`
`Multiple
`Sclerosis
`
`ath Ss Gala so) alee = dog pod 8a tame eee p
`
`Edited by
`
`
`
`CEDRIC $. RAINE
`
`
`
`
`
`HENRY F. McFARLAND
`
`REINHARD HOHLFELD
`
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`
`
`
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`Merck 2012
`TWi v Merck
`IPR2023-00049
`
`

`

`
`
`UNIVERSITY OFILLINOIS-URBANA
`
`ITI
`
`3 0112 085359922
`
`
`
`
`
`Multiple
`clerosis
`
`9780702028113
`
`ISBN 978-0-7020-2811-3
`
`

`

`Multiple Sclerosis:
`A Comprehensive Text
`
`WL.
`360
`
`4ane45
`
`0
`
`Edited by
`Cedric S. Raine rnp ose rrepath
`Professor, Departments of Pathology (Neuropathology),
`Neurology and Neuroscience,
`Albert Einstein College of Medicine,
`New York, USA
`
`Henry F. McFarland mo
`Chief, Neuroimmunology Branch, and Clinical Director,
`National Institute of Neurological Disorders and Stroke,
`National Institutes of Health, Bethesda,
`Maryland, USA
`
`Reinhard Hohlfeld uo
`Professor and Director of the Institute for Clinical Neuroimmunology,
`Ludwig-Maximilians University, Klinikum Grosshadern,
`institute for Clinical Neuroimmunology,
`Munich, Germany
`
`SAUNDERS
`
`=
`
`EDINBURGH LONDON NEW YORK OXFORD PHILADELPHIA ST LOUIS SYDNEY TORONTO 2008
`
`

`

`SAUNDERS
`ELSEVIER
`
`An imprint of Elsevier Limited
`
`© 2008, Elsevier Limited, All rights reserved.
`
`No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by
`any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of
`the Publishers. Permissions may be sought directly from Elsevier's Health Sciences Rights Department,
`1600 John F. Kennedy Boulevard, Suite 1800, Philadelphia, PA 19103-2899, USA: phone: (41) 215 239
`3804; fax: (+1) 215 239 3805; or, e-mail: hea/thpermissions@elsevier.com. You may also complete your
`request on-line via the Elsevier homepage (http:/Avww.elsevier.com), by selecting ‘Support and contact’ and
`then ‘Copyright and Permission’.
`
`ISBN 978-0-7020-2811-3
`
`British Library Cataloguing in Publication Data
`A catalogue recordfor this book is available from the British Library
`
`Library of Congress Cataloging in Publication Data
`A catalogue record for this bookis available from the Library of Congress
`
`Note
`Knowledge and bestpracticein this field are constantly changing. As new research and experience broaden
`our knowledge, changesin practice, treatment and drug therapy may become necessary or appropriate.
`Readers are advised to check the most current information provided(i) on procedures featured or(ii) by the
`manufacturer of each productto be administered, to verify the recommended dose or formula, the method
`and duration of administration, and contraindications.It is the responsibility of the practitioner, relying on
`their own experience and knowledge ofthe patient, 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 Editors assume anyliability for any injury and/or damage to persons or
`property arising out of or related to any use of the material contained in this book.
`
`The Publisher
`
`BOOKAID—Sabre Foundation
`
`Working together to grow
`libraries in developing countries
`www.elsevier.com | www.bookaid.org | www.sabre.org
`ELSEVIER
`
`your source for books,
`IRSAIS journals and multimedia
`in the health sciences
`www.elsevierhealth.com
`
`Printed in China
`
`The
`publisher's
`policyis to use
`paper manufactured
`from sustainable forests
`
`

`

`the reason
`Why another book on multiple sclerosis? To us,
`was obvious — the terrain of multiple sclerosis (MS)
`is vast
`and ever-changing. So muchis happening that concepts forged
`just 2 years ago are already passé. Whether viewed from the
`platform of the health professional responsible for the day-to-
`day care of the patient or the scientist working to unravel what
`makes this a unique disease, MS has overthe last decade evolved
`into a condition necessitating multidisciplinary approaches to
`both its management and understanding. One needs only to
`peruse the profiles of the personnel associated with an MS care
`center(particularly one located in an academic setting} to appre-
`ciate the enormousarray of skills and treatments now available
`to the patient. For the scientific investigator,
`the rapidity of
`developments in recent years has been quite intimidating as
`genetics,
`immunology and molecular biology have assumed
`center stage, a fact reflected daily in our language,
`tools and
`techniques. In short, MS is a moving target and, as a conse-
`quence, we need to keep adjusting our sights. This bookis the
`latest adjustment.
`Why a ‘comprehensive’ textbook? In the past, authors of
`texts on MS have shied away from broad-fronted coverage, with
`the preface of one renowned 1985 tome announcing ‘it is no
`longer possible even to attempt a comprehensive work on mul-
`
`Preface
`
`
`
`
`Cedric S. Raine,
`New York City, NY, USA
`
`tiple sclerosis’. If that were the case 20-plus years ago when
`the number of treatments for the MS patient was virtually
`zero and the diagnostic tools and research options were limited
`(to say the least), imagine the scope of the endeavor today! We
`have for certain come a long way since the 1980s — just look
`how muchis out there now for the patient! With more than
`half-a-dozen approved and effective drugs specifically designed
`for MS, and dozens in advanced stages of clinical trials and/or
`awaiting approval,
`there is a wealth of new information to
`report. Thus, because the horizonis brighter than ever before
`for those affected with or involved in the condition, we think
`the timeis ripe for a fresh look at the status of MS asa clinical
`problem, for the latest coverage on expandingprospects for the
`patient, andfor a state-of-the-art re-evaluation of changes occur-
`ring within the nervous system. Since any approach to MS,
`scientific or care-related,
`is almost guaranteed to embrace the
`combined skilis of several disciplines,
`for an individual
`to
`embark single-handed upon the preparation of a text on the
`subject might understandably be deemed over-ambitious. There-
`fore, fully cognizantof the challenge and somewhat intimidated
`by recently published excellent works on the subject, the present
`Anglo-American-Germaneditorial alliance was assembled, each
`
`editor having one foot firmly planted in MS andthe otherin a
`
`Henry F. McFarland,
`Washington, DC, USA
`
`Reinhard Hohifeld,
`Munich, Germany
`
`

`

`PREFACE
`the National Institute of Neurological Diseases and Stroke.It
`is largely as a result of her energy and insight that we are
`where we are today andfor this we owe her a debt of gratitude.
`Thanks in part
`to work supported by agencies like those
`Sylvia created, we no longer doubt that the quality of life for
`the MS patient can be improved, that the clinical course can
`be beneficially modified, that the immunological assault on
`the nervous system can be assuaged,
`that axonal damage
`can be reduced, and that myelin repair is feasible - the
`challenge is to correct these anomalies simultaneously in the
`MSpatient. True, many issuesstill need to be resolved(like
`whether MSis a single disease or a collection of variants}, and
`we recognize that no book on MS will ever be really complete
`since, like the canvas of the master painter, details can always
`be added.
`For helping us bring the most recent advances in MStogether
`in one volume, we thankthe contributors, each of whom has
`striven to provide a didactic narrative that is both comprehen-
`sive and current. Wefeel that any reader entering into a dialogue
`with this book will emerge refreshed, fulfilled and brimming
`with anticipation about issues such as what the next clinical
`trial will bring, what
`triggers this devastating disease and
`whether more able symptomatic treatments will be uncovered.
`Weare not unawarethatthis will not be the last word on MS
`and that it will be the latest for a brief-window of time only,
`but we are confident that it will remain a major source of
`knowledge for many years to come.
`
`field different from the other two. Our principal task was to
`compile a comprehensive Table of Contents replete with out-
`standing contributors, with long track records in bothbasic and
`clinical research. We have invested heavily in the project and
`are highly satisfied with the result, which is not a dogmatic,
`subjective treatise reflecting personal viewpoints but rather a
`series of succinct and interlocking contributions (actually 31
`chapters) from a unique team of clinicians and investigators
`never before assembled whosecollective skills traverse the entire
`landscape of MS.
`What will the book achieve? Considering that MS canstill
`be difficult to define both clinically and pathologically, and
`that not too long ago (to some of us, at least), diagnosis was
`regarded as proven only after autopsy or biopsy {McDonald &
`Halliday 1977), we feel that the present coverage more than
`does justice to the field since it portrays MS as a definable
`entity and sets what we hope is a new gold-standard forits
`characterization. Parenthetically, after a long dormancy,
`it
`took a lay person (Sylvia Lawry}, not a neurologist or a scien-
`tist, to bring MS into the limelight and to give it the promi-
`nence it deserves. Sylvia was seeking guidance in 1945 to help
`her brotherafflicted with MS when she ran a short announce-
`ment in the New York Times asking people with MS to contact
`her, a venture that culminated with the recognition of this as
`an important disease and the establishment of Multiple
`Sclerosis Societies around the world. Her efforts were also
`pivotal in the formation in the USA of what is now known as
`
`vi
`
`

`

`
`
`
`
`Halima El-Moslimany mo
`Post-doctoral Fellow in Multiple Sclerosis,
`The Corinne Goldsmith Dickinson Center for Multiple
`Sclerosis, Mount Sinai School of Medicine, New York, USA
`
`Contributors
`
`Oluf Andersen mp Php
`Professor of Neurology, Institute of Neuroscience and
`Physiology, University of Gothenburg, Gothenburg,
`Sweden
`
`Brenda L. Banwell up FRcPc
`Assistant Professor of Pediatrics (Neurology) and Associate
`Scientist, Research Institute, The Hospital for Sick Children,
`University of Toronto, Canada
`
`Clare J. Fowler Face
`Professor, Institute of Neurology; Consultant in Uro-
`Neurology, National Hospital for Neurology and
`Neurosurgery, University College London Hospitals, London,
`UK
`
`Ralph H. B. Benedict Pho
`Associate Professor of Neurology, Erie County Medical
`Center, Buffalo, USA
`
`Jeffrey L. Bennett mp Php
`Associate Professor of Neurology and Ophthalmology,
`Departments of Neurology and Ophthalmology, University of
`Colorado, Health Sciences Center, Denver, Colorado, USA
`
`Monika Bradl Pho
`Head of Cellular Neuroimmunology Group, Medical
`University Vienna, Center for Brain Research, Division of
`Neuroimmunology, Vienna, Austria
`
`Mark P. Burgoon Php
`Assistant Professor, Department of Neurology, University of
`Colorado, Health Sciences Center, Denver, Colorado, USA
`
`Fredric K. Cantor mp
`Adjunct Investigator, Neuroimmunology Branch, NINDS,
`NIH, Bethesda, Maryland, USA
`
`Stacey S. Cofield php
`Assistant Professor of Biostatistics, Department of
`Biostatistics, University of Alabama at Birmingham, Alabama,
`USA
`
`Gary R. Cutter php
`Professor of Biostatistics, Departmentof Biostatistics,
`University of Alabama at Birmingham, Alabama, USA
`
`Klaus Dornmair PHD
`Head of Research Group, Ludwig-Maximilians University,
`Klinikum Grosshadern, Institute for Clinical
`Neuroimmunology, Munich, Germany
`
`Claude Genain wo
`Associate Professor, California Pacific Medical Center
`Research Institute (Neurosciences], San Francisco, California,
`USA
`
`Donald H. Gilden up
`Louise Baum Professor and Chairman, Departments of
`Neurology and Microbiology, University of Colorado, Health
`Sciences Center, Denver, Colorado, USA
`
`Gavin Giovannoni me che PhD FCP FRCP FCPath
`Professor of Neurology, Institute of Cell and Molecular
`Science, Barts and The London Queen Mary's School of
`Medicine and Dentistry, London, UK
`
`Ralf Gold up
`Professor and Chair, Department of Neurology, St Josef-
`Hospital, Ruhr-University Bochum, Germany
`
`Douglas S. Goodin up
`Director of the Multiple Sclerosis Center, Department of
`Neurology, University of California, San Francisco, California,
`USA
`
`Stephen L. Hauser mp PHD
`Chair and Robert A. Fishman Distinguished Professor,
`Department of Neurology, University of California, San
`Francisco, California, USA
`
`Reinhard Hohlfeld uo
`Professor and Director of the Institute for Clinical
`Neuroimmunology, Ludwig-Maximilians University, Klinikum
`Grosshadern, Institute for Clinical Neuroimmunology,
`Munich, Germany
`
`Monique Dubois-Daleq uo
`Honorary Professor, Pasteur Institute, Paris, France; Guest at
`National Institute of Neurological Disorders and Stroke Porter
`Neuroscience Research Center, Bethesda, Maryland, USA
`
`Vinay Kaisi macs
`Registrar in Uro-Neurology, National Hospital for Neurology
`and Neurosurgery, University College London Hospitals,
`London, UK
`
`vii
`
`

`

`CONTRIBUTORS
`
`
`
`Ludwig Kappos wp
`Professor of Neurology, Department of Neurology,
`Universitatsspital Basel, Basel, Switzerland
`
`Jirg Kesselring mo
`Professor of Neurology and Neurorehabilitation, Universities
`of Bern and Ziirich, Switzerland; Chair of Neurorehabilitation,
`Universita Vita e Salute, San Raffaele, Milano, Italy
`
`Jeffery D. Kocsis pnp
`Professor of Neurology, Department of Neurology, Yale
`University School of Medicine; Associate Director, Center for
`Neuroscience and Regeneration Research, VA Medical Center,
`West Haven Connecticut, USA
`
`Tanya J. Lehky mp
`Director, Clinical EMG Laboratory, EMG Branch, NINDS,
`NIH, Bethesda, Maryland, USA
`
`Catherine Lubetzki mp psci
`Professor of Neurology, Université Pierre et Marie Curie,
`Faculté de Médecine, Paris; Assistance Publique-H6pitaux de
`Paris, Hépital de la Salpétriére, Paris, France
`
`Fred D. Lublin uo
`Saunders Family Professor of Neurology; Director, The
`Corinne Goldsmith Dickinson Center for Multiple Sclerosis,
`Mount Sinai Medical Center, Mount Sinai School of
`Medicine, New York, USA
`
`Samuel K. Ludwin ms che FRoP(C)
`Professor of Pathology, Department of Pathology and
`Molecular Medicine, Queens University and Kingston General
`Hospital, Kingston, Ontario, Canada
`
`Henry F. McFarland up
`Chief, Neuroimmunology Branch, and Clinical Director,
`National Institute of Neurological Disorders and Stroke,
`National Institutes of Health, Bethesda, Maryland, USA
`
`Roland Martin mo
`Research Professor, Institute for Neuroimmunology and
`Clinical MS Research, Center for Molecular Neurobiology
`Hamburg (ZMNH], University Medical Center Eppendorf,
`Hamburg, Germany
`
`Trevor Owens PhD
`Professor, Medical Biotechnology Centre, Center for Medical
`Biotechnology, Syddansk Universitet, Odense, Denmark
`
`Chris H. Polman mp Phd
`Professor of Neurology, VU Medical Center, Amsterdam, The
`Netherlands
`
`Maura Pugliatti vo
`Research Assistant in Neurology, Institute of Clinical
`Neurology, Medical Faculty, University of Sassari, Sassari,
`Italy
`
`Michael K. Racke mo
`Professor of Neurology, Department of Neurology,
`Department of Molecular Virology, Immunology and Medical
`Genetics, The Ohio State University Medical Center,
`Columbus, Ohio, USA
`
`Cedric S. Raine PhD DSe FRCPath
`Departments of Pathology (Neuropathology), Neurology and
`Neuroscience, Albert Einstein College of Medicine, New York,
`USA
`
`Stephen M. Rao php
`Professor of Neurology, Department of Neurology, Cell
`Biology, Neurobiology and Anatomy, Medical College of
`Wisconsin, Milwaukee, Wisconsin, USA
`
`Stephen C. Reingold Pro
`Research Counsellor, National Multiple Sclerosis Society,
`New York City, New York; President Scientific and Clinical
`Review Associates LLC, Salisbury, Connecticut and New York
`City, USA
`
`Giulio Rosati up
`Professor of Neurology and Head ofInstitute of Clinical
`Neurology; Dean of Medical Faculty, University of Sassari,
`Sassari, Italy
`
`Randall T. Schapiro up
`Director, The Schapiro Center for Multiple Sclerosis,
`Minneapolis Clinic of Neurology, Minneapolis; Clinical
`Professor of Neurology, University of Minnesota,
`Minneapolis, Minnesota, USA
`
`Aaron E.Miller uo
`Medical Director, Corinne Goldsmith Dickinson Center for
`Multiple Sclerosis; Professor of Neurology, Mount Sinai
`School of Medicine, New York, USA
`
`Neil J. Scolding FRCP PhD
`Burden Professor of Clinical Neurosciences, Department of
`Neurology, University of Bristol, Institute of Clinical
`Neurosciences, Frenchay Hospital, Bristol, UK
`
`David H. Miller mB chs MD FRACP FRCP
`Professor of Clinical Neurology, Departmentof
`Neuroinflammation, Institute of Neurology, University
`College London, London, UK
`
`John H. Noseworthy mp FRcPc
`Professor and Chair, Department of Neurology, Mayo Clinic
`College of Medicine, Rochester, Minnesota, USA
`
`Jorge R. Oksenberg Php
`Professor, Department of Neurology, School of Medicine,
`University of California at San Francisco, California, USA
`
`Gregory P. Owens Php
`Associate Professor, Department of Neurology, University of
`Colorado, Health Sciences Center, Denver, Colorado, USA
`
`Mireia Sospedra mp
`Research Associate Institute for Neuroimmunology and
`Clinical MS Research, Center for Molecular Neurobiology
`Hamburg (ZMNH), University Medical Center Eppendorf,
`Hamburg, Germany
`
`Alan J. Thompson mp FRCP FRCPI
`Garfield Weston Professor of Clinical Neurology and
`Neurorehabilitation, Department of Brain Repair and
`Rehabilitation, Institute of Neurology, University College
`London, London, UK
`
`Edward J. Thompson phD MD DSc FRCPath FRCP
`Emeritus Professor of Neurochemistry and Honorary
`Consultant at the National Hospital for Neurology and
`Neurosurgery, The Institute of Neurology, London, UK
`
`viii
`
`

`

`
`
`
`Contributors
`
`Bob W. van Oosten mp PhD
`Neurologist, VU University Medical Center, Amsterdam, The
`Netherlands
`
`Heather A. Wishart eno
`Associate Professor of Psychiatry, Dartmouth Medical School,
`Lebanon, New Hampshire, USA
`
`Stephen G. Waxman Mp PhD
`Professor and Chairman, Department of Neurology, Yale
`University Medical School, New Haven, USA; Director,
`Center for Neuroscience and Regeneration Research, VA
`Medical Center, West Haven, CT, USA
`
`Brian G. Weinshenker wo Fracp(c)
`Consultant in Neurology, Mayo Clinic; Professor of
`Neurology, Mayo Clinic College of Medicine, Rochester, USA
`
`Xiaoli Yu Php
`Instructor, Department of Neurology, University of Colorado,
`Health Sciences Center, Denver, Colorado, USA
`
`Bernard Zale mp psci
`Directeur de Recherche, Institut National de la Santé
`et de la Recherche Médicale, and Université Pierre et
`Marie Curie Unit 711, Hépital de la Salpétriére, Paris,
`France
`
`Dean M. Wingerchuk mp Frep(c)
`Consultant in Neurology, Mayo Clinic; Assistant Professor
`of Neurology, Mayo Clinic College of Medicine, Scottsdale,
`USA
`
`SimoneP. Zehntner PHD
`Director, Small Animal Imaging Laboratory, Brain Imaging
`Center, Montreal Neurological Institute, Montreal, Quebec,
`Canada
`
`

`

`

`

`Contents
`
`SECTION1
`Multiple sclerosis:
`history and clinical manifestations
`214
`14. Genetics of multiple sclerosis
`Section editor: H. F. McFarland
`J. R. Oksenberg, S. L. Hauseraeee
`1
`1. History of multiple sclerosis
`Infectious agents and multiple sclerosis
`J. Kesselring
`
`J. L. Bennett, X. Yu, D. H. Gilden, M. P. Burgoon,
`G. P. OwenseeEee
`2. Clinical features in multiple sclerosis
`10
`H. El-Moslimany, F. D. Lublin
`
`192
`Immunology of multiple sclerosis
`13.
`M. Sospedra, R. Martinee
`
`1
`
`15.
`
`226
`
`16. Models of chronic relapsing experimental
`237
`autoimmune encephalomyelitis
`C. S. Raine, C. P. Genaina
`
`3. Unusual presentations and variants of idiopathic
`24
`central nervous system demyelinating diseases
`D. M. Wingerchuk, B. G. Weinshenker————SSSSSSS
`17. Genetic manipulations of experimental autoimmune
`encephalomyelitis in the mouse
`261
`S. P. Zehntner, T. Owensa
`
`4. Pediatric multiple sclerosis
`B. L. Banwell
`SS
`
`43
`
`18. Biology of myelin
`55
`5. Diagnosis of multiple sclerosis
`B. Zale, C. Lubetzki
`
`C. H. Polman, B. W. van Oosteneeaee
`19. New tools forinvestigating the immunopathogenesis
`of multiple sclerosis: principles and applications
`M. Braal, K. Dornmair, R. Hohifeld
`
`274
`
`286
`
`6. Neuroimaging in multiple sclerosis
`D. H. Miller
`rr
`
`69
`
`7. Cerebrospinalfluid analysis in multiple sclerosis
`G. Giovannoni, E. J. Thompson
`
`SECTION 3
`Multiple sclerosis:
`treatment and prospects
`Section editor: R. Hohifeld
`
`303
`
`8. Natural history of multiple sclerosis
`O. Andersen
`
`. Epidemiology of multiple sclerosis
`M. Pugliatti, G. Rosati
`
`a 9
`
`10. Neurophysiological studiesin multiple sclerosis
`F. K, Cantor, T. J. Lehky
`
`SECTION 2
`Multiple sclerosis:
`pathophysiology and biology
`Section editor: C. S. Raine
`
`11. The neuropathology of multiple sclerosis
`S. K. Ludwin, C. S. Raine
`
`12. Neurophysiology of demyelination
`J. D. Kocsis, S. G. Waxman
`
`141
`
`151
`
`151
`
`178
`
`20.
`
`Immunomodulatory therapy:critical appraisaloftrial
`303
`results and marketing claims
`J. H. NoseworthySo
`
`21. Treatment of multiple sclerosis with disease-modifying
`315
`therapies
`D. S. Goodin, L. Kappos
`
`22. Escape therapies and managementof multiple
`333
`sclerosis
`H. El-Moslimany, A. E. Miller
`
`23. Novel and promising therapeutic strategies in
`353
`multiple sclerosis
`M. K. Racke, R. Gold
`
`xi
`
`88
`
`100
`
`121
`
`

`

`CONTENTS
`
`
`
`24. Moving towards remyelinating and neuroprotective
`therapies in multiple sclerosis
`N. J. Scolding, M. Dubois-Daicq
`
`25. Symptomatic therapies for multiple sclerosis
`R. T. Schapiro
`
`26. Bladder and sexual dysfunction in multiple sclerosis
`V. Kalsi, C. J. Fowler
`27. Neuropsychological aspects of multiple sclerosis
`H. A. Wishart, R. H. B. Benedict, S. M. Rao
`
`366
`
`383
`
`391
`
`401
`
`29. Design and analysis ofclinicaltrials in
`multiple sclerosis
`H. F. McFarland
`
`30. The role of data monitoring committees in multiple
`sclerosis clinical trials
`S. C. Reingold
`
`31. Outcome measures in multiple sclerosis
`S. S. Cofield, G. R. Cutter
`
`28. Rehabilitation of multiple sclerosis
`A. J. Thompson
`
`A413
`
`Index
`
`425
`
`438
`
`449
`
`459
`
`xii
`
`

`

`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`

`

`TREATMENT AND PROSPECTS
`LLLe— keRR_NRoeee
`
`immunomodulatory regimen in MS can be considered to be evi-
`dence-based.'!* Patients should be evaluated every 3-6 months
`using the EDSS and the Multiple Sclerosis Functional Composite
`score (MSFC). If worsening is apparent on clinical examination,
`as determined by the EDSS and MSFC,
`the patient should
`undergo an MRI of the brain with gadolinium.If clinical worsen-
`ing is present, escalation of treatment with either a different
`disease-modifying agent or a nonspecific immunosuppressantfor
`the managementof disease may be considered at this stage.
`Clearly, clinical relapses often produce a sustained effect on
`disability. Lublin et al found residual deficit months after the
`first in-study relapse among placebo-treated patients who par-
`ticipated in the trials of the disease-modifying agents.'° Also,
`evidence suggests that inflammation contributes to cumulative
`neurological impairment,'”* e.g. the observation by Weinshen-
`ker et al that patients who have an increased frequency of
`relapses in the first years of MS have a higher risk of later dis-
`ability.'? In the CHAMPStrial of patients who had a positive
`MRI at the time of their initial neurological event, the best
`predictors of the development of clinically definite MS over a
`short
`interval were the presence of gadolinium-enhancing
`lesions and satisfaction of the Barkhof MRI criteria! for dis-
`semination in space.”
`Recent functional MRI studies have suggested that relapse
`recovery involves adaptive recruitment of networks of additional
`brain regionsto restore function.?!** Therefore, multiple attacks
`may gradually erode the reserve available for recruitment and,
`consequently, some might consider that any attack is an indica-
`tion of suboptimal treatment response. Most neurologists would
`agree that patients who are still having frequent attacks on
`disease-moditying therapy are suboptimal responders, especially
`if serial examinations demonstrate progression of neurological
`impairment. Insidious progression also indicates a suboptimal
`treatment response but, in the absenceof signs of active inflam-
`mation, has negative implications for a response to any immu-
`nosuppressive agent. An important issue is whether to use MRI
`findings alone to determine suboptimal response. New enhanc-
`ing lesions are associated with increased relapse rates and
`increased T2 lesion burden, and may be associated with progres-
`sion of disability in the short term in patients with RRMS.*”8
`Since the disease-modifying agents, particularly the IFNs, reduce
`the number of new T2. lesions, an increasing T2 lesion burden
`in a patient on therapy might be considered indicative of a
`suboptimal response.***° However, because existing US Food
`and Drug Administration {(FDA)-approved disease-modifying
`therapies are only moderately effective in reducing MRI activity
`and because the correlation of T2, disease burden on brain MRI
`with clinical activity is weak, using change in MRI alone as a
`basis for changing treatment is problematic.
`A task force of MS specialists convened by the National
`Multiple Sclerosis Society of the USA recently recommended
`criteria for determining suboptimal response to therapy and
`changing treatment. The task force advised that patients remain
`on a medication for at least a year before a judgment of subop-
`timal response is made.*! Suboptimal responders would then be
`patients who had experienced more than one attack per year or
`had failed to show a reduction from the pretreatment relapse
`rate. The patient can also be considered a suboptimal responder
`if there has been an increase in the EDSS of 1 point from a
`baseline score of 3.0-5.5 or a 0.5 point increase from a baseline
`score of 6.0 or greater. The task force cautioned, however, about
`basing a decision to change treatment on deterioration in EDSS
`score that was associated with an acute exacerbation, because
`of the potential for recovery.
`Although new activity on the MRI is a cause for concern, the
`task force opposed switching therapy on the basis of changes on
`regularly scheduled or periodic MRIs alone, in the absence of
`clinical activity. However, ongoing MRIactivity after an attack
`
`has occurred could support a decision to change treatment. While
`a significant increase of T2 disease burdenis a cause for concern
`the extent of change thatis consideredsignificant was not estab.
`lished. While current agents do not completely suppress new
`lesion activity, Cohen etal stated that brainstem andspinal cord
`lesions are more worrisomeandthat the presence of newlesions
`in those regions is sufficient reason to alter therapy.**
`The frequency at which the physician should obtain MRIs
`also remains controversial. The Multiple Sclerosis Treatment
`Consensus Group advises obtaining MRI scans only if thereis
`any change in EDSS or MSFC."* Cohen et al suggest that MRIs
`should be obtained when treatment is changed,
`in order to
`provide an updated baseline to determine the effectiveness of
`the new therapy.” If surveillance scans are to be done,
`the
`studies are helpful only in thefirst few years of disease and not
`after 5 years if there is little change clinically. According to
`the NMSS taskforce, all patients should have a baseline brain
`MRI, and spinal cord MRIif the patient has myelopathic symp-
`toms.*! Thepatients should report any suspected relapse, which
`would then require prompt neurological examination?! MRI
`scans should be obtained in suspected suboptimal responders
`to support decisions to change therapy and should be obtained
`to establish a new baseline if change of therapy occurs.?! If
`patients are developing progressive impairment, with subtle
`relapse activity, a follow-up MRI is needed.
`Subtle symptoms affecting activities of daily living, even in
`the absence of a change on examination, can also be indicative
`of a suboptimal response to treatment if the symptom accumu-
`lation is stepwise.*” However, potential effects of medications,
`sedation, increased spasticity, sleep disturbances and comorbid
`medical conditions must be excluded before attributing changes
`to a suboptimal response. Cohen et al*? also suggested that
`patients developing multifocal disease affecting multiple neuro-
`logical systems while on therapy could be considered subopti-
`mal responders. A patient who experiences progressive motor
`or cognitive impairment sufficient to disrupt daily activities
`could be regarded as a suboptimal responder.
`Rio and his group re-examined in 2006 the question of sub-
`optimal response to IFNB.* They followed 393 patients with
`RRMSwhoweretreated with IFNB. Variouscriteria were exam-
`ined in an attempt to define nonresponse to IFNB, including
`numberof relapses, disability progression or both. They found
`that the mostclinically relevant criterion of response to IFNBis
`disability progression. Disability progression was defined as an
`increase in the EDSS of 1.5 points for patients with a baseline
`EDSS of 0; an increase of 1 point for scores from 1.0-5.0, and
`an increase of 0.5 points for scores equal to or higher than 5.5.
`Natalizumab, which is discussed in Chapter 21, was re-
`introduced to the market in July 2005 with a risk management
`program, known as TOUCH@®, to minimize the potential of
`harm from the development of PML. Twocases of that oppor-
`tunistic viral infection of the brain had occurred in patients who
`had received a combination of natalizumab and weekly inter-
`feron B-la for more than 2. years.**°° Now, natalizumab, which
`reduced relapse rate by 68% and slowed EDSS progression in
`the monotherapy AFFIRM trial,°° is a reasonable option for
`patients who are having an inadequate response to interferon
`or glatiramer and are willing to accept the uncertain level of risk
`associated with the use of that monoclonal antibody against the
`adhesion molecule, «481 integrin (VLA-4).
`Irrespective of the specific criteria applied, the physician who
`decides a patientis failing currently approved disease-modifying
`therapy faces a bewildering number of agents that might be
`potentially beneficial. The rest of this chapter will focus on the
`individual drugs and procedures that are currently available.
`These drugs can be classified in a variety of ways, including their
`route of administration (Table 22.1}, whetherthey are used alone
`or in combination (Table 22.2}, or by their class (Table 22.3).
`
`
`
`334
`
`

`

`Escape therapies and management
`
`. Nonpharmacological
`approaches
`
`
`
` TABLE 22.1 Drugs for the management of multiple sclerosis, by route of administration
` Drugs taken orally
`
` Drugs taken byinjection
`
`
`
`
`
`
`
`
`
`
`
`TABLE 22.2 Therapies for the managementof multiple
`sclerosis, by method of use
`
`
`
`
`
`
`Therapies used by themselves
`Therapies used in
`combination with
`
`
`interferon-B
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Sulfasalazine
`
`|
`
`
`
`
`
`
`
`
`MITOXANTRONE
`
`
`Mitoxantrone (Novantrone} was the first drug approved by the
`FDAfor treatment of patients with secondary progressive MS
`(SPMS} or with a worsening relapsing disease course.*” This
`approval was based on the results of a multicenter, randomized,
`placebo-controlled phaseIII trial.5 Like Adriamycin and dauno-
`rubicin, mitoxantrone is an anthracenedione, which is used as
`an antineoplastic agent alone or in combination therapy for the
`treatment of prostate cancer, non-Hodgkin’s lymphoma and
`acute nonlymphocytic leukemia.***°
`Mitoxantrone intercalates
`into DNA through hydrogen
`bonding, causing crosslinks and strand breaks.** It also inter-
`feres with DNA topoisomerase II.*° When DNAisreplicated or
`transcribed, the topological formation of DNAisaltered, result-
`ing in a DNA molecule that is not in the correct formation,
`making it impossible to undergo further transcription or replica-
`tion.“' DNA topoisomerase II is an enzyme that helps in the
`separation of two intertwined daughter DNA molecules after
`DNAreplication by the transient formation of double-strand
`breaks.** The transient breaks allow the DNA molecules to
`separate and then rewind into the correct topological formation
`prior to ligation. Mitoxantrone affects replication by inhibiting
`
`
`
`TABLE 22.3 Classes of drug studied in the managementof
`multiple sclerosis
`
`Antineoplastic agents
`
`Immunosuppressants
`Cyclophosphamide
`Mitoxantrone
`| Azathioprine
`Methotrexate
`Rituximab
`| Steroids
`| Mycophenolate mofetil
`
`| Cladribine
`Intravenous immunoglobulin
`Tacrolimus
`
`
`
`Alemtuzumab
`
`| Daclizumab
`
`topoisomerase II in dividing and nondividing cells. Most phar-
`macokinetic data in humans were generated through its use in
`cancer patients receiving daily doses of this drug.****
`Mitoxantrone is 80% plasma-protein-bound andits half-life
`is approximately 1-3 hours. The drugis extensively distributed
`in various tissues and metabolized primarily in the liver. In MS,
`someofits beneficial clinical effects are believed to be attribut-
`able to the suppression of replication of autoreactive T cells, B
`cells and macrophages.*” In vitro studies demonstrated t