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

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

Table of contents :
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

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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 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


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


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


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



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



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



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.


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.)



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).


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.)



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



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: ●

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


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












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



















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%


prostate cancer

Malignant thymoma and SCLC


75% 100%

66% 100%

50% 50%




SCA 24 (18–80) – 58%

14 1/3 25%*

na – 5%

64 (9–84) 1 12%


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%






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.


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).



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


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



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).


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



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 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).


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


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.


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]



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).


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).



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



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


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)


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).


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).


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.



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).


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 ( 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 ( Unlike bevacizumab, the neuropathy was most often observed after 1 year (50%) and 2 years (25%), which makes a cumulative effect likely.


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



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


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



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.


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.



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.



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.



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


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


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



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


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]



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


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



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


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.

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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 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


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]



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.


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


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.




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



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



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



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



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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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]



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



Table 85.1 Neurologic complications of liver transplantation over time


Time epoch






Peripheral nerve


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


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



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


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



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



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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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]



Table 86.1 Causes of intestinal failure requiring intestine transplantation Children


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



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.


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).


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.

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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: 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

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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 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]



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


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


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



Gastrostomy tube

Duodenojejunal anastomosis PV Aorta Vascular graft, SMV

PV Jejunostomy tube Vascular graft, SMA

Aortic Condult

Chimney ileostomy


Ileocolic anastomosis Transplanted Native




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


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,



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).


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).



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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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]



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



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

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

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


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



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).


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.


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


First choice


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.



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.


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.



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


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.



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).


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.


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.



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



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


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



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


Symptom progression

Classic presentation


Distal symmetric polyneuropathy


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.



Table 90.7 Stages of neurosyphilis Neurosyphilis stage


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



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



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

Table 90.11


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



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



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. 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


Abacavir Emtricitabine


Delavirdine Efavirenz

Didanosine Lamivudine Stavudine Etravirine


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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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]



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


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



(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


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.


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).


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,



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).


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


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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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.


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. en/index.html. World Health Organization (WHO) (2012b). Accessed 10/29/2012 diseases/mumps/en/. World Health Organization (WHO) (2012c). Accessed 10/29/2012. diseases/Rubella_map_schedule.jpg. World Health Organization (WHO) (2013). Accessed 10/22/2013. 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.



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


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).



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).



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.


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


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



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


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,



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


(>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



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,


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


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



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.



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



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]



Table 96.1 Rickettsiales (Rhizobiales), epidemiologic features

Clinical group


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


Cat scratch fever


Human monocytic ehrlichiosis


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


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


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


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



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



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


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



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).


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



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.



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]



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.



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,



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



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



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


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



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



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



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).


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


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



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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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]



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.)


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


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



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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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]



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


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.)



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