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Multiple Sclerosis 2 Edited by W. Ian McDonald, Ph.D., F.R.A.C.P., F.R.C.P. Professor Emeritus of Neurology, Institute of Neurology, University College, London and John H. Noseworthy, M.D., F.R.C.P.C. Department of Neurology, Mayo Clinic/Mayo Foundation, Rochester, Minnesota An Imprint of ElsevierScience Butterworth-Heinemann is an imprint of Elsevier Science. Copyright 2003, Elsevier Science (USA). All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopy, recording, or any information storage and retrieval system, without permission in writing from the publisher. Medicine is an ever-changing field. Standard safety precautions must be followed but as new research and clinical experience broaden our knowledge, changes in treatment and drug therapy may become necessary or appropriate. Readers are advised to check the most current product infor- mation provided by the manufacturer of each drug to be administered to verify the recommended dose, the method and duration of administration, and contraindications. It is the responsibility of the treating physician, relying on experience and knowledge of the patient, to determine dosages and the best treatment for each individual patient. Neither the Publisher nor the author assumes any liability for any injury and/or damage to persons or property arising from this publication. Every effort has been made to ensure that the drug dosage schedules within this text are accurate and conform to standards accepted at time of publication. However, as treatment recommenda- tions vary in the light of continuing research and clinical experience, the reader is advised to verify drug dosage schedules herein with information found on product information sheets. This is espe- cially true in cases of new or infrequently used drugs. (cid:2)∞ Recognizing the importance of preserving what has been written, Elsevier Science prints its books on acid-free paper whenever possible. Library of Congress Cataloging-in-Publication Data Multiple sclerosis 2 / edited by W. Ian McDonald and John H. Noseworthy. p. ; cm. — (Blue books of practical neurology ; 27) Includes bibliographical references and index. ISBN0-7506-7348-6 1. Multiple sclerosis. I. Title: Multiple sclerosis two. II. McDonald, W. Ian. III. Noseworthy, John H. IV. Series. [DNLM: 1. Multiple Sclerosis. WL360 M96255 2003] RC377 .M8393 2003 616.8¢34—dc21 2002026294 British Library Cataloguing-in-Publication Data Acatalogue record for this book is available from the British Library. The publisher offers special discounts on bulk orders of this book. For information, please contact: Manager of Special Sales Elsevier Science The Curtis Center Independence Square West, Suite 300 Philadelphia, PA19106 Tel: 215-238-7800 Fax: 215-238-7362 For information on all Butterworth–Heinemann publications available, contact our World Wide Web home page at: http://www.elsevier.com 10 9 8 7 6 5 4 3 2 1 Printed in the United States of America To those with multiple sclerosis who have taught us about it and inspire us to seek lasting answers to the challenges they face each day. Contributing Authors Douglas L. Arnold, M.D., F.R.C.P.(C) Professor of Neurology and Neurosurgery, McGill University; Director, Clinical Research Unit and Magnetic Resonance Spectroscopy Unit, Montreal Neurological Institute, Montreal, Quebec, Canada Alexei N. Boiko, M.D. Professor,Department of Neurology, Moscow University, Moscow, Russia W. Brück, M.D. Department of Neuropathology, Charité, Humboldt University, Berlin, Germany Zografos Caramanos, M.A. Research Assistant, Department of Neurology and Neurosurgery, McGill Uni- versity; Research Assistant, Magnetic Resonance Spectroscopy Unit, Montreal Neurological Institute, Montreal, Quebec, Canada Alastair Compston, M.D. Department of Neurology, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom Patricia K. Coyle, M.D. Professor of Neurology; Director, SBMS Comprehensive Care Center, School of Medicine, State University of New York Stony Brook; Attending Neurolo- gist, Department of Neurology, University Hospital Medical Center, Stony Brook George C. Ebers, M.D. Action Professor of Clinical Neurology, University of Oxford; Head of Depart- ment, Department of Clinical Neurology, Radcliffe Infirmary, Oxford, United Kingdom ix x Contributing Authors Franz Fazekas, M.D. Department of Neurology and MR Institute, Karl-Franzens University, Graz, Austria Jacqueline Foong, M.R.C.Psych, M.Phil. Honorary Senior Lecturer, Department of Clinical Neurology, Institute of Neurology; Consultant, Department of Neuropsychiatry, The National Hospital for Neurology and Neurosurgery, London, United Kingdom Jennifer A. Freeman, B. App. Sci., Ph.D., M.C.S.P. Honorary Lecturer, Institute of Neurology, London; Senior Lecturer, Institute of Health Studies, Plymouth University, Devon, United Kingdom Anke Hensiek, M.D. Department of Neurology, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom Reinhard Hohlfeld, M.D. Chairman and Director, Department of Neurology, Institute for Clinical Neuroimmunology, University of Munich, Germany Jürg Kesselring, M.D. Professor of Clinical Neurology and Neurorehabilitation, Universities of Bern and Zürich; Head of the Department of Neurology, Rehabilitation Center, Bern, Switzerland Hans Lassmann, M.D. Division of Neuroimmunology, Brain Research Institute, University of Vienna, Austria Fred D. Lublin, M.D. Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai Medical Center, New York Claudia F. Lucchinetti, M.D. Assistant Professor of Neurology, Mayo Clinic and Foundation, Rochester Roland Martin, M.D. Chief, Cellular Immunology Section, Neuroimmunology Branch, NINDS, NIH, Bethesda W. Ian McDonald, Ph.D., F.R.A.C.P., F.R.C.P. Professor Emeritus of Neurology, Institute of Neurology, University College, London, United Kingdom Luanne Metz, M.D. Associate Professor, Department of Clinical Neurosciences, University of Calgary; MS Clinic Director, Foothills Hospital, Calgary, Canada Contributing Authors xi David H. Miller, M.D. Institute of Neurology and The National Hospital for Neurology and Neuro- surgery, London, United Kingdom John H. Noseworthy, M.D., F.R.C.P.C. Department of Neurology, Mayo Clinic/Mayo Foundation, Rochester Donald W. Paty, M.D. Professor, Division of Neurology, University of British Columbia, Vancouver, Canada Stephen C. Reingold, Ph.D. Research Programs Department, National Multiple Sclerosis Society, New York Moses Rodriguez, M.D. Department of Neurology, Mayo Clinic, Rochester Maria A. Ron, Ph.D., M.R.C.P., F.R.C.Psych. Professor of Clinical Neurology, Institute of Neurology; Consultant, Depart- ment of Neuropsychiatry, The National Hospital for Neurology and Neuro- surgery, London, United Kingdom Richard Roxburgh, M.D. Department of Neurology, University of Cambridge, Addenbrooke’s Hospital, Cambridge, United Kingdom Peter Rudge, M.D. Honorary Senior Lecturer, Institute of Neurology; Consultant Neurologist, National Hospital for Neurology and Neurosurgery, London, United Kingdom A. Carlos Santos, M.D. Assistant Professor, Medical Clinic—Image Center, University of Sao Paulo— Ribeirao Preto Medical School; Neuroradiologist, Department of Radiology, Ribeirao Preto Clinical Hospital, Sao Paulo, Brazil Kenneth J. Smith, M.D. Neuroinflammation Research Group, Guy’s, King’s, and St. Thomas’School of Medicine, King’s College, London, United Kingdom Mats Söderström, M.D. Associate Professor, Department of Ophthalmology, Karolinska Institute; Senior Consultant, Department of Ophthalmology, Huddinge University Hos- pital, Huddinge, Sweden Alan J. Thompson, M.D., F.R.C.P., F.R.C.P.I. Garfield Weston Professor of Clinical Neurology and Neurorehabilitation, Insti- tute of Neurology, University College, London, United Kingdom xii Contributing Authors G.K. Vorobeychi, M.D. Resident, Division of Neurology, University of British Columbia, Vancouver, Canada Brian G. Weinshenker, M.D., F.R.C.P.C. Department of Neurology, Mayo Clinic, Rochester Dean M. Wingerchuk, M.D., F.R.C.P.C. Department of Neurology, Mayo Clinic, Scottsdale Series Preface The Blue Books of Practical Neurology denotes the series of monographs pre- viously named the BIMR Neurology series, which was itself the successor of the Modern Trends in Neurologyseries. As before, the volumes are intended for use by physicians who grapple with the problems of neurological disorders on a daily basis, be they neurologists, neurologists in training, or those in related fields such as neurosurgery, internal medicine, psychiatry, and rehabilitation medicine. Our purpose is to produce monographs on topics in clinical neurology in which progress through research has brought about new concepts of patient management. The subject of each book is selected by the Series Editors using two criteria: first, that there has been significant advance in knowledge in that area and, second, that such advances have been incorporated into new ways of managing patients with the disorders in question. This has been the guiding spirit behind each volume, and we expect it to continue. In effect, we empha- size research, both in the clinic and in the experimental laboratory, but princi- pally to the extent that it changes our collective attitudes and practices in caring for those who are neurologically afflicted. Arthur K. Asbury Anthony H.V. Schapira Series Editors xiii Preface The past decade has been arguably the most exciting ever in terms of progress in our understanding of multiple sclerosis and how to treat it. To give a com- prehensive account of the disease and its management now requires a large clin- ical reference. This is not the aim of the present book. Rather, it is to concentrate on selected topics in which our understanding has advanced at the basic or the clinical levels. In particular we have aimed to provide a practical approach to diagnosis and management of the different forms of the disease encountered by the practicing neurologist. A notable change in the past decade has been the placement of the person with multiple sclerosis at the center of discussions about the disease and its management and the recognition that decisions about priorities in research should derive from a partnership between investigators and people with the disease. This change in orientation is reflected in the contents of the book. In addition to chapters on drug treatment, there are accounts of the role of reha- bilitation and of the cognitive, psychological, and social impacts of the disease, an appreciation of which is essential to good management. In structuring the book we have kept in mind the needs of neurologists in training as well as those in practice. We hope that both groups will find this new volume on Multiple Sclerosis of value. W.I. McDonald J. Noseworthy xv 1 The Diagnosis of Multiple Sclerosis W. Ian McDonald, Franz Fazekas, and Alan J. Thompson The diagnosis of the established case of multiple sclerosis (MS) is easy: It simply requires the demonstration of abnormal physical signs indicating the presence of lesions at two necessarily separate sites in the central nervous system (CNS), in an individual with a history of at least two episodes of neu- rological disturbance of the kind seen in MS, and that there is no better expla- nation for the clinical picture. These essential classical criteria for the diagnosis of MS1 can be fulfilled by clinical assessment alone. Most neurologists, however, like to have the reassurance of confirmatory investigations, usually an abnormal magnetic resonance imaging (MRI) study, though abnormal evoked potentials (EPs) and cerebrospinal fluid (CSF) analysis are also helpful. Diagnostic problems arise in two main contexts. The first, particularly impor- tant when the question of disease-modifying therapy is being considered, occurs when the patient is seen early in the course of the disease, at a stage when the clinical evidence for dissemination in time and space is inconclusive. The second occurs when there are unusual features present, such as progression from onset,2 aphasia, or epilepsy. To overcome these problems, a number of sets of diagnostic criteria have been proposed over the years. The principles are the same in all. Since 1983, the results of EP and CSF examination have been formally included in what became known as the Poser criteria.3 These criteria, which have served well, were developed just as MRI became available. Though its diagnostic usefulness seemed obvious, there was insuffi- cient experience with it to incorporate the results of its use. Experience with MRI in MS since then has been enormous, and for this reason a meeting was convened in London in July 2000 under the auspices of the National MS Society of the United States and the Multiple Sclerosis International Federation. The charge to the International Panel was to review existing criteria and to refine them in the light of present knowledge. It was agreed that the criteria should be evidence based. Two consequences follow. First, because of present limita- tions in our knowledge, particularly about temporal factors in the evolution of lesions, the criteria for establishing dissemination in time appear rather 1

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