the mystery ofthe origin ofmultiple sclerosis -...

Journal of Neurology, Neurosurgery, and Psychiatry 1986;49:113-123

The mystery of the origin of multiple sclerosisWI McDONALD

From the Institute of Neurology, The National Hospitalfor Nervous Diseases, London

SUMMARY Our present understanding of the aetiology and pathogenesis of multiple sclerosis isdiscussed in relation to the views of Sir William Gowers. He perceived that both environmental andgenetic factors might be implicated in the aetiology of the disease. Evidence for the former was firstreported in 1903, but has become convincing only in the past 20 years; the nature of the environ-mental factor remains obscure. Evidence for a genetic influence on susceptibility has accumulatedsince the 1 930s, the most compelling coming from the recent Canadian twin study. The number andmode of operation of the genetic factors is still uncertain, but there is evidence for the implicationof genetically controlled cellular immune mechanisms in the pathogenesis of the disease. The preciserelationship between transient changes in immunological status and the development ofnew lesionshas yet to be defined; magnetic resonance imaging (MRI) promises to play a significant role in thisanalysis because of its sensitivity in detecting abnormalities in multiple sclerosis. MRI is not in itselfspecific; it is probable that the similar appearances in multiple sclerosis and cerebral vascular diseaseboth derive at least in part from the influence of astrocytic gliosis on proton content and distribution.The significance of the gliosis is uncertain. Gowers believed that the primary defect in multiplesclerosis lay in the astrocyte. Recent observations on the immunological functions of this cell in vitrosuggest that it could be involved early in the pathogenesis of the lesion.

The title of this review is a quotation from the secondedition of Gowers' Manual ofDiseases of the NervousSystem published in 1893.' It is as apt a beginningtoday for a discussion of the cause and the nature ofmultiple sclerosis as it was then. What strikes themodern reader of the Manual is the precision ofGowers' observations, the elegance of the language inwhich he describes them, and his range. He encom-passed not only clinical description and the pathologyof the nervous system, but much more in medicinebesides. His haemocytometer was in use until our ownday and his Manual and Atlas of Ophthalmoscopy2established the role of the ophthalmoscope not only inneurology but in general medicine as well: there onereads descriptions of the retinopathies of uraemia,diabetes and leukaemia, of retinal tubercles and ofwhat we would now recognise as acute ischaemic optic

Based on the Ninth Gowers Memorial Lecture. Gowers used the term"insular" instead of "multiple" sclerosis but I have preferred to usethe modern term throughout.

Address for reprint requests: Professor WI McDonald, The NationalHospital for Nervous Diseases, Queen Sq, London WCIN 3BG, UK

Received 18 June 1985. Accepted 6 July 1985

neuropathy following haemorrhage.Gowers was a great teacher. Through his writings

his influence spread far beyond those who were fortu-nate enough to work for him at University CollegeHospital and Queen Square. Weir Mitchell3 touch-ingly acknowledged his indebtedness on the occasionof Gowers' knighthood at the diamond jubilee ofQueen Victoria: "... Your book on nervous diseasestands for us all as the best of the many great textbooks-It has been the rich mine from which thematerial for many treatises has been taken-It is thebook to which I turn first when my own knowledgefails-...". Gowers' didactic tendency was pervasiveand when he saw an opportunity to dispel confusionin other disciplines he took it. A good example was hisconcern about the difficulty of notating accurately therange over which hearing loss occurs in disease, occa-sioned by the muddled translation of one of his worksinto German. He noted the confusion in the musicalliterature as well and devised a rational system whichhe promoted in both the musical4 and the medicalpress,' regrettably without success.One of the topics within neurology which interested

Gowers was multiple sclerosis.6 In this review of itsaetiology and pathogenesis I propose to explore therelationship between our understanding of the diseaseand his.

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Aetiology

There is now abundant evidence that there are twoclasses of factor involved: environmental and genetic.

Environmental factorsGower's own comments were restricted to the per-sonal environment of the individual patient. He notedthat "among the influences to which it has been imme-diately ascribed, the most frequent are exposure tocold....'' He made no comment on the geographicaldistribution of the disease, the first such observationcoming from Byron Bramwell,' father of one of hisformer pupils, in the same volume of the Review ofNeurology and Psychiatry which contained the medi-cal version of Gowers' paper on musical notation.

Bramwell reviewed his own experience in privateand hospital practice in Edinburgh and compared itwith the recently published experience of a group ofneurologists in New York. One in 58 of Bramwell'spatients had multiple sclerosis compared with one in219 of the pooled American cases. Bramwell wasaware of the possible sources of error in comparisonsof this kind, but concluded that the difference in fre-quency between the two places was real.The next report of a possible geographical

difference came from within the United States. In 1922Davenport8 noted that multiple sclerosis was morecommon as a defect of drafted men from the northernStates than the southern. A new attempt to define theinfluence of location on risk was made9 in 1950 whenmortality data again showed a higher risk in northernthan southern states.9 This trend was soon confirmedby careful prevalence studies. 0 Unexpectedly low fre-quency of multiple sclerosis was also found in SouthAfrica.1 There was now an explosion of epi-demiological studies. They led to the general conclu-sion that for northern European Caucasoid popu-lations, the risk of developing multiple sclerosisincreases as one goes further from the Equator in boththe northern and the southern hemispheres: multiplesclerosis is more common in Scotland (where itapproaches 200 per 100,000)12 - 14 than in the south ofEngland'5 and in the South Island than in the Northof New Zealand.'6 As one might expect there aresome variations in the relationship between latitudeand reported prevalence. 7 18 Some may be due to thestudy in small populations ofwhat is, after all, a ratheruncommon disease; and the quality of investigationsvaries. However, as will become clear, some of thevariations are undoubtedly real and important for ourunderstanding of the aetiology of the disease.A new discovery was made in the 1970s: that there

are variations in risk associated with migration. InCaucasoid populations, migration between northernEurope and South Africa,'9 and in the USA, between

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northern states and southern,"-" is associated witha reduction in risk provided the move takes place inchildhood. The number of patients involved in theseinvestigations is however rather small, and as Dr EDAcheson (personal communication) has pointed out"in the study of multiple sclerosis the epidemiologicalmethod as employed up to the present has been oper-ating at the limits of its power." Nevertheless theconsistency of the observations suggests that there issomething in them. The evidence that the risk ofdeveloping multiple sclerosis depends upon where anindividual spends his first 15 years or so suggests thatthere is an environmental factor involved in the causa-tion of multiple sclerosis.

Poskanzer et a123 noted the similarity between theprevalence pattern of multiple sclerosis and that ofpoliomyelitis, and suggested that the environmentalfactor was infective. Some impetus has been given tothis interpretation by the observation of clusters ofcases in restricted regions. Such clusters have beenrecognised for many years but interpreting theirsignificance has been difficult because clustering canoccur as a statistical effect, without biologicalsignificance. A remarkable example has been reportedrecently from the Faroe Islands.24 Between 1943 and1960, 24 cases appeared and there has been only onefurther case since. Such clustering of cases in spaceand time strongly suggests that an environmental fac-tor was operating. It was argued that it was infective,and possibly related to the advent of the British Armyjust before the "epidemic" began.Two consequences of the infective hypothesis can

be tested epiderniologically. The first is that adultmigrants from a high risk area should have an evenhigher risk of developing multiple sclerosis aftermigrating to a low risk area if, as Poskanzer et al23suggested, the infectious agent is more common in thelatter. Neither of two American studies provided evi-dence that this is so.2126 The second is that youngmigrants from a low to a high prevalence area shouldhave an increased risk ofdeveloping the disease. Thereis some evidence that this may be so in Afro-Asianmigrants to Israel,27 and three cases of multiplesclerosis have been found amongst 3451 half-Vietnamese migrants to Paris, corresponding with anunexpectedly high crude prevalence rate of 89 per100,000.28 The total numbers in these investigationsare even smaller than in the others just mentioned,and at this stage one cannot say more than that theresults are consistent with the hypothesis of an infec-tive origin for the disease. More data are needed.

In summary, the balance of evidence suggests thatthere is an environmental factor in the cause of multi-ple sclerosis. The working hypothesis is that it is infec-tive but the epidemiological evidence is not conclu-sive. Neither is there direct confirmation of infection.



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The mystery of the origin of multiple sclerosis

The question has been reviewed elsewhere.29 Suffice itto say that a disease resembling multiple sclerosis hasnot been transferred from man to animals, that thesame virus has not been isolated from different casesin different centres, and that the raised titre of anti-bodies against measles found in groups of patientswith multiple sclerosis is not specific either to measlesor to multiple sclerosis. Finally, the virus-like particlessometimes reported in multiple sclerosis brain can,with one possible exception, be accounted for in otherways.30

Genetic factorsIn my account of the epidemiology of multiple sclero-sis I have so far ignored an important point: for someraces the risk of developing the disease is low and littleinfluenced by latitude. Multiple sclerosis is rare orabsent in the Bantu and appears to be rare in theEskimo"7 and the Hungarian gypsy.3' The gypsies areracially distinct from the Caucasoids in Hungary, hav-ing migrated from north India to the Balkans in thesecond century and then to the rest of Europe about500 years ago.32 In the Caucasoids the prevalence ofmultiple sclerosis is 37 per 100,000 whereas in thegypsies only two cases have been identified in all theneurological departments of the five Transdanubiancounties serving a population of 110,000 gypsies.3'Since the Hungarian figures are based on hospitalstatistics it will be important to determine whether thedifference is confirmed by mortality and prevalencedata based on systematic case ascertainment.The best studied non-Caucasoid population is the

Japanese. All investigations have shown that the prev-alence is much lower than in Caucasoids living atcomparable latitudes.33 The prevalence in Sapporo(430 north) for example is 2:100,000 and in Boston,USA (420 north) is 41 per 100,000.15A particularly interesting study has been carried out

on the west coast of the United States.34 The preva-lence in Los Angeles in Caucasoids is 21-6 per 100,000;it rises to 68i7 in Washington State. In the Japanese itis only about 6 per 100,000 in both regions. A low risk(based on mortality data) is also seen in the Chinese25but what makes the Japanese data especially inter-esting is that unlike the Chinese, they have little ten-dency to remain in fairly closed ethnic groups in theseregions, that is they more nearly share the environ-ment of the Europeans amongst whom the risk is somuch higher.34 The evidence suggests that there is aprotective genetic influence in orientals.Gowers' considered the genetic component in the

aetiology of multiple sclerosis in the Manual': "directheredity.... is quite exceptional; indirect inheritanceis more common, shown by a family history of insan-ity, epilepsy, or some form of chronic paralysis". Hedoes not enlarge on the nature of "indirect inher-

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itance" but the context suggests that he believed thatthere exists some general kind of genetic predis-position to neurological disease. In 1908 he was one ofthe opening speakers at a symposium held at theRoyal Society of Medicine on heredity in disease, buthe did not develop his views either on the nature ofindirect inheritance or on the genetic factor in theaetiology of multiple sclerosis. Indeed, he commentedthat multiple sclerosis is "another affection in whichheredity might be expected, according to one view ofits nature, but no facts have suggested it".35 Thoughexcited by the scientific study of heredity, he thoughtthat at that time the study of genetics in human dis-ease was "still at the stage of random observation"."And thus it remained in relation to multiple sclero-

sis until the 1930s when Curtius36 made a good casefor a significant familial incidence of the disease. Prattet al37 reviewed in 1951 the world literature and addedfurther cases of their own, recording that in a total of310 cases the familial incidence was 6-5%. Manyreports of familial multiple sclerosis followed. InNorthern European Caucasoids the overall familialincidence turns out to be roughly 10%.3839

Stronger evidence for a genetic factor comes fromthe study of twins. A number of studies have sug-gested that it is more common for both of a pair oftwins to develop multiple sclerosis if they are mono-zygotic than if they are not. The data have beenreviewed recently.39 The incidence of concordancevaries between different populations but overall theconcordance rate does seem to be higher in the mono-zygotic twins (29%) than in the dizygotic (13%).However studies of concordance for disease in twinsare usually subject to bias; concordant pairs are morelikely to be identified than discordant.39 The system-atic study that Dr George Ebers40 is carrying out inCanada is therefore of special interest. He and hiscolleagues contacted 5,000 patients with multiplesclerosis and enquired of each whether he or she hada twin. The incidence of twinning was 1/80, theexpected incidence in the general population, whichsuggests that the risk of ascertainment bias has beenminimised. They then personally examined every liv-ing twin. About 1:3 of the monozygotic pairs wereconcordant compared with 1:40 of the dizygotic pairs.Moreover this low concordance in the non-identicaltwins was similar to that for siblings, amongst whom,as we have just seen, the risk is higher than in thegeneral population. These observations providestrong evidence for the implication of a genetic factorin the aetiology of multiple sclerosis.The HLA system It has become clear that there is anassociation between multiple sclerosis and the 6thchromosome and in particular with the HLA regionwhich is concerned with the genetic control ofimmunemechanisms. The strongest associations are with the



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D or DR loci, which are probably equivalent. Formost populations of Northern European origin, thereis a strong association between multiple sclerosis andthe gene products Dw2 and DR2. The association isseen in Northern Europeans wherever they live, inNorthern Europe and Scandinavia itself, NorthAmerica, Australia and New Zealand.4" -4 Our datafor London are representative: DR2 is found in 19%of the control population and 55% of patients withmultiple sclerosis.44 It should be noted that thestrength of the association in general decreases as onegoes further south in Europe and that it is ratherweaker in the United States than in Northern Europeitself and Australia, probably because of the greatermixture of populations in America. Such genetic mix-ture probably also accounts for the association ofmultiple sclerosis with Dw2 in the American negro;Dw2 is very rare in native black Africans.45The story is however more complicated. In Arabs,

we found that the association was not with DR2 butwith DR446 and no association has been found in theJapanese47 or the Israelis.48 Most surprising of all isthe observation that there is no significant differencein the proportion of people with multiple sclerosiswho are Dw2 or DR2 positive as compared with thenormal population in the Orkney and ShetlandIslands,49 and in Aberdeen (D Francis, JR Batchelor,WI McDonald, AW Downie and JEC Hem,unpublished results)-despite the very high preva-lence rates. But as Compston50 has pointed out inrelation to the Orkneys and Shetlands, the incidenceof Dw2 or DR2 in the multiple sclerosis group issimilar to that in other Northern European groupswith the disease, and the reason why no differenceswere found in comparison with the normal populationmay be the unusually high incidence of Dw2 or DR2in the normal controls. In other words, multiplesclerosis is particularly common in this population inwhich Dw2 and DR2 is also common.The question now arises whether DR2 is the critical

factor which confers susceptibility to multiple sclero-sis. The answer is almost certainly not, for severalreasons. First, as I have just shown, the association isnot universal. Secondly, in familial multiple sclerosisthere is less haplotype sharing than would be expectedfrom the population studies, although there is morethan would be expected from the relationshipsbetween affected individuals.5 52 Thirdly, if oneaccepts at face value the Hungarian data30 one findsa remarkable thing. As already mentioned, the preva-lence of multiple sclerosis in the Caucasoids is 37 per100,000 and in the gypsies it appears to be only 2 per100,000. The incidence ofDR2 in the Caucasoids is ofthe expected order: 19 5% in the controls and 42-7%in the patients with multiple sclerosis; but in the con-trol gypsy population the incidence of DR2 is very

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high indeed (56.5%) yet the prevalence of the diseaseis very lOW.3132 The fact that both the known cases areDR2 positive is unhelpful, because of the small num-bers. Finally, in a twin study carried out in the USAthere were two pairs of non-identical twins concor-dant for multiple sclerosis; in both pairs only one wasDw2 positive.53The first conclusion that can be drawn from this

mass of apparently discordant data is that the fre-quency with which an association is found betweenthe HLA system and multiple sclerosis suggests that ithas some significance. Secondly, Dw2 and DR2 are inthemselves neither necessary nor sufficient to lead tothe development of the disease. What then might thesignificance of the various associations be? One possi-bility is that each is conferring susceptibility on itsown population and that the environmental factor isdifferent in different regions. The Hungarian datawould be hard to reconcile with this interpretation.An alternative possibility is that DR2 and DR4 areacting as markers in their respective populations for acommon, hitherto unidentified single susceptibilitygene in the HLA region; there are after all an enor-mous number of candidates. The D region is the sub-ject of intensive investigation at present. There arenow 99 specificities recognised serologically and 25 bycell typing.54 The great majority have still to be exam-ined in relation to multiple sclerosis. Severalinvestigators5556 have argued for the view that thereis a single susceptibility gene, and indeed for its beingrather common and dominantly inherited,56 the lowincidence of the disease being explained by variationsin "dose" of the environmental factor and the age atwhich it is received.

There is a third possibility: that more than onegenetic factor is involved. There are now severalreports suggesting that such is the case. Two lociwithin the HLA region concerned with the control ofpolymorphisms in the complement pathways havebeen implicated. An association with the Bf locus hasbeen found in Australia57 and London,44 but not inNorth Rhine/Westphalia58 or Aberdeen (D Francis,JR Batchelor, WI McDonald, AW Downie & JECHern, unpublished observations). An association withthe C4 locus has also been reported in a familystudy.59 There are two reports of an association witha locus on the 14th chromosome coding for immu-noglobulin heavy chains,606' but in one of thesereports the significance was reduced to borderline lev-els when a larger group (admittedly including less wellstudied cases) was included.60 The present data areinadequate to permit firm conclusions about the roleof other genetic factors to be drawn.

In summary, in most but not all populations multi-ple sclerosis is associated with certain genetic charac-teristics. The best documented are those coded for in



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the HLA region of the 6th chromosome, in particularthe HLA antigens themselves. Less well documentedassociations implicate the complement pathways, andthe control of antibody structure. How these associ-ations relate to the environmental factor is notknown. Some may influence susceptibility to the dis-ease, others severity of it. It is possible that in neithercase have we yet identified the most important associ-ations. The next step is to seek true linkages using thenew techniques of DNA analysis which have provedso successful in, for example, Huntington's chorea.

PathogenesisI now wish to look more closely at the "origin" ofmultiple sclerosis referred to in the title of this review.In its context the idea included pathogenesis. Thegenetic associations suggest that an immune mech-anism may be involved: all those so far implicated areconcerned in one way or another with the immuneresponse. Moreover, it is known that the liability todevelopment of certain conventional autoimmune dis-eases such as thyrotoxicosis and chronic active hepa-titis, is influenced by an individual's HLA profile.6263There are four main lines of evidence that there is anabnormality of the immune mechanism in multiplesclerosis.

First, it has been known for over 20 years that thereis a modest increase in the titre of antibodies againstmeasles and related viruses in both the serum andcerebrospinal fluid of patients with multiple sclero-SiS 6465

Secondly, it is now well established that about 90%of patients with multiple sclerosis have evidence ofabnormal synthesis of gamma globulin in the centralnervous system: oligoclonal bands are present at elec-trophoresis, and the amount of gamma globulin syn-thesised by the brain is increased.66 Very recently,Compston and his colleagues have shown a highlysignificant reduction in the concentration of the termi-nal component of the complement cascade, Cg, in thecerebrospinal fluid.67

Thirdly, the lesions themselves contain immu-nologically competent cells. Dawson68 establishedearly this century that the plaques of demyelinationare orientated around small venules which in earlylesions are surrounded by mononuclear cells. Some-times the perivascular cuff can be traced into normal-appearing adjacent white matter, suggesting that thecellular infiltration precedes extension of the myelindamage. The cuffs contain lymphocytes and plasmacells. Monoclonal antibody techniques show that thelymphocytes are mostly T cells,6970 probably more ofthe helper type than the suppressor, which corre-sponds with the relative proportions of these typesfound in the CSF of patients with multiple sclerosis.7'In the lesions themselves, T cells are present at the

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active edge and extend into the adjacent normalappearing white matter.72The fourth line of evidence that an immune mech-

anism is involved in multiple sclerosis comes from thestudy of the numbers of helper and suppressor cells inperiphbral blood. The number of T suppressor lym-phocytes falls at the time of a relapse73 and in theearly stages of acute optic neuritis,74 a conditionwhich has the particular advantage that the onset canbe defined reasonably easily. But there has not beenuniversal agreement either about the observations inmultiple sclerosis or about their interpretation. Twomain criticisms have been made. First, that the obser-vations were wrong. Some experienced investigatorssimply did not find consistent changes in thehelper/suppressor ratio. However, agreement is lack-ing about the best methods for identifying and count-ing T lymphocyte subsets and different approacheshave been adopted in different laboratories. The sec-

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IFig I (a) X-ray CT scan of the brain from a patient withmultiple sclerosis. Note the low attenuation in the peri-ventricular white matter. (b) MRI scan (spin-echosequence) of the same patient as in (a). The periventricularabnormalities are more extensive and an additional discreetlesion is visible in the right frontal lobe. The changes aremore extensive posteriorly. (c) MRI scan from a healthycontrol subject. (d) MRI scan from a patient aged 53 withBinswanger's disease.



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Fig 2 (a) Multiple sclerosis: myelin preparation from the frontal lobe. (b) Section near (a) stainedfor fibrillaryastrocyte processes. (c) Binswanger's disease: myelin preparation from the occipital lobe. (d) Section near (c) stained forfibrillary astrocyte process. (By courtesy of Dr Ivan .Janota. (c) and (d) are reproduced by permission of ChurchillLivingstone, publishers"').ond criticism has been that if changes did occur theywere unrelated to the disease process. It is known forexample that there are diurnal variations in the ratioof helper to suppressor cells,75 and falls in the num-bers ofT suppressor cells can occur without symptom-atic change in the patient.74 The absence of a cor-relation between clinical relapse and T-suppressor celllevels does not necessarily imply that the cellularchanges are unrelated to disease activity, since, as willbecome clear, lesions often develop without accom-panying symptoms.

These are important issues which need to beresolved. Serial investigations are needed on largenumbers of patients all of whom are carefullyobserved clinically and who are bled at the same timeof day. It is noteworthy that so far positive results

have been found more often in such large serial stud-ies. A second requirement is the development of bettermethods for detecting new lesions in the brain.

Magnetic Resonance Imaging (MRI)Three years ago Dr Ian Young and his colleagues atthe Hammersmith Hospital made the important dis-covery that in multiple sclerosis many more lesions inthe brain could be demonstrated by MRI scanningthan by x-ray scanning.76 Figure la shows an x-rayCT scan from a patient with multiple sclerosis.Regions of low attenuation are visible in the whitematter around the ventricles. An MRI scan using aspin-echo sequence (fig 1 b) shows that the peri-ventricular abnormalities are more extensive. We haveseen such changes in 59 of 60 consecutive patients with

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clinically definitive multiple sclerosis aged 17 to 70years (mean 38)." In addition there is a discreet lesionin the frontal lobe which had not been suspected fromthe x-ray scan. We have not seen regions of alteredsignal from the periventricular region in 36/37 healthycontrol individuals aged 19 to 62 years (mean 38) (figlc), although in keeping with the occasional surprisediscovery of the pathological changes of multiplesclerosis at necropsy7879 one apparently healthy con-trol subject showed MRI appearances indistinguish-able from those of multiple sclerosis. Others havereported periventricular changes in individuals overthe age of 60.80Such dramatic pictures serve to remind the modern

neurologist that abnormalities in the periventricularregion are characteristic of multiple sclerosis.Hallervorden8" went so far as to say that if they werenot present at necropsy, the diagnosis should be indoubt. It is fascinating that Cruveilhier82 in hisdescription of the pathology of multiple sclerosis inthe great Atlas published between 1835 and 1842described lesions ("degeneration grise") in the corpuscallosum in one of his first cases with spinal and cere-bellar symptomatology. Gowers' emphasised that theextent of the periventricular lesions increases posteri-orly, as fig lb shows.The question now is whether it is possible positively

to identify new lesions. Certainly multiple abnormal-ities may be seen in patients having their first clinicalepisode suggestive of multiple sclerosis. We have seenmultiple cerebral lesions in 17 of 28 patients withisolated optic neuritis and in a similar proportion ofpatients with isolated acute brainstem symptoms. It istempting to suggest that the presence of lesions remotefrom the site related to the symptoms indicates thatthere have been previous silent episodes of neu-rological damage and that the patient already hasmultiple sclerosis. Such a conclusion is premature. Itis possible that in some of these patients the opticneuritis or the brain symptoms were the sole symp-tomatic expression of a more widespread but never-theless monophasic pathological process. Our serialstudy of patients with isolated symptoms should helpto resolve this problem.One of the first priorities of the MRI group at

Queen Square has been to look at the specificity of thechanges for multiple sclerosis.77 The diffuse peri-ventricular changes and focal lesions seen in CT scansof patients with multiple sclerosis resemble thosefound in patients with evidence of diffuse cerebralvascular disease. We therefore investigated 23 patientswith cerebral vascular disease aged 23 to 80 years(mean 61 years) including patients with late onsetepilepsy and CT scan evidence of lesions consistentwith lacune, acute stroke, transient global amnesia,and Binswanger's disease (cerebral vascular disease,

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hypertension and dementia). All showed focal lesions,some small and indistinguishable from the focallesions seen in multiple sclerosis (fig lb) others largerand corresponding with the territory of medium andlarge cerebral vessels. Nineteen of the 23 showed peri-ventricular changes (fig 1) which in some patientsappeared to be smoother in outline than those ofmultiple sclerosis, but in others were indistinguishablefrom them.What do the MRI abnormalities represent? Is it

oedema, which occurs in the acute lesions of bothmultiple sclerosis and vascular disease? Oedema altersthe MRI signal, but cannot account for the changes inthe chronic lesions. Is it, so to speak, myelin loss?Probably not, since it seems that myelin-bound pro-tons contribute relatively little to the MRI signal fromnormal brain.83 Is it astrocytic gliosis, which is vigo-rous in both multiple sclerosis and vascular disease? Iwould like to look at this possibility a little moreclosely.

Figure 2a from a patient with multiple sclerosis is amyelin preparation from the frontal lobe. An adjacentsection stained for glial fibrils (fig 2b) reveals theintensity of the astrocytic gliosis. Figure 2c shows amyelin preparation from the occipital lobe in a patientwith Binswanger's disease and fig 2d shows the glialpreparation. The changes are similar to those in mul-tiple sclerosis. Microscopically however there areimportant differences;84 in multiple sclerosis thereis a relative preservation of axons whereas inBinswanger's disease the picture is purely degener-ative. The common ground between the lesions ofmultiple sclerosis and Binswanger's disease is the glio-sis. The replacement of myelin by astrocytic processeswould increase the water content per unit volume andthus alter the MRI signal. It is also conceivable thatthe signal may be modified by changes in the macro-molecular environment provided by the glial fibrils.

There is perhaps some danger of expecting toomuch of MRI too soon. Specificity is one problem:quantitation of the changes in the brain is anotherwhich urgently needs to be solved before MRI can beused in one of its potentially most useful roles, that ofmonitoring treatment. These problems can be over-come and in other respects it is hard to underestimateits importance. Existing techniques offer the possi-bility of new clinico-pathological insights for exampleinto the mechanism of the memory defects which arecommon even early in the course of multiple sclero-sis,85 and into the affection of the sense of smell. Thedistribution of the MRI changes suggests that struc-tures mediating olfaction may be involved in multiplesclerosis. Standard texts make little reference to thepossibility, but Gowers records that the olfactory"nerve" (in reality the tract) is often abnormal.' Dr FScaravilli and I (unpublished) have been able- to



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confirm readily the presence of Cruveilhier's "degen-eration grise" in the olfactory tract where there isextensive loss of myelin histologically. Althoughpatients rarely complain of abnormalities of the senseof smell, Pinching86 in the course of a study under-taken for another purpose, found definite abnormal-ities in 15 of 22 patients with multiple sclerosis.A third way in which MRI promises to be helpful

is in elucidating the nature and sequence of eventsduring the development of the plaque. There is someevidence that the vessels in the plaque are abnormallypermeable: CT scans may show enhancement withiodine-containing agents, and there is leakage oftrypan blue into plaques at necropsy.87 In the retinatoo there is evidence of abnormal permeability. In arecent investigation sheathing (the ophthalmoscopicsign of perivascular cuffing) of the peripheral retinalvessels was observed in 14 of 50 consecutive patientswith acute isolated optic neuritis persenting to theMoorfields Eye Hospital.88 At fluorescein angio-graphy, the dye leaked from the sheathed segments ofthe vessels. The timing of the permeability changes inrelation to the evolution of the lesion is however notknown. The development of contrast agents such asthose recently used in the study of tumours by theHammersmith group89 raises the possibility of serialstudies of the blood-brain barrier during life in multi-ple sclerosis. Looking further to the future, the newesttechnical advances indicate that it may be possiblesoon to study metabolism by NMR spectroscopy infocal regions of the individual patient's brain selectedfrom magnetic resonance images of it.To return to the pathogenesis of multiple sclerosis,

there is, in summary, good evidence for the existenceof immunological abnormalities in patients with thedisease, but it is not established whether the tissuedamage is actually produced immunologically orwhether, as some have suggested, the immunologicalchanges are a consequence of demyelination producedin some other way.90 Demyelination can be producedby allergic means, most notably in experimental aller-gic encephalomyelitis. In an important recent experi-ment Watanabe et a!9' have discovered a mechanismby which experimental viral infection can lead to thesecondary development, after a delay and in theabsence of recoverable virus, of allergic demyelinationof the central nervous system. This is a potentiallyimportant model with which to explore the patho-genesis of multiple sclerosis.Gowers developed his ideas about pathogenesis at

some length in the Manual,1 and concluded that mul-tiple sclerosis was primarily a disorder of the neu-roglia. "It is" he said "essentially a process of morbidgrowth but may sometimes commence as an inter-stitial inflammation." This quotation comes from theunpublished third edition of Vol. II (sadly now miss-

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ing, though the relevant page is reproduced in fac-simile in Critchley's biography6). In this manuscripthe goes further. He notes "the tendency of residualembryonal tissue to overgrow in adult life" and sug-gests "that the islets of sclerosis may start from pointsof developmental origin."The idea of a neuroglial origin for multiple sclerosis

derives originally from Rindfleisch92 and Charcot93and may come as a surprise to the modern neurologistfor whom research on multiple sclerosis has longfocused on myelin. But as a comparison of figs 2a andb shows, glial proliferation is as striking as demy-elination. It is generally assumed that the proliferationis simply a consequence of the myelin loss, but recentexperiments suggest that this may be too simple aview.

Different glial cell types can now be identified usingspecific antibody markers combined with fluorescentdyes9495 and can be grown in 99% pure culture. It isthus feasible to investigate the properties of individualtypes of cell. Fontana et a!9697 have used these tech-niques to explore the relationship between astrocytesand the immune system. In culture they mixed ratastrocytes with rat T-lymphocytes from a line whichhad been sensitised to myelin basic protein. The twocell types showed no affinity. The next step was to addmyelin basic protein. If this is done to a pure cultureof the sensitised T-lymphocytes, there is no reactionbecause the antigen must be presented by a cell (forexample the macrophage) bearing on its surface theimmune-associated (Ta) protein. When myelin basicprotein was added to the lymphocytes in the presenceof astrocytes from rats of the same strain a strikingseries of changes occurred. Within 24 hours the T-lymphocytes were closely adherent to the astrocytes.By 48 to 72 hours the T-cells were transformed intoblast cells and were proliferating vigorously. It waspossible to show that the reaction was specific tomyelin basic protein by demonstrating that it did notoccur when a different antigen was added to the mixedculture. It was also possible to show that the reactionwould not occur unless the lymphocytes and astro-cytes had the same genetic background. They showedthat the astrocytes which had been in contact with thesensitised cells did indeed express the required Ia pro-tein on their surface, by staining with an appropriatemonoclonal antibody. Finally, in other experiments itwas established that astrocytes release a substanceclosely similar to interleukin- I which is released by theusual antigen-presenting cell in other tissues, the mac-rophage.

It is clear from these experiments in tissue culturethat T-lymphocytes which are such a prominent fea-ture of the plaque of multiple sclerosis can be stimu-lated by specific antigens which are presented to themby astrocytes. If the properties in vivo are similar (and



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this has yet to be shown) the possibility arises that theastrocytic response in multiple sclerosis may not all bea consequence of damage, but an integral part of itspathogenesis. It is therefore of particular interest thatcells bearing Ia proteins (which in man are the DRproteins) are present in the normal-appearing whitematter beyond the active edge of the plaque in multi-ple sclerosis at a stage when T cells are present butthere is not yet any myelin breakdown.71 The nextstep will be to determine whether they are astrocytesor macrophages or a mixture of the two.

Conclusion

What can we now say about the origin of multiplesclerosis? That it is a disease produced by an environ-mental agent in genetically susceptible individuals inwhom there is an abnormality of the immune mech-anism. But many of the mysteries that perplexedGowers remain. We do not know the nature of theenvironmental agent, nor do we understand thesequence of events which follows exposure to it, northe mechanism of tissue damage. We still have nosatisfactory explanation for the apparent cycles ofquiescence and activity in the disease and we do notknow what determines whether a patient will diewithin 5 years of the first symptom or be fit after 50years. But progress should now be more rapid. Basicresearch is providing new insights and suggesting newkinds of obseryation which should be made onpatients; they are becoming feasible through the appli-cation of recent remarkable technical advances suchas MRI and the use of monoclonal antibodies to thestudy of the disease.

I am indebted to many people: to Lady Shiffner, SirWilliam Gowers' granddaughter, for allowing meaccess to his papers and for permission to quote fromWeir Mitchell's letter to him; to Dr Ivan Janota of theInstitute of Psychiatry for the histological prepara-tions; to my colleagues at the Moorfields Eye Hospitaland in the MRI group at the National Hospital,Queen Square for allowing me to use unpublishedmaterial; and to the physicians and surgeons of bothhospitals for referring patients. The MRI Unit wasprovided by a generous grant from the MultipleSclerosis Society. Most of the work has been sup-ported by the Medical Research Council.

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