McAlpine's
`MULTIPLE SCLEROSIS
`
`Page 1 of 163
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`Por NOC (1918-1986)
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`Page 2 of 163
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`

`

`--
`
`McAlpine's
`MULTIPLE SCLEROSIS
`
`FOURTH EDITION
`
`A lastair Compston PhD FRCP FMedSci
`Professor of Neurology, University of Cambridge, Cambridge, UK
`
`Christian Confavreux MD
`Professor of Neurology, HOpital Neurologique, Hospices Civils de Lyon and Universit~ Cl.ude Bernard,
`Lyon, France
`
`Hans Lassmann MD
`Professor of Neuroimmunology, Center for Brain Research. Medical Univel5ity of Vienna. Vienna, Austria
`
`Ian McDonald PhD FRCP FMedsci
`Professor Emeritus of Clinical Neurology, Institute of Neurology, University College London, London, UK
`
`David Miller MD FRCP FRACP
`Professor of Clinical Neurology, Institute of Neurology, University College London, and Cons11ltant
`Neurologist, National Hospital for Neurology and Neurosurgery, London, UK
`
`John Noseworthy MD FRCPC
`Professor and Chair, Department or Neurology, Mayo Clinic College of Medicine, Rochester, MN, USA
`
`Kenneth Smith PhD
`Professor of Neuropi1ysiology and Head oi 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, PlanQgg-Martinsried, Germany
`
`, .. ..,
`
`11 1 ~, -~ 11 ■
`
`., ...
`
`Page 3 of 163
`
`

`

`CHURCHILL
`LlVINGSTONE
`El.SEV!F.R
`
`CJ 2006, Elsevier Inc. All rights reserved.
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`First published December 2005
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`First edition 1985
`Second edition 1992
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`Page 4 of 163
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`

`

`Contents
`
`Preface to the fourth edition
`
`SECTION 1
`THE STORY OF MULTIPLE SCLEROSIS
`
`1 The story of multiple sclerosis
`Alciswir Compston, Hans· Lassmann and Ian ,'vfc-Donald
`The evolving concept of multiple sclerosis
`Naming and classifying the disease: 1868-1983
`Clinical descriptions of multiple sclerosis: 1838-1915
`l'L'rsonal accounts or multiple sclerosis: 1822-1998
`rhe social history or multiple sclerosis
`rhe pathogenesis and clinicdl anatomy of multiple
`sclerosis 1849-1977
`The laborc1tory science of multiple sclerosis: 1913--1981
`Discovery at glia and remyelination: 1858-1983
`The aetiology ot multiple sclerosis: 1883-1976
`Attitucies to the treatment of multiple sclerosis: 1809-1983
`
`viii Gender differences in susceptibility
`familial multiple sclerosis
`Candidate genes in multiple scleros,s
`Systematic genome screening
`Les,om frorn genetic studies of experirnc,ntal autoin1rnun0
`encephalorny!'litis
`3 Conclusion
`
`4 The natural history of multiple sclerosis
`3
`3 Chri.,tian C:onfann,ux a.nd Alastair C omj•.1·t,m
`7 Methodologiral considerations
`13
`The outcome landmarks of multiple sclerosis: depend<'r,t
`21
`variables
`The onscl or mul liplc sclerosis
`The over al I cou rsc of rn u ltipl e ,clerosis
`2 4
`39
`The prognosis in multiple sclerosis
`Survival in multiple sclerosis
`45
`54 Disease mechanisms underlying the clinicJI course
`62
`lntercurrent life events
`Conclusion
`
`SECTION 2
`THE CAUSE AND COURSE OF MULTIPLE SCLEROSIS
`
`2 The distribution of multiple sclerosis
`Alasrair Compston aud Cliris1ia11- C,m_/iwreux
`The rationJle for ep1demiologicJI studies in multiple
`sclerosis
`Definitions and statistics in epidemiology
`Slrategies for epidemiological studies in multiple sclerosis
`The geography of multiple sclerosis
`Multiple sclerosis in Scandinavia
`Multiple sclerosis in the United Kingdom
`Multiple sclerosis in lhe United States
`Mulliple sclerosis iri Car1alla
`Multiple sclerosis in Australia and New Zealand
`Multiple sclerosis in Continentill Europe
`Multiple sclerosis in the Middle East
`Multiple sclerosis in Africa
`Multiple sclerosis in Asia and the Far East
`Multiple sclerosis in migrants
`Epidernics and clusters of multiple sclerosis
`The environmental factor in multiple sclerosis
`
`7 l
`
`59
`
`5 The origins of multiple sclerosis: a synthesis
`Alastair C ompston, Hart11111t W,,kerle and Ian McDonald
`Summary of the problem
`The geography and phcnolype of multiple sclerosis
`The environrnental fattor in multiple sdeJosis
`Genetic susci,ptibility and multiple sclerosis
`71
`Genetics and the European population
`71 Multiple sclerosis: an evolutionary hypothesis
`75
`76
`77 SECTION 3
`81 THE CLINICAL FEATURES AND DIAGNOSIS OF
`33 MULTIPLE SCLEROSIS
`85
`6 The symptoms and signs of multiple sclerosis
`86
`Jan ivlcOonald a11d 1llas1<1.ir Comps1.on
`87
`92 Multiple sclerosis as a neurologiec1I illness
`93 Syn1ptoms at onset of the disease
`94
`Symptoms and signs in the course of the disease
`95
`Individual symptoms and signs
`1 oo Asso(iated disPases
`1 OS Multiple sclerosis in childhood
`Conclusion
`
`3 The genetics of multiple sclerosis
`Alnstai'r Compsron and Hartmut v¼eleerle
`Genclic analysis of rnulliple sclerosis
`Methods of qenetic analysis
`Racial susceptibility
`
`113
`
`7 The diagnosis of multiple sclerosis
`1 13 Oai1id Miller, l1m McDm1ald and K(mnetli Smith
`114 Diagnostic criteria for multiple srlerosis
`123 Selection of investigations
`
`126
`126
`136
`163
`
`175
`180
`
`183
`
`183
`
`193
`197
`202
`209
`221
`228
`243
`269
`
`273
`
`273
`273
`276
`279
`281
`284
`
`235
`
`287
`
`287
`291
`298
`300
`341
`343
`346
`
`3Li7
`
`347
`350
`
`V
`
`Page 5 of 163
`
`

`

`Contents
`
`Magnetic resonarKe 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
`
`8 The differential diagnosis of multiple sclerosis
`Duvid Miller a11dAlas1air Cumpston
`The spectrum of disorders mimicking multiple sclerosis
`Diseases that may cause multiple lesions of the central
`nervous system and also often follow a relapsing(cid:173)
`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, Ta11 McDonald and Alast<lir 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 t he best position
`'Patilognomonic' versus 'unheard of' features of multiple
`sclerosis
`
`SECTION 4
`THE PATHOGENESIS OF MULTIPLE SCLEROSIS
`
`10 The neurobiology of multiple sclerosis
`Alastair Compston, Hans Lassmann and Kenneth Smith
`Organization in the central nervous system
`Cell biology of the central nervous system
`Macroghal lineages in the rodent and human nervous
`system
`Interactions between glia and axons
`Oemyelination
`Axon degeneration and recovery of function
`Remyellnation
`
`11 The immunology of inflammatory demyelinating
`disease
`Harimut Wekerle and Hans Lassmann
`Multiple sclerosis as an autoimmune disease
`Immune responses: innate and adaptive
`T lymphocytes
`B lymphocytes
`Autoimmunity and self -t olerance in t he central
`nervous system
`Regulation of central nervous system autoimmune
`responses
`Immune reactivity in the central nervous system
`
`vi
`
`386
`
`389
`
`389
`
`390
`41 3
`
`422
`435
`436
`
`439
`
`439
`
`441
`445
`
`445
`
`446
`
`446
`
`447
`
`449
`
`449
`450
`
`455
`463
`469
`477
`483
`
`491
`
`491
`492
`494
`504
`
`505
`
`Pathogenesis of demyelination and tissue damage
`3 5 I
`Peripheral blood biomarkers for multiple sclerosis
`373
`380
`and disease activity
`383 Markers of multiple sclerosis and disease activity in
`cerebrospi nal fluid
`
`12 The pathology of multiple sclerosis
`Ha.ns Lassniatm and Har1m11t Wekerlc
`Introduction
`Pathological classification of demyelinating diseases
`The demyelinated plaque
`lmmunopathology of inflammation
`Demyelination and ol1godendroglial damage
`Remyelination
`Axonal pathology
`Grey matter pathology and cortical plaques
`Astroglial react ion
`Abnormalities in the 'normal' w hite matter of patients
`with multiple sclerosis
`Distribution of lesions 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 tra11scriptome and proteome
`Association of multiple sclerosis w ith other diseases
`Conclusion
`
`536
`
`540
`
`547
`
`557
`
`557
`557
`559
`564
`572
`582
`584
`587
`589
`
`589
`590
`
`592
`593
`
`594
`
`596
`598
`599
`
`13 The pathophysiology of multiple sclerosis
`601
`Ke11ncth Smith, Ian McDonald, David Miller and Hans Lassmann
`Introduction
`60 I
`Methods for exploring the pathophysiology 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
`610
`
`627
`
`634
`
`649
`658
`
`14 The pathogenesis of multiple sclerosis: a pandect
`661
`l fans Lass111am1, Kenneth Smit Ir, J-Iartmul Wekerle and Alastair
`Compston
`Core features in the neuropathology of multiple sclerosis
`The pathophysiology o f f unctional deficits and recovery
`The relation between inflammation and neurodegeneration in
`multiple sclerosis
`The role of autoimmunity in multiple sclerosis
`Complexity and heterogeneity in m ultiple sclerosis
`
`665
`666
`667
`
`661
`663
`
`SECTION 5
`THE TREATMENT OF MULTIPLE SCLEROSIS
`
`15 Care of the person with multiple sclerosis
`524
`530 David Miller; John Noseworrhy a11d Alastair Conirsron
`
`669
`
`67 1
`
`Page 6 of 163
`
`

`

`[
`
`General cipproach to the care of µaople with
`multiple sclerosis
`The early stages of disease: mini1T1al disability
`Thf! 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
`677
`679
`
`680
`681
`
`16 Treatment of the acute relapse
`683
`John Noseworthy, Christian Confavn•ux and Alllstair Compston
`The features of active multiple sclerosis
`683
`The treiltment of relapses
`686
`Other approaches to t he treatment of acute relapse
`690
`Treatment of acute optic neuritis
`692
`Management of other isolated syndromes and acute
`disseminated encephalomyelltis
`Adverse effects
`Mode of action of cortico,teroids
`Practice guidelines
`
`694
`695
`696
`699
`
`17. The treatment of symptoms in multiple sclerosis
`and the role of rehabilitation
`Jo/m No.mvurihy, David Miller and Alastair Compston
`The general principles of symptomatic treatment in
`multiple sclerosis
`Disturhanc.es of autonomic function
`Mobility and gait disturbance
`Fatigue
`Disturbances of brainstern function
`Perturbations of nerve conduction
`Cognitive function
`Vi.sual loss
`
`701
`
`701
`701
`712
`717 References
`718
`721
`724
`725
`
`Index
`
`Contents
`
`Rehahilitation in multiple sd~rosis
`Conclusion
`
`18 Disease-modifying treatments in multiple sclerosis
`Jo/111 Nuse11,orthy, DaPid Miller and Alastair Compsl01t
`The aims of disease-modifying t reatment
`The principles of evidence-based prescribing in
`multiple sclerosis
`The role of magnetic resonance imaging in clinical trials
`Drugs that st imulate the immune response
`Drugs that nonspecifically suppress th11 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
`i llaswir Crmtf>stnn, David Miller and John N usewurihy
`A perspective on the recent history of therapeutic endeavour in
`multiple sclerosis
`Sett ing an agenda: t he window of therapeutic opportunity
`Prospects for the treatment of progressive multiple sclerosis
`Remyelination and axon regeneration
`Tailoring treatment to defined groups
`Postscript
`
`726
`728
`
`729
`
`729
`
`733
`734
`738
`742
`755
`784
`79 1
`801)
`801
`802
`
`803
`
`803
`803
`805
`806
`810
`81 O
`
`811
`
`947
`
`vii
`
`Page 7 of 163
`
`

`

`SECTION ONE THE sroRY 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 sderosis. They speak for the
`many denied these cultural conduits for expressing the hopes
`and fears of young adults facing an uncertain neurological future.
`AB 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(cid:173)
`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(cid:173)
`ently infinite variety of symptoms, but with certain recurring
`themes, and an unpredictable course. For the neurologist, mul(cid:173)
`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(cid:173)
`gist, it is a condition in which the disease processes produce a
`remarkable array of abnormalities in electrical conduction. 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(cid:173)
`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
`
`attainable yet stubbornly elusive. What follows is not a conven(cid:173)
`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(cid:173)
`nating disease began with the studies of Jean-Martin Charcot
`(1825-1893) at the Salpetriere in the last three decades of the
`19th century. Charcot referred variously to his disease as la
`sclerose en plaques disseminees, la sclerose multiloculaire or la
`sclerose generalisee. 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(cid:173)
`mige Sklerose, multiple Hirnsklerose 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 sclerose en plaques
`persisted in France ( and translated in Italian as sclerosi in plache).
`According to Pierre Marie (l 853-1940) polynesic sclerosis was
`preferred by some authorities (Marie 1895). Consistency of
`nomenclature began in the 1950s 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 l.lA-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
`
`3
`
`Page 8 of 163
`
`

`

`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).
`
`Middlesex Hospital, London, where one of the neurology wards
`is named after him. After receiving the International Federation
`of Multiple Sclerosis Societies' first Charcot award, McAlpine
`wrote to one of his co-authors:
`
`... the Charcot Award 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 ken ...
`
`4
`
`Receiving his medical education in Cambridge and at the
`Middlesex Hospital, Nigel Compston graduated in 1942 and
`served in the Royal Army Medical Corps. Despite the close asso(cid:173)
`ciation with Douglas McAlpine, which culminated in the publi(cid:173)
`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 need.a monument
`[ to the man] look around you).
`
`Page 9 of 163
`
`

`

`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 1940s 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(cid:173)
`tiple sclerosis, of whom a proportion were consecutive examples
`seen at onset, and these formed the basis for his clinical descrip(cid:173)
`tions and classification of the disease. In summarizing features of
`the clinical course, McAlpine, Compston and Lumsden empha(cid:173)
`sized a number of special features - the symmetry of bilateral
`lesions, paroxysmal manifestations of demyelination, the ·pre(cid:173)
`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(cid:173)
`lished in 1894) with absent tendon reflexes (also with Homer'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(cid:173)
`tionship between cervical spondylosis and spinal cord demyeli(cid:173)
`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)
`
`Naming and classifying the disease: 1868- 1983
`
`,
`
`1
`
`...........
`--···
`
`----·······
`fLJl_fLfl
`= ,, n _ ~-------·-·····
`ouo n~
`
`A
`
`B
`
`__ ,.. ......
`
`4
`
`.. - -
`
`-··
`
`C
`
`---------------
`----------
`n
`
`D
`
`Figure 1.2 (A) Relapses with early and increasing disability.
`(B) Many short attacks, tending to increase in duratio.n and
`severity. (C) Slow progression from onset, superimposed r'elapse,
`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 disabi lity 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(cid:173)
`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
`l.lD) . Matthews combined rich clinical experience of neuro(cid:173)
`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
`
`t
`
`__J
`
`5
`
`Page 10 of 163
`
`

`

`1 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(cid:173)
`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 CJD when these became major public health issues
`in the 1990s.
`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(cid:173)
`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 insufficient evidence for
`scattered lesions); and discarded. Ten years later, Poser (1965)
`surveyed l 09 neurologists working throughout the world, but
`mostly in North America, and found (predictably) that, using
`these criteria, certain cases presented greater diagnostic difficul(cid:173)
`ties than others. The problems apparently did not reflect local
`medical cultural differences or the personal experience· of indi(cid:173)
`vidual practitioners. But until the mid-l 980s, 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 white
`
`matter' parts of the central nervous system, occurring in episodes
`generally lasting > 24 hours and separated by;::,: 1 month, or with
`progression over 6 months, in a person aged 10- 50 years at
`onset, and in whom a competent observer could find no better
`explanation.
`In Multiple Sclerosis: a Reappraisal, McAlpine et al (1972)
`focus ed 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(cid:173)
`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(cid:173)
`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 s