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`For NDC [1918—1986]
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`Portrait by Howard Morgan. Reproduced by permission or Harveian Librarian, Royal College of Physicians of London.
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`Commissioning Editor: Susan Pioli
`Project Development Manager: Louise Cook
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`Page 2 of 163
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`

`

`
`
`Alastair Compston PhD FRCP FMedSci
`Professor of Neurology, University of Cambridge, Cambridge, UK
`
`Christian Confavreux MD
`Professor of Neurology, HOpilaI Neurologique, Hospices Civils de Lyon and Universite Claude Bernard,
`Lyon, France
`
`Hans Lassmann MD
`Pro essor of Neuroirnmunology, Center lor Brain Research, Medical University of Vienna, Vienna, Austria
`
`Ian McDonald PhD FRCP FMedSci
`Pro essor Emeritus of Clinical Neurology. Institute of Neurology, UniverSity College London, London, UK
`
`
`
`‘
`
`David Miller MD FRCP FRACP
`Pro essor of Clinical Neurology, Institute of Neurologl’. University College London, and Consultant
`Neurologist, National Hospital for Neurology and Neurosurgery. London, UK
`
`John Noseworthy MD FRCPC
`Fro essor and Chair, Department of Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA
`
`Kenneth Smith PhD
`Pro essor of Neurophysiology and Head of Neuroinflammation Group, King's College London School of
`Medicine at Guy‘s, London. UK
`
`Hartmut Wekerle MD
`Professor and Director, Max Planck Institute of Neurobiology, PIanogg-Martinsried, Germany
`
`CHURCHILL
`LIVINGSTONE
`
`ELEVEIR
`
`I
`
`
`
`Page 3 of 163
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`Page 3 of 163
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`

`

`
`
`CHURCHILL
`LIVINGSTONE
`ELSEVIER
`
`2006, Elsevier inc. All rights reserved.
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`First published December 2005
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`Page 4 of 163
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`

`

`Contents
`
`Preface to the fourth edition
`
`viii
`
`SECTION 1
`THE STORY OF MULTIPLE SCLEROSIS
`1
`
`
`The story of multiple sclerosis
`1
`Alastair Coriips‘tmt, Hams Lu.5‘.\'iiic’iilii moi [rm i‘VIc'Drmrth
`The evolvmg concept of multiple sclerosis
`Naming and classifying the disease: 1868—1983
`Clinical descriptions of multiple sclerosis: 18384915
`Personal accounts of multiple sclerosis: 1822—1998
`The social history of multiple sclerosis
`The pathogenesis and clinical anatomy of multiple
`sclerosis: 1849—1977
`
`The laboratory science of multiple sclerosis: 1913771981
`Discovery of glia and remyelination: 1858—1983
`The aetiology of multiple sclerosis: 1883—1976
`Attitudes to the treatment of multiple sclerosis: 180971983
`
`SECTION 2
`THE CAUSE AND COURSE OF MULTIPLE SCLEROSIS
`
`The distribution of multiple sclerosis
`2
`Ainstcrir Coriipsioii and Christian. Corri'biirreux
`The rationale for epidemiological studies in multiple
`sclerosis
`
`
`
`
`
`Definit‘ons and statistics in epidemiology
`Stra egies for epidemiological studies in multiple sclerosis
`'he geography of multiple sclerosis
`xiui ipe sclerosis in Scandinavia
`xiul ipe sclerosis in the United Kingdom
`ul ipe scleroSIS in the United States
`vilil ipe sclerosis in Canada
`Lil ipe sclerosis in Australia and New Zealand
`UI ipe sclerosis in Continental Europe
`ul ipe sclerosis in the Middle East
`ul ip e sclerosis in Africa
`LII ip e sclerosis in Asia and the Far East
`Mul ipe sclerosis in migrants
`Epidemics and clusters of multiple sclerosis
`he environmental factor in multiple sclerosis
`
`
`
`The genetics of multiple sclerosis
`3
`Alastair Coritpstori curd Hartiimt Witter}?
`Genetic analysis of multiple sclerosis
`Methods of genetic analysis
`Racial susceptibility
`
`Page 5 of 163
`
`3
`
`3
`3
`T
`13
`21
`
`24
`
`39
`45
`54
`62
`
`69
`
`71
`
`71
`
`71
`75
`76
`7?
`81
`83
`85
`86
`87
`92
`93
`94
`95
`100
`105
`
`113
`
`113
`114
`123
`
`Gender differences in susceptibility
`Familial multiple sclerosis
`Candidate genes in multiple sclerosrs
`Systematic genome screening
`Lessons from genetic studies of experimental autoimmune
`ericephalomyelitis
`Conclusion
`
`The natural history of multiple sclerosis
`4
`Christian. Confcwreux and .‘Iirrxtair Compstim
`Methodological constderations
`The outcome landmarks of multiple sclerosis: dependent
`variables
`
`The onset of multiple sclerosis
`The overall course of multiple sclerosis
`The prognosis in rnultipie sclerosis
`Survival in multiple sclerosis
`Disease mechanisms underlying the clinical course
`Intercurrent life events
`Conclusion
`
`The origins of multiple sclerosis: a synthesis
`5
`Aiasmir Corirpstou, Hartmirt Wtieerie and ion McDonoiii
`Summary of the problem
`The geography and phenotype of multiple sclerosrs
`The environmental factor in rnuitipie sclerosis
`Genetic susceptibility and multiple sclerosis
`Genetics and the European population
`Multiple sclerosis: an evolutionary hypothesis
`
`SECTION 3
`THE CLINICAL FEATURES AND DIAGNOSIS OF
`MULTIPLE SCLEROSIS
`
`The symptoms and signs of multiple sclerosis
`6
`tori McDonald and AIasini'r Campsion
`Multiple sclerosis as a neurological illness
`Symptoms at onset of the disease
`Symptoms and signs in the course of the disease
`Individual symptoms and signs
`Associated diseases
`Multiple sclerosis in childhood
`Conclusion
`
`The diagnosis of multiple sclerosis
`7
`David Miiicr,
`lam McDonald and Kenneth Smith
`Diagnostic criteria for multiple sclerosis
`Selection of investigations
`
`
`
`26
`’26
`‘36
`63
`
`75
`80
`
`83
`
`'83
`
`93
`97
`202
`209
`22|
`228
`243
`269
`
`273
`
`273
`2.73
`276
`279
`ZSI
`284
`
`285
`
`237
`
`287
`291
`298
`300
`341
`343
`346
`
`347
`
`347
`350
`
`
`
`__‘1__a-lh._
`
`Page 5 of 163
`
`

`

`Contents
`
`
`
`Pathogenesis of demyelination and tissue damage
`Peripheral blood biomarkers for multiple scler0sis
`and disease activity
`Markers of multiple sclerosis and disease activity in
`cerebrospinal fluid
`
`12 The pathology of multiple sclerosis
`Hans Lassmami and Harimut H’eiaerie
`introduction
`
`Pathological classification of demyelinating diseases
`The demyelinated plaque
`immunopathology of inflammation
`Demyelination and oligodendrogliai damage
`Remyelination
`Axonal pathology
`Grey matter pathology and cortical plaques
`Astroglial reaction
`Abnormalities in the 'normal' white matter of patients
`with multiple sclerosis
`Distribution of |esrons in the nervous system
`is there evidence for an infectious agent in the lesions of
`multiple sclerosis?
`Dynamic evolution of multiple sclerosis pathology
`Differences between acute, relapsing and progressive
`multiple sclerosis
`Molecular approaches to the study of the multiple sclerosis
`lesion: profiling of transcriptome and proteorne
`Assodation of multiple sclerosis with other diseases
`Condudon
`
`536
`
`540
`
`547
`
`557
`
`55?
`557
`559
`564
`572
`582
`584
`587
`589
`
`589
`590
`
`592
`593
`
`594
`
`596
`598
`599
`
`Magnetic resonance imaging
`Evoked potentials
`Examination of the cerebrospinal fluid
`A strategy for the investigation of demyelinating disease
`Updating the McDonald diagnostic criteria and the prospect
`of future revisions
`
`The differential diagnosis of multiple sclerosis
`8
`David Miller and Alastair Campston
`The spectrum of disorders mimicking multiple sclerOsis
`Diseases that may cause multiple lesions of the central
`nervous system and also often follow a relapsing—
`remitting course
`Systematized central nervous system diseases
`isolated or monosymptomatic central nervous system
`syndromes
`Non—organic symptoms
`How accurate is the diagnosis of multiple sclerosis?
`
`9 Multiple sclerosis in the individual and in groups:
`a conspectus
`David Miller; {on McDonald and Alastair Compston
`The typical case
`Isolated syndromes and their outcome judicious use of
`investigations and critique of the new diagnostic criteria
`Comorbidity and associated diseases
`Situations in which alternative diagnoses should be
`considered
`
`When to ignore ‘inconvenient‘ laboratory results or clinical
`findings: taking the best position
`'Pathognomonic' versus ‘unheard of“ features of multiple
`Sclerosis
`
`351
`373
`330
`383
`
`386
`
`389
`
`389
`
`390
`413
`
`422
`435
`436
`
`439
`
`439
`
`441
`445
`
`445
`
`446
`
`446
`
`SECTION 4
`THE PATHOGENESIS OF MULTIPLE SCLEROSIS
`44?
`
`
`1D The neurobiology of multiple sclerosis
`Airutoir Compston, Hams Lassmann and Kenneth. Smith
`Organization in the central nervous system
`Cell biology of the central nervous system
`Macroglial lineages in the rodent and human nervous
`system
`interactions between glia and axons
`Demyelination
`Axon degeneration and recovery of function
`Remyelination
`
`11 The immunology of inflammatory demyelinating
`disease
`Harrow: Wekerfe and Hans Lassmam
`Multiple sclerosis as an autoimmune disease
`immune responses: innate and adaptive
`T lymphocytes
`B lymphocytes
`Autoimmunity and self-tolerance in the central
`nervous system
`Regulation of central nervous system autoimmune
`responses
`immune reactivity in the central nervous system
`
`vi
`
`449
`
`449
`450
`
`455
`463
`469
`477
`483
`
`491
`
`491
`492
`494
`504
`
`505
`
`524
`530
`
`Page 6 of 163
`
`13 The pathophysiology of multiple sclerosis
`Kenneth Smith, Ian McDonald, David Mdiet and Ham Lassmmm
`601
`introduction
`
`601
`
`Methods for exploring the pathophyslology of
`multiple sclerosis
`Relapsing—remitting multiple sclerosis: loss of function
`Relapsing—remitting multiple sclerosis: recovery of function
`and remission
`
`PhySiological explanations for clinical symptoms in multiple
`sclerosis
`Permanent loss of function in the context of disease
`progression
`Conclusion
`
`602
`61 D
`
`627
`
`634
`
`649
`658
`
`66f
`
`14 The pathogenesis of multiple sclerosis: a pandect
`Hans Lassmarm, Kenneth Smith, Hartmut Wakerie and Alastair
`Compstort
`Core features in the neuropathology of multiple sclerosis
`The pathophysrology of functional deficits and recovery
`The relation between inflammation and neurodegeneration in
`multiple sclerosis
`The role of autoimmunity in multiple sclerosis
`Complexity and heterogeneity in multiple sclerosis
`
`661
`663
`
`665
`666
`667
`
`SECTION 5
`THE TREATMENT OF MULT|PLE SCLEROSIS
`669
`
`
`15 Care of the person with multiple sclerosis
`David Milfer, John Noseworthy and Aiaism-r'r Compston
`
`671
`
`Page 6 of 163
`
`

`

`General approach to the care of people with
`multiple sclerosis
`The early stages of disease: minimal disability
`The middle stages of disease: moderate disability
`The later stages of disease: severe disability
`Guidelines for the management and investigation of
`multiple sclerosis
`Conclusion
`
`671
`673
`6??
`679
`
`680
`681
`
`683
`
`16 Treatment of the acute relapse
`John Noseworrhyj Christian Confam'wx and Alastair Compsron
`683
`The features ot active multiple sclerosis
`686
`The treatment of relapses
`690
`Other approaches to the treatment of acute relapse
`692
`Treatment of acute optic neuritis
`Management of other isolated syndrorries and acute
`disseminated encephalomyelitis
`Adverse effects
`Mode of action of corticosteroids
`Practice guidelines
`
`694
`695
`696
`699
`
`17. The treatment of symptoms in multiple sclerosis
`and the role of rehabilitation
`
`l'oilm Noteworthy, David Miller and Alastair Compston
`The general principles of symptomatic treatment in
`multiple sclerosis
`Disturbances of autonomic function
`Mobility and gait disturbance
`Fatigue
`Disturbances of brainstern function
`Perturbations oi nerve conduction
`Cognitive function
`visual loss
`
`7’01
`
`701
`701
`?12
`717
`7’18
`721
`724
`F25
`
`Contents
`
`Rehabilitation in multiple Sclerosis
`Conclusion
`
`18 Disease-modifying treatments in multiple sclerosis
`John Noseworrhyj David Miller and Alastair Compsion
`The aims of disease-modifying treatment
`The principles of evidence—based prescribing in
`multiple sclerosis
`The role of magnetic resonance imaging in clinical trials
`Drugs that stimulate the immune response
`Drugs that nonspecifically suppress the immune response
`The beta interferons
`
`Molecules that inhibit T-cell—peptide binding
`Treatments that target T cells
`Agents inhibiting macrophages and their mediators
`Recent miscellaneous treatments
`
`Postscript
`
`19 The person with multiple sclerosis: a prospectus
`[Huston Crmtpxton, David Miller and John Nuseworihy
`A perspective on the recent history of therapeutic endeavour in
`multiple sclerosis
`Setting an agenda: the window of therapeutic opportunity
`Prospects for the treatment of progressive multiple sclerosis
`Remyelination and axon regeneration
`Tailoring treatment to defined groups
`Postscript
`
`References
`
`Index
`
`?26
`7'28
`
`HQ
`
`729
`
`7'33
`1’34
`738
`7'42
`755
`784
`7‘91
`800
`801
`802
`
`803
`
`803
`803
`805
`806
`810
`810
`
`81 '1
`
`947
`
`
`
`Page 7 of 163
`
`Page 7 of 163
`
`

`

`SECTION ONE THE STORY OF MULTIPLE SCLEROSIS
`
`
`
`The story of multiple sclerosis
`
`Alastair Compston, Hans Lassmann and Ian McDonald
`
`THE EVOLVING CONCEPT OF MULTIPLE
`SCLEROSIS
`
`Multiple sclerosis was first depicted in 1838. The unnamed
`patient was French,
`the illustrator a Scotsman.
`In the six
`decades that followed, French and German physicians provided
`a coherent clinicopathological account of the disease. By the
`beginning of the 20th century, a disease that only a few years
`earlier had merited individual case reports had become one of
`the commonest reasons for admission to a neurological ward.
`Now, multiple sclerosis is recognized throughout the world,
`with around 2.5 million affected individuals incurring costs in
`billions of dollars for health care and loss of income. But these
`crude statistics conceal the harsh reality of a frightening and
`potentially disabling disease. In writing, in musical expression,
`or through images on canvas, talented individuals have portrayed
`the personal experience of multiple sclerosis. They speak for the
`many denied these cultural conduits for expressing the hopes
`and fears of young adults facing an uncertain neurological future.
`As multiple sclerosis became better recognized in the early
`part of the 20th century, ideas began to formulate on its cause
`and the pathogenesis. Research over the last 50 years has illumi-
`nated the mechanisms of tissue injury, and the therapeutic era —
`which will surely culminate in the application of successful
`strategies both for limiting and repairing the damage - has now
`begun: For the patient, multiple sclerosis threatens an appar-
`ently infinite variety of symptoms, but with certain recurring
`themes, and an unpredictable course. For the neurologist, mul-
`tiple sclerosis is a disorder of young adults diagnosed on the
`basis of clinical and paraclinical evidence for at
`least
`two
`demyelinating lesions affecting different sites within the brain
`or spinal cord, separated in time. For the pathologist, multiple
`sclerosis is a disorder of the central nervous system manifesting
`as acute focal inflammatory demyelination and axonal loss with
`limited remyelination, leading to the chronic multifocal sclerotic
`plaques from which the disease gets its name. For the physiolo-
`gist, it is a condition in which the disease processes produce a
`remarkable array of abnormalities in electrical c0nduction. For
`the clinical scientist, multiple sclerosis is the prototype chronic
`inflammatory disease of the central nervous system in which
`knowledge gained across a range of basic and clinical neuro-
`science disciplines has already allowed rational,
`if not fully
`effective, strategies for treatment. For all these groups, multiple
`sclerosis remains a difficult disease for which solutions seem
`
`Page 8 of 163
`
`
`
`attainable yet stubbornly elusive. What follows is not a conven-
`tional history of achievements in the field of multiple sclerosis
`but is intended as background to the chapters that follow. It is
`the story of multiple sclerosis.
`
`NAMING AND CLASSIFYING THE DISEASE:
`1868—1983
`
`Few would disagree that the serious study of human demyeli-
`nating disease began with the studies of Jean-Martin Charcot
`(1825—1893] at the Salpétriere in the last three decades of the
`19th century. Charcot referred variously to his disease as la
`sclérose en plaques dissemine’es, la sclérose multiloculaire or la
`sclérose generalisée. These names were translated in the New
`Sydenham Society edition of his lectures (which spread his
`influence amongst the English-speaking world] as disseminated
`(cerebrospinal) sclerosis. This name was preferred to insular
`sclerosis or lobular and diffuse sclerosis, under which the first
`cases had been reported in England, Australia and the New
`World. It was in Germany that the term multiple Sklerose was
`used from the outset (with variations including multiple inselfor-
`mige Sklerose, multiple Himsklerose and multiple Sklerose des
`Nervensystems). This term was occasionally used elsewhere but
`disseminated sclerosis soon became the accepted name amongst
`English-speaking physicians, even though scle’rose en plaques
`persisted in France (and translated in Italian as sclerosi in plache).
`According to Pierre Marie (1853—1940) polynesic sclerosis was
`preferred by some authorities (Marie 1895). Consistency of
`nomenclature began in the 19505 with the formation of lay
`patient support organizations. Consensus was eventually
`achieved with the publication of Multiple Sclerosis written by
`Douglas McAlpine (1890—1981], Nigel Compston (1918—1986]
`and Charles Lumsden (1913—1974) (Figure 1.1A—C; McAlpine
`et al 1955), since when the condition has universally been
`known as multiple sclerosis. The group of investigators assembled
`around McAlpine met informally at a ‘Disseminated Sclerosis
`Club’ to which others interested in the disease were invited.
`
`Apart from McAlpine, those known to have attended included
`Sydney Allison (1899—1978], Malcolm Campbell (1909-1972),
`Nigel Compston and John Sutherland (1919—1995).
`Douglas McAlpine came from a prominent industrialist family
`in Great Britain. He had a distinguished military career in both
`world wars, serving as a neurologist in the Middle East and
`India, and was appointed in 1924 to the consultant staff of the
`
`
`
`Page 8 of 163
`
`

`

`hm .
`
`1M 1"
`
`
`
`
`
`CHAPTER ONE The story of multiple sclerosis
`
`
`
`Figure 1.1 (A) Douglas McAlpine
`(1890—1981); (B) Nigel Compston
`(1918—1986); (C) Charles Lumsden
`(1913—1974); (D) Bryan Matthews
`(1920—2001).
`
`
`
`
`
`Receiving his medical education in Cambridge and at the
`Middlesex Hospital, London, where one of the neurology wards
`is named after him. After receiving the International Federation Middlesex Hospital, Nigel Compston graduated in 1942 and
`of Multiple Sclerosis Societies’ first Charcot award, McAlpine
`served in the Royal Army Medical Corps. Despite the close asso—
`wrote to one of his co—authors:
`ciation with Douglas McAlpine, which culminated in the publi—
`cation of Multiple Sclerosis, his subsequent career was as a
`general physician at the Royal Free Hospital in London, where
`the clinical haematology ward is named after him. He was for
`many years treasurer of the Royal College of Physicians of
`London. His memorial in the College garden (after Wren) is:
`Si monumentam requiris, circumspice (if you needa monument
`[to the man] look around you).
`
`i
`...the CharcotAward has come my way. Special praise was
`given in N.Y to our first book. Without your constant help it
`would never have seen the light of day
`your letter shall be
`kept as a memento of our happy time together. You made me
`see light in matters that were then (and still some are)
`beyond my hen...
`
`
`
`'
`
`
`
`
`
`‘
`
`i
`l
`
`_—-__—__——__d
`Page 9 of 163
`
`Page 9 of 163
`
`

`

`
`
`EFF—“‘—
`'
`I'
`
`
`
`
`
`
`
`Educated at Aberdeen University, Charles Lumsden learned
`the techniques of tissue culture and immunocytochemistry
`(with Elvin Kabat, see below) in the United States during the
`late 19405 after serving, amongst other places, in the Faroe Islands
`with the Royal Army Medical Corps. He applied laboratory
`methodologies to the study of demyelinating disease, publishing
`the first papers on experimental autoimmune encephalomyelitis
`from the United Kingdom. As Professor of Pathology in the
`University of Leeds, Lumsden was Vigorous in his defence of
`pathology as the primary discipline of medicine. A shrewd but
`shy man, who painted and played the Violin with distinction, he
`acquired the reputation for seldom changing his opinion since
`his position was not often wrong.
`McAlpine accumulated clinical records on 1072 cases of mul-
`tiple sclerosis, of whom a proportion were consecutive examples
`seen at onset, and these formed the basis for his clinical descrip-
`tions and classification of the disease. In summarizing features of
`the clinical course, McAlpine, Compston and Lumsden empha—
`sized a number of special features — the symmetry of bilateral
`lesions, paroxysmal manifestations of demyelination, the ‘pre-
`dictable evolution of individual lesions according to anatomical
`principles, the variety of words used by patients to describe motor
`and sensory symptoms, early disappearance of the abdominal
`reflexes, the frequency of pupillary hippus (as distinct from the
`Marcus Gunn pupil, which curiously was not mentioned despite
`having been described in 1904), and occasional upper limb
`wasting (illustrated by Oppenheim in his textbook, first pub-
`lished in 1894) with absent tendon reflexes (also with Horner's
`syndrome in the case of patient WJ). Throughout, McAlpine
`and Compston relate their analyses to the lives and experiences
`of individual patients, placed in social context and identifiable to
`any archival scout by their initials and case numbers. McAlpine
`and Compston used classical neuroanatomical principles of fibre
`organization within the spinothalamic tract and dorsal columns
`to explain the march of sensory symptoms as inflammation (and
`demyelination) spread laterally through the laminations, and
`vertically to involve neighbouring segments. The authors dealt at
`length with features of the natural history that had not previously
`been described in such detail, pointing out the systematic reduction
`in relapse rate with time, the interval between the presenting
`and first subsequent attack depending on mode of presentation,
`the relationship between age at onset and the progressive course
`from onset, and aspects of prognosis — observations that were
`summarized in a much reproduced cartoon depiction of the
`course of multiple sclerosis (see Figure 1.2). Their differential
`diagnoses, organized by syndrome, addressed the complex rela-
`tionship between cervical spondylosis and spinal cord demyeli—
`nation,
`the nosological status of Devic's disease and acute
`disseminated encephalomyelitis (each considered distinct from
`but easily confused with multiple sclerosis) and emphasized the
`need for diagnostic caution in the context of a family history,
`especially when this involved a stereotyped phenotype amongst
`affected individuals.
`
`In conversation, Nigel Compston was never in doubt that he
`carried the main burden of collating this information and writing
`the first manuscript version of Multiple Sclerosis. McAlpine was
`responsible for subsequent editions, working with Lumsden and
`(Sir) Donald Acheson, an epidemiologist later appointed Chief
`Medical Officer to the Department of Health in the United
`Kingdom. Soon after publication of the second edition (1972)
`
`
`I_
`
`Figure 1.2 (A) Relapses with early and increasing disability.
`(B) Many short attacks, tending to increase in duration and
`severity. (C) Slow progression from onset, superimposed relapse,
`and increasing disability. (D) Slow progression from onset without
`relapses. (E) Abrupt onset with good remission followed by long
`latent phase. (F) Relapses of diminishing frequency and severity;
`slight residual disability only. From McAlpine et al (1955) with
`permission.
`
`McAlpine approached one of us (WIMcD) with a view to him
`taking over the role of clinical author. McDonald felt that the
`time was not right. After the death of both McAlpine and
`Lumsden, the publishers handed over editorship of Multiple
`Sclerosis to Bryan Matthews (1920—2001) for the 1985 edition
`with Acheson, Richard Batchelor and Roy Weller. Matthews also
`saw through the press a second edition of McAlpine’s Multiple
`Sclerosis (1991) with (Dame) Ingrid Allen, Christopher Martyn
`and the present editor. He contributed to the third edition
`published in 1998.
`Quintessentially whimsical and dry to the point of dehy-
`dration, Bryan Matthews brought natural charm and personal
`diffidence to his dealings with patient and profession, securing
`the admiration and deep affection of both fraternities (Figure
`1.1D). Matthews combined rich clinical experience of neuro-
`logical disease with original
`research contributions;
`these
`credentials together with a marvellous literary Style made
`famous his writings on neurology. He is most often quoted for
`
`
`
`
`
`
`
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`Page 10 of 163
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`
`CHAPTER ONE The story of multiple sclerosis
`
`his world weary but nonetheless affectionate opening to
`Practical Neurology:
`
`there can be few physicians so dedicated to their art that
`they do not experience a slight decline in spirits on learning
`that their patient‘s complaint is of dizziness
`
`The son of the Dean of St Paul’s, and brought up in a strict
`household with a nanny who doubled as a lion tamer, Matthews
`was educated at Marlborough College and at Oxford. Appointed
`in 1954 as the only neurologist in a large area of England (based
`in Derby), he gained unrivalled first-hand experience of neuro-
`logical disease and provided expertise in neurophysiology and
`neuroradiology. Later, he held academic appointments in
`Manchester and, as professor of neurology, in Oxford. He it was
`who perceived the need for surveillance of Creutzfeldt—Jakob
`disease (CJD) (his only comment during examination of the
`present editor’s PhD thesis was to offer congratulations on
`incorrectly spelling both parts of that eponymous disorder), and
`made possible the study of bovine spongiform encephalopathy
`and variant C] D when these became major public health issues
`in the 19905.
`
`John Kurtzke (1988) has reviewed the history of diagnostic
`classifications in multiple sclerosis. We are also indebted to
`Charles Poser for additional observations and insights. Diagnostic
`criteria were originally introduced for epidemiological purposes
`in order to weight the diagnosis in the absence of pathological
`proof. In his 1931 survey of north Wales, Allison classified cases
`as typical; early (in which disseminated sclerosis was neverthe-
`less the most likely diagnosis); impossible to assess through lack
`of adequate documentation; and doubtful because the symptoms
`and signs were inconclusive (Allison 1931). But the first attempt
`at criteria that could be used systematically was provided by
`Allison and Millar (1954) who classified disseminated sclerosis
`as: early (few physical signs but a recent history of remitting
`symptoms); probable (soon changed to early probable or latent:
`no reasonable doubt about the diagnosis); possible (findings
`suggesting the diagnosis and no other cause found but the
`history static or progressive and with insdfficient evidence for
`scattered lesions); and discarded. Ten years later, Poser (1965)
`surveyed 109 neurologists working throughout the world, but
`mostly in North America, and found (predictably) that, using
`these criteria, certain cases presented greater diagnostic difficul-
`ties than others. The problems apparently did not reflect local
`medical cultural differences or the personal experience of indi—
`vidual practitioners. But until the mid-19805, all surveys of
`multiple sclerosis continued to use the Allison and Millar
`criteria with some modifications within categories,
`including
`introduction of the term (clinically)
`‘definite’
`(Bauer et al
`1965). Broman et al 1965 first sought to integrate the findings
`on cerebrospinal
`fluid examination into diagnostic criteria,
`providing three subclasses within each category of clinically
`probable, latent and possible multiple sclerosis. Weighting was
`dependent on typical, normal or atypical changes in an integral
`evaluation of immunoglobulin concentration, total protein and
`cell count. The principles developed by Kurtzke in classifying
`United States army veterans, on which consensus was later
`reached by a panel of examining neurologists, were formalized
`by Schumacher et al (1965), who categorized definite cases as
`showing objective evidence for disease affecting 2 2 white
`
`matter parts of the central nervous system, occurring in episodes
`generally lasting >24 hours and separated by 2 1 month, or with
`progression over 6 months,
`in a person aged 10~SO years at
`onset, and in whom a competent observer could find no better
`explanation.
`in Multiple Sclerosis: a Reappraisal, McAlpine et al (1972)
`focused on the difficult end of the diagnostic spectrum, defining
`latent probable multiple sclerosis as cases in which there was a
`history of relapsing-remitting symptoms and physical signs but
`little or no disability. Probable multiple sclerosis could be diag-
`nosed when the symptoms were relapsing, the signs typical and
`the spinal fluid abnormal ~ ideally with normal myelography.
`Possible multiple sclerosis was used to describe cases with
`clinical evidence for white matter lesions, and no better expla-
`nation than multiple sclerosis to explain the condition. Further
`modifications adopted by Rose et al
`(1976) were revised
`definitions for probable multiple sclerosis (two episodes but
`signs at a single site or a single episode with signs of widespread
`disease) and possible disease (two episodes with no or few
`signs). The McDonald and Halliday (1977) criteria added a
`definition for proven multiple sclerosis (histological evidence
`from autopsy or biopsy), refined the early probable or latent
`category (two episodes and a single affected site or a single
`episode and two affected sites), and tackled in more detail the
`difficult issues of progressive probable (progressive history with
`multiple sites affected), progressive possible (progressive history
`affecting a single site), and suspected multiple sclerosis (one
`episode at a single site unless the optic nerves were affected).
`They introduced evoked potentials for‘the first time as para-
`clinical tests to aid in diagnosis. Further revisions suggested by
`Bauer et al (1980) were restriction of clinically probable mul—
`tiple sclerosis to patients with a relapsing history but insufficient
`signs, or plenty of signs but only a single episode — the early
`probable and latent categories of McDonald and Halliday
`(1977) — with abnormal spinal fluid, and no better explanation.
`Clinically possible multiple sclerosis amounted to the history
`and signs of one episode affecting a single site but without spinal
`fluid information — and, still, no better explanation.
`'
`Against
`this background,
`the Poser committee introduced
`criteria that were widely accepted and provided a gold standard
`until the end of the millennium (C.M. Poser et al 1983). They
`inco