that ical signs are flaccid paralysis of the extremities, signifioften occurs from systemic injuries and loss of autocant abdominal breathing (from phrenic nerve palsy), loss nomic tone. Reperfusion injury after this initial hypoperof rectal tone, and priapism. Documentation of abnormal fusion worsens the already ongoing free radical autonomic reflexes is particularly important in the unconproduction and lipid peroxidation that peaks at about scious patient that cannot participate in a motor and sensory exam. Markers of myelopathy such as clonus do not 48 hours (Lukacova et al., 1996). Cell excitotoxicity from manifest themselves in the acute setting. Rather, patients injury-induced glutamate release causes similar acute phase intracellular cascades that are seen in TBI. Necroin spinal cord shock are areflexic. sis stems from the direct primary injury and continues Spinal cord injury is classified as complete (no motor, over the next week (Ducker et al., 1971). Impact can be sensory or autonomic function exists below the injury, made only to prevent further primary injury, such as which occurs in about 50% of injuries), or incomplete strict immobilization and spinal fixation. Apoptosis, (some measure of function is retained) (Tator and on the other hand, is an energy-dependent process that Fehlings, 1991). There are several incomplete spinal cord injury syndromes that can be diagnosed primarily on the occurs around the area of primary injury. This is the physical examination. Brown-Se´quard is a hemicord pathologic process that has potential for improvement with interventions. Post-traumatic spinal cord edema injury occurring in 2–4% of traumatic SCI, and most occurs within hours of injury and can exacerbate the often resulting from penetrating injury such as a stab compression from extrinsic bony fractures. The inflamwound. Contralateral sensory dissociation and ipsilateral matory cascade that is initiated within the spinal cord weakness below the lesion are the hallmark features, but within hours of injury has both neurotoxic (Bethea there is significant variation due to uncrossed contribuet al., 1999) and neuroprotective (Cheng et al., 1994) tions of most spinal cord tracks. It has a relatively good prognosis with up to 90% regaining ambulation (Roth effects, and it remains unclear how these pathways could et al., 1991). Central cord syndrome occurs in hyperexbe manipulated to reduce secondary injury to neural tissue. After 2 weeks, macrophage infiltration and scar fortension injuries, often when there is coexisting cervical mation is generally considered irreversible as the injury spondylosis (Schneider et al., 1954). These patients have passes into the subacute phase (Rowland et al., 2008). upper more than lower extremity weakness. This is due Several phenomenon can arise as a result of SCI. A to cervical fibers being more medial and therefore more syrinx can form that does not properly communicate susceptible to central watershed area ischemia than with external CSF spaces, and can accumulate over time lower extremity fibers. The pain and sensory loss is variable, but often described as cape-like across the shouland worsen myelopathy. The etiology of a postders with numbness more in the hands. Football players traumatic syrinx is unclear, but may be related to pulsatile surges of CSF or coalescence of microcysts that have can have “burning hands syndrome” after axial load or formed during the apoptotic process (Kao et al., 1977; hyperextension/flexion cervical spine injury due to the Greenberg, 2001). Arachnoiditis can be caused both same decussating pain tracts being affected (Maroon, from the initial trauma and from recurrent surgeries. 1977). Outcome is generally favorable for ambulation It involves scarring of the dura layers to varying degrees but variable for hand function.

NEUROTRAUMATOLOGY Other cord syndromes include anterior cord syndrome and cruciate paralysis. Anterior cord syndrome results from anterior spinal artery occlusion or compression from fracture or disc herniation (Schneider, 1956). Patients have bilateral motor loss below the lesion and contralateral dissociated sensory loss (from posterior columns remaining intact). It is important to obtain imaging to uncover surgical etiologies (i.e., disc herniation and fracture impingement), but overall the prognosis for recovery of function is poor because of the vascular nature of the ischemic insult. Cruciate paralysis is characterized by bilateral > unilateral upper extremity weakness with less involvement of the lower extremities. It occurs after cervicomedullary junction injury, often from traumatic fracture of cervical (C) vertebrae 1 or 2 with atlantoaxial instability. The anatomic basis for cruciate paralysis was described by Wallenberg (1901), and is due to the specific organization of decussating corticospinal tract fibers at the level of pyramids, as the crossing arm fibers lie deeper in the ventral cord (Dickman et al., 1990) and cross more rostrally than leg fibers (Bell, 1970). There may also be involvement of the spinal tract of cranial nerve V and the spinothalamic tract centrally, leading to unilateral face and upper extremity hyperalgesia that is usually transient. After either halo or surgical fixation of associated instability or fracture the majority of patients experience improvement in symptoms. Conus medullaris and cauda equina syndromes can uncommonly arise from acute spinal cord compression in the lumbar spine such as traumatic two or three column fracture. These fractures cause retropulsion of bony fragments into the spinal canal that impinge upon neural elements. The conus is located at the end of the spinal cord, most commonly at lumbar (L) vertebrae 1 or 2 in adults. Conus medullaris syndrome is usually acute in onset, mildly painful, and shows symmetric motor loss, areflexia, saddle anesthesia, with prominent bladder dysfunction. This is contrasted with cauda equina syndrome, caused by compression of different roots that arise from just above the conus, and usually presents as painful radiculopathy with asymmetric motor weakness and often a unilateral sensory loss. Both are treated as surgical emergencies when radiographic evidence of compression is found on MRI and CT. Outcomes are similar for both entities in terms of return of function and residual bowel and bladder problems, and anterior and posterior approach surgeries play a vital role for decompression and stabilization (Kingwell et al., 2008). Several scales have been devised to standardize SCI grading. The American Spinal Injury Association (ASIA) scoring system grades 10 motor segments in upper and lower extremities (ASIA, 2002). The score

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sheet is shown in Figure 113.4. A score is given for each segment from 0 (no contraction) to 5 (full against resistance) on both left and right sides for a total possible score of 100. C5 (deltoid) down to sacral (S) 1 (gastrocnemius) are tested. There is also a sensory score that tests light touch and pinprick in the C2 to S4–5 dermatomes, with a maximum score of 112 for both. The sensory and motor score are summed to give a letter grade to the severity of impairment from A (complete) to E (intact). The absence of any sensory function around the anus (in addition to total motor and sensory loss) signifies a complete injury, or A. The most cephalad level of function is designated. Functional outcome scales associated with the ASIA also exist, and many studies have been performed comparing intraobserver variation. A scoring system had been devised previously called the Frankel scale (Frankel et al., 1969), but has largely been replaced due to the lack of specificity. The ASIA is the most utilized scale currently for immediate assessment, although guideline review by the joint spine sections of both neurologic surgery associations in the US in 2001 could only recommend its use as an option, as no class I evidence exists (Spine Section, 2001).

Imaging The cornerstone of radiographic decision-making is subjective and objective findings on history and physical exam. Approximately 56% of patients who have a cervical SCI have an associated fracture, compared to 100% and 85% for thoracic and lumbar SCI (Pickett et al., 2006). Some 20% of patients who have a SCI have another injury to the spine at different segment, so a high level of suspicion for multilevel imaging should be exercised. Areas of the spine with reported pain and tenderness to palpation should raise clinical suspicion. The Eastern Association of Surgery for Trauma (EAST) criteria are the most commonly used algorithm for choosing the appropriate cervical spine imaging to rule out injury (Marion et al., 1998). In an awake, neurologically intact patient not reporting neck pain and without distracting injury or acute intoxication, EAST guidelines dictate that no imaging is necessary and the patient can be cleared clinically. If any of the above parameters are not met, then three-view cervical X-rays supplemented with CT imaging in questionable areas should be obtained. CT is particularly sensitive for C1 and C2 fractures that can be missed on plain X-rays, and should be obtained on any comatose trauma patient. Any patient with neurologic deficit should get immediate spine subspecialty consultation, and then emergent CT and MRI, as no one modality can pick up all injuries. Plain X-rays have a more limited value in the modern world of CT technology access. They are still useful for

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E.C. PERRY III ET AL.

Fig. 113.4. ASIA scoring sheet.

rapid screening of polytrauma patients, dynamic testing (such as flexion extension X-rays) during spinal clearance, and for surveillance of in-line traction and closed reduction techniques. CT is the gold standard, particularly with coronal, sagittal and 3D reconstructions, to allow multiple stereotactic views of bony relationships (see Fig. 113.5). CTA can be easily supplemented to evaluate vascular structures such as the vertebral artery as it courses through the cervical transverse foramen. CT myelogram can be used when the patient is unable to tolerate an MRI, or there is a contraindication such as metal in the spinal canal. MRI is a more time-consuming study, but it is critical in the patient that has a SCI with neurologic deficit, especially if the patient is unconscious and cannot participate in an exam. This modality definitively reveals possibly operative pathology that other imaging cannot, such as a ruptured/herniated traumatic disc or an epidural hematoma. STIR sequences of the MRI can show ligamentous injury such as the transverse ligament dorsal to the dens of C2, and the posterior interspinous ligaments (see

Fig. 113.6). These are important for determination of spinal stability. MRI is crucial to rule out SCIWORA. Intrinsic injury to the cord can be identified, providing prognostic information in explaining deficit such as contusion or edema. MRI does have shortcomings when obtained more than 72 hours after injury. Changes noted in intrinsic or extrinsic tissue may be reactive hyperemia rather than true injury. Therefore, an MRI should be obtained early after the event, as documented in the EAST protocol for appropriate spine clearance.

Management ACUTE MEDICAL MANAGEMENT OF SPINAL CORD INJURY The following principles guide our acute management of SCI. Appropriate volume resuscitation at the scene of the accident is paramount during the initial period after injury. In the field, patients should be placed in hard cervical collars, or even better, on a rigid backboard with sandbag or tape immobilization of the neck and head. Thoracic-lumbar-sacral precautions should be initiated

NEUROTRAUMATOLOGY

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Fig. 113.5. Traumatic fracture dislocation of T7, 8, 9 with kyphotic angulation and complete spinal cord injury (SCI) after being ejected from a car. Patient underwent long segment posterior fusion and kyphotic correction the day after injury to facilitate mobilization to SCI rehabilitation.

Fig. 113.6. Traumatic fracture of the dens with spinal cord injury (SCI) after a high-speed boating accident. The MRI STIR sequence above shows hyperintensity and trauma to interspinous ligaments that added to his instability. This patient underwent halo reduction followed by C1/2 posterior fixation and was discharged to TBI/SCI rehabilitation.

in the field with placement of patients on rigid backboards, and continued with careful logroll precautions during hospital examinations to maintain spinal alignment. Airway protection and oxygenation are key, particularly in high cervical cord injuries where aspiration is a risk and phrenic nerve injury might be present. Oxygenation should be maintained with a PaO2 > 60. Patients who cannot control their airway should have fiber optic intubation techniques used. Intravenous steroids should be administered if the patient has reached the care facility within the appropriate time frame. Randomized controlled trials (NASCIS I, II, III) using methylprednisolone showed improved neurologic outcomes up to a year from injury when

appropriate dosing was given within 8 hours of injury (Bracken et al., 1990, 1992). The presumed mechanism of action is the improvement in microvascular perfusion (Anderson et al., 1983) and reduction of lipid perioxidation and secondary injury (Means et al., 1981; Anderson et al., 1985). Steroids have been associated with longer hospital stays, likely due to increased infectious complications, so this must be taken into account in the overall care of the patient (McCutcheon et al., 2004). The use of steroids is the standard of care in the US, but the debate is more active in other countries where data are more equivocal. Aggressive hemodynamic support should be instituted, including placement of arterial line. Maintenance

1766 E.C. PERRY III ET AL. of blood pressure is critical in the initial stages of SCI, (Austin and Fehlings, 2008). There remains great hope and MAP should be kept over 90 mmHg (Levi et al., that transplanted neural stem cell lines may be able to 1993) with the use of vasopressors if necessary. Spinal interact with limited in vivo regenerative mechanisms shock must be treated aggressively to reduce secondary at an as yet unknown level. Targeted therapies in develischemic injury (Chesnut, 1996). The clinician should opment include blocking myelin-inhibiting signal transalways remember shock can be hemorrhagic, neuroduction via the Rho-ROCK pathway, and enzymatic genic, or both. Shock in patients with injuries below thobreakdown of restrictive glial scar tissue (Rowland racic (T) level 6 should be considered hemorrhagic until et al., 2008). proven otherwise, as unopposed sympathetic tone predominates below T6 and usually causes relatively eleSURGICAL MANAGEMENT OF SPINAL CORD INJURY vated SBP (see autonomic dysreflexia discussion below). Patients require admission to the ICU for frequent There is extensive literature on the specific management neurologic examination and monitoring. Placement of a of specific fracture types that is beyond the scope of this foley catheter is essential to decompress any neurogenic text, but basic tenets guide the decision between rigid bladder. Imaging should be obtained in a safe, appropribracing versus closed reduction and surgical correction. Some fractures can be treated conservatively with either ate, and timely fashion. Deep venous thrombosis (DVT) halo immobilization or hard cervical collar, particularly prophylaxis should be started as soon as possible. SCI patients with reduced mobility of the limbs are at in elderly patients who have less tolerance for major increased risk for DVT. Often paraplegic patients will surgery. Many fractures, if given enough time, will fuse get prophylactic inferior vena cava filters to prevent lower in some form of reasonable alignment, but this may extremity clots from becoming symptomatic pulmonary require prolonged immobilization of the injured segemboli. Patients should get rapid secondary evaluation ment. The ultimate goal of surgical intervention is early of other injuries, as identification of any serious medical mobilization to reduce the incidence of bed-bound complications, such as pneumonia, DVT, and decubitus risk factors that may impact surgical intervention. ulcers. To facilitate this, surgery is now usually perAnother important sequela of SCI that should be addressed rapidly should it occur is autonomic dysreformed immediately or soon after injury. There is some flexia (AD). Patients with injuries above T6 are at risk debate in the literature about the timing of decompresfor this possibly life-threatening problem, which is charsion of traumatic central cord syndrome. In the past it acterized by acute > 20% increase in SBP and heart rate, was felt that early decompression could worsen the associated sympathetic nervous system outflow signs deficit. Surgeons often waited for several weeks while (sweating, vasodilation and flushing), and headache or spinal cord edema resolved, and reported outcomes after subacute decompression were improved (Chen blurred vision (Furlan and Fehlings, 2008). Below T6 is et al., 1997) compared to conservative management. where greater splanchnic tracts originate, and spinal cord damage above this removes bulbospinal regulatory Early surgery was reserved for the deteriorating patient input. Massive sympathetic surges cause the myriad of whose weakness could be definitively correlated to the signs and symptoms. Although more common in chronic traumatic lesion. More recent studies have again shown SCI, the incidence of AD in acute SCI is almost 6% that ASIA outcomes are no different with early (within (Krassioukov et al., 2003). SBP can rapidly rise to over 4 days of trauma) or late decompression (more than 4 250 mmHg, and IPH, seizure or death can result if days after trauma) (Chen et al., 2009). In-line cervical traction is a method of reducing fracuntreated. Basic treatments for AD involve avoidance tures to a more anatomic alignment. Indications include: of noxious stimuli below the level of injury (such as bladder irritation), although the exact trigger is often tough immobilization for unstable fractures while awaiting surto elucidate. During dysreflexic episodes, the patient is gical decision-making, and reduction of certain types of rapidly put upright, clothes loosened, bladder/bowel irricervical fractures with neurologic deficit, especially in tation ruled out, and given sublingual nifedipine to bring medically unstable patients. Currently, the most common down the SBP (Consortium for Spinal Cord Medicine, use is to reduce and temporarily stabilize a distracted or 1997). Other prophylactic treatments such as terazosin “locked” fracture in anticipation of definitive operative fixation. This can be achieved by either two-point cranial have been shown to be effective in eliminating recurrent tong placement or with four-point halo ring and vest appliepisodes (Vaidyanathan et al., 1998). Historically, randomized drug trials with comcation. The reduction is achieved in stepwise fashion using pounds such as tirilazad, GM-1 ganglioside, naloxone, gradually increasing axially distracting weight, followed and nimodipine have been largely unsuccessful in by careful serial neurologic exams and screening X-rays. improving outcomes in SCI. Recently, blockage of oliTraction is contraindicated in some distracting fractures godendrocyte Fas-mediated apoptosis has been studied due to significant ligamentous instability and dislocation,

NEUROTRAUMATOLOGY and in any case should only be performed by a subspecialty spine surgeon. Operative reduction is considered more the standard now for the majority of mechanically unstable fractures, as techniques, instrumentation and training have progressed. Neurologic deficit that can be attributed to a fracture or compression is also an indication for surgery. Patients with penetrating injury and CSF leak require repair to prevent meningitis. Intraoperatively, several techniques are used to maximize a good outcome. Electrophysiologic monitoring, including sensory and motor potentials, is used for pre- and intraoperative comparison to ensure alignment manipulations and decompressions are not having an immediate detrimental effect on function. Anesthesia is actively involved in this process, utilizing fiber optic intubation, special endotracheal tube monitoring, and careful maintenance of SBP. In recent years, the use of intraoperative imaging has increased the success of hardware placement. This includes C-arm fluoroscopy, 3D reconstruction of C-arm images, and O-arm CT. There are several general surgical techniques to address specific traumatic pathology. Fractured and compressive posterior elements of the spine including lamina and medial facets can be removed to decompress the thecal sac, or remove an epidural hematoma. Should it be required, any subsequent reduction is easier with the posterior bony elements absent and allows for careful manipulation to re-establish proper spinal alignment after traumatic deformity. In the thoracic and lumbar spine, vertebral body compression fractures can be decompressed from the back with careful retraction of the thecal sac or sacrifice of a thoracic nerve root to gain access to the retropulsed bone. In the cervical spine, traumatic disc herniation is approached from the front, with a discectomy and usually subsequent anterior plating. The anterior approach to lower thoracic and lumbar spine can be combined with posterior approaches for two column fractures with significant (> 75%) height loss. In those cases, a metallic cage is inserted to substitute for the vertebral body removed. If a segment is inherently unstable from trauma but does not require reduction or decompression of bony elements, in situ fixation can be performed to stabilize the segment. This usually involves thoracolumbar pedicle or cervical lateral mass screws with connecting rods bent to the proper kyphotic or lordotic curve. If by decompressing a traumatized segment the spine will be made unstable, a fusion is undertaken to remove motion from that segment. The fusion can be obtained by incorporating implanted hardware (such as pedicle screws and rods, or anterior plates and screws) with harvested bony autograft. The goal of these surgeries is to prevent a

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pseudarthrosis, or false joint, from forming. The fusion process is very dependent on the quality of bone of the patient. Relative deficiencies can be supplemented with osteogenic products such as bone morphogenic protein. Pediatric spine trauma has a special set of considerations. Temporary internal fixation is often performed in children who are still growing, but require fixation of unstable segments to reverse or prevent progression of neurologic deficit. Screws and rods are inserted, the child followed for a period of time to look for clinical and radiographic evidence of segmental fusion. Then the hardware is removed to allow for continued growth of other bony elements. Fixation with adult instrumentation is performed on all children over 8 years old. Children aged 2–8 years are treated with a modified instrumentation that allows for the rapid growth of this age group, while infants that require procedures usually get a temporary fusion with cast immobilization. Orthotics are often employed to supplement fusion and promote early mobilization. Examples of these include a cervical thoracic orthotic (CTO) and a thoracic-lumbar-sacral orthotic (TLSO). Once fixation of fusion is performed, therapy is employed to get the patient up out of bed and prevent postoperative deconditioning and DVTs.

CONCLUSION TBI and SCI cause significant morbidity and mortality. Outcomes can be influenced by appropriate medical management to limit secondary insults. Diligent clinical and radiographicevaluationisvitaltodetermineisthereisatreatable decline in function. Surgery has a definitive role for hemorrhage evacuation, fracture decompression and spinal stabilization. Continued research is needed to find new candidate drugs to treat TBI and SCI. More randomized controlled surgical trials should be performed to validate whenthereisimprovementinneurotraumaoutcomes.However,inacutesettingswithlife-threateninghemorrhagesand adeterioratingneurologicexamination,suchrandomization will continue to prove problematic. Therefore, the role of the neurosurgeon for decisive action when required will remain critical.

ABBREVIATIONS AD AED ASIA C CBF CCF CPP CSF CT

autonomic dysreflexia anti-epileptic drug American Spinal Injury Association cervical cerebral blood flow cavernous carotid fistula cerebral perfusion pressure cerebral spinal fluid computed tomography

1768 CTA DAI DVT EAST EDH GCS ICH ICP IPH L MAP MLS MRI NASCIS PCO2 S SBP SCI SCIWORA

E.C. PERRY III ET AL. computed tomography angiography diffuse axonal injury deep venous thrombosis Eastern Association of Surgery for Trauma epidural hematoma Glasgow Coma Scale intracranial hemorrhage intracranial pressure intraparenchymal hemorrhage lumbar mean arterial pressure midline shift magnetic resonance imaging North American Spinal Cord Injury Study partial pressure of carbon dioxide sacral systolic blood pressure spinal cord injury spinal cord injury without radiographic abnormality

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Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 114

Neurology in the developing world 1 2

B.S. SINGHAL1* AND SATISH V. KHADILKAR2 Department of Neurology, Bombay Hospital Institute of Medical Sciences, Mumbai, India

Department of Neurology, Grant Medical College and Sir J. J. Group of Hospitals and Bombay Hospital Institute of Medical Sciences, Mumbai, India

INTRODUCTION The worldwide global burden of disease due to neurologic illnesses, estimated at 4.2% in 1995 (Murray and Lopez, 1996), is expected to increase in the coming years. These illnesses have, until recently, received less attention in developing countries (defined as countries with low and middle income having 2008 Gross National Income (GNI) per capita below US$11 905) (Source: Country Classification World Bank, 2010) because they were considered chronic, not amenable to treatment, and too expensive to manage. We are now beginning to understand the major social and economic impact of these illnesses in the developing world. The publication Atlas: Country Resources for Neurological Disorders 2004 is a rich source of information on neurologic services in different regions of the world including the developing world. It shows the gross disparity in the neurologic care between the developed and the developing nations. Delivery of neurologic care in developing countries varies depending on the needs and resources of the country and the availability of medical and paramedical personnel. Currently there is a gross mismatch between the burden of neurologic disorders and the availability of resources including health professionals. In several developing countries, there are only a handful of neurologists serving large populations. In some countries like Bhutan there is no neurologist (Duncan, 2007). To compound the problem, neurologists tend to settle in metropolitan areas, while the rural majority remains underserved. With the increase in life expectancy, we expect a significant rise in the burden of noncommunicable neurologic disorders such as Alzheimer’s disease, Parkinson’s disease, and strokes in the developing countries. This will add to the already existing burden of

infectious diseases and nutritional disorders. Cultural practices, superstitious beliefs, and social stigma attached to diseases such as epilepsy deprive a large section of the population in these countries of available treatments, resulting in a large treatment gap (Meinardi et al., 2001). In several developing countries, medical expenses are borne by the patient and family members. Medical insurance and government support are usually lacking. The financial burden is heavy and includes direct costs of outpatient consultation, investigations, inpatient care, medications and transport (patients from rural areas often have to travel long distances to urban health care centers). The indirect cost includes the loss of earnings due to unemployment during illness and convalescence. In the large majority of these countries, there are no disability benefits. Although recent years have witnessed major advances in the management of neurologic disorders, these have not reached the majority of patients in the developing regions, due to factors such as financial constraints and a paucity of neurologists. Developing countries face a wide variation in the organization of neurologic services, education, and training and in the prevalence and presentations of neurologic illnesses. The World Health Organization (WHO) publication Neurological Disorders: Public Health Challenges has addressed several of these issues in the developing countries (Neurological Disorders, 2006).

HEALTHCARE SYSTEMS IN THE DEVELOPING WORLD AND THEIR IMPACT ON NEUROLOGIC CARE Each nation in the developing world has a different combination of public and private provision of neurologic care depending on its healthcare system. Consequently, the standards of care vary considerably at the primary,

*Correspondence to: Dr. B.S. Singhal, 131 MRC, Bombay Hospital Institute of Medical Sciences, 12 New Marine Lines, Mumbai 400 020, India. Tel: þ91-022-2206-8787/98-2104-6214, E-mail: [email protected]

1774 B.S. SINGHAL AND S.V. KHADILKAR secondary, and tertiary levels. The concept that neuroTertiary care logic care can be provided, at least in part, at the primary Tertiary neurologic care provides advanced managecare level was an important shift in healthcare planning. ment and rehabilitation for neurologic illnesses, adopts a multidisciplinary approach, and attempts to provide emerging new therapies. This specialized form of care Primary care is usually provided by teaching hospitals and some other Developing countries have, by and large, accepted the well equipped hospitals. These institutions serve as trainstrategy evolved for primary health care by the Almaing and research centers. They require adequate staff Ata Declaration (1978). It aims to provide health for and equipment. Sufficient funds are needed to provide all by its easy accessibility, cultural acceptability and the desired quality of tertiary care. Regrettably, in sevreduced cost. Due to the shortage of doctors in the develeral developing countries, only a few centers receive adeoping countries, primary health care training is also quate financial support. In recent years, the private imparted to nurses and community health workers. corporate sector has taken the initiative to provide addiSeveral developing countries have integrated this contional tertiary care centers in some countries. cept into their healthcare system. For example after Guinea-Bissau gained independence from Portugal, its government introduced a nationwide primary health HUMAN RESOURCES, TRAINING, care system (de Jong, 1996). Training was imparted to AND EDUCATION staff members (mainly nurses) at health centers, some Developing countries suffer from an inadequate number of whom then trained and supervised volunteer village of trained neurologists. Often, it is left to the general health workers. The nurses received quarterly superviphysician to provide neurologic care. The number of sion, with emphasis on case management and the use neurologists per 100 000 population differs significantly of medications. Ultimately this training improved the in developing and developed nations, ranging from 0.03 ability of health workers to diagnose epilepsy and other in Africa and 0.07 in South East Asia to 4.84 in Europe common conditions. Continuing supervision of health (Atlas, 2004). There is also a major shortage of trained workers by nurses and physicians from secondary mednurses, paramedical staff, and rehabilitation services ical centers was an essential component for the success in the developing countries. All this results in a huge burof this program (de Jong, 1996). Similar initiatives have den of work for the neurologists, who find it difficult to been undertaken by several other developing countries devote sufficient time to each patient. In the absence of The community health workers and “barefoot doctors” adequate support staff, the neurologist has also to perof China have proved to be a great help in providing priform the duties of the specialist nurse and social worker. mary health care. Moreover, because they work in the It is not unusual for neurologists to be on call 24 hours a community, primary care teams are easily able to recogday for attending to emergencies. Not much time is left nize factors such as social stigma, family problems, and for collecting epidemiologic data or doing clinical cultural factors that affect neurologic treatment. research (Khadilkar and Wagh, 2007). The schedule and structure of neurology training programs vary from one country to another. For example, Secondary care there are no formal neurologic postgraduate training Secondary care is provided by district or regional hospiprograms available in several Arab countries. Overall, tals that offer outpatient consultation and inpatient serthere are 24 residency programs (ranging from one in vices including emergency care. The staff at the Morocco to 12 in Egypt) and 162 neurology residents secondary health centers includes neurologists, inter(ranging from seven in Morocco to 120 in Egypt). In connists, residents, nurses, and trained technicians. Laboratrast, there are 133 neurology residency programs and tory facilities, electrophysiology, and computerized 1428 residents in North America (Benamer and Shakir, tomography (CT) scans are usually available at these 2009). India has, at present, 38 postgraduate neurology centers. Secondary care centers also provide technical training centers with 84 candidates taking the examinaand administrative support to primary care clinics in tion each year. In several countries, a diploma or degree their district or region. In some countries, such as India, is awarded to certify the training in neurology. However, mobile care teams from the district hospitals provide continuing education programs and the system of support to the primary care centers for common neuroaccreditation are still lacking. The available training prologic problems such as epilepsy (Gourie-Devi, 2008). grams for nursing and rehabilitation are also scarce. To Similarly, neuro-caravans of Senegal are effectively improve neurologic services, regional neurologic associreaching out to its rural communities (Aarli et al., 2007). ations and societies have been established in several

NEUROLOGY IN THE DEVELOPING WORLD countries. These societies hold conventions and seminars to improve standards of neurologic care in their respective countries. Many of them have joined the World Federation of Neurology (WFN) to meet the overall goal of improving human health worldwide by promoting prevention and care of neurologic disorders. During the WFN meetings, (earlier held once in 4 years and now to be held once in 2 years from 2011) neurologists from all regions gather to enhance their knowledge and share important data and experiences. The WFN conference held in Delhi (India) in 1989 served the cause of promoting neurology in India. It is hoped that the continuing efforts of the WFN will similarly raise the standard of neurologic care in the developing regions of Africa. The WFN education committee is promoting neurology education by initiating programs like the neurology training program in Honduras (Medina et al., 2007) which serves as a model for other developing nations. In addition, WFN has also offered a continuing medical education program to 43 countries with limited resources. This program has succeeded in improving the neurologic skills of the participants. To deal with the complexities of neurologic disorders and the recent advances in various fields of neurology, several international and national subspeciality groups have been established, such as the World Stroke Organization, the International League Against Epilepsy, and the Movement Disorder Society. So far, there are few or no subspecialists in most developing countries. Pediatric neurology still has to take root in several of these countries. Only a handful of pediatric neurologists are available for the large pediatric population of India. In most of these countries, the neurologic problems of children are handled by the few adult neurologists or by general pediatricians. Besides adequate human resources, another important aspect of neurologic care is the availability of tools and equipment to facilitate diagnosis. Recent years have witnessed major advances in laboratory techniques and imaging procedures such as CT and magnetic resonance imaging (MRI) scans. These tools require expertise and funds, both of which are scarce in the developing regions. For optimal inpatient care of patients with neurologic disorders, it is important to have an adequate number of hospital beds with trained nurses and designated wards or units. Such an organized system is usually lacking in the developing countries where patients are managed on beds allocated to internal medicine (Atlas, 2004). Shortages of beds mean that on occasion patients have to be looked after on “floor beds.” Neurologic emergencies are managed in general intensive care units by residents and nurses who have limited knowledge of neurology. Despite the availability of scientific medicine (often considered as “Western medicine”), patients in several

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developing countries seek help from practitioners of indigenous medicine and homeopathy. This can be attributed to cultural beliefs, nonavailability of cures for neurodegenerative conditions such as motor neuron disease, and pseudo claims of cure by practitioners of unproven alternative medicine. The high cost and, at times, the nonavailability of essential drugs cause patients to seek help from such healers. Unfortunately, at this time there are few governmental regulations for such practitioners in the majority of developing countries.

COMMON NEUROLOGIC DISEASES IN THE DEVELOPING WORLD The frequency and presentation of common neurologic illnesses vary significantly in the diverse regions of the developing world. These differences arise from differences in ethnic background, geographic location, cultural practices, and lifestyle. Although small epidemiologic studies have been attempted in some developing countries, the information is largely derived from hospital-based data which have their limitations. Infections, stroke, head trauma, and epilepsy account for a large share of common illnesses seen in the developing world.

Epilepsy Epilepsy is a major public health concern, affecting an estimated 50 million people worldwide. Of these, nearly 80% live in the developing countries. The WHO’s Atlas: Epilepsy Care in the World describes the global dimensions of the medical, sociological, psychological, and financial consequences of epilepsy (Atlas, 2005). Developing countries are maximally affected by these consequences. Several studies have reported that a large proportion of patients with epilepsy in these countries never receive appropriate treatment. A recent systematic analysis of the magnitude of the treatment gap in resource-poor countries found an overall rate of 56% (Mbuba et al., 2008). The main causes of this large treatment gap include high cost of treatment, nonavailability of antiepileptic drugs (AEDs), and faith in traditional treatments, superstitions, and cultural beliefs. A significant number of patients, although diagnosed and initiated on treatment, soon discontinue drugs, due to their inability to afford the treatment and ignorance of the effects of discontinuation. A study from India reported that 43% discontinued their treatment after 1 year (Das et al., 2007). The social stigma attached to this condition creates further difficulties in its management. The quality of life of patients with epilepsy is affected by the prejudices prevalent in society. Epileptic children often find it difficult to be accepted in schools.

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Finding suitable employment and arranging marriages (especially for women) also become major issues. Although precise epidemiologic data from developing countries are not available, the prevalence of epilepsy is believed to be higher as compared to the developed nations. There are wide variations in prevalence rates in different geographic regions and even within these regions. In developed countries, the lifetime prevalence rate for epilepsy ranged from 3.5 to 10.7 per 1000 personyears (Forsgren et al., 2005). In developing countries, the lifetime prevalence rates for active epilepsy varied from 1.5 to 14 per 1000 person-years in Asia (Mac et al., 2007), from 5.1 to 57.0 per 1000 person-years in Latin America (Burneo et al., 2005), and from 5.2 to 74.4 per 1000 person-years in sub-Saharan Africa (Preux and DruetCabanac, 2005). The increased occurrence of birth trauma, head injuries, infections such as tuberculous meningitis, viral encephalitis, and infestations such as neurocysticercosis is responsible for the higher prevalence of epilepsy in the developing world. Most people with epilepsy in the developing countries are diagnosed and treated by primary and secondary care physicians with no specific training or expertise in epilepsy management. The electroencephalogram (EEG) serves as a useful tool to define the type of epilepsy and the epileptic syndrome and has become available in several developing countries. However, most EEG laboratories in resource-poor countries are managed by laboratory technicians and paramedical personnel with no formal training in recording and interpreting EEGs. Consequently, EEG results are frequently misinterpreted, leading at times to overdiagnosis of epilepsy and unnecessarily prolonged AED therapy. Patients with adultonset focal seizures or unsatisfactory seizure control require brain MRI, which is either not available or not performed as per the appropriate imaging protocol. Several new AEDs have recently become available for the management of epilepsy. They are considered safer with fewer drug interactions. However, these newer agents are expensive and beyond the reach of many patients in developing countries. Nearly 25% of patients with epilepsy have refractory seizures. They need to be managed in comprehensive epilepsy centers which are scarce. Adequate facilities for epilepsy surgery in select cases are also not available in the majority of these countries. The regional epilepsy associations, in close collaboration with international organizations for epilepsy and the WHO are doing their best to improve the quality of epilepsy care in these regions.

Headache Headache disorders affect 15–20% of the general population. Although few population-based prevalence

studies of headache are available in the developing countries, it is believed to be as prevalent as elsewhere in the world. Primary care physicians are usually the first to be consulted. Therefore it is necessary for them to effectively diagnose and treat primary causes of headaches such as migraine, tension headache, and medication overuse headache. They should also be able to exclude uncommon but serious causes of secondary headaches such as meningitis, subarachnoid hemorrhage and intracranial space-occupying lesions and expeditiously refer them to secondary or tertiary centers. There can be regional variations of the trigger factors for common tension headache or migraine. Stress levels may vary depending on cultural and socioeconomic background. In India, the habit of not having breakfast and observing frequent fasts are listed as common triggers for migraine (Ravishankar, 2004). Triptans and other migraine medications have proved beneficial, but are infrequently used due to their high costs and nonavailability in many regions. Realizing the importance of headache as an important cause of disability, the WHO launched the “Lifting the Burden” campaign in March 2004 in a formal partnership with international nongovernmental organizations such as the World Headache Alliance, the International Headache Society, and the European Headache Federation (Steiner, 2004).

Central nervous system infections Despite the availability of effective antibiotics and vaccines, infectious diseases still result in high mortality, severe disability, and a heavy economic burden for individuals, families, and health systems in the developing countries. As a region, Africa is characterized by the greatest infectious disease burden and, overall, the weakest public health infrastructure among all the developing regions in the world (Davis and Lederberg, 2001). Tuberculosis, malaria, and acquired immunodeficiency syndrome (AIDS) are the leading causes of death. Some diseases such as poliomyelitis, leprosy, and syphilis have virtually disappeared in the developed world, but are still endemic in the developing regions. Overcrowding, poor resources, and lack of effective disease control programs result in a high prevalence of infectious diseases. AIDS accounts for high mortality in the developing regions with sub-Saharan Africa being most affected. Nearly 70% of all HIV-infected patients and 90% of all cases of maternal–fetal transmission are seen in the sub-Saharan region (Towards Universal Access, 2008). Neurologic complications occur in nearly 39–70% of patients with AIDS. Tuberculosis, toxoplasmosis, cryptococcal meningitis, and cytomegalovirus encephalitis are the common opportunistic infections seen in AIDS patients. Lack of resources and financial constraints

NEUROLOGY IN THE DEVELOPING WORLD make it difficult to care for these patients. Awareness of the illness, use of preventive measures such as condoms and affordable antiretroviral treatment would go a long way in mitigating the suffering of these patients. Viral encephalitis due to known and unknown viruses is frequently seen in the developing regions. The type of infection often depends on the geographic location. Japanese B encephalitis is a leading cause of encephalitis in Asia and results in high mortality and morbidity, especially in children. Equine viral encephalitis is common in Colombia and Venezuela (Watts and Oberste, 2000). An outbreak of encephalitis due to Nipah virus was described in pig farm workers in Malaysia (Chua et al., 1999). Subacute sclerosing panencephalitis, rarely seen in the West, continues to be prevalent in children of South Asia and the Middle East where measles immunization is still not universal. Through the Global Polio Eradication Initiative program of the WHO (2003), most countries had been declared free of poliomyelitis by 2008, except for Afghanistan, India, Nigeria, and Pakistan (Global Polio Eradication Initiative, 2008). Regrettably, several lives are still lost every year due to rabies in Asia and Africa, which occurs largely due to the bite of nonvaccinated rabid stray dogs. Outbreaks of acute hemorrhagic conjunctivitis with occasional neurologic complications caused by EV70 virus and other enteroviruses have occurred intermittently in Asia (Wadia et al., 1983). Among the mycobacterial diseases, neurologic complications of tuberculosis (TB) account for high mortality and morbidity in the developing world. In 2008, there were an estimated 8.9–9.9 million incident cases of TB (7.4 million in Asia and sub-Saharan Africa), 9.6–13.3 million prevalent cases, 1.1–1.7 million deaths from TB among HIV-negative people and an additional 0.45– 0.62 million TB deaths among HIV-positive people (Global Tuberculosis Control, 2009). Often the diagnosis is delayed, resulting in high rates of complications such as hydrocephalus, strokes, cranial nerve palsies, and paraparesis. HIV infection and multidrug resistance have made TB a more complex and deadly disease. Bacterial meningitis continues to be an important cause of mortality and morbidity, especially below the age of 15 years. Streptococcus pneumoniae and Neisseria meningitidis are responsible for 80% of cases (van de Beek et al., 2006). The highest incidence of meningococcal meningitis is found in sub-Saharan Africa – known as the meningitis belt. This region extends from Senegal in the west to Ethiopia in the east (Gessner et al., 2010). Leprosy is still is a major health issue in the developing regions of Asia, Africa, and South America. It must be remembered as an important cause of mononeuritis multiplex and symmetric, predominantly sensory polyneuropathy, even in the absence of obvious skin lesions.

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The diagnosis of this treatable condition is often delayed because of late presentation due to associated social stigma. Malaria is responsible for the death of at least 1 million people every year, 90% of whom live in sub-Saharan Africa. The highest death toll occurs in children under 5 years of age (World Malaria Report, 2008). Despite available prevention and treatment, the burden of malaria remains high. In the developing world there is a tendency to empirically treat all fevers with antimalarials. In the rural areas, there is also large-scale underdiagnosis of malaria because many patients do not seek or are unable to reach healthcare. Of the various forms of malaria, cerebral malaria caused by Plasmodium falciparum takes the highest toll of life. The philanthropic Bill and Melinda Gates Foundation has taken an active interest in reducing malaria-associated morbidity and mortality. Cysticercosis is a major health problem, especially in Africa, Asia, and Latin America. The eggs of Taenia solium contaminate the soil. Human beings acquire cysticercosis through contaminated food items. Therefore vegetarians and others who do not eat pork also acquire cysticercosis. Neurocysticercosis is a frequent cause of epilepsy (Medina et al., 1990; Rajshekhar et al., 2003). It may also present with headache, transient stroke-like symptoms, cognitive decline, and even hydrocephalus. The lack of basic sanitary facilities is one of the important causes for its high prevalence in these regions. The WHO has emphasized that all endemic countries should adopt policies and strategies for the control of taeniasis and cysticercosis. Other conditions largely seen in sub-Saharan Africa include sleeping sickness (African trypanosomiasis) caused by the protozoan parasite Trypanosoma, through the bite of tsetse flies, and cerebral schistosomiasis, caused by Schistosoma japonicum. Cerebral schistosomiasis may present with seizures, headache, or spinal cord dysfunction. Today, with frequent overseas travel and migration, physicians in the developed nations need to be alert to the possibility of such illnesses occurring in their regions.

Stroke Stroke is one of the leading causes of mortality and morbidity in the world. There is a paucity of accurate stroke prevalence data in the developing regions. According to WHO estimates, death from stroke in the low and middle income countries accounted for 85.5% of stroke deaths worldwide in 2005 (Strong et al., 2007). With the increase in life expectancy, urbanization, and changes in lifestyle, the burden of stokes in the developing countries will continue to rise in the coming years. By 2020, it is estimated

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that 19 out of 25 million annual stroke deaths will be in developing countries (Lemogoum et al., 2005). There are regional and intraregional variations in the prevalence, severity and type of stroke in different developing countries. A review of stroke epidemiology in Latin America and the Caribbean revealed a higher stroke mortality in these regions than in developed countries. Diabetes and hypertension were the major risk factors (Lavados et al., 2007). In China, the total ageadjusted incidence of stroke was similar to that of developed countries. The age-adjusted stroke prevalence has varied from 260 to 719 per 100 000 in different regions of China (Liu et al., 2007). The prevalence of stroke was higher in the urban areas than in rural areas. The prevalence of hemorrhagic strokes was higher than in the West, with the figure reaching as high as 55.4% in the city of Changsha in China (Yang et al., 2004). Similarly, the occurrence of intracranial atherosclerosis was high in China (Wong et al., 2007). Hypertension was reported to be the most important risk factor for stroke in China. Of other Asian regions, the prevalence of stroke has varied from 90–222 per 100 000 in India to 690 per 100 000 in Thailand (Poungvarin, 1998). In Africa, although the overall stroke prevalence was lower than in high-income countries, the prevalence of severe and disabling strokes was much higher. The agestandardized mortality and case fatality for stroke were also higher than in the developed world (Mensah, 2008). Besides, the mean age of stroke patients in sub-Saharan Africa was lower, at 58 years, which is about 10–15 years younger than patients in developed countries (Bonita and Truelsen, 2003). Cerebral hemorrhage was the leading cause of fatal stroke in sub-Saharan Africa (Connor et al., 2007). Hypertension was the most significant risk factor in this region. Among Arab countries, the annual stroke incidence ranged from 27.5 to 63 per 100 000 and prevalence was between 42 and 68 per 100 000 population. Ischemic stroke was the commonest subtype in all series except Sudan where intracerebral hemorrhage accounted for 41% of strokes. Hypertension, diabetes mellitus, hyperlipidemia, and cardiac disease were the commonest risk factors (Benamer and Grosset, 2009). Other risk factors in the developing regions include infections such as CNS tuberculosis and syphilis, rheumatic valvular heart disease, and cerebral venous thrombosis. Stroke management in the West has benefitted greatly by the establishment of dedicated stroke units and the availability of special treatment procedures such as thrombolysis, stenting, and endarterectomy. These facilities are only available in very few centers in some developing countries. The majority of them do not have, as yet, any access to the above procedures. Patients in rural areas are deprived of basic stroke care due to shortage of trained medical personnel and nonavailability of

CT scan. At present, the emphasis has to be on increasing public awareness and focusing on preventable risk factors such as hypertension, smoking, diabetes, and hyperlipidemia to reduce the burden of stroke in the developing world. The Global Stroke Initiative, a collaborative effort between the WHO, the International Stroke Society, and the WFN and the efforts of the national stroke organizations will go a long way in the prevention and management of stroke in these countries.

Alzheimer’s disease Alzheimer’s disease and vascular dementia are the leading causes of dementia in the world. An expert group, working for Alzheimer’s Disease International, estimated that 24.2 million people are affected by dementia worldwide (Ferri et al., 2005). Of these, nearly 60% live in the low and middle income countries. With increase in life expectancy it is expected that the number of patients with Alzheimer’s disease will rise significantly in these countries. Well-designed epidemiologic research is lacking in developing countries. Several studies have suggested that the prevalence of dementia may be considerably lower in developing than in the developed world (Hendrie et al., 1995; Chandra et al., 1998; Prince, 2000). These data may reflect underdetection in the early stages and lower exposure to environmental risk factors. In India, early signs of dementia in the elderly are often attributed to a normal aging process (Chandra et al., 2006). Several treatable conditions such as nutritional deficiency (B12 deficiency), hypothyroid state, and infections such as tuberculous meningitis, or infestations such as cysticercosis should be excluded as a cause of dementia in the developing countries. HIV infection has also become an important cause of dementia especially in Africa. Caring for persons with dementia is becoming increasingly difficult in the developing world. Earlier, these persons were well looked after because of the joint family system with a large number of family members living together, especially in the rural areas. Today, migration to urban areas, nuclear families, working women, children going overseas, the “single child family” in China, and the high mortality rates of young HIV individuals in Africa have reduced the number of family members who can care for the demented persons. The behavioral and psychological symptoms of dementia significantly increase the burden of the caregivers and are the main cause for institutionalization. The cost of antidementia drugs such as the anticholinesterase inhibitors and antipsychotic drugs and expenses for inpatient care have proved beyond the reach of many in the developing regions. The 10/66 group, with links to Alzheimer’s Disease International, is carrying out population-based research into dementia and aging in low and middle

NEUROLOGY IN THE DEVELOPING WORLD income countries. The term “10/66” refers to the twothirds (66%) of people with dementia living in low and middle income countries and the 10% or less of population-based research that has been carried out in these regions (Prince et al., 2004).

Multiple sclerosis Multiple sclerosis (MS) is a common disorder, especially in the West, predominantly affecting young individuals. Over time, a significant number of these patients get disabled and wheelchair-bound. As with the other neurologic conditions discussed above, there is a lack of epidemiologic data concerning MS from developing countries, especially in Asia and Africa. The Atlas: Multiple Sclerosis Resources in the World (2008) published by the WHO and the Multiple Sclerosis International Federation (MSIF) provides useful global information on MS. The prevalence of MS has been reported to be low in the developing countries. However, with the growth of neurology and newer diagnostic procedures, especially MRI, MS is being increasingly diagnosed in these regions. Whether or not the increased numbers reflect an ongoing change in prevalence awaits epidemiologic analysis. Unlike in the past when Iran was considered a low prevalence region for MS, a recent epidemiologic study from the province of Isfahan in Iran reported the period prevalence of MS to be 35.5 per 100 000 making it a medium to high-risk region for MS (Etamadifar et al., 2006). The precise reasons for the relatively low prevalence of MS in developing countries are not known. Both genetic and environmental factors may be playing a significant role. In studies where persons have migrated from low-risk to high-risk regions, it was noted that they carried the risk of the region where they were born, emphasizing the role of environmental factors (Elian and Dean, 1987). However, in the small population of Parsis (about 70 000) who migrated from Iran and settled in India for well over 200 years, the prevalence of MS was high (21 per 100 000) as compared to the general population (Bharucha et al., 1988). We do not know if it is related to their ethnic origin or their lifestyle in India, which is akin to that of Western society. MS in the developing countries, as elsewhere, also affects the young (average age of onset around 25–30 years) and is more common in women than men. In Asia, two forms of clinical presentations have been described: (1) clinical features restricted to optic nerve and spinal cord (designated as optico spinal MS (OS MS) or Asian MS) (Kuroiwa et al., 1977); (2) manifestations involving cerebellum, brainstem, cerebral white matter, optic nerve, and spinal cord (Western MS). Although there

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are no well conducted studies, the course of MS is believed to be similar to that in the West. Neuromyelitis optica (NMO) is reported to be more frequent in Asia and Africa than in the West. It occurs both as a monophasic and a relapsing illness. These patients have longitudinally extensive myelitis (>3 vertebral segments) with normal brain MRI, or if abnormal, atypical for MS, thus satisfying the revised criteria for NMO (Wingerchuk et al., 2006). Data regarding the presence of aquaporin 4 in NMO in these countries are not available. Acute disseminated encephalomyelitis (ADEM), another CNS demyelinating disorder, is as frequent as in the West. In the past, several cases of ADEM occurred following the Semple type of antirabies vaccine. This has now significantly reduced with the introduction of human diploic cell vaccine. Intravenous methylprednisolone for the acute episode of MS and most drugs for symptomatic treatment are available in the developing regions. However, the treatment gap is large due to the limited access to neurologic services. Disease-modifying agents for MS such as b-interferons and glatiramer acetate are prohibitively expensive for most patients. Rehabilitation services are also limited. Fortunately, in several of these countries, active support groups in association with MSIF are playing an active role in increasing the awareness of MS and helping the patients and their caregivers. Although MS is a frequent cause of noncompressive myelopathy in the developing countries, several cases of myelopathy remain undiagnosed. Clusters of myeloneuropathies of unknown etiology have been reported from India, Africa, Seychelles, Caribbean islands, Jamaica and Colombia. Tropical myeloneuropathies due to B12 deficiency, other nutritional deficiencies, cyanide intoxication due to cassava consumption, and lathyriasis have been described from the developing countries (Roma´n et al., 1985). Tropical spastic paraparesis due to HTLV1 virus (HAM/TSP) as a cause of myelopathy occurs frequently in the Caribbean islands and Africa (Proietti et al., 2005). Eales’ disease, causing visual affection in young males due to periphlebitis, vascular proliferation, and retinal hemorrhage, occurs frequently in India. It is occasionally associated with an acute or subacute severe myelopathy (Singhal and Dastur, 1976).

Parkinson’s disease and movement disorders Parkinson’s disease (PD) has a worldwide occurrence, affecting 1–2% of individuals over the age of 65 years. The overall prevalence of PD has varied widely from 18 to 418 per 100 000 persons (Zhang and Roma´n, 1993). There is a paucity of epidemiologic data on PD in the developing regions. The prevalence in rural Tanzania (Africa) was 20 per 100 000 persons (Dotchin et al.,

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2008), while in China it was reported to be similar to that of developed countries (Zhang et al., 2005). In India, although the prevalence in the general population was low (16–27 per 100 000), a high prevalence of 328.3 per 100 000 was reported in the Parsi population (Bharucha et al., 1988). This difference in prevalence rates may be due to environmental risk factors or variations in genetic susceptibility. The clinical features of PD in developing countries are the same as elsewhere. Cases of early onset PD below the age of 40 years (juvenile and young onset) with a presumed genetic basis are also seen. However, many cases remain undiagnosed due to the limited number of neurologists. Drugs for the management of PD are available in most developing countries. However, not all patients can afford the cost of long-term medication. Therefore, the treatment gap in developing countries is large. Facilities for deep brain stimulation and other surgical procedures in advanced PD are currently available only in a minority of centers of some developing countries. A wide spectrum of hyperkinetic movement disorders is seen in developing regions. Due to the high prevalence of rheumatic fever in Asia and Africa, Sydenham’s chorea occurs more frequently in these regions (Karpatis and Currie, 1999). Huntington’s disease (HD), a dominantly inherited neurodegenerative disorder, has an occurrence of around 70 per million in persons of Western European descent, but only one per million people of Asian and African descent (Walker, 2007). One of the world’s highest prevalence rates is seen in the isolated population of the Lake Maracaibo region of Venezuela, where HD affects up to 7000 per million people (Avila-Giron, 1973). X-linked recessive dystonia, called Lubag’s disease, has been reported almost exclusively in male natives of Panay Island in the Philippines. The initial dystonic movements later get overshadowed by the parkinsonian features as the disease advances slowly over 10–15 years (Lee et al., 2001). Wilson’s disease (WD), an autosomal recessive genetic disorder of copper metabolism, may present with either predominantly hepatic or neurologic involvement (Das and Ray, 2006). WD patients may present with a wide range of movement disorders such as parkinsonian features, chorea, dystonia, myoclonus and tics. WD is common in countries such as India where consanguineous marriages are common (Taly et al., 2009). The Movement Disorder Society and its regional chapters are surveying the educational needs of developing countries, arranging various programs to improve the care of patients with movement disorders. It is hoped that an increased number of neurologists with special interest in movement disorders, along with community and government support, will ease the burden of movement disorder diseases.

Traumatic brain injury Traumatic brain injury (TBI) is a leading cause of death and disability throughout the world. It is especially frequent in the developing countries. The major causes of TBI include road traffic injuries (RTI), falls, and violence. In India, RTI and falls accounted for 45–60% and 20–30% of TBI respectively (Puvanachandra and Hyder, 2009). In Eastern China, 61% of TBI were due to RTI; of these, approximately one-third were motorcyclists, 31% pedestrians, while motor-vehicle passengers accounted for 14% (Wu et al., 2008). Latin American and Caribbean nations also reported a high occurrence of RTI, accounting for 66% of all TBI (Puvanachandra and Hyder, 2008). A similar pattern was observed in Africa, with Nigeria recording a high RTI figure of 80% of all TBI (El-Gindi et al., 2001). Several reasons account for the large number of road traffic accidents in developing countries. These include a relatively high number of vehicles combined with inadequate number and poor condition of roads, careless driving, and disregard of safety regulations such as wearing of helmets and safety belts. Driving while facing oncoming traffic, reckless overtaking and wandering of stray animals on the roads also increase the risk of accidents. Stiff penalties for driving under the influence of alcohol are also not strictly enforced. RTI and falls often prove fatal at the site of the accident. Life is also lost during transportation. Services for immediate assistance and quick transportation to medical centers are not well developed in the majority of developing countries. The availability of trained paramedics is scarce; ambulance drivers and attendants often lack the requisite training and skills to provide optimum care during transportation. Although some specialized trauma care centers and neurosurgical services have become available in some developing countries, they are grossly insufficient to meet the needs of the population. In order to decrease the burden of TBI in developing countries, there is an urgent need to improve infrastructure, provide better roads, develop highquality trauma care centers, and strictly enforce safety regulations.

CONCLUSION Nearly all neurologic illnesses occurring in developed countries are also seen in the developing world, but with varied frequency and clinical presentations. The high prevalence of neurotuberculosis, HIV-AIDS, malaria, and TBI significantly contribute to the disease burden in the developing world. The incidence of noncommunicable diseases including Alzheimer’s disease, Parkinson’s disease, and stroke is expected to increase due to increasing life expectancy, urbanization, and changing lifestyle.

NEUROLOGY IN THE DEVELOPING WORLD It is therefore imperative that nations in the developing world strive hard to streamline and optimize their healthcare delivery systems to meet these challenges. Strategies should be in place to improve the health infrastructure, provide an adequate number of trained medical personnel, and make available essential drugs and procedures at affordable prices to all patients with neurologic disorders. Rehabilitation services, which are largely scarce, need to be greatly improved in these countries. With the incorporation of information technology and telemedicine, it should be possible to provide medical services even in the remote areas of the developing countries. In recent times, the international and regional neurologic organizations are actively promoting the cause of neurology in the developing countries. While progress has been made particularly in the last decade, more efforts are rapidly needed to improve neurologic care in the developing world. The beginnings have been made but a large distance still needs to be covered.

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Index NB: Page numbers in italics refer to figures and tables.

A Abciximab 1639 Abdominal aortic aneurysm (AAA) 225–226 Abducens nerve (cranial nerve VI) 307 Abetalipoproteinemia (ABL) 623–624 ABO compatibility 1238 Abscess brain see under Brain conditions spinal epidural 1532 tuberculous 1494, 1494 ‘Absences’(‘absent-mindedness’) 184 Absent cough reflex 1240 Absidia 1383, 1396 Acanthamoeba spp 1287–1288, 1411 Acanthophis spp 992 Acarbose 817, 818–819 Accessory nerve (cranial nerve XI) 308 Acebutolol 1636 Acenocumarol 1638–1639 Aceruloplasminemia 853, 860 Acetaminophen 953 Acetylcholinesterase inhibitors 1628 Acetyl-L-carnitine 1090 Achondroplasia 551–564 craniovertebral dislocation 444 homozygous 560 management 553, 560–561, 561 neurologic complications 552–560, 552 Aciclovir 388, 1246, 1380–1381, 1380 Aciclovir-resistant herpes simplex virus type 1 (HSV-1) 1380 Acid-base disorders 366, 375–377, 376 clinical findings 375–376 gastrointestinal drugs 634, 638–639 laboratory investigations 376 management 376–377 pathophysiology 376 see also specific conditions terminology 375 Acidemia, defined 375 Acidosis, defined 375 Acoustic neuromas 1188 Acquired hemophilia 1052–1053 Acquired hepatocerebral degeneration (AHD) 663 Acquired immunodeficiency syndrome see AIDS Acquired phosphorus disorders 874 Acquired rubella infection 1349–1350 Acquired thrombophilia 1063, 1065, 1067

Acrodermatitis chronica atrophicans (ACA) 1576 Acromegaly 691–692, 697–698 Activated partial thromboplastin time (APTT) 86–87 ACTIVE (Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events) 121, 138 Acupuncture, fibromyalgia 523 Acute adrenal crisis (Addisonian crisis) 757 Acute areflexic paralysis 378 Acute cellular rejection (ACR) 1239, 1239 Acute coronary syndrome (ACS) 93, 94, 95 anticoagulation 101–103 antiplatelet therapy 101, 102 atherosclerotic plaques 99–100 etiology 96 nonischemic chest pain 96–97 thrombolysis 103–104, 104 Acute disseminated encephalomyelitis (ADEM) 1779 Acute dystonic reactions 635, 636 Acute encephalomyelitis 1346 Acute encephalopathy 79 Acute inflammatory demyelinating polyneuropathy (polyradiculoneuropathy) (AIDP) see Guillain–Barre´ syndrome (GBS) Acute intermittent porphyria (AIP) 841–842, 843, 844–846 seizures 846–847 treatment 846–847 Acute ischemic stroke 5 anticoagulation 66 thrombolysis 86 vascular/intensive care neurology 5 Acute liver failure (ALF) 645–659 artificial liver support systems 655–656 clinical presentation 646–647, 646 historical perspective 645–646 laboratory test/imaging 647–649, 648, 649, 650 management 649–651 cerebral edema 651–655, 652 outcome 655 transplants 649 Acute lymphoblastic leukemia (ALL) 1031, 1038, 1039 central nervous system (CNS) 1040

Acute lymphoblastic leukemia (ALL) (Continued ) clinical presentation 1039 leukostasis 1040–1041 treatment 1134, 1135 venous sinus thrombosis (VST) 1041 Acute motor axonal neuropathy (AMAN) 845 Acute myeloid leukemia (AML) 1038–1039 central nervous system (CNS) 1040 treatment 1134 Acute myelomonocytic leukemia (AAML), clinical presentation 1039 Acute myelopathy 1524 causes 1522, 1524–1525 Acute myocardial infarction (AMI) 93–111 clinical findings/diagnostic criteria 96 epidemiology 93–94 etiology 96 future directions 106 historical perspective 93 laboratory investigations 96–97, 97 management 100–104 intensive care 45–46 neuroimaging 97–99, 98, 99 pathology 99–100 prevention 104–106 prognosis 106 risk factors 94–96 thrombolysis 44–45, 45 Acute myopathy of intensive care 1234–1235 Acute painful neuropathy (APN) (insulin neuritis) 815 Acute promyelocytic leukemia (APL) 1040–1041 Acute renal disease see Renal disease, acute/chronic Acute renal failure (ARF) 1116 Acute respiratory distress syndrome (ARDS) 280, 1676 Acute respiratory failure see Respiratory failure (RF), acute/chronic Acute reversible cerebral angiopathy, diagnosis criteria 1729 Acute spinal fractures 455 Acute syphilitic meningitis 1533 Acute transverse myelitis 1525, 1540 Acute uremic encephalopathy 383–384 Adalimumab 601

I2 Adamkiewicz artery 224–225 ADAMTS13 protease 1114–1115, 1119, 1120 Addisonian crisis (acute adrenal crisis) 757 Addison’s disease (AD) 755–756, 799–800, 801 pathophysiology 755–756 Adefovir dipivoxil (Hepsera®) 679 mechanism of action 679 neurotoxicity 676, 679 Adenine deaminase (ADA) deficiency 828, 832 Adenomas gonadotropin-producing 693–694 nonfunctional 694 pituitary 685, 687–688, 1186–1187, 1187 thyroid-stimulating hormone (TSH)producing 693 Adenosine 132–133, 132 Adenosine diphosphate (ADP) receptor inhibitors 1129 Adenylsuccinate lyase (ADSL) deficiency 828, 831 ADEPT (Alzheimer’s Disease AntiInflammatory Prevention Trial) 580 Adrenal gland 749–772 disorders see Adrenal insufficiency (AI); Adrenal medulla disorders; Adrenoleukodystrophy (ALD)/ adrenomyeloneuropathy (ALM); Cushing syndrome (CS); Hyperaldosteronism function 749–750 historical perspective 621–623 Adrenal insufficiency (AI) 754–759 clinical manifestations 757–758, 757 destructive lesions 755–756 developmental defects 756 diagnosis 758–759 etiology/pathogenesis 754–757 historical perspective 754 secondary 689 steroidogenesis, impaired 756–757 treatment 759 Adrenal medulla disorders 765–766 clinical manifestations 765–766 diagnosis 766 etiology 765 historical perspective 765 treatment 766 Adrenalectomy, neurocardiogenic injury 20 Adrenocortical autoantibodies (ACA) 759 Adrenocorticotrophic hormone (ACTH) 686, 749 acromegaly 691–692 adrenal insufficiency (AI) 759 Allgrove syndrome 756 Cushing syndrome (CS) 750, 752–754 -dependent Cushing’s disease 692–693 excess 692 Adrenoleukodystrophy (ALD)/ adrenomyeloneuropathy (ALM) 759–762 clinical manifestations 760, 761

INDEX Adrenoleukodystrophy (ALD)/ adrenomyeloneuropathy (ALM) (Continued ) diagnosis 760–762, 762, 763 historical perspective 760 treatment 762 Adrenomyeloneuropathy (ALM) see Adrenoleukodystrophy (ALD)/ adrenomyeloneuropathy (ALM) ADVANCE (Action in Diabetes and Vascular Disease) trial 778–779 Advance care planning (ACP) 1222–1223 Adverse event, defined 1549 Advisory Committee on Immunization Practices (ACIP) 1554, 1555 African American ethnicity 93, 94, 95 African vipers (Bitis) 992–993 bush (Atheris) 992–993 AGE (advanced glycosylation end product) pathway 777 Agency for Health Care Research in Quality (USA) 1603 Aging comorbidities, hemophilia 1054 folic acid deficiency 931–932 premature 881 Aging Study Amsterdam 881–882 Agkistrodon spp 992–993 Agkistrodon halys 992–993 Agomelatine 1642 AIDS 755, 923 developing world 1776–1777 tropics 1527 tuberculosis (TB) 1485 vacuolar myelopathy (VM) 1529, 1530 Air stacking concept 284 AIRE gene 799 Akathisia 636 Akinetic mutism 1272 AL (immunoglobulin light chain) amyloidosis 1033, 1083, 1084, 1085, 1094–1096 central nervous system (CNS) 1085, 1095–1096 classification 1083, 1094 diagnostic criteria 1086, 1095 peripheral nervous system (PNS) 1084, 1095 ALADIN (Alpha-Lipinoic Acid in Diabetic Neuropathy) studies 779 Alagille syndrome, genetics 53 Albendazole 1426, 1433, 1434, 1436 gnathostomiasis 1431–1432, 1539 neurocysticercosis 1455, 1537 Albraxane 1202 Albumin 1758–1759 Albumin-collodion microencapsulated activated charcoal (ACAC) hemoperfusion 655 Alcohol 257 Aldose reductase inhibitors (ARIs) 779, 821 Alemtuzumab 507 Alendronate 878 ‘A-lines’ 41–42 Alitretinoin 1212–1213

Alkalemia, defined 375 Alkalosis defined 375 treatment 377 Alkylating agents 1134 adverse effects 1199–1201, 1208–1210, 1652 Allgrove (triple A) syndrome 756 Allograft procurement, lung 1238 Allograft recipients, intestinal 1287 Allopurinol 1654 Allylamines 1649 Alma-Ata Declaration (1978) 1774 Alpha-2d ligands 519, 521 a-Lipinoic acid (ALA) 779 Alteplase 104 Aluminum, excessive exposure 852 Alveolar echinococcosis 1426–1427 clinical manifestations 1426 diagnosis 1426–1427 pathogen 1426 prevention 1427 treatment 1427 Alzheimer-characteristic proteins 497–498 Alzheimer’s disease (AD) 9 breathing 247 developing world 1778–1779 folic acid deficiency 931–932 iron disorders 861 NSAIDs 581 vitamin B12 931–932 Alzheimer’s Disease International 1778–1779 Amantadine 1504 adverse effects 1641, 1641 American Academy of Neurology (AAN) 34, 52, 1221–1222 American Academy of Pediatrics (AAP) 1551 Cardiology and Cardiac Surgery Section 12 American Association of Poison Control Centers 898 American Association of Sleep Medicine (AASM) 261 American Association for the Study of Liver Diseases (AASLD) 653 American College of Cardiology (ACC) 83, 103, 157 Clinical Competence Statement on Invasive Electrophysiology Studies, Catheter Ablation and Cardioversion 139–140 American College of Chest Physicians (ACCP) 86–87, 290, 298, 300, 1638 Conference on Antithrombotic and Thrombolytic Therapy 118–119, 119 American College of Rheumatology (ACR) 450, 463, 465, 513, 514 American Diabetes Association 817 American Heart Association (AHA) 26–27, 28, 103, 111, 202–203, 1600, 1635 Cardiopulmonary Resuscitation and Emergency Care 30

INDEX American Heart Association (AHA) (Continued ) Clinical Competence Statement on Invasive Electrophysiology Studies, Catheter Ablation and Cardioversion 139–140 Heart Disease and Stroke Statistics 93 infective endocarditis 56, 83, 85–86 American Pain Society (APS) 518 American Porphyria Foundation 846 American Society for Testing and Materials International 97 American Spinal Injury Association (ASIA) 1763, 1764, 1766 American Stroke Association (ASA) 1635 Secondary Stroke Prevention Guidelines 1020 American Thoracic Society (ATS) 1338, 1490 Amfetamines 1644 Amikacin 1492, 1532 Amine, precursor uptake and decarboxylase (APUD) cells 803–804 5-Amino-4-imidazolecarboxamide ribotide transformylase/IMP cyclohydrolase (ATIC) deficiency 828, 831–832 Aminoglutethimide 754 Aminoglycosides 1490, 1492, 1646 Aminolevulinic acid (ALA) 843, 845 d-Aminolevulinic acid synthase (ALAS) 839–841, 843, 844, 846 Amiodarone 132, 133, 1637 Amisulpride 1642 Amitriptyline 515, 1090 Amlodipine 1636 Amoebiasis 1407, 1410–1411, 1410, 1410 Amoxicillin 1470, 1480 AMPAr-Abs (antibodies) 1162 limbic encephalitis (LE) 1168 Amphiphysin-Abs (antibodies) 1163 limbic encephalitis (LE) 1166, 1169 Amphotericin B 1248–1249, 1329–1330, 1329 Amphotericin B deoxycholate (AmBd) 1388–1389, 1395 Ampicillin 1247, 1379–1380 Amylin analog 820–821 Amyloid-b-related angiitis (ABRA) 487–488 Amyloidosis 1257 see also AL (immunoglobulin light chain) amyloidosis Amyotrophic lateral sclerosis (ALS) 247, 275–276 motor disability 1221 palliative care 1220, 1222–1223 Amyotrophy 776 Anagrelide 1075, 1133 Anakinra 459, 507 Analgesic drugs 1645–1651 Anaplasma spp 1403 Anaplastic astrocytoma 1184 Ancylostoma brasiliense 1432 Ancylostoma duodenale 1432

Anderson’s disease (chylomicron retention disease (CRD)) 623, 624 Androctonus 993 Androgen receptor insensitivity syndrome 793–796 Anemias 1003–1014 bone marrow failure syndromes 1009–1011 aplastic anemia 1010 background 1009 Fanconi’s anemia (FA) 1010 lead poisoning 1010–1011 pure red cell aplasia (PRCA) 1010 of chronic disease (AOCD) 1008 clinical consequences 1006–1007 definition/pathophysiology 1005–1006 diagnostic approach 1006 hemolytic 1011–1013 autoimmune (AIHA) 1012 background 1011 diagnosis/clinical findings 1011 glucose 6-phosphate deaminase (G6PD) deficiency 1012 hemoglobinopathies 1013 hereditary spherocytosis 1012 paroxysmal nocturnal hemoglobinuria (PNH) 1012–1013 treatment 1011–1012 iron deficiency 1007–1008, 1125–1126 causes 1007 clinical findings 1007–1008 laboratory findings 1008 treatment 1008 megaloblastic 927, 929–930, 930, 1009, 1125–1126 myelodysplastic syndromes (MDS) 1009 pernicious see Pernicious anemia (PA) vitamin deficiency see Vitamin B12 deficiency see also Folic acid deficiency Aneurysmal subarachnoid hemorrhage (aSAH) 1603, 1604 Angioma, cutaneous 1569–1573 Angiostrongylus cantonensis/ costaricensis 1432–1433, 1537–1538, 1538 clinical manifestations 1433 diagnosis 1433 epidemiology 1432 pathogen 1432–1433 therapy 1433 Angiostrongylus costaricensis see Angiostrongylus cantonensis/ costaricensis Angiostrongylus mackerras 1432–1433 Angiostrongylus malayensis 1432–1433 Angiotensin-converting enzyme (ACE) inhibitors 12, 165 Angiotensin-receptor blockers (ARBs) 165 Anion gap 375 acidosis 375 metabolic acidosis 376 Anisakiasis 1435 clinical manifestations 1435

I3 Anisakiasis (Continued ) diagnosis 1435 epidemiology 1435 pathogen 1435 therapy 1435 Anisakis spp 1431 Anisakis simplex 1435 Ankylosing spondylitis (AS) 440–441, 457 Annals of Surgery (Bigelow) 29 Anopheles spp 1429, 1514 Ant stings 995 Anterior cord syndrome 1763 Anthrax vaccine 1555–1556 Anthrax Vaccine Adsorbed (AVA) 1556 Anthrax Vaccine Expert Committee (AVEC) 1556 Antiallergic drugs 1651–1654 Anti-a4 integrin (natalizumab) 507, 601, 1607–1608 Antiandrogens 1655 Antiangiogenic drugs 1205, 1213 Antiarrhythmic drugs 132–136, 132, 1636, 1637 Antibacterial agents see Antibiotics Antiberiberi factor 891 Antibiotics 1120, 1247, 1479–1480, 1575–1576 adverse effects 388, 1203, 1211, 1644–1645, 1646 bacterial meningitis 1367–1369, 1368 infective endocarditis 83–84, 84 Antibodies 1160–1163, 1161 Antibody-mediated rejection (AMR) 1239, 1239 Anticholinergic drugs 1641, 1641 Anticoagulants 56, 86, 101–103, 1153 adverse effects 65–66, 1126, 1131–1132, 1638–1639 Anticoagulation system 1061, 1062 Anticonvulsants see Antiepileptic drugs (AEDs) entries Antidepressants 519–523, 519, 1332–1333, 1642 see also Tricyclic antidepressants (TCA) Antidiarrheal drugs 638 Antidiuretic hormone (ADH) 365, 367–369, 371, 750, 812 Antiemetic drugs 633–637, 634, 1655, 1656 Antiepileptic drugs (AEDs) 711–712, 1221 adverse effects 1639–1640, 1640 brain metastases 337, 1153 diabetic neuropathy 780, 781, 781 traumatic brain injury (TBI) 1628, 1758 Antiepileptic drugs (AEDs), hepatic/renal disease 417–432 dose adjustments 425 elimination 417, 418 specific drugs 417–429, 418 hemodialysis 427 Antiestrogens 1655 Antifolate analogs 1135 Antifungal agents 1388–1391, 1395 adverse effects 1645, 1649 Antigonadotrophin-releasing agents 1655 Antihelminthics (antihelmintics) 1539, 1650

I4 Antihistamines 1651–1654 Antihypertensive agents 9, 165, 165 adverse effects 1635–1636, 1636 Anti-inflammatory drugs 1645–1651 Antilipemic drugs 1636–1637, 1638 Anti-Ma-2 antibody syndrome 788, 789–792, 791, 793 Anti-Ma-2 protein antibodies 791 Antimalarials 1650 Antimetabolites 1134 adverse effects 1203–1204, 1205–1208, 1652 Antimicrobial therapy see Antibiotics Antimicrotubule agents 1135 Antimigraine agents 1650–1651 Antineoplastic drugs 1645, 1652 Antineutrophil cytoplasmic antibodies (ANCA) 1106 Anti-N-methyl-D-aspartate receptor (NMDAR) antibodies 791 antibody encephalitis 787, 792 antibody syndrome 787, 788, 789–792, 791, 793 Anti-osteoporotic agents 1655 Antiparasitic agents 1645, 1650 Antiparkinsonian drugs 1641, 1641 Antiphospholipid antibodies (APLA) 465, 466, 1063 Antiphospholipid syndrome (APLS) 289–290, 466, 1566–1567, 1600–1602 antibody positivity 1600 anticoagulant considerations, pregnancy 1602, 1603 catastrophic 1601–1602 diagnosis/treatment 1600 geoepidemiology 1600 manifestations CNS, treatment 1602 criteria 1601 non-criteria 1601 seronegative 1602 a2-Antiplasmin deficiency 1056 Antiplatelet agents 65, 86, 101, 479, 1020 adverse effects 1639 classification 101, 102 hematologic disorders 1129–1130, 1131, 1132 Antipsychotics 1642–1643 Antiretroviral therapy (ART) see Highly active antiretroviral therapy (HAART) Antiseizure medications 1231 Antispastic drugs 1640–1641 Antithrombotic agents 86–87, 1130–1131, 1635–1639 Antithrombotic Trialists’ Collaboration 101 Antithymocyte globulin (ATG) 1278–1279 Antithyroid agents 813–814, 813, 1655 Antithyroid antibodies 725 Anti-TNF (tumor necrosis factor) agents 718–719, 1718–1719 anti-TNF-a 598, 599, 601 Antitumor antibiotics 1652

INDEX Antitumor necrosis factor-a agents 479, 485–486 Antivenom 995, 997 Antiviral agents 1645, 1648 Anti-Yo antibody syndrome 788, 789–792, 791, 793 Anti-Yo (PCA-1) antibodies 791 Anton syndrome 35 Anxiety 465 Aortic bioprosthetic heart valves 64 Aortic diseases 223–238 calcific stenosis 62–63 neurologic complications 225–233 aortic aneurysm 225–226 aortic coarctation 54, 231–232, 231 aortic dissection 226–227 aortic surgery 229–231, 233–234, 233 giant cell arteritis (GCA) 227–229, 228 syphilis aortitis 232–233 Takayasu’s arteritis (TA) 229–231, 229, 230 spinal cord blood supply 223–225, 224 Apical ballooning syndrome see Stress cardiomyopathy Apis dorsata 995 Apis mellifera scutellata 995 Apixaban 122, 139, 295, 1639 Aplastic anemia 1010 Apnea-hypopnea index (AHI) 253, 261, 262 obstructive sleep apnea syndrome (OSAS) 257, 258, 260 Apolipoprotein B (APOB) 623–624 Apoplexy parathyroid 744 pituitary 686–687, 744 Aprepitant 637 Aquaporin (AQP) 396–397 Arachidonic acid pathway 577, 578 Arachnoiditis 1747 Araneomorphae 994 Arctic Sun® system 954 Argatroban 1131, 1132 Arginine vasopressin (antidiuretic hormone) 365, 367–369, 371, 750, 812 Armillifer spp 1436 Armillifer armillatus 1436 Arrhythmia 129–150 direct complications 129–131 cognition disorders 130–131 obstructive sleep apnea syndrome (OSAS) 258 stroke/cerebrovascular disease 129–130 epilepsy 175 syncope 171 treatment complications cardiology procedures 139–143 cardiopulmonary resuscitation (CPR) 131–132 cardiovascular surgery 143–144 drugs 132–139 see also Catheter ablation Arsenic trioxide 1204

Arsphenamine 1461–1462 Artemisinin 1517 Arterial gas embolism (AGE) see Decompression illness (DCI) Arterial hypertension 258 Arterial ischemic stroke (AIS) 405–407, 408–409 essential thrombocythemia (ET) 1076 inflammatory bowel diseases (IBD) 598 pre-eclampsia 1598–1602 risks 1066–1068 Arterial neuro-Behc¸et syndrome (NBS) 1710 Arterial tortuosity syndrome (ATS) 571 description 571 neurologic complications 571 Arteriovenous malformations (AVMs) hereditary hemorrhagic telangiectasia (HHT) 1572 pregnancy 1604 radiotherapy (RT) 1189, 1193 Artesunate 1517 Arthrogryposis multiplex congenita (AMC) 1610 Arthropod-borne viruses 1378, 1379, 1381 Artificial liver support devices (ALSD) 655 Arts syndrome 828, 830 Ascaridia 1433 Ascaris lumbricoides 1433, 1539 Ascorbic acid see Vitamin C deficiency Aseptic meningitis 322, 579–580, 579 ibuprofen-induced meningitis 1648 Asiatic arboreal pit viper (Trimeresurus complex) 992–993 Aspart 815 Aspergillosis 1385, 1390, 1395–1396 Aspergillus spp 1041, 1383 clinical syndromes 1301–1302, 1385, 1386, 1387, 1535 aspergillosis 1385, 1390, 1395–1396 endocarditis 67–68 echinocandins 1389 imaging 1387, 1390 investigation 1386, 1387 transplantation 1248, 1248, 1278–1279, 1287–1288 Aspergillus flavus 1386, 1395–1396 Aspergillus fumigatus 1232, 1241, 1248, 1395–1396, 1532 liver transplantation 1261, 1262 Aspergillus niger 1395–1396 Aspergillus terreus 1395–1396 Aspirin 101, 113, 199, 953, 1129, 1571 adverse effects 1639, 1647, 1648 infective endocarditis 69, 86 intracranial hemorrhage 138 stroke 122, 578–579, 580, 581 Astasia/astasia-abasia 183 Asymmetric lower limb neuropathy 776 Asymptomatic neurosyphilis 1464, 1533 Atalimuma 507 Ataxia cerebellar see Cerebellar ataxia degenerative 9

INDEX Ataxia (Continued ) fragile X-associated ataxia syndrome (FXTAS) 793 Friedreich’s (FA) 9 gait 183–184 gluten (GA) 609–611, 610 myoclonic 612–613 Atenolol 1636 ATHENA (A Trial with Dronedarone to Prevent Hospitalization or Death in Patients with Atrial Fibrillation) trial 134 Atheris 992–993 Atherosclerosis Risk in Communities (ARIC) study 130 Atlantoaxial subluxation 442 Atlas: Country Resources for Neurological Disorders 2004 (WHO) 1773 Atlas: Epilepsy Care in the World (WHO) 1775–1776 Atlas: Multiple Sclerosis Resources in the World (WHO/MSIF) 1779 Atomoxetine 1644, 1645 Atorvastatin 9 Atovaquone 1325 ATP7A gene 626, 853 ATP7A-related conditions copper transport disorders 853–854, 853 distal motor neuropathy (DMN) 853, 854 neuropathy 853 ATP7B-related copper transport disorders 854–857 Atractaspididae 987 ATRIA study (atrial fibrillation-related thromboembolism) 119, 119 Atrial aneurysm surgery 194 Atrial fibrillation (AF) 117–118 arrhythmia 129 catheter ablation 153, 155 internal cardioversion 140 external cardioversion 139 intracranial hemorrhage 138 preoperative 144 rheumatic valvular heart disease (RVHD) 61–62 warfarin 122–123, 123 Atrial flutter 62 Atrial myxoma 211–216, 211 natural history 214–215, 214 pathology 215–216 structural neurologic complications 212–214 systemic effects 212 Atrial septal aneurysms 52 surgery 200 Atrial tachyarrhythmias 118 Atrial vein isolation 143–144 Attention deficit hyperactivity disorder (ADHD) 1644 Attenuated Streptococcus 75–76 Atypical neuroaxonal dystrophy (ANAD) 859–860 Australian elapids 992

Australian National Polio Reference Library 1527 Autoantibodies 501–502 Autoimmune diseases 1694 Autoimmune hemolytic anemias (AIHA) 1012 Autoimmune polyendocrine syndromes (APS) 799 Autoimmune polyglandular syndrome, type I (APSI) 799–801, 800 clinical findings 800 historical perspective 799–800 laboratory investigations 800 management 801 neuroimaging 800 pathology 801 Autoimmune polyglandular syndrome, type II (APSII) (Schmidt’s syndrome) 801–802 clinical findings 801 historical perspective 801 laboratory investigations 801–802 management 802 natural history 801 neuroimaging/pathology 802, 802 Autoimmune polyglandular syndrome, type III (APSIII) 802–803 clinical findings 803 historical perspective 803 laboratory investigations 803 management 803 natural history 803 neuroimaging/pathology 803 Autoimmune-mediated destruction of glandular tissue 799 Autonomic dysreflexia (AD) 1766 Autonomic nervous system (ANS) autonomic failure 172, 174 diabetic neuropathy (DAN) 773, 774–775, 781–782 diphtheria 1357 dysautonomia 517 insufficiency 353 pancreas transplantation 1283–1285, 1284 paraneoplastic disorders (PNS) 1171–1172 with pseudo-obstruction 1172 renal disease 390–391 rheumatoid arthritis (RA) 452 scleroderma (systemic sclerosis) (SSc) 469 Sj€ ogren’s syndrome (SS) 471 tetanus 1509 Autosomal dominant polycystic kidney disease (ADPKD) 1251 Avermectins 1650 Axillary artery catheterization 6–7 Axonal and demyelinating neuropathy 1273 5-Azacitidine (Vidaza®) 1133 5-Aza-2´deoxycitidine (decitabine) 1133 Azasetron 636

I5 Azathioprine 354, 459, 485–486, 507, 1231, 1613 giant cell arteritis (GCA) 229, 481 neuro-Behc¸et syndrome (NBS) 1718–1719, 1720 neurosarcoidosis 325, 326, 327 Azithromycin 1403–1404 Azole drugs 1389, 1395 Azoospermia 794

B B cell lymphomas 1263 Babesia spp 1406–1410 Babinski sign 1545 Bacillus anthracis 1556 Baclofen 1090, 1332, 1640 Bacterial infection 1247–1248, 1554–1556 Bacterial meningitis 68, 1361–1375 clinical presentation 1363–1365 cerebrospinal fluid (CSF) shunts, infection 1365 community-acquired 1363–1365 post-traumatic 1365 epidemiology 1361–1362 genetics 1362 management 1365–1373, 1366, 1367 adjunctive therapies 1366, 1369–1372 antimicrobial therapy 1367–1369, 1368 cerebrospinal fluid (CSF) analysis 1365–1367 lumbar puncture, repeat 1373 recurrent 1372–1373 outcome 1372, 1373 pathophysiology/pathology 1362–1363, 1364 Bacterial myelopathy 1530–1532 Bacterial toxins 988 Bacteroides spp 80–81 Bair Hugger™ rewarming technique 953–954 Balamuthia mandrillaris 1411 Balloon kyphoplasty, complications 1747–1748, 1748 Banana spiders 994 Banded sea snake (Hydrophis fasciatus atriceps) 992 Barbiturate coma, traumatic brain injury (TBI) 1628 Barbiturates 1624, 1630, 1631 ‘Barefoot doctors’ 1774 Bariatric beriberi 589 Bariatric surgery 587–592 copper deficiency myelopathy (CDM) 590 metabolic disorders 591–592 miscellaneous disorders 592 neurologic complications 588–589, 588 nutritional deficiency 588, 588, 591–592 vitamin B1 deficiency 589 see also Obesity Bartonella spp 80–81, 1403 Bartonella henselae 1530 Bartter’s syndrome 872 Basal ganglia calcifications 377 Basal-bolus regimen 814

I6 Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 454 Bath Ankylosing Spondylitis Functional Index (BASFI) 454 Baylisascariasis 1539–1540 Baylisascaris procyonis 1537–1538, 1538, 1539–1540 Beaked sea snake (Enhydrina schistose) 992 Becker muscular dystrophy (BMD) 10–12, 11, 125 Bee stings 995 Behavioral problems brain metastases 1145 fibromyalgia 517 management 263 neurosarcoidosis 311 Behc¸et syndrome (BS) 1703–1723 diagnosis/manifestations 1703–1705, 1704 laboratory investigations 1705 epidemiology 1703 nervous system see Neuro-Behc¸et syndrome (NBS) pathology/pathogenesis 1705–1707 Bell, Sir Charles 435 Bell’s palsy 775 Benign angiopathy of central nervous system (BACNS) 1725–1726, 1726 Benzimidazoles 1426, 1650 Benznidazole 1414 Benzodiazepines 636–637, 1508–1509, 1625, 1631, 1640 adverse effects 1640, 1644 Benzylpenicillin see Penicillin G Bereavement care 1223 Beriberi 891 bariatric 589 dry 896–897 infantile 897 b-Blockers 12, 165 Betamethasone 1613 Betrixaban 139 Bevacizumab 339–340, 1152–1153, 1184, 1584 adverse effects 1205, 1213 Bicarbonate 375 Biguanides 816–818, 1654 Bilharziasis (schistosomiasis) 1419–1421, 1535–1536 diagnosis 1420, 1535–1536 differential diagnosis 1536 epidemiology 1419, 1535 features 1420, 1535 microbiology 1535 neuroimaging 1535, 1536 pathogen 1419–1420, 1419 pathogenesis 1535 treatment 1421, 1536 Bing–Neel syndrome 1033, 1093–1094 Bioartificial liver (BAL) 655–656 BIOMED Study of Stroke Care Group 106 Bioprosthetic heart valves 64–65 Biotin see Vitamin B7 deficiency; Vitamin B8 deficiency

INDEX Bismuth 638 Bisphosphonates 536–537, 878, 1090–1091 Bites see Venomous bites Bitis 992–993 Bivalirudin 1131, 1132 Black box warning 326–327 Black snake (Pseudechis) 992 Blastocystis spp 1410 Blastomyces 1535 Blastomyces dermatitidis 1383, 1384, 1385, 1397 Blastomycosis 1385, 1397 Blastomycosis spp 1386 BCR-ABL tyrosine kinase inhibitors 1133 Bleeding disorders see Congenital bleeding disorders; Hematologic disorders, treatment Bleeding risk, warfarin 122–123 Bleomycin 1211 Blind-loop syndrome 1541 Bloch–Sulzberger syndrome see Incontinentia pigmenti (IP) Blood culture, cerebrospinal fluid (CSF) analysis 1367 Blue spotted sea snake (Hydrophis cyanocinctus) 992 Body mass index (BMI) 587 Body temperature 945–958 heat exchange, mechanisms 947 heat-related illness 948–949 clinical features 948, 948 laboratory studies 948–949 management 949 therapeutic manipulation 954–955 internal methods 954 external methods 954 see also Fever; Hyperthermia; Hypothermia Bone marrow failure syndromes see under Anemias Bone marrow transplantation (BMT) 1022, 1295–1305 historical perspective 1295–1296 Bone mineral density (BMD) 741–742, 869, 876 Border zone cerebral infarction 131 Borderline lepromatous leprosy 1573–1575 Borderline tuberculoid leprosy 1573–1575 Bordetella parapertussis 1358 Bordetella pertussis 1358, 1555–1556 Borrelia 1532, 1533, 1534–1535 Borrelia afzelii 1476 Borrelia burgdorferi 1532–1533, 1576–1577 see also Lyme disease Borrelia burgdorferi sensu lato 1476 Borrelia burgdorferi sensu stricto 1476 Borrelia garinii 1476 Borrelia recurrentis 1534–1535 Borreliosis see Lyme disease Bortezomib (Velcade®) 1032, 1089, 1090, 1136–1137 adverse effects 1200, 1203, 1652 Bortezomib-induced peripheral neuropathy (BiPN) 1089 Boston Circulatory Arrest Trial 55

Boston Collaborative Drug Surveillance Program 134–135 Bothrops 992–993 Botulinum toxin 1332, 1640–1641 Boyle’s Law 959, 965 Brachial artery catheterization 5–6 Brachial plexopathy 199, 199, 345–346, 1192–1193 Bradycardia 140 Brain conditions abscess 68, 79, 81, 83, 1147, 1149, 1248 amoebic 1407, 1410–1411, 1410, 1410 anomalies, congenital heart disease (CHD) 53–54 biopsy 1326 edema 365, 1261–1262, 1262 embolism 67–68 global injury 1191–1192 metastases see Brain metastases necrosis 1191 trauma see Traumatic brain injury (TBI) tumors see Brain tumors see also Inherited neurodegeneration with brain iron accumulation (NBIA) Brain metastases 335–340, 792, 1141–1157 clinical findings 336, 1144–1145, 1145 diagnostic procedures 1146–1149 known cancer patients 1145, 1146–1149, 1147, 1148 suspected cancer patients 1149 differential diagnosis 1149–1150 incidence 335–336, 336, 1143–1144 pathology/pathophysiology 1145–1146 primary tumors 726, 1143–1144 treatment 336–340, 1150–1153, 1150 chemotherapy 339, 1152–1153 hormone therapy 1152–1153 interstitial brachytherapy 339 molecular targeted agents 339–340, 1152–1153 stereotactic radiosurgery (SRS) 338–339, 1151–1152 supportive drugs 1153 surgery 337–338, 1151 whole-brain radiation therapy (WBRT) 337, 340, 1150–1151, 1152 Brain Tumor Study Group 1184 Brain tumors 726, 1580–1584 neurocutaneous disorders 1580–1584 pregnancy 1614–1616, 1615 Brain-heart connection 20, 26 Brainstem auditory evoked responses (BAERs) 315, 316 breathing control 241–243, 242 disease 245–247, 247 encephalitis 351 Brainstem auditory evoked response (BAER) 761 Branch retinal artery occlusion 198 Branched-chain amino acids (BCAA) 670–671 Bratton–Marshall reaction 831

INDEX BRAVO (Blockade of the IIb/IIIa Receptor to Avoid Vascular Occlusion) trial 101 Breast cancer 1144 Breast feeding 1606, 1608 Breath holding spells 175 Breathing 239–250 Cheyne–Stokes respiration pattern (CSRP) 263–264, 264, 278 neuroanatomy 241–243, 251–252 cortical control 241, 242 subcortical/brainstem control 241–243, 242 neurochemical control 244–245 neurologic conditions 245–248, 246 central (CNS)/peripheral nervous system (PNS) 246, 248 cortex/subcortical structures/ brainstem 245–247, 247 neuromuscular junction disorders 248 spinal cord diseases 247–248 physiologic control 243–244 pacemaker neurons 243–244, 244 rhythm generation 243 Brentuximab 1205 British Infection Society 1490 British Medical Journal 75–76 British Thoracic Society 1338 Bromides 846 Bromocriptine 697–698, 810, 811, 1655 Bronchiolitis obliterans syndrome (BOS) 1239, 1239 Bronchodilators 1655 Brown snake (Pseudonaja) 992 Brucella spp 80–81, 1531, 1532 Brucella abortus 1531 Brucella melitensis 1531 Brucella ovis 1531 Brucellosis 1531–1532, 1531 Brugia malayi 1429 Brugia timori 1429 Bruns–Garland syndrome 776 Bruxism 257 Buerger disease 488 clinical features 488, 488 Buformin 816 Bulbar dysfunction 1356 ‘Bull neck’ 1356 Bungarus spp 991–992 Bungarus caeruleus 991–992 Bungarus candidus 991–992 Bungarus fasciatus 991–992 Bungarus multicinctus 989, 990, 991–992 Bungarus niger 991–992 Bupivacaine 994 Bupropion 1644, 1645 Burkitt lymphoma (BL) 1030–1031 ‘Burning feet’ symptom 1542–1543 ‘Burning hands syndrome’ 1762 Busulfan 1075, 1210, 1299 Buthus 993 Buthus matensi Karsch 993–994

C Cabergoline 697–698, 810, 811, 1655 Cadmium, excessive exposure 852 Cafe´ au lait spots 1581–1582, 1581 Calcific valvular heart disease 62–63 Calcineurin inhibitors (CNI) 675–677 heart transplantation 1231 liver transplantation 1260 mechanisms of action 675 neurotoxicity 675–676, 676, 1245–1246, 1246 specific complications 676–677 treatment 677 Calcitonin (CT) 737, 866, 878 Calcium 737–738, 865, 868 malabsorption 1286 Calcium channel blockers 31, 165 Calcium glutonate 870 California Encephalitis Project 1377 Call syndrome see Reversible cerebral vasoconstriction syndrome (RCVS) Call–Fleming syndrome see Reversible cerebral vasoconstriction syndrome (RCVS) Callitroga (screwworms) 1436 Calloselasma rhodostoma 992–993 Campylobacter jejuni 9–10, 1552, 1611 Cancer, radiation 1745 Candida spp 1383, 1384, 1385, 1386, 1389 central nervous system (CNS) 1394–1395 endocarditis 67–68 imaging 1388, 1389 investigation 1386, 1387 meningitis 1385, 1386 transplantation 1232, 1278–1279, 1301–1302 Candida albicans 1301–1302, 1385, 1386, 1394 Candida glabrata 1301–1302, 1394–1395 Candida krusei 1301–1302 Candidal infections 1389, 1394–1395 Candidiasis 1385 Cannabinoids 519, 522–523 Cannon, Walter B 19 Capecitabine 1204, 1207 Capreomycin 1490, 1491, 1492 Capsaicin 780 Carbamazepine 677, 847, 1153, 1231, 1234 adverse effects 1640, 1640, 1644 elimination 418, 422, 425, 427 Carbapenems 1646 Carbimazole 813 Carbohydrates, absorption 622 Carbon dioxide 375 Carbon ions 1183 Carbon monoxide (CO) intoxication 971–980 clinical findings 973–974, 973 acute intoxication 974 chronic intoxication 974 delayed neuropsychiatric syndrome 974, 975

I7 Carbon monoxide (CO) intoxication (Continued ) diagnosis 974–975 differential diagnosis 976 laboratory tests 975–976 neuroimaging 976 pathology 972, 973 pathophysiology 971–973, 972 prognosis 977–978 treatment 976–977 Carboplatin 339, 1134, 1200 Carcinoma, ovarian 791–792 Carcinoma-associated retinopathy 351 Cardiac arrest 25–39 epidemiology 26–28 in-hospital 26–27 out-of-hospital 27–28 imaging 34 long-term complications 34–35 neurologic complications 25–26 prognosis 31–34 treatment 28–31 basic measures 28–29 neuroprotective pharmacology 31 sedation/neuromuscular blockade 30–31 seizure control/prevention 31 therapeutic hypothermia 29–30 Cardiac arrhythmia see Arrhythmia Cardiac asystole 175 Cardiac autonomic neuropathy (CAN), diabetic 10 Cardiac catheterization 194, 196–197 -related stroke 95–96 Cardiac involvement, Fabry disease (FD) 1564 Cardiac lesions 52 Cardiac myxomas 1566 Cardiac surgery/interventions 193–208 clinical findings 193–196 historical perspective 193 investigations 202–203 management 203–204 natural history 201–202 pathology 196–201 Cardiac syncope 171, 179 clinical features 171 etiology 171 pathophysiology 171 treatment 186 Cardiac tests/procedures 41–48 acute myocardial infarction, management 45–46 future directions 46 historical perspective 41 laboratory investigations 45 neurologic complications 41–45 central nervous system (CNS) 43–45 peripheral nervous system (PNS) 41–43 Cardiac Transplant Research Database (CTRD) 1233 Cardiac tumors 209–222 clinical triad 209–211

I8 Cardiac tumors (Continued ) cardiac dysfunction 209–210 constitutional symptoms 210–211 embolic phenomena 211 diagnosis 217–218 echocardiography 217 imaging 217 pathology 218 neurologic complications 209–222 primary 209, 210, 216 secondary 216–217 specific 211–217 surgery 194–195, 200–201 treatment/prognosis 218–219 Cardiocerebral resuscitation (CCR) 26 Cardiogenic embolism 1598 Cardiology arrhythmia 139–143 interventional see Cardiac surgery/ interventions movement disorders/ neurodegenerative diseases 8–9 neuromuscular disorders 9–13 paroxysmal events 7–8 vascular/intensive care neurology 3–7 management 7 pathophysiology 3–5, 4 Cardiomyopathy 111–129 atrial fibrillation (AF) 117–118, 122–123, 123 bleeding risk, warfarin 122–123 classification 111, 112 definition 111 left ventricular dysfunction 113–115, 115 mitochondrial dysfunction 125–126 patent foramen ovale (PFO) 112–113 risk stratification schemes 118–122, 119, 120, 122 stress cardiomyopathy 115–117 Cardiopulmonary bypass (CPB) 1238 Cardiopulmonary resuscitation (CPR) arrhythmia 131–132 survival rates 27–28 see also Cardiac arrest Cardiovascular disorders autonomic neuropathy (CAN) 774–775 Behc¸et’s syndrome 1705 Obstructive sleep apnea syndrome (OSAS) 258 Paget’s disease 878 primary hyperparathyroidism (PHPT) 867 respiratory failure (RF) 280 surgery 143–144 see also Cardiology Cardiovascular drugs 1635–1639 Cardiovascular implantable electronic devices 85–86 Carfilzomib 1089–1090, 1203 Carmustine (BCNU) 1208–1209 Carney’s complex (CC) 211, 1562, 1566 Carotid artery dissection 964 Carotid cavernous fistula (CCF) 1604

INDEX Carotid sinus massage 186 Carotid sinus syndrome (CSS) 175, 176 Carotid-cavernous fistula 567–568 characteristics/management 567–568 mechanisms/frequency 567 spontaneous 567, 574 Carpal tunnel syndrome (CTS) 390, 401, 449, 450 diabetes mellitus (DM) 775 pregnancy 1608–1609 Carpet vipers 992–993 CASCADE (Concerted Action on Seroconversion to AIDS and Death in Europe) cohort 1339 Caspofungin 1248 CASPR2-Abs (antibodies) 1161 limbic encephalitis (LE) 1167 Cataplexy/cataplexy-like episodes 182, 183 Cataracts, radiation 1745 Catastrophic antiphospholipid syndrome (CAPS) 466 Catastrophic life events 26 Catastrophic thinking 517 Catecholamines 20 Catechol-O-methyl transferase (COMT) inhibitors 1641 Catheter ablation 151–160 clinical history 151–154 genetics 155 historical perspective 151 laboratory investigations 155 management 156 natural history 154–155 neuroimaging 155 pathology 156 Catheter angiography 1692, 1735 complications 1743–1745, 1744 Catheterization, complications 5, 43–44 Cauda equina syndrome 456, 1763 Cauliflower ear 458 Cefepime 1379–1380, 1644 Cefotaxime 1369, 1479, 1480 Ceftazidime 1369 Ceftriaxone 88, 1379–1380, 1532 bacterial meningitis 1369 Lyme disease 1479, 1480, 1533 neurosyphilis 1337, 1468–1469 Cefuroxime axetil 1480 Celecoxib 580 Celiac disease (CD) 624–625 see also Gluten-related diseases (GRD) CellCept see Mycophenolate mofetil (MMF) Cement extravasation 1747 Cement leakage 1747 Center for Epidemiologic Studies Depression (CES-D) scale 881–882 Centers for Disease Control and Prevention (CDC) 587, 1324–1325, 1465–1466 neurosyphilis 1468, 1469–1470, 1534 tuberculosis (TB) 1338, 1490 vaccines 1549, 1553 Centers for Medicare and Medicaid Services 283

Central American mountain pit vipers (Cerrophidion) 992–993 Central Brain Tumor Registry in the United States (CBTRUS) 1187–1188 Central cord syndrome 1762 Central diabetes insipidus (DI) 690 Central hyperthermia syndromes 639 Central hypothyroidism (CH) 689 Central nervous system (CNS) AL amyloidosis 1095–1096 angiitis see Primary angiitis of central nervous system (CNS) bleeding, treatment 1051 breathing 246, 248 cardiac tests 43–45 chemotherapy complications 1205–1213 dialysis patients 395–400, 396 Ehlers–Danlos syndromes (EDS) 570 fibromyalgia 516–517 fungal infections see Fungal infections HAART penetration effectiveness 1340 heart transplantation 1229, 1230, 1232, 1233 helminthic infestation 1414–1436 hemolytic uremic syndrome (HUS) 1113, 1115–1118, 1118 hemophilia 1053 immunosuppressants 676 infections, developing world 1776–1777 infective endocarditis 68, 79 inflammatory bowel diseases (IBD) 596, 600–601 intestinal transplantation (ITx) 1272, 1273 leukemias 1040 liver transplantation 1262–1263 Lyme disease 1475 lymphoma 1035 see also Primary central nervous system lymphoma (PCNSL), HIVassociated malignancies 1278–1279 metastases 1143 monoclonal gammopathy of undetermined significance (MGUS) 1088 multiple myeloma (MM) 1090–1092 neuro-Behc¸et’s syndrome (NBS) 1708–1711, 1712 pancreas transplantation 1278–1279, 1281–1282 paraneoplastic neurologic syndromes (PNS) 1160, 1163–1170 parasympathetic outflow tracts 4 parenchymal disease 309–312, 322–323 plasma cell disorders 1085 renal disease 383–388 renal transplantation 1247–1251, 1252 scleroderma (SSc) 468, 469 sickle cell disease (SCD) 1015 Sj€ ogren’s syndrome (SS) 470 small bowel transplantation 1278–1279, 1287–1288 sympathetic outflow tracts 4

INDEX Central nervous system (CNS) (Continued ) thrombosis 1075 toxoplasmosis see Toxoplasmosis entries tuberculosis (TB) see under HIVinfected patients; Tuberculosis, central nervous system (CNS) vitamin D 879–882 Waldenstr€om macroglobulinemia (WM) 1093–1094 Central neurogenic hyperventilation 375–376 Central pontine (extrapontine) myelinolysis (CPM) 368, 1278–1279 Central retinal artery occlusion 198 Central sensitization, fibromyalgia 516 Central sleep apnea (CSA) 263–266 classification 278 primary 263, 263 respiratory failure (RF) 278 Central venous catheterization 43 access catheters 44, 45 Centruroides 988, 993, 994 Centruroides exilicauda 993 Cephalosporins 1247, 1369, 1379–1380, 1403–1404, 1533 adverse effects 1646 Cerastes 992–993 Cerebellar ataxia 708 see also Subacute cerebellar degeneration (SCD) Cerebellar degeneration 347, 349–351 see also Subacute cerebellar degeneration (SCD) Cerebral amyloid angiopathy (CAA) 487–488 Cerebral aneurysms 54, 54, 213, 1719 Cerebral angiography 1732–1733, 1735, 1736 Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) 123, 1614 Cerebral edema 371–372 management 651–655, 652 Cerebral effects, neuroanesthesia 1625, 1627 Cerebral embolism 51, 51 air 153–155, 156 cardiac catheterization 43–44 Cerebral hemorrhage 1778 Cerebral hypoperfusion 170–176 Cerebral imaging 217 Cerebral infarctions patent foramen ovale (PFO) 113 ‘silent’ 1016 Cerebral malaria 1514–1515, 1517 Cerebral metastases 791–792 Cerebral performance categories (CPC) 28 Cerebral perfusion pressure (CPP) 651, 1753 Cerebral schistosomiasis 1777 Cerebral vasculitis 475–494, 1104 diagnosis 476

Cerebral vasculitis (Continued ) differential diagnosis 475, 476 infectious origin 476–477 inflammatory bowel diseases (IBD) 598–599 noninfectious inflammatory 477–488, 477 patient evaluation 475–476, 476 rheumatoid arthritis (RA) 451–452, 452 Cerebral vasospasm 1725 Cerebral venous sinus thrombosis (CVST) 407–408, 408 essential thrombocythemia (ET) 1076 inflammatory bowel diseases (IBD) 599–600 inherited thrombophilia 1064–1065 neuro-Behc¸et syndrome (NBS) 1708–1709, 1710–1711, 1715, 1717, 1718 polycythemia vera (PV) 1075 pregnancy 1605–1606 primary myelofibrosis (PMF) 1078 risks 1064–1066 hyperthyroidism 723 treatment 1719–1720 Cerebral venous thrombosis (CVT) see Cerebral venous sinus thrombosis (CVST) Cerebral/spinal cord ischemia 233–234, 569–570 characteristics/management 569–570 mechanisms/frequency 569–570 Cerebrospinal fluid (CSF) analysis 1365–1367 blood culture 1367 fungal infections 1386 Hashimoto’s encephalopathy (HE) 725 Henoch–Sch€ onlein purpura (HSP) 1107 neuro-Behc¸et syndrome (NBS) 1715 sarcoidosis 315 serum markers, inflammation 1367 shunts, infection 1365 skin biopsy 1367 Cerebrotendinous xanthomatosis (CTX) 1562, 1586–1587 clinical symptoms 1586, 1587 diagnosis/testing 1587 radiology 1586–1587 treatment 1587 Cerebrovascular disorders arrhythmia 129–130 congenital heart disease (CHD) 51–52, 51 Ehlers–Danlos syndromes (EDS) 570 Henoch–Sch€ onlein purpura (HSP) 1103–1104 HIV 1322 homocystinuria 572 characteristics/management 572 mechanisms/frequency 572 infective endocarditis 77–79 inflammatory bowel diseases (IBD) 597–599

I9 Cerebrovascular disorders (Continued ) intestinal transplantation (ITx) 1272, 1274–1275 Loeys–Dietz syndrome (LDS) 571 multiple organ transplantation 1311 neuropsychiatric systemic lupus erythematosus (NPSLE) 465 osteogenesis imperfecta (OI) 573 pseudoxanthoma elasticum (PXE) 571–572 radiotherapy (RT) 1193 renal transplantation 1251 Sneddon syndrome (SS) 1566–1567 Cerebrovascular phenomenon, intracranial hemorrhage (ICH) 1016 Cerrophidion 992–993 Certolizumab 601 Cervical artery dissection (CAD) 567, 568, 569, 574 characteristics/management 568 mechanisms/frequency 568 Cervical spinal cord injury (SCI) 276–277, 1629 Cervical spine stenosis, surgery 547, 547, 548 Cervical thoracic orthotic (CTO) device 1767 Cestodes (tapeworms) 1414, 1422–1428 Cetirizine 1654 CHADS score 118–122, 120, 122, 123, 142 Chagas disease 1413–1414 Chalastic attacks 182 Charcot–Marie–Tooth (CMT) disease pregnancy 1612 respiratory failure (RF) 277 Charcot–Marie–Tooth inherited neuropathy (CMTX5) 830 CHARGE (coloboma, heart disease, choanal atresia, retarded growth, genital/urinary anomalies, ear anomalies and deafness) syndrome 52, 53 CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance) trial 101 Chemokines 507 Chemotherapy 1199–1218 adverse effects 388 agents inducing neuropathy 1200 brain metastases 339, 1152–1153 central nervous system (CNS) 1205–1213 alkylating agents 1208–1210 antibiotics 1211 antimetabolites 1205–1208 biologic/targeted therapies 1212–1213 mitotic spindle inhibitors 1210–1211 chemobrain 1213 Hodgkin lymphoma (HL) 1035 leukemia/lymphoma/multiple myeloma (MM) 1134–1136 peripheral nervous system (PNS) complications 1199–1205

I10 Chemotherapy (Continued ) alkylating agents 1199–1201 antibiotics 1203 antimetabolites 1203–1204 biologic/targeted therapies 1204–1205 mytotic spindle inhibitors 1201–1203 prevention/rehabilitation 1205 proteasome inhibitors 1203 Chenodeoxycholic acid (CDCA), cerebrotendinous xanthomatosis (CTX) 1587 Chest wall disorders 265, 266 Cheyne–Stokes respiration pattern (CSRP) 263–264, 264, 278 Chickenpox see Varicella zoster virus (VZV) Child–Pugh score 665 Children achondroplasia 552, 554 arterial ischemic stroke (AIS) 1067–1068 bacterial meningitis 1369 cerebral venous sinus thrombosis (CVST) 1065–1066 congenital heart disease (CHD) 52–53, 55, 56 excessive sleepiness 254 heart transplantation 1234–1235 Lyme disease 1474 obstructive sleep apnea (OSA) 251, 254, 261 percutaneous coronary intervention (PCI) 197 respiratory problems 561 sickle cell disease (SCD) 1020 sudden death 556 tuberculous meningitis (TBM) 1487, 1490–1492 ChimeriVax-JE vaccine 1554 Chinese krait (Bungarus multicinctus) 989 Chlamydia spp 80–81 Chlorambucil 1209, 1718–1719 Chloramphenicol 1646 Chloromas (granulocytic sarcomas) 1040 Chloroquine 325, 326 Chlorpromazine 634, 951 ‘Chokes’ 962 Choking 254 Cholestatic hepatic failure 1286 Cholesterol emboli syndrome (CES) 1562, 1564–1566 clinical presentation 1564–1565 cutaneous 1565, 1565 neurologic 1565 diagnosis 1565–1566, 1565 treatment 1566 Cholesterol-lowering agents 9 Chordoma 445, 446 Chorea 715–716 polycythemic 1075 Choreoathetosis 56 Choriocarcinoma 217 Chronic gastrointestinal pseudoobstruction 1160

INDEX Chronic graft-versus-host disease 1302 Chronic inflammatory demyelinating polyneuropathy (polyradiculoneuropathy) (CIDP) 841, 845, 1088, 1333, 1611 Chronic kidney disease (CKD) see Renal disease, acute/chronic Chronic lymphoblastic leukemia (CLL) 1040–1041 Chronic morning headache (CMH) 254 Chronic myelogenous (myeloid) leukemia (CML) 1039, 1040–1041 treatment 1132, 1133 Chronic myelopathy 1524 Chronic myeloproliferative diseases 1073–1081 definitions 1073–1074 neoplasms (MPN) 1038–1039, 1132–1133 Chronic obstructive pulmonary disease (COPD) 279–280, 281 Chronic respiratory failure see Respiratory failure (RF), acute/chronic Chronic retroviral myelopathy 1527–1530 Chronic uremic encephalopathy 383–384 Churg–Strauss angiitis 484–486 clinical features 485, 485 treatment 485–486 Chvostek’s sign 377, 743 Chylomicron retention disease (CRD) (Anderson’s disease) 623, 624 Ciclosporin 326, 354, 485–486, 507, 1613, 1718–1719 adverse effects 601, 675, 676, 1201, 1245, 1278–1279 transplantation 1231, 1260, 1281–1282 Ciguatera 964, 988 Ciguatoxin 996 Cilindrocarpum lucidum 1299–1300 Cimetidine 638–639 Cinarizine 1642 Ciprofloxacin 1403–1404 Cisapride 637, 782, 1656 Cisplatin 1089, 1090, 1134 adverse effects 1200, 1200, 1208 Citalopram 520 Citrobacter spp 1113–1114, 1114 Cladophialophora bantiana 1383 Cladosporiosis 1385 Cladribine 1134, 1204, 1207–1208 Classic dermatomyositis (CDM) see Idiopathic inflammatory myopathy (IIM) Claudication, spinal stenosis 542–543 Clebopride 1656 Cleveland Family Study 253 Clindamycin 1324–1325, 1357, 1517 Clinical Immunization Safety Assessment (CISA) Network 1549 Clinical target volume (CTV) 1181–1182 Clinically amyopathic dermatomyositis (CADM) see Idiopathic inflammatory myopathy (IIM) Clodronate 536 Clofarabine 1208

Clofazimine 1575–1576 Clofibrate 1638 Clonazepam 846, 1640 Clonidine 1636, 1640 Clopidogrel (Plavix®) 101, 581, 1129, 1639 Clostridium spp 80–81 Clostridium botulinum 988, 996, 1640–1641 Clostridium difficile 1113–1114, 1114 Clostridium tetani 988, 1506, 1507 CLOTS (Clots in Legs Or sTockings after Stroke) trials 294, 296 Clotting function 1595–1596 c-Myc gene 1031 Clozapine 1642 Cluster headache 259 Coagulation factors VII/IX inhibition 1052 scheme 1062 tests 1050 Coagulopathies 1126–1128 ‘Coasting’ phenomenon 923 Cobalamin (Cbl) see Vitamin B12 deficiency Cobb syndrome 1562, 1572–1573, 1572 Cobras (Naja) 989, 991 Coccidioides spp 1386, 1397–1398, 1535 Coccidioides immitis 1383, 1384, 1385, 1397–1398 Coccidioidomycosis 1385, 1397–1398 Cochrane meta-analysis 294, 296 Cochrane reviews 507, 670–671, 1575–1576, 1759–1760 Cochrane Stroke Group Trials 118 CODACS (Consciousness Disorders After Cardiac Surgery) trial 144 Code of Federal Regulations (Regulations) 1549 Coenurosis 1428 diagnosis 1428 epidemiology 1428 pathogen 1428 signs/symptoms 1428 treatment 1428 Coenurus spp 1422 Coenzyme Q10 31 Cogan’s syndrome (CS) 483, 1717 clinical features 483 Cognition drugs 1641–1642, 1642 Cognitive behavioral therapy (CBT) 518 Cognitive dysfunction arrhythmia 130–131 atrial fibrillation 117–118 brain metastases 1145 congenital heart disease (CHD) 52–53, 53 dialysis patients 387, 397, 399–400 end of life (EOL) phase 1220 folic acid deficiency 934 neuro-Behc¸et syndrome (NBS) 1710 neuropsychiatric systemic lupus erythematosus (NPSLE) 464–465 neurosarcoidosis 311 obstructive sleep apnea syndrome (OSAS) 255

INDEX Cognitive dysfunction (Continued ) postoperative (POCD) 1630 treatment 1221 see also Neurocognition COL3A1 gene 565–567, 1567–1568 Colchicine 1650, 1718–1719 Cold pressure test 391 Collagenopathy 1567 Colubridae 987 Coma barbiturate 1628 hypothyroidism 705–706 Common pathway 1045–1046 Community Aging and Dementia Project 931 Community-acquired bacterial meningitis 1361, 1363–1365 Compartment syndrome 1053 Complement therapy 1120 Complex sleep apnea syndrome (cSAS) 264 Comprehensive psychopathologic rating scale (CPRS) 868–869 Compression neuropathy 775 Computed tomography (CT) brain metastases 1148, 1149 cardiac arrest 34 complications 1745–1746 hemolytic uremic syndrome (HUS) 1116, 1117 myelography 544–545 reversible cerebral vasoconstriction syndrome (RCVS) 1731–1732, 1732, 1733 single-photon emission (SPECT) 515, 1715 Concussive convulsions 179 Conduction 947 Cone snail venom 988 Confusion/delirium end of life (EOL) phase 1220 treatment 1221 Congenital adrenal hyperplasia 756 Congenital bleeding disorders 1045–1046 fibrinolytic pathway deficiencies 1056 homeostasis, pathophysiology 1045–1046, 1046 management, treatment centers 1058 overview 1047 rare 1054–1056 diagnosis 1054–1055 genetic testing 1055 management 1055–1056, 1055 prophylaxis 1056 symptoms 1054 see also Hemophilia; Platelet function disorders; von Willebrand disease (VWD) Congenital central hypoventilation syndrome (CCHS) (Ondine’s curse) 245–246, 278 alveolar (CCAHS) 265 Congenital heart disease (CHD) 49–60 brain anomalies 53–54

Congenital heart disease (CHD) (Continued ) cerebral aneurysm/aortic coarctation 54, 54 cerebrovascular complications 51–52, 51 clinical features 49, 50 cognitive disturbances 52–53, 53 genetics 53 historical perspective 49 incidence 49–50 infective embolism 52 laboratory investigations 53, 56 management 56 complications 54–56 signs/symptoms 51 surgical procedures 49, 50 Congenital hypothyroidism (CH) 703–705 clinical/radiologic features 704 etiology 704 pathogenesis 704 treatment/prognosis 704–705 Congenital phosphorus disorders 874 Congenital rubella syndrome (CRS) 1349, 1350 clinical manifestations 1350 Congestive heart failure (CHF) 258 Conivaptan 810, 812 Conjugate vaccines 1550 Connective tissue disorders (CTDs) 1567–1569 idiopathic inflammatory myopathy (IIM) 496, 499–500, 501 inherited 565–576 neurologic manifestations 565–574, 566 see also Scleroderma; Sj€ ogren’s syndrome (SS); Systemic lupus erythematosus (SLE) Conscious state, abnormal 1259–1261, 1260 Consciousness, impaired 1287–1288 Continuous chest compressions (CCC) 26 Continuous positive airway pressure (CPAP) 254, 260–261, 262 Continuous renal replacement therapy (CRRT) 400 Contrast media 1746 Contrast-induced nephropathy (CIN) 1745 Conus medullaris syndrome 1763 Convection 947 Coomb’s test 1011 Cooperative Cardiovascular Project 104–105 Cooperative Study of Sickle Cell Disease (CSSCD) 1016 Copper disorders 851–858 acquired copper deficiency 853, 857 acquired copper toxicosis 857–858 ATP7A-related transport disorders 853–854, 853 ATP7B-related transport disorders 854–857 deficiency myelopathy (CDM), bariatric surgery 590 malabsorption 626–627 metabolism 851–852, 852

I11 Coral snakes (Micrurus) 992 Cordylobia anthropophaga 1436 Cornea verticillata 1564 Coronary artery bypass grafting (CABG) 194, 195, 197–199, 199 stroke and 93, 198 Coronary artery dilators 1636, 1637 Coronary artery disease (CAD) 111, 906 Coronary artery stents (CAS) 99, 99 Coronary heart disease (CHD) 93 Cortex, disease 245–247, 247 Cortical blindness 35 transient 44, 44, 197 Cortical cerebellar degeneration 897–898 Cortical control, breathing 241, 242 Corticospinal tract disorders 715 Corticosteroids (CS) adverse effects 1269–1270, 1278–1279, 1645–1647 bacterial meningitis 1370 brain tumor 337, 1150, 1153, 1220–1221 breast feeding 1608 cerebral vasculitis 481, 483, 485–486, 487 connective tissue disorders (CTDs) 469–470, 471 gnathostomiasis 1539 helminthic infection 1429, 1433, 1434, 1435 hemolytic uremic syndrome (HUS) 1120 Henoch–Sch€ onlein purpura (HSP) 1108 idiopathic inflammatory myopathy (IIM) 506–507 intracranial pressure (ICP) 1759 leprosy 1513–1514 lung cancer 341–342, 354 Lyme disease 1480 mononeuropathy 1333–1334 multiple myeloma (MM) 1090–1091 neurocysticercosis 1456 neuromuscular conditions 1275, 1613 paraneoplastic neurologic syndromes (PNS) 1173 sarcoidosis 321, 322, 323, 327 spinal stenosis 546 tuberculosis (TB) 1338, 1490–1492 Corticotrophin-releasing hormone (CRH) 749, 750 ACTH levels 692 adrenal insufficiency (AI) 759 Cortrosyn test 759 Corynebacterium diphtheriae 1355, 1356 Co-trimoxazole (Bactrim®) see Trimethoprimsulfamethoxazole (TMP-SMX, TMP-SMZ) Cough reflex, absent 1240 Cough syncope 175, 177 Coumarins 1638–1639 COX-2 inhibitors 580 Coxiella spp 1403 Coxiella burnetii 79, 80–81, 1403–1404 Cranial nerve disorders diphtheria 1356 hypothyroidism 708–709

I12 Cranial nerve disorders (Continued ) palsies 322 radiotherapy (RT) 1192 Cranial neuritis 1474 Cranial neuropathy 307–308 diabetic mellitus (DM) 775 inflammatory bowel diseases (IBD) 597 Paget’s disease of bone (PDB) 530 Cranial vault lymphomas, clinical presentation 1036–1037 Craniocervical junction anomalies 554–556, 555 dislocation 435 Craniopharyngiomas, radiotherapy (RT) 1188–1189 Craniotomy 1760 Craniovertebral dislocation 433–448 anatomic concepts 436–437 causes 436 clinical features 437–438 progressive craniovertebral subluxation 437–438 traumatic craniovertebral subluxation 438, 438, 439 congenital malformations 441, 445 historical perspective 435 neuroimaging 438–440, 440 neurologic complications 436, 438, 440–446 craniovertebral junction 441, 445, 445, 446, 446 Cranium, fractures 1752 Creatine kinase (CK), raised 714 Creatine monohydrate 506 Cremophor 1202 CREST (calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactyly, teleangiectasia) syndrome 468 Creutzfeldt–Jakob disease (CJD) 811 Critical flicker frequency (CFF) 665 Critical illness myopathy (CIM) 751–752, 754, 1674–1675 lung transplantation 1240 outcome/prognosis 1680 pathophysiology 1675–1676 risk factors 1675 Critical illness myopathy-polyneuropathy 1278–1279 Critical illness neuromyopathy (CINM) 1675 Critical illness polyneuropathy (CIP) 1674 outcome/prognosis 1680 pathophysiology 1675–1676 risk factors 1675 Crohn’s disease (CD) see Inflammatory bowel diseases (IBD) Crotalinae 992–993 Crotalus 992–993 Crotalus atros 993 Crotalus durissus durissus 993 Crotalus durissus terrificus 990, 992–993 Crotalus horridu 993 Crotalus scutulatus 993

INDEX Crow–Fukase syndrome see POEMS syndrome Cruciate paralysis 1763 Cryoglobulinemia 1083, 1084, 1087, 1096 peripheral nervous system (PNS) 1096 Cryoprecipitate 1127 Cryothermy 157 Cryptococcal meningitis, HIV-associated 1248–1249, 1328–1330, 1391–1394, 1393, 1394 clinical features 1328–1329 diagnosis 1329 epidemiology 1328 imaging 1329 intracranial pressure, raised 1330 pathogenesis 1328 treatment 1329–1330, 1329 antiretroviral therapy (HAART) 1330 prophylaxis 1330 Cryptococcosis 1385 Cryptococcus spp 1252, 1328–1329, 1387, 1535 Cryptococcus neoformans 1328, 1329–1330, 1383, 1384, 1386, 1389–1390, 1391 investigation 1386 transplantation 1232, 1241, 1262 Cryptococcus neoformans var gattii 1328, 1391 Cryptococcus neoformans var neoformans 1328, 1385, 1391 Cryptogenetic drop attacks, women 182–183, 183 Cryptosporidium spp 1410 Crystalline aqueous penicillin 1468, 1470 Cuba Neuropathy Field Investigation Team 1543 Cuban epidemic myeloneuropathy 1542–1543 clinical manifestations 1543–1544 epidemiology 1543 etiology 1544 treatment/prevention 1544 Cucurbita pepo 1445 Culex spp 1429 Cunninghamella 1383, 1396 CURE (Clopidogrel in Unstable Angina to prevent Recurrent Events) trial 101 percutaneous coronary intervention subset (PCI-CURE) 103 Cushing syndrome (CS) 750–754 clinical manifestations 750–752, 752, 753, 754 diagnosis 752–754 etiology 750, 751 historical perspective 750 treatment 754 Cushing’s disease ACTH-dependent 692–693 management 698 Cutaneomeningospinal angiomatosis (CMA) see Cobb syndrome Cutaneous manifestations angioma 1569–1573 Carney complex (CC) 1566, 1566

Cutaneous manifestations (Continued ) neurofibromas 1581–1582 see also Neurocutaneous disorders CV2/CRMP5-Abs (antibodies) limbic encephalitis (LE) 1166, 1169 subacute cerebellar degeneration (SCD) 1164 Cyanide 1544–1545 Cyanocobalamin deficiency 591 Cyclooxygenase (COX) 577–578, 579 inhibitors 580, 1129 Cyclophosphamide (CTX) 459, 471, 507, 1108, 1173, 1718–1719 adverse effects 1210 cerebral vasculitis 479, 483, 485–486, 487 neurosarcoidosis 325, 326, 327 Cyclops spp 1427–1428, 1429 Cycloserine 1491, 1492 CYP27A1 gene 1586 Cyproheptadine 951, 1654 Cystic echinococcosis see Hydatid disease Cystic fibrosis 1280 Cysticerci characteristics 1447 immune response 1448 involution stages 1447, 1447 tissue reaction 1447–1448, 1448 Cysticercosis 1445, 1777 Cysticercus cellulosae 1423–1424 Cysticidal drugs 1455 Cytarabine see Cytosine arabinoside (ARa-C) Cytomegalovirus (CMV) heart transplantation 1232, 1233 hemolytic uremic syndrome (HUS) 1114, 1114 liver transplantation 1263 mononeuropathy 1333–1334 progressive polyradiculopathy 1334 renal transplantation 1249 serology mismatch 1238 treatment 1380 Cytomegalovirus (CMV) encephalitis 1377, 1379 diagnosis 1380 focal 1232 treatment 1381 Cytomegalovirus (CMV) encephalitis, HIV-associated 1330–1331 clinical features 1330–1331 diagnosis 1331 prevention 1331 treatment 1331 Cytosine arabinoside (cytarabine) (ARa-C) 1134, 1135, 1263 adverse effects 1200, 1203, 1206–1207 Cytotoxic drugs 1694

D

Dabigatran (Pradaxa®) 121–122, 139, 295, 1131 Dabigatran etexilate, adverse effects 1639 Daboia palaestinae 993 Daboia russelii 988, 990, 992–993

INDEX Daboia siamensis 993 Dacarbazine 1209 Dantrolene 951 Dapsone 1575–1576 Dasatinib (Sprycel®) 1133 Data and Safety Monitoring Board (DSMB) 122, 1021–1022 Daunorubicin 1211 Death adder (Acanthophis) 992 Decompression illness (DCI) 959–970 arterial gas embolism (AGE) 959–960, 967 case examples 966–967 clinical manifestations 960–962, 961 decompression sickness (DCS) 959, 966–967 diagnosis 960–962, 963, 964 epidemiology 960, 960, 961 long-term consequences 965–966 prevention 962–963 treatment 963–965 adjunctive therapy 965 first aid 963–965 recompression 965 Decompression sickness (DCS) see Decompression illness (DCI) Decompressive craniectomy 1759–1760 DECRA study (Australia) 1759–1760 Deep hypothermic circulatory arrest (DHCA) 55 Deep venous thrombosis (DVT) 1767 brain metastases 1153 spinal cord injury (SCI) 1766 see also Venous thromboembolism (VTE) Deer tick virus, encephalitis 1378 Deferasirox 1020–1022 Deferoxamine 1020–1021 Defibrillators, implantable 141 complications 157 Degenerative ataxias 9 Degos disease (malignant atrophic papulosis/Kohlmeier-Degos disease) 1562, 1567 Deinagkistrodon 992–993 Delirium see Confusion/delirium Deltaretrovirus 1527 Dementia arrhythmia 131 cardiology 9 dialysis 397, 399–400 folic acid deficiency 931–932 HIV 1322 vascular (VaD) 9, 931–932, 1778 see also Alzheimer’s disease (AD) Demyelinating disorder 466, 600 and axonal neuropathy 1273 Dendroaspis spp 990, 992 Dendroaspis angusticeps 990, 992 Dendroaspis jamesoni 992 Dendroaspis polylepis 992 Dendroaspis viridis 992 Dendrobatidae 996 Deoxyguanosine kinase (dGK) deficiency 828, 832–833

Department of Health and Human Services (USA) 1338 Depot Ara-C (DepoCyt®) 1203 Depressed skull fracture 1760 repair 1760 Depression 254 folic acid deficiency 931–932, 933–934, 933 hypothyroidism 706–707 obstructive sleep apnea syndrome (OSAS) 255–256 vitamin D 881–882 Dermatobia hominis 1436 Dermatomyositis (DM) see Idiopathic inflammatory myopathy (IIM) Desferrioxamine 397 Desflurane 1626, 1627, 1630–1631 Desirudin 1639 Desmopressin acetate (DDAVP) 810, 812, 1051–1052, 1057, 1132 Developing world 1773–1782 healthcare systems 1773–1774 primary care 1774 secondary care 1774 tertiary care 1774 human resources/training/education 1774–1775 neurologic diseases, common 1775–1780 see also Tropical myeloneuropathy; Tropical myelopathy Developmental defects 756 Developmental delay 557–558 Device-associated meningitis 1369 Devic’s disease 1540 Dexamethasone 341, 506, 1379–1380, 1492–1493, 1613 bacterial meningitis 1369–1371 brain tumors 337, 1153, 1220–1221 tropical myelopathy 1545, 1537, 1539 Dextromethorphan 1655 Dextrose 819 DGUOK gene 832–833 Diabetes Complications and Control Trial (DCCT) 776–777, 778–779 Diabetes insipidus (DI) 370, 370 central 690 nephrogenic 372 Diabetes mellitus (DM) drugs 814–821 neuropathy see Diabetic neuropathy pancreas transplantation 1280 Diabetes mellitus (DM) type 1 (T1DM) 773, 801 drugs 814, 817, 820–821 Diabetes mellitus (DM) type 2 (T2DM) 773, 774 drugs 779, 814, 815, 816, 817, 817, 820–821 Diabetic autonomic neuropathy (DAN) 773, 774–775, 781–782 Diabetic cardiac autonomic neuropathy (CAN) 10 Diabetic ketoacidosis (DKA) 377 Diabetic neuropathy 773–785 classification/clinical findings 774–776

I13 Diabetic neuropathy (Continued ) asymmetric lower limb neuropathy 776 autonomic neuropathy (DAN) 773, 774–775 cranial neuropathy 775 focal/multifocal neuropathies 775 limb mononeuropathy 775 selective small fiber polyneuropathy 774 sensory/sensory motor polyneuropathy 774 trunk mononeuropathy 775–776 historical perspective/epidemiology 773–774 laboratory investigations 776 pathophysiology 777–778, 777 AGE pathway 777 hexosamine pathway 777–778 neurotrophic factors/nerve repair 778 oxidative stress 777 polyol pathway 777 protein kinase C (PKC) pathway 778 risk factors 776–777 treatment 778–782 autonomic neuropathy (DAN) 781–782 disease state modifiers 778–780 neuropathic pain 781 pain-controlling agents 780–781 Diabetic peripheral neuropathy (DPN) 776–777 Diagnostic biopsy 1148 Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) 144 Dialysis dementia 397, 399–400 Dialysis disequilibrium syndrome (DDS) 386, 396–397 clinical presentation 386 pathogenesis 386 therapy 386, 386 Dialysis encephalopathy syndrome 387–388 clinical symptoms 388 diagnosis 387–388 treatment 388 Dialysis patients 395–404 central nervous system (CNS) 395–400, 396 cognitive impairment 387, 397, 399–400 peripheral nervous system (PNS) complications 396, 400–401 3,4-Diaminopyridine 354 Diazepam 31, 1508–1509 Diclofenac 580, 1648–1649 Dicumarol 1638–1639 Diethylcarbamacin 1429 Diffuse axonal injury (DAI) 1753, 1755 Diffuse head injury 1755 Diffuse leukoencephalopathy 1150 Diffuse noxious inhibitory control (DNIC) 516 Diffuse peripheral neuropathy 707–708 DiGeorge syndrome 53

I14 Digestive tract drugs 1655–1656, 1656 Digit Symbol Test (DST) 663–664, 664 Digitalis purpurea 133, 133 Digoxin 132, 133 Dihydroergotamine 1651 Dihydropyrimidinase (DHP) deficiency (dihydropyrimidinuria) 834, 834 Dihydropyrimidine dehydrogenase (DPD) deficiency 834 Diltiazem 132, 133–134, 1636 Dipeptidyl peptidase (DPP-4) inhibitors 819–820 Diphenhydramine 636–637, 1651–1654 Diphosphonates 1655 Diphtheria 1355–1357 clinical features 1356–1357 epidemiology 1355–1356 immunization 1358 diphtheria-tetanus-pertussis (DTP) vaccine 1358, 1550, 1555–1556, 1651 laboratory features 1357 outcome 1357 pathogenesis/pathology 1356 treatment 1357 Diphyllobothrium dendriticum 1428–1429 Diphyllobothrium latum (fish tapeworm) 918, 1422, 1428–1429, 1541 clinical manifestations 1429 diagnosis 1429 epidemiology 1428–1429 pathogen 1429 therapy 1429 Dipyridamole 1129–1130, 1639 Direct thrombin inhibitors (DTIs) 1131, 1131, 1132, 1639 Disc herniation, acute myelopathy 1524–1525 Discovertebral destruction 456 Disease-modifying therapies (DMTs) 1607–1608 Disopyramide 132, 134, 187 Distal motor neuropathy (DMN), ATP7Arelated 853, 854 Distal symmetric polyneuropathy (DSP) 1321, 1332–1333, 1335 clinical features 1332 diagnosis 1332 treatment 1332–1333 Diuretics 12, 165, 866 Dive tables 962 Divers Alert Network (DAN) 960, 961 Diving see Decompression illness (DCI) DMPK gene 796 DNA methyltransferase inhibitors 1133–1134 Docetaxel 1202, 1210 Dofetilide 132, 134 Dolasetron 636, 637 Dolichovespula 995 Domperidone 185, 636, 1642, 1656 Donepezil 1642 Dopamine 517, 811, 1637 Dopamine agonists (DA) 519, 522, 697, 811, 1641

INDEX Dopamine dysregulation syndrome 1641 Dopamine receptor-blocking drugs (DRBDs) 1642–1643, 1643 Dorsolateral myelopathy 1544 ‘Doughnut appearance’ 1679–1680 Down syndrome craniovertebral dislocation 435, 443 genetics 52, 53 Doxorubicin 1203, 1211 Doxycycline 625, 628, 1379–1380, 1403–1404, 1429, 1517 Lyme disease 1479–1480, 1480, 1533 neurosyphilis 1337, 1468–1469 D-penicillamine 856–857 Dreaming, excessive 254 Dronabinol 638 Dronedarone 132, 134 ‘Drop attacks’ 181–184 cryptogenetic, women 182–183, 183 Droperidol 639, 1642, 1656 Drug-induced conditions central sleep apnea (CSA) 264 encephalopathy 1299 hyperthermia see under Hyperthermia hypomagnesemia 871 inflammatory bowel diseases (IBD) 601 movement disorders (DIMD) 635, 638 multiple myeloma (MM) 1089–1090 neurotoxicity 1245–1247 posterior reversible encephalopathy syndrome (PRES) 1692, 1695 renal failure (RF) 388 see also Iatrogenic neurology Dual antiplatelet therapy 581 Duchenne muscular dystrophy (DMD) 10–12, 11, 125 respiratory failure (RF) 277 Duke criteria infective endocarditis 81, 82 stroke 67 Duloxetine 520, 780, 781 Dural metastases 345 Dwarfism see Achondroplasia Dystonic spasms 635 Dystrophinopathies 10–12, 11, 124–125 Dystrophy, hereditary 1612

E Eastern Association for the Surgery of Trauma (EAST) 298, 1763 Eastern equine encephalitis virus 1378 diagnosis 1380 Echinocandins 1389, 1395, 1649 Echinococcosis 1425–1427 cystic see Hydatid disease Echinococcus spp 1287–1288, 1422 Echinococcus granulosus 1425–1427 Echinococcus multilocularis 1425, 1426–1427 Echis 992–993 Echocardiography 80, 80, 185, 217 transesophageal (TEE) 7–8 Eclampsia defined 1597 long-term effects 1597–1598

Eclampsia (Continued ) posterior reversible encephalopathy syndrome (PRES) 1692, 1693–1694, 1696 treatment 1604 Eculizumab 507, 1120 Edema, traumatic brain injury (TBI) 1753 Education developing world 1774–1775 fibromyalgia 518 Eflornithine 1412 Egyptian cobra (Naja haje) 987, 989 Ehlers–Danlos syndrome (EDS) 570–571 description 570 neurologic complications 570–571 type IV 1562, 1567–1568, 1567 type IX (occipital horn syndrome (OHS)) 853, 853 vascular see Vascular Ehlers–Danlos syndrome (vEDS) Ehrlichia spp 1403 Elapidae 987, 991–992 Elastinopathy 1567 Electrical cardioversion 139–140 Electrical injuries see Thermal injuries Electrocardiography (ECG) monitoring 185 thermal injuries 982, 983 Electrocution, defined 981 Electroencephalography (EEG) brain metastases 1149 cardiac arrest 32–33 Hashimoto’s encephalopathy (HE) 725 hemolytic uremic syndrome (HUS) 1116–1117, 1118 Electrolyte disturbances 366 see also specific conditions Electromyography (EMG) 502, 1679 Electrophysiologic studies 185 procedures 142 Embolism anticoagulation 66 arterial gas (AGE) see Decompression illness (DCI) cardiac tumors 212–213 cerebral see Cerebral embolism congenital heart disease (CHD) 52 defined 93 infective endocarditis 67–68, 85, 85 saddle 296 stroke 95 see also Thromboembolism, catheter ablation; Venous thromboembolism (VTE) Emery–Dreifuss muscular dystrophy (EDMD) 11, 12, 125 Enalapril 1636 Enalaprilat 165, 165 Encainide 132, 134 Encephalitic (furious) rabies 1501–1502 Encephalitis 1377–1381 clinical presentation 1378 diagnosis 1378–1379, 1380 etiology 1377–1378 granulomatous 1411

INDEX Encephalitis (Continued ) HIV 1322 Japanese (JE) 1554 Toxoplasma (TE) 1323, 1324 treatment 1379–1381, 1380 Encephaloduroarteriosynangiosis (EDAS) 1022 Encephalomyelitis 1475–1476 Encephalopathy acute 79 coronary artery bypass grafting (CABG) 198 dialysis see Dialysis encephalopathy syndrome gluten 612, 612 Hashimoto’s see Hashimoto’s encephalopathy (HE) heart transplantation 1232 hematopoietic stem cell transplantation (HSCT) 1297–1299 hepatic see Hepatic encephalopathy (HE) hypertensive 1104 hypothyroidism 705–706 infective endocarditis 68–69 intestinal transplantation (ITx) 1271–1272, 1271, 1274 lung transplantation 1241 multifocal 348 neurosarcoidosis 310–311, 311 portosystemic see Portosystemic encephalopathy small bowel transplantation 1287–1288 uremic see Uremic encephalopathy Wernicke’s see Wernicke’s encephalopathy (WE) see also Hypertension/hypertensive encephalopathy; Posterior reversible encephalopathy (leukoencephalopathy) syndrome (PRES/PRLS) End of life (EOL) phase 1219–1227 bereavement care 1223 decision-making 1221–1222 advance care planning (ACP) 1222–1223 euthanasia/physician-assisted suicide (PAS) 1222 nontreatment 1222 palliative sedation 1222 neurologic signs/symptoms 1219–1220 cognitive dysfunction/delirium 1220 impaired motor function/immobility 1220 raised intracranial pressure (ICP) 1219 seizures 1219–1220 supportive treatment 1220–1221 cognitive dysfunction/delirium 1221 impaired motor function/immobility 1221 raised intracranial pressure (ICP) 1220–1221 seizures 1221

Endemic ataxic polyneuropathy (tropical ataxic myeloneuropathy (TAN)) 1542–1543 Endocarditis infective see Infective endocarditis noninfective 69–70 Endocrine disorders 310 Carney complex (CC) 1566, 1566 fibromyalgia 517 obstructive sleep apnea syndrome (OSAS) 257–258 primary brain tumors 726 Endocrine therapy 809–824 adverse effects 1204 brain metastases 1152–1153 diabetes mellitus (DM) 814–821 hormone-related drugs 1654, 1655 hypothalamic/pituitary hormones/ analogs 809–812, 810 thyroid/parathyroid agents 812–814 End-stage renal disease (ESRD) 384, 385, 395, 1245 dementia 399–400 periodic limb movement disorder (PLMD) 398–399 polyneuropathy 400–401 sleep disorders 398 stroke 400 Engel, George L 19 Enhydrina schistose 992 Enoxaparin 1132 Entamoeba histolytica 1407, 1410–1411, 1410, 1410 Entecavir (Baraclude®) 676, 680 Enterococcus spp 52, 68, 1532 Enteroviruses 1378, 1380 Entrapment neuropathy 450–451, 450, 707, 775 Ependymomas, radiotherapy (RT) 1185 Ephedrine 187 Epicardial radiofrequency vein isolation 143–144 Epidemiology of Diabetes Interventions and Complications (EDIC) 778 Epidermal growth factor receptor (EGFR) inhibitors 1152–1153 Epidermoid spinal tumors 1747 Epidural disease, multiple myeloma (MM) 1090–1091, 1090, 1091 Epidural hematomas (EDH) 530, 1752, 1760, 1761 Epilepsy cardiology 8, 8 developing world 1775–1776 folic acid deficiency 932–933 gluten-related diseases (GRD) 613, 613 multiple organ transplantation 1310 neurocutaneous disorders 1584–1590 pregnancy 1606–1607 sudden unexplained death (SUDEP) 8, 22–23 vitamin D 882

I15 Epileptic transient loss of consciousness (TLOC) 175, 177–178, 179, 184 clinical features 177–178, 178 falls 182 pathophysiology 178 Eplerenone 764–765 E-Aminocaproic acid (EACA) 1128 Epstein–Barr virus (EBV) Burkitt lymphoma (BL) 1030–1031 encephalitis 1378, 1379 diagnosis 1380 treatment 1380 heart transplantation 1232, 1233 hemolytic uremic syndrome (HUS) 1114, 1114 Hodgkin lymphoma (HL) 1034 intestinal transplantation (ITx) 1270 serology mismatch 1238 Eptifibatide 1639 Epworth Sleepiness Scale 260 Ergocalciferol 745 Ergotamine 1650, 1654 Ergotism 1650 Eribaxaban 139 Eribulin 1203 Erythromycin 1337, 1357, 1468–1469 Erythromycin lactobionate 782 Erythropoiesis-stimulating agents (ESAs) 1009 Erythropoietin 782, 1006, 1205 Escherichia coli (E. coli) 1369, 1532, 1540–1541 hemolytic uremic syndrome (HUS) 1113–1114, 1117–1118 Eslicarbazepine, elimination 418, 422–423, 425, 427 Esmolol 132, 134, 165, 165 Esomeprazole 638–639 Essential thrombocythemia (ET) 1075–1077 clinical characteristics 1075–1076 defined 1073 diagnostic criteria 1076 JAK2 gene 1073–1074 neurologic manifestations 1076–1077, 1077 treatment 1077, 1132 Estramustine 1209 Etanercept 507, 718–719, 1719 Ethambutol 1490, 1491 Ethanol 376–377 Ethionamide 1490, 1491, 1492 Ethosuximide 1640, 1640 elimination 418, 425, 427, 428 Ethylene glycol toxicity 375–376 Etomidate 698, 754, 1625, 1625, 1631 Etoposide 1203, 1210–1211 EURAP Epilepsy Pregnancy Registry 1606–1607 European Association for the Study of Diabetes 817 European Diabetes (EURODIAB) Prospective Complications Study 776–777

I16 European Federation of Neurological Societies (EFNS) Task Force 1173 European Group on Graves’ Orbitopathy 718–719 European Headache Federation 1776 European Heart Survey 119, 122–123 European League Against Rheumatism (EULAR) 450, 466–467 fibromyalgia 518, 521–522 Henoch–Sch€onlein purpura (HSP) 1102, 1102 European Medicines Agency (EMA) 809, 813 European Neuromuscular Centre (ENMC) 496 European Society of Cardiology 80 infective endocarditis 83–84, 84, 85, 86–87 Task Force for the Diagnosis and Management of Syncope 174 Task Force on Prevention, Diagnosis and Treatment of Infective Endocarditis 75 Euthanasia 1222 Evaporation 947 Everolimus 1231, 1289–1290 Excessive daytime sleepiness (EDS) 254, 398 Exenatide 817, 820 Exercise 185, 518 Expanded Disability Status Scale (EDSS) 1717 Expert Consensus Panel, cardiomyopathy definition 111 Extended criteria donors (ECD) 1237 External cardioversion 139–140 Extracorporeal membrane oxygenation (ECMO) 55, 201–202, 1238 Extrapyramidal disorders 183–184, 351 Eye involvement 1568, 1704 ‘Eye of the tiger’ image 860 Ezetimibe 1638 Ezogabine 418, 425, 427, 429

F Fabry disease (FD) 123, 1561–1564, 1562 clinical features 1561–1564 cardiac involvement 1564 cutaneous 1561 neurologic 1561–1564 ophthalmologic 1564 renal manifestations 1564 diagnosis/counseling 1564 treatment 1564 ‘Face of the giant panda’ sign 856, 856 Facial baroparesis 964 Facial cutaneous angioma 1570 Facial nerve (cranial nerve VII) 307–308 Facial palsies 964 Facial paralysis 1533 ‘Facies lactrodectismica’ 994–995 Factor Xa antagonists 139 Factor Xa inhibitors 295, 1130–1131, 1639 Fainting larks 175

INDEX Falls accidental 184 epileptic 182 gait ataxia/extrapyramidal disorders 183–184 muscle weakness 184 psychogenic 184 Famciclovir 1380–1381 Familial expansive osteolysis, clinical characteristics 534 Familial glucocorticoid deficiency (PGD) 756 Familial hypobetalipoproteinemia (FHBL) 623, 624 Familial hypocholesterolemia 623–624 Familial oncogene derangements 799 Familial Paget’s disease, clinical characteristics 534 Familial paraganglioma 765 Famotidine 638–639 Fanconi’s anemia (FA) 1010 Fasciculins 990 Fascioscapulohumeral muscular dystrophy (FSHD) 1612 FAST trial 1132 Fat metabolism 591 Fatigue, sarcoidosis 328 Favaloro, Rene´ 41 FBN1 gene 569 Felbamate 846 elimination 418, 425, 427, 428 Femoral artery catheterization 7 Femoral nerve, cardiac surgery 197 Fenoldopam 165, 165 Fentanyl 1626, 1758 Fever 951–953 causes 952 clinical features 951–952 laboratory findings 952 management 953 Fibrinolysis 1595–1596 Fibrinolytic pathway deficiencies 1047, 1056 Fibro fog 513–514, 521 Fibroelastomas 218 papillary 216 Fibromyalgia 513–528 clinical presentation 513–514 diagnostic criteria 514 epidemiology 514 genetics 516 historical perspective 513 laboratory investigations 515 management 517–523 complementary 523 pharmacologic 518–523, 519 nonpharmacologic 518 natural course 514–515 neuroimaging 515–516 functional magnetic resonance imaging (fMRI) 101 positron emission tomography (PET) 515–516 proton magnetic resonance spectroscopy (H-MRS) 516

Fibromyalgia (Continued ) single-photon emission computed tomography (SPECT) 515 obstructive sleep apnea syndrome (OSAS) 259–260 pathophysiology 516–517 autonomic dysautonomia 517 central nervous system (CNS) 516–517 endocrine influences 517 peripheral influences 516 Fibromyalgia Impact Questionnaire (FIQ) 514, 518 ‘Final Push’ strategy (WHO on leprosy) 1512–1513 Fingolimod 507, 1607–1608 Flatworms (platyhelminths) 1414, 1419–1429 Flecainide 132, 134, 1637 Flexion contractures syndrome 758 Flucloxacillin 1369 Fluconazole 1329–1330, 1329 Fluctuating vigilance 177–178, 184 Flucytosine 1248–1249, 1329–1330, 1329, 1389 Fludarabine 1134, 1201, 1207 Fludrocortisone 185, 187, 781 Flukes 1419–1422 Flunarizine 1642 Fluorinate pyrimidines 1652 Fluoroquinolones 1490, 1492, 1646 Fluorosis 1547–1546 5-Fluorouracil (5-FU) 834, 1200, 1201, 1204, 1207 Fluoxetine 520 Flupirtine 1649–1650 Fluprednisolone 1647 Flutter VRPI® 283 FMR1 gene 793, 794–795 Focal deficits amyotrophy 1681 brain metastases 1145 mass lesions, fungal infection 1385 neurocysticercosis (NCC) 1449 neuropathies, diabetes mellitus (DM) 775 radionecrosis 1150 reversible cerebral vasoconstriction syndrome (RCVS) 1728 Folate see Folic acid deficiency Folic acid (folate) deficiency 927–943, 1125–1126 bariatric surgery 591 clinical dissociation 935–936 disorders 937 epilepsy 932–933 folate metabolism 928–929, 928 inborn errors 935, 935 historical perspective 927–928 homocysteine/depression/dementia/ aging 931–932 megaloblastic anemia 927, 929–930, 930, 1007 metabolic mechanisms 928, 936–938, 937

INDEX Folic acid (folate) deficiency (Continued ) neural tube defects (NTDs) 932, 934–935 neuropsychiatric disorders 930–931 short bowel syndrome 1286 treatment 933–934, 933 cognitive function 934 depression 933–934, 933 Follicle-stimulating hormone (FSH) 686 acromegaly 691–692 excess 693–694 hyperprolactinemia 690–691 secondary hypogonadism 689–690 Fomepizole 376–377 Fondaparinux 1130–1131 Food and Drug Administration (FDA) acute stroke 156 dabigatran 121 deferasirox 1020–1021 endocrine therapy 809 implantable devices 1746 metoclopramide 635 multiple sclerosis (MS) 1607–1608 mycophenolate mofetil 326–327 nephrogenic systemic fibrosis (NSF) 97–99 pregabalin 1332–1333 pregnancy 1603 ribavirin 679 serotonin syndrome (SS) 1651 stroke 1639 sunitinib 1213 thionamides 813 vaccines 1549, 1552, 1554 Foreign accent syndrome 1260 Forssmann, Werner 41 Fosaprepitant 637 Foscarnet 1331, 1380, 1381 Fosphenytoin, malaria 1517 Fotemustine 1208–1209 Fractionated heparin 1719–1720 Fractionated radiation therapy (RT) 341–342 Fractures, cranium 1752 Fragile X syndrome 793–795, 794 clinical findings 794 historical perspective 793 laboratory investigations 794–795 management 795 natural history 794 pathology 794 Fragile X-associated tremor/ataxia syndrome (FXTAS) 793 Framingham Heart Study 118–119, 161, 904, 931 Framingham risk score 111 Frascati classification, neurocognitive disorders 1338–1339, 1339 French Vasculitis Study 482–483 Fresh frozen plasma (FFP), coagulopathies 1126–1127, 1131–1132 Friedreich’s ataxia (FA) 9 Frog venom 988 ‘Frozen bone’ 536

FTL (ferritin light polypeptide) gene 860 Fulminant hepatic failure 1258, 1261, 1262, 1262 Functional magnetic resonance imaging (fMRI) 101 Fungal infections 1383–1401 central nervous system (CNS) 1248–1249 clinical syndromes 1385–1386, 1385 epidemiology 1383 imaging 1387–1388, 1388, 1389, 1390, 1391, 1392, 1393 laboratory diagnosis 1386–1387 cerebrospinal fluid (CSF) 1386 markers 1387 PCR-based assays 1387 serum antigens/antibodies 1386 myelopathy 1535 pathogenesis 1384–1385, 1384 pathogens 1383–1384 predisposing factors 1384 specific infections 1391–1398 therapy 1388–1391, 1395 antifungal agents 1388–1391, 1395 surgery 1390–1391 Furosemide 1628–1629, 1758–1759

G GABAB-Abs (antibodies) 1162 limbic encephalitis (LE) 1166, 1168 Gabapentin 521, 780, 846–847, 1332–1333, 1640 adverse effects 1640, 1640 elimination 418, 425, 426, 427 Gain-of-sodium disorders 370 Gait disorders 183–184, 1145 Galantamine 1642 Galen 241 Gallium nitrate 878 Gambierdiscus toxicus 996 Gamma knife 1152, 1189 g-Aminobutyric acid (GABA) 843 Ganciclovir 1331, 1333–1334, 1380, 1381 Ganglionated plexus ablation 143–144 Garin–Boujadoux–Bannwarth syndrome 1475, 1480 Gastric H2-receptor inhibitors 1655 Gastric outlet obstruction (GOO) 1241 Gastric protonic pump inhibitors 1655–1656 Gastroesophageal reflux (GER) 260 Gastrointestinal complications Behc¸et’s syndrome (BS) 1705, 1717 primary hyperparathyroidism (PHPT) 867 respiratory failure (RF) 281 treatment 782 Gastrointestinal drugs 633–643, 634 acid-related disorders 634, 638–639 antiemetics 633–637 central hyperthermia syndromes 639 laxatives 634, 638 motility 634, 637–638 antimotility 634, 638 promotility 634, 637–638 neurologic adverse effects 634

I17 Gastroprokinetic drugs 1655 Gatifloxacin 1491 Gemcitabine 1203, 1208 Gemfibrozil 1638 Gemtuzumab ozogamicin (GO or Mylotarg®) 1136 Genital ulcers 1704 Genitourinary drugs 1655–1656, 1656 Genitourinary neuropathy 782 Genitourinary tract cancers 1144 Germ cell tumors, radiotherapy (RT) 1185 Germinomas 1185 Giant cell arteritis (GCA) 227–229, 228, 479–481 clinical features 480, 480 hypothyroidism 711 Giant cell vasculitis 477 Giardia spp 1113–1114, 1114 Gitelman’s syndrome 872 Glandular tissue, autoimmune-mediated destruction 799 Glasgow Coma Scale (GCS) 29, 116, 1365, 1366, 1373, 1756 traumatic brain injury (TBI) 1754, 1754, 1755, 1758, 1760 Glatiramer acetate (GA) 1607–1608 Glia cells, fibromyalgia 517 Glibenclamide (glyburide) 817, 818 Gliclazide 817, 818 Glimepiride 817, 818 Glioblastoma multiforme (GBM) 299, 1263 Glioblastoma, radiotherapy (RT) 1184 Gliomas, low-grade 1184 Glipizide 818 Global brain injury 1191–1192 Global Polio Eradication Initiative (WHO) 1777 Global Stroke Initiative (WHO/ISS/WFN) 1778 Glossopharyngeal nerve (cranial nerve IX) 308 ‘Gloves and socks’ syndrome 1351 Gloydius 992–993 Glucagon-like peptide-1 (GLP-1) receptor analog 820 Glucocorticoids 31, 866, 1357, 1719–1720, 1737–1738 Glucose-6-phosphatase (G6Pase) deficiency 828, 833 Glucose-6-phosphate deaminase (G6PD) deficiency 1012 a-Glucosidase inhibitors 818–819 Glutamine 1261 Gluten-related diseases (GRD) 607–619 diagnosis 608–609, 608 epidemiology 608 neurologic manifestations, spectrum 609–614 epilepsy 613, 613 gluten ataxia (GA) 609–611, 610 gluten encephalopathy 612, 612 gluten neuropathy 611–612 myelopathy 614, 614 myoclonic ataxia 612–613 myopathy 613–614, 614

I18 Gluten-related diseases (GRD) (Continued ) stiff man syndrome (SMS) 614 pathogenesis 614–616, 615 Glyburide 817, 818 Glycerol 1371 Glycogen storage disease (GSD) type I (von Gierke disease) 833 Glycopeptides 1646 Glycoprotein IIB/IIIA antagonists 1129 Glycosides (digitalis) 1637 Glycyrrhetinic acid 373 Glycyrrhiza glabra 373, 374 Gnathostoma spp 1430–1432 Gnathostoma doloresi 1430–1431 Gnathostoma hispidum 1430–1431 Gnathostoma malaysiae 1430 Gnathostoma nipponicum 1430–1431 Gnathostoma spinigerum 1430–1431, 1432, 1433, 1537–1539, 1538, 1539 Gnathostomiasis 1430–1432, 1432, 1538–1539, 1539 clinical manifestations 1431 diagnosis 1431 epidemiology 1430 pathogen 1430–1431 treatment 1431–1432 Gold salts 1650 Gonadotropin-releasing hormone (GnRH) 689–691 Gout 827–829, 828 GRACE (Global Registry of Acute Coronary Events) trial 101–103 Graduated compression stockings (GCS) 296 Graft rejection 1278–1279 Graft-versus-host disease (GVHD) 1313, 1314 Gram-negative bacteria (bacilli) 67, 81–83 Granisetron 636, 637 Granulocytic sarcomas (chloromas) 1040 Granulomatosis see Wegener disease Granulomatous encephalitis 1411 Gravely ill, neuropathy 751–752 see also Critical illness entries Graves’ disease 714, 716–717 seizures 722 Graves’ ophthalmopathy 716–719 clinical features 716–717, 717 diagnostic tools 717–718 pathogenesis 718 prognosis 719 treatment 718–719 Gray-out 172 Green mamba 990, 992 Grisel’s syndrome 442–443 Gr€onblad–Strandberg syndrome see Pseudoxanthoma elasticum (PXE) Gross tumor volumes (GTV) 1181–1182 Growth hormone (GH) 686 acromegaly 691–692 deficiency 690 excess 691 fibromyalgia 517

INDEX Growth hormone-releasing hormone (GHRH) 691 Guanylic monophosphate (GMP) 830 Guidant PRIZM AVT 141 Guillain–Barre´ syndrome (GBS) (AIDP) 841, 842, 845, 1333 cardiology 9–10 decompression illness (DCI) 964 inflammatory demyelinating polyneuropathy (IDP) 1333 influenza vaccine 1552, 1553 nephrotic syndrome 410 pregnancy 1611 renal transplantation 1251 respiratory failure (RF) 276 Gulstonian lectures (1885), malignant endocarditis 75–76 Gummas 1465, 1467–1468 GUSTO-1 (Global Utilization of Streptokinase and TissuePlasminogen Activator (tPA) for Occluded Coronary Arteries) trial 45, 103–105, 106 GUSTO-V (Global Use of Strategies To Open Coronary Arteries) trial 100

H H1N1 influenza A 1114, 1114 H1-receptor antagonists 1651–1654 HACEK group gram-negative bacilli 75, 80–81 Hadju–Cheney syndrome 444 Haemophilus influenzae 1367, 1369, 1611 Haemophilus influenzae type B (Hib) 1361–1362, 1370 vaccine 1550, 1554–1555, 1556–1557, 1651 Halothane 1625, 1627 Handbuch der Neurologie 1445 Hand-foot syndrome 1204 Hardwick’s sea snake (Lapemis curtus) 992 HARP syndrome (hypo-blipoproteinemia, acanthocyosis, retinitis pigmentosa, pallidal degeneration) 859 Hartnup disease 902–904 HAS-BLED score 122–123, 123 Hashimoto’s encephalopathy (HE) 724–725 clinical features 724 diagnosis 725 antithyroid antibodies 725 differential 725 tests 725 neuropathology 725 pathophysiology 724–725 treatment 725 Hashimoto’s thyroiditis (HT) 724–725 Head trauma, cardiology 6–7 Headache brain metastases 1144 cerebral venous thrombosis (CVT) 1605–1606 chronic morning (CMH) 254 cluster 259

Headache (Continued ) developing world 1776 giant cell arteritis (GCA) 228 gluten-related diseases (GRD) 612 Henoch–Sch€ onlein purpura (HSP) 1105 hyperthyroidism 723 intestinal transplantation (ITx) 1270–1271, 1274 intracranial pressure 1220–1221 medication overuse (MOH) 582 migraine 7–8, 964, 1736–1737, 1776 multiple organ transplantation 1312 neuro-Behc¸et syndrome (NBS) 1710–1711, 1710 neurocysticercosis (NCC) 1450 neuropsychiatric systemic lupus erythematosus (NPSLE) 465 obstructive sleep apnea syndrome (OSAS) 254, 259 Paget’s disease of bone (PDB) 530 pancreas/small bowel transplantation 1278–1279 pituitary adenomas 688 polycythemia vera (PV) 1074–1075 pregnancy 1613–1614 small bowel transplantation 1287–1288 thunderclap see Reversible cerebral vasoconstriction syndrome (RCVS) Head-up tilt test 185–186 Healthcare systems, developing world 1773–1774 Hearing loss 530, 878 Heart Disease and Stroke Statistics (AHA) 93 Heart transplantation 1227–1236 heart-lung transplantation 1313 long-term aspects 1230–1235 central nervous system (CNS) 1232, 1233 children 1234–1235 encephalopathy 1232 immunosuppression 1231–1232 peripheral nervous system (PNS), complications 1234 seizures 1233–1234, 1235 stroke 1233, 1235 postoperative complications 1230 central nervous system (CNS) 1230 peripheral nervous system (CNS) 1230 preoperative evaluation 1229–1230 central nervous system (CNS) 1229 peripheral nervous system (PNS) 1230 Heart valves, prosthetic 63–65 Heat-related illness see under Body temperature Heavy metals, disorders of 852 see also Copper disorders; Iron disorders Helicobacter pylori 638, 917, 918, 1007, 1541 HELLP syndrome, pre-eclampsia-induced 1596, 1597 Helminthic infestation 1414–1436, 1415

INDEX Hemangiomas, vertebral 1616 Hematin 846 Hematocrit (HCT) 1005–1006 Hematologic agents 136–138, 137, 138 Hematologic disorders, treatment 1125–1141 anticoagulation 1126, 1131–1132 intracranial hemorrhage (ICH) 1131–1132, 1131 benign disorders 1125–1131, 1126 antifibrinolytic agents 1128 antiplatelet agents 1129–1130 antithrombotic agents 1130–1131 replacement therapies 1125–1128 leukemias 1040–1041 lymphomas 1037–1038 malignancies 1126, 1132–1137 chronic myeloproliferative neoplasms 1132–1133 leukemias/lymphomas/multiple myeloma (MM) 1134–1137 myelodysplasia 1133–1134 Hematopoietic progenitors 1078 Hematopoietic stem cell therapy 762 Hematopoietic stem cell transplantation (HSCT) chronic graft-versus-host disease 1302 encephalopathy 1297–1299 metabolic 1297–1299 treatment-induced 1299 historical perspective 1295–1296 immunosuppression 1299–1301 infection 1301–1302, 1302 multiple organ, combined 1314 neurologic complications 1296–1297 allogeneic HLA-matched transplantation 1296 reduced-intensity allogeneic transplantation 1296–1297 Heme biosynthetic pathway 839–840, 840 Hemiscorpion lepturus 988, 994 Hemodialysis, antiepileptic drugs (AEDs) 427 Hemoglobin (HGB) 1005–1006, 1008, 1012 Hemoglobinopathies 1013 Hemolytic anemias see under Anemias Hemolytic uremic syndrome (HUS) 1113–1123 clinical manifestations 1115 definition 1113 diagnosis 1118–1119, 1119 epidemiology/etiology 1113–1115, 1114 atypical (aHUS) 1114 thrombotic thrombocytopenic purpura (TTP) 1114–1115 typical 1113–1114 neurologic findings/sequelae 1115–1118, 1118 pathophysiology 1115 atypical (aHUS) 1115 typical 1115 treatment 1120 antibiotics 1120 cobalamin replacement 1120

Hemolytic uremic syndrome (HUS) (Continued ) complement therapy 1120 immunotherapy 1120 plasma infusion/plasmapheresis 1120 transplantation 1120 Hemophilia 1045, 1046–1052 acquired 1052–1053 classification 1049 clinical manifestations 1047, 1049–1050 frequency, bleeding 1049 symptoms, bleeding 1049–1050 coagulation factors VII/IX inhibition 1052 diagnosis 1050 coagulation tests 1050 genetic testing 1050 epidemiology 1046 genetics 1046–1049 management 1050–1052, 1051, 1055 neurologic manifestations 1053–1054 age-related comorbidities 1054 central nervous system (CNS) 1053 peripheral nervous system (PNS) 1053–1054 treatment centers 1058 HEMORR2HAGES scheme 122–123, 123 Hemorrhage brain metastases 1149 intracerebral (ICH) see Intracerebral hemorrhage (ICH) intracranial see Intracranial hemorrhage (ICH); Intracranial hemorrhage/aneurysms intraparenchymal 5 polycythemia vera (PV) 1075 subarachnoid (SAH) see Subarachnoid hemorrhage (SAH) Hemorrhagic complications 570 characteristics/management 570 mechanisms/frequency 570 Hemorrhagic stroke decompression illness (DCI) 964 pregnancy 1602–1605 Henderson–Hasselbalch formula 375 Henoch–Sch€ onlein purpura (HSP) 1101–1112 diagnostic criteria 1102, 1102 differential diagnosis 1107–1108 etiology/pathogenesis 1102–1103 historical perspective 1101 investigations 1106–1107 antineutrophil cytoplasmic antibodies (ANCA) 1106 cerebrospinal fluid (CSF) analysis 1107 imaging 1107 nonspecific laboratory findings 1106 management 1108 nervous system manifestations 1103–1106 epidemiology 1103 pathology 1102 prognosis 1108

I19 Henoch–Sch€ onlein purpura (HSP) (Continued ) systemic disease 1101 Heparin 65, 105, 299, 1638 fractionated 1719–1720 unfractionated see Unfractionated heparin(UFH) see also Low molecular weight heparin (LMWH) Heparin-induced thrombocytopenia (HIT) 137, 295, 1638 and thrombosis (HITT) 1130–1131 Heparinoids 1638 Hepatic disease see Antiepileptic drugs (AEDs), hepatic/renal disease Hepatic drugs 675–682, 676 Hepatic encephalopathy (HE) acute liver failure (ALF) 646, 646, 661 classification 661–662, 662 portosystemic see Portosystemic encephalopathy types 661 Hepatic myelopathy (HM) 663 Hepatitis A virus (HAV) 1651 Hepatitis B virus (HBV) 678–680, 1333–1334 vaccine 1550, 1553, 1651 Hepatitis C virus (HCV) 678–680, 1333–1334 Hepatocyte infusion 656 Hereditary hemochromatosis (HH) 860 Hereditary hemorrhagic telangiectasia (HHT) 1562, 1571–1572 clinical manifestations 1571–1572 arteriovenous malformations (AVMs) 1572 mucocutaneous telangiectasias 1571–1572, 1571 neurologic 1572 diagnosis/genetic testing 1572 Hereditary motor and sensory neuropathy IV (HMSN IV) 1579 Hereditary neuropathy/dystrophy/ myopathy, pregnancy 1612 Hereditary spherocytosis 1012 Hereditary xanthinuria 828, 833 Herpes simplex encephalitis (HSE) 1149 Herpes simplex virus (HSV), encephalitis 1232, 1252, 1378 Herpes simplex virus type 1 (HSV-1) encephalitis 1377, 1378–1379 diagnosis 1380 treatment 1380–1381, 1380 heart transplantation 1232 renal transplantation 1249 Herpes simplex virus type 2 (HSV-2) 1232 Herpes simplex virus type 6 (HSV-6) 1232 Herpes viruses 1249, 1527 Herpes zoster ophthalmicus (HZO) 1562, 1569, 1569 Herpes zoster (zona/shingles) 1577–1578 clinical manifestations 1577–1578 cutaneous 1577 neurologic 1577–1578 diagnosis 1578

I20 Heterometrus fulvipes 993 Heterometrus longimanus 993–994 Heterometrus scaber 993 Heterometrus spinifer 993–994 Hexamethylmelamine 1210 Hexosamine pathway 777–778 High density lipoproteins (HDL) 624 High-altitude periodic breathing 264 High-grade glioma (HGG) 1222 Highly active antiretroviral therapy (HAART) cryptococcal meningitis 1330 HIV 1321, 1323 -associated neurocognitive disorder (HAND) 1340 /tuberculosis (TB) coinfection 1338, 1338 Hodgkin lymphoma (HL) 1034 primary central nervous system lymphoma (PCNSL) 1326 progressive multifocal leukoencephalopathy (PML) 1328 Hippocrates 1506 Hirudin (lepirudin) 1131 Histamine 2 (H2) blockers 638–639 Histoplasma antigen 1386, 1398 Histoplasma capsulatum 1383, 1384, 1389–1390, 1398 Histoplasmosis 1385, 1398 HIV Medicine Association (IDSA) 1324–1325, 1329, 1331 HIV-infected patients 755, 1319–1344 developing world 1776–1777 etiology/diagnostic approach 1321, 1322 hemolytic uremic syndrome (HUS) 1114, 1114 HIV-associated dementia (HAD) 1339–1340, 1340, 1778 HIV-associated neurocognitive disorder (HAND) 1321, 1338–1340 classification 1338–1339, 1339 clinical features 1339, 1340 diagnosis 1339–1340 prevalence 1339 treatment 1340 HIV-associated vacuolar myelopathy (VM) 1321, 1326, 1331–1332 clinical features 1331–1332, 1529 diagnosis 1332 epidemiology 1331 incidence/prevalence 1331 pathology 1331 treatment 1332 Hodgkin lymphoma (HL) 1034 myelopathy 1322, 1529–1530, 1529 neuromuscular disorders 1332–1334 neurosyphilis 1334–1337, 1533–1534 clinical features 1334–1337, 1336, 1534 diagnosis 1334–1336, 1467, 1467, 1534 epidemiology 1334–1337, 1462, 1533–1534 laboratory findings 1336 natural history 1465–1466

INDEX HIV-infected patients (Continued ) neuropathology 1534, 1534 stages 1336 treatment 1336–1337, 1337, 1469–1470 opportunistic infection 1323–1331 pathogenesis, neurologic complications 1321–1323, 1322 primary central nervous system lymphoma (PCL) 1028–1029 spinal cord disorders 1331–1332 tuberculosis (TB), central nervous system (CNS) 1337–1338, 1485, 1488, 1494–1495 clinical features 1337 diagnosis 1337–1338 neuroimaging 1338, 1489 pathogenesis 1337 treatment 1338, 1338, 1490–1492 HMG-CoA reductase inhibitors 1636–1637, 1638 Hodgkin lymphoma (HL) 1034–1035 Hodgkin Reed–Sternberg cells (HRS) 1034 ‘Hole-in-donut’ appearance 1537 Holt–Oram syndrome, genetics 53 Home mechanical ventilation (HMV) 285 Homeostasis, disorders of 1104–1105 Homocysteine (Hcy) 917, 919–921, 923, 931–932 Homocystinuria 572–573 description 572 neurologic complications 572–573 Homozygous achondroplasia 560 Hormonal disorders 410 hyperfunction 690–694 Hormone therapy see Endocrine therapy Horned vipers (Cerastes) 992–993 Horner’s syndrome 7 Hornet stings 995 Hu-Abs (antibodies) 1161, 1162–1163 limbic encephalitis (LE) 1166, 1168 subacute cerebellar degeneration (SCD) 1164 Human herpes virus-6 (HHV-6) encephalitis 1377, 1379 diagnosis 1380 treatment 1381 focal encephalitis 1232 liver transplantation 1262–1263 pancreas/small bowel transplantation 1278–1279 renal transplantation 1249 treatment 1380 Human immunodeficiency virus see HIV-infected patients Human papilloma virus (HPV) 1554 Human parvovirus B19 1350–1351 clinical manifestations 1351 diagnosis 1351 epidemiology 1350 treatment/prognosis/prevention 1351 Human rabies immunoglobulin (HTIG) 1504

Human resources, developing world 1774–1775 Human T cell lymphotropic virus-1 (HTLV-1) 1527–1529, 1540 clinical features 1527–1528 differential diagnosis 1529 epidemiology 1527 imaging 1528 laboratory findings 1528 neuropathology 1528–1529 public health measures 1529 treatment 1529 virology 1527 Human T cell lymphotropic virus-2 (HTLV-2) 1527, 1529 Human tetanus immunoglobulin (TIG) 1508, 1509 Huntington’s disease (HD) 1780 Hydatid disease 1425–1426 clinical manifestations 1425 diagnosis 1425 epidemiology 1425 pathogen 1425 therapy 1425–1426 Hydralazine 165, 165, 1697 Hydrocephalus 308–309, 309, 322 achondroplasia 444, 552–554, 553, 554 Hydrochlorothiazide 764–765 Hydrophiinae 992 Hydrophis cyanocinctus 989, 992 Hydrophis fasciatus atriceps 992 Hydrosoluble vitamins 889–914 ascorbic acid see Vitamin C deficiency future trends 910 historical perspective 891–895 investigations 894 niacin (nicotinic acid) see Vitamin B3 deficiency overview 892 pantothenic acid see Vitamin B5 deficiency pyridoxine (pyridoxal) see Vitamin B6 deficiency riboflavin see Vitamin B2 deficiency thiamin see Vitamin B1 deficiency HydroxoCbl 923 Hydroxycarbamide 1075 Hydroxychloroquine 325, 326, 628 5-Hydroxytryptamine 3 (5-HT3) receptor antagonists 636–637 Hydroxyurea (HU) 1021, 1132–1133, 1208 Hymenoptera venom 988 Hyperaldosteronism 763–765 clinical manifestations 764 diagnosis 764 etiology 764 primary hyperaldosteronism 764 secondary hyperaldosteronism 764 historical perspective 763–764 treatment 764–765 Hyperbaric oxygen (HBO) 977 Hypercalcemia 378, 865–866 associated disorders 738–742 causes 739

INDEX Hypercalcemia (Continued ) classification 865–866 clinical features 866 renal transplantation 1251–1252 treatment 741–742, 866 Hypercapnia 273 Hyperchloremic acidosis 375 Hypercoagulability 405–407, 406 Hyperekplexia 182 Hyperglycemia 328, 1251, 1286 Hyperkalemia 374–375 clinical findings 374 laboratory investigations 374, 375 management 374–375 terminology 374 Hyperkinetic movement disorders 1780 Hyperlipidemia 407 Hypermagnesemia 378, 873–874 clinical manifestations 873–874 treatment 874 Hypernatremia 369–372 clinical findings 369–370 historical perspective/terminology 369 laboratory investigations 370, 370, 371 management 370, 371–372 pathophysiology 370–371 Hyperosmolar therapy, traumatic brain injury (TBI) 1628 Hyperparathyroidism primary see Primary hyperparathyroidism (PHPT) pseudopseudohyperparathyroidism 745 secondary 742–743, 744 tertiary 742–743, 744 Hyperperfusion syndrome (HS) 234, 1695 Hyperphosphatemia 378, 379, 875 classification 875 clinical manifestations 875 treatment 875 Hyperplasia, pituitary 686 Hyperprolactinemia 690–691, 691 Hypertension (HTN) arterial 258 nephrotic syndrome 407 primary hyperparathyroidism (PHPT) 867, 869 pulmonary 258 see also Hypertension/hypertensive encephalopathy Hypertension/hypertensive encephalopathy 161–168 clinical findings 162 genetics 163 Guillain–Barre´ syndrome (GBS) 9–10 historical perspective/terminology 161 laboratory investigations 162 management 164–166 natural history 162 neuroimaging 162–163, 163, 164 pathology 163–164, 164 Hypertensive encephalopathy 1104 posterior reversible encephalopathy syndrome (PRES) 1692, 1693

Hypertensive encephalopathy (Continued ) treatment 1697 see also Hypertension/hypertensive encephalopathy Hyperthermia drug-induced 949–951 clinical features 949–951 laboratory studies 951 management 951 malignant 1612 pathogenesis 947 Hyperthyroid myopathy 712–714 clinical features 712–713 inflammatory 714 investigations 713 skeletal muscle changes 713–714 treatment/prognosis 714 raised creatine kinase (CK) 714 Hyperthyroidism 712–725 associated conditions 723–724 corticospinal tract disorders 715 encephalopathy see Hashimoto’s encephalopathy (HE) mental/psychiatric disorders 722–723 movement disorders 715–716 myopathy see Hyperthyroid myopathy ophthalmopathy see Graves’ ophthalmopathy paralysis see Thyrotoxic hypokalemic periodic paralysis (TPP) peripheral neuropathy 714–715 seizures 722 thyroid storm 721–722 Hypertonic saline 1757–1759 Hypertrophic cardiomyopathy 124 Hyperventilation, bacterial meningitis 1371–1372 Hyperviscosity syndrome 1093 Hypervolemic hypernatremia 370 Hypervolemic hyponatremia 367, 368–369 Hypnale 992–993 Hypnotics 1644 Hypoalbuminemia 377 Hypocalcemia 377–378, 377, 742–745, 870 causes 743 classification 870 clinical features 743–745, 870 pathophysiology 742–743 treatment 745, 870 Hypoglossal nerve (cranial nerve XII) 308 Hypoglycemia 177, 818 insulin treatment 815 total parenteral nutrition (TPN) 1286 Hypogonadism 328 secondary 689–690 Hypokalemia 372–374 clinical findings 372 laboratory investigations 373, 373 management 373–374 pathophysiology 373, 374 periodic paralysis 372 terminology 372, 373 Hypomagnesemia 377–378, 739 classification 872 clinical manifestations 872–873

I21 Hypomagnesemia (Continued ) drug-induced 871 etiologies 741, 742 functional hypoparathyroidism 871 neurologic manifestations 741 renal transplantation 1252 treatment 873 Hypomelanosis of Ito (HI) 1562, 1588 cutaneous manifestations 1588 neurologic manifestations 1588 Hyponatremia 365–369 clinical findings 366–367, 367 historical perspective/terminology 365, 367 laboratory investigations 367–368, 368 management 367, 368–369, 369 pathophysiology 368 renal transplantation 1252 Hypoparathyroidism/ pseudohypoparathyroidism 377, 871–872, 874 clinical manifestations 871 treatment 871–872 Hypophosphatasia 878–879 clinical manifestations 879 diagnosis 879 treatment 879 Hypophosphatemia 378, 739, 874–875 classification 874 clinical manifestations 874 etiologies 741, 741 neurologic manifestations 741 treatment 875 Hypopituitarism 688–689 Hypoplastic left heart syndrome (HLHS) 1234 Hypothalamic hormones/analogs 809–812, 810 Hypothalamic ‘osmostat’ 310 Hypothalamic-pituitary-adrenal (HPA) axis 517 evaluation 686, 690 Hypothermia accidental 953–954 clinical features 953, 953 laboratory studies 953, 954 management 953–954 effects 1631 intracranial pressure (ICP) 1759 pathogenesis 947–948 therapeutic 29–30, 954–955, 955 traumatic brain injury (TBI) 1628 Hypothermia After Cardiac Arrest (HACA) Study Group 26, 29–30 Hypothermic circulatory arrest (HCA) 234 Hypothyroid myopathy 709–711 clinical features 709–710, 710 investigations 710 pathology 710–711 pathophysiology 711 treatment/prognosis 711 Hypothyroidism 328, 703–711 associated neurologic conditions 711–712 cerebellar ataxia 708

I22 Hypothyroidism (Continued ) congenital see Congenital hypothyroidism (CH) cranial nerve disorders 708–709 encephalopathy/coma/seizures 705–706 mental changes 706–707 myopathy see Hypothyroid myopathy peripheral neuropathy 707–708 secondary 689 sleep disorders 708 Hypotonic hyporesponsive episode (HHE) 1555–1556 Hypoventilation 263–266, 280, 281 Hypovolemic hypernatremia 370 Hypovolemic hyponatremia 367–368, 367 Hypoxanthine-guanine phosphoribosyltransferase deficiency (HPRT) 828, 830–831, 830 Hypoxemia 265–266, 273, 280, 281 Hypoxia 274 Hypoxic-ischemic encephalopathy 197, 274

I Iatrogenic neurology 1635–1671 antiallergic drugs 1651–1654 antiarrythmics/inotropes/coronary artery dilators 1636, 1637 antibiotics 1644–1645, 1646 anticoagulants 1638–1639 antidepressant drugs 1642 antiepileptic drugs (AEDs) 1639–1640, 1640 antifungal agents 1645, 1649 antihypertensive agents 1635–1636, 1636 anti-inflammatory/analgesic drugs 1645–1651 antilipemic drugs 1636–1637, 1638 antineoplastic drugs 1645, 1652 antiparasitic agents 1645, 1650 antiparkinsonian drugs 1641, 1641 antiplatelet agents 1639 antipsychotics/dopamine receptorblocking drugs (DRBDs) 1642–1643, 1643 antispastic drugs 1640–1641 antiviral agents 1645, 1648 cognition drugs 1641–1642, 1642 genitourinary/digestive tract drugs 1655–1656, 1656 hormone-related drugs 1654, 1655 immunomodulatory drugs 1645, 1653 metabolism drugs 1654–1655 psychostimulants 1644, 1645 respiratory tract drugs 1655 sedatives/hypnotics 1644 thrombolytics 1637–1638 vaccines 1645, 1651 IBMPFD (inclusion body myopathy, Paget disease of bone, frontotemporal dementia) disorder 533, 534 Ibritumomab (Zevalin®) 1136 Ibuprofen 1571 Ibuprofen-induced meningitis 1648

INDEX Ibutilide 132, 134 Idebenone 9 Idiopathic inflammatory myopathy (IIM) 495–512, 1160, 1160, 1172 classification 496 clinical features 498–499, 498, 500 epidemiology 497 etiopathogenesis 497–498 laboratory investigations 501–505 autoantibodies 501–502 electromyography (EMG) 502 muscle biopsy 502–505, 503, 504 serum creatine kinase (sCK) activity 501 skin biopsy 502 management 505–507 corticosteroids 506–507 future therapeutic prospects 507 second-line treatment 507 natural history 499–501 neuroimaging 505, 506 Idiopathic myelofibrosis (IMF) 1132 Idiopathic reversible cerebral vasoconstriction syndrome (RCVS) 1726 Ifosfamide 1200, 1201, 1201, 1210 IFRT (involved-field radiotherapy) 1035 IGG- and IGA-related neuropathy 1088 IGM-related peripheral neuropathy anti-MAG negative and/or no detectable antibody 1084, 1087–1088 anti-MAG positive 1084, 1085–1087 Imatinib 1133, 1205 Imatinib mesylate (Gleevec™) 1133 Imipenem 1247, 1644 Immobility, end of life (EOL) phase 1220 Immune reconstitution inflammatory syndrome (IRIS) 1330 antifungal agents 1389–1390 antiretroviral therapy induced- 1325 cytomegalovirus encephalitis (CMV) 1331 syphilis 1466 tuberculosis 1338 Immune-inflammatory disorders 1540 Immunity, pregnancy 1596 Immunoglobulins 1173 Immunomodulatory drugs (IMiDs) 1136, 1645, 1653 Immunosuppressants 1120, 1613 adverse effects 675, 676, 1246, 1278–1279 posterior reversible encephalopathy syndrome (PRES) 1692, 1694, 1698 transplantation 677–678, 1231–1232, 1246, 1268, 1281–1282, 1299–1301 Impaired glucose tolerance (IGT) 773 Implants cardiac defibrillators (ICDs) 141, 202–203 complications 157 cardiovascular electronic devices 85–86 risks 1746 Impotence 254

Inactive sclerotic phase, defined 533–535 Inclusion body myositis (IBM) see Idiopathic inflammatory myopathy (IIM) Incontinentia pigmenti (IP) (Bloch–Sulzberger syndrome) 1562, 1587–1588 clinical symptoms 1587–1588 central nervous system (CNS) 1587–1588 cutaneous 1587–1588, 1588 ophthalmologic 1587–1588 diagnosis 1588 radiology 1588 treatment 1588 Incretin mimetics 820 Indometacin 1274 Induction agents, neuroanesthesia 1624–1625, 1625 Infantile beriberi 897 Infantile neuroaxonal dystrophy (INAD) 859–860 Infectious Diseases Society of America (IDSA) 1338, 1393 HIV Medicine Association 1324–1325, 1329, 1331 Infectious myelopathy 1522, 1525–1540 Infective (bacterial) endocarditis 56, 67–69, 75–92 antithrombotic therapy 69 cardiac surgery 69 classification 75 historical aspects 75–76 clinical aspects 76–79 central nervous system (CNS) 79 cerebrovascular manifestations 77–79 neurologic manifestations 77, 79 systemic/cardiac/multiorgan manifestations 76–77 complications cerebrovascular 67–68 noncerebrovascular 68–69 definition 75 diagnosis 79–81 diagnostic criteria 81, 82 echocardiography 80, 80 electrocardiography 80 laboratory 80 neurologic complications 81, 83 pathogenic agent 80–81 epidemiology 76 pathophysiology 76 prevention 83 prognosis 81–83 treatment 83–88 antimicrobial 83–84, 84 antithrombotic 86–87 cardiac surgery 84–85, 85, 85, 87 cardiovascular implantable electronic devices 85–86 intracranial infections 88 mycotic aneurysms 87–88 neurologic complications 86, 87

INDEX Infective (bacterial) endocarditis (Continued ) thrombolysis, stroke 86 Infective embolism 52 Infecundity 793–796 Inferior vena cava (IVC) filters 296, 298 Infertility 793–796 causes 793, 794 Inflammatory bowel diseases (IBD) 595–605 cerebrovascular complications 597–599 anti-TNF-a therapy 598, 599 arterial ischemic stroke (AIS) 598 cerebral venous thrombosis (CVT) 599–600 pathophysiology 598 vasculitis 598–599 neurologic manifestations 596–597, 596 central nervous system (CNS) 596, 600–601 cranial neuropathy 597 demyelinating disease 600 medication-induced 601 pathophysiology 596–597 peripheral nervous system (PNS) 596, 597 prevalence 596 psychiatric syndromes 601 Inflammatory demyelinating polyneuropathy (IDP) 1333, 1335 treatment 1333 Inflammatory joint disorders 440–442 see also Rheumatoid arthritis (RA) Inflammatory myopathy, pregnancy 1612 Inflammatory neuropathy/myopathy 278–279 Inflammatory spondyloarthropathy 454–457 acute spinal fractures 455 cauda equina syndrome 456 clinical features 454 discovertebral destruction 456 laboratory investigations 455 neurologic aspects 455 pathogenesis 454–455 Infliximab 479, 507, 601, 1719 neurosarcoidosis 325, 326, 327 Influenza vaccine 1550, 1552 influenza A (HIN1) 1553 trivalent inactivated vaccine (TIV) 1552–1553 Inhalation agents, neuroanesthesia 1625–1626, 1627 Inherited neurodegeneration with brain iron accumulation (NBIA) 858–860 type 1: pantothenate kinase-associated neurodegeneration 859, 859 type 2: classic infantile neuroaxonal dystrophy (INAD)/atypical neuroaxonal dystrophy (ANAD) 859–860 aceruloplasminemia 853, 860

Inherited neurodegeneration with brain iron accumulation (NBIA) (Continued ) idiopathic neurodegeneration with brain iron accumulation 860 neuroferritinopathy 860 Inherited thrombophilia 1061–1063, 1064–1065, 1064, 1066–1067 Inhibitory Control Test (ICT) 665 Inner ear barotrauma 964 Inner ear decompression sickness (IEDCS) 963 Inosine monophosphate (IMP) 827, 830 Inotropes 1636, 1637 Institute of Medicine (IOM) 1551 Insufflation-exsufflation devices 284 Insulin tolerance test (ITT) 759 Insulin/analogs 814–816, 815, 816 age constraints 814, 815 diabetic ketoacidosis (DKA) 377 intermediate and long-acting 811 neuritis 815 short- and rapid-acting 811 structure/bioavailability 815 Intensity-modulated radiotherapy (IMRT) 342, 1182–1183, 1186, 1187–1188 Intensive care unit (ICU) tetanus 1509 see also Cardiology, vascular/intensive care neurology Intensive care unit-acquired weakness (ICUAW), focal 1681 Intensive care unit-acquired weakness (ICUAW), generalized 1673–1685 clinical presentation 1673–1674 critical illness myopathy (CIM) 1674–1676, 1680 critical illness neuromyopathy (CINM) 1675 critical illness polyneuropathy (CIP) 1674, 1675–1676, 1680 definitions 1673 diagnostic methods 1678–1680 electromyography (EMG) 1679 laboratory tests 1680 muscle/nerve biopsy 1679–1680 nerve stimulation 1678–1679 differential diagnosis 1677–1678, 1678 incidence 1674 myasthenia gravis (MG) 1676 outcome/prognosis 1680 pathophysiology 1675 prolonged neuromuscular junction (NMJ) block 1676, 1677 rhabdomyolysis 1676–1677 Interferon-a (IFN-a) 485–486, 1504, 1718–1719 adverse effects 1201, 1204 Interferons (INF) 678–679, 1075, 1381, 1607–1608, 1719 adverse effects 676, 678–679, 1201, 1212, 1653 mechanisms of action 678 Interleukins (IL) 1201, 1212, 1653 Intermediate leprosy 1573–1575

I23 Intermittent hemodialysis (IHD) 400 Intermittent pneumatic compression (IPC) 294–295 Internal cardioversion 140 Internal target volume (ITV) 1181–1182 International Classification of Headache Disorders (ICHD-II) 254, 1726 International Classification of Sleep Disorders (ICSD2) 251, 261 International Collaboration on Endocarditis-Prospective Cohort Study 76, 77, 81–83 International Committee for Standardization in Hematology 1016–1017 International Headache Society 1729, 1776 International HIV dementia scale 1339–1340 International League Against Epilepsy 1775 International Liaison Committee on Resuscitation (ILCOR) 28, 30 Advanced Life Support Task Force 30 International Myositis Assessment and Clinical Studies Group (IMACS) 507 International Normalized Ratio (INR) 113, 120, 140 International Pancreas Transplant Registry 1280 International Prognostic Scoring System (IPSS) 1009 International Society for Heart and Lung Transplantation (ISHLT) 1238 International Society for Hepatic Encephalopathy and Nitrogen Metabolism (ISHEN) 663–664 International Stroke Society (ISS) 1778 International Stroke Trial 296–297 International Subarachnoid Aneurysm Trial 1604 International Verapamil SR-Trandolapril Study (INVEST) 93 International Workshop on Primary Hyperparathyroidism (Third) 869 Interstitial brachytherapy 339 Interstitial lung disease (ILD) 499, 500, 501 Interventional cardiology see Cardiac surgery/interventions Intestinal allograft recipients 1287 Intestinal failure 1306 defined 1305–1307 Intestinal transplantation (ITx) 1267–1276 immunosuppression 1268 indications/contraindications 1267, 1268 isolated 1308 -liver 1308–1309 neurologic complications 1268–1275 clinical presentation 1270–1273 diagnostic approach/management 1273–1275 epidemiology 1269 etiology 1269–1270, 1270 surgical procedures 1267–1268

I24 Intra-aortic balloon pump (IABP) 201 Intra-arterial digital angiography 79, 81 Intracerebral hemorrhage (ICH) 5, 198 management 103–104, 105 pregnancy 1604 renal disease 387 Intracranial hemorrhage (ICH) 1760 management 1759 pancreas/small bowel transplantation 1278–1279 sickle cell disease (SCD) 1016 treatment 1131–1132, 1131 Intracranial hemorrhage (ICH)/aneurysms characteristics 568 infective endocarditis 68, 78 management 103–104, 105, 568 mechanisms/frequency 568 venous thromboembolism (VTE) 296–297, 298, 299–300, 568 warfarin 138, 138 Intracranial hypertension 1449–1450 Intracranial infections, treatment 88 Intracranial masses 1628–1629 Intracranial plasmacytoma 1091 Intracranial pressure (ICP), increased 177, 400, 1219, 1753–1754, 1758 acute liver failure (ALF) 645, 650, 651–655 anesthesia 1623–1625, 1626–1628 Lund concept 1371 management 1330, 1758–1760 monitors 649–650 treatment 1220–1221 Intraocular cysticerci 1450 Intraparenchymal hemorrhage 5 Intraparenchymal mass lesions 310, 310, 315, 322 Intravascular large B cell lymphoma 1033, 1034 Intravenous immunoglobulin (IVIg) 485–486, 1127, 1333–1334, 1381 123 Iodine-metaiodobenzylguanidine (IMIBG) scintigraphy 8–10 Irbesartan 138 Irinotecan 1212 Iron disorders 858–861 acquired diseases, excess/deficiency 861 acquired neurodegenerative disorders 861 anemia see under Anemias deficiency, anemias 1125–1126 genetic systemic iron accumulation with neurologic features 860–861 metabolism 858, 858 restless leg syndrome (RLS) 861 see also Inherited neurodegeneration with brain iron accumulation (NBIA) Iron-induced organ injury 1020–1021 Irradiation see Radiotherapy (RT) Ischemic infarction 1278–1279, 1287–1288 Ischemic lesions, brain metastases 1149 Ischemic optic neuropathy 198 Ischemic stroke acute see Acute ischemic stroke

INDEX Ischemic stroke (Continued ) cardiac catheterization 43–44 infective endocarditis 67–68, 77–78, 78 large artery atherosclerosis 574 Marfan syndrome (MFS) 574 neurosarcoidosis 311 transient see Transient ischemic attacks (TIAs) Isoflurane 1625, 1627, 1630–1631 Isolated adrenocorticotrophic hormone (ACTH) deficiency 756 Isolated amnesia 35 Isoniazid 1247–1248, 1495, 1646 tuberculous meningitis (TBM) 1490, 1491, 1492 Isoprenaline 132, 134 Isoprinosine 1348–1349 Isoproterenol 132, 134 Italian Society for Haemostasis and Thrombosis (SISET) 296, 297 Itraconazole 1532 Ivermectin 1429, 1431–1432, 1435, 1436 Ivory vertebrae 535 Ixabepilone 1200, 1203 Ixodes ticks 1473–1474, 1479, 1576

J JAK2 gene 1073–1074, 1076, 1077–1078 Japanese encephalitis (JE) 1378, 1379 diagnosis 1380 vaccines 1554 Jarisch–Herxheimer reaction 1469 Jaw claudication 228 JC polyomavirus 1263, 1378 diagnosis 1380 heart transplantation 1232 progressive multifocal leukoencephalopathy (PML) 1232 renal transplantation 1250 JE-VAX vaccine 1554 Jewel AF 141 ‘Jumping Frenchmen of Maine’ 180 Juvenile dermatomyositis (JDM) see Idiopathic inflammatory myopathy (IIM) Juvenile Paget’s disease, clinical characteristics 534

K Kallmann syndrome 689–690, 796 Kanamycin 1491, 1492 Kaplan–Meier event rate 114 Katayama fever 1419–1420 Kayser–Fleischer (KF) rings 854–855, 855 Kearns–Sayre syndrome (KSS) 11, 13 Kennedy’s disease 794, 795 historical perspective 795 laboratory investigations 795 management 795 natural history 795 pathology 795 Kernig’s sign 1514–1515 Ketamine 1090, 1504, 1624–1625, 1625, 1631 Ketoconazole 698, 754

Ketolides 1646 Kidney-pancreas transplantation 1313–1314 King’s college criteria, acute liver failure (ALF) 649, 650, 655 Kinky hair disease (Menkes disease) 626, 851, 853, 853 Klebsiella spp 1301 spinal epidural abscess 1532 Klebsiella pneumoniae 1369 Klippel–Trenaunay–Weber syndrome 1573 Kohlmeier-Degos disease 1562, 1567 Konzo 1540, 1543 Korsakoff psychosis 897, 900 Kraits (Bungarus) 991–992 Kyphoplasty 342–343 Kyphosis 559

L La Crosse virus 1378, 1380 Labetalol 165, 165, 1636, 1697 Lacosamide 780 elimination 418, 424–426, 425, 427 beta-Lactam antibiotics 1247 Lactate dehydrogenase (LDH) 1011 Lactic acidosis 591–592 Lactitol 670 Lactulose 670 Lacunar infarcts 115, 115 Lambert–Eaton myasthenic syndrome (LEMS) 10, 353–354, 1160, 1160, 1171 antibodies 1161 subacute cerebellar degeneration (SCD) 1164 treatment 1173 Lamivudine (Epivir-HBV®) 676, 679 Lamotrigine 846, 1332–1333, 1640, 1640 elimination 418, 423, 425, 427 Lance–Adams syndrome 35 Lance-heads (Bothrops) 992–993 The Lancet 1551 Lanreotide 697, 810, 810, 811 Lansoprazole 638–639 Lapemis curtus 992 Large artery atherosclerosis 574 Large-vessel encephalitis 1577–1578 Laryngeal nerve injury, recurrent 1240 Laser assisted uvulopalatoplasty (LAUP) 262 L-Asparaginase 1201, 1211, 1652 Late-delayed toxicity, radiation therapy 1150 Lathyrism 1547–1546 Lathyrus 1547–1546 Lathyrus sativus (chickling pea) 1547–1546 Laticauda spp 992 Laticauda colubrine 992 3L. laticauda 989 Laticauda semifasciatus 992 Latrodectus spp 988, 994–995 Latrodectus geometricus 994 Latrodectus mactans 994 ‘Laughing gas’ see Nitrous oxide (N2O)

INDEX Laurence–Moon–Bardet–Biedl syndrome 796 Laxatives 634, 638 Lead, excessive exposure 852, 1010–1011 Left atrial appendage, percutaneous closure 142–143 Left ventricular assist devices (LVADs) 201, 202 Left ventricular dysfunction 113–115, 115 Left ventricular noncompaction 124 Legionella spp 80–81 Leigh’s disease 898 Leiurus quinquestriatus quinquestriatus 993–994 Lenalidomide 1032, 1090, 1136, 1204, 1652 Leonine facies 1573–1575, 1574 Lepirudin (hirudin) 1131 Leprosy 1509–1514, 1562, 1573–1576 classification 1509–1510, 1510 clinical manifestations 1573–1575 cutaneous 1574 developing world 1777 diagnosis 1575 investigations/diagnosis 1511–1512 biopsy 1511–1512, 1513 electrophysiology 1511 radiology 1511, 1512 serology 1511 lepromatous 1573–1575 neurology 1510–1511 pathophysiology 1511 treatment 1512–1514, 1513, 1575–1576 Leptomeningeal (LM) manifestations leukemias 1039–1040 lymphomas 1036–1037 metastases 343–345, 344 multiple myeloma (MM) 1091 rheumatoid arthritis (RA) 451 Leptospira 1532 Lesch–Nyhan disease 828, 830–831, 830, 832, 835 variants 831, 835 Letrozole 1152–1153 Leucovorin 1324–1325, 1325 Leukemias 1030, 1038–1041 classification 1027, 1038 clinical presentation 1039–1041 central nervous system (CNS) 1040 leptomeningeal (LM) 1039–1040 peripheral nervous system (PNS) 1041 spinal cord 1040 vascular/hematologic 1040–1041 hematopoietic stem cells 1027, 1028 treatment 1134–1137 Leukoencephalopathy progressive see Progressive multifocal leukoencephalopathy (PML) entries renal transplantation 1252 see also Posterior reversible encephalopathy (leukoencephalopathy) syndrome (PRES/PRLS) Leuprolide 1655 Levamisole 1433, 1653

Levetiracetam 677, 846–847, 1153, 1274, 1640, 1640 elimination 418, 423–424, 425, 427 Levodopa 1641, 1641 Levofloxacin 1491, 1492 Levosulpiride 638 Levothyroxine sodium 812, 813 Lgi1-Abs (antibodies) 1161 limbic encephalitis (LE) 1167 Lhermitte’s sign 559, 1090–1091, 1190–1191, 1200, 1542 Libman–Sacks endocarditis 70 Lidocaine 156, 780 adverse effects 132, 134–135, 1637 Lidoflazine 31 ‘Life settings’, sudden cardiac death (SCD) 19 ‘Lifting the Burden’ (WHO campaign) 1776 Lightning see Thermal injuries Lille scoring system 1078 Limb symptoms 1356–1357 mononeuropathy 775 Limbic encephalitis (LE) 1160, 1160, 1165–1169, 1166 antibodies 1161, 1162 lung cancer 347, 348–349, 350, 354–355 neuronal cell surface antigen antibodies (NSA-Abs) 1165–1166 AMPAr-Abs 1168 GABABr-Abs 1166, 1168 neurophil-Abs 1167 NMDAr-Abs 1167–1168 VGKC-Abs/Lgi1-Abs/CASPR2-Abs 1166, 1167 onconeuronal antibodies (ON-Abs) 1168–1169 Amphiphysin-Abs 1166, 1169 CV2/CRMP5-Abs 1160, 1166, 1169 Hu-Abs 1166, 1168 Ma2-Abs 1166, 1169 seronegative 1169 subacute cerebellar degeneration (SCD) 1164 treatment 1173 Limited cutaneous scleroderma (ISSc) 468 Lincosamides 1646 Line Tracing Test (LTT) 663–664, 664 Linear accelerators (Linac) 1152, 1183, 1183 Linguatula serrata 1436 Liothyronine sodium 812, 813 Lipids 621–622 Lipirudin 1132 a-Lipoic acid 1090 Lipopeptides 1646 Liraglutide 817, 820 Lispro 815 Listeria 1252 Listeria meningitis 1247 Listeria monocytogenes 1232, 1241, 1361–1362, 1369 Lithium 388 Live attenuated influenza vaccine (LAIV) 1550, 1552

I25 Live attenuated monovalent vaccine (LAMV) 1553 Livedo racemosa 1566–1567 Liver disorders see Acute liver failure (ALF) Liver transplantation 1257–1266 abnormal conscious state 1259–1261, 1260 brain edema 1261–1262, 1262 central nervous system (CNS) infection 1262–1263 malignant tumors 1263 historical perspective 1257–1258, 1258, 1259 immunosuppressants 677–678 neurologic features 1258–1259, 1259 neuromuscular complications 1263–1264 seizures 1261 Liver-intestine transplantation 1308–1309 Living donor liver transplantation (LDLT) 655 L-methionine 923 Locked-in syndrome 245–246 Loeys–Dietz syndrome (LDS) 571 description 571 neurologic complications 571 Lomustine (CCNU) 1184–1185, 1208–1209 Long bones, Paget’s disease of bone (PDB) 531 Lorazepam 1517 Lorenzo’s oil 762 L-ornithine-L-aspartate (LOLA) 670 Losartan 1636 Lovastatin 762, 1638 Low back pain, pregnancy 1610 Low density lipoproteins (LDLs) 623–624, 749–750 Low molecular weight heparin (LMWH) 297, 298, 1605–1606 adverse effects 137, 137, 1638 hematologic disorders 1130, 1131, 1132 venous thromboembolism (VTE) 295–297, 298–300 Lower airway obstruction 265–266 Lower extremity mononeuropathy/ radiculopathy 1609 Lower jaw protrusion prosthesis 262 Lower limb neuropathy, asymmetric 776 Low-grade gliomas, radiotherapy (RT) 1184 Loxosceles spp 994–995 Lubag’s disease 1780 Lumbar puncture 81 complications 1747 meningitis 1365, 1366, 1367 repeat 1373 Lumbar spine stenosis, surgery 546 Lumbosacral plexopathy 592, 776 Lund concept 1371, 1753 Lung Allocation Scoring (LAS) system (UNOS) 1238 Lung cancer 335–362 brain metastases 1143–1144 metastases 335–346 paraneoplastic disorders 346–355

I26 Lung cancer (Continued ) autoimmunity 346–348, 347 clinical syndromes 347, 348–354, 350 overview 346, 346 treatment/outcomes 354–355 Lung transplantation 1237–1243 allograft procurement 1238 background 1237 candidate evaluation 1238 heart-lung transplantation 1313 neurologic complications 1239–1241 absent cough reflex 1240 critical illness myopathy/neuropathy 1240 encephalopathy 1241 gastric outlet obstruction (GOO) 1241 metabolic deficits 1241 neuromuscular deficits 1240 perioperative 1239 peroneal nerve injury 1240 postoperative 1240 recurrent laryngeal nerve injury 1240 sedation/ventilator weaning 1240 neuropsychological effects 1241 outcomes 1238–1239, 1239 procedure 1238 Luteinizing hormone (LH) 686 acromegaly 691–692 excess 693–694 hyperprolactinemia 690–691 secondary hypogonadism 689–690 Lyme disease (borreliosis) 1473–1483, 1532–1533, 1533, 1540 clinical findings 1473–1476, 1474, 1475, 1576, 1576 neurocutaneous 1562, 1576–1577 diagnosis 1576–1577 differential diagnosis 1479 laboratory investigations 1476–1478, 1477 management 1479–1480, 1480 neuroimaging 1478 pathology/pathogenesis 1478–1479 treatment 1577 Lymphatic filarioses 1429 Lymphocyte predominant (LP) cells 1034 Lymphocytic leukemia 1038 Lymphocytic meningitis 1533 Lymphomas 1027–1038, 1030 B cell 1263 classification systems 1027, 1029 clinical presentation 1035–1038 central nervous system (CNS) 1035 infectious disease 1037 leptomeningeal (LM) 1036–1037 paraneoplastic 1038 peripheral nervous system (PNS) 1037 spinal cord 1035–1036 vascular/hematologic 1037–1038 hematopoietic stem cells 1027, 1028 Hodgkin (HL) 1034–1035 non-Hodgkin’s 1028–1034, 1029 renal transplantation 1250, 1252 treatment 1134–1137 Lymphomatosis cerebri 1030

INDEX Lymphoplasmacytic lymphoma see Waldenstr€ om’s macroglobulinemia (WM) Lymphoproliferative disorders 1282 Lysine analogs 1128 Lyssavirus 1501

M Ma2-Abs (antibodies), limbic encephalitis (LE) 1166, 1169 McArdle’s disease 833 McConnell’s sign 292 Machado Joseph’s spinocerebellar ataxia 794 Macrocephaly 552–554, 553, 554 Macrolides 1646 Magnesium 31, 737–738, 846–847, 872–873, 1286 Magnesium sulfate 1508–1509, 1697, 1737–1738 Magnetic resonance angiography 1692 Magnetic resonance imaging (MRI) brain metastases 1145, 1146–1149 cardiac arrest 34 complications 1746–1747 coronary artery stents (CAS) 99, 99 diffusion-weighted (DW-MRI) 1117, 1147, 1147 functional (fMRI) 101 hemolytic uremic syndrome (HUS) 1116, 1117 myocardial infarction (MI) 97, 98, 99 perfusion 1147 reversible cerebral vasoconstriction syndrome (RCVS) 1731–1732, 1734, 1735 spectroscopy 1147, 1148 spinal stenosis 545, 545 Maintenance of Wakefulness Test (MWT) 261 Malabsorption syndromes 621–632 causes/symptoms 622–623 neurologic dysfunction 623–628 nutrient absorption 621–622 Maladaptive behavior, fibromyalgia 517 Malaria 1514–1517 developing world 1777 diagnosis 1515, 1515 future research 1517 hemolytic uremic syndrome (HUS) 1114, 1114 management 1517 neuroimaging 1515 neurologic manifestations 1514–1515 pathogenesis 1516, 1516 vaccine 1517 Malayan pit viper (Calloselasma rhodostoma) 992–993 Malignant atrophic papulosis 1562, 1567 Malignant endocarditis, Gulstonian lectures (1885) 75–76 Malignant hyperthermia 949–951, 1612 management 951 Mambas (Dendroaspis) 990, 992 Manganese, excessive exposure 852

Mannitol 1262, 1628–1629, 1757–1759 Marantic endocarditis 69–70 Marfan syndrome (MFS) 569–570 description 569 diagnostic criteria 569 ischemic stroke 574 neurologic complications 569–570 Maroteaux–Lamy syndrome (MPS type VI) 444–445, 573 Marshall criteria, traumatic brain injury (TBI) 1756, 1757 Mass lesions fungal infection 1385 HIV 1322 Maxillomandibular advancement (MMA) 262 Maze procedure 143 Mean arterial pressure (MAP) 31, 645, 651 Mean corpuscular volume (MCV) 1006 Measles encephalomyelitis 1348 Measles virus 1345–1349 clinical manifestations 1346, 1346 diagnosis 1347, 1347, 1348 epidemiology 1345 measles-mumps-rubella (MMR) vaccine 1349, 1350, 1550–1551, 1550, 1651 treatment/prognosis/prevention 1348–1349 Meat intoxication syndrome 661 Mebendazole 1426, 1433 Mecasermin 810, 812 Mechanical circulatory devices 196, 196, 201 Mechanical heart valves 65 Mechanical ventilation 279 chronic airflow obstruction 279–280 complications 280–281, 280, 281 home (HMV) 285 prolonged (PMV) 283 weaning from 281–283, 281, 282 modes/protocol-driven 282–283 parameters 282 Mechlorethamine 1209 Medical Outcomes Study Short-Form Health Survey (SF-36) 507, 514, 536 Medical Research Council (UK) 1487–1488 Medicare 94, 104–105, 122 Medication overuse headache (MOH) 582 Medline 117, 118 Medtronic GEM III AT 141 Medullary carcinoma of the thyroid (MCT) 805, 806 Mefloquine 1517 Megaloblastic anemias 927, 929–930, 930, 1009, 1125–1126 Megestrol 1152–1153 Meglitinides 820 Melano brain metastasis 1580–1581, 1580 Melanoma 1144, 1146 Melarsoprol 1412 MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) syndrome 130, 410–411

INDEX Memantine 1642 MEN1 gene 804 Meningeal disease 232–233, 308, 308, 309 Meningiomas, radiotherapy (RT) 1187–1188 Meningitis 1577–1578 aseptic 322, 579–580, 579 bacterial see Bacterial meningitis belt 1361–1362 cryptococcal 1248–1249 HIV 1322 leukemic 1039–1040 Listeria 1247 multidrug-resistant (MDR) 1491, 1492 neonatal 1369 nosocomial 1362, 1369 oesinophilic 1537–1538, 1538 physician-associated 1362 purulent 1411 shunt-associated 1369 spontaneous 1369 tuberculous see Tuberculous meningitis (TBM) Meningococcal vaccine 1550, 1554–1555, 1651 Meningomyelitis 1534 syphilitic 1464–1465, 1534 Meningoradiculopathy 1533, 1533 Meningovascular syphilis 1464, 1533 Menkes disease (MD) (kinky hair disease) 626, 851, 853, 853 Mental disturbances Henoch–Sch€onlein purpura (HSP) 1105 hyperthyroidism 722–723 hypothyroidism 706–707 see also Psychiatric manifestations Mercury, excessive exposure 852 Meropenem 1369 Mesobuthus tamulus 988, 993–994 Metabolic disorders acid-base 375 acidosis 375–376 bariatric surgery 591–592 bone disease 443–445 encephalopathy 1278, 1297–1299 Henoch–Sch€onlein purpura (HSP) 1105 lung transplantation 1241 multiple myeloma (MM) 1091–1092 posterior reversible encephalopathy syndrome (PRES) 1694 renal transplantation 1251–1252 transient loss of consciousness (TLOC) 184 Metabolism drugs 1654–1655 Metachronous presentation 1144 Metastatic disease 213–214 brain see Brain metastases lung cancer 335–346 spinal see Spinal epidural metastases Metazoa (opisthokonta) 1404–1414, 1436 Metformin 1541, 1746 diabetes mellitus (DM) 816, 817–818, 817, 820 Metformin-associated lactic acidosis 1746 Methadone 1649

Methanol 375–376, 1090 Methimazole 813–814, 1655 Methohexital 1624 Methotrexate (MTX) 459, 507, 1613, 1718–1719 adverse effects 1201, 1203, 1205–1206 acute/subacute 1205–1206 chronic 1206 cerebral vasculitis 479, 486 giant cell arteritis (GCA) 229, 481 leukemia/lymphomas 1135 sarcoidosis 324–326, 325, 327 Methyl alcohol intoxication 1543 Methylcobalamin 779 Methyldopa 1636 Methylenetetrahydrofolate reductase (MTHFR) 598, 929, 932, 935 5,10-Methylene-THF 928 L-Methylfolate 779 Methylmalonic acid (MMA) 917, 919–921, 923 Methylmalonic aciduria 1541 Methylphenidate 1644, 1645 Methylprednisolone 323, 325, 506, 1608, 1718, 1719 5-Methyltetrahydrofolate (5-MTHF) 779, 928–929 Methylthiouracil 813 Metoclopramide 634–636, 639, 782 adverse effects 388, 1642, 1656 Metoprolol 132, 135 Metriphonate 1546 Metrix system 141 Metronidazole 88, 601, 1212, 1508, 1646 Metyrapone 698, 754, 759 Metyrosine 766 Mexiletine 132, 135, 1637 Microadenomas 1186–1187 Microalbuminuria 407 Microangiopathic hemolytic anemia 1113 Microcephalophis gracilis gracilis 992 Microscopic polyangiitis 486 clinical features 486 Microsomal triglyceride transfer protein (MTP) gene 623–624 Microtubule-stabilizing agents 1210–1211 Micrurus spp 992 Micrurus nigrocinctus 992 Midazolam 1260–1261, 1504, 1625, 1625, 1631, 1758 Mid-borderline leprosy 1573–1575 Midodrine 185, 187, 781 Miglitol 817, 818, 819 Migraine 7–8, 964, 1736–1737, 1776 Migraine Intervention with STARflex Technology (MIST-1) study 7–8 Milnacipran 520–521 Milrinone 1738 Mineral metabolism disorders 737–748 see also specific disorders Mineralizing microangiopathy 1041 Mini Mental State Examination (MMSE) 130–131, 707, 1191–1192 Minimal hepatic encephalopathy (mHE) 661–662, 663–665, 664, 666

I27 Minocycline 1512–1513 Misonidazole 1204, 1205, 1212 Misoprostol 1649 Mitiglinide 820 Mitochondrial disorders 756, 794, 796 cytopathies 12–13 pregnancy 1612 Mitomycin C 1201, 1211 Mitotane 698 Mitotic spindle inhibitors 1201–1203, 1210–1211 Mitoxantrone 1212, 1607–1608 Mitral annulus calcification (MAC) 63 Mitral bioprosthetic heart valves 64–65 Mitral stenosis 62 Mitral valve prolapse (MVP) 63 Mixed connective tissue disease (MCTD) 442, 468 Mixed thrombophilia 1063–1064, 1065, 1067 MMR (measles-mumps-rubella) vaccine 1349, 1350, 1550–1551, 1550, 1651 Modafinil 1644, 1645 Model for end stage liver disease (MELD) 655 Model Spinal Cord Injury Systems 1761 Modified neurosyphilis 1465 Molecular adsorbent recycling system (MARS) 655 Molecular targeted agents 339–340, 1152–1153 Molluscum contagiosum 1328–1329 Molybdenum cofactor deficiency 828, 833 Monoamine oxidase (MAO) A inhibitors 1642 Monoamine oxidase (MAO) B inhibitors 1641, 1641 Monobactams 1646 Monoclonal antibodies 1136 adverse effects 1205, 1213, 1653 Monoclonal gammopathy of undetermined significance (MGUS) 1031–1032, 1031, 1083–1088, 1086, 1087 central nervous system (CNS) 1088 clinical presentation 1037 peripheral neuropathy 1084, 1085–1088 Monogenea 1414 Mononegavirales order 1501 Mononeuritis multiplex (MM) HIV-infected patients 1333–1334, 1335 leprosy 1510 Mononeuropathy dialysis patients 401 HIV-infected patients 1333–1334, 1335 infective endocarditis 79 limb 775 lower extremity 1609 upper extremity 1608–1609 renal disease 390 trunk 775–776 ‘Montauk knee’ 1473 Montreal Cognitive Assessment test (MoCA) 1191–1192, 1339–1340 Mood disorder 465, 706–707

I28 Morphine 1626 Morquio–Brailsford syndrome (type V) 444–445 Mosapride 638 Motor function, impaired end of life (EOL) phase 1220 treatment 1221 Motor neuron disease 352 Mouth breathing, children 254 Movement Disorder Society 1775, 1780 Movement disorders 56 cardiology 8–9 developing world 1779–1780 drug-induced 635, 638 hyperthyroidism 715–716 Moxifloxacin 1491, 1492 Moyamoya 1022 MPL gene 1076, 1077–1078 Mucocutaneous telangiectasias 1571–1572, 1571 Mucopolysaccharidoses (MPS) 444–445, 573–574 description 573 neurologic complications 573–574 types 573 Mucor 1383, 1396 Multicenter AIDS Cohort study 1339 Multicenter Study of Hydroxyurea (MSH) 1021 Multidisciplinary approach 518, 552 Multidrug-resistant (MDR) meningitis 1491, 1492 Multifocal encephalopathy 348 Multifocal motor neuropathy (MMN), pregnancy 1611–1612 Multiple acyl-CoA dehydrogenation deficiency (MADD) 901–902 Multiple endocrine neoplasia (MEN) 799, 803–806, 803 Multiple endocrine neoplasia (MEN), type 1 (Wermer’s syndrome) 685, 803, 804–805 clinical findings 804 historical perspective 804 laboratory investigations 804–805 management 805 natural history 804 neuroimaging 805 neuropathology 805 Multiple endocrine neoplasia (MEN), type 2 803, 804 Multiple endocrine neoplasia (MEN), type 2A (Sipple syndrome) 765, 803, 805–806 historical perspective 805 laboratory investigations 805 management 806 natural history 805 neuroimaging 805–806 Multiple endocrine neoplasia (MEN), type 2B 765, 803, 804, 806 historical perspective 806 laboratory investigations 806 management 806 natural history 806

INDEX Multiple endocrine neoplasia (MEN), type 2B (Continued ) neuroimaging 806 neuropathology 806 Multiple endocrine syndromes (MES) 799–808 Multiple myeloma (MM) 1031–1034, 1031 central nervous system (CNS) 1090–1092 classification 1089 clinical presentation 1037 peripheral nervous system (PNS) 1089 plasma cells 1083, 1084, 1085, 1086, 1087, 1088–1092 smoldering 1031–1032, 1083, 1086, 1088 staging system 1088 treatment 1134–1137 -related neuropathy 1089–1090 Multiple organ transplantation 1305–1317 heart-lung 1313 hematopoietic stem cell (HSCT), combined 1314 kidney-pancreas 1313–1314 neurologic complications 1309–1313, 1309 alterations of consciousness/ behavior 1310 cerebrovascular complications 1311 epilepsy 1310 headache 1312 infection 1311–1312 neuromuscular 1312–1313 see also Multivisceral/intestinal (MVI) transplantation Multiple Sclerosis International Federation (MSIF) 1779 Multiple sclerosis (MS) ankylosing spondylitis (AS) 457 brain metastases 1150 decompression illness (DCI) 964 developing world 1779 nephrotic syndrome 410–411 vs neuro-Behc¸et syndrome (NBS) 1716 pregnancy see under Pregnancy respiratory failure (RF) 277–278 thyroid disease 726 tropics 1540 vitamin D 882 Multiple sleep latency test (MLST) 180–181, 260–261, 398 Multisystem atrophy (MSA) 8–9, 246–247 Multivisceral/intestinal (MVI) transplantation 1305–1309, 1306, 1308, 1308 isolated intestine 1308 liver-intestine 1308–1309 pediatric 1309 Mumps virus 1345–1349 clinical manifestations 1346–1347 diagnosis 1348 epidemiology 1345–1346 measles-mumps-rubella (MMR) vaccine 1349, 1350, 1550–1551, 1550, 1651

Mumps virus (Continued ) treatment/prognosis/prevention 1349 Muromonab (OKT3) 1246, 1268, 1269–1270, 1274, 1278–1279 Murray Valley encephalitis virus 1378 Muscle biopsy 1679–1680 Muscle disorders 10–12, 11 Ehlers–Danlos syndromes (EDS) 570–571 primary hyperparathyroidism (PHPT) 739–741 Sj€ ogren’s syndrome (SS) 471 weakness 184, 1252, 1357 see also Intensive care unit-acquired weakness (ICUAW), generalized Muscle relaxants 1626–1628 Musculoskeletal involvement Behc¸et’s syndrome 1705 gastric bypass 592 scleroderma (systemic sclerosis) (SSc) 468 Myasthenia Gravis Foundation of America 279 Myasthenia gravis (MG) 10, 410 hypothyroidism 711 intensive care unit (ICU) 1676 neuroanesthesia 1628 pregnancy 1610–1611 thyroid disease 726 Mycobacterium africanum 1485 Mycobacterium avium 755, 1485 Mycobacterium bovis 1485 Mycobacterium leprae see Leprosy Mycobacterium tuberculosis 318, 1232, 1247–1248, 1273, 1532 see also Tuberculosis (TB), central nervous system (CNS) Mycophenolate mofetil (MMF) 459, 507, 1613 adverse effects 676, 678 cerebral vasculitis 479, 485–486 sarcoidosis 324, 325, 326–327 transplantation 1231, 1260, 1280 Mycoplasma spp 80–81 Mycoplasma pneumoniae 1530 Mycoses Study Group (USA) 1394 Mycotic aneurysms 68, 78–79, 79 treatment 87–88 Myelitis acute transverse 1540 with oesinophilic meningitis 1537–1538, 1538 tuberculous 1495 varicella zoster 1577–1578 Myelodysplastic syndrome (MDS) 1009, 1038–1039 treatment 1133–1134 Myelography complications 1747 computed tomography (CT) 544–545 spinal stenosis 544 Myeloma see Multiple myeloma (MM) Myelomatosis 446, 446 Myeloneuropathy see Tropical myeloneuropathy

INDEX Myelopathy 351–352 achondroplasia 557 gluten-related diseases (GRD) 614, 614 Henoch–Sch€onlein purpura (HSP) 1105 HIV see under HIV-infected patients necrotizing 1040 neurosarcoidosis 312, 312 Paget’s disease of bone (PDB) 535 spinal stenosis 543 tropical see Tropical myelopathy vacuolar (VM) see under HIV-infected patients Myeloproliferative neoplasm (MPN) see Chronic myeloproliferative diseases Mygalomorphae 994 MYH9 gene 1057 Myiasis 1436 Myocardial infarction (MI) 111, 115 see also Acute myocardial infarction (AMI) Myocardial injury 5, 6–7 Myoclonic ataxia 612–613 Myoclonic encephalopathy 410–411 Myodenylate deaminase deficiency 828, 833 Myoglobinuria, thermal injuries 982–983, 984 Myopathy 354 critical illness see Critical illness myopathy (CIM) dialysis patients 401 gluten-related diseases (GRD) 613–614, 614 hereditary 1612 idiopathic see Idiopathic inflammatory myopathy (IIM) inflammatory 1612 intestinal transplantation (ITx) 1273, 1273 sarcoidosis 313, 323 Myositis disease activity (MYOACT) 507 damage (MYODAM) 507 Myotonic (muscular) dystrophy (MMD) 11, 12–13, 794, 795–796 historical perspective 795, 796 laboratory investigations 796 natural history 796 neuroimaging 790, 791–792 treatment 796 type 1 12, 1612 Myxedema coma 705–706 clinical features 705 laboratory investigations 705–706 management 706 Myxedematous madness 706 Myxoma 200–201, 218 see also Atrial myxoma Myxosarcoma 216

N Nabilone 522 Naegleria spp 1411 Naegleria fowleri 1411 Naja spp 989, 991

Naja haje 987, 989 Naja kaouthia 989, 991 Naja mandalayensis 991 Naja melanoleuca 991 Naja mossambica 991 Naja naja 989, 991 Naja nigricollis 989, 991 Naja oxiana 991 Naja philippinensis 991 Naja sagittifera 991 Naja siamensis 991 Naja sputatrix 991 Naja sumatrana 991 Naloxone 1649 Naproxen 580, 1649 Narcolepsy 257 Natalizumab 507, 601, 1607–1608 Nateglinide 817, 820 NATHAN 1 (Neurological Assessment of Thioctic Acid In Diabetic Neuropathy) trial 779 National Arthritis Data Workgroup 514 National CPR (NCPR) registry 26–27 National Heart, Lung and Blood Institute (NHLBI) 1018, 1021–1022 National Hospital Discharge Survey 1229 National Institute for Health and Clinical Excellence (NICE) 83 National Institutes of Health (NIH) 868, 869–870, 1015, 1324–1325, 1480 Alzheimer’s Disease AntiInflammatory Prevention Trial (ADEPT) 580 Stroke Scale (NIHSS) 66, 156, 296–297, 962 National Multiple Sclerosis Society 1607–1608 National Registry of Atrial Fibrillation 122 National Registry of Cardiopulmonary Resuscitation (NRCPR) 27 National Registry of Myocardial Infarction 105 National Spinal Cord Injury Database 1761 Nationwide Inpatient Sample of Health Care Cost and Utilization Project (USA) 1603 Necator americanus 1432 Necrotizing autoimmune myopathy (NAM) see Idiopathic inflammatory myopathy (IIM) Necrotizing vasculitis 481–482 Needle damage 1681 Nefazodone 1642 Neisseria gonorrhea 1461 Neisseria meningitidis 1367, 1369, 1777 bacterial meningitis 1361–1362, 1369 Nelarabine 1204, 1208 Nelson’s syndrome 698 Nematodes (roundworms) 1429–1436 Neonatal meningitis 1369 Neonatal myasthenia (NMG) 1610 Neoplastic diseases, renal transplantation 1250–1251 Nephrogenic systemic fibrosis (NSF) 97–99, 1746–1747

I29 Nephrotic syndrome 405–416 causes 405, 406 infection 407 neurologic manifestations 405, 406, 407–411, 407 diagnosis/therapy/prognosis 411 pathophysiology 405–407, 406 Nerve entrapment 707, 775 rheumatoid arthritis (RA) 450–451, 450 Nerves biopsy 1679–1680 deafness 1543 repair 778 root compression 555, 559–560 stimulation 1678–1679 Neural tube defects (NTDs) 932, 934–935 Neurally-mediated (reflex) syncope (NMS) 174–176, 179 clinical features 174 etiology 175–176, 175, 176 pathophysiology 174–175 treatment 187 Neurasthenia 513 Neuroanesthesia 1623–1633 cerebral effects 1625, 1627 disease states 1628–1629 fundamentals 1624 historical perspective 1623–1624 induction agents 1624–1625, 1625 inhalation agents 1625–1626, 1627 neurophysiologic monitoring 1630–1632, 1631 neuroprotection 1630 opioids/muscle relaxants 1626–1628 peripheral nervous system (PNS)/ positioning injuries 1629–1630 postoperative cognitive dysfunction (POCD) 1630 Neuro-Behc¸et syndrome (NBS) 1704, 1707–1712, 1707 arterial 1710 cognitive changes 1710 diagnostic criteria 1708 diagnostic studies 1712–1715 cerebrospinal fluid (CSF) 1715 neuroimaging 1712–1715, 1713, 1714 SPECT studies 1715 differential diagnosis 1715–1717 headache 1710–1711, 1710 intra-axial 1709–1710, 1715–1717, 1716 extra-axial 1708–1709, 1716 neuro-psycho-Behc¸et syndrome 1710 peripheral nervous system (PNS) 1711, 1712 prognosis 1718 secondary neurologic involvement 1712 subclinical 1711–1712 treatment 1718–1720 intra-axial 1718–1719 extra-axial 1719–1720 Neuroborreliosis 1474, 1533, 1533 Neurocognition Frascati classification 1338–1339, 1339 see also under HIV-infected patients vitamin D 881

I30 Neurocutaneous disorders 1559–1594, 1562 brain/peripheral nerve tumors 1580–1584 cutaneous angioma 1569–1573 epilepsy 1584–1590 peripheral nervous system (PNS) 1573–1580 stroke 1561–1569 vascular 1569 Neurocysticercosis (NCC) 1149, 1422–1425, 1445–1459, 1536–1537 clinical features 1422–1423, 1448–1450, 1449, 1537 control measures 1456 diagnosis 1423, 1423, 1424, 1450–1454 criteria 1454, 1454 immunologic 1453–1454 epidemiology 1445–1446, 1537 etiopathogenesis 1446–1448, 1447 cysticerci 1447–1448, 1448 Taenia solium, life cycle 1446–1447, 1446 historical perspective 1445 imaging 1450–1453, 1537, 1538 laboratory findings 1450, 1537 pathogen 1422 pathogenesis 1537 prevention 1424 treatment 1424, 1454–1456, 1537 cysticidal drugs 1455 surgery 1456 symptomatic 1455–1456 Neurodegeneration with brain iron accumulation see Inherited neurodegeneration with brain iron accumulation (NBIA) Neurodegenerative diseases, cardiology 8–9 Neurodermatology see Neurocutaneous disorders Neuroendocrine disorders 184 Neuroferritinopathy 860 Neurofibromatosis type 1 (NF1) (von Recklinghausen’s neurofibromatosis) 765, 1562, 1581–1582 clinical symptoms 1581–1582 cutaneous 1581–1582, 1581 ophthalmologic 1581–1582 orthopedic 1581–1582 diagnosis 1582 Neurofibromatosis type 2 (NF2) 1562, 1582–1584 clinical symptoms 1582–1583 cutaneous 1582–1583 neurologic tumors 1582–1583, 1583 ocular 1582–1583 diagnosis 1583 radiology 1583 treatment 1584 Neurofilarioses 1429 clinical manifestations 1429 diagnosis 1429 epidemiology 1429

INDEX Neurofilarioses (Continued ) pathogen 1429 therapy 1429 Neurogenic cardiac events, management 7 Neurogenic claudication 543 Neurogenic compression theory 543 Neurogenic pulmonary edema (NPE) 248 Neurogenic stunned cardiomyopathy 6, 6, 9–10 Neuroimaging, complications 1743–1750 catheter angiography 1743–1745, 1744 computed tomography (CT) 1745–1746 magnetic resonance imaging (MRI) 1746–1747 myelography/lumbar puncture 1747 vertebroplasty 1747–1748, 1748 Neurokinin receptor antagonists 636–637 Neuroleptic malignant syndrome (NMS) 639, 949–951, 950 hypothyroidism 712 management 951 Neurological Disorders: Public Health Challenges (WHO) 1773 Neurolymphomatosis 1037 Neuromas, radiotherapy (RT) 1188 Neuromuscular blocking agents (NMBA) 30–31, 1676 Neuromuscular disorders (NMD) Ar-Abs (antibodies) 1161–1162, 1161 limbic encephalitis (LE) 1167–1168 cardiology 9–13 Henoch–Sch€ onlein purpura (HSP) 1105–1106 HIV-infected patients 1332–1334 intestinal transplantation (ITx) 1273, 1273, 1275 lung transplantation 1240 multiple organ transplantation 1312–1313 pancreas transplantation 1282 pregnancy 1608–1613 primary hyperparathyroidism (PHPT) 867–869 respiratory failure (RF), acute/chronic 273–275, 284–285 sleep-related hypoventilation 265, 266 Neuromuscular junction (NMJ) block 1676, 1677 Neuromuscular junction (NMJ) disorders 10, 248 Neuromyelitis optica (NMO) 1779 Neuromyopathy (CINM), critical illness 1675 Neuromyotonia 352 Neuronal cell surface antigen antibodies (NSA-Abs) limbic encephalitis (LE) 1165–1166 paraneoplastic neurologic syndromes (PNS) 1161–1162 Neuronal degeneration 581 Neuron-specific enolase (NSE) 33–34 Neuro-onchocercosis 1429–1430 Neuro-ophthalmologic problems Henoch–Sch€onlein purpura (HSP) 1105 obstructive sleep apnea syndrome (OSAS) 259

Neuropathy Impairment Score (NIS) 779 Lower Limbs (NIS-LL) 779 Neurophil-Abs (antibodies), limbic encephalitis (LE) 1167 Neuroprotective pharmacology 31 Neuropsychiatric manifestations carbon monoxide (CO) intoxication 974, 975 folic acid deficiency 930–931 primary hyperparathyroidism (PHPT) 867–869 Neuropsychiatric systemic lupus erythematosus (NPSLE) 463, 464–466, 465 cerebrovascular disease 465 cognitive dysfunction 464–465 demyelinating lesions 466 diagnosis 466–467 headache 465 incidence 464 management 467–468 pathogenesis 466 psychosis/mood changes/anxiety 465 seizures 465 Neuro-psycho-Behc¸et syndrome 1710 Neuropsychological effects, lung transplantation 1241 Neurosarcoidosis 305 clinical findings 306–308, 307 definitions 313–314 differential diagnosis 314–316, 315 treatment 325 ‘Neuro-Sweet disease’ (NSD) 1717 Neurosyphilis 232–233, 1461–1472 clinical manifestations, syphilis 1464 diagnosis 1466–1468, 1467 epidemiology 1462 historical perspective/nomenclature 1461–1462 HIV see under HIV-infected patients pathogenesis 1462–1464 treatment 1468–1470 types 1464–1466, 1465 Neurotraumatology 1751–1772 brain injury see Traumatic brain injury (TBI) historical perspective 1743–1745 spinal cord see Spinal cord injury (SCI) Neurotrophic factors/nerve repair 778 Neutral protamine Hagedorn (NPH) 814, 815 New England Journal of Medicine 28, 29–30 New Orleans criteria, minor head trauma 1756 New York Heart Association (NYHA) 62, 819 Niacin see Vitamin B3 deficiency Nicardipine 165, 165, 1697 Nicotinamide adenine dinucleotide phosphate (NADPH) 1012 Nicotinic acid see Vitamin B3 deficiency Nifedipine 1636 Nifurtimox 1412, 1414 Nilotinib (Tasigna®) 1133

INDEX Nimodipine 31, 1737–1738 Nimustine (ACNU) 1208–1209 NINDS (National Institute of Neurological Disorders and Stroke) intravenous thrombolysis trial 203 Nissi–Alzheimer arteritis 1463 Nitrates 1637 Nitroglycerine 165 Nitrosoureas 1201, 1208–1209 Nitrous oxide (N2O) (‘laughing gas’) 918, 937, 1541, 1626, 1631 effects 1627, 1630–1631 Nizatidine 638–639 Nocardia 1232, 1247, 1252, 1278–1279 Nocardia asteroides 1037, 1532 Nocturia 254 Nocturnal sweats 254 Nonanion gap metabolic acidosis 375, 376 Nonarteritic optic neuropathy (NAON) 259 Nonbacterial thrombotic endocarditis (NBTE) 69 Nonclassic paraneoplastic neuropathies 1170–1171 Nonclassic rabies 1502 Nongerminomatous tumors 1185 Non-Hodgkin’s lymphomas 1028–1034, 1029 Noninsulin blood glucose lowering drugs 816–821, 817 Noninvasive ventilation (NIV) 275–276, 277, 281, 284–285 Non-nucleoside reverse-transcriptase inhibitors (NNRTIs) 1324–1325 Nonretroviral agents 1648 Nonsecretory myeloma 1032, 1083, 1092 Non-selective COX inhibitors 1647–1649 Non-small-cell lung cancer (NSCLC) brain metastases 1143–1144, 1151, 1152 dipeptidyl peptidase (DPP-4) inhibitors 819–820 see also Lung cancer Nonspecific or overlap myositis see Idiopathic inflammatory myopathy (IIM) Non-ST elevation MI (NSTEMI) 93, 101–103 Nonsteroidal anti-inflammatory drugs (NSAIDs) 577–584 adverse effects 582, 583, 1647–1649 arachidonic acid pathway 577, 578 aseptic meningitis 579–580, 579 diabetic neuropathy 782 enzyme cyclooxygenase (COX) 577–578, 579 fever 953 hypophosphatasia 879 medication overuse headache (MOH) 582 neuronal degeneration 581 overdose/intoxication 582–583 Reye’s syndrome 582 spinal stenosis 546 stroke, risks 580–581 Non-valvular atrial fibrillation (NVAF) 62

Noonan syndrome 53 Norepinephrine reuptake inhibitors (NRI) 1642 Norepinephrine-dopamine reuptake inhibitors (NDRI) 1642 Normovolemic hyponatremia 367–369, 367 North American Spine Society (NASS) 298 Norwegian Medical Birth Registry 1610 Nosocomial meningitis 1362 post-traumatic 1369 Notechis 992 NovoSeven® 1128 Nucleoside analogs 1133–1134 5’-Nucleotidase associated pervasive development disorder (NAPDD) 828, 832 Nucleus pulposus embolism 1525 clinical features 1525 differential diagnosis 1525 epidemiology 1525 imaging 1525, 1526 neuropathology 1525 pathogenesis 1525, 1526 treatment 1525 ‘Numb chin’ phenomenon 1039–1040 Number Connection Tests (NCT) 663–664, 664 Nutrient absorption 621–622 Nutritional disorders 1306 bariatric surgery 591–592 deficiency, bariatric surgery 588, 588 myeloneuropathy 1540–1544 Nutritional polyneuropathy (dry beriberi) 896–897

O Obesity 587 obstructive sleep apnea syndrome (OSAS) 253, 255, 256, 257 Obesity hypoventilation syndrome (OHS) 278 Obstructive sleep apnea (OSA)/syndrome (OSAS) 251–263 breathing control 251–252 clinical observation 260 clinical presentation 253–255 comorbidities 257–260 definitions 251 diagnostic criteria 261 gender differences 256 genetics 253 imaging 256 neuropsychiatric symptoms 255–256 pathophysiology 252, 253 prevalence 253 respiratory failure (RF) 278 risks/predisposing factors 257 severity, estimation 260 sleepiness, assessment 260–261 treatment 261–263 behavior management 263 oral appliances 262 pharmacologic 262

I31 Obstructive sleep apnea (OSA)/syndrome (OSAS) (Continued ) positive airway pressure (PAP) therapy 261–262 surgical procedures 262 Occipital horn syndrome (OHS) 853, 853 Octreotide 697, 810–811, 810 Ocular symptoms neurofibromatosis type 2 (NF2) 1582–1583 see also Ophthalmologic manifestations Oculomotor nerve (cranial nerve III) 307 Oesinophilic meningitis, with myelitis 1537–1538, 1538 Oestrus ovis (sheep botfly) 1436 Ofloxacin 1512–1513 Ohm’s Law 983 OKT3 see Muromonab-OKT3 Olanzapine 1642 ‘Old world vipers’ 992–993 Olfactory nerve (cranial nerve I) 307 Oligodendrogliomas, radiotherapy (RT) 1184–1185 Omalizumab 485–486 Omeprazole 638–639 On a form of chronic inflammation of the bones (osteitis deformans) (Paget) 529 Onchocerca volvulus 1429–1430 Onconeuronal antibodies (ON-Abs) limbic encephalitis (LE) 1168–1169 opsoclonus myoclonus (OM) 1170 paraneoplastic neurologic syndromes (PNS) 1159, 1162–1163 Ondansetron 636–637, 1656 Ondine’s curse see Congenital central hypoventilation syndrome (CCHS) ‘Onion bulb’ formation 1579 Ontario Prehospital Advanced Life Support Study 27–28 Open mouth ventilation 185 Ophiophagus hannah 991 Ophthalmologic manifestations Fabry disease (FD) 1564 incontinentia pigmenti (IP) 1587–1588 neurofibromatosis type 1 (NF1) 1581–1582 Sj€ ogren–Larsson syndrome (SLS) 1589 Sturge–Weber syndrome (SWS) 1571 see also Ocular symptoms Opiates 1649 Opioids 1260–1261, 1626–1628, 1631, 1649 diabetic neuropathy 780–781, 781 fibromyalgia 519, 521–522 Opisthokonta (metazoa) 1404–1414, 1436 Opisthotonos 377 Opsoclonus 1278–1279 Opsoclonus-myoclonus (OM) 351, 354, 1160, 1160, 1169–1170 onconeuronal antibodies (ON-Abs) 1170 Optic chiasm injury, radiotherapy (RT) 1192 Optic nerve (cranial nerve II) 307 decompression 1760 injury, radiotherapy (RT) 1192

I32 Optic neuritis 351 Optic neuropathy 1544 Oral aphthae, Behc¸et syndrome (BS) 1704 Oral appliances 262 Organization to Assess Strategies for Ischemic Syndromes (OASIS) program 93 Orienta 1403 Ornithoctoninae 994 Oropharyngeal secretions 283 Orotic acid phosphoribosyltransferase (OPRT) 827, 833, 834 Orotic aciduria 833–834, 834 Orotidine monophosphate decarboxylase (OPD) 827 Orthomyxoviridae 1345 Orthopedic manifestations, neurofibromatosis type 1 (NF1) 1581–1582 Orthoretrovirinae subfamily 1527 Orthostatic (postural) hypotension (OH) 171–174, 179 clinical features 171–172 etiology 172–174, 173, 174 pancreas transplantation 1282 pathophysiology 172 initial 172 delayed 172 treatment 186–187 Ortoidine-5’-monophosphate (OMP) 833, 834 Osler, William 75–76 Osler–Weber–Rendu syndrome see Hereditary hemorrhagic telangiectasia (HHT) Osmolytes 368 Osmoprotection 370–371 Osteitis deformans 529 Osteoarthritis 537 Osteoblastic phase, defined 533–535 Osteogenesis imperfecta (OI) 444, 573 description 573 neurologic complications 573 Osteolytic disorder 535 Osteolytic phase, defined 533–535 Osteomalacia 444 Osteoporosis 875–876 clinical manifestations 876 etiology 875 sarcoidosis 328 treatment 876 Osteosclerotic myeloma see POEMS syndrome Outcome Measures in Rheumatology Clinical Trials (OMERACT) 524 Ovaries/testis, disease of 787–798 clinical findings 788, 789, 790, 791 historical perspective 787–789, 788 laboratory investigations 791 management 792–793 natural history 789–791 neuroimaging 791–792 neurologic disorders 793–796, 794 pathology 792 OVID databases 118

INDEX Oxaliplatin 1134, 1200–1201, 1200 Oxamniquine, bilharziasis 1545 Oxazolidinone 1646 Oxcarbazepine 847, 1153, 1640, 1640 elimination 418, 422, 425, 427 Oxidative stress 777 Oxybarbiturates 1624 Oxygen parameters 274, 274 ‘Oxygen window’ 965 Oxyuranus spp 992

P Pacemaker neurons, breathing 243–244, 244 Pacemakers 140–141 complications 157 Paclitaxel 1135–1136, 1202, 1210 Paediatric Rheumatology European Society (PRES) 1102, 1102 Paediatric Rheumatology International Trials Organization (PRINTO) 1102, 1102 Paediatric Sleepiness Scale 261 Paget’s disease of bone (PDB) 529–540, 876–878 clinical characteristics 530–531, 534, 877–878 craniovertebral abnormalities 435, 443–444, 443 diagnosis 878 genetics 532–533 historical perspective 529 laboratory investigations 532 management 535–537 natural history 531–532 neuroimaging 532 pathology 533–535 sarcoma 531–532, 536 treatment 878 Pain-controlling agents 780–781 PAIR technique 1425–1426 Palla’s pit viper (Agkistrodon halys) 992–993 Palliative care see End of life (EOL) phase Palmar-plantar erythrodysesthesia (PPE) 1204 Palonosetron 636, 637 Pamidronate 536, 878 Pancreas transplantation 1279–1285 diabetes 1280 islet 1280 kidney-pancreas transplantation 1313–1314 neurologic benefit 1282–1285 autonomic neuropathy 1283–1285, 1284 peripheral neuropathy 1283 neurologic complications 1280–1281, 1281 central nervous system (CNS), infection 1281 first postoperative month 1278 immunosuppression 1281–1282 neuromuscular complications 1282 orthostatic hypotension 1282

Pancreas transplantation (Continued ) perioperative 1277–1278 post-transplant lymphoproliferative disorders (PTLD) 1282 six months after 1278–1279 period preceding 1277 Pancuronium 1509 Pantoprazole 638–639 Pantothenate kinase-associated neurodegeneration (PKAN) 859, 859, 860 Pantothenic acid see Vitamin B5 deficiency Papillary fibroelastoma 216 Paracetamol 1371 Paracoccidioides brasiliensis 1384 Paradoxical embolism 1068 Paragonimiasis 1421–1422 clinical manifestations 1421 diagnosis 1421–1422 epidemiology 1421 pathogen 1421 treatment 1422 Paragonimus 1421 Paragonimus westermani 1421 Paralysis see Thyrotoxic hypokalemic periodic paralysis (TPP) Paralytic (dumb) rabies 1502 Paralytic shellfish poisoning (PSP) 964, 996 Paramyxoviridae 1345 Paranasal sinus overpressurization 964 Paraneoplastic encephalitis 787 Paraneoplastic encephalomyelitis (PEM) 1160, 1160, 1165 Paraneoplastic neurologic syndromes (PNS) 346–355, 1159–1179 central nervous system (CNS), specific disorders 1160, 1163–1170 clinical management 1172–1173 treatment 1173 tumor identification 1172 diagnosis 1160, 1160, 1161 epidemiology 1159–1160 pathogenesis/antibodies 1160–1163, 1161 neuronal cell surface antigen antibodies (NSA-Abs) 1161–1162 onconeuronal antibodies (ON-Abs) 1159, 1162–1163 peripheral nervous system (PNS), specific disorders 1170–1172 Paraneoplastic neuro-ophthalmologic manifestations 789, 791 Paraneoplastic presentation, lymphomas 1038 Paraneoplastic progressive necrotizing myelopathy 1040 Paraneoplastic syndromes 787–789, 788, 791–792 Parasites central nervous system (CNS) 1248 see also Metazoa (opisthokonta); Protozoa Parasitic myelopathy 1535–1540 Parasympathetic outflow tracts 4 Parathyroid apoplexy 744

INDEX Parathyroid hormone (PTH) 813, 814, 872 analogs 813, 814 disorders 737–748, 813, 865 Parathyroidectomy (PTX) 868, 871 Parenchymal CNS disease 1492–1494 Parenchymal neurocysticercosis 1451, 1452, 1453 Parenchymatous neurosyphilis 1465 Parkinsonian disorders 8–9 Parkinsonism, metoclopramide-induced 636 Parkinson’s disease (PD) 636 breathing 246 cardiology 8–9 developing world 1779–1780 iron disorders 861 nonsteroidal anti-inflammatory drugs (NSAIDs) 581 respiratory failure (RF) 278 venous thromboembolism (VTE) 292 vitamin D 881 Paroxetine 520 Paroxysmal events, cardiology 7–8 Paroxysmal nocturnal hemoglobinuria (PNH) 1012–1013 Pasireotide 810 Patent foramen ovale (PFO) 7–8, 51–52, 112–113, 194 surgery 200 Pathergy phenomenon 1704–1705 ‘Pavor mortis’ 994–995 Pediatric intracranial pressure (ICP), increased 1759 Pediatric multivisceral/intestinal (MVI) transplantation 1309 Pediatric spine trauma 1767 Pediculus humanus (human body louse) 1534–1535 Pegvisomant 697–698, 810, 812 Pelamis platurus 992 Peliosis rheumatica 1101 Pellagra 626, 891, 902–903 bariatric surgery 591 Pelvic bone, Paget’s disease of bone (PDB) 531 Pelvic neurologic symptoms, ovarian tumors 789, 791–792 Pemoline 1644 Penicillin 1357, 1369, 1508, 1646 Lyme disease 1479, 1480, 1533, 1577 neurosyphilis 1336–1337, 1465–1466, 1468 Penicillin G 1337, 1468, 1534 benzathine 1468, 1469–1470, 1508, 1534 Pentastomiasis 1436 Pentobarbital 1262 Pentostatin 1134, 1208 Perchlorates 813, 814 Percutaneous coronary intervention (PCI) 194, 194, 196–197 Percutaneous vertebroplasty 342–343 Perfluorocarbon emulsions (PFCs) 965 Pergolide 811

Periodic alternating gaze deviation (PAGD) 646 Periodic limb movement disorder (PLMD) 257, 398–399 Peripartum cardiomyopathy (PPCM) 1598 Peripheral facial nerve palsy 321–322 Peripheral nervous system (PNS) 9–10 AL amyloidosis 1095 bortezomib-induced (BiPN) 1089 breathing 246, 248 cardiac surgery complications 197 cardiac tests 41–43 chemotherapy complications 1199–1205 cryoglobulinemia 1096 Cuban epidemic myeloneuropathy (CEM) 1544 diabetic neuropathy (DPN) 776–777 dialysis patients 396, 400–401 Ehlers–Danlos syndromes (EDS) 570–571 fibromyalgia 516 heart transplantation 1230, 1234 HIV 1322 hyperthyroidism 714–715 hypothyroidism 707–708 inflammatory bowel diseases (IBD) 596, 597 injuries 200 intestinal transplantation (ITx) 1273 leukemias 1041 lymphomas 1037 monoclonal gammopathy of undetermined significance (MGUS) 1084, 1085–1088 multiple myeloma (MM) 1089 neuro-Behc¸et syndrome (NBS) 1711, 1712 neurocutaneous disorders 1573–1580 neuropsychiatric systemic lupus erythematosus (NPSLE) 466 obstructive sleep apnea syndrome (OSAS) 259 pancreas transplantation 1283 paraneoplastic neurologic syndromes (PNS) 1170–1172 plasma cell disorders 1084 POEMS syndrome 1092, 1093, 1578 positioning injuries 1629–1630 renal disease 388–391 renal transplantation 1251 sarcoidosis 312–313, 323 scleroderma (systemic sclerosis) (SSc) 468–469 sickle cell disease (SCD) 1016 Sj€ ogren’s syndrome (SS) 470–471 thalidomide-induced (TiPN) 1090 Waldenstr€ om macroglobulinemia (WM) 1093 Permetrexed 339 Pernicious anemia (PA) 915, 917, 921, 922, 923 folic acid deficiency 927, 929–930, 930, 936–937

I33 Pernicious anemia (PA) (Continued ) progressive 927 tropics 1541 Peroneal nerve injury 1240 Persistent intracranial pressure (ICP), increased 1759–1760 Pertussis 1358 hemolytic uremic syndrome (HUS) 1114, 1114 immunization 1358 diphtheria-tetanus-pertussis (DTP) vaccine 1358, 1550, 1555–1556, 1651 Phaeohypomycosis spp 1385 PHASE (Pre-Hospital Survival Evaluation) study 27 Phaseolus vulgaris 1544 Phenformin 816 Phenobarbital 677, 1153, 1231, 1504, 1640 elimination 418, 421, 425, 427 seizures 846, 1234 Phenothiazines 634 Phenoxybenzamine 766 Phenprocoumon 1638–1639 Phenylbutazone 1649 Phenylbuterate 762 Phenytoin 677, 1153, 1231, 1517, 1628 adverse effects 1640, 1640 elimination 417–420, 418, 425, 427 seizures 846, 847, 1234, 1274 Pheochromocytomas 805–806 PHES (psychometric hepatic encephalopathy score) 665 Phosphoribosylpyrophosphate synthase (PRPS) 828, 829–830 Phosphorus disorders, congenital/acquired 874 homeostasis 737–738 Phosphorus-32 1189 Photons 1183 Phrenic nerve injury 199 catheter ablation 154 electrophysiologic procedures 142 Phrenic neuropathy 1681 Physician-assisted suicide (PAS) 1222 Physician-associated meningitis 1362 Pica 1007 Pickwick morphotype 257 Pickwickian syndrome (obesity hypoventilation syndrome (OHS)) 278 Picture-frame sign 535 PIGA gene 1012–1013 Pioglitazone 817, 819, 820 Pipecuronium 1509 ‘Pit vipers’ 992–993 Pituitary hormones/analogs 809, 810 anterior 811–812 posterior 812 Pituitary lesions 410, 683–702 adenomas 685, 687–688 radiotherapy (RT) 1186–1187, 1187 apoplexy (Sheehan syndrome) 756–757, 1604–1605 central diabetes insipidus (DI) 690

I34 Pituitary lesions (Continued ) future directions 699 growth hormone (GH) deficiency 690 hormonal hyperfunction 690–694 hypopituitarism 688–689 hypothalamic-pituitary axis, evaluation 686, 690 imaging 694–695, 694, 695 metastases 345 neurologic manifestations 685–688, 686 pituitary/target hormones 686 prolactin deficiency 690 secondary conditions adrenal insufficiency (AI) 689 hypogonadism 689–690 hypothyroidism 689 tumors see Pituitary tumors Pituitary tumors 686, 687, 695–699 growth predictors 695 medical management 697–698 radiotherapy 698–699 surgical management 695–696, 696 postoperative complications 696–697 PLA2G6 gene 859, 860 PLAATO (Percutaneous Left Atrial Appendage Transcatheter Occlusion study) device 142–143 Planning target volume (PTV) 1181–1182 Plant alkaloids 1652 Plasma cell disorders 1083–1100 cryoglobulinemia see Cryoglobulinemia macroglobulinemia see Waldenstr€ om’s macroglobulinemia (WM) myeloma, nonsecretory 1083, 1092 see also Multiple myeloma (MM) POEMS syndrome see POEMS syndrome solitary plasmacytoma 1083, 1084, 1089, 1092 see also Monoclonal gammopathy of undetermined significance (MGUS) Plasma infusion/plasmapheresis 1120 Plasmacytoma intracranial 1091 solitary 1083, 1084, 1089, 1092 Plasminogen activator inhibitor-1 (PAL-1) deficiency 1056 Plasmodium falciparum 1514, 1515, 1516, 1517 Plasmodium knowlesi 1514 Plasmodium malariae 1514 Plasmodium ovale 1514 Plasmodium vivax 1514 Platelet function disorders 1057–1058 anatomy/physiology 1057 diagnosis 1057–1058 symptoms, bleeding 1047, 1057 treatment 1055, 1058 Platinum-based agents 1134, 1652 adverse effects 1199–1200, 1201, 1208 PLATO (Platelet Inhibition and Patient Outcomes) trial 101 Platyhelminths (flatworms) 1414, 1419–1429

INDEX Platyzoa 1414 p-aminosalicylic acid (PAS) 1491, 1492 Plexiform neurofibromas 1581–1582 Plexopathy brachial 199, 199, 345–346, 1192–1193 lumbrosacral 592, 776 pregnancy 1610 Plicamycin 878 Pneumococcal vaccines 1550, 1554–1555, 1651 Pneumococcus spp 1532 Pneumocystis carinii 1232, 1246, 1248 Pneumocystis jiroveci 1323, 1325, 1328–1329 PNM system (WHO) 1426–1427 Podophyllin 1203 Podophyllotoxins 1152 Poecilotheriinae 994 POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein, skin changes) (Crow–Fukase) syndrome 845, 1032, 1083, 1084, 1087, 1092–1093, 1578–1579 clinical features 1037, 1578 laboratory studies/diagnosis 1578, 1579 peripheral nervous system (PNS) 1092, 1093 treatment 1578–1579 Poiseuille’s Law 41 Poliomyelitis 1527, 1553 Poliovirus vaccine 1550, 1553, 1651 Polyarteritis nodosa (PAN) 482–483 clinical features 482, 482 Polycythemia 51 Polycythemia vera (PV) 1074–1075 clinical characteristics 1074 defined 1073 diagnostic criteria/risk assessment 1074 JAK2 gene 1073–1074 neurologic symptoms 1074–1075 thrombosis/hemorrhage 1075 treatment 1075, 1132 Polyenes 1388–1389, 1395, 1649 Polyglandular autoimmune syndrome 750 type I 871 Polymixin 1646 Polymyalgia rheumatica 711 Polymyositis (PM) see Idiopathic inflammatory myopathy (IIM) Polyneuropathy critical illness see Critical illness polyneuropathy (CIP) dialysis patients 400–401 distal see Distal symmetric polyneuropathy (DSP) endemic ataxic 1542–1543 infective endocarditis 79 inflammatory chronic demyelinating polyneuropathy (CIDP) 841, 845, 1088, 1333, 1611 see also Guillain–Barre´ syndrome (GBS); Inflammatory demyelinating polyneuropathy (IDP)

Polyneuropathy (Continued ) nutritional (dry beriberi) 896–897 sensory/sensory motor 353, 774 small fiber 774 see also POEMS syndrome Polyol pathway 777 Polysomnography (PSG) 260, 261 Pomalidomide 1032, 1090 Porocephalalosis 1436 Porocephalus spp 1436 Porphyria 839–849 background 839–841, 840 clinical presentation 841–842 decompression illness (DCI) 964 diagnosis 845–846 nervous system dysfunction, mechanisms 843–845 risk factors 842–843 treatment 846–847 Portogonyaulax spp 996 Portosystemic encephalopathy 661–674 clinical findings 661–663, 662 differential diagnosis 663 historical perspective 661 laboratory investigations 666–667 management 670–671 minimal hepatic encephalopathy (mHE) 661–662, 663–665, 664, 666 natural history 665–666 neuroimaging 667–669, 667, 668 pathology/pathophysiology 669–670 Posaconazole 1329–1330 Positioning injuries 1629–1630 Positive airway pressure (PAP) therapy 261–262 Positron emission tomography (PET) brain metastases 1148, 1149 fibromyalgia 515–516 Post Lyme disease syndrome 1476 Post-cardiac arrest syndrome 26 Posterior ischemic optic neuropathy (PION) 1629–1630 Posterior reversible encephalopathy (leukoencephalopathy) syndrome (PRES/PRLS) 161, 384–385, 452, 1108, 1213, 1245–1246, 1687–1701 causes 1692–1695, 1692 clinical features 1687–1688, 1688 dialysis patients 397–398 Guillain–Barre´ syndrome (GBS) 9–10 heart transplantation 1230 Henoch–Sch€ onlein purpura (HSP) 1104 infection 1694 intestinal transplantation (ITx) 1271–1272 nephrotic syndrome 409–410, 410 neuroradiologic features 1688–1692, 1688 additional sequences 1690–1692 catheter/magnetic resonance angiography 1692 conventional imaging 1688–1690, 1689, 1690 pancreas/small bowel transplantation 1278–1279

INDEX Posterior reversible encephalopathy (leukoencephalopathy) syndrome (PRES/PRLS) (Continued ) pathological features 1696–1697 pathophysiology 1695–1696 Rapamune (sirolimus) 1246 reversible cerebral vasoconstriction syndrome (RCVS), overlap 1727 total body irradiation (TBI) 1299 treatment 1697–1698 Postherpetic neuralgia (PHN) 1577–1578 Posthypoxic myoclonus (PHM) 35 Postpartum angiopathy see Reversible cerebral vasoconstriction syndrome (RCVS) Post-resuscitation disease 26 Postsynaptic toxins 989–990 Post-transplant lymphoproliferative disorder (PTLD) 1233, 1241 classification 1233 intestinal transplantation (ITx) 1270 multivisceral and intestinal (MVI) transplantations 1313, 1314 pancreas transplantation 1282 small bowel transplantation 1287–1288 Post-traumatic bacterial meningitis 1365 Postural tachycardia syndrome (PoTS) 172, 173 Posture see Orthostatic hypotension (OH) Potassium chloride 721 Potassium perchlorate 813 Pott’s disease 446, 1530, 1531 Powassan virus 1378, 1380 Praeder–Labhart–Willi syndrome 796 Pramipexole 522 Pramlintide 817, 820–821 Prasugrel 1129, 1639 Pravastatin 1638 Praziquantel 1421, 1422, 1426, 1429, 1545 neurocysticercosis 1455, 1537 Prazosin 994, 1636 Precocious presentation, brain metastases 1144 Prednisolone 1513–1514, 1608, 1613, 1718 Prednisone 459, 481, 506, 1333, 1470, 1545 lung cancer 354 pregnancy 1608, 1613 sarcoidosis 321–322, 323, 325 Pre-eclampsia humoral factors 1597 hypertension/stroke risk mitigation 1598 long-term effects 1597–1598 posterior reversible encephalopathy syndrome (PRES) 1693–1694 role of placenta 1597 stroke 1596–1598 ischemic 1598–1602 treatment 1604 Pregabalin 521, 780, 1332–1333 elimination 418, 425, 426, 427 Pregnancy 1595–1622 brain tumors 1614–1616, 1615 epilepsy 1606–1607 future directions 1616–1617

Pregnancy (Continued ) headache 1613–1614 primary 1614 secondary 1614 multiple sclerosis (MS) 1607–1608 disease-modifying therapies (DMTs) 1606, 1607–1608 predictions 1607 relapse rates 1607 neuromuscular disease 1608–1613 acquired inflammatory demyelinating polyneuropathy (AIDP) 1611 chronic inflammatory demyelinating polyneuropathy (CIDP) 1611 hereditary neuropathy/dystrophy/ myopathy 1612 immunosuppressant treatment 1613 inflammatory myopathy 1612 lower extremity mononeuropathy/ radiculopathy 1609 upper extremity mononeuropathy/ radiculopathy 1608–1609 multifocal motor neuropathy (MMN) 1611–1612 myasthenia gravis (MG) 1610–1611 outcomes 1612–1613 plexopathy 1610 spinal cord disorders 1616 stroke 1595–1606 cerebral venous thrombosis (CVT) 1605–1606 epidemiology 1595 hemorrhagic 1602–1605 maternal physiologic changes 1596 underlying mechanisms 1595–1596 vascular endothelial dysfunction 1595, 1596–1598 Pregnancy in Multiple Sclerosis Group (PRIMS) 1607 Premature aging, vitamin D 881 Premature ventricular contractions (PVCs) 130 Prenatal stress 517 Pressure control ventilation (PCV) 279 Pressure palsy 1681 Presynaptic toxins 990 Pre-syncope 172 Prevention of Venous Thromboembolism After Acute Ischemic Stroke with Low Molecular Weight Heparin (PREVAIL) study 296–297, 300 Preventive Services Task Force (USA) 1654 Prickly heat 948 Primary angiitis of central nervous system (PACNS) 486–487, 1725–1726, 1736 clinical features 486–487, 486 diagnosis 487 differential diagnosis 487 Primary brain gliomas 1149 Primary brain tumors 726 Primary care, developing world 1774 Primary central nervous system lymphoma (PCNSL) 1028–1030 brain metastases 1149

I35 Primary central nervous system lymphoma (PCNSL) (Continued ) clinical presentation 1036 radiotherapy (RT) 1185–1186 Primary central nervous system lymphoma (PCNSL), HIV-associated 1321, 1326–1327 brain biopsy 1326 clinical presentation 1326 management 1326–1327 neuroimaging 1326 pathogenesis 1326 Primary central sleep apnea (CSA) 263, 263 Primary cerebral angiitis 1736 Primary dural lymphoma, clinical presentation 1036 Primary graft dysfunction (PGD) 1238, 1239 Primary headache disorder 1450 thunderclap 1726 Primary hyperparathyroidism (PHPT) 738–742, 866–870 clinical/biochemical features 739–741, 867 cardiovascular manifestations 867 gastrointestinal manifestations 867 neurologic/muscular manifestations 739–741 neuromuscular/neuropsychiatric manifestations 867–869 renal manifestations 867 skeletal manifestations 867 diagnosis 866 etiology 866 management 869–870 pathophysiology 738–739 Third International Workshop 869 treatment 741–742 Primary myelofibrosis (PMF) 1077–1078 clinical characteristics 1077 defined 1073 diagnostic criteria/risk assessment 1077–1078 JAK2 gene 1073–1074 neurologic manifestations 1078 treatment 1078 Primary ovarian failure (POF) 793–796, 794 Primary plasma cell leukemia 1032 Primary sleep apnea of infancy 264–265 Primidone 418, 421, 425, 427 PRISM (Randomised Trial of Intensive versus Symptomatic Management of Paget’s Disease) trial 536 PRKAR1A gene 1566 Probenecid 1534 Procainamide 132, 135 Procarbazine 1184–1185, 1201, 1201, 1210 Prochlorperazine 634, 639 Procyclidine 636–637 PRODIGE study, low molecular weight heparin (LMWH) 299 Progressive craniovertebral subluxation 437–438

I36 Progressive multifocal leukoencephalopathy (PML) 1149, 1378, 1379 intestinal transplantation (ITx) 1272 JC polyomavirus 1232, 1263 liver transplantation 1263 rituximab 1278–1279 treatment 1136 Progressive multifocal leukoencephalopathy (PML), HIVassociated 1327–1328 clinical presentation 1327 diagnosis 1327–1328, 1327 epidemiology 1327 pathogenesis 1327 treatment 1328 Progressive polyradiculopathy 1334, 1335 Progressive systemic sclerosis (PSS) 468 Prolactin 686, 690 Prolactin blocking agents 1655 Prolactinomas 687, 691, 697 Prolonged mechanical ventilation (PMV) 283 Promethazine 634, 639, 1642 Pro-opiomelanocortin (POMC) 750 Propafenone 132, 135 Propionibacterium acnes 318 Propofol 846–847, 1260–1261, 1262, 1624, 1625, 1630 Propofol infusion syndrome 1677, 1758 Propranolol 187, 721, 1274, 1571 adverse effects 132, 135, 1636 Propylthiouracil (PTU) 813–814, 813 Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) 293 Prostacyclin 1738 Prostaglandin E 56 Prosthetic heart valves 63–65 Protamine 1132 Protease inhibitors (PIs) 1324–1325, 1340, 1494 Proteasome inhibitors 1136–1137, 1203 PROTECT AF study, warfarin treatment 143 Protein 622 Protein kinase C (PKC) pathway 778 Protein S100B 34 Prothrombin complex concentrates (PCCs) 1128, 1131–1132 Proton magnetic resonance spectroscopy (H-MRS) 516 Proton pump inhibitors 638–639 Proton radiobiology 1183 Protozoa 1404–1414, 1407 PRPS1 gene 830 PSE-Syndrom-Test 663–664, 664, 665 Pseudechis spp 992 Pseudohyponatremia 365 Pseudohypoparathyroidism see Hypoparathyroidism/ pseudohypoparathyroidism Pseudomonas aeruginosa 1369, 1532 Pseudonaja spp 992

INDEX Pseudopseudohyperparathyroidism 745 Pseudotumors, hemophilic 1053–1054 Pseudoxanthoma elasticum (PXE) (Gr€ onblad–Strandberg syndrome) 571–572, 1568 clinical features 571, 572, 1568 cutaneous manifestations 1568 eye involvement 1568 vascular manifestations 1568 diagnosis/management 1568–1569, 1569 neurologic complications 571–572 Psychiatric manifestations hyperthyroidism 722–723 hypothyroidism 706–707 inflammatory bowel diseases (IBD) 601 neurocysticercosis (NCC) 1450 porphyria 842 see also Mental disturbances Psychiatric transient loss of consciousness (TLOC) 179, 180–181, 184 clinical features 180–181, 180 etiology/pathophysiology 181 falls 184 Psychogenic pseudosyncope see Psychiatric transient loss of consciousness (TLOC) Psychosis 465 Psychostimulants 1644, 1645 Puerperium see Pregnancy Pufferfish 964, 988 Pulmonary cement embolization (PCE) 1747–1748 Pulmonary disorders angiography 293 embolism (PE) see Venous thromboembolism (VTE) hypertension 258 obstructive sleep apnea syndrome (OSAS) 258 parenchymal/vascular pathology 266 vein isolation 143–144 Pure red cell aplasia (PRCA) 1010 Purified protein derivative (PPD) 1247–1248 Purine analogs 1200 Purine metabolism, disorders of 827–833 inborn errors of metabolism, indicators 835 nucleoside phosphorylase (PNP) deficiency 828, 832 overview 827, 828 PURSUIT (Platelet glycoprotein IIb/IIIa in Unstable angina. Receptor Suppression using Integrin Therapy) trial 101–103 Purulent meningitis 1411 Pyrazinamide 1490, 1491, 1495 Pyridostigmine 185, 354, 781, 1628 Pyridoxine (pyridoxal) see Vitamin B6 deficiency Pyrimethamine 1325 Pyrimidine analogs 1134, 1395, 1649

Pyrimidine metabolism, disorders of 833–835, 834 catabolic disorders 835 inborn errors of metabolism, indicators 835 nucleotide depletion and overactive cytosolic 5’-nucleotidase 834, 834 overview 827

Q Quality of life (QOL) 868–869, 870 Quatember and Maly Clocktest 261 Quinagolide 810, 811 Quinidine 132, 136, 1637 Quinine 1517

R R173W gene 841 Rabeprazole 638–639 Rabies 1501–1506 clinical features 1501–1502 diagnosis 1502–1504, 1505 differential diagnosis 1502 encephalitis 1378, 1379 diagnosis 1380 management 1504 natural history 1504 pathogenesis/pathology 1502, 1503 prevention 1504–1506 post-exposure treatment 1506, 1506 vaccines 1504–1506, 1506, 1550, 1553–1554 renal transplantation 1250 Radial artery catheterization 5 Radiation see Radiotherapy (RT) Radiation Therapy Oncology Group (RTOG) 1191, 1326 study 9802 1184, 1185–1186 Radiculomyelitis 1495 Radiculoneuritis 1474–1475 Radiculopathy 456, 1322, 1334, 1335 lower extremity 1609 upper extremity 1608–1609 Radiofrequency ablation (RFA) 262 Radioimmunotherapy 1136 Radiosensitizers 1200, 1204, 1212 Radiosurgery 1186–1187, 1188, 1189, 1190 stereotactic see Stereotactic radiosurgery (SRS) Radiotherapy (RT) 947, 1181–1198 biology 1183, 1183 -induced conditions 1150 irradiation process 1181–1183, 1182 neurosarcoidosis 325 normal tissue, effects on 1189–1193 early 1190 delayed 1190–1191 late 1191–1193 sarcoidosis 327 treatment, neurologic disease 1184–1189 benign tumors 1186–1189 malignant tumors 1184–1186 nontumor indications 1189 Ramosetron 636

INDEX Ranirestat 779 Ranitidine 638–639 Rapamune/rapamycin see Sirolimus Rattlesnakes (Crotalus) 992–993 Reactive arthritis 457 Recluse (violin) spiders 994 Recombinant factor VIIa (NovoSeven®) 1128 Recombinant vaccines 1550 Recurrent laryngeal nerve palsy 726 Red blood cells (RBC) 1005–1006 distribution width (RDW) 1006, 1008 Refsum disease 1562, 1579–1580 clinical manifestations 1579 diagnosis/treatment 1579 Regional wall motion abnormality (RWMA) 6–7 186Re-HEDP, adverse effects 1655 Relapsing polychondritis (RP) 457–459 clinical findings 457–458 diagnosis 458 natural history 458 pathogenesis/treatment 458–459 RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial 119–120, 121–122 Remethylation defects 935, 935 Remifentanil 1626–1628 Renal disease, acute/chronic 383–394 central nervous system (CNS) complications 383–385 renal replacement therapy 385–388 peripheral nervous system (PNS) disorders 388–391 see also Antiepileptic drugs (AEDs), hepatic/renal disease; Dialysis patients Renal manifestations Fabry disease (FD) 1564 primary hyperparathyroidism (PHPT) 867 Renal replacement therapy 385–388 Renal transplantation 1245–1255 central nervous system (CNS) 1247–1250 bacterial infection 1247–1248 fungi 1248–1249 parasites 1248 viral infection 1249–1250 cerebrovascular disease 1251 diagnostic approach 1252–1253, 1252 drug-related neurotoxicity 1245–1247 calcineurin inhibitors (CNI) 1245–1246, 1246 immunosuppression 1246 steroids 1246 metabolic causes 1251–1252 neoplastic diseases 1250–1251 peripheral neuropathy 1251 treatments, neurologic 1253 Renzapride 638 Repaglinide 817, 820 Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) 663–664 Reperfusion injury 20, 25–26

Replacement therapies 385–388, 1125–1128 Rescue ICP trial 1759–1760 Reserpine 20 Respiratory disorders achondroplasia 556–557 acid-base 375 acidosis 375–376 acute respiratory distress syndrome (ARDS) 280 alkalosis 375–376 muscle weakness 1357 see also Breathing Respiratory failure (RF), acute/chronic 273–288 classification 273 diagnosis 273–275, 274 management principles 279–283 acute respiratory distress syndrome (ARDS) 280 mechanical ventilation 279–283, 280, 281, 282 noninvasive ventilation (NIV) 281 neuromuscular disease (NMD) 273–275, 284–285 home mechanical ventilation (HMV) 285 muscle function devices 284 noninvasive ventilation (NIV) 284–285 oropharyngeal/tracheobronchial secretions 283 specific diseases 275–279 types 273 Respiratory tract drugs 1655 Restless legs syndrome (RLS) 257 dialysis patients 398–399 iron disorders 861 renal disease 390 RET gene 804, 806 Reteplase 104 Retigabine 418, 425, 427, 429 Retinal degeneration 354 Retinal injury, radiotherapy (RT) 1192 Retinoids 1201, 1204, 1212–1213, 1652 Retinopathy, carcinoma-associated 351 Retroviral agents 1648 Retroviridae family 1527 Return of spontaneous circulation (ROSC) 28–30 Reversible cerebral vasoconstriction syndrome (RCVS) 1599–1600, 1599, 1650, 1725–1741 causes/associated conditions 1726–1727, 1727 posterior reversible encephalopathy syndrome (PRES), overlap 1727 clinical findings 1727–1729 demographics 1727–1728 diagnostic criteria 1729, 1729, 1730 focal deficits/seizures 1728 general examination 1729 thunderclap headache 1726, 1728 differential diagnosis 1734–1737 exertion/sexual activity 1737

I37 Reversible cerebral vasoconstriction syndrome (RCVS) (Continued ) migraine 1736–1737 primary cerebral angiitis 1736 thunderclap headache 1730, 1734–1736, 1737 etiology/pathophysiology 1727, 1737 future directions 1738 historical perspective 1725–1726 laboratory investigations 1731 management 1737–1738 natural history 1729–1731, 1731 neuroimaging 1731–1734 abnormalities, timing 1734 brain computed tomography (CT)/ magnetic resonance imaging (MRI) 1731–1732, 1732, 1733, 1734, 1735 cerebral angiography 1732–1733, 1735, 1736 pathology 1733 ultrasound 1733 nomenclature 1726 posterior reversible encephalopathy syndrome (PRES) 1692 postpartum 1726–1727 terminology 1725–1726, 1726 Reversible posterior leukoencephalopathy syndrome (RPLS) see Posterior reversible encephalopathy (leukoencephalopathy) syndrome (PRES/PRLS) Reversible splenial lesion syndrome 369 Reye’s syndrome 582, 645–646 Rhabdomyolysis intensive care unit (ICU) 1676–1677 renal transplantation 1252 Rhabdomyoma 216 Rhabdoviridae family 1501 Rhesus macaque monkey, Lyme disease 1475 Rheumatic mitral valve disease 61–62 Rheumatic valvular heart disease (RVHD) 61–62 Rheumatoid arthritis (RA) 449–454 atlantoaxial subluxation 440, 453 autonomic nervous system (ANS) dysfunction 452 cerebral vasculitis 451–452, 452 classification criteria 450 craniocervical dislocation 435, 440, 441–442, 442 leptomeningeal (LM) involvement 451 management 452–453 nerve entrapment 450–451, 450 prognosis 454 subclinical neurologic disease 449, 450 treatment, complications 453–454 vasculitic neuropathy 451 Rhinocerebral syndromes, fungal infection 1386 Rhinocerebral zygomycosis 1385, 1396–1397, 1397 Rhizomucor 1383, 1396 Rhizopus 1383, 1396

I38 Ri-Abs (antibodies) 1164 Ribavirin (Rebetol®) 676, 679, 1348–1349, 1381, 1504 mechanism of action 679 neurotoxicity 679 Riboflavin see Vitamin B2 deficiency Rickettsia 1403 Ridley–Jopling classification, leprosy 1509–1510, 1510 Rifabutin 1247–1248, 1338, 1494, 1495 Rifampicin (rifamycin/rifampin) 1357, 1512–1513, 1575–1576, 1646 tuberculosis (TB) 1247–1248, 1338, 1494 tuberculous meningitis(TBM) 1490, 1491, 1492 Rikettsiae (Rhizobiales/Rickettsiales) 1403–1404 clinical manifestations 1403, 1405 epidemiology 1404 pathogens 1403 therapy 1403–1404 Riley–Day syndrome 172 Risedronate 878 Risperidone 1642 Rituximab (Rituxan®) 485–486, 718–719, 1120, 1136, 1170, 1173 Riva-Rocci, Scipione 161 Rivaroxaban 139, 295, 1639 Rivastigmine 1642 Rochester (Minnesota) Epidemiology Project 1462 Rocuronium 1509 Rofecoxib 580, 1649 Ropinirole 522 Rosiglitazone 819 Rotavirus vaccine 1651 Roundworms 1414, 1429–1436 Royal College of Physicians, Gulstonian Lectures (1885) 75–76 Royal Medico-Chirurgical Society 529 Rubella virus 1349–1350 clinical manifestations 1349–1350 acquired rubella infection 1349–1350 congenital rubella syndrome (CRS) 1350 diagnosis 1350 epidemiology 1349 measles-mumps-rubella (MMR) vaccine 1349, 1350, 1550–1551, 1550, 1651 treatment/prognosis/prevention 1350 Rubitecan 1212 Ruboxistaurin 779 Rufinamide 418, 425, 427, 428–429 Russell’s viper (Daboia russelii) 988, 990, 992–993

S Saddle embolism 296 S-adenosylmethionine (SAM) 928, 928, 929, 1206, 1541 St Louis encephalitis virus 1378, 1379, 1380 Salicylates 1648 Salmonella spp 1532 SAR1B gene 624

INDEX Sarcoidosis 305–334 brain metastases 1149–1150 clinical course 313 clinical findings 305–313, 306 CNS parenchymal disease 309–312 hydrocephalus 308–309, 309 meningeal disease 308, 308, 309 myopathy 313 neurosarcoidosis see Neurosarcoidosis peripheral neuropathy 312–313, 323 epidemiology/pathophysiology/genetics 317–320, 319 historical perspective 305 investigations 313–317 differential diagnosis 313–314, 315 laboratory 306, 314–316 neuroimaging 308, 309, 312, 316–317, 317 management 321–328 alternative treatments 321, 324–327, 325 radiation therapy 327 supportive care 327–328 surgical considerations 324 treatment 321–323, 321 pathology 320–321, 320 Sarcoma, Paget’s 531–532, 536 sarcomatous transformation 531 SAVE (Survival and Ventricular Enlargement) trial 113, 114 Saw-scaled (carpet) vipers (Echis) 992–993 Saxagliptin 817, 820 Scandinavian Glioblastoma Study Group 1184 SCD-HeFT (Sudden Cardiac Death in Heart Failure Trial) 114 Schilder–Addison disease 760 Schilling test 921 Schistosoma 1419–1421, 1419, 1535–1536 Schistosoma haematobium 1419–1420, 1535 Schistosoma japonicum 1420, 1535, 1777 Schistosoma mansoni 1420, 1535 Schistosomiasis see Bilharziasis Schmidt’s syndrome see Autoimmune polyglandular syndrome, type II (APSII) Scleroderma (systemic sclerosis) (SSc) 468–470 autonomic nervous system (ANS) 469 central nervous system (CNS) 468, 469 musculoskeletal involvement 468 neurologic complications 464, 468 peripheral nervous system (PNS) 468–469 treatment 469–470 SCN1A gene 1358 Scoliosis 559 Scopolamine 187 Scorpionida 993 Scorpions see under Venomous bites Scurvy 891, 908–910 Sea kraits (Laticauda) 992

Sea snakes 989, 992 Second International Study of Infarct Survival (ISIS-2 Collaborative Group) 105 Secondary adrenal insufficiency 689 Secondary care, developing world 1774 Secondary hyperparathyroidism 742–743, 744 Secondary hypogonadism 689–690 Secondary hypothyroidism 689 Secondary intracranial hypertension 365 Sedatives 519, 522, 1240, 1644 Seizures bacterial meningitis 1372 brain metastases 1144–1145 cardiac arrest 31 cardiac catheterization 197 cardiac surgery 55 chronic 1149 coronary artery bypass grafting (CABG) 198 decompression illness (DCI) 964 dialysis, causes 386, 386 end of life (EOL) phase 1219–1220 heart transplantation 1230, 1233–1234, 1235 Henoch–Sch€ onlein purpura (HSP) 1105 hyperthyroidism 722 hypothyroidism 706 infective endocarditis 69 intestinal transplantation (ITx) 1272, 1273, 1274 liver transplantation 1261 neurocysticercosis (NCC) 1448–1449 neuropsychiatric systemic lupus erythematosus (NPSLE) 465 neurosarcoidosis 311–312, 323 obstructive sleep apnea syndrome (OSAS) 259 pancreas/small bowel transplantation 1278 posterior reversible encephalopathy syndrome (PRES) 1696 psychogenic nonepileptic 180–181 reversible cerebral vasoconstriction syndrome (RCVS) 1728 small bowel transplantation 1287–1288 treatment 846–847, 1221 Seldinger technique 41 Selective COX-2 inhibitors 1649 Selective nerve root block (SNRB) 1642 Selective serotonin norepinephrine reuptake inhibitors (SSNRIs) 776, 781 Selective serotonin reuptake inhibitors (SSRIs) 519, 520, 678–679, 781, 1642, 1651 Selegiline 1641 Selenium 31 deficiency 591 Selenocosmiinae 994 Semple vaccine 1554 Semustine (methyl-CCNU) 1208–1209 Sensorineural hearing loss (SNHL) 201, 1544

INDEX Sensory/sensory motor polyneuropathy 353, 774 Sepsis 1694 Sepsis syndrome 281 Sequential compression devices (SCDs) 291, 294–295, 296, 297, 298–299 Serial Dotting Test (SDT) 663–664, 664 Serotonin 3 receptor antagonists 636–637 Serotonin 5-HT3 receptor antagonists 519, 522 Serotonin reuptake inhibitors 187 Serotonin syndrome (SS) 639, 949–951, 950, 1651 treatment 951 Serotonin-norepinephrine reuptake inhibitors (SNRIs) 519, 520–521, 1642 Sertindole 1642 Sertraline 520 Serum angiotensin-converting enzyme (SACE) 314 Serum creatine kinase (sCK) activity 501 Setrons 636–637, 639 Severe combined immunodeficiency (SCID) 832 Severe hypermagnesemia 871 Sevoflurane 1626, 1627, 1630–1631 SF-36 questionnaire (health-related quality of life) 507, 514, 536, 868–869 Sheehan syndrome 756–757, 1604–1605 Shellfish 988 Shiga toxin (Stx) 1115, 1120 Shiga toxin-producing Escherichia coli (STEC) 1113–1114, 1114, 1115, 1118 Shigella spp, hemolytic uremic syndrome (HUS) 1113–1114, 1114, 1120 Shingles see Herpes zoster Shock 1694 Shock liver 645–646 Short bowel syndrome (SBS) 1286, 1305–1307 Shunt-associated meningitis 1369 Sick sinus syndrome (SSS) 130, 141 Sickle cell disease (SCD) 1015–1027 clinical findings 1015–1016 genetics 1018–1019 historical perspective 1015 laboratory investigations 1016–1017 management 1020–1022 natural history 1016 neuroimaging 1017–1018 pathology 1019–1020 Sildenafil 782, 1654 Silent cerebral infarct 1016 Silent lesions 77 Silent myocardial infarction 94 Simvastatin 1638 ‘Single child family’ (China) 1778–1779 Single-nucleotide polymorphisms (SMPs) 1362 Single-photon emission computed tomography (SPECT) 515, 1715 Sinus node dysfunction 140–141 Sipple syndrome see Multiple endocrine neoplasia (MEN), type 2A

Sirolimus (rapamune/rapamycin) 1246, 1275 adverse effects 676, 677–678 transplantation 1231, 1260, 1281–1282, 1289–1290 Sitagliptin 817, 820 Situational syncope 174 Sj€ ogren–Larsson syndrome (SLS) 1562, 1589–1590 clinical symptoms 1589 cutaneous 1589 neurologic 1589 ophthalmologic 1589 diagnosis/testing 1589 radiology 1589–1590 treatment 1590 Sj€ ogren’s syndrome (SS) autonomic nervous system (ANS) 471 central nervous system (CNS) 470 muscle involvement 471 neurologic complications 464, 470 peripheral nervous system (PNS) 470–471 treatment 471 Skeletal manifestations hyperthyroid myopathy 713–714 primary hyperparathyroidism (PHPT) 867 Skin biopsy 1367 Skin lesions, Behc¸et’s syndrome (BS) 1704 Skull base, metastases 345 Paget’s disease of bone (PDB) 530 Skull fractures depressed 1760 repair of depressed 1760 traumatic brain injury (TBI) 1758 ‘Slapped cheek’ rash 1351 Sleep-related disorders 257 dialysis patients 398 hypothyroidism 708 nonobstructive idiopathic alveolar hypoventilation 265 sleep apnea syndrome (SAS) 398, 556 ‘sleep attacks’/sleepiness 177, 180–181, 184 sleeping sickness, African 1412, 1413, 1777 see also Central sleep apnea (CSA); Obstructive sleep apnea (OSA)/ syndrome (OSAS) Sleep-related hypoventilation /hypoxemia, lower airway obstruction 265–266 neuromuscular/chest wall disorders 265, 266 pulmonary parenchymal/vascular pathology 266 Small bowel transplantation 1285–1290 diagnostic evaluation 1289 neurologic complications 1277–1278 perioperative 1286–1287 postoperative 1278–1279, 1287–1288, 1287 short bowel syndrome 1286

I39 Small bowel transplantation (Continued ) total parenteral nutrition (TPN) 1286 neuropathology 1288, 1289 period preceding 1277 treatment 1289–1290 Small fiber polyneuropathy 774 Small tyrosine kinase inhibitors 1205, 1213 Small-cell lung cancers (SCLC) antibodies 1162–1163 brain metastases 1143–1144, 1146, 1150, 1151 Lambert–Eaton myasthenic syndrome (LEMS) 1171 limbic encephalitis (LE) 1168, 1169 subacute cerebellar degeneration (SCD) 1164 subacute sensory neuropathy (SSN) 1170 see also Lung cancer Smallpox vaccine 1552 Small-vessel encephalitis 1577–1578 Smoking 257 Smoldering myeloma (SM) 1031–1032, 1083, 1086, 1088 Snakes see under Venomous bites Sneddon’s syndrome (SS) 1562, 1566–1567 Snoring 253–254 Society of Critical Care Medicine (SCCM) 951 Sodium nitroprusside 165, 165, 1636, 1697 Sodium oxybate 522 Solitary plasmacytoma 1083, 1084, 1089, 1092 extramedullary 1032 SOLVD (Studies of Left Ventricular Dysfunction) trial 111–112, 114, 119 Somatosensory evoked potentials (SSEPs) 1630–1631 cardiac arrest 32–33 Somatostatin 810–811 Somatostatin analogs (SSA) 697, 810–811 Somatropin 810, 811–812 Somatropin agonists 811–812 Somatropin antagonists 812 Sones technique 41 Sorafenib 1213 SOSTM1 gene 532–533 Sotalol 132, 136 South American trypanosomiasis (Chagas disease) 1413–1414 SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial 105 Sparganosis 1427–1428 clinical manifestations 1428 diagnosis 1428 epidemiology 1427 pathogen 1427–1428 treatment 1428 Speech apraxia 1272 Spiders see under Venomous bites Spinal arachnoiditis 1450 Spinal cord disorders 247–248, 1331–1332, 1616 compression 964, 1186, 1186

I40 Spinal cord disorders (Continued ) ischemia see Cerebral/spinal cord ischemia leukemias 1040 lymphomas 1035–1036 myelopathy 964 neurocysticercosis 1451–1453 neurosyphilis 1465, 1465 sarcoidosis 312 tropics see Tropical myelopathy tuberculosis (TB) 1495–1496 Spinal cord injury (SCI) 794, 796, 1761–1767 clinical evaluation 1762–1763, 1764 epidemiology 1761 etiology 1521, 1522 imaging 1763–1764, 1765 management 1764–1767 acute 1764–1766 surgical 1766–1767 pathophysiology 1761–1762 without radiographic abnormality (SCIWORA) 1761 Spinal epidural abscess 1532, 1532 Spinal epidural metastases 340–343 incidence/clinical features 340–341, 341 treatment 341–343 Spinal fractures, acute 455 Spinal headache 1747 Spinal intramedullary metastases 343 Spinal muscular atrophy (SMA) 277 Spinal neurocysticercosis 1538 Spinal stenosis 541–550 causes 542 classification 541 definition 541 diagnosis 543–546 differential 545–546 neurophysiology 545 physical examination 543–544 symptoms 543 epidemiology 541–542 historical perspective 541 imaging 544–545 computed tomography (CT) 544–545, 544 magnetic resonance (MRI) 545, 545 radiographs 544 management 546–547 operative 546–547, 547, 548 nonoperative 546 outcome 547–548 pathophysiology 542–543 claudication 542–543 myelopathy 543 narrowing/stenosis 542, 542 spondyloarthropathies 457 Spinal syndromes, fungal infection 1386 Spinal vascular syphilis 1534 Spine Injury Study Group 1761–1762 Spine, Paget’s disease of bone (PDB) 531, 535 Spinocerebellar ataxia, Machado Joseph’s 794

INDEX Spirochaeta pallida 1461 Spirochetal myelopathy 1532–1535 Spirometra spp 1422, 1427–1428 Spirometra mansoni 1431 Spironolactone 764–765 Spondylitis, tuberculous 1495–1496 Spondyloarthritis, acute myelopathy 1524–1525 Spondylodiscitis 79 Spondyloepiphyseal dysplasia 444 Spontaneous carotid-cavernous fistula 567, 574 Spontaneous meningitis, adults 1369 Sporadic inclusion body myositis (sIBM) see Idiopathic inflammatory myopathy (IIM) Sri Lankan hump-nosed pit viper (Hypnale) 992–993 ST elevation MI (STEMI) 93, 101 ‘Staggers’ 962 Stanford Sleepiness Scale 260 Staphylococcus spp 68 Staphylococcus aureus 1369, 1532, 1532 see also Infective endocarditis Staphylococcus epidermidis 67 STARFlex closure device 113 Starr–Edwards valves 65 ‘Starry sky’ appearance 1537 Statins 1636–1637, 1638 Status cataplecticus 180–181 Status epilepticus (SE) 8 Stem cell transplantation (SCT) 1009, 1035 Stereotactic biopsy 1149 Stereotactic radiosurgery (SRS) 1189, 1191–1192 brain metastases 338–339, 1151–1152 Steroidogenesis, impaired 756–757 Steroids 1173, 1513–1514, 1628–1629, 1676 adverse effects 601, 1201, 1246, 1647 bacterial meningitis 1369–1370, 1371 cerebral vasculitis 479, 483 giant cell arteritis (GCA) 229, 481 neuro-Behc¸et syndrome (NBS) 1719–1720 transplantation 1231, 1268, 1274 tuberculosis (TB) 1490–1493 Stiff man syndrome (SMS) 352, 410–411, 614 ‘Stocking and glove ’ pattern 774 STOP (Stroke Prevention Trial in Sickle Cell Anemia) study 1018, 1020, 1021–1022 STOP II 1020 Streptococcus spp 1532 Streptococcus agalactiae 1361–1362, 1367 Streptococcus bovis 77, 81 Streptococcus pneumoniae 1367, 1369, 1777 bacterial meningitis 1361–1362, 1369, 1372, 1373 hemolytic uremic syndrome (HUS) 1114, 1114, 1115, 1120 Streptococcus suis 1369 Streptococcus viridans 79, 81 Streptokinase 104

Streptomycin (SM) 1490, 1491, 1492 Streptozotocin 1208–1209 Stress cardiomyopathy (Takotsubo cardiomyopathy/apical ballooning syndrome ) 6, 20, 22, 22, 26, 115–117 ‘String of beads’ appearance 1650 Stroke aortic surgery 234 arrhythmia 129–130 arterial ischemic 405–407, 408–409 cardiac surgery 54–55 coronary artery bypass grafting (CABG) 93, 198 developing world 1777–1778 dialysis patients 400 electrophysiologic procedures 142 essential thrombocythemia (ET) 1076 external cardioversion 139–140 heart transplantation 1233, 1235 hypertension 165 hyperthyroidism 723–724 obstructive sleep apnea syndrome (OSAS) 258 pregnancy see under Pregnancy primary myelofibrosis (PMF) 1078 respiratory failure (RF) 275, 275 sickle cell disease (SCD) 1015–1016 sudden death after 23 syndromes, fungal infection 1386 valvular surgery 199–200 venous thromboembolism (VTE) 291–292 see also Acute ischemic stroke; Acute myocardial infarction (AMI); Arterial ischemic stroke (AIS), risks; Cardiomyopathy Stroke Data Bank 129 Strongylida hookworms 1432–1433 Strongyloides 1287–1288 Strongyloides stercoralis 1435–1436 clinical manifestations 1435 diagnosis 1435–1436 epidemiology 1435 hyperinfection syndrome 1429 pathogen 1435 therapy 1436 Sturge–Weber syndrome (SWS) 1562, 1570–1571 clinical manifestations 1570–1571, 1570 ophthalmologic 1571 radiologic features 1570, 1571 treatment 1571 Subacute cerebellar degeneration (SCD) 1160, 1160, 1163–1165 autoantibodies 1164–1165 clinical/biological characteristics 1163 onconeuronal antibodies (ON-Abs) 1163 CV2/CRMP5-Abs 1164 Hu-Abs 1164 Ri-Abs 1164 Tr-Abs 1161, 1164 VGCC-Abs 1164 Yo-Abs 1163–1164 seronegative 1165

INDEX Subacute combined degeneration (SCD) 590, 919, 929, 934–935, 1542 spinal cord 927 Subacute measles encephalitis 1346, 1348 Subacute sclerosing panencephalitis (SSPE) 1345, 1346, 1346 treatment 1348–1349 Subacute sensory neuronopathy (SSN) 352, 876, 1160, 1160 antibodies 1162–1163 Subarachnoid hemorrhage (SAH) 116, 298, 1629 pregnancy 1602–1604 reversible cerebral vasoconstriction syndrome (RCVS) 1730, 1734 vascular/intensive care neurology 5–6, 6 Subarachnoid neurocysticercosis 1451, 1453 Subclavian steal syndrome (SSS) 175, 198 Subcortical structures breathing 245–247, 247 disease 245–247, 247 Subcutaneous neurofibromas 1581–1582 Subdural hematomas (SDH) 387, 554, 1752, 1753, 1760, 1761 Succinylcholine 1628 Sudden cardiac death (SCD) 19–24 classification 19 clinical manifestations 21–22 electrical conduction abnormalities 21–22, 21 stress cardiomyography 22, 22 definition 19–20 historical perspective 19 pathophysiology/histopathology 20 precipitants 20–21, 20 preventive strategies 23 specific scenarios 22–23 Sudden death in adults 556 in children 556 unexplained, in epilepsy (SUDEP) 8, 22–23 Sufentanil 1626 Suffocation 254 Sulfadiazine 1324–1325, 1325 Sulfamethoxazole see Trimethoprim/ sulfamethoxazole (TMP-SMX, TMP-SMZ) Sulfonamides 818, 1646 Sulfonylureas (SU) 816, 820, 1654 Sunitinib 1213 Superficial siderosis (SS) 861 Superficial venous thrombosis (SVT) see Venous thromboembolism (VTE) Supraventricular arrhythmias 153 Supraventricular tachycardia 130 Suramin 1200, 1204, 1652 Surgery, cardiac see Cardiac surgery/ interventions Susac syndrome 1717

Sustained Treatment of Paroxysmal-AF trial 157 Sweet disease (SD) 1717 SWITCH (Stroke with Transfusions Changing to Hydroxyurea) trial 1021–1022 Sydenham’s chorea 1780 SYDNEY 2 (Symptomatic Diabetic Neuropathy) trial 779 Sympathetic outflow tracts, central nervous system (CNS) 4 Symptomatic hydrocephalus 345 Synacthen test 759 Synchronized intermittent mandatory ventilation (SIMV) 279 Synchronous presentation 1144 Syncope see Transient loss of consciousness (TLOC)/syncope Syndrome of inappropriate secretion of antidiuretic hormone (SIADH) 842, 843, 1486 hypernatremia 372 hyponatremia 365, 367–369, 368 Syphilis aortitis 232–233 clinical manifestations 1464 meningovascular 1464 see also Neurosyphilis Syphilitic meningomyelitis 1464–1465, 1534 Syringobulbia-myelia 557, 557 Systemic amyloidosis, clinical presentation 1037 Systemic disorders, nephrotic syndrome 407 Systemic inflammatory response syndrome (SIRS) 650 Systemic lupus erythematosus (SLE) 442, 463–468 antiphospholipid syndrome (APLS) 466 incidence 464 management 467–468 neurologic manifestations 464 neuropsychiatric syndromes see Neuropsychiatric systemic lupus erythematosus (NPSLE) Systemic Lupus International Collaborating Clinics (SLICC) 464 Systemic sclerosis (SSc) see Scleroderma Systemic vasculitis 458

T Tabes dorsalis 1465, 1533–1534, 1534 Tacrolimus 675, 676, 1275 neurotoxicity 1245, 1269–1270, 1271, 1278–1279 central nervous system (CNS) 1281–1282 small bowel transplantation 1287–1288 transplantation 1231, 1260, 1268, 1274, 1280 Tadalafil 782, 1654 Taenia spp 1428 Taenia multiceps 1428

I41 Taenia solium (pig tapeworm) 1422, 1536–1537, 1777 see also Neurocysticercosis (NCC) Taeniasis 1445 Taipan (Oxyuranus) 992 Takatsuki syndrome see POEMS syndrome Takayasu disease 477–479 classification 476, 478 clinical features 478–479, 478 differential diagnosis 479 prognosis 479 treatment 479 Takotsubo cardiomyopathy see Stress cardiomyopathy Tamoxifen 1152–1153, 1201, 1212, 1655 Tapeworms 1414, 1422–1428 fish see Diphyllobothrium latum pig see Taenia solium Tardive dyskinesias (TD) 635, 638 Targeted therapies 1136–1137, 1204–1205, 1212–1213 molecular 339–340, 1152–1153 Taxanes 1135, 1152 adverse effects 1135–1136, 1202, 1210 Tegaserod 638 Telangiectasias, mucocutaneous 1571–1572, 1571 Telbivudine (Tyzeka®) 676, 680 Temozolomide 339, 1184–1185, 1209 Temperature see Body temperature Temporal arteritis see Giant cell arteritis (GCA) Tenatoprazole 638–639 Tenecteplase 31, 104 Teniposide 1203, 1210–1211 Tenoxicam 965 10/66 group, dementia 1778–1779 Teriparatide 813, 814, 879 Terminal arbor degeneration 1202 Tertiary care, developing world 1774 Tertiary hyperparathyroidism 742–743, 744 Testicular germ cell tumors 787 Testis see Ovaries/testis, disease of Tetanus 1506–1509 clinical findings 1506–1508, 1507 complications 1508 differential diagnosis 1508 immunization 1509 diphtheria-tetanus-pertussis (DTP) vaccine 1358, 1550, 1555–1556, 1651 management 1508–1509 autonomic dysfunction 1509 intensive care unit (ICU) 1509 resource poor settings 1508–1509 natural history 1508 prophylaxis 1509 Tetany 377, 377 Tetracycline 625, 1337, 1468–1469, 1646 Tetrahydrofolate (THF) 917, 928 Tetratiomolybdate 856 Thalidomide 1136, 1513–1514 adverse effects 1200, 1204, 1212, 1652 multiple myeloma (MM) 1032, 1089, 1090

I42 Thalidomide-induced peripheral neuropathy (TiPN) 1090 Theophylline 1655 Thermal injuries 981–986 clinical findings 981–982 future directions 985 historical perspective 981 laboratory investigations 982–983 electrocardiography (ECG) monitoring 982, 983 myoglobinuria 982–983 management 983–985 excision/wound care 984–985 fluid resuscitation 983–984 myoglobinuria clearance 984 rehabilitation 985 trauma, associated 984 natural history 982 neuroimaging 983 pathology 983, 983 Thermogard VP® system 954 ThermoSuit® system 954 Thiamazole 813 Thiamin see Vitamin B1 deficiency Thiazide diuretics 745 Thiazolidinediones 819 Thienopyridine therapy 101 Thimerosal (thiomersal) 1556 Thiobarbiturates 1624 Thionamides 813–814 6-Thiopurines 1134 Thiopental 31, 1624, 1625 Thiotepa 1201, 1209 Thor inhibitors, heart transplantation 1231 Thoracic aortic aneurysms 225–226 Thoracic-lumbar-sacral orthotic (TLSO) 1767 Thoracoabdominal aortic aneurysm (TAAA) 226, 227, 233–234, 233 Thrombin inhibitors 139, 295 Thromboembolic stroke 964 Thromboembolism, catheter ablation atrial fibrillation (AF) 151–153, 152 during 154, 155, 156 supraventricular/ventricular arrhythmias 153 Thromboembolism, venous see Venous thromboembolism (VTE) Thrombolysis acute coronary syndrome (ACS) 95, 103–104, 104 acute ischemic stroke 86 acute myocardial infarction 44–45, 45 Thrombolysis In Myocardial Infarction (TIMI) study 101–103 Thrombolytic drugs, adverse effects 1637–1638 Thrombophilic states 1061–1072 arterial ischemic stroke (AIS), risks 1066–1068 acquired thrombophilia 1067 children 1067–1068 inherited thrombophilia 1066–1067 mixed thrombophilia 1067 paradoxical embolism 1068

INDEX Thrombophilic states (Continued ) cerebral venous sinus thrombosis (CVST), risks 1064–1066 acquired thrombophilia 1065 children 1065–1066 epidemiology/symptoms 1064 inherited thrombophilia 1064–1065, 1064 mixed thrombophilia 1065 definition 1061 venous thromboembolism (VTE), risks 1061–1064, 1062 acquired thrombophilia 1063 inherited thrombophilia 1061–1063 lipoprotein(a) 1064 mixed thrombophilia 1063–1064 Thromboprophylaxis 294–296, 295, 299–300 Thrombosis, polycythemia vera (PV) 1075 Thrombotic microangiopathy 1113 Thrombotic thrombocytopenic purpura (TTP) 1005, 1113, 1119 epidemiology/etiology 1114–1115 hematologic disorders 1129 treatment 1120 Thromboxane synthase inhibitors 1129–1130 Thrombus 111–112 Thunderclap headache 1650 see also under Reversible cerebral vasoconstriction syndrome (RCVS) Thyroid disease 703–735 miscellaneous disorders 726 ophthalmopathy see Graves’ ophthalmopathy see also Hyperthyroidism; Hypothyroidism Thyroid hormones 812–813, 813 Thyroid storm 721–722 Thyroid-stimulating hormone (TSH) 686 acromegaly 691–692 central hypothyroidism (CH) 689 excess 693 -producing adenomas 693 Thyrotoxic hypokalemic periodic paralysis (TPP) 719–721 clinical features 719–720 neurologic features 719 non-neurologic features 719–720 diagnosis 720 management 720–721, 720 emergency treatment 721 prevention 721 underlying hyperthyroidism 721 pathophysiology 720 Thyrotropin (TSH) see Thyroid stimulating hormone (TSH) Thyroxine 711 Tiabendazole 1433, 1435 Tiagabine 846 adverse effects 1640, 1640 elimination 418, 425, 426, 427 Ticagrelor 1129 Tickborne encephalitis virus 1378 diagnosis 1380

Ticlopidine (Ticlid®) 1129, 1639 Tiger snake (Notechis) 992 Tilt-table testing 517 Tinel’s sign 1510 Tinzaparin 299 Tipifarnib 1205 TIPSS (transjugular intrahepatic portosystemic shunt) 662 Tirofiban 1639 Tityus 988, 993–994 Tityus serrulatus 993–994 Tizanidine 1332, 1640 TNM (tumor-nodes-metastasis) system 335 TO-ACT (Thrombolysis Or Anticoagulation for Cerebral Venous Thrombosis) trial 1605–1606 Tocainide 132, 136 Tocilizumab 459, 479, 1719 Tolvaptan 810, 812 Topiramate 1640, 1640 elimination 418, 424, 425, 427 Topoisomerase inhibitors 1135, 1204, 1212 Topotecan 1212 Tositumomab (Bexxar®) 1136 Total body irradiation (TBI) 1295–1296, 1299, 1300 Total iron binding capacity (TIBC) 1008 Total parenteral nutrition (TPN) 1286, 1305–1307 Tourette’s syndrome, management 1644 Toxic myeloneuropathy 1544–1545 Toxocara canis/cati 1431, 1434–1435, 1538, 1539 clinical manifestations 1434–1435 diagnosis 1435 epidemiology 1434 pathogen 1434 therapy 1435 Toxocariasis 1539 Toxoplasma gondii 1232, 1248 see also Toxoplasmosis entries Toxoplasmosis, HIV-associated 1323–1326 clinical manifestations 1323 human infection 1323 laboratory diagnosis 1324 neuroimaging 1324, 1324 prophylaxis 1325–1326, 1325 Toxoplasma encephalitis 1324 treatment 1324–1325, 1325 response 1325 Toxoplasmosis, renal transplantation 1248, 1248, 1252 Tr-Abs (antibodies), subacute cerebellar degeneration (SCD) 1161, 1164 Tracheobronchial secretions 283 Training, developing world 1774–1775 Train-of-four muscle twitch assessment 30–31 Tramadol 519, 522, 780–781 Tranexamic acid (AMCA) 1128 Trans-4-hydroxy-2-nonenal (HNE) 831

INDEX Transcranial Doppler (TCD) monitoring 155 Transesophageal echocardiography (TEE) 7–8, 52, 139–140 Transfusion, reactions/risks 1127–1128 Transfusion-related acute lung injury (TRALI) 649–650, 1127–1128 Transient cortical blindness 44, 44, 197 Transient ischemic attacks (TIAs) cardiomyopathy 111, 113–114, 118–119 dialysis patients 400 essential thrombocythemia (ET) 1075–1076 heart transplantation 1233 infective endocarditis 67 neurosarcoidosis 311 polycythemia vera (PV) 1074–1075 primary myelofibrosis (PMF) 1078 syncope 175 vertebrobasilar 181 Transient loss of consciousness (TLOC)/ syncope 169–193 causes 170–181, 170 medical 180 neurologic 176, 177, 179–180 syncopal, cerebral hypoperfusion 170–176 nonsyncopal 176–181, 179 definitions 169 diagnostic workup 184–186 clinical history 179, 185 investigations 185–186 physical examination 185 differential diagnosis 181–184, 181 ‘absences’/‘absent-mindedness’ 184 ‘drop attacks’ 181–184 epidemiology 169–170 recognition 179 treatment 186–188 syncopal 186–187 nonsyncopal 170, 187 driving restrictions 187–188 Transient unresponsiveness in elderly 183 Transplantation acute liver failure (ALF) 649 hemolytic uremic syndrome (HUS) 1120 see also specific organs Trastuzumab 1152–1153, 1205 Trauma acute myelopathy 1524 see also Neurotraumatology Traumatic brain injury (TBI) 6–7, 298, 688, 1751–1761 bacterial meningitis 1372 clinical evaluation 1754–1755, 1754 developing world 1780 epidemiology 1751–1752, 1752 imaging 1755–1757, 1755, 1756, 1764 Lund concept of pathophysiology-based management 1753 management 1757–1760 acute medical 1757–1758 intracranial hemorrhage (ICH) 1759

Traumatic brain injury (TBI) (Continued ) intracranial pressure (ICP), increased 1758–1760 surgical guidelines 1760 neuroanesthesia 1628 outcomes 1760–1761 pathophysiology 1752–1754 Traumatic craniovertebral subluxation 438, 438, 439 Traumatic transient loss of consciousness (TLOC) 181 Trazodone 1642 Trematodes (flukes) 1414, 1419–1422 Tremor 715 Treponema 1532 Treponema pallidum see Neurosyphilis Tretinoin 1212–1213 Triazoles 1649 Trichinella spp 1433–1434 Trichinellosis 1433–1434 clinical manifestations 1434 diagnosis 1434 pathogen 1434 therapy 1434 Trichoderma polysporum 1299–1300 Triclabendazole 1422 Tricyclic antidepressants (TCA) adverse effects 1642 diabetic neuropathy 780, 781, 781 fibromyalgia 519–520, 519 Trientine 856, 857 Triethylenetetramine 856–857 Trigeminal nerve (cranial nerve V) 307 Trigeminal neuralgia, radiotherapy (RT) 1189, 1190 Trimeresurus complex 992–993 Trimethoprim 1646 Trimethoprim-sulfamethoxazole (TMPSMX, TMP-SMZ) 628, 1246, 1247, 1248, 1532 toxoplasmosis 1323, 1325, 1325 Triple A (Allgrove) syndrome 756 Triple-symptom complex 1703 Triptans 8, 1274, 1571, 1651 TRITON-TIMI 38 (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with PrasugrelThrombolysis in Myocardial Infarction) trial 101 Trochlear nerve (cranial nerve IV) 307 Troglitazone 819 TROICA (Thrombolysis in Cardiac Arrest) trial 31 Tropheryma whipplei 80–81, 627, 628 Tropical myeloneuropathy 1521–1522 ataxic neuropathy (TAN) 1542–1543 historical perspective 1523 nutritional 1540–1544 toxic 1544–1545 Tropical myelopathy 1521–1548 acute myelopathy, causes 1522, 1524–1525 disc herniation/spondyloarthritis 1524–1525

I43 Tropical myelopathy (Continued ) trauma 1524 vascular 1525 clinical aspects 1524 etiologies 1522 historical perspective 1522–1524, 1523 immune-inflammatory disorders 1540 acute transverse myelitis 1540 multiple sclerosis (MS) 1540 infectious myelopathy 1522, 1525–1540 bacterial 1530–1532 chronic retroviral 1529–1530 fungal 1535 parasitic 1535–1540 spirochetal 1532–1535 vacuolar see under HIV-infected patients viral 1527 nutritional myeloneuropathy 1540–1544 toxic- 1542–1544 Vitamin B12 see vitamin B12 (cobalamin (Cbl)) deficiency toxic myeloneuropathy 1544–1545 cyanide 1544–1545 fluorosis 1547–1546 lathyrism 1547–1546 Tropical (nutritional) amblyopia 1543 Tropical sprue (TS) 625 Tropisetron 522, 636 Trousseau’s sign 377, 743 Trypanosoma 1777 Trypanosoma brucei 1412–1413 Trypanosoma brucei gambiense 1412–1413 Trypanosoma brucei rhodesiense 1412–1413 Trypanosoma cruzi 1407, 1413–1414 TSC1 gene 1584 TSC2 gene 1584 Tsetse flies 1412 Tuberculoid tuberculoid leprosy 1573–1575 Tuberculomas (tuberculous granulomas) 1149, 1492–1494, 1493 Tuberculosis (TB), central nervous system (CNS) 1485–1499 clinical findings 1486–1496 developing world 1777 etiologic agent 1485 HIV see under HIV-infected patients pathogenesis 1485–1486, 1486 renal transplantation 1247–1248, 1252 spinal cord 1530, 1530, 1531 Tuberculosis-associated immune reconstitution inflammatory syndrome (TB-IRIS) 1495 Tuberculous abscess 1494, 1494 Tuberculous meningitis (TBM) 1486–1492 associated features 1487 cerebrospinal fluid (CSF) findings 1488, 1488 complications 1489–1490 diagnosis 1488–1489 management 1490–1492, 1491 multidrug-resistant (MDR) meningitis 1491, 1492 neuroimaging 1489, 1489

I44 Tuberculous meningitis (TBM) (Continued ) prognosis 1492 signs/symptoms 1487 Tuberculous myelitis 1495 Tuberculous spondylitis 1495–1496 Tuberous sclerosis complex (TSC) 1562, 1584–1586 clinical symptoms 1584–1585 cutaneous 1584, 1585 neurologic 1584–1585 diagnosis/genetic testing 1586, 1586 Tumor necrosis factor (TNF) blockade 453 Tumor necrosis factor-a (TNF-a) 507 inhibitors 481 Tumors brain see Brain tumors cardiac see Cardiac tumors central nervous system (CNS) 1250–1251, 1263 flare syndrome 1209 identification 1172 neurologic 1582–1583, 1583, 1584 ovarian 789, 791–792 pituitary see Pituitary tumors primary 1143–1144 radiotherapy (RT) 1184–1189 resection 1149 spinal cord 1616 TNM (tumor-nodes-metastasis) system 335 Turner syndrome, genetics 53 Tyrosine kinase inhibitors 1205, 1213, 1652

U Ulcerative colitis (UC) see Inflammatory bowel diseases (IBD) Ulcers genital 1704 oral 1704 Ultrasound 1733 venous duplex (VDU) 291, 293, 294, 300 UMOD gene 827–829 Undersea and Hyperbaric Medical Society 156 Unfractionated heparin (UFH) 137, 137, 1077, 1130, 1131, 1132 adverse effects 137, 137, 1638 hematologic disorders 1077, 1130, 1131, 1132 intracranial hemorrhage (ICH) 297, 298–299 venous thromboembolism (VTE) 295, 296–297, 300 Unilateral lower compartment syndrome 592 United Kingdom Prospective Diabetes Study (UKPDS) 773–774, 778–779 United Network for Organ Sharing (UNOS) 1238 Unstable angina (UA) 93, 99–100 Unsteady gait 1145 UPB1 gene 835 Upper extremity mononeuropathy/ radiculopathy 1608–1609 Urapidil 1697

INDEX Urea derivatives 818 Urea transporters (UTs) 396–397 Ureidopropionase deficiency 834, 835 Uremic encephalopathy 383–385, 384 acute vs chronic 383–384 clinical symptoms 384, 385 diagnosis 384–385 dialysis patients 395–396 pathogenesis 384 therapy 385, 385 Uremic myopathy, renal disease 391 Uremic polyneuropathy (PNP) 388–390 clinical picture 389 diagnosis 389 pathogenesis 389 therapy 389–390 Uridine-5-monophosphate (UMP) 827, 833–834 synthase 833 Urtoxazumab 1120 US Navy Diving Manual 962, 965 US Navy Treatment Table 6 protocol 156 Uveo-parotid fever 305 Uvulopalatopharyngoplasty (UPPP) 262

V Vaccinations 1549–1557 bacterial vaccines 1554–1556 viral vaccines 1550–1554 mechanisms of action 1550, 1550 Vaccine Adverse Events Reporting System (VAERS) 1549, 1551, 1553, 1554, 1556 Vaccine Safety Datalink (VSD) 1549, 1553 VACTERL (vertebral anomalies, imperforate anus, cardiac anomalies, tracheoesophageal fistula, renal anomalies, limb anomalies) 53 Vacuolar myelopathy (VM) see under HIV-infected patients Vagus nerve (cranial nerve X) 308 Valaciclovir 1380–1381 Valdecoxib 580 Valganciclovir 1232, 1331 VALIANT (VALsartan In Acute myocardial iNfarcTion) trial 94, 100 Valproic acid (valproate) 846, 847, 1324–1325 adverse effects 1640, 1640 brain metastases 337, 1153 elimination 418, 420–421, 425, 427 Valsalva maneuver 51–52, 1738 Valvular heart disease 61–74 anticoagulation, complications 65–66 calcific 62–63 infective endocarditis see Infective endocarditis mitral valve prolapse (MVP) 63 noninfective endocarditis 69–70 prosthetic heart valves 63–65 bioprosthetic 64–65 mechanical heart valves 65 rheumatic (RVHD) 61–62 Valvular surgery 194, 195, 199–200

Vancomycin 1369, 1371, 1379–1380 Vapreotide 810 Vardenafil 782, 1654 Varicella zoster virus (VZV) encephalitis 1377, 1378, 1379 diagnosis 1380 treatment 1381 infection heart transplantation 1232 mononeuropathy 1333–1334 renal transplantation 1249 treatment 1380 vaccine 1550, 1551–1552, 1651 Vascular compression theory 543 Vascular conditions acute myelopathy 1525 dementia (VaD) 9, 931–932, 1778 endothelial dysfunction 1595, 1596–1598 hemostasis 1596 leukemias 1040–1041 lymphomas 1037–1038 neurology see Cardiology, vascular/ intensive care neurology neuropathy 310–311, 311, 451 pattern reaction 1719 pseudoxanthoma elasticum (PXE) 1568 ‘steal’ syndrome 877–878 zoster 1569 Vascular Ehlers–Danlos syndrome (vEDS) 565–568 description 565–567, 566, 567 diagnostic criteria 567 neurologic complications 567–568 Vasculature in Uppsala Seniors, perspective investigation (PIVUS) 115 Vasculitis 598–599 see also Cerebral vasculitis Vasopressin 812 Vasopressin analogs 812 Vasopressin antagonists 812 Vasospasm, neurocardiogenic injury 20 Vasovagal syncope 174, 175 Velocardiofacial syndrome, genetics 52, 53 Venereal Disease Research Laboratory (VDRL) 1334–1336, 1533–1534 Venezuelan equine encephalitis virus 1378, 1380 Venlafaxine 520, 780, 1090 Venomous bites 987–1003 historical perspective 987 insect stings 995 clinical manifestations/treatment 995 natural toxins 996 pathophysiology 988–990 nervous system, effects 988–989 neurotoxins 989–990, 990 scorpions 988, 993–994 clinical manifestations 994 management 994 snakes 988, 990–993 elapidae 987, 991–992 epidemiology 990–991 management 996–997

INDEX Venomous bites (Continued ) viperidae 987, 992–993 spiders (Araneae) 988, 994–995 clinical effects 994–995 treatment 995 tick paralysis 988, 995–996 venom 987–988, 988 apparatus 987 Venous duplex ultrasonography (VDU) 291, 293, 294, 300 Venous emboli 51 Venous sinus thrombosis (VST) 1041 Venous thromboembolism (VTE) 289–304 epidemiology 289–292, 290 general principles 292–300 presentation/diagnosis 292–294, 294 risks 1061–1064, 1062 treatment issues 294–296 acute conditions 296 neurologic/neurosurgical disease 296–300 screening 300 thromboprophylaxis 294–296, 295, 299–300 Ventilators, weaning from 1240 Ventricula neurocysticercosis 1451 Ventricular arrhythmias, catheter ablation 153 Ventriculitis 1577–1578 Verapamil 132, 136, 1636, 1737–1738 Verotoxin 1115, 1117–1118 Vertebral artery dissection, decompression illness (DCI) 964 Vertebral canal stenosis 557, 558–559, 558 Vertebral column malalignment 559, 559, 560 Vertebral hemangiomas 1616 Vertebrobasilar transient ischemic attacks (TIAs) 181 Vertebroplasty, complications 1747–1748, 1748 Very long chain fatty acids (VLCFA) 759–761, 762 Very low density lipoproteins (VLDLs) 623–624 Vespa 995 Vespula vulgaris 995 Vestibular syncope 181–182 Vestibulocochlear nerve (cranial nerve VIII) 308 Veterans Affairs Cooperative Study Group on Antihypertensive Agents 161 Cooperative Study on Valvular Heart Disease 64 Diabetes Trial (VADT) 778–779 Normative Aging Study (USA) 931 VGCC-Abs (antibodies) 1161, 1164 VGKC-Abs (antibodies) 1161 limbic encephalitis (LE) 1166, 1167 Vigabatrin 846, 1584–1585, 1640 elimination 418, 425, 426–427, 427 Vildagliptin 817, 820 Vinblastine 1201–1202

Vinca alkaloids 1089, 1135, 1152 adverse effects 1200, 1201–1202, 1210 Vincristine 1089, 1090, 1184–1185, 1201–1202 Vindesine 1201–1202 Vinorelbine 1201–1202 Violin spiders 994 Viperidae 987, 992–993 Viperinae 992–993 Viral encephalitis developing world 1777 serology/CSF studies 1380 Viral infection, central nervous system (CNS) 1249–1250 Viral myelopathy 1527 Viral vaccines 1550–1554 Virchow, Rudolf 93 Visual evoked potentials (VEP) 315, 316 VITACOG trial 934 Vitamins absorption 622 adverse effects 1654–1655 see also Hydrosoluble vitamins Vitamin A deficiency, short bowel syndrome 1286 Vitamin B1 (thiamin) deficiency 891, 896–901 bariatric surgery 589 biochemical function 896 clinical findings 896–898 genetics 898 laboratory investigations 894, 898 management 900–901 natural sources 896 neuroimaging 898, 899 overview 892 pathology 898–900 toxicity 898 Vitamin B1 (thiamine) deficiency, short bowel syndrome 1286 Vitamin B2 (riboflavin) deficiency 901–902 chemical function 901 clinical findings 901–902 genetics 901, 902 headache 1274 laboratory investigations 894, 902 management 902 natural sources 901 neuroimaging 902 overview 892 pathology 902 toxicity 902 Vitamin B3 (niacin/nicotinic acid) deficiency 891, 902–904 bariatric surgery 591 biochemical function 902 clinical findings 903 genetics 903–904 laboratory investigations 894, 903 management 904 natural sources 902–903 neuroimaging 903 overview 892 pathology 904

I45 Vitamin B5 (pantothenic acid) deficiency 904–905 clinical findings 905 laboratory investigations 894, 905 management 905 natural sources 904 overview 892 short bowel syndrome 1286 Vitamin B6 (pyridoxine/pyridoxal) deficiency 779, 905–908 biochemical function 905 clinical findings 906–907 genetics 907 homocysteine concentration 931, 934 laboratory investigations 894, 907 management 907–908 natural sources 906 neuroimaging 907 overview 892 pathology 907 Vitamin B7 (biotin) deficiency, short bowel syndrome 1286 Vitamin B8 (biotin) deficiency laboratory investigations 894 overview 892 Vitamin B9 (folate) deficiency see Folic acid deficiency Vitamin B12 (cobalamin (Cbl)) deficiency 915–926, 1541–1542 absorption 1541 bariatric surgery 591 causes 588, 591–592 clinical manifestations 592 coenzyme form 1541 diagnosis 1542 epidemiology 1541 functions/kinetics 916–917, 916 hematologic disorders 1125–1126 hemolytic uremic syndrome (HUS) 1120 historical perspective 1541 investigations 592 megaloblastic anemia 1007 neurologic manifestations 1541–1542 neuropathology 1542 pathogenesis 1541 requirements/sources 915–916 short bowel syndrome 1286 terminology 915 treatment 1542 see also Folic acid deficiency Vitamin C (ascorbic acid) deficiency 891, 908–910 biochemical function 908 clinical findings 908–909 genetics 909 laboratory investigations 894, 909 management 909–910 neuroimaging 909 overview 892 pathology 909 Vitamin D deficiency bariatric surgery 591 calcium 865 central nervous system (CNS) 879–882 disorders 881–882 fibromyalgia 523

I46 Vitamin D deficiency (Continued ) homeostasis 737–738 hypercalcemia 741–742, 865–866 hypocalcemia 377, 742–743, 744, 745, 870 hypoparathyroidism 871–872 neurogenesis 880 production/presence 879–880 short bowel syndrome 1286 Vitamin E deficiency 623 short bowel syndrome 1286 Vitamin K treatment 1131–1132 Voglibose 818, 819 Vogt–Koyanagi-Harada syndrome (VKH) 1717 Volume control ventilation (VCV) 279 von Gierke disease 833 von Hippel-Lindau disease 765 von Recklinghausen’s neurofibromatosis see Neurofibromatosis type 1 (NF1) von Willebrand disease (VWD) 1045, 1046, 1056–1057 clinical presentation 1047, 1056 diagnosis 1056–1057 treatment 1055, 1057 types 1056 Voodoo’ Death (Cannon) 19 Voriconazole 1248, 1329–1330

W W198X gene 841 Waldenstr€om’s macroglobulinemia (WM) (lymphoplasmacytic lymphoma) 1033, 1083, 1085, 1086, 1093–1094 central nervous system (CNS) 1093–1094 clinical presentation 1037 peripheral nervous system (PNS) 1093 Wall motion abnormalities (WMA) 6 Wallenberg’s syndrome 437–438 WAPS (warfarin in the antiphospholipid syndrome) study 1067 Warfarin 62, 70, 113, 200, 295, 1131 adverse effects 137, 137, 138, 1638–1639 bleeding risk 122–123, 123 cardiomyopathy 118, 120, 121–122 intracranial hemorrhage (ICH) 1131–1132, 1131 valvular heart disease 65, 66 Warfarin-Aspirin Recurrent Stroke Study (WARSS) 112 Wasp stings 995 WATCH (Warfarin and Antiplatelet Therapy in Chronic Heart Failure) trial 120 WATCHMAN® (Left Atrial Appendage Closure Technology) device 143 Water restriction strategy 368–369 Waterhouse–Friederichsen syndrome 1363 Watershed cerebral infarction 131 Weakness muscle 184, 1252, 1357 see also Intensive care unit-acquired weakness (ICUAW), generalized

INDEX Wegener disease (ANCA-associated granulomatous vasculitis) 483–484 clinical features 484 Wells criteria, venous thromboembolism (VTE) 293–294 Wermer’s syndrome see Multiple endocrine neoplasia (MEN), type 1 Wernicke–Korsakoff syndrome 896, 897 Wernicke’s encephalopathy (WE) 386–387, 397 bone marrow transplantation 1299 intestinal transplantation (ITx) 1272 laboratory investigations 898 malabsorption 625–626 management 900 neuroimaging 898, 899 pathology 900 vitamin B1 589, 897, 899 West Haven criteria, encephalopathy 646 West Nile virus encephalitis 1378, 1379 diagnosis 1380 treatment 1381 renal transplantation 1249–1250, 1252 Western equine encephalitis virus 1378 diagnosis 1380 Whipple’s disease (WhD) 627–628 White matter abnormalities, gluten-related diseases (GRD) 612, 612 Whole killed vaccines 1550 Whole-body 18F-FDG PET scan 1149 Whole-brain radiation therapy (WBRT) 337 brain metastases 1150–1151, 1152 prophylactic 340 Widow spiders 994–995 Williams syndrome, genetics 53 Wilson’s disease (WD) 626, 851, 853, 854, 1257, 1780 clinical features 854–855 diagnosis 855–856, 856 physiopathology 854 treatment 856–857 WIN 3 ( Randomized Trial of Interventions to Improve Warfarin Adherence) trial 120 Wohlfahrtia 1436 Wolbachia 1429 Wolff–Parkinson–White (WFW) syndrome 130 Women with epilepsy (WWE) 1606–1607 Worcester Heart Attack Study 94 World Federation of Neurology (WFN) 1774–1775, 1778 World Headache Alliance 1776 World Health Organization (WHO) bilharziasis 1535 endocrine drugs 809 epilepsy 1775–1776 essential thrombocythemia (ET) 1076 leprosy 1512–1514 monoclonal gammopathy of undetermined significance (MGUS) 1031 multidrug-resistant (MDR) meningitis 1492

World Health Organization (WHO) (Continued ) multiple sclerosis (MS) 1779 myeloid and lymphoid neoplasms 1027, 1029 neurological disorders 1773 osteoporosis 875 paragonimiasis 1422 PNM system 1426–1427 polycythemia vera (PV) 1074 primary myelofibrosis (PMF) 1077–1078 rabies 1504–1506 stroke 1777–1778 syphilis 1468, 1469 tetanus 1506 tuberculosis (TB) 1485 vaccines 1556–1557 World Stroke Organization 1775 Wuchereria bancrofti 1429

X Xanthine oxidase deficiency (hereditary xanthinuria) 828, 833 Xeroderma pigmentosum (XP) 1562, 1579 clinical manifestations 1579 diagnosis/treatment 1579 Ximelagatran 139, 1639 X-linked cutis laxa see Occipital horn syndrome (OHS)

Y Yellow fever vaccine 1550, 1554, 1555 Yellow-bellied sea snake (Pelamis platurus) 992 Yersinia spp 1113–1114, 1114 Yo-Abs (antibodies) 1161, 1163 subacute cerebellar degeneration (SCD) 1163–1164 Yohimbine 781–782 Young Adult Myocardial Infarction and Ischemic Stroke (YAMIS) study 1068 Yttrium-90 (Y-90) 1136, 1189

Z Zidovudine 1340, 1340 Zinc salts 856–857 Ziprasidone 1642 Zivkovic study 1287–1288 Zoledronic acid (zoledronate) 536, 878 Zollinger–Ellison syndrome (ZES) 804–805 Zolpidem 522 Zona see Herpes zoster Zonisamide 1640 elimination 418, 425, 427–428, 427 Zopiclone 522 Zoster vaccine, adverse effects 1651 see also Herpes zoster (zona/shingles); Varicella zoster virus (VZV) Zygomycetes spp 1385, 1386, 1397 Zygomycosis 1385