Postgrad Med J: first published as 10.1136/pgmj.68.801.507 on 1 July 1992. Downloaded from Postgrad Med J (1992) 68, 507- 516 i) The Fellowship of Postgraduate Medicine, 1992

Reviewing multiple sclerosis Alastair Compston University ofCambridge Neurology Unit, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK

Introduction In recent years, publishers have responded to the his textbook was first published by Oxford Univer- need for publications that summarize complex sity Press in 1933. Brain came straight to the point topics but formerly the review article was less in his 'critical review'; drawing comparisons popular, and students of neurological medicine between the neurological manifestations of then depended more on textbook accounts of encephalitis lethargica and the encephalo- diseases affecting the nervous system. No work has myelitides that follow exanthematous disease and so dominated the 20th century and influenced vaccination, he interpreted the pathological obser- neurologists in the English speaking world as vations as having established disseminated Russell Brain's Diseases of The Nervous System. sclerosis as an infective disease - a point of view When John Walton took on the task ofcompleting first proposed by Marie in 1895.2 Brain provided the 7th edition, published in 1969, 'Brain' had been statistical evidence in favour ofGuillain's assertion continuously in print since 1933; he subsequently that disseminated sclerosis was second only to produced the 8th and 9th editions, in 1977 and syphilis as the most frequent disease ofthe nervous 1985, respectively, and with colleagues is now system, and provided the first hospital- and copyright. preparing the 10th edition. Thus, Lord Brain and population-based statistics, accurately defining the Lord Walton have reviewed developments in relationship between disease duration and rates for clinical neurology over a period in which more has prevalence, incidence and mortality. Brain recog- been learned about the nervous system in health nized that the geographical distribution ofmultiple and disease than at any other time in history. One sclerosis was uneven; he delineated regional trends reviewer, opining that the 8th edition represented that have subsequently been confirmed, and excellent new wine in an old and valued bottle, identified the innate susceptibility and resistance of drew attention to the therapeutic shifts catalogued northern Europeans and Blacks, respectively. http://pmj.bmj.com/ by 'Brain' down the 20th century. In 1933, the Brain accepted that the disease occasionally occur- symptoms of Parkinson's disease could be allev- red in sibling pairs but in line with his views on the iated by riding in a motor car; in 1992, this requires cause, he was adamant that familial disseminated striatal transplantation of fetal mesencephalic sclerosis arose from common environmental neurones. The observations that have been made exposure and not the influence of genetic factors. and the task ofdistinguishing fact from fiction so as Subsequent experience has shown that his views on best to document the accumulation of knowledge the sex incidence were wrong, females being more on September 29, 2021 by guest. Protected has probably been more difficult with respect to commonly affected than males. multiple sclerosis than for any other aspect of His reading of the pathological literature was clinical neuroscience. sophisticated and very little of substance has since been added. Drawing heavily on the observations of Dawson,3 Brain described a sequence in which Quarterly Journal of Medicine: 1930 perivascular infiltration of lymphocytes and plasma cells is followed by phagocytosis ofmyelin, Having written a 'Critical review: disseminated fibroglial overgrowth and some axonal loss; and he sclerosis' in 19301 Dr Russell Brain was already an noted shadow plaques, now thought to be authority on multiple sclerosis when, as assistant indicative of remyelination. In discussing the dist- physician to the London Hospital and to the ribution oflesions throughout the nervous system, Hospital for Epilepsy and Paralysis, Maida Vale, Brain emphasized the co-location of plaques and rich vascular networks around the ventricles, under the pial membranes and in the spinal cord. In a scholarly section on the pathogenesis of Correspondence: Professor D.A.S. Compston, Ph.D., disseminated sclerosis, Dr Brain restated the doct- F.R.C.P. rine of neurobiology left by Cajal and his students Postgrad Med J: first published as 10.1136/pgmj.68.801.507 on 1 July 1992. Downloaded from 508 A. COMPSTON del Rio Hortega and Penfield, describing the mor- Brown-Sequard lesions, hyperaesthesia at the phological and anatomical arrangements offibrous border of sensory levels, impaired colour vision, and protoplasmic astrocytes, assigning a muscle wasting, and symptoms arising from phagocytic role to microglia but confessing to affection ofthe conus medullaris; finally, he quoted ignorance on the function of oligodendrocytes. He statistics relating to the high frequency of pointed out that the early vascular lesion indicated disseminated sclerosis after an episode of optic invasion of the nervous system by a systemic and neuritis. infective factor, capable ofprovoking the astroglial Fever therapy, induced by malaria, typhoid reaction that he regarded as the essential vaccine and other organic or microbial pyrogens, pathogenic feature ofthe disease. However, Russell featured prominently in Brain's account of treat- Brain argued that factors distributed in the cere- ment. There was no hint of adverse effects. The brospinal fluid could as easily gain access to the study in which Purves Stewart treated 70 cases of brain parenchyma through the Virchow-Robin disseminated sclerosis with a vaccine derived from spaces, as could material crossing the vessel walls. cultures of the putative 'spherula insularis' virus, Section five ofBrain's review dealing with 'exper- and which he claimed would arrest the disease, alter imental transmission and bacteriology' analysed a the colloidal gold curve and eradicate the organism controversial episode. There had been many from the cerebrospinal fluid, was cited8 with the attempts to repeat the observations of Bullock4 conclusion that removal of the organism from that disseminated sclerosis could be transmitted to <10% of cases placed considerable difficulties in animals by innoculation ofa spirochaete recovered the way of therapeutic enthusiasm for Miss from affected individuals. This culminated in the Chevassut's discoveries. Instead, the usual list of report by Chevassut that the organism 'spherula metal therapies - arsenic, silver, mercury and insularis', designated as a virus, could be cultured antimony - was given, and agents such as sodium from the cerebrospinal fluid of more than 90% of salicylate or X-irradiation were mentioned; Brain patients with disseminated sclerosis but not cont- concluded that the 'the multiplication of remedies rols.5 Brain quickly disposed of the spirochaetal is eloquent of their inefficacy'. theory of disseminated sclerosis but took a more Russell Brain's first review of disseminatedcopyright. reserved position with respect to Miss Chevassut, sclerosis ended where it began; after marshalling suggesting that technical factors may have made it the evidence from 218 publications and detailing difficult for her directly to visualize the organism in the clinical and pathological similarities between the spinal fluid or the nervous tissue itself; he was disseminated sclerosis and transitional forms of distinctly lenient on the failure to transfer this neuromyelitis optica, post exanthematous and vac- organism to monkeys - work that had been cinial encephalomyelitis, and encephalitis periax- reported by Sir James Purves Stewart;6 notwith- alis diffusa, he settled on the view that these standing uncertainty about the causal role of demyelinating diseases differed only in the extent to http://pmj.bmj.com/ 'spherula insularis' in disseminated sclerosis, Brain which virulence of the initiating but as yet extolled the virtues of using its detection as a unidentified causative agent, and variations in host diagnostic test. 'Spherula insularis' disappeared immunity, influenced the clinical phenotype. He abruptly from interest following an incident at the regarded the syndrome ofdisseminated sclerosis as Royal Society of Medicine, the details of which having a common pathogenesis with an inherent have been preserved through oral neurological capacity for recovery throughout the course. Brain

history.7 suggested that the tendency to relapse would, when on September 29, 2021 by guest. Protected In his clinical account of disseminated sclerosis, fully understood, provide a clue to the nature of Brain identified typical manifestations of the immunity and lead to a cure for the disease. disease, its common syndromes, and the clinical courses to be expected. His estimates for frequency of relapsing compared with primarily progressive Brain's Diseases ofthe Nervous System, 1st disease would be consistent with contemporary Edition, 1933 views, as would the peak ages and extremes of onset; furthermore, he drew from personal In returning to this topic 3 years later,9 Russell experience in stressing that the course might evolve Brain emphasized the clinical rather than fully within a few months or remain stable over biological aspects of the disease. Disseminated several decades. His clinical description was sclerosis was, not unreasonably, included in the notable for its account of the mental state (spes chapter on infections of the nervous system, and sclerotica), the occurrence of convulsions, early treated separately from acute disseminated or post descriptions of internuclear ophthalmoplegia, infectious forms of encephalomyelitis, and pupillary hippus (but not the Marcus Gunn abnor- disseminated myelitis with optic neuritis. Not mality), Lhermitte's phenomenon, trigeminal much had happened to reshape Brain's views on neuralgia, the useless hand of Oppenheim, the aetiology or pathogenesis, although he now Postgrad Med J: first published as 10.1136/pgmj.68.801.507 on 1 July 1992. Downloaded from REVIEWING MULTIPLE SCLEROSIS 509

preferred to consider the glial reaction as secon- Royal Society', although he did publish articles dary, or at least sequential to the perivascular that justified the statement that in him biological inflammation and demyelination; the aetiological science has lost one of the most promising of its status of the spirochaete and Miss Chevassut's recent recruits. Although Dr Brain devoted a few virus - now described as a filtrable agent - lines in the 1933 edition to a catalogue of tests that remained uncertain and heredity was still not might be employed in assessing co-ordination of regarded as a risk factor. His description of the movement, he might have borrowed from Barbel- symptoms again emphasized the amytrophic form lion the child's satisfaction in coaxing a button to and the occurrence of convulsions; a case of slip into its hole; 'all grown up people have bilateral internuclear opthalmoplegia had been forgotton how difficult and complex such opera- observed, as had examples of Homer's syndrome, tions are'. Sadly, nothing other than tact, judge- deafness, pathological laughter and crying, and ment, metals and fevers could be offered by way of trophic changes in the extremities. Brain's seven treatment 14 years after Barbellion's death; even symptom groups included progressive spinal the use of liver had disappointed Dr Brain. disease in older cases, onset with hemiplegia or Brain's discussion of the encephalomyelitides - conus lesions and the accelerated or Marburg form. which he believed all resulted from opportunistic A rather formal approach to differential diagnosis infection secondarily affecting individuals listed neurosyphilis and the hereditary ataxias, with immunocompromised by a primary agent- is special mention of the Drew family of Walworth,10 interesting for its further evidence of Brain's whose neurological disorder mimicked dissemi- adherence to the direct viral doctrine of nated sclerosis (and is still attracting attention from demyelinating disease. Treatment was aimed at neurologists), sub-acute combined degeneration of reducing intracranial pressure, by lumbar puncture the cord, tumour and encephalitis lethargica. Both or hypertonic glucose osmosis. These were com- in the earlier review and in the 1933 edition, Brain mon conditions and there had been a prolonged commented on the special tendency for patients to epidemic ofpost vaccinial encephalomyelitis in the exaggerate or entirely fake the manifestations of 1920s so that Russell Brain re-iterated the advice of disseminated sclerosis. the Vaccination Order of 1929 that 'it is not copyright. Brain assigned a poor prognosis to young rather generally expedient to press for the vaccination of than middle aged patients, and those with brain- persons of adolescent years who have not stem involvement by comparison with spinal previously been vaccinated unless they have been in disease. And he recommended the personal contact with a case of smallpox'. Immune serum account of the disease written by Bruce Frederick from a previously vaccinated individual was Cummings under the pseudonym W.N.P. Barbel- recommended. Brain seemed a little uncomfortable lion, first published on 31 March 1923 as The in separating encephalomyelitis complicating Journal of a Disappointed Man." Cummings was measles from other forms and only gave it a special http://pmj.bmj.com/ born at Barnstable on 7 September 1889 and died, heading because of Ford's recent definitive review aged 30, on 22 October 1919 at Gerrards Cross. He of the subject. In the 1930s, pain in the eyes borrowed his pseudonym from the front of a sweet occurring as part of Devic's disease could be shop in Bond Street. Despite developing symptoms treated with mustard leaves or leeches applied to due to multiple sclerosis in early adult life, and the temples. dispirited by the example of his parents who both Uncertainty can be seen in Brain's discussion of

had paralytic neurological disorders, Cummings encephalitis periaxalis diffusa; too many cases were on September 29, 2021 by guest. Protected taught himself entomology and obtained a post at familial, the term encephalitis suggested the Natural History Museum; Barbellion aped inflammation but this was presumptive, and the Mark Twain in ensuring that news ofhis death - 31 progressive paralysis and central visual failure were December 1917 - was prematurely announced so atypical of disseminated sclerosis - all of which that he might enjoy reading notices of his book indicated that these childhood disorders had a written in the belief that they would not reach the different aetiology from other forms of author's eyes. But his diary was declared 'an demyelinating disease. Subsequent editions of the acerbic bid for immortality, written by a smart alec textbook saw a gradual separation of these condi- rotter' and sadly he only enjoyed the literary tions into the group of leucodystrophies and fantasy for 18 months; others have suggested that related degenerative disorders he even may have accelerated his departure by following contemporary advice to take arsenic and strychnine on a weekly basis. H.G. Wells identified Brain's Diseases ofthe Nervous System, 2nd the egoist in Barbellion but - himself an incurable Edition, 1940 scientific romantic - sympathized with the hope- lessness of Barbellion's thwarted scientific dreams; In writing a preface to the second edition of his 'not for him the Croonian lecture, the listening textbook, in March 1940,i2 Dr Brain specified that Postgrad Med J: first published as 10.1136/pgmj.68.801.507 on 1 July 1992. Downloaded from 510 A. COMPSTON he had separated conditions that had become example of an inherent defect in oligodendrocyte known as the demyelinating diseases.'3 Illustra- function.'8 Analogies were made with swayback, tions were provided for the commoner diseases by known at that time to be treatable with copper.'9 Dr Dorothy Russell and Professor H.M. Turnbull; Major alterations to the 1940 edition were and references - many selected from the French therefore the introduction of the term and German literature - were appended to each demyelinating disease, the attempt at classification, section. Brain offered a classification that has the recognition ofexperimental allergic encephalo- survived all subsequent editions of the book with myelitis, the emergence of ideas on the biology of little modification. Small differences of emphasis the oligodendrocyte, the introduction ofmorbidity were apparent in the largely unchanged accounts of statistics, and the concept of immunological and the acute disseminated encephalomyelitides; Brain inherited factors in the aetiology. regarded spontaneous encephalomyelitis in adults as more common than the post exanthematous childhood forms and he separated the neurological Brain's Diseases ofthe Nervous System, 3rd complications of varicella from other childhood Edition, 1947 post exanthematous disorders on the basis of its clinical and pathological manifestations. The third edition20 introduced topics in which Significantly, he had noted the first description special experience had been gained during the of experimental allergic encephalomyelitis in second world war - in the main, descriptions of monkeys'4 and so shifted abruptly to the view that peripheral nerve injuries, nutritional disorders of demyelinating disorders were due to an allergic the nervous system, and the introduction ofpenicil- reaction in the brain and not direct viral infection. lin. Sciatic neuritis was renamed prolapsed lumbar Significant changes were also made to the section intervertebral disc, and affections of the brachial on disseminated sclerosis which was defined as a plexus and thoracic outlet were introduced. The disorder characterized by focal lesions early in the psychological aspects ofneurology received special course later followed by progressive disease. His attention. reading of the pathological papers of Dawson,3 The section on demyelinating disease contained copyright. Putnam'" and Greenfield'6 presented a much very few changes. Hurst's hypothesis that myelin clearer view of the sequence of perivascular lym- breakdown was mediated by enzymatic degrada- phocytic infiltration, myelin ingestion by fat tion, outlined in his G.E. Rennie lecture delivered granule cells, myelin degeneration, fibroglial pro- to the Royal Australasian College ofPhysicians on liferation, and some axonal loss leading to the 26 September 1941 in Melbourne, was included2' formation of the 'sclerotic plaque'. In an expanded but not his descriptive paper separating acute account of the aetiology, Brain admitted the haemorrhagic leucoencephalitis from the other 'modern tendency to stress constitutional factors' encephalomyelitides.22 In his account of http://pmj.bmj.com/ and summarized the evidence on heredity from disseminated sclerosis, Dr Brain re-inserted a note Curtius' monograph."7 He quoted a series, on its history from his 1930 review concluding that presumably ofpersonal cases, in which exposure to Cruveilhier in 1835 and Carswell in 1838 first a range oftriggers - infections, pregnancy, surgical illustrated the lesions. This controversial matter of operations, electric shock, carbon monoxide priority had been discussed by Putnam23 in 1938 poisoning and trauma - occurred shortly before and since by others.24 Russell Brain overlooked the presentation. Brain revised his figure for the fre- important paper by Kabat25 describing the quency of disseminated sclerosis in the United quantification of immunoglobulin in the cerebros- on September 29, 2021 by guest. Protected Kingdom (200/million living people), noting that pinal fluid of patients with disseminated sclerosis; urban cases were more common than rural, that in several subsequent editions, only the colloidal cases in childhood occurred rarely and that only gold curve was described - abnormalities of which 7% of patients developed the disease after the age merely reflect the antibody changes that Kabat had of 50; the sex ratio was reversed 3:2 in favour of identified. women. Brain's account ofsymptoms was based on a personal series of 100 consecutive cases, motor symptoms predominating over visual and sensory Brain's Diseases ofthe Nervous System, 4th Edition, or miscellaneous manifestations. Again he 1951 emphasized the interval that may occur between optic neuritis and a subsequent episode - the Russell Brain had reconsidered his views on longest survivor of his experience being 29 years demyelinating disease when he returned to the from diagnosis; disease duration averaged 13.6 topic in 1951;26 he wished to emphasize that axon years. In 1940, Brain included encephalitis peri- cylinders were often involved in the disease process axalis diffusa (renamed Schilder's disease) in the and he felt ambivalent about the conclusion that section on 'diffuse sclerosis' and proposed this as an myelin destruction was necessarily the primary Postgrad Med J: first published as 10.1136/pgmj.68.801.507 on 1 July 1992. Downloaded from REVIEWING MULTIPLE SCLEROSIS 511

change. He sensed a growing belief that progress in what is now known as 'McAlpine's Multiple understanding the demyelinating diseases would Sclerosis' in the 1955 edition of his textbook, result from studies of the experimental models first although this may have been added at proof stage mentioned in the second edition. Although int- since no details were included, and he did not ravenously injected antibodies recognizing cons- follow McAlpine's nosological lead in adopting the tituents ofthe nervous system would not reproduce term 'multiple sclerosis' despite this having been the pathological features of post infectious used in Germany and the United States since the encephalomyelitis, Brain accepted as proven the end of the 19th century. But his account of the claim that the human and experimental diseases aetiology of disseminated sclerosis was much were allergic. Spontaneous acute disseminated influenced by McAlpine and his colleagues: he encephalomyelitis was no longer considered to be quoted their rates for the frequency of familial distinct from post infectious encephalomyelitis of disease (6.5%), and the 1952 paper on the natural childhood. Brain described the discussion that had history of disseminated sclerosis33'34 reporting that taken place with respect to the relationship between 14.4% ofcases have a history ofphysical trauma in the acute focal myelinoclasis ofMarsden and Hurst the 3 months preceding the onset ofnew symptoms (1932) but continued not to cite Hurst's paper;22 and establishing a relationship between the part and his reading of the literature on experimental traumatized and the anatomical basis for new demyelination now made him uneasy about the symptoms - guidelines not yet superceded and still suggested relationship between disseminated used in exchanges between neurological specialists, sclerosis and swayback.27 The changes that could solicitors and their clients. Based on the Middlesex be detected in the cerebrospinal fluid were still not Hospital study, Brain again up-dated his figures for noted and he remained loyal to the memory of prevalence to 1:2,400 (42/100,000) for England and Barbellion now dead for 32 years; there were no Wales and 1:1,570 for Scotland (64/100,000) - new therapeutic suggestions. establishing the latitudinal differential that remains unexplained to this day. After 32 years in which advice to clinicians on the differential diagnosis of Brain's Diseases ofthe Nervous System, 5th disseminated sclerosis had not changed, Brain copyright. Edition, 1955 omitted encephalitis lethargica and introduced cervical spondylosis as a cause of ataxic weakness The title page of the 1955 edition,28 barely keeping of the upper limbs with spastic paraparesis which up with plain Dr Brain's progress, announced that might be confused with disseminated sclerosis. Sir Russell (since 1952) had been created a baronet (in 1954). In the 5th edition, Brain identified important new work on acute disseminated Brain's Diseases ofthe Nervous System, 6th encephalomyelitis resulting from publication ofthe Edition, 1962 http://pmj.bmj.com/ influential paper from Newcastle in 1953;29 and McAlpine's recommendations30 for distinguishing With the sixth edition,35 Oxford University Press acute disseminated sclerosis from acute changed the format of Brain's Diseases of the disseminated encephalomyelitis - fever, bilateral Nervous System. The paper, print size and line optic neuritis, spinothalamic sensory loss and spacing increased although the octavo format was areflexia characterizing the latter, in which recur- maintained: the bigger book, no longer bound in rences could occasionally be expected, were noted. red buckram with gold lettering on the spine and on September 29, 2021 by guest. Protected It is in this section that Brain, following Miller,29 with the title blindstamped in black on the front first referred, albeit cautiously, to the use of cover, now appeared with a decorated spine in gold corticosteroids in the treatment of demyelinating and black anticipating the elevation ofits author to disease. Acute haemorrhagic leuco-encephalo- the peerage in 1964. A number of important myelitis earned a section of its own based on a changes were introduced in the section on somewhat delayed reading of the paper by Hurst22 disseminated sclerosis - a term which Brain con- and those of Brain's colleagues from the London tinued to use; the detection of an abnormally high Hospital. gamma globulin by paper electrophoresis was Whilst the Newcastle group under the leadership mentioned for the first time citing the work from of Henry Miller was collating cases of acute Newcastle of Schapira and Park36 but not Kabat's disseminated encephalomyelitis in preparation of 20 year old report.25 For several decades, Brain had the definitive papers of 1953 and 1956,29,3 Douglas drawn on personal anecdotes in assessing the McAlpine and his assistant (the E.G. Fearnsides prognosis for life and the interval between the scholar of the University of Cambridge) were presenting and subsequent attacks but he now analysing 666 cases seen at the Middlesex Hospital; found it convenient to quote from McAlpine on the advance publication copies of their book32 were in average annual relapse rate (0.4/year), frequency of circulation by January 1955 and Brain referred to progression from onset, and average disease dura- Postgrad Med J: first published as 10.1136/pgmj.68.801.507 on 1 July 1992. Downloaded from 512 A. COMPSTON

tion in fatal cases (20 years). Drawing once again sponsibility for revising the premier neurological on the experience ofdemyelinating disease from the textbook of the day.' Newcastle school, Brain accepted the clinical im- Dr Walton saw no need to alter Brain's pression that corticotrophin might help in an acute classification of demyelinating disease although exacerbation but he concluded that there was no work from the Medical Research Council convincing evidence for the value of maintenance Demyelinating Disease Unit in Newcastle was treatment with prednisolone.37 incorporated; central pontine myelinolysis, des- Brain had stuck with the 1940 classification of cribed in 19594' appeared in the table and with a demyelinating disease listing encephalitis periaxalis brief textual account of four cases, three of whom diffusa (Schilder's disease), centrolobar sclerosis, were alcoholic. A few extra lines were included on encephaloleucopathia scleroticans, progressive relationships between the pathology of encephalo- degenerative subcortical encephalopathy, leucodys- myelitis following vaccination against rabies; and trophy, leuco-encephalopathia myeloclastica acute cerebellar ataxia was re-instated as a variant primitiva, encephalomyelomalacia chronica of acute disseminated encephalomyelitis, compli- diffusa, concentric demyelination (Balo's disease) cating ECHO, Coxsackie and varicella infections. and the infantile varieties (Krabbe's, Scholz's and The nosological status ofDevic's disease was again Pelizaeus-Merzbacher's diseases) as synonyms debated, Walton siding with opinion in the revised (not to mention tongue twisters) for diffuse version of McAlpine's monograph42 and reverting sclerosis. This difficult group of diseases had to the position that neuromyelitis optica was recently been carefully scrutinized by J.G. simply a form of multiple sclerosis. Greenfield38 and Brain inserted a paragraph which Disseminated sclerosis had become multiple sought to improve on this descriptive soup. sclerosis but no new insights could be offered on the Greenfield had distinguished sudanophilic aetiology, other than the suggestion that the leucodystrophy (familial in childhood and sporadic disease arose from an auto-immune response in the in young adults - Schilder's disease), from central nervous system. Even though the risk of Pelizaeus-Merzbacher (familial and childhood developing multiple sclerosis was increased by 15 onset), Krabbe's disease with infantile onset and times for the first degree relatives of an affectedcopyright. characteristic globoid cells, and metachromatic individual, nurture was deemed to be a more leucodystrophy - a condition which Brain and important aetiological force than nature. The Greenfield had described in 195039 and which he relative importance of extrinsic triggers was now thought should be included in the chapter on reviewed - surgery and pregnancy carrying a low the lipidoses. risk, vaccination appearing to be of more impor- tance and the situation with respect to trauma not having materially altered. The epidemiological deliberations ofAcheson42 favoured the concept of http://pmj.bmj.com/ Brain's Diseases ofthe Nervous System, 7th multiple sclerosis as a disorder associated with Edition, 1969 certain locations rather than race, implying an extrinsic aetiological factor with a long latent Lord Brain died on 29 December 1966, 2 years after period; but then, as now, its nature remained he was elected to fellowship of the Royal Society, elusive. A number of subtle alterations were working to the last on the journal Brain which he included in the account of symptoms - wild had edited since 1954. Sir George Pickering, proximal upper limb tremor and feelings of swell- writing in the Dictionary of National Biography, ing and tightness in posterior column sensory on September 29, 2021 by guest. Protected credited him with four lasting discoveries - median involvement being notable additions. The detailed nerve compression in the carpal tunnel, disc pro- assessment of spinal fluid that was to dominate lapse as a cause of cervical myelopathy, car- research into multiple sclerosis for several years to cinomatous neuropathy, and endocrine exophthal- come was hinted at by the inclusion of results on mos. Apart from the description ofmetachromatic quantitative and qualitative tests for estimation of leucodystrophy he made no original discoveries gamma globulin. And the prolonged follow-up of relating to human demyelinating disease. However, first cases described in the first edition of McAl- his 1930 review ofdisseminated sclerosis is a classic pine's Multiple Sclerosis43 was used to supplement paper; there was little need to alter many of his morbidity statistics, emphasizing benign forms and views over the next 30 years but, with only a few suggesting that a mild course in the first 5 years lacunes, he was alert to most developments as they carried a favourable long-term prognosis. In dis- occurred, being much influenced by work of the cussing treatment, John Walton deviated from the Newcastle school. It was therefore appropriate that dogmatic line taken by Brain in six previous his executors and publishers should invite John editions. Gone were the recommendations for Walton, then Professor of Neurology in the arsenic, fever therapy and intrathecal tuberculin; in University of Newcastle upon Tyne, to take re- came prolonged courses of corticotrophin lasting Postgrad Med J: first published as 10.1136/pgmj.68.801.507 on 1 July 1992. Downloaded from REVIEWING MULTIPLE SCLEROSIS 513

up to 10 weeks for the management of relapse, Lumsden42 were taken as indicating that patho- diazepam for spasticity, and propantheline for the logically there was no distinction to be drawn unstable bladder. between the various forms of acute monophasic In discussing diffuse sclerosis, Walton began to and relapsing demyelination. feel uneasy about the inclusion ofSchilder's disease Walton's account of multiple sclerosis men- and spongy degeneration of the white matter - tioned recent developments in neurovirology, in- although sub-acute sclerosing panencephalitis and cluding the claim that a paramyxovirus could be the spongiform encephalopathies had not recovered from the brain tissue of patients with obviously contaminated this material in earlier multiple sclerosis' - sadly, as it now turns out, no editions. The advent of nerve conduction studies more robust than Miss Chevassut's spherulal was a further cause for concern in the classification claims - and the first experiments providing a of these diseases and metal therapy was no longer scientific explanation for the pathophysiology of advocated. onset and recovery from symptoms.49 In a penet- rating review of the aetiology, Walton marshalled the evidence for viral infection based on population Brain's Diseases ofthe Nervous System, 8th serology, analysis of cerebrospinal fluid immuno- Edition, 1977 globulin and comparative epidemiology; he drew attention to the recently described associations Dr Walton wrote in his preface to the eighth edition" with alleles of the histocompatibility system,50 and that he had extensively revised the section on concluded that multiple sclerosis is a disorder of demyelinating diseases in 1969 (but the chapter immune response within the nervous system, con- that appeared in 1977) deviated more from the ditioned by inherited predisposition, to a variety of model instituted in 1933 than any previous viral agents of which measles may be one - a revision. Biochemical, immunological and viro- formulation that had lost no impact since first logical studies had started to illuminate the stated by Brain in 1930. John Walton's account of neurobiology of the complex unit formed by the epidemiological statistics documented a further myelin sheath and its nutrient glial cell. Walton increase in the rates for prevalence, re-affirmed the copyright. vigorously restated Brain's view that the solution geographical trends, identified high-risk groups in to many of these disorders lay in understanding all geographical areas, suggested that racial suscep- their immunology, arguing that this would be aided tibility contributed to the distribution of multiple by the investigation of experimental allergic sclerosis, and demonstrated an aetiological inter- encephalomyelitis which was active in the New- play between environmental and genetic factors. castle department at that time; he felt the need to In describing the changes in cerebrospinal fluid,

relocate more subcategories of diffuse sclerosis Walton identified the long-neglected paper of http://pmj.bmj.com/ leaving only Schilder's disease, centrolobar Kabat25 reporting the increase of immunoglobulin sclerosis, progressive degenerative subcortical but still giving a conventional account of the encephalopathy and Balo's disease, whilst remain- colloidal gold curve. The distinction was made ing ambivalent about the status of X-linked reces- between quantitative and qualitative immuno- sive adrenoleucodystrophy,45 which appeared for globulin abnormalities and new findings on the the first time. concentrations of immunological mediators Walton could now be more precise about the released by inflammatory cells, capable of deg- aetiology of acute disseminated encephalomyelitis, rading myelin, were described. But Walton did not on September 29, 2021 by guest. Protected rejecting outright the long held view that the feel that any ofthese tests had influenced the ability various forms arose from activation of an ubi- to diagnose multiple sclerosis early in the course. quitous opportunistic demyelinating virus and Paroxysmal symptoms appeared in the clinical leaning heavily on experimental studies in favour of description of multiple sclerosis for the first time - the lymphocyte-mediated immunological hypo- the 1958 paper of Matthews51 having previously thesis. Acute cerebellar ataxia in children received been ignored. The prototypic symptom complexes yet more prominence but Walton felt unsure were classified as Charcot's triad, generalized, whether this differed from the syndrome of opsoc- ocular, sensory, cerebral, spinal (progressive, lonus and jerking extremities - now known to be unilateral and sacral), brainstem, and the acute associated with neuroblastoma in childhood and form which was described in detail but not encephalitis or paraneoplasia in adults. None ofthe identified eponymously as the Marburg variant.52 cases of neuromyelitis optica followed-up in Edin- The differential diagnosis still included meningo- burgh from 1937, and reported by Scott after up to vascular syphilis and tabes dorsalis - perhaps only 30 years46'47 had developed recurrent demyelina- a temporary anachronism - and for the first time tion, suggesting that Devic's disease was not after included other inflammatory disorders which could all a variant ofmultiple sclerosis; but in turning to mimic the spinal consequences of demyelination, the pathology of multiple sclerosis, the views of notably Behcet's disease but not sarcoidosis. Good Postgrad Med J: first published as 10.1136/pgmj.68.801.507 on 1 July 1992. Downloaded from 514 A. COMPSTON

and bad prognostic features were identified but the ofthe section on the aetiology ofmultiple sclerosis; overall impression of a more benign disease than not only was it necessary to document the growing previously recognized emerged from scrutiny of list of HLA antigen associations reported in Kurtzke's cohort of male cases in which >50% different populations of patients with multiple had survived >35 years.53 Walton's account of the sclerosis, but population serology had implicated treatment of multiple sclerosis provided a much specific viral triggers operating in genetically more comprehensive description of symptomatic susceptible individuals. Walton adopted the con- measures than before, emphasizing the extent to sensus view that no single agent was responsible for which spasticity, bladder and paroxysmal symp- the interplay between genes and environment, and toms could be managed. The assessment of treat- that exposure occurred repeatedly in early life. He ment made it necessary to devise scales for compar- did not attempt to catalogue the observations made ing individual cases or groups5m but there was no with respect to immunological changes in the good news on the efficacy ofspecific immunological peripheral blood, but suggested that the target remedies - some of which are still being used - for antigen for the immunological process might be influencing the long-term course of the disease, identified through studies of cerebrospinal fluid. even though the short-term role of corticotrophin Several years experience with evoked potential had been defined." Barbellion had not been forgot- methods had provided laboratory methods for ton. supplementing clinical evidence for the diagnosis Recognition of the range of conditions in which and the demonstration offocal areas ofdemyelina- central pontine myelinolysis might occur had tion using computerized tomography was recom- altered but the association with hyponatraemia mended. The suggestion that nuclear resonance was still not explicit. Diffuse sclerosis continued to imaging was likely to be even more successful was pose difficulties; even with the removal of familial prophetic of the most significant development in sudanophilic diffuse sclerosis, Pelizaeus-Mer- the investigation ofpatients with multiple sclerosis bacher disease, Krabbe's diffuse sclerosis and since before Brain first wrote on the subject in metachromatic leucodystrophy - and the diversion 1930." Immunological and immunogenetic charac- of Binswanger's subcortical encephalopathy which terization of patients with multiple sclerosis hadcopyright. never secured a comfortable place in the chapter on not helped in assigning an accurate prognosis; and demyelinating disease - Balo's concentric sclerosis J. Gould58 joined Barbellion in giving a personal and Schilder's disease still worried Walton in terms account of the disease. Walton had hoped to of classification and aetiology despite their provide some additional encouragement that the stereotyped clinical descriptions. Tests for meta- immunological approach to treatment might chromatic material were advocated in differentiating influence the long-term course of the disease, and these conditions but brain biopsy might be needed although hints of success had at the time been http://pmj.bmj.com/ in a difficult case where genetic counselling, a term reported using azathioprine with antilymphocyte not previously employed, was to be arranged. globulin and thoracic duct drainage, transfer fac- tor, copolymer 1 and dietary treatment, no therapy could unequivocably be recommended for the Brain's Diseases ofthe Nervous System, 9th multitude of patients. Edition, 1985

The 1985 edition of Brain's textbook56 included Conclusions on September 29, 2021 by guest. Protected further major departures from the 1933 produc- tion, appearing in double column quarto format. Taken with the 1930 Quarterly Journal ofMedicine Responding to the growing evidence for an review, the account of disseminated sclerosis con- immunological basis to the pathogenesis, Walton tained in the first edition of Brain's Diseases ofthe wrote an account of immunology and the nervous Nervous System was penetrating, ahead of its time system based on a lecture given at the first congress and definitive; most of the opinions given by of neuroimmunology in Stresa. Immunology had Russell Brain, and his predictions, were later for a short while been influenced by the ability to shown to be correct and it could be argued that identify and enumerate sub-populations of lym- little ofconceptual substance has since been added; phocytes which were assigned discrete functions nevertheless, clear shifts of emphasis and intellec- regulating networks ofanti-idiotypic cells involved tual unease were always apparent in his accounts of in suppressing cellular and antibody-mediated res- acute disseminated encephalomyelitis, and he ponses; and the opportunity to assign allelic never felt comfortable with the nosological status phenotypes provided clear evidence for the genetic of the leucodystrophies. Brain was clearly much control of immune responsiveness. The detailed influenced by the studies and writings of the neuroimmunological observations relating to neurological school that developed under Henry demyelinating disease required extensive revision Miller in Newcastle; and his successor as head of Postgrad Med J: first published as 10.1136/pgmj.68.801.507 on 1 July 1992. Downloaded from REVIEWING MULTIPLE SCLEROSIS 515

the department at the Newcastle General Hospital knowledge and modern interpretations neatly was a natural heir to authorship of the premier inserted - the stitches barely being visible. Author- English textbook of neurology. Walton's re- ship for the section on demyelinating disease now writing of the section on demyelinating disease for passes into new hands; it is sincerely to be hoped the eighth edition ranks with Brain's original that the newest wine will not disturb this distin- version in its breadth and intellectual authority; it guished old bottle. combines the best of Brain with contemporary

References 1. Brain, W.R. Critical review: disseminated sclerosis. Q J Med 26. Brain, W.R. Diseases ofthe Nervous System, 4th ed. Oxford 1930, 23: 343-391. University Press, London, 1951, pp. xxii + 1002 (495-530). 2. Marie, P. Lectures on Diseases of the Spinal Cord. New 27. Campbell, A.M.G., Daniel, P., Porter, R.J., Russell, W.R., Sydenham Society, London, 1895, pp. 131-136 (English Smith, H.V. & Innes, J.R.M. Disease of the nervous system translation). occurring among research workers on sway-back in lambs. 3. Dawson, J.D. The histology of disseminated sclerosis. Trans Brain 1947, 70: 50-58. R Soc Edin 1916, 50: 517-740. 28. Brain, Sir W.R. Diseases of the Nervous System, 5th ed. 4. Bullock, W.E. The experimental transmission of Oxford University Press, London, 1955, pp. xviii + 996 disseminated sclerosis to rabbits. Lancet 1913, ii: 1185-1186. (495-532). 5. Chevassut, K. The aetiology ofdisseminated sclerosis. Lancet 29. Miller, H.G. Acute disseminated encephalomyelitis treated 1930, i: 552-560. with A.C.T.H. Br Med J 1953, i: 177-183. 6. Braxton Hicks, J.A., Hocking, F.D.M. & Purves Stewart, J. 30. McAlpine, D. Acute disseminated encephalomyelitis: its Disseminated sclerosis: pathological and biochemical sequelae and its relationship to disseminated sclerosis. Lancet changes produced by a virus cultivated from the cerebro- 1931, i: 846-852. spinal fluid. Lancet 1930, i: 612-618. 31. Miller, H.G., Stanton, J.B. & Gibbons, J.L. Para-infectious 7. McDonald, W.I. Attitudes to the treatment of multiple encephalomyelitis and related syndromes. Q J Med 1956, 25: sclerosis. Arch Neurol 1983, 40: 667-670. 427-505. 8. Purves Stewart, J. A specific vaccine treatment in 32. McAlpine, D., Compston, N.D. & Lumsden, C.E. Multiple disseminated sclerosis. Lancet 1930, i: 560-564. Sclerosis. Livingstone, Edinburgh, 1955, pp. viii + 304. 9. Brain, W.R. Diseases of the Nervous System, 1st ed. Oxford 33. Pratt, R.T.C., Compston, N.D. & McAlpine, D. The familial copyright. University Press, London, 1933, pp. xvi + 699 (350-361, incidence ofdisseminated sclerosis and its significance. Brain 366-369, 389-402). 1951, 74: 191-232. 10. Ferguson, F.R. & Critchley, M. A clinical study of a 34. McAlpine, D. & Compston, N.D. Some aspects ofthe natural heredofamilial disorder resembling disseminated sclerosis. history of disseminated sclerosis. Q J Med 1952, 21 (new Brain 1929, 52: 203-225. series): 135- 167. 11. Barbellion, W.N.P. (B.F. Cummings) The Journal of a 35. Brain, Lord. Diseases of the Nervous System 6th ed. Oxford Disappointed Man. Chatto and Windus, London, 1919. University Press, London, 1962, pp. xiv + 879 (431-463). 12. Brain, W.R. Diseases ofthe Nervous System, 2nd ed. Oxford 36. Schapira, K. & Park, D.C. Gamma globulin studies in University Press, London, 1940, pp. xx + 950 (469-505). multiple sclerosis and their application to the problem of

13. Ferraro, A. Primary demyelinating processes of the central diagnosis. J Neurol Neurosurg Psych 1961, 24: 121-124. http://pmj.bmj.com/ nervous system. Arch Neurol Psych 1937, 37: 1100-1160. 37. Miller, H., Newell, D.J. & Ridley, A. Multiple sclerosis. Trials 14. Rivers, T.M. & Schwentker, F.F. Encephalomyelitis accom- of maintenance treatment with prednisolone and soluble panied by myelin destruction experimentally produced in aspirin. Lancet 1961, i: 127-129. monkeys. J Exp Med 1935, 61: 689-702. 38. Greenfield, J.G. In: J.G. Greenfield, W. Blackwood, W.H. 15. Putnam T.J. & Adler, A. Vascular architecture of the lesions McMenemy, A. Meyer & R.M. Norman (eds) of multiple sclerosis. Arch Neurol Psych 1937, 38: 1-15. Neuropathology. Arnold, London, pp. 640. 16. Greenfield, J.G. & King, L.S. Histopathology of the cerebral 39. Brain, W.R. & Greenfield, J.G. Late infantile metachromatic lesions in disseminated sclerosis. Brain 1936, 59: 445-458. leuco-encephalopathy, with primary degeneration of the 17. Curtius, F. Multiple Sklerose und Erbanlage. Leipzig, Thiene, interfascicular oligodendroglia. Brain 1950, 73: 291-317. 1933. p. 215. 40. Brain, Lord & Walton, J.N. Brain's Diseases of the Nervous on September 29, 2021 by guest. Protected 18. Greenfield, J.G. A form of progressive cerebral sclerosis in System, 7th ed. Oxford University Press, London, 1969, pp. infants associated with primary degeneration of the interfas- xvi + 1062 (476-512). cicular glia. Proc R Soc Med 1932, 26: 690-697. 41. Adams, R.D., Victor, M. & Mancall, E.L. Central pontine 19. Innes, J.R.M. Swayback: a demyelinating disease of lambs myelinolysis. Arch Neurol Psych 1959, 81: 154-172. with affinities to Schilder's encephalitis and its prevention by 42. McAlpine, D., Lumsden, C.E. & Acheson, E.D. Multiple copper. J Neurol Neurosurg Psych 1939, 2: 323-324. Sclerosis: a Re-appraisal. Livingstone, Edinburgh, 1965, 20. Brain, W.R. Diseases ofthe Nervous System, 3rd ed. Oxford p. 415. University Press, London, 1947, pp. xx + 987 (480-516). 43. McAlpine, D. The benign form of multiple sclerosis: a study 21. Hurst, E.W. Demyelination: a clinico-pathological and ex- based on 241 cases seen within three years of onset and perimental study. Med J Aust 1941, 2: 661-666. followed up until the tenth year or more ofthe disease. Brain 22. Hurst, E.W. Acute haemorrhagic leuco-encephalomyelitis, a 1961, 84: 186-203. previously undefined entity. Med J Aust 1941, 2: 1-6. 44. Walton, J.N. Brain's Diseases ofthe Nervous System, 8th ed. 23. Putnam, T.J. The centenary ofmultiple sclerosis. Arch Neurol Oxford University Press, Oxford, 1977, pp. xvi + 1277 Psych 1938, 40: 806-813. (526-568). 24. Compston, D.A.S. The 150th anniversary of the first depic- 45. Schaumburg, H.H., Powers, J.M., Suzuki, K. & Raine, C.S. tion of the lesions of multiple sclerosis. J Neurol Neurosurg Adreno-leukodystrophy (sex linked Schilder disease); ultra- Psych 1988, 51: 1249-1252. structural demonstration ofspecific cytoplasmic inclusions in 25. Kabat, E.A., Moore, D.H. & Landow, H. An electrophoretic the central nervous system. Arch Neurol 1974, 31: 210-213. study of the protein components in cerebrospinal fluid and 46. Scott, G.I. Ophthalmic aspects of demyelinating diseases. their relationship to the serum proteins. J Clin Invest 1942, 21: Proc R Soc Med 1961, 54: 38-42. 571-577. Postgrad Med J: first published as 10.1136/pgmj.68.801.507 on 1 July 1992. Downloaded from 516 A. COMPSTON

47. Scott, G.I. Optic disc oedema. Trans Ophthal Soc UK 1967, 54. Kurtzke, J.F. A new scale for evaluating disability in multiple 87: 733-753. sclerosis. Neurology 1955, 5: 580-583. 48. ter Meulen, V., Koprowski, H., Iwasaki, Y., Kackell, Y.M. & 55. Rose, A.S., Kuzma, J.W., Kurtzke, J.F., Namerow, N.S., Muller, D. Fusion of cultured multiple-sclerosis brain cells Sibley, W.A. & Tourtellotte, W.W. Cooperative study in the with indicator cells: presence of nucleocapsids and virions evaluation of therapy in multiple sclerosis: ACTH vs and isolation of parainfluenza-type virus. Lancet 1972, ii: placebo-final report. Neurology 1970, 20: 1-59. 1-5. 56. Walton, Sir J.N. Brain's Diseases ofthe Nervous System, 9th 49. McDonald, W.I. Pathophysiology in multiple sclerosis. Brain ed. Oxford University Press, Oxford, 1985, pp. xi + 701 1974, 97: 179-196. ' (295-321). 50. Jersild, C., Svejgaard, A. & Fog, T. HL-A antigens and 57. Young, I.R., Hall, A.S., Pallis, C.A., Legg, N.J., Bydder, multiple sclerosis. Lancet 1972, i: 1240-1241. G.M. & Steiner, R.E. Nuclear magnetic resonance imaging of 51. Matthews, W.B. Tonic seizures in multiple sclerosis. Brain the brain in multiple sclerosis. Lancet 1981, ii: 1063-1066. 1958, 81: 193-206. 58. Gould, J. Disabilities and how to live with them: multiple 52. Marburg, 0. Die sogennante 'akute multiple sklerose'. Jahr- sclerosis. Lancet 1982, ii: 1208- 1210. buch Psychiat Neurol 1906, 27: 211-312. 53. Kurtzke, J.F. Multiple sclerosis death rates from underlying cause and total deaths. Acta Neurol Scand 1972,48:148-162. copyright. http://pmj.bmj.com/ on September 29, 2021 by guest. Protected