J. Neurol. Neuirosurg. Psychiat., 1964, 27, 522

Clinical studies of multiple sclerosis in Israel1Part II A comparison between European and Afro-Asian patients2

MILTON ALTER, URI LEIBOWITZ, AND LIPMAN HALPERN

From the Department of Neurology, Hadassah University Hospital, Jerusalem, Israel, and the Department ofNeurology, University of Minnesota Hospital, Minneapolis 14, Minnesota, U.S.A.

The prevalence of multiple sclerosis decreases from ahigh rate in temperate latitudes to low rates inlatitudes near the equator. This general trend hasbeen noted both in the northern and southernhemispheres (Davenport, 1922; Ulett, 1948; Kurlandand Westlund, 1954; Acheson and Bachrach, 1960;Alter, Allison, Talbert, and Kurland, 1960; Alter,Halpern, Kurland, Bornstein, Leibowitz, andSilberstein, 1962; Acheson, 1961; Sutherland,Tyrer, and Eadie, 1962; Saint and Sadka, 1962;Dean, 1961; Spota and Brage, 1951). In view of thedecline in prevalence with geographical latitude itbecomes pertinent to inquire whether a systematicvariation in the clinical manifestations of multiplesclerosis also exists. For example, is the diseasealso milder where it is less common; is prognosisworse where there is a high prevalence; are certainsymptoms peculiar to a particular geographic locale?There are only a few studies in which the possible

relationship between clinical characteristics ofmultiple sclerosis and prevalence has been explored.Westlund and Kurland (1953) reported that theprevalence of multiple sclerosis in Winnipeg,Canada, was six times higher than in New Orleans,Louisiana, a community more than one thousandmiles father south, but no appreciable clinicaldifference was discerned between patients in the twocommunities. However, the validity of the clinicalcomparison may be questioned as different neurolo-gists had examined the patients in each community.Later, Kurland and Westlund (1954) suggested thatage at onset of illness tended to be younger in com-munities with higher prevalence. Alter et al. (1960)compared clinical features of patients identified inHalifax, Nova Scotia, and Charleston, South Caro-lina. The prevalence of multiple sclerosis was twoand one-half times lower in the southern community.The comparison revealed that in the southern com-'This study was supported by grant no. 265 from the National MultipleSclerosis Society.?Part I of this study, 'A clinical analysis based on a country-widesurvey', by U. Leibowitz, L. Halpern, and M. Alter was published inthe Arc/tives ofNeurology (10, 502-512) in 1964.

munity there was a slightly lower average age atonset, a higher percentage of relapsing cases, ahigher exacerbation rate, and a higher percentage ofseverely disabled patients. Alter et al. (1960), inanother study, compared Negro patients born in thenorthern part of the United States with Negroes bornin the southern part. The study revealed someclinical differences between the two groups. Amongthe northern-born Negroes, average age at onset wasearlier, there were proportionately more females,retrobulbar neuritis as an initial symptom occurredmore commonly, and a relapsing course was reportedby a higher proportion. All Negroes included in thestudy, however, had been diagnosed at the Neuro-logical Institute of New York and the possibilityexisted that the southern-born Negroes included inthe study were not representative of southernNegroes in general. On the basis of the studies citedit would seem that clinical manifestations of multiplesclerosis may differ in regions of different prevalencebut additional supporting evidence is needed.

In Israel, an unusual opportunity was afforded toexamine the question anew. Israel's populationcontains representatives from every continent andmany different countries, including regions of highand low prevalence of multiple sclerosis. The in-habitants number approximately two million andmay be divided into three groups of about equal size:native-born Israelis, European immigrants, andAfro-Asian immigrants. Before 1949, the majorityof immigrants were European; between 1949 and1954 Afro-Asian immigration increased sharply;since 1954, immigration was from both Europe andAfro-Asian countries and was relatively small. Im-migration from America has also been small (Statis-tical Abstract of Israel, 1961). An extensive networkof medical facilities staffed by well-trained personnelexists throughout the country. The major populationcentres have modern hospitals with departments ofneurology. All segments of the population have accessto the same medical facilities. A national health in-surance scheme makes the cost of medical care

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nominal. Political factors tend to isolate Israel fromher neighbours so that medical care is customarilyobtained within the country and all affected areeasily accessible. Immigration policies of the statewere such that individuals with chronic illnesseswere not excluded. These unusual and perhapsunique conditions make Israel an ideal area for studyof patients from a cross-section of many areas of theworld.A country-wide survey of multiple sclerosis was

completed by 1961 by Alter et al. (1962). The surveyrevealed that multiple sclerosis was more than sixtimes as prevalent in Europeans as in Afro-Asians.The present study compared clinical characteristicsbetween the Afro-Asians and the European group.As native-born Israelis had a prevalence similar tothat of the Afro-Asians, Israeli patients were groupedwith Afro-Asians in the clinical comparison.

CASE FINDING METHOD

In order to identify patients with multiple sclerosisliving in Israel, medical records of all hospitals,referral clinics, and facilities for caring for thechronic sick were reviewed for the period 1955-59.Physicians with a private neurological practice werequestioned and mortality data at the Central Bureauof Statistics were studied. At each source of informa-tion, patients were listed who had been diagnosed ashaving multiple sclerosis or one of five clinicallysimilar conditions, i.e., primary lateral sclerosis,non-traumatic paraplegia, optic or retrobulbarneuritis, cerebellar ataxia, and myelopathy. Afterscrutiny of case notes, patients who clearly had adisease other than multiple sclerosis were discarded.Patients who died or left Israel before 1 January1960 were also excluded. Of the 580 who remained,520 were re-examined by us. A modification of thediagnostic criteria formulated by Allison and Millar(1954) was applied and two categories of cases wereaccepted: probable and possible multiple sclerosis.Of the 520 in the provisional list, 282 patients werefinally accepted as having multiple sclerosis and wereliving in Israel on 1 January 1960. Additional detailsregarding diagnostic criteria and case selection arereported in an earlier communication (Alter et al.,1962).In the present study, 13 of the 282 accepted cases

were excluded because of inadequate clinical infor-mation. The remaining 269 were divided into twogroups as follows: 208 of European origin (includingone patient born in Argentina) and 61 from Afro-Asian countries. The two groups were comparedfor a number of clinical characteristics. It is well toemphasize that the diagnostic criteria and methodof case selection were the same for each group.

RESULTS

PREVALENCE The prevalence of multiple sclerosisin Israel on 1 January 1960 was 15 per 100,000population. If the European and Afro-Asian groupswere considered separately, prevalence rates were31-3 and 5-1 per 100,000 population respectively.Age-specific rates for the two populations are listedin Table I. Although the age composition of the twopopulations differ in that a much higher percentageof Afro-Asians are under 20, it is important to notethat the prevalence is higher for Europeans in eachage-group category. Difference in prevalence cannot,therefore, be attributed to differences in the age com-position of the two populations.

TABLE INUMBER OF PATIENTS, NUMBER IN GENERAL POPULATION,AND AGE SPECIFIC PREVALENCE RATE BY DECADES AND

AREA OF ORIGIN (ISRAEL, 1960)Origin

Europe Afro-Asia

Age No. of Popula- Rate No. of Popula- RatePatients tion per Patients tion per

100,000 100,000

>2020-2930-3940-4950-5960-6970-79UnknownTotal

0154368641332

208

71,641 - 8 708,603 1-169,805 21-5 23 194,806 11-8134,480 32-0 10 120,344 8-3158,636 42-9 1 1 70,641 15-6130,910 48-9 8 55,025 14-564,938 20 0 - 28,533 -34,171 8-8 1 16,308 61

0664,581 313 61 1,194,260 5 1

AGE OF PATIENTS ON PREVALENCE DAY AND AT ONSETOF SYMPTOMS The age of patients in each group wasdetermined on 1 January 1960. The mean age ofEuropeans was 46-9 years while that of Afro-Asianswas 34-6 years. It has already been pointed out thatthe Afro-Asian population was younger on theaverage than the European. Therefore, it is notsurprising that the mean age of Afro-Asian patientson prevalence day was also younger.The mean age at onset of illness was 34-2 years

among Europeans and 27-4 years among Afro-Asians. Although the difference is statisticallysignificant (p<0 001), it probably reflects thedifference in age composition of the two populationsand should not be accepted as necessarily indicatinga tendency for earlier onset among the low pre-valence group.

Since prevalence of multiple sclerosis was con-siderably higher among Europeans than amongAfro-Asians, it was of interest to determine whetherlonger residence in the European environmentaffected the age at onset of the disease. A correlationwas obtained between age at onset and 'exposure'.

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The 'exposure' period for patients with onset whilestill in Europe was the number of years from birthto onset. For Europeans with onset in Israel,exposure equalled the years from birth to immigra-tion. Exposure for Afro-Asians was the number ofyears from birth to immigration. The regression linefor Europeans did not differ significantly from thatplotted for Afro-Asian immigrants (T = -0 426).When patients with onset under 20 years of age wereconsidered, the slopes of regression lines for Euro-peans and Afro-Asians still were not significantlydifferent. It would appear that residence in a highprevalence environment did not influence age at onsetof illness more than residence in a low prevalenceenvironment. Comparison of risk of developingmultiple sclerosis as a function of length of 'expo-sure' would have been of interest. The risk, however,could not be derived owing to lack of data on age atimmigration for the general population.

DURATION OF ILLNESS In order to assess whethermultiple sclerosis has a longer average duration fora group with high prevalence than for a group withlow prevalence it would be advisable to follow thepatients from onset to death. An attempt at longterm follow-up has been made by Allison (1950) forpatients identified in Britain. Another approachutilizes life-table methods (Kolb, 1950; MacLeanand Berkson, 1951). Life-table methods were notfeasible in Israel because of lack of accurate life tabledata. Instead, the duration from onset to prevalenceday (1 January 1960) was compared. A mean dura-tion of 12-7 years was found for Europeans whilefor Afro-Asians the mean duration was 7-2 years.Here again, the fact that Afro-Asian patients wereon the average younger than European patientsmay account for the apparent shorter duration ofillness. The difference, in any event, is not statistic-ally significant.

CLINICAL TYPES Virtually any combination ofsymptoms and signs may be found in a particularpatient with multiple sclerosis. Nevertheless, amongthe patients encountered in the survey, all could beclassified at the time of examination into one of thefollowing clinical types:

Disseminated type 1 Patients with exacerbationsand remissions of neurological deficit were classifiedas 'disseminated-recurrent' multiple sclerosis ifexamination gave evidence of scattered centralnervous system lesions. Such patients were classifiedas disseminated-recurrent type even if they had en-tered a progressive phase.2 Progressive, in which some patients insisted that

their course was steadily progressive. On examina-

tion, however, evidence of disseminated lesions of thekind common in multiple sclerosis was found.

3 Recurrent optic neuritis, i.e., patients whose solesymptom was attributable to unilateral optic orretrobulbar neuritis were excluded. However, if oneeye and then the other was affected, after an intervalof at least three months, evidence of 'scattering' wasat hand and the patients were classified as the dis-seminated-optic neuritis form of multiple sclerosis.Patients with bilateral, simultaneous optic neuritiswere difficult to classify because conditions other thanmultiple sclerosis are perhaps more commonly thecause. Hierons and Lyle (1959) showed that bothoptic nerves are occasionally affected simultane-ously in patients who later develop neurologicalsigns compatible with multiple sclerosis. We wereinclined, however, to consider patients who had onlyone attack of bilateral simultaneous optic neuritisas having insufficient evidence to warrant the labelof multiple sclerosis.4 Spinal-optic: some patients presented with in-

volvement of both optic nerves and spinal cord. If asingle such episode had occurred it was difficultto decide whether Devic's disease or multiplesclerosis was the correct diagnosis. We were reluc-tant to accept a patient as having multiple sclerosisunless the subsequent course included additionalattacks.

5 Spinal recurrent: some patients had severalattacks, all of which were limited clinically to thespinal cord. On examination, evidence of neuro-logical deficit was also limited to the spinal cord.

Spinal progressive type A proportion of patientshad a slowly progressive paraparesis. On examina-tion spasticity of lower limbs and often posteriorcolumn impairment was found. After careful studyto rule out other conditions which could producethe same clinical picture, e.g., cord compression,multiple sclerosis remained as a likely diagnosis.

Spino-cerebellar type In another form of mul-tiple sclerosis, cerebellar ataxia was the most

TABLE IINUMBER AND PERCENTAGE OF PATIENTS BY CLINICAL

TYPE AND AREA OF ORIGIN (ISRAEL, 1960)Origin

Europel Afro-Asia

No. ofPatients No. of Patients

DisseminatedRecurrent 100 (50%)Progressive 25 (12%)RBN recurrent 5 (2%)Spinal-optic 3 (1 %)Spinal recurrent 14 (7%)

Spinal progressive 43 (22%)Spino-cerebellar 11 (6%)Total 2011 (100%)'Seven European cases, clinical type unknown

Type

34 (56%.)4(7%)

2 (3%)4 (6%.)14 (23%,)3 (5 Y)

61 (100%Y,)

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prominent sign. Frequently, pyramidal signs werean associated finding. Cerebellar ataxia due tomultiple sclerosis had to be differentiated carefullyfrom the hereditary spino-cerebellar degenerativedisorders. A family history of similar cases with onsetat about the same age and the presence of cardiacand skeletal anomalies influenced us against accept-ing certain ataxic patients as having multiplesclerosis.

After classifying the patients into the above moreor less arbitrary groups, European and Afro-Asianpatients were compared. Table I[ shows a remarkablecorrespondence between the European and the Afro-Asian groups as regards the distribution of clinicaltypes.

PRESENTING SYMPTOMS The presenting symptomscould be allotted to one of the following nine cate-gories:Motor Complaints of weakness, paralysis, drag-

ging a leg, and stiffness are included.Sensory Numbness, tingling, pins and needles,

electrical sensation, loss of sensation, and pain areexamples.

Combined sensoty and mnotor If both motor andsensory complaints occurred at the onset, the patientwas tabulated separately in this category.

Visual Loss of vision, blurring, a cloud or veilover one eye are representative.

Diplopia This category is self-explanatory.Cerebellar and/or vestibular Complaints of im-

balance, unsteadiness, staggering, drunken walk,trembling of a limb; also, symptoms of turning,dizziness, and light-headedness are included.

Sphincter disturbance Urgency, hesitancy, in-continence, precipitancy were listed here.Mixed If complaints referable to more than one

of the above categories occurred, the patients weretabulated in the 'mixed' category.

TABLE IIINUMBER AND PERCENTAGE OF PATIENTS BY PRESENTING

SYMPTOM AND AREA OF ORIGIN (ISRAEL, 1960)Origin

Europe' Afro-Asia

No. No.Symnptom

Motor 83 (41 %)Sensory 27 (13%)Combined motor-sensory 12 (6%)Visual 29 (14%)Diplopia 6 (3%)Cerebellar-vestibular 14 (7 %)Sphincter 4 (2%)Mixed 25 (12%)Miscellaneous 3 (2 %)Total' 2031 (100%)'Five European cases, presenting symptom unknown

18 (29%)8 (13%)9 (15%)8 (13%)1 (2%)8 (13%)1 (2%)7 (11%)1 (2%)

61 (100%)

Miscellaneous Complaints which did not fit inany of the above groups were listed here, e.g., aseizure, mental or emotional aberration.The various presenting symptoms and percentage

affected in each group are given in Table III. Againa remarkable similarity between Europeans and Afro-Asians is apparent.

CLINICAL COURSE In many series, about two-thirdsof patients have a clinical course characterized byremissions and exacerbations while one-third have achronic-progressive or static course (Brown andPutnam, 1939; Alter et al., 1962; Carter, Sciarra, andMerritt, 1950; Lazarte, 1950). The proportion ofrelapsing cases in Israel conforms to the general ex-perience. Of European patients, 620% reported aremitting-relapsing course whilst 66% of Afro-Asians had remissions and exacerbations. Thus, noappreciable difference in the percentage of exacerba-tion cases was discernible between high and low pre-valence groups.

EXACERBATION RATE Typically, multiple sclerosisprogresses in fits and starts. The frequency of exacer-bations and remissions may reflect the severity of theillness. Therefore, a comparison of European andAfro-Asian patients in this regard was of interest.'Exacerbation' had first to be defined: a neurologicalsymptom or sign not previously present or re-appearance of a symptom or sign after it had beenabsent for at least three months. Minor fluctuationsin status such as increased fatigue or slight change inability to balance or coordinate were not accepted asconstituting 'exacerbation'. By way of illustration, apatient without eye symptoms who began to havevisual impairment or a patient with previouslynormal visual fields who showed a scotoma was re-garded as having an exacerbation provided thechange occurred after a quiescent period of at leastthree months. An episode of paraesthesia or demon-stration of a Babinski response in a patient whopreviously had flexor plantar responses is anotherexample. If such a change occurred within less thanthree months of another episode, the change was re-garded as part of the earlier attack. The three-monthinterval was set quite arbitrarily but some cut-offpoint applied systematically in all patients wasnecessary. Since examinations were not performedregularly on patients it is obvious that a change ofneurological status of which the patient was notaware would be missed in the tabulation. Therefore,computation of exacerbation rates may well containan error of indeterminate size. There is no reason tobelieve, however, that such an error would be greaterfor one group than for the other.

'Exacerbation rate' is the number of exacerbationsper person-year duration of illness (McAlpine and

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Compston, 1952; Brown and Putnam, 1939;Alexander, Berkeley, and Alexander, 1958). When all164 exacerbating cases were considered together, arate of 0O28 per person-year of illness resulted, i.e.,approximately one every three to four years. Euro-peans showed 025 and Afro-Asians 0 49 exacerba-tions per person-year of illness. Lest the inference bedrawn that the exacerbation rate tended to be higherin Afro-Asians, it must be stressed that the averageduration of illness was shorter for Afro-Asians thanfor Europeans. It has been shown by other investiga-tors (McAlpine and Compston, 1952; Muiller, 1949,1951) that the exacerbation rate tends to begreater in the earlier years of illness. Since Afro-Asians included more cases with shorter duration, itwould be expected that the exacerbation rate amongthem would be higher than for Europeans.

In order to circumvent the difficulty inherent inthe above comparison, patients with disease ofequal duration were compared (Table IV). When in-equalities in duration of illness were controlled, theexacerbation rate was almost identical for each group.

TABLE IVNUMBER OF PATIENTS AND RATE OF EXACERBATION PERPERSON-YEAR OF ILLNESS BY DURATION OF ILLNESS AND AREA

OF ORIGIN (ISRAEL, 1960)Origin

Europe Afro-Asia

Years No. of Rate of No. of Rate ofCases Exacerbation Cases Exacerbation

pean individuals to Israel before the onset of illnessdid not ameliorate the clinical course when measuredin terms of the exacerbation rate. It is appreciatedthat the exacerbation rate does not necessarily reflectthe severity of the clinical course. Conceivably, one

patient might suffer more attacks but recover more

completely than another patient. Moreover, a singleepisode resulting in paraplegia might be consideredmore severe than several which left a small scotomaor slight ataxia as a residual effect. Accordingly,disability was also compared.

DISABILITY In grading disability, a modification ofHyllested's (1961) criteria was used. Thus a 'moder-ately' disabled group (grades 1-3) and a 'severely'disabled group (grades 4-6) were established. Inanalysing the data for all patients, 51% were

moderately disabled and 49% severely disabled on

examination. However, 48% of the European groupwas moderately disabled as compared with 61% ofthe Afro-Asian group; 52% of Europeans were

severely disabled as compared with 39% of Afro-Asians. Here, again, one must not conclude that theAfro-Asians necessarily had a less disabling form ofmultiple sclerosis. Recall that the mean duration ofillness was shorter for the Afro-Asian group andthat disability may be expected to increase withgreater duration of illness.When disability for Europeans and Afro-Asians

was compared for groups with equal duration ofillness (Table V), disability was not consistentlygreater in either group; indeed, the difference in dis-

During the wholecourse of the disease 124 0-25During the years

1-51 104 0 40During the years

6-10' 72 0-10'in patients who were ill five years at least2In patients who were ill 10 years at least

40 0-49

Duration of TotalIllness (yr.) No.

TABLE V19 0-39

NUMBER OF PATIENTS AND NUMBER AND PERCENTAGE

4 0-13 SEVERELY DISABLED BY DURATION OF ILLNESS AND AREA OF

ORIGIN (ISRAEL, 1960)

It is to be noted, too, that the exacerbation ratetended to decrease appreciably with longer duration,and thus additional support is provided for the con-tention that exacerbations are concentrated in theearly years of illness.The European patients with an exacerbating course

were divided into those who had spent the first fiveyears after onset of illness in Europe and those whohad spent the first five years after onset of illness inIsrael. Of the 33 patients in the former group, anexacerbation rate of 0 35 per person-year of illnesswas found. The exacerbation rate for the 53 patientsin the latter group was 0-45 per person-year ofillness. Thus, the exacerbation rate for the first fiveyears of illness was approximately the same forEuropean patients whether they lived in Europe orin Israel, after onset of illness. Migration of Euro-

No.SeverelyDisabled

Total No.No. Severely

Disabled

0-5 44 14 (32%) 32 12 (37%)6-10 44 23 (52%) 15 5 (33%)11-15 52 31 (60%) 6 4 (67%)16+ 65 38 (59%) 8 3 (38%)

Total' 205' 106 (52%) 61 24 (39%)' Three European cases, duration unknown

ability for each five-year duration period was notsignificant. The degree of disability might conceivablybe influenced by the length of 'exposure' to theEuropean environment. Therefore, the percentageof severely disabled European patients was assessedfor varying lengths ofresidence in Europe (Table VI).No trend was discerned, so that longer residence in

Origin

Europe Afro-Asia

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TABLE VINUMBER OF EUROPEAN PATIENTS AND NUMECENTAGE SEVERELY DISABLED BY AGE AT IMI

ISRAEL

Age at Immigration' No. of Cases21)'r.)

0-9 510-19 3720-29 6430-39 4540-49 3250+ 21

Total2 204''Age at immigration equals years of 'exposure' to Eument'Four cases, age at immigration unknown

Europe apparently was not associated Mproportion of severely disabled individi

DISCUSSION

Although the prevalence of multipleconsiderably higher among EuropeansAfro-Asians in Israel, there is remarkatin the clinical characteristics of the ditwo groups. The clinical types, presentinjcourse of illness, exacerbation rate, andisability on examination were almo:Mean age at onset and mean duration ofless for Afro-Asians than for Europeadifference probably reflects the higher piyoung people in the Afro-Asian populalOur results suggest that the clinical mz

of multiple sclerosis do not vary desldifferences in prevalence. We have not tsupport the notion that clinical manifeswith geographical latitude. What does tconstancy of the clinical picture implypossible aetiological factors?The relation between prevalence and g

latitude has been interpreted to meanvironmental factor influences the frequdisease and is presumably of aetiological(Kurland and Westlund, 1954). It woulcable to expect that in areas of low preeffect of the aetiological agent on patierameliorated. Accordingly, later onset, lcbation rate, and less disability for a givof illness might have been expected arAsians. On the other hand, it could bethe 'attenuated' aetiological agent wouldthe most susceptible, and, therefore, onlycases would be apparent in areas of lowThe finding of an almost identical clinic.the high and low prevalence group isand difficult to explain. The inference tothat once affected, a patient is likely to r

clinical course whether he lives in a high or in a lowBER AND PER- prevalence area. Sutherland et al. (1962) came to aMIGRATION TO similar conclusion on the basis of cases ascertained

in Australia. Moreover, exacerbations of the diseaseNo. of Severely may not necessarily require re-exposure to a detri-Disabled mental factor, for otherwise number and rate of

3 (60%) exacerbations would have been higher in Europeans.20 (54%) It is possible that the same aetiological agent24 (38 ') causes such radically different manifestations in25 (56%)17 (53%) alleged low prevalence areas that clinicians have not16 (76%) come to appreciate that a particular clinical picture is

105 (51%)ropean environ- allied to multiple sclerosis. Where the disease is rare

only cases with a clinical picture like that encounteredin temperate regions would be recognized and diag-nosed. The five clinical entities other than multiple

vith a higher sclerosis included in the present survey may not haveuals. included the disease form common in low prevalence

areas. This hypothesis may, for example, explain theobservations in Japan where multiple sclerosis isallegedly rare but neuromyelitis optica is common

sclerosis is (Okinaka, McAlpine, Miyagawa, Suwa, Kuroiwa,than among Shiraki, Araki, and Kurland, 1960). Other factors)le similarity which might affect the comparability of Europeansease in the and Afro-Asian groups should be considered.g symptoms, Some selection of clinical material might bed degree of caused by a difference in attitude toward medicalst identical. care among Europeans and Afro-Asians. In onef illness were group, there might be a tendency to consult ains, but the physician even for mild complaints, but severelyroportion of affected may be cared for at home, or vice-versa. Wetion. feel that no such difference exists between the twoanifestations groups in Israel.pite marked The patients ascertained in Israel are immigrantsbeen able to for the most part (25 are born in Israel). One may;tations vary question whether individuals who came to Israel are.he apparent like individuals in the region of origin. When pre-as regards valence of the disease was examined by country of

origin (Alter et al., 1962), it appeared that rates ingeographical the immigrants resembled the rates in countries ofthat an en- origin where such data were available. It cannot, ofiency of the course, be said with assurance that the disease in theimportance immigrants is necessarily like that of individuals who

d be reason- remained behind. It is important to point out thatwvalence the medical status did not serve as a bar to admission toits would be Israel and in many cases whole communities were)wer exacer- transported as a unit. It seems unlikely, though, that,en duration selection of immigrants could account for the simil-mong Afro- arity in clinical picture between Europeans andargued that Afro-Asians.I only affect Afro-Asians, as a group, have a lower economicmore severe status than Europeans. However, economic factorsprevalence. in Israel are of negligible importance as a selecting

al picture in factor for medical care, since a national healthunexpected scheme keeps the cost of medical care down.be drawn is It should be mentioned that some authors suspectun a similar genetic rather than environmental factors to be of

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aetiological importance (Myrianthopoulos andMackay, 1960). Perhaps the environmental factorpostulated to be of aetiological significance is uni-formly distributed but genetically susceptible indi-viduals are concentrated in temperate zones. On thisassumption, the clinical characteristics for susceptiblegroups would be expected to be similar. The gradualdecline in prevalence from temperate zones to thetropics would be difficult to reconcile with the notionof varying concentrations of genetically susceptibleindividuals. Migration and difference in racial strainsin temperate and tropical regions would be expectedto produce clumping of susceptible individuals andabrupt changes in prevalence rather than a gradualdecline toward the equator.

Several factors suggested as being of aetiologicalimportance may be re-examined in the light of ourclinical findings. Acheson and Bachrach (1960)suggested that different exposure to light among in-dividuals in tropical and temperate regions mightplay a role in the pathogenesis of multiple sclerosis.If the effect of light were purely quantitative, theclinical manifestations of the disease would not beexpected to be similar in high and low prevalenceareas. Individuals who dwell in regions with amplesunlight should have milder disease than those whoseexposure to light is less. In order to reconcile thissuggestion of Acheson and Bachrach (1960) withour clinical observations, we would have to postu-late that the affected individuals in the low preva-lence environment had had less exposure to lightthan was characteristic of unaffected individualsof their area, e.g., that individuals who developthe disease remain indoors more. While such adifference seems unlikely, a priori, it could be testedby appropriate questioning of patients.The same arguments could be advanced against

the idea that temperature or dietary fat or radiationwere of pathogenic importance in multiple sclerosis.The affected individual in the low prevalence en-vironment would have to share in common with theaffected of the high prevalence environment not onlythe kind, but also the degree, of exposure to thepathogenic agent.

Poskanzer, Schapira, and Miller (1963) havecompared epidemiological characteristics of multiplesclerosis and poliomyelitis and have suggested thepossibility that a polio-like infection sets the stage formultiple sclerosis. As in multiple sclerosis, a lowerfrequency of poliomyelitis is seen in tropical regionsthan in temperate regions. The few cases of polio-myelitis which do develop in tropical areas areclinically similar to those in temperate zones. Here theanalogy between poliomyelitis and multiple sclerosisapplies well. However, the thesis that a virus of anykind, let alone a polio-like virus, might be of patho-

genic significance in multiple sclerosis suffers fromthe lack of pathological support.Adams and Imagawa (1962) have suggested that a

common infection like measles might damage thenervous system in certain individuals, releasingantigenic material. Later the material could give riseto auto-immune reactions characterized by demye-lination. However, a recent study by Reed, Sever,Kurtzke, Huebner, and Kurland (1963) of titres inblood and spinal fluid against a large numberof viral agents failed to provide evidence for aninfectious-allergic aetiology of multiple sclerosis.Efforts to culture a slow growing virus like that whichproduces visna in sheep from patients with multiplesclerosis likewise failed (Thormar and von Magnus,1963).The European and Afro-Asian groups differ in

many cultural and ethnic characteristics. The geo-climatic factors to which the two groups were exposedbefore immigration to Israel also were dissimilar in'many respects. Yet, clinical characteristics weresimilar in the two groups. It would appear that thetcultural, ethnic and geoclimatic variables exert little;effect on clinical manifestations of multiple sclerosis.Nevertheless, the variables should not be dismissedias being of no importance. Their study may yet dis-close a clue to account for the striking difference in;prevalence between the two groups.

SUMMARY

Israel's population includes immigrants from every,continent and many different countries of the worldA country-wide survey completed in 1961 discloses'282 patients with multiple sclerosis. Of these, 204were of European origin and 61 were of Afro-Asianorigin, including 25 native Israelis. The prevalence ofmultiple sclerosis was more than six times higher iEuropeans than in Afro-Asians.

Despite the large difference in prevalence, thelclinical characteristics of the disease were remark-vably similar in the two groups. No significant~differences could be discerned when presenting,symptoms, course of illness, exacerbation rate, anddisability on examination were compared. A similadpercentage of disseminated, spinal progressive, and;spino-cerebellar types was found in each group.-Apparent earlier age at onset of illness for Afro-iAsians was attributed to the fact that the AfroJAsians have a lower mean age in the general population than Europeans. The duration of residence iIthe European environment ('exposure') did noinfluence age at onset nor subsequent disability.

Various factors which have been suggested aibeing of aetiological importance were discussed irjthe light of the clinical observations of the present

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study. It appears that once an individual is affectedwith multiple sclerosis, domicile does not influencethe clinical manifestations appreciably.

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