Handbook of Multiple Sclerosis pdf

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Series Introduction
Multiple sclerosis (MS) is a common disease of the central nervous system, affecting
young women in particular. This disease can devastate the professional and social life of
those affected. There has been a recent explosion in knowledge about how to diagnose
MS and understand its pathophysiological mechanisms as well as provide efficacious treat-
ment. The third edition of the Handbook of Multiple Sclerosis has documented the impres-
sive and dramatic advances that have occurred. In particular, the immunopathology of the
disease is now well established. MS at one time was considered an untreatable disease;

however, now there are many therapeutic approaches. As Dr. Cook states, these advances
have led to a reduction in disability and a dramatic increase in the quality of life for
patients suffering with this potentially disabling disease.
This edition of the Handbook of Multiple Sclerosis provides clinicians with informa-
tive and detailed information regarding almost every aspect of MS. For health care profes-
sionals working with MS patients, this book provides an invaluable resource. Treatment
modalities are thoroughly discussed and comments are given about the ongoing research
in MS, which will lead to better understanding and treatment in the future.
William C. Koller
iii

Preface
Only ten years have passed since publication of the first edition of the Handbook of Multi-
ple Sclerosis, and impressive advances have been made in our understanding of multiple
sclerosis (MS), particularly with regard to its natural history, immunopathology, lesion
evolution based on imaging techniques, and therapy. Physicians are now in a much better
position to prescribe medications that can modify disease course, decrease lesion burden,
and alleviate symptoms. Many patients can look forward to fewer exacerbations, a slower
rate of deterioration, and a better quality of life. Although current treatments are only
palliative, the exciting prospect of medications that can prevent further disability, and
even promote recovery from fixed neurological deficits, no longer seems so remote.
Increased funding for MS research from a variety of sources, including federal fund-
ing agencies, the pharmaceutical industry, and national MS societies worldwide, has led
to more scientists and clinicians partaking in basic and clinical studies directed toward
finding the cause and cure of this enigmatic disorder. Patients are much better informed
about cutting-edge treatments and ongoing clinical trials through information available
on the Internet.
Over the next few years, we can expect further advances in our knowledge about
genetic susceptibility and environmental factors causing MS, and about the interaction
between those factors and the immune response that results in lesion pathogenesis. This

should lead to better-focused research and more rapid development of effective therapies.
This edition of the Handbook of Multiple Sclerosis will provide the reader with the
most up-to-date and detailed information currently available about all aspects of MS. It
should provide a valuable resource to anyone interested in this disease, be it patient, stu-
dent, clinician, or scientist. I am very grateful to the contributors, who are world leaders
in MS research and treatment. This book is dedicated to those individuals who bravely
cope with MS on a daily basis, their devoted friends and family members, and their caring
physicians.
Stuart D. Cook
v

Contents
Series Introduction William C. Koller iii
Preface v
Contributors xi
PART I. ETIOPATHOGENESIS
1. The History of Multiple Sclerosis 1
W. I. McDonald
2. The Epidemiology of Multiple Sclerosis 15
William Pryse-Phillips and Fiona Costello
3. The Genetics of Multiple Sclerosis 33
Jan Hillert and Thomas Masterman
4. Experimental Models of Virus-Induced Demyelination 67
Mauro C. Dal Canto
5. Evidence for a Viral Etiology of Multiple Sclerosis 115
Stuart D. Cook
6. Experimental Models of Autoimmune Demyelination 139
Fred D. Lublin
7. Evidence for Immunopathogenesis 163
Ute Traugott

8. Autoantibodies in Demyelinating Disease 193
Anne H. Cross, Jeri-Anne Lyons, and John L. Trotter
vii
viii Contents
PART II. CLINICAL PATHOLOGIC FEATURES
9. Clinical Features 213
Aaron E. Miller
10. Cognitive Impairment in Multiple Sclerosis 233
Jill S. Fischer
11. Loss and Restoration of Impulse Conduction in Disorders of Myelin 257
Stephen G. Waxman
12. Pathology of Multiple Sclerosis 289
John W. Prineas
13. Axonal Injury in Multiple Sclerosis 325
Carl Bjartmar and Bruce D. Trapp
14. Cerebrospinal Fluid 347
John N. Whitaker, Khurram Bashir, and Etty N. Benveniste
15. Laboratory Tests: Evoked Potentials 377
Marc R. Nuwer
16. Neuroimaging and the Use of Magnetic Resonance in
Multiple Sclerosis 403
Lael A. Stone, Nancy Richert, and Henry F. McFarland
PART III. THERAPEUTIC CONSIDERATIONS
17. The Natural History of Multiple Sclerosis 433
Sandra Vukusic and Christian Confavreux
18. Prognostic Factors in Multiple Sclerosis 449
Orhun H. Kantarci and Brian G. Weinshenker
19. Therapeutic Considerations: Rating Scales 465
Richard Rudick, Brian G. Weinshenker, and Gary Cutter
20. Therapeutic Considerations: Treatment of the Acute Exacerbation 493

Raymond Troiano
21. Interferon-␤-1b: Prophylactic Therapy in Multiple Sclerosis 503
Kenneth P. Johnson and Peter A. Calabresi
22. Therapeutic Considerations: Prophylactic Therapy with
Interferon-␤-1a 519
Lawrence Jacobs
Contents ix
23. Prophylactic Therapy—Glatiramer Acetate (Copaxone) 541
Hillel Panitch
24. Treatment of Multiple Sclerosis with Intravenous Immunoglobulin 561
Peter Rudge
25. Immunosuppressive Drugs 579
Mariko Kita and Donald E. Goodkin
26. Treatment of Multiple Sclerosis: Bone Marrow Reconstitution,
Total Lymphoid Irradiation, and Plasma Exchange 593
George P. A. Rice
27. Symptomatic Therapy 601
Randall T. Schapiro
28. Symptomatic Treatment and Rehabilitation in Multiple Sclerosis 609
Charles R. Smith and Labe Scheinberg
29. Experimental Therapies with T-Cell Vaccines, Oral Myelin, and
Monoclonal Antibodies in Multiple Sclerosis 635
Suprabha Bhat and Jerry S. Wolinsky
30. Future Immunotherapies 653
Christine Rohowsky-Kochan
Index 667

Contributors
Khurram Bashir, M.D. Department of Neurology, University of Alabama at Bir-
mingham, Birmingham, Alabama

Etty N. Benveniste, Ph.D. Department of Cell Biology, University of Alabama at Bir-
mingham, Birmingham, Alabama
Suprabha Bhat, M.D. Department of Neurology, The University of Texas—Houston,
Health Science Center, Houston, Texas
Carl Bjartmar, M.D., Ph.D. Department of Neurosciences, Lerner Research Institute,
Cleveland Clinic Foundation, Cleveland, Ohio
Peter Calabresi University of Maryland Medical Center, Baltimore, Maryland
Christian Confavreux, M.D. Service de Neurologie A, Ho
ˆ
pital Neurologique, Lyon,
France
Stuart D. Cook, M.D. University of Medicine and Dentistry of New Jersey and New
Jersey Medical School, Newark, New Jersey
Fiona Costello, M.D. Memorial University of Newfoundland, St. John’s, Newfound-
land, Canada
Anne H. Cross, M.D. Department of Neurology and Neurosurgery, Washington Univer-
sity School of Medicine, St. Louis, Missouri
Gary Cutter, Ph.D. AMC Cancer Institute, Denver, Colorado
Mauro C. Dal Canto, M.D. Departments of Pathology (Neuropathology) and Neurol-
ogy, Northwestern University Medical School, Chicago, Illinois
xi
xii Contributors
Jill S. Fischer, Ph.D. Mellen Center for Multiple Sclerosis Treatment and Research,
Cleveland Clinic Foundation, Cleveland, Ohio
Donald E. Goodkin, M.D. Department of Neurology, UCSF/Mt. Zion MS Center, San
Francisco, California
Jan Hillert, M.D., Ph.D. Karolinska Institutet at Huddinge University Hospital, Hud-
dinge, Sweden
Lawrence Jacobs, M.D. Department of Neurology, School of Medicine and Biomedical
Sciences, State University of New York at Buffalo, Buffalo, New York

Kenneth P. Johnson, M.D. Department of Neurology, University of Maryland Medical
Center, Baltimore, Maryland
Orhun H. Kantarci, M.D. Department of Neurology, Mayo Clinic and Foundation,
Rochester, Minnesota
Mariko Kita, M.D. Department of Neurology, UCSF/Mt. Zion MS Center, San Fran-
cisco, California
Fred D. Lublin, M.D. Corinne Goldsmith Dickinson Center for Multiple Sclerosis,
Mount Sinai School of Medicine, New York, New York
Jeri-Anne Lyons, Ph.D. Department of Neurology and Neurosurgery, Washington Uni-
versity School of Medicine, St. Louis, Missouri
Thomas Masterman, B.A., B.S. Karolinska Institutet at Huddinge University Hospital,
Huddinge, Sweden
W. I. McDonald, Ph.D., FRCP Royal College of Physicians, London, England
Henry F. McFarland, M.D. Neuroimmunology Branch, National Institute of Neurolog-
ical Disorders and Stroke, National Institutes of Health, Bethesda, Maryland
Aaron E. Miller, M.D. Maimonides Medical Center and State University of New York
Health Science Center at Brooklyn, Brooklyn, New York
Marc R. Nuwer, M.D., Ph.D. Department of Neurology, UCLA School of Medicine,
and Department of Clinical Neurophysiology, UCLA Medical Center, Los Angeles, Cali-
fornia
Hillel Panitch, M.D. Department of Neurology, University of Maryland School of Med-
icine, Baltimore, Maryland
John W. Prineas, M.D., FRCP Veterans Administration Medical Center, East Orange,
New Jersey, and Institute of Clinical Neurosciences, Department of Medicine, The Univer-
sity of Sydney, Sydney, Australia
Contributors xiii
William Pryse-Phillips, M.D., FRCP, FRCP(C) Memorial University of Newfound-
land, St. John’s, Newfoundland, Canada
George P. A. Rice, M.D., FRCPC The Multiple Sclerosis Clinic, London, Ontario,
Canada

Nancy Richert, M.D., Ph.D. Laboratory of Diagnostic Radiology Research, Clinical
Center, National Institutes of Health, Bethesda, Maryland
Christine Rohowsky-Kochan, Ph.D. University of Medicine and Dentistry of New
Jersey and New Jersey Medical School, Newark, New Jersey
Peter Rudge, FRCP The National Hospital for Neurology and Neurosurgery, London,
England
Richard Rudick, M.D. Mellen Center for Multiple Sclerosis Treatment and Research,
Cleveland Clinic Foundation, Cleveland, Ohio
Randall T. Schapiro, M.D. Fairview MS Center and University of Minnesota, Minne-
apolis, Minnesota
Labe Scheinberg, M.D. Professor Emeritus, Department of Neurology, Albert Einstein
College of Medicine, New York, New York
Charles R. Smith, M.D. Multiple Sclerosis Comprehensive Care Center, St. Agnes Hos-
pital, White Plains, New York
Lael A. Stone, M.D. Mellen Center for Multiple Sclerosis Treatment and Research,
Cleveland Clinic Foundation, Cleveland, Ohio
Bruce D. Trapp, Ph.D. Department of Neurosciences, Lerner Research Institute, Cleve-
land Clinic Foundation, Cleveland, Ohio
Ute Traugott, M.D. New York Medical College, Valhalla, St. Agnes Hospital, White
Plains, and Bronx Lebanon Hospital, Bronx, New York
Raymond Troiano, M.D. University of Medicine and Dentistry of New Jersey and New
Jersey Medical School, Newark, New Jersey
John L. Trotter, M.D. Department of Neurology and Neurosurgery, Washington Uni-
versity School of Medicine, St. Louis, Missouri
Sandra Vukusic, M.D. Service de Neurologie A, Ho
ˆ
pital Neurologique, Lyon, France
Stephen G. Waxman, M.D., Ph.D. Department of Neurology and PVA/EPVA Neuro-
science Research Center, Yale University School of Medicine, New Haven, and Rehabili-
tation Research Center, VA Connecticut, West Haven, Connecticut

xiv Contributors
Brian G. Weinshenker, M.D. Department of Neurology, Mayo Clinic and Foundation,
Rochester, Minnesota
John N. Whitaker, M.D. Department of Neurology, University of Alabama at Bir-
mingham and The Neurology and Research Services of the Birmingham Veterans Medical
Center, Birmingham, Alabama
Jerry S. Wolinsky, M.D. Department of Neurology, The University of Texas–Houston,
Health Science Center, Houston, Texas
1
The History of Multiple Sclerosis
W. I. MCDONALD
Royal College of Physicians, London, England
I. INTRODUCTION: THE EARLY HISTORY OF MULTIPLE SCLEROSIS
The first depiction of the central nervous system in what we now recognize as multiple
sclerosis was published by Carswell (1) in 1838. As Compston (2) has established, Cruveil-
hier’s pictures soon followed (3). To them were attached the first brief clinical descriptions.
Valentiner (4) in 1856, working in the Department of Frerichs (who had also described
cases of multiple sclerosis), reported exacerbations and remissions, and—it is interesting
to note—mental changes as well. In 1864 Fromann (5) described and illustrated demyelin-
ation.
Thus the main clinical and pathological characteristics of multiple sclerosis were
already recognized by the mid-1860s. It was Charcot (6), however, who in 1868 drew
the threads together, adding new observations and making prescient pathophysiological
interpretations in his magisterial lectures.
Babinski (7,8) described further important histological details, illustrating, for exam-
ple, macrophages containing debris alongside axons denuded of myelin. Thetermsegmental
demyelination could not be used of central demyelination at that time, since—on the author-
ity of Ranvier (9)—nodes were held not to exist on central nerve fibers. (It is interesting to
note, in passing, that Babinski’s drawings of normal central fibers show short gaps in the
myelin that surely must benodes,thoughhe does not label them as such.He had,inhisthesis,

already disagreed with Charcot on a point of detail; perhaps he did not wish to contradict
explicitly another great contemporary figure of the Parisian scientific world.)
II. THE TWENTIETH CENTURY
The history of the growth of understanding of multiple sclerosis in the twentieth century
is one of growing complexity, since disciplines as various as particle physics, molecular
1
2 McDonald
biology, and population genetics have provided techniques and approaches that have
helped to elucidate different aspects of the disease. It is convenient to consider the evolu-
tion of our knowledge under a number of headings.
A. Pathology
Marburg (10), early in the new century, described acute, rapidly fatal multiple sclerosis
and emphasized the importance of axonal degeneration in many lesions. But it was Dawson
(11) who, in 1916 provided the definitive histological account of the disease in his huge
monograph. Little was then added until the introduction of the electron microscope to
human neuropathology in the 1960s, followed by the application of the techniques of
histochemistry and immunohistochemistry in the past three decades. The occurrence of
remyelination was established and the patterns of myelin breakdown were documented
(12–16). A rich variety of immunopathological changes in the lesions (and in the normal-
appearing white matter) has been documented (see reviews in Refs. 17 and 18), though
a coherent scheme for the initiation and evolution of the lesion making sense of both the
immunopathology and the neuropathology, including that of the glia, has still to be estab-
lished (see below).
B. Neurobiology
The importance of an understanding of the development and maintenance of neurons and
their supporting structures is crucial to an understanding of the pathogenesis of multiple
sclerosis and of repair mechanisms that compensate for the damage and are so strikingly
effective in the early stages of the disease. The recognition by Raff and colleagues (19,20)
of the different elements in the glial cell lineage in rodents was an important advance, as
was the demonstration that similar cells exist in the central nervous system of adult human

beings (21). Growing numbers of factors that influence cell division, differentiation, and
migration are being recognized (see reviews in Refs. 22 and 23). How they interact in
the normal and diseased nervous system is a major area of current investigation.
C. Pathophysiology
Charcot (6) was explicit that the areas of demyelination cause the symptoms of multiple
sclerosis, and it is implicit in his account that loss of function was due to block of electrical
conduction. Holmes (24) deduced from a postmortem study of spinal cord compression
that demyelination must lead to conduction block. The first demonstration that this is so
came, however, only during the Second World War, when Denny-Brown and Brenner
(25), who were investigating the mechanisms of nerve injury, showed experimentally that
chronic compression of a motor nerve could produce focal demyelination and that stimula-
tion distal to such a lesion resulted in muscular contraction, whereas stimulation proximal
to it did not.
The late 1940s saw a rapid development in the understanding of conduction in nor-
mal nerve; in particular, Huxley and Sta
¨
mpfli (26) proved the existence of saltatory con-
duction in myelinated fibers. It then became of physiological interest to define the details
of the consequences of demyelination. In the early 1960s, conduction block was demon-
strated directly by recording from the lesion itself and the adjacent histologically normal
fibers, and a new phenomenon, slowing of conduction, was demonstrated in single fibers
(27–29) as well as in compound action potentials (30,31). Similar properties were soon
History of Multiple Sclerosis 3
identified in demyelinated central nerve fibers (32). The latter single-fiber study revealed
intermittent conduction block, which resulted in irregular transmission of impulses, thus
providing evidence for a speculation of Charco (6) a century earlier. In the 1970s the
marked thermolability of fibers traversing a demyelinating lesion was demonstrated
(33,34), and it was found that demyelinated axons can acquire the ability to conduct contin-
uously, as in unmyelinated fibers (35). Restoration of conduction was shown to depend
on the development of large numbers of sodium channels in the denuded internodal axon

(36,37). It was later shown that a similar increase in the number of sodium channels occurs
in surviving demyelinated axons in multiple sclerosis lesions (38). It is reasonable to
conclude that this is a crucial element in remission.
Remyelination in the central nervous system was convincingly demonstrated experi-
mentally by Bunge et al. (39) in 1961 and was later shown to restore secure conduction
(40). As already mentioned, remyelination occurs in multiple sclerosis. Recent evidence
suggests that under certain circumstances it may be extensive, though in many lesions at
postmortem it is scanty and confined to the edges of lesions (12,41). The role of remyelina-
tion in different lesions at different ages and perhaps in different individuals (is it, for
example, more extensive in benign multiple sclerosis?) has still to be defined.
What of the mechanism of the irrecoverable deficit that develops in most patients
after the initial relapsing and remitting phase, in which recovery from individual relapses
is often virtually complete? The use of magnetic resonance imaging (MRI) and magnetic
resonance spectroscopy (MRS) techniques sensitive to neuronal and axonal loss has in
the past 5 years provided evidence that the degenerative element in the pathological pro-
cess (known since Charcot (6) and repeatedly reaffirmed; see review in Ref. 42) plays an
important part (44–47) (see review in Ref. 48). It is nevertheless likely that failure of
the early recovery mechanisms with the reappearance of conduction block in chronically
demyelinated fibers also contributes (49).
D. Diagnosis
A practical consequence of the demonstration of slowing of conduction in demyelinated
fibers was the introduction of the evoked potential method as a diagnostic technique. In
the 1960s there had been a rapid development of nerve conduction studies as an aid to
pathological diagnosis in peripheral neuropathy: demyelinating neuropathies were associ-
ated with marked slowing of conduction, while degenerative neuropathies were not. Re-
cording of cerebral evoked potentials after peripheral stimulation had become feasible
with the introduction of averaging techniques by Dawson (50). They were being increas-
ingly used in the 1960s in the physiological investigation of cerebral function and had
been studied in neuronal diseases affecting the cerebral cortex (51). Martin Halliday and
I therefore decided to see whether evoked potentials could be used diagnostically in a way

analogous to nerve conduction studies—given that, as in the peripheral nervous system,
experimental degenerative lesions were not associated with slowing of conduction,
whereas demyelinating lesions were (52). We started with the visual evoked potentials
(VEP) in optic neuritis. Its potential value was at once clear: substantial delays were seen
in more than 90% of cases (53). Exploitation of the somatosensory and brainstem auditory
evoked potentials along similar lines quickly followed (see review in Ref. 54). The tech-
nique quickly became established as an invaluable noninvasive diagnostic procedure in
the assessment of patients suspected of having multiple sclerosis (55). Overall abnormali-
ties were found in 70% of patients with clinically definite multiple sclerosis, although the
4 McDonald
changes were not specific. From the point of view of pathophysiology, the evoked potential
techniques have provided invaluable confirmation of mechanisms of symptom production
predicted from animal studies (56,57).
Cerebrospinal Fluid Analysis.
Lumbar puncture was introduced by Quinke (58) and Wynter (59) in the late nineteenth
century, and by 1925 it was well established that multiple sclerosis was associated with
a particular abnormality known as the ‘‘paretic colloidal gold curve’’ (from its association
with syphilitic general paralysis of the insane) (60). This abnormality is now known to
be due to the presence of oligoclonal IgG. The demonstration of the latter depended on
the application of electrophoresis to cerebrospinal fluid, first by Kabat et al. (61) in 1942.
Later the introduction of polyacrylamide gels and isoelectric focusing increased the sensi-
tivity to over 90%, though the specificity remains as poor as it was in the 1920s. Interpreta-
tion of the meaning of the observed abnormalities—as in evoked potentials and MRI—
still depends on the clinical and other investigative contexts.
Magnetic Resonance Imaging
The demonstration in 1981 that MRI reveals abnormalities in multiple sclerosis represents
a landmark in the history of our understanding of the disease (62). That these abnormalities
correspond with plaques at postmortem was soon shown, and it became clear that MRI
abnormalities are found in more than 95% of patients with clinically definite disease (63–
65). As the following section recounts, the exploitation of MRI and MRS has also led to

new insights into the pathogenesis of the disease.
E. Pathogenesis
While there was general agreement in the nineteenth century on the pathological changes
in the nervous system in multiple sclerosis, there was a sharp division of opinion between
Rindfleisch (66) and Charcot (6) on the mechanisms that lead to their development. Rind-
fleisch concluded that the primary change was inflammation. Charcot, on the other hand,
took the view that the initial change was hyperplasia of the glia. The inflammatory hypoth-
esis gradually gained support in the latter part of the twentieth century because of the
similarity in the histology of multiple sclerosis and the T cell–mediated demyelinating
disease experimental allergic encephalomyelitis, especially in its chronic relapsing form
(13). Support also came from the similarities between the acute form of experimental
disease and acute disseminated encephalomyelitis, and especially from fatal cases of en-
cephalomyelitis following antirabies inoculation (67) in the 1970s. But it was the develop-
ment of MRI and MRS in the 1980s and 1990s that provided compelling evidence for
the role of inflammation in the evolution of the new lesion.
It has already been mentioned that the abnormalities on standard MRI correspond
with lesions at postmortem. In the 1980s it was found that some lesions exhibit enhance-
ment after the injection of gadolinium-DTPA, while some do not (68,69). Experimental,
postmortem, and biopsy correlations provided good evidence that in this context enhance-
ment indicates an increase in the permeability of the blood-brain barrier in association with
inflammation (70). Serial studies at intervals as short as 1 week showed that enhancement
(signaling inflammation) is the earliest event detectable by MRI in most lesions in
relapsing/remitting and secondary progressive multiple sclerosis (71). It seems, however,
that a few lesions in these forms of the disease (72,73) and the majority of the lesions in
History of Multiple Sclerosis 5
primary progressive multiple sclerosis (74) do not show evidence of inflammation by these
methods. The situation is a complex one, since, at postmortem, inflammatory cells are
present in primary progressive multiple sclerosis, though in smaller numbers than in sec-
ondary progressive multiple sclerosis (75).
MRS revealed that myelin breakdown occurs early in the inflammatory phase of

the lesion (76). It is generally assumed that it is a consequence of the immune-mediated
inflammation. However, Lassmann and colleagues (18,77), on the basis of biopsy and
postmortem studies, have recently suggested that inflammation and demyelination may
occur independently of each other and have proposed that several distinct pathogenetic
mechanisms may exist in different clinical subgroups of patients with multiple sclerosis.
F. Etiology
What initiates the pathogenetic processes that lead to the pathology we see at postmortem
and lead to the symptomatology we see during life? Charcot (6) confessed that it was not
possible to have a clear idea of the cause of multiple sclerosis at the time that he lectured.
By the last decade of the nineteenth century, however, the discovery that certain acute
illnesses were caused by bacteria led to Marie’s conviction (without evidence) that infec-
tion would be found to be the cause of multiple sclerosis (78). Some not very convincing
evidence for infection (by spirochetes or the ‘‘spherula insularis’’) was adduced in the
first part of the twentieth century but did not survive close examination (see review in
Ref. 79). The conviction that a viral infection is the direct cause of multiple sclerosis has
from time to time been held equally vehemently and with equally little objective support.
And so it remains: though spontaneously occurring demyelinating diseases due to viral
infection in animals are well recognized, repeated efforts to demonstrate persistent viral
infection in multiple sclerosis have failed. That, however, does not exclude the possibility
that infection—perhaps viral—might play a role in initiating the disease or in precipitating
relapse. Indeed there is evidence that the latter is the case (80). What of the former? This
brings us to a consideration of the epidemiology of multiple sclerosis.
G. Epidemiology
The earliest recognition (81) that there are differences in the frequency of multiple sclero-
sis in different populations came in 1903. Further evidence emerged from the consideration
of the morbidity in ex-servicemen in the United States after the First World War (82).
After the Second World War, Dean (83) observed an unexpectedly low prevalence of
multiple sclerosis in South Africa. This observation was quickly followed by extensive
epidemiological studies in many parts of the world (see review in Ref. 84). It soon became
clear that there were real differences in the frequency of multiple sclerosis in different

populations: it is an order of magnitude less prevalent among Orientals than among indi-
viduals of northern European origin. Among the latter the frequency varies with place of
birth, residence, and age at migration (when this has taken place). These observations
have been interpreted as indicating the existence of an environmental factor or factors in
the cause of multiple sclerosis, and apparent spatiotemporal clusters of cases have been
taken to support this view (85). What these factors might be, however, remains uncertain.
Genetic Factors
The epidemiological data and, in particular, the relative rarity of multiple sclerosis among
Orientals suggested the operation of genetic factors influencing susceptibility. The familial
6 McDonald
occurrence of multiple sclerosis has been recognized since early in the twentieth century.
Families usually share environments, but three sets of observations indicated that genetic
factors are important: there is a higher concordance rate among monozygotic (about 30%)
than dizygotic (about 2%) twins (86,87); adoptees living with the parent or a sibling with
multiple sclerosis do not have an increased risk of developing the disease (88); and half
siblings have a significantly lower risk of developing multiple sclerosis than full siblings,
there being no difference in risk for those reared together and those reared apart (89). But
given that about 70% even of monozygotic twins are not concordant and not all twin
studies have yielded the same results, it is clear that genetic factors play only a part in
the etiology of the disease.
How might the genetic factors operate? The observation of an association between
the HLA system and multiple sclerosis was a promising start, but the recent results of
large international collaborative investigations have made it clear that there is not a single
major susceptibility locus and that a number of genetic factors other than those related
to the HLA region are involved (90–94) (see review in Ref. 95). The mechanism of suscep-
tibility thus remains elusive.
H. Treatment
Physicians, of course, must try to help their patients whether or not the mechanism of the
disease is fully understood. In the nineteenth century as now, treatments were designed
partly to relieve symptoms and partly to modify the course of the disease. The treatments

used for Augustus D’Este in the 1830s and 1840s [and recorded in meticulous detail by
him (96)] had a basis rational enough to his physicians but are wholly without basis from
our perspective (79).
Treatments Based on Theories of Etiology
Marie’s (78) advocacy of infection as the cause of multiple sclerosis was accompanied
by his recommendation that mercury should be used for its ‘‘disinfective properties.’’
Because of their effectiveness in syphilis, organic arsenical compounds were recom-
mended when a spirochete was thought to be the cause (97). In 1924 the fashion changed
to malarial treatment (with the same rationale) (98). But malaria was not readily available
for transmission in northern Europe; therefore, intramuscular injections of typhoid vaccine
or sterile milk three times weekly were used instead to induce the supposedly beneficial
fever. But as Denny-Brown (who had experience of administering these treatments when
he was a resident at Queen Square) later commented (99), they were ‘‘seldom beneficial
and sometimes disastrous.’’ Although the spirochetal theory was largely abandoned by
1929, arsenic continued to be used for another 30 years. McAlpine still had an arsenic
clinic in the Middlesex Hospital in the 1950s. Marie’s idea of chronic bacterial infection
still lingered until that time, and tonsillectomy to eradicate it was still recommended (100).
Treatments Based on Theories of Pathogenesis
Marie (78) in the late nineteenth century had also recommended iodide to modify the
sclerosis which Charcot (6) believed was the primary disease mechanism. Putnam (101),
in the 1930s, noting the perivenular arrangement of the plaques at postmortem, concluded
that the pathogenesis was ischemic and used anticoagulants to prevent thrombosis in the
venules he thought he saw that but others before and after did not. The ischemic theory
was revived in the 1980s (though the pathology had not changed) and led to the widespread
History of Multiple Sclerosis 7
use of hyperbaric oxygen, which, as expected, was not shown to be of benefit. Swank
(102) and later Baker et al. (103) advocated a metabolic pathogenesis on the basis of
epidemiological and postmortem biochemical studies. The resulting use of polyunsaturated
fatty acid regimes did not, however, confer convincing benefit (104).
By far the most influential pathogenetic theory has been that of autoimmunity. Al-

though the initiating event must necessarily be different, it was logical to try to modify
the immune response. In principle three approaches are possible. The first to be employed
was immunosuppression: nonspecific methods (using, for instance, cyclophosphamide,
azathioprine, cyclosporine, or total lymphoid irradiation) have not proved convincingly
effective, though a metanalysis of azathioprine has suggested that a further trial, probably
in combination with other treatments such as beta interferon, may be worthwhile (105).
Mitoxantrone, another nonspecific immunosuppressant, depresses MRI evidence of dis-
ease activity over a 6-month period, though whether this is translated into clinical benefit
remains to be seen (106). Turning to more specific forms of immunotherapy, anti-CD4
antibodies have proved ineffective (107), though the humanized monoclonal antibody
Campath-1H has a dramatic effect on MRI activity (108,109). Whether clinical benefit
justifying the not inconsiderable risk of side effects will follow is currently under investi-
gation.
Historically, the second approach to be used was induction of tolerance, though two
decades elapsed before convincing benefit was shown. Glatairimer acetate has now been
shown to reduce the relapse rate by about one-quarter and possibly to slow progression,
though the latter claim requires confirmation (110).
The third approach was immune modulation using the interferons, though they were
originally employed for their antiviral properties. Interferon beta-1b (111) and beta-1a
(112,113) reduce the relapse rate by about one-third. It has been reported that in secondary
progressive multiple sclerosis, interferon beta-1b slows progression of disability (114).
These issues are discussed in detail elsewhere in this volume.
The results of these recent trials—showing a modest effect in changing the course
of the disease—are encouraging, not least because they reflect the power of clinical trials
utilizing improved design and greater rigor of conduct of therapeutic investigations. The
process of refinement of trial design and methods of analysis is still continuing. It is
interesting to review how the present position was reached. Undoubtedly the most impor-
tant step forward was the introduction of statistics, the methods of which grew out of the
concerns of physicians, physiologists, anthropologists, and what we would now call social
scientists in the nineteenth century to deal with data derived from populations [see review

by Matthews (115)]. The great debates in Paris in the 1830s and 1840s, in Germany in
the 1880s, and in London at the turn of the century gradually led to an agreed methodology.
The next crucial contributions were Fisher’s (116) The Design of Experiments in 1935 and
then the introduction of the principle of randomization by Bradford Hill; the triumphant
vindication of this approach in a chronic disease came in 1948, with the trial of streptomy-
cin in tuberculosis (117).
Coming specifically to multiple sclerosis, the first important step was the introduc-
tion by Kurtzke (118) in 1955 of a scale that provided a way of measuring the physical
impact of the disease on the patient. He pointed out its limitations, and they are widely
agreed on. Modifications have been introduced, but the Kurtzke scale remains central to
clinical trials. Criteria for diagnosis were accepted at a meeting of the New York Academy
of Sciences (119) in 1965; in 1983, they were refined to include the results of investigations
(120). In the same year the National Multiple Sclerosis Society of the United States (the
8 McDonald
founding of which by Sylvia Lawry in 1946 must itself be counted as a major step in the
history of multiple sclerosis) held a meeting of great significance for the design of clinical
trials for therapeutic agents in multiple sclerosis (121). The necessity for the double-blind
placebo-controlled trial was agreed on.
In the 1990s, three significant developments have taken place. First, there has been
the realization of just how large clinical trials must be if valid conclusions about therapeu-
tic effectiveness are to be drawn. The natural history data of Weinshenker et al. (122,123)
have been exploited to good effect. Second, MRI has been introduced as a method for
monitoring treatment. It is at its best in screening putative therapies for an effect on ‘‘dis-
ease activity.’’ However, the methods so far used—as the interferon beta trials so clearly
show—relate but weakly to an effect on progression of disability. The prospect for improv-
ing the relationship between MRI and clinical data is, however, good (124).
The very success of the recent clinical trials has paradoxically created a major prob-
lem for the future. Given that we now have treatments that modify (albeit modestly) the
course of multiple sclerosis, it is no longer ethically justifiable to carry out such large,
prolonged, double-blind placebo-controlled trials as were needed to demonstrate the effec-

tiveness of the recently licensed products. A new approach is needed, and as the twenty-
first century begins, an international group of investigators is working under the auspices
of the International Federation of Multiple Sclerosis Societies to do just that.
III. CONCLUSION
This short account of the history of demyelinating disease has been written from the stand-
point of the medical scientist. But as physicians our concern is equally with individuals
and their suffering. It is important that we know what it is like to experience multiple
sclerosis. A number of accounts have appeared in writing, in the cinema, and on television.
None is more effective than the first, by Augustus D’Este (an illegitimate grandson of
King George III of England), who kept a diary of his illness, which began 16 years before
Carswell’s (1) depiction of the pathology and ended fatally 20 years before Charcot’s (6)
account. It was published, with a commentary, after the Second World War (96). It is still
worth reading today.
ACKNOWLEDGMENT
This chapter is based on a paper on the history of demyelinating disease published in
Affection demyelinisantes—collection traite de neurologie. Rueil Malmaison: Groupe Li-
aison S.A., 1998.
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