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 World Federation of Neurology
Seminars in Clinical Neurology

Ted Munsat, MD
Series Editor

DYSTONIA
Joseph Jankovic, MD, Chair

EPILEPSY: GLOBAL ISSUES FOR THE PRACTICING NEUROLOGIST

Jerome Engel, Jr., MD, PhD, Chair

STROKE: SELECTED TOPICS

Julien Bogousslavsky, MD, Chair

MULTIPLE SCLEROSIS
Joel Oger, MD, FRCPC, FAAN, Chair
Adnan Al-Araji, MB ChB, FRCP (Glasg.), Chair
 World Federation of Neurology
Seminars in Clinical Neurology

Multiple Sclerosis for the Practicing Neurologist

Joel Oger, MD, FRCPC, FAAN Adnan Al-Araji, MB ChB, FRCP (Glasg.)
Professor of Neurology Consultant Neurologist
Director Multiple Sclerosis Clinic Neurology Department
University of British Columbia University Hospital of North Staffordshire,
Vancouver, Canada Princes Road, Hartshill,
Stoke on Trent, Staffs
United Kingdom

José A. Cabrera-Gómez, MD, PhD, Luisa Giordano, MD Gavin V. McDonnell MB, BCh,
FAAN Resident (Hons), MD, FRCP (UK)
Professor of Neurology Divisione Universitaria di Neurologia Consultant Neurologist
President of the Cuban Multiple Sclerosis Ospedale S. Luigi Gonzaga Department of Neurology
Society Universita’ di Torino Royal Victoria Hospital
Multiple Sclerosis Clinic Torino, Italy Grosvenor Road
International Neurological Restoration Belfast
Center (CIREN) Robert M. Herndon, MD Northern Ireland, United Kingdom
Havana, Cuba Professor of Neurology
University of Mississippi Jackie Palace, BM, DM, FRCP
Marinella Clerico, MD School of Medicine Consultant Neurologist
Senior Researcher Jackson, Mississippi Honorary Senior Lecturer
Dipartimento di Scienze Cliniche e Radcliffe Hospital
Biologiche Jun-ichi Kira, MD, PhD Oxford, United Kingdom
Divisione Universitaria di Neurologia Department of Neurology
Ospedale S. Luigi Gonzaga Neurological Institute Randall T. Schapiro, MD
Universita’ di Torino The Schapiro Center for Multiple Sclerosis
Graduate School of Medical Sciences
Torino, Italy at The Minneapolis Clinic of Neurology
Kyushu University
Giulia Contessa, MD Fukuoka, Japan and
Resident Clinical Professor of Neurology
Divisione Universitaria di Neurologia Martin A. Lee, BM, BCh, MA, University of Minnesota
Ospedale S. Luigi Gonzaga Minneapolis, Minnesota
MRCP, DPhil
Universita’ di Torino Consultant Neurologist
Torino, Italy Norfolk and Norwich University Hospital
B. S. Singhal, MD, FRCP (Lond.),
Colney Lane FRCP (Edin.), FAMS
Luca Durelli, MD Norwich, United Kingdom Professor and Head
Associate Professor Department of Neurology
Dipartimento di Scienze Cliniche e Bombay Hospital Institute of Medical
Biologiche Sciences
Director Mumbai, India
Divisione Universitaria di Neurologia
Ospedale S. Luigi Gonzaga
Universita’ di Torino
Torino, Italy

Series Editor
Theodore L. Munsat, MD
Professor of Neurology Emeritus
Tufts University School of Medicine
Boston, Massachusetts

New York
Demos Medical Publishing, LLC.
386 Park Avenue South
New York, NY 10016
Visit our website at www.demosmedpub.com

© 2007 by World Federation of Neurology. All rights reserved.

This work protected under copyright under the World Federation of Neurology and the fol-
lowing terms and conditions apply to its use:

Photocopying
Single photocopies of single chapter, may be made for personal use as allowed by national
copyright laws. Multiple or systematic copying is permitted free of charge for educational
institutions that wish to make photocopies for non-profit educational classroom use, but not
for resale or commercial purposes.
Permission of the World Federation of Neurology is required for advertising or promotional
purposes, resale and all forms of document delivery.
Permissions may be sought directly from the World Federation of Neurology, 12 Chandos
Street, London W1G 9DR, UK.

Derivative Works
Tables of Contents may be reproduced for internal circulation but permission of the World
Federation of Neurology is required for resale of such material.
Permission of the World Federation of Neurology is required for all other derivative works,
including compilations and translations.

Notice
No responsibility is assumed by the World Federation of Neurology for any injury and/or
damage to persons or property as a matter of products liability, negligence or otherwise, or
from any use of operation of any methods, products, instructions, or ideas contained in the
material herein. Because of the rapid advances in the medical sciences, in particular, inde-
pendent verification of diagnoses and drugs dosages should be made.

First edition 2007

Library of Congress Cataloging-in-Publication Data

Multiple sclerosis for the practicing neurologist / faculty, Joel Oger … [et al.]. — 1st ed.
p. ; cm. — (World Federation of Neurology seminars in clinical neurology ; v. 5)
Includes bibliographical references.
ISBN-13: 978-1-933864-02-0
ISBN-10: 1-933864-02-8
1. Multiple sclerosis. 2. Neurologists—Practice. I. Oger, Joel. II. Series.
[DNLM: 1. Multiple Sclerosis. WL 360 M95643 2006]
RC377.M85 2006
616.8'34—dc22
2006018234

1 3 5 7 9 8 6 4 2
Made in the United States of America
Dedication

This book is dedicated to Donald Winston Paty, MD,

who was born in China in 1936 to a family of United
States missionaries. In 1943 Don moved to the
United States where he later completed his educa-
tion in New York and Georgia. He received his med-
ical diploma from Emory University in 1962, fol-
lowed by an internship at Duke University, and a
residency at Emory. During that time he took a civil
service position in Borneo with the US Public Health
Service where he provided medical care for the vol-
unteers of the Peace Corps.
Dr. Paty then became involved in a research fel-
lowship at the Demyelinating Diseases Research
Unit in Newcastle-upon-Tyne, England, where he
was introduced to neuroimmunology. He moved to
London, Ontario in Canada where he became a fac-
ulty member of The University of Western Ontario in
the Department of Neurosciences chaired by Dr.
Barnett. He created the concept of the Multi-
Disciplinary Research Multiple Sclerosis Clinics with
their systematic follow-up. As a result, large datasets on multiple sclerosis (MS) were gener-
ated that have become the gold standard for MS epidemiological research around the world.
Dr. Paty was very instrumental in the creation of the Canadian MS database.
In 1980 Dr. Paty moved to Vancouver and by applying sound neurological clinical principles
he defined the potential contribution of magnetic resonance imaging (MRI) to the treatment of
MS. In a series of sequential studies he described the course of lesions in the brain of MS
patients. Focusing on T2 weighted images obtained at regular monthly intervals, he unraveled
the dynamics of the demyelinating lesions with new lesions appearing, increasing in size, and
shrinking, independently of each other but resulting in a disease burden that could be meas-
ured, quantified, and compared. The MRI findings were the “point d’orgue” which allowed for
the approval of Interferon Beta-1b and subcutaneous Beta-1a in the treatment of relapsing-
remitting MS. A fundamentally new approach was born that greatly influenced the treatment of
MS in the following two decades and Don was highly involved in its development.
He received many prestigious awards including the first Dystel Prize and the Charcot Prize.
In 2004, Don received the Canadian Meritorious Service Medal for the use of MRI in the diag-
nosis and treatment of MS. He played a key role in the development of the MS Society of
Canada and contributed greatly to the scientific committee of the National MS Society. Don
was a vital part of the two committees who have defined the diagnostic criteria for MS in the
second half of the 20th century. His influence helped to create the concept of “Laboratory
Supported MS,” a designation he stressed should be used only for clinical trial and research
purposes. The book, Multiple Sclerosis by Donald W. Paty and George C. Ebers, Oxford
University Press, 1999, has become a milestone.

v
EPILEPSY: GLOBAL ISSUES FOR THE PRACTICING NEUROLOGIST

Despite his tremendous successes Don remained humble and approachable. He was the
most supporting of mentors. He was extremely supportive of new ideas and studies that were
brought to him with a level of enthusiasm that he would embrace. His support of young
researchers in countries where MS study had not been traditional was particularly remarkable.
His domination in the field culminated with the World meeting in Vancouver where every
participating neurologist had the impression of being his private guest. Shortly after that meet-
ing he became a citizen of the world and lectured in over 30 countries
Perhaps even more precious was Don’s mission as an educator and a mentor. Don men-
tored a whole generation of MS teachers and investigators in London Ontario including:
George Ebers, George Rice, John Noseworthy, Brian Weinshenker, and Tom Feasby. In
Vancouver, many fellows came from around the world to further their training including:
Adnan Al-Araji (Iraq), Alexis Boyko (Russia), Cavit Boz (Turkey), Philippe Cabre (French
Western Indies), José Cabrera-Gomez (Cuba), Gilles Edan (France), Roger Hintzen and
Raymond Hupperts (The Netherlands), Gaven McDonnell (Northern Ireland), Claude Vaney
(Switzerland), and Ernest Willougyby (New Zealand).
But above all, Don was an attentive physician, devoted to his patients and they adored
him.

Joel Oger, MD, FRCPC, FAAN

vi
Preface

Over the last 15 years, interest in multiple sclerosis (MS) has increased probably more than
for any other neurologic disorder. This arises from the simultaneous occurrence of magnetic
resonance imaging (MRI) technology that has permitted clinicians to image the pathologic
process and the development of therapeutical agents that have brought hope to patients. The
neurologist is now better able to diagnose, follow, and treat these young patients compared
to only accompanying the patient in the course of their disease a couple of decades ago.
However, the progress in diagnosis and therapy has been overemphasized by some (with
encouragement from the pharmaceutical industry), and many voices are beginning to call for
more measured statements of success. It is unconscionable to ignore the hype that has recent-
ly accompanied these new discoveries in the diagnosis and treatment of MS.

Seminars from the World Federation of Neurology (WFN) focus on the needs of neurologists
practicing in developing countries. At a time when MS is shown to be present all over the
world and multiple reports suggest its increasing frequency in developing countries, it is
essential that physicians in less-developed countries be wary of following the seductive attrac-
tion of new technologies being emphasized in the developed world.

This book places the emphasis on the clinical issues faced by neurologists practicing in devel-
oping countries when dealing with MS patients. We strongly feel that the diagnosis of MS is
possible and acceptable without the use of high-cost confirming tests such as MRI. In paral-
lel, treatment options not involving excessively costly disease-modifying drugs have been
stressed. Although some of the immunosuppressants have not had a complete endorsement
by evidence-based medicine, the association of high-dose steroids for relapses and long-term
“soft” immunosuppressants such as azathioprine may very well be more effective than gen-
erally recognized and probably not much less effective than are disease-modifying drugs.
They are certainly less costly, although a stable view of the cost–benefit comparison has not
been reached at this time.

This book represents a high level of cooperation between many different people from different
origins. It is an example of international cooperation across continents, countries, and religions.

Joel Oger, MD, FRCP, FAAN

Adnan Al-Araji, MB ChB, FRCP (Glasg.)

vii
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Editor’s Preface

The mission of the World Federation of Neurology (WFN, wfneurology.org) is to develop

international programs for the improvement of neurologic health, with an emphasis on devel-
oping countries. A major strategic aim is to develop and promote affordable and effective
continuing neurologic education for neurologists and related health care providers. With this
continuing education series, the WFN has launched a new effort in this direction, with this
volume being the fifth course made available. The WFN Seminars in Neurology uses an
instructional format that has proven to be successful in controlled trials of educational tech-
niques. Modeled after the American Academy of Neurology's highly successful Continuum,
we use proven pedagogical techniques to enhance the effectiveness of the course. These
include case-oriented information, key points, multiple choice questions, annotated refer-
ences, and abundant use of graphic material.
In addition, the course content has a special goal and direction. We live in an economic
environment in which even the wealthiest nations have to restrict health care in one form or
another. Especially hard pressed are countries where, of necessity, neurologic care is often
reduced to the barest essentials or less. There is general agreement that much of this prob-
lem is a result of increasing technology. With this in mind, we have asked the faculty to pres-
ent the instructional material and patient care guidelines with minimal use of expensive tech-
nology. Technology of unproven usefulness has not been recommended. However, at the
same time, advice on patient care is given without compromising a goal of achieving the very
best available care for the patient with neurologic disease. On occasion, details of certain
investigative techniques are pulled out of the main text and presented separately for those
interested. This approach should be of particular benefit to health care systems that are
attempting to provide the best in neurologic care but with limited resources.
These courses are provided to participants by a distribution process unusual for continu-
ing education material. The WFN membership consists of 86 individual national neurologic
societies. Societies that have expressed an interest in the program and agree to meet certain
specific reporting requirements are provided a limited number of courses without charge.
Funding for the program is provided by unrestricted educational grants. Preference is given
to neurologic societies with limited resources. Each society receiving material agrees to con-
vene a discussion group of participants at a convenient location within a few months of
receiving the material. This discussion group becomes an important component of the learn-
ing experience and has proved to be highly successful.
Our fifth course addresses the important area of multiple sclerosis. The Co-Chairs of this
course, Professors Joel Oger and Adnan Al-Araji, have selected an outstanding faculty of
experts. We very much welcome your comments and advice for future courses.

Theodore L. Munsat, M.D.

Professor of Neurology Emeritus
Tufts University School of Medicine
Boston, Massachusetts

ix
This page intentionally left blank
Contents

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .vii

Editor’s Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .ix

1. Etiology of Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1

Jun-ichi Kira, MD, PhD

2. Clinical Features of Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . .7

Gavin V. McDonnell, MB, BCh (Hons), MD, FRCP (UK)

3. Special Investigations in Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . .19

Adnan Al-Araji, MB ChB, FRCP (Glasg.)

4. The Diagnosis and Differential Diagnosis in Multiple Sclerosis . . . . . . .33

Martin Lee, BM, BCh, MRCP, MA, DPhil and Jackie Palace, BM, DM, FRCP

5. Symptomatic Management of Multiple Sclerosis . . . . . . . . . . . . . . . . . .51

Randall T. Schapiro, MD

6. Corticosteroids in the Treatment of Multiple Sclerosis . . . . . . . . . . . . .59

B.S. Singhal, MD, FRCP (Lond.), FRCP (Edin.), FAMS

7. Immunotherapy of Multiple Sclerosis:

Theoretical Basis and Practical Approach . . . . . . . . . . . . . . . . . . . . . .65
Joel Oger, MD, FRCPC, FAAN

8. Rehabilitation in Multiple Sclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . .75

José A. Cabrera-Gómez, MD, PhD, FAAN

9. Multiple Sclerosis Scales . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .85

Robert M. Herndon, MD

xi
CONTENTS

10. Clinical Trials in Multiple Sclerosis:

Basic and Reading Between the Lines . . . . . . . . . . . . . . . . . . . . . . . . .97
Marinella Clerico, MD, Luisa Giordano, MD,
Giulia Contessa, MD, and Luca Durelli, MD

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .107

xii
CHAPTER 1 KEY POINTS

■ MS is regarded as an

ETIOLOGY OF MULTIPLE SCLEROSIS autoimmune disease

targeting CNS myelin.

Jun-ichi Kira, MD, PhD ■ MS is heterogeneous with

regards to its clinical course
and preferential sites of
involvement.

Multiple sclerosis (MS) is an inflammatory (MRI) studies revealed that RR-MS and SP-
demyelinating disease of the central nervous MS showed a much higher frequency of
system (CNS). Although the mechanisms gadolinium-enhanced lesions than PP-MS.
involved in MS remain elusive, it is general- Genetic studies also demonstrated that HLA
ly hypothesized to be an autoimmune dis- association was distinct between RR-MS and
ease that targets CNS myelin. MS is thought PP-MS. Furthermore, interferon-␤ is only
to be caused by a complex interaction effective in RR-MS and SP-MS, not in PP-MS.
between genetics and environment. To date, These observations argue against MS being a
the strongest and most consistently associat- single disease and support the notion that
ed factors have been shown to be class II MS is etiologically heterogeneous.
major histocompatibility complex (MHC) In East Asians, MS severely and selective-
genes, namely, human leukocyte antigen ly affects the optic nerve and the spinal cord
(HLA)-DRB1*1501-DQA1*0102-DQB1*0602 (opticospinal MS; OS-MS). This form of MS
alleles, thus supporting the autoimmune has a higher age of onset, a higher female to
hypothesis. In addition, to date, no single male ratio, frequent relapse, and results in
pathogen has consistently been found to be severe disability when compared with con-
incriminated in MS. However, epidemiologic ventional MS. It rarely involves a secondary
surveys demonstrated that upper respiratory progressive course. MS in Africans has simi-
infections were significantly associated with lar features to that in East Asians. Using
MS relapse. Therefore, various types of spinal cord MRI, longitudinally extensive
infectious pathogens might trigger an spinal cord lesions extending over several
autoimmune response against CNS myelin in vertebral segments were shown to be rela-
genetically susceptible individuals through tively common in OS-MS (about 50% of all
molecular mimicry between infectious patients), but are extremely rare in the MS
agents and CNS myelin components or found commonly in Caucasian populations.
through the liberation of self-proteins by tis- Cerebrospinal fluid (CSF) in OS-MS shows
sue destruction, thus culminating in inflam- an absence of oligoclonal IgG bands and
matory demyelinating disease. marked pleocytosis with occasional CSF
neutrophilia. In agreement with these CSF
CLINICAL STUDIES INDICATE MS findings, spinal cord lesions extending into
HETEROGENEITY the white and gray matters show severe tis-
Most MS patients begin with relapsing-remit- sue destruction, with heavy macrophage and
ting MS (RR-MS), followed by a progressive neutrophil infiltrations in addition to many
course of MS (secondary progressive MS; SP- lymphocytes. These findings suggest that a
MS), although 10% to 20% of patients show distinct mechanism operates in this condi-
progressive onset from the beginning with- tion. Therefore, MS seems to be heteroge-
out relapse (primary progressive MS; PP- neous according to its clinical course and
MS). PP-MS affects older populations and preferential sites of involvement; however,
predominantly males, and it has a poor the mechanisms responsible for this distinc-
prognosis. Magnetic resonance imaging tion are still unknown.

1
MULTIPLE SCLEROSIS FOR THE PRACTICING NEUROLOGIST

KEY POINT MS PATHOLOGY INDICATES stances from microglia, or ischemic or

HETEROGENEOUS MECHANISMS hypoxic stress may be a trigger for oligoden-
■ MS pathology involves
inflammatory
FOR DEMYELINATION droglial apoptosis, but the cause still remains
demyelination, but distinct MS lesions are mainly located in the white to be clarified.
patterns of demyelination matter of the CNS. The nature of these As mentioned, OS-MS shows extensive
occur among clinical lesions is demyelination with relative sparing necrotic lesions preferentially in the spinal
subtypes and individuals. of axons. Remyelination is visible in acute- cord and optic nerves and is characterized
stage lesions, but is rare in chronic lesions, by neutrophilic infiltration. These pathologic
thus suggesting a temporal loss of the features are distinct from classical MS lesions
remyelinating capability of oligodendro- but seem to be similar to those reported in
cytes. However, a recent study using myelin relapsing NMO. Severe forms of OS-MS
basic protein (MBP) immunostaining indicat- appear to be identical to relapsing NMO, yet
ed that demyelination in the cortical gray the identity of both conditions is still a mat-
matter (cortical plaques) was also frequently ter of debate. However, small foci of classi-
encountered. This is usually rather difficult cal demyelinating lesions in the periventric-
to visualize using ordinary hematoxylin and ular white matter of the brain are also found
eosin staining. In all lesions, varying degrees in OS-MS and relapsing NMO, which might
of infiltration occur, both by macrophages suggest that both conditions represent one
immunoreactive for myelin proteins and by extreme type of MS.
lymphocytes consisting predominantly of T
cells. All these findings are compatible with NEURODEGENERATION IN MS
the autoimmune hypothesis targeting CNS Disability largely depends on axonal loss in
myelin. MS. Axon degeneration first occurs during
Recent studies on biopsied and autopsied acute demyelinating attacks and second dur-
materials suggest the existence of a hetero- ing the chronic progressive phase. MRI and
geneous pathology of demyelination. magnetic resonance spectroscopy (MRS)
Evidence includes (a) sharply demarcated undertaken in MS patients during the early
demyelinating lesions with infiltration by course of illness (less than 5 years) indicate
perivenous inflammatory cells (T cells and that brain atrophy and loss of axonal integri-
macrophages), which was accompanied ty occur in the early course of the disease.
with abundant remyelination; (b) deposition According to results of clinical trials of
of immunoglobulins (mainly IgG) and com- immunomodulatory drugs, reduction of
plement C9neo antigen along with disrupted relapse and new lesion formation are associ-
myelin sheaths, in addition to inflammatory ated with a decrease of disease progression
infiltrates; (c) predominant oligodendrocyte and brain atrophy in RR-MS. On the con-
apoptosis, as shown by nuclear condensa- trary, in SP-MS, neither disease progression
tion and fragmentation, that was character- nor brain atrophy is suppressed by the
ized by an early loss of myelin-associated drugs, yet new lesions on brain MRI are
glycoprotein (MAG); and (d) the nonapop- reduced, thus suggesting the existence of
totic death of oligodendrocytes in the irreversible axonal damaging processes at
periplaque white matter adjacent to active this stage.
inflammatory demyelination. These patterns Pathologic studies reveal that large
may be observed in different patients or in amounts of axonal loss occur in acute MS
one individual. Although the majority of MS lesions, with infiltration of T cells and
lesions are characterized by inflammatory macrophages, suggesting a close relation of
cell infiltrates, heterogeneous mechanisms axonal loss at this stage with inflammation.
are suggested to cause demyelination. Axonal transection is seen in the distal accu-
Another MS pathology recently has been mulation of proteins, such as amyloid pre-
described in newly forming lesions. cursor proteins, transported by axonal flow,
Extensive oligodendroglial apoptosis and at the site of axonal damage, and a correla-
microglial activation with few or no lympho- tion between the numbers of CD8+ T cells
cytes or myelin phagocytes were observed. and the extent of axonal damage also was
Viral infection, secretion of cytotoxic sub- found. Therefore, acute axonal transaction

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