The social epidemiology of multiple sclerosis

The Science of the Total Environment, 90 (1990) 163-190 Elsevier Science Publishers B.V., Amsterdam - - Printed in The Netherlands

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THE SOCIAL EPIDEMIOLOGY OF MULTIPLE SCLEROSIS

GEORGE W. LOWIS

Skidmore College, Saratoga Springs, N Y 12886-1632 (U.S.A.) (Received April 15th, 1989; accepted May llth, 1989)

ABSTRACT

Building upon the accumulated demographic and sociocultural data dealing with the epidemiology of multiple sclerosis, a discussion and critical evaluation is offered of the most important social epidemiological features of this disease: (i) age and sex; (ii) availability of medical services; (iii) stress; (iv) ethnicity; (v) house pets; (vi) social-physical interaction; (vii) urban rural residence; (viii) nutrition; (ix) socio-economic status; (x) population migration; and (xi) sanitation. Although the etiology of MS remains a mystery, sufficient evidence exists to connect demographic and sociocultural factors to the etiology and distribution of this disease.

INTRODUCTION

Multiple sclerosis (MS) is a serious neurological disease of unknown cause, often progressive and fatal, affecting men and women in the prime of their life in Europe and North America. It consists pathologically of an increasing deterioration (demyelinization) of the central nervous system (CNS). There is no known, effective treatment for MS except for supportive physical and emotional therapy. Since it continues to remain a disease of unknown etiology, numerous investigators have turned to epidemiology. As a matter of fact, the one area of research that has yielded significant information pertaining to the probable nature of MS is epidemiology. One of the most recent explanations, for example, suggestive of how this disease may be acquired concerns a viral etiology, and the strongest evidence favoring a virus is based primarily on epidemiological considerations (Poskanzer, 1968; Leibowitz and Alter, 1973; Johnson, 1975; Cook and Dowling, 1980; Nathanson, 1980). Epidemiology is one of three methods devised by the medical sciences to study and understand health and disease. The other two are the clinical and experimental methods (Hollingshead, 1961, pp. 5 ~ ; Siegrist, et al., 1986, p. 247). The clinical approach is built upon the direct observations of individuals with symptoms of disease. Medical doctors will, for example, by their examination of patients determine the extent to which disease is present. The experimental method is focused upon the examination and manipulation of disease data in the laboratory or in clinical practice. Typically, these medical agents are involved with analyzing photographic images of the patient via X-rays and CAT scans, or with fluids, excretions, or tissues taken from the bodies of

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patients, as with blood samples. The epidemiological method is the study of the occurrence and distribution of diseases in entire groups or populations, and of the factors that influence this occurrence and distribution. Specifically, it attempts to determine who in a particular population develops a disease, and when and under what circumstances the disease develops (Gruenberg, 1954; Kurtzke, 1966). MEDICAL AND SOCIAL EPIDEMIOLOGY

Medical epidemiology Virtually all of the empirical research in the epidemiology of MS has been conducted by medical epidemiologists. This is not surprising since research in this field requires that neurologically trained medical doctors be directly involved for accurate identification of the disease process in the patient population (Kurtzke, 1984, p. 265). Medical epidemiologists are medical personnel who approach the study of their subject matter from a particular intellectual and methodological frame of reference. Medical epidemiology, especially as it is reflected in MS research, is the study of the distribution of disease in a population, as such a distribution is affected by biological and/or environmental factors, including geographic, demographic and sociocultural. Due to the wide ranging scope of their inquiry, medical epidemiologists typically focus on two or more of these four variables in their research. Several features of MS are especially significant for the medical epidemiologist and deserve explicit mention. First, it is an uncommon disease, even in countries or regions where its frequency is relatively high. Second, while there are many hypotheses concerning the factor or factors responsible for causing MS, none have been conclusively and empirically verified. Numerous researchers, however, have proposed that the study of this disease according to its geographic distribution constitutes the single most important clue in providing insight into etiology (Alter et al., 1962; Kurland et al., 1965; Kurtzke, 1967, 1968b). In fact, one of the most consistent patterns to emerge from medical epidemiological research is the tendency to focus on the rates (prevalence and incidence) of this disease and consequently on its geographic distribution. (Incidence means the attack rate or the number of new cases each year, while prevalence refers to the total number of persons suffering from the disease at any one time.) These studies support the view that there is an uneven geographic distribution in the frequency of MS throughout the world. Two different interpretations have emerged to account for this pattern of distribution. According to one explanation, MS is a function of geographic latitude, i.e. the higher the latitude the more common the disease (Alter et al., 1962, 1973; Kurland et al., 1965; Alter, 1968). Consequently, MS is uncommon in the tropical and subtropical areas of both the Northern and Southern Hemispheres, and relatively more prevalent in the temperate regions of Europe and North America. An alternative interpretation of the same data, offered by

165 Kurtzke (1975, 1977, 1980), is that MS is distributed i'n bands of different frequency or risk (high, medium, and low). The high-risk zone, with prevalence rates of over 30 per 100 000 population, includes Northern and Central Europe, the northern United States, southern Canada, southern Australia, and New Zealand. The medium-risk zone has prevalence rates of 5 2 5 per 100000 population, and incorporates the southern United States, Hawaii, southwestern Norway, northern Scadinavia, southern Europe, Israel, one white group of South Africa, and most of Australia. The low-risk zone, with rates of < 5 per 100000, includes Asia, northern South America, Alaska, Greenland, the Caribbean region including Mexico, and most of Africa and the Middle East. For several reasons, the latter explanation appears to be more tenable and casts serious doubt that MS rates are simply a function of geographic latitude. First, MS rates may be similar in places having different geographic latitudes (Kurtzke, 1980). Various investigators have, for example, recently reported MS prevalence rates of > 30 per 100000 in small population groups in Italian communities (Dean et al., 1979, 1981; Rosati et al., 1980; Savettieri et al., 1981, 1986; Granieri and Rosati, 1982; Morganti et al., 1984), which, if accurate, places Italy in a high-risk MS zone similar to that found in countries with different (higher) latitudes in Northern and Central Europe. Second, MS rates may differ considerably in places having the same geographic latitude (Kurtzke, 1980). Kurtzke has demonstrated the lack of a simple relation with latitude by observing that "at 40° north latitude, MS was of high frequency in the Americas, of medium frequency in Europe, and of low frequency in Asia." Although medical epidemiologists have not as yet been able to establish the factor or factors responsible for the geographic distribution of MS, most investigators continue to favor a multi-causal approach utilizing biological and environmental variables (Leibowitz, 1971; McAlpine et al., 1972; Alter et al., 1973; Kurtzke et al., 1979; McLeod, 1982; Ellison et al., 1984). The biological and geographic components are not, however, viewed singularly as significant factors in explaining the frequency and distribution of MS, and a purely genetic or geographic basis for this disease is deemed unlikely. On the other hand, in the last few decades there has been an increased recognition of the important relationship between demographic and sociocultural factors and MS. A growing body of research has consistently shown that both the causes (etiology) and distribution (epidemiology) of MS are frequently associated with these two variables.

Social epidemiology Researchers who have demonstrated the increasing importance of demographic and sociocultural factors in MS are mainly, but not always (Antonovsky et al., 1965, 1967, 1968; Beebe et al., 1967; Mayer, 1981; Lowis, 1986, 1988a,b), medical epidemiologists. In fact, much of the MS research conducted by medical epidemiologists would be called social epidemiology or medical sociology if carried out by sociologists in the health and illness sphere. What

166 these researchers have in common, however, is their focus on disease as this process is relevant to demographic factors and influenced by the sociocultural environment. The demographic factor has to do primarily with people in their quantitative aspects: that is, the number and concentration of people who live within a particular society or region; the rates at which people are born, reproduce, become ill and die; and the movements of people within or between societies. As social and cultural patterns have been demonstrated to influence health and disease patterns, demographic factors have been increasingly incorporated in epidemiological investigations. The sociocultural part of the environment can be taken to include all those social and cultural factors that are the products of human learning and ingenuity. Specifically, this part of the environment is represented by culturally based ways of thinking (ideas) and doing things (norms), which are peculiar to every society and group, together with the kinds of social interaction and relationships that people engage in as members of human groups. Of special interest to the social epidemiologist is the distribution of MS within and between groups rather than in individuals. Since MS tends to be distributed cross-culturally among diverse groups, the social epidemiologist is interested in ascertaining whether there are differences and why. If there are differences, are these based on age, sex, ethnic, or socioeconomic criteria? If particular groups have noticeably high or low MS rates, what kinds of factors, sociocultural and/or social-psychological, may be impacting on the lives of these people? How does migration from one country or region to another affect MS frequency? Do people living in technologically complex societies have a greater probability of acquiring this disease than those living in economically underdeveloped areas? In particular, are there health consequences associated with living in environments that are heavily urbanized, industrialized, and '~westernized"? All of these questions and issues reflect demographic and sociocultural concerns, and research on them relates directly to the social epidemiology of MS. Sufficient demographic and sociocultural data have been collected to enable us to identify and discuss the most important social epidemiological features of this disease. These include data of the relationships between rates of MS and age, sex, ethnicity, population migration, nutrition and sanitary habits, life stress, availability of medical services, socioeconomic status, social-physical contact, pet ownership, and urban-rural residence patterns. SEX AND AGE Two of the most consistent features of the epidemiological pattern of MS concern age and sex distributions. First, it is a disease which is rarely diagnosed in individuals under 15 years or over 55 years of age (Johnson, 1975; Detels, 1978). As for when MS is acquired, most investigators agree that the risk of acquiring this disease is probably determined in the early childhood years (Beebe et al., 1967; Dean, 1975; Acheson, 1977) or at adolescence - - about

167 15 years of age (Alter, 1968; Kurtzke et al., 1970; Alter and Okihiro, 1971) - with a very long latent period before symptoms appear (Acheson, 1972; Alter, 1978). Approximately two-thirds of all persons experience the onset of symptoms between 20 and 40 years of age (Leibowitz et al., 1964). An interesting variation of this proposition is offered by Visscher et al. (1981a), who found that MS patients tend to make more multiple changes of residence during the first 20 years of life than controls, and that therefore a greater opportunity exists for exposure to, or contact with, one or more environmental agents such as, for example, viruses. Several researchers, however, have recently hypothesized that MS is not completely determined in early life in all individuals (Visscher et al., 1977) and that causative factors may still be operating in the adult years (Detels et al., 1972). Second, although a handful of investigators have reported no greater susceptibility to MS among females (Detels, 1978), most surveys agree that MS attacks women more frequently than men (Haerer, 1976; Acheson, 1977; Kurtzke et al., 1979; Visscher et al., 1981b) at a ratio of approximately two to one (Detels, 1978), and on the average at a slightly earlier age (Alter, 1968; Acheson, 1972, 1977; Baum and Rothschild, 1981). Specifically, the disease appears most commonly among women at age 30, and in men several years later (Acheson, 1972; Baum and Rothschild, 1981). AVAILABILITYOF MEDICALSERVICES The question of whether the frequency of MS (high or low) might be explained by the availability of medical care or services, and accessibility to diagnostic facilities, is dealt with by many investigators. Virtually all agree that there is no significant correlation between the distribution of MS and the distribution of medical facilities in the surveyed areas (Acheson and Bachrach, 1960; Kurtzke, 1965, 1968a; Oh and Calhoun, 1969; Ashitey and Miller, 1970; Wfithrich and Rieder, 1970; Hornabrook, 1971; Shepherd and Downie, 1978; Lauer and Firnhaber, 1984). In an Israeli study, for example, it was determined that the difference in MS prevalence among native-born Israelis and various immigrant groups (e.g., those from North Africa and Europe) is not likely due to differences in medical care since medical care facilities are uniformly available and all individuals have equal access to the same high-quality medical facilities (Alter et al., 1962). Similarly, in a nationwide study in Finland of all cases of MS, a clear non-random concentration of MS was observed in the south-western region of the country which could not be explained in terms of the availability of medical facilities, inclusive of physicians, hospital beds, and hospital admissions (Rinne et al., 1968). STRESS

Some suggestion of a possible relation between life stress and the onset of MS does appear in the early literature (McAlpine, 1946; Adams et al., 1950), but it was only recently that two Canadian studies were conducted to determine

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whether this alleged relation could be confirmed. In one study, more case than control subjects had a history of severe or prolonged emotional stress (Warren et al., 1982b), whereas in the other, significantly more patients than controls reported they had experienced both unusual stress in the 2-year period prior to onset age, and a greater number of stressful life situations (Warren et al., 1982a). Both studies do, in fact, confirm a relationship between life stress and the development of MS. However, since no attempt was made to measure how important stress is relative to other variables, it is difficult to judge how valuable this information is in regard to the etiology of this disease. Further, it has not yet been clearly established whether stress is a precipitating or causal factor in MS (La Rocca, 1984). Guided by the knowledge, however, that stress can be one of the components of any disease (Dodge and Martin, 1970) or serious mental and physical health consequences (Langner and Langner, 1963; Scotch, 1963; Syme and Reeder, 1967; Jenkins, 1971a,b, 1976; House, 1974; Cooper and Marshall, 1976; Kasl, 1978), this factor is worthy of continued MS investigation. ETHNIC FEATURES IN MS: RACE, RELIGION, AND NATIONALITY

Race Data in the racial distribution of MS show that this disease is present in the three principal racial groups in the world, comprising white, oriental, and black populations. There is sufficient evidence, however, that not all racial groups are equally susceptible to this disease. Comparatively, it is most commonly found among white populations, with non-whites (orientals and blacks) having a much reduced risk of developing MS (Alter and Harshe, 1975; Kurtzke, 1980). Sufficient evidence also exists that the risk of this disease in the three racial groups tends to be variable and that variability in susceptibility is especially pronounced among white populations.

Unequal susceptibility Highest MS rates have been recorded in regions of the world that have predominantly white populations (Kurtzke, 1980). The risk of acquiring the disease is high, for example, in the British Isles (Poskanzer et al., 1963a; Dean et al., 1976, 1977), Northern and Central Europe (Alter et al., 1962; Dean, 1967), Iceland (Nathanson et al., 1978), and the northern United States (Visscher et al., 1977). Even in regions of the world where the three races live side by side, there is a tendency for whites to experience MS more often than non-whites. This is especially prominent in the United States, where non-whites have much lower rates than whites regardless of residence, north or south, east or west (Acheson and Bachrach, 1960; Beebe et al., 1967; Alter and Harshe, 1975; Haerer, 1976; Kurtzke et al., 1979; Kurtzke, 1980; Morariu and Linden, 1980). The low MS risk of non-whites is reflected in the prevalence data of blacks living in Africa (Dean, 1967; Bird and Kerrich, 1969; Foster and Harries, 1970;

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Dean and Kurtzke, 1971; Ames and Louw, 1977), and the United States (Alter, 1962; Beebe et al., 1967; Oh and Calhoun, 1969; Peacock et al., 1969; Haerer, 1976; Kurtzke et al., 1979; Morariu and Linden, 1980). There is also a reduced risk of acquiring this disease among orientals living in Asia (Okinaka et al., 1960, 1966; Barlow, 1967; Kurtzke et al., 1968; Kuroiwa, 1973, 1978, 1982; Hung et al., 1976; Japan Medical Research Foundation, 1976; Kuroiwa et al., 1977; Kuroiwa and Iwashita, 1977, Imagaki et al., 1980; Shibasaki, 1984) and other parts of the world such as South Africa (Dean, 1967) and the United States (Kuroiwa and Okihiro, 1969; Alter et al., 1971; Detels et al., 1972, 1976, 1977; Kurtzke, 1980). These findings, supporting a uniformly higher risk for this disease among whites and lower risk among blacks and orientals, suggest that genetic factors alone may influence susceptibility to MS. Additional data from the U.S., however, negate that possibility, as they show that prevalence in all three racial groups tends to increase in frequency with increasing geographic latitude. Specifically, each racial group exhibits the same geographic gradient of high rates in the north and lower rates in the south (Kurtzke et al., 1971, 1979; Kurtzke, 1980). These latter findings confirm the importance of an environmental agent regardless of race, thereby suggesting that genetic factors alone are not responsible for the distribution of this disease.

Variability in susceptibility High, moderate, and low rates of MS have been recorded for white populations in various parts of the world. Whereas the risk of acquiring this disease is high in Great Britain (Dean et al., 1976, 1977), it has been observed in varying frequency of moderate to low in South African whites (Dean, 1967), and in immigrants from countries in southern Europe and Afro-Asia to the United Kingdom (Dean et al., 1976, 1977) and Israel (Alter and Bornstein, 1962; Alter et al., 1962, 1964). Multiple sclerosis risk is low, on the other hand, for persons of Mexican extraction living in the United States (Enstrom and Operskalski, 1978) and Mexico (Alter and Olivares, 1970); it is low also among Arab populations in the Middle East (Hamdi, 1975; Berginer et al., 1982; Radhakrishnan et al., 1985), and in persons of Indian background living in South Africa (Dean, 1967) and India (Bharucha and Umarji, 1961; Mathew et al., 1971; McAlpine et al., 1972; Dastur and Singhal, 1973; Singhal and Wadia, 1975; Nair and Sahasranam, 1978; Verma and Ahuja, 1982). Although MS is absent in South African blacks (Dean, 1967), and appears only infrequently in the colored population of South Africa (Ames and Louw, 1977), it has been recorded in comparatively large numbers in American blacks (Acheson and Bachrach, 1960; Haerer, 1976; Morariu and Linden, 1980). There is evidence, also, that an increase in MS frequency among non-whites can and does occur (Ames and Louw, 1977). Also, although Vietnam is classified as a low-risk region (Kurtzke, 1980), a high crude rate was recently ascertained among persons of half-Vietnamese extraction (i.e. offspring of Vietnamese mothers and French fathers) who had been born in Vietnam and brought to France as infants to be raised (Kurtzke and Bui, 1980).

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These data demonstrate that MS risk among white and non-white populations in various parts of the world tends to be variable, and suggest that genetic factors alone are not responsible for the distribution of this disease. An exogenous (environmental) factor, as yet unidentified, probably plays an important role is this distribution.

Religion and nationality In two nationwide surveys conducted in Israel in 1960 (Alter et al., 1962; Leibowitz and Alter, 1973) and 1966 (Leibowitz et al., 1971, 1973), and in epidemiological investigations of Spanish-speaking ethnic groups in the United States (Enstrom and Operskalski, 1978) and Mexico (Alter and Olivares, 1970), an overall pattern of MS was uncovered in which religion and nationality alone do not appear to be key explanatory variables.

Israeli studies In the 1960 Israeli study, place of birth data were collected for immigrants to, and natives of, Israel. Highest prevalence rates were found for Northern and Central European-born immigrants (descendants of English, Dutch, German, French, Polish, and Czech settlers), with considerably lower rates prevailing for native-born Israelis and immigrants from countries in Southern Europe, North Africa, and Asia (Alter, et al., 1962). In the 1966 study, the sample population consisted of only one ethnic group, that of native-born and reared Israelis who were one generation removed from their European (Ashkenazim) or Afro-Asian (Sephardim) immigrant parents. Virtually identical but high rates were found for this group, like those reported earlier in the 1960 study for European immigrants (Leibowitz et al., 1971, 1973). These MS rate fluctuations among Jewish immigrants and native-born Israelis lend strong support to the hypothesis that exogenous factors, not genetic, play a significant role in the distribution of MS. Which factor or factors in the environment may be responsible for the rate differences is, of course, yet to be determined. It appears unlikely that nationality and religion are implicated in the etiology of MS unless it can be shown that there are sharp differences in cultural values, based on national origin and/or religious affiliation, among the three ethnic groups. None of the data, however, in these Israeli studies suggest that the nationality status of group members (i.e. their European, Afro-Asian or Israeli backgrounds) or their religious preference for Reform, Conservative, or Orthodox ideology lead ultimately to a unique life style and consequently to a greater susceptibility to MS.

Spanish-speaking studies In an American study conducted in California by Enstrom and Operskalski (1978) an analysis was undertaken of state mortality records of persons who had died from MS to determine the frequency of this disease among two ethnic groups of Spanish~Americans, the foreign-born (immigrant) and California-

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born (native). Compared with all "other white Californians", who had high age-adjusted MS death rates (0.83 per 100000 population), the 2500000 immigrant and California-born Spanish-Americans had a low rate of 0.27. These MS rates among the three aforementioned ethnic groups may reflect either genetic or environmental influences. Comparison, however, of the 620 000 foreign-born group, mostly from Mexico, with the California-born Spanish-Americans revealed an extremely low death rate (0.07) for the former which was one-sixth the rate (0.42) for the 1330 000 California-born SpanishAmericans. These data, by contrast with the first set, lend support to the hypothesis that environmental factors, not genetic, influence the MS death rate among Spanish-Americans, which is, according to the authors, among the lowest of any subpopulation in the U.S. In the Mexican study, involving a population of 600 000 government workers and their dependents, in the Federal District of Mexico City, Alter and Olivares (1970) identified only nine cases of MS, yielding an extremely low prevalence rate of 1.6 per 100 000 population. Community data on where the patients lived showed that it is the most urbanized and technologically advanced area in Mexico, but does not enjoy the best of health standards: it had a high rate of enteric diseases, such as dysentery and typhoid, reflecting poor environmental sanitation. A pattern of low but variable MS rates characterize the Spanish-speaking ethnic groups. In as much as MS rates differed considerably in the California study, between the two Spanish-American groups, immigrant and native-born, and between the Spanish-American groups and the "other white group", environmental factors are probably implicated. Whether these environmental factors are tied to the nationality or religious status of members of these groups is yet to be determined. Unless, however, it can be shown that there are sharp differences in the cultural values associated with nationality and religion between the Spanish-speaking groups and the "other white group", and that these differences influence MS susceptibility, these two ethnic factors alone are probably not related to MS. To the extent, however, that MS rates for Spanish-speaking ethnic groups in the U.S. and Mexico are uniformly low, another explanation may be advanced for this pattern of distribution. Biological factors may be present in the genetic makeup of Spanish-speaking groups, and may consequently influence susceptibility to MS. As descendants of those Spaniards and other Europeans who intermarried with the North American Indians from the 16th century to date, they may, in fact, occupy a genetically distinct position (Griffin, 1968; Meier and Rivera, 1972). Or the ethnic life-style of these groups may be responsible. In regard to the ethnic hypothesis, and whether nationality and religion are implicated in MS, data from both studies fail to address comprehensively the nationality and religious status of Spanish-speaking groups, and how these ethnic variables may be reconciled with the consistently low MS rates of these groups. What these and other studies reveal, however, about the subculture of Spanish-speaking groups, is that it tends to be ethnically homogenous; i.e., group members are white, economically disadvantaged (Grebler et al., 1970), and principally Spa-

172 nish-speaking Roman Catholics. Also, much of their diet has traditionally been based on protein consumption from corn and beans with relatively small amounts of animal protein and fat (Millan 1942; United Nations Statistical Yearbook, 1966). Finally, their mode of life tends to be similar in that they live in relatively urbanized, technologically complex societies. The question of whether the ethnic homogeneity of Spanish-speaking groups leads ultimately to a unique life-style for each of these groups, sufficient to influence MS rates, remains unanswered. Until additional studies focus on this question satisfactorily, it appears plausible to hypothesize for the present that nationality and religion alone are not etiologically connected to MS. Other environmental factors are most likely implicated. HOUSE PETS AND THEIR ILLNESSES Evidence that has been gathered on whether a relationship exists between MS and animals has focused principally on exposure to, or contact with, animals and animal illness, mainly dogs as pets and dog illness such as canine distemper virus. At first these studies offered statistical correlations that appeared promising. Numerous studies, for example, established a relationship between MS and exposure to, or contact with, animals (Antonovsky et al., 1965; Cook and Dowling, 1977; Jotkowitz, 1977; Cook et al., 1978a) and animal illness (Campbell et al., 1947; Cook et al., 1978a,b, 1980, 1985; Cook and Dowling, 1982a,b; Warren et al., 1982b; Dean et al., 1985). More numerous, however, are studies where these relationships have not been, or could not be, replicated. Most importantly these studies have not been able to establish meaningful empirical correlations between MS and the aforementioned measures, including contact with, or exposure to, animals (Alter and Speer, 1968; Koch et al., 1974; Nathanson et al., 1978; Bunnell et al., 1979; Poskanzer et al., 1980; Read et al., 1982; Norman et al., 1983; Anderson et al., 1984) and animal illness (Krakowka and Koestner, 1978; Nathanson et al., 1978; Kurtzke and Priester, 1979; Poskanzer et al., 1980; Vandevelde and Meier, 1980; Appel et al., 1981; Norman et al., 1983). SOCIAI~PHYSICAL INTERACTION This factor focuses on the proposition that MS may be associated with the extent and degree to which people maintain social interaction or relationships and/or physical proximity with each other. Several investigators have collected data to show that there is no connection between MS and socialphysical interaction (Cendrowski, 1985; Isager et al., 1980). More significant, however, are the many researchers who have found connections between MS and social-physical interaction (Eastman et al., 1973; Murray, 1976; Kurtzke and Hyllested, 1979, 1986; Poskanzer et al., 1981; Kurtzke et al., 1982; Rosati et al., 1986). The most interesting and empirically convincing studies are those conducted in Iceland (Kurtzke et al., 1982) and the Faroe Islands, a small group

173 of Danish Islands lying between Norway and Iceland (Kurtzke and Hyllested, 1979, 1986). The hypothesis is offered that Faroe Island inhabitants experienced three separate epidemics of MS (Kurtzke and Hyllested, 1986), and the residents of Iceland one epidemic (Kurtzke et al., 1982), following their occupation by foreign troops during World War II (1940-1945). Suggested etiological agents in both regions are the occupying troops and/or their baggage. Specifically, in the Faroes, the first MS epidemic is believed to have been introduced by British troops during 1941-42 with the two additional epidemics resulting from transmission of this disease by affected Faroese to other Faroese (Kurtzke and Hyllested, 1986). Prevalence rates for all MS cases in Iceland for the decennial years 1904-1975 show that the greatest increase occurred in the series of 1944 versus 1954; from 36 per 100 000 population in 1944 to 53 per 100000 in 1954 (Kurtzke et al., 1982). This is a period of time that coincides with the initial British, Canadian, and American military presence in Iceland. If these findings are valid and MS did indeed occur in the form of epidemics, MS is not only an acquired disease but also a transmissable one (Kurtzke and Hyllested, 1986). URBAN-RURALRESIDENCE Previous studies, attempting to correlate MS with rural and urban residential status, have produced conflicting results. In some studies a higher MS risk was found to be associated with persons living in urban communities (Dassel, 1960; Morariu et al., 1974; Verdes et al., 1978; Lensky, 1979), while others stressed a higher risk in rural communities (Swank et al., 1952; Rinne et al., 1966; Millar, 1971; WikstrSm, 1975; Rosati et al., 1978; Shepherd and Downie, 1980; Lauer and Firnhaber, 1985). In still other studies no connection between living in urban or rural communities and MS could be found (Hyllested, 1956; Poskanzer et al., 1963a,b, 1980; Cendrowski, 1965; Rischbieth, 1966; McCall et al., 1969; Acheson, 1972; Neutel, 1980). The most convincing data, however, come from a number of technically immaculate case-control studies conducted in the U.S. and Israel, in which some, as yet unidentified, risk factor linked to urbanization or urban living is implicated in the tendency of MS cases being concentrated mainly in urban communities. In the American study, comprising a large sample of exservicemen, the risk of MS was approximately four times greater in men who had lived in the northeastern part of the United States and in the large urban and metropolitan population centers; the fewest cases were found in the southwest and rural regions (Beebe et al., 1967). Urban living, in fact, or some variable associated with it, was the most powerful discriminant between cases and controls uncovered in their analysis. In a series of Israeli studies, spanning several decades, prevalence rates were determined for native-born Israelis and immigrants to Israel by country of origin. Initially, the highest rates were found in immigrants from Europe, with considerably lower rates being recorded for native born Israelis and

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immigrants from Afro-Asia (Alter et al., 1962). Within one generation, however, higher rates, closer to that of the European than Afro-Asian immigrants, were found for native-born Israelis whose fathers had been born in Europe and in Afro-Asia (Leibowitz et al., 1971, 1973). Included as a possible determining factor for the variable rates is the Western technologically developed way of life (Leibowitz et al., 1971); i.e. the extent to Which industrialization and urbanization are present in the subculture or life-style of the native-born and immigrant groups. In still another study, patients were compared with matched controls regarding environmental exposure to a variety of etiological factors. Significant differences were found in that more patients than controls had lived most of their lives in urban communities of over 500 000 people (Antonovsky et al., 1965). The hypothesis that MS, in the Israeli native-born and immigrant groups, may be influenced by the technological factor is intriguing and worthy of further investigation. This is especially necessary since researchers have already significantly tied other diseases such as diabetes, obesity, hypertension, and a variety of circulatory problems to the processes of urbanization and economic development (Cassel and Tyroler, 1961; Tyroler and Cassel, 1964; Prior, 1971; Cassel, 1973; Labarthe et al., 1973; Omran, 1979; Bodley, 1982; Joralemon, 1982). If such a relationship exists, environmental factors, industrial and urban in nature, are probably implicated in the etiology of MS. NUTRITION

The role that dietary factors play, as regards both type and amount of food, in the etiology of MS remains uncertain. Some investigators have proposed that dietary habits are of little or no importance in the etiology of MS (Westlund and Kurland, 1953a,b; Antonovsky et al., 1965; Cendrowski et al., 1969; Koch et al., 1974). Other researchers have, however, implicated a specific diet factor, deficiency, or excess (Swank, 1950, 1953, 1955, 1956, 1960, 1970; Swank et al., 1952; Swank and Bourdillon, 1960; Agranoff and Goldberg, 1974; Alter et al., 1974; Butcher, 1976; Murray, 1976), and have suggested that differences may exist between the patient and the general population in regard to the types of food eaten (Alter et al., 1962; Detels et al., 1977; Enstrom and Operskalski, 1978). In ongoing epidemiological and experimental research, spanning over two decades, Swank and his colleagues have implicated a high-fat diet as an etiological agent in MS. In the first of his European studies, Swank (1950) correlated changes in the dietary intake before, during, and after World War II with the yearly incidence of MS during the same period. He found that the incidence of MS in entire populations may be related directly to the amount of fat in the diet. Nutrition in those countries believed to have a low incidence of the disease (e.g., Italy and Japan) tends to be low in fats, whereas in countries where the incidence is high (e.g., Denmark and Germany) the diet is relatively high in fats. In a later study of the geographic distribution and incidence of MS in Norway, Swank et al. (1952) reported that MS rates were higher in the inland

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farming and dairying districts, where high-fat intake exists, particularly milk and animal fat, than among the seacoast communities where fish form a large component of the diet. In an experimental attempt to test his low-fat hypothesis, Swank instituted a diet low in saturated fats among MS patients (Swank, 1953, 1955, 1956, 1960, 1970; Swank and Bourdillon, 1960). He found that patients with MS benefitted by a low-fat diet in that there were fewer deaths, less disability and fewer exacerbations among such patients during approximately 20 years of observation. Confirmation of the Swank thesis, that high-fat consumption might be significant in causing MS, comes from empirical studies in Israel (Alter et al., 1962) and Nova Scotia (Murray, 1976), and a comprehensive review of dietary and prevalence data in many countries (Alter et al., 1974). There is, however, at least one conflicting report in the literature in which satisfactory results with MS have been obtained experimentally with a high-fat diet (Crane, 1950). Still other researchers have presented evidence implicating dietary factors other than fat in the etiology of MS. In a review of the geographic distribution of this disease, Shatin (1964) proposed that the frequency of MS could be positively correlated with the geography of cereal cultivation. The incidence of this disease was higher in wheat-growing areas (e.g., Winnipeg, Canada), but lower in corn-growing regions (e.g., New Orleans, Louisiana). The consumption of gluten-containing grains (e.g., wheat), he concluded, may be responsible for increasing susceptibility to MS. Another dietary hypothesis has been presented by Goldberg (1974a,b), who postulated that the prevalence and geographic distribution of MS correlates negatively with the availability of vitamin D and calcium available in the environment, either from sunshine or diet. The combined action of two nutritional factors (vitamin D and calcium) and a geographic factor (sunshine) aid in the biochemical growth of normal myelin. A shortage of these factors, however, '~for a group of genetically susceptible individuals results in myelin having abnormal composition.., with the consequence of a heightened predisposition for MS" (Goldberg, 1974b). Goldberg's thesis is based upon the action of vitamin D and calcium in reducing the risk of MS. In a recent investigation, Warren (1982) suggested that a lack of sufficient vitamin A or selenium and vitamin E, in the diets of young infants, is a necessary but not a sufficient condition for the possible onset of MS in later life. Finally, several studies have been successful in demonstrating a close correlation between a high prevalence of MS and a high consumption of dairy produce, e. g. milk and milk products (Agranoffand Goldberg, 1974; Butcher, 1976). Two of the more prominent dietary explanations have linked MS to the consumption of large quantities of animal fat (Swank, 1950; Swank et al., 1952) and milk and milk products (Agranoff and Goldberg, 1974; Butcher, 1976). Both propositions, however, are unlikely to be true since it has already been established that MS is uncommon among the Afrikaans-speaking white South Africans who consume large quantities of milk and butter and eat a high-fat diet. Also, blacks in many parts of Africa consider milk as an important food, yet the disease is virtually absent among them (Dean, 1967, 1974).

176 SOCIOECONOMIC STATUS Conflicting evidence exists that MS is a disease primarily of the economically and socially advantaged and of persons employed in particular kinds of occupations. There is some data, especially in the early literature, that suggest that workers employed in particular occupations are at a greater risk, such as, for example, those in agricultural pursuits (Steiner, 1938; Swank et al., 1952), chemicals or organic solvents (Amaducci et al., 1982) and laboratory research of swayback disease, a neurological disease of lambs (Campbell et al., 1947; Dean et al., 1985). A plethora of investigations have also established that MS attacks mainly those in the higher socioeconomic groups, its prevalence being related to affluent living standards and above average educational, occupational, and/or economic positions (Registrar-General, 1958; Miller et al., 1960; Beebe et al., 1967; Breland and Currier, 1967; Oh and Calhoun, 1969; Russell, 1971; Alter, 1972; Singhal and Wadia, 1975; Haerer, 1976; Hoffman et al., 1981; Visscher et al., 1981b). The strongest evidence for MS being tied to the higher socioeconomic groups comes from a study of American World War II veterans with MS (Beebe et al., 1967), and two surveys of British MS patients (Miller et al., 1960; Russell, 1971). In the Beebe et al. (1967) study, MS was found to be directly related to socioeconomic status, educational level, and AGCT (Army General Classification Test) score. The higher the socioeconomic status, educational level, and AGCT score, the greater the risk of MS. Data from the British counties of Northumberland and Durham show that a disproportionate number of MS patients belonged to the higher social classes: 20% to Classes I and II and 75% to Classes I-III (Miller et al., 1960). A similar upper class gradient was also reported by Russell (1971) in that the highest proportion of patients were located in the highest social classes (I and II) and the majority of male patients were employers, managers, and professional workers. Evidence, however, from investigations in other parts of the world have reported different patterns of relationship between MS and socioeconomic status. In a recent Italian study, for example, researchers found that MS attacks persons living mainly in rural communities characterized by the lowest standard of living (Rosati et al., 1978). Still other studies have reported little or no correlation between occupation and the risk of disease (Kurland et al., 1955; Lauer and Firnhaber, 1984) and MS and socioeconomic status (Kurland, 1952; Westlund and Kurland, 1953a,b; Antonovsky et al., 1965, 1967; Leibowitz et al., 1966; Acheson, 1972, 1977; Agranoff and Goldberg, 1974; Koch et al., 1974). POPULATION MIGRATION One of the most fruitful subjects of epidemiological research has been the study of immigrant and/or migrant populations to or from different MS risk areas throughout the world. The basic rationale for such study is that, should differences in prevalence be found among people of the same race living in different environments, it might provide us with further information as to the nature of the environmental factor or factors responsible for MS, as well as to the age of acquisition of this disorder.

177 Prevalence studies of migrants consist of persons who either migrate from high to lower or low to higher MS risk areas. Broadly speaking, data from these studies are interpreted as exhibiting two empirical patterns. First, adult migrants tend to retain much of the MS risk (high, medium, or low) of their birthplace or region of origin (Alter et al., 1977; Kurtzke, 1980). (Risk is defined according to the interpretation offered earlier that MS is distributed in bands of different frequency or risk comprising high, medium, and low prevalence zones.) Most prevalence studies have been of persons who migrate from high prevalence to lower prevalence areas. It is, therefore, not surprising that the best evidence for MS risk retention comes from these investigations rather than from those of persons who migrate from low prevalence to higher prevalence regions. Second, these studies emphasize that age of migration is critical for risk retention (Kurtzke, 1980), with most studies agreeing that the childhood or adolescent period (< 15 years of age) is most important.

Migration from high prevalence to lower prevalence areas In studies of migrant groups moving from high- to lower-risk areas, evidence for migrants retaining the high MS risk of their birthplace or region of origin is strong (Alter et al., 1977; Kurtzke, 1977, 1980; Alter, 1978; Kurtzke et al., 1979). Such studies have been reported from South Africa (Dean, 1967; Kurtzke et al., 1970; Dean and Kurtzke, 1971) and Israel (Alter et al., 1962, 1966). They show that white migrants from Great Britain and northern and central Europe (high prevalence areas) have higher prevalences than do native-born whites in Israel or South Africa, which are respectively medium- and low-risk prevalence areas. Migrants, in fact, have almost the same high risk of developing MS in their newly adopted country as in their country of birth. Additional evidence for high-risk retention comes from two investigations from the United States. Alter and Okihiro (1971) found that prevalence among migrants to Hawaii (medium-prevalence area) resembled the rate in their place of birth. Those born in high-risk regions (e.g., northern and central Europe and north central United States) had the highest MS rates, whereas rates among migrants from medium- and low-risk regions of the United States resembled the rate reported by other investigators in those regions. From mortality data collected of American-born migrants to Washington and California, Detels et al. (1972) confirmed that migrants from high-prevalence areas to lower-prevalence areas had higher mortality from MS than persons born in these lower-prevalence areas. Worldwide studies also demonstrate that, for migrants moving from a highto a lower-risk zone, age of adolescence is critical for risk retention (Alter and Harshe, 1975; Kurtzke, 1980). If migration occurs before 15 years of age, persons tend to acquire the lower risk of the new environment (country, region or residence) into which they have migrated; consequently their risk of later developing MS is reduced. If, however, migration occurs at age 15 or older, persons tend to retain the high risk of their birthplace, and thus have a much greater risk of later developing this disease. This pattern has been established

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in Israel (Alter et al., 1966, 1978; Alter, 1973), Hawaii (Alter and Okihiro, 1971; Alter et al., 1971), and South Africa (Dean 1967; Kurtzke et al., 1970; Dean and Kurtzke, 1971). These findings reveal that early enough migration, from highto lower-risk regions, reduces the risk of MS. They suggest also that an important environmental factor is probably operating in the etiology of this disease during the first 15 years of life, and that exposures occurring in early life play a role in determining the likelihood of developing MS (Detels, 1978; Detels et al., 1978). Age 15 appears to be the important age status separating those migrants who carry with them the high risk of their birthplace (older than 15) from those (younger in age) who acquire a lower risk.

Migration from low-prevalence to higher-prevalence areas The effect of migration, and evidence for risk retention, is less well defined among persons moving from low- to higher-prevalence areas. Studies by Dean et al. (1976, 1977) reveal that MS among immigrants from low-risk countries to Great Britain is rare in persons of Asian, African, and West Indian ethnic origin. Among immigrants to Israel from Afro-Asian countries, who moved from a low- to an intermediate-risk zone, MS is also low (Alter and Bornstein, 1962; Alter et al., 1962, 1964, 1977, 1978; Leibowitz et al., 1969, 1971, 1973). American data from the West Coast indicate that migrants from low-risk areas tend to retain their low rates, whether they migrate to high-risk (Washington) or low-risk (California) states. Specifically, migrants to both of these states from other low-risk states in the United States had low MS rates, which suggests they may have acquired protection before migration (Detels et al., 1972, 1976; Visscher et al., 1977). All three sets of data confirm the propositions that place of birth is also important for persons migrating from low- to higherrisk regions, and that persons born in low-risk areas do not increase their risk of acquiring MS upon moving to higher-risk regions. A contrary pattern emerges, however, when age of adolescence is introduced. Such a viewpoint is provided by other researchers who offer evidence that, if migrants move sufficiently early in life from low- to higher-risk areas, the risk of MS can be increased. In research conducted by Kurtzke and Bui (1980) involving a population of 3379 half-Vietnamese (persons born in Vietnam but raised in France) three cases of MS were identified, yielding a high crude prevalence rate of 89 per 100 000. All three patients had developed symptoms about 15 years after immigration 'tat ages 17, 22, and 16 respectively for migration at ages 3, 6, and 1 years". In an earlier investigation involving immigrants from Indonesia to The Netherlands three cases of MS were recorded by Dassel (1972). Although not definitely established, they were probably white and members of a small group of immigrants (Kurtzke, 1977, 1980). Their clinical onsets were at ages 25, 23, and 17 years and took place respectively 8, 9, and 7 years after their arrival in Holland. These two sets of data provide evidence that the risk of MS can be increased by migration in childhood or adolescence from a low- to a high-risk area, and that MS is

179 probably acquired long before clinical onset. In other data, derived from an American study of World War II and the Korean conflict, white male veterans with MS, plus controls, were compared in regard to their residences at birth, and entry on active duty (EAD) into military service (Kurtzke et al., 1985). Migrants were defined as those whose birth and EAD tier differed. Based on high-, medium-, and low-prevalence rates three north-south tiers were identified, north, middle, and south. Entry on active duty averaged about 24 years for World War II veterans. The general migration pattern uncovered was one where those born in either the northern or middle tier states who moved south, and were living there at EAD, decreased their risk of acquiring MS; those, however, born in the middle tier states who moved north, and were residing there at EAD, increased their risk. These data provide evidence that there is a clear change in the risk of migration between birth and EAD, and that those persons moving north (from low to higher prevalence) tend to increase their MS risk, whereas those migrating south (from high to lower prevalence) decrease it. Further, the findings implicate an environmental factor in the etiology of MS, and suggest that the risk of MS is acquired years before symptom onset. Although the data do not provide the exact age at which this operates, it is hypothesized that this might be fixed at about age 20 among migrants from low- to higher-risk areas (Kurtzke et al., 1985, p. 678). SANITATION Data have been collected to show that there is no connection between the development of MS and the quality (good or bad) of sanitation in a community (Cendrowski, 1965; Cendrowski et al., 1969; Koch et al., 1974; Lauer and Firnhaber, 1984), and that there is no difference between patients and controls in regard to sanitation standards and MS (Antonovsky et al., 1968; Poskanzer et al., 1980). There is more evidence, however, although not empirically conclusive, supporting the hypothesis that there is a correlation between the quality of environmental sanitation (water and air) in a community and the frequency (high or low) of MS in that community. Multiple sclerosis rates are higher in regions where environmental sanitation is good Numerous investigators have observed that, compared with controls, patients live in better environments with superior sanitary facilities (Antonovsky et al., 1965; Leibowitz et al., 1966), and that high MS rates tend to be found among persons who enjoy superior sanitary facilities (Singhal and Wadia, 1975; Poskanzer et al., 1980), and in areas where sanitary standards are good (Dean et al., 1977). If MS is indeed related to the quality of sanitation, MS frequency should increase in environments which improve their level of sanitation. Good evidence for this comes from Israel where, according to one researcher close to the Israeli epidemiological scene, that country has over the

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last 30 years dramatically improved its environmental health standards (Alter, 1972, pp. 108 and 126), while simultaneously experiencing a highly variable but upward fluctuation in MS rates among its immigrant and native-born population (Leibowitz et al., 1971, 1973). The hypothesis - - that the improved level of sanitation in an environment may be at least one factor involved in explaining higher MS rates - - should continue to be seriously entertained. Multiple sclerosis rates are lower in regions where environmental sanitation is poor

If the hypothesis that MS is related to the quality of sanitation is correct, then this alternate scenario is also possible - - that MS frequency should be low in technologically advanced countries with poor sanitation facilities (Alter, 1972, p. 113). This has, in fact, been observed to exist in both Japan (Alter, 1972) and Mexico City (Alter and Olivares, 1970), where less than adequate environmental sanitation facilities exist, and MS rates are low. In the latter study, community data on where the patients lived showed that it is technologically the most advanced area in Mexico, but does not enjoy the best of health standards: it has a high rate of enteric diseases, e.g. dysentery, typhoid, gastritis, and parasitic and infectious diseases, reflecting poor environmental sanitation. Although these studies tend not to be in agreement as to the exact nature of the relationship between MS frequency and the quality of environmental sanitation, the principal pattern of relationship is clearly one where the frequency of MS (dependent variable) is tied to the quality of sanitation standards (independent variable). CONCLUSIONS AND FUTURE RESEARCH

The contradictory results that tend to dominate so much of the epidemiological data of MS cannot easily be explained away, and few definitive conclusions are possible. However, a number of explanations for these contradictions center around the methodology of the investigator, the peculiar nature of MS, and the reactions of the patient population to this disease. Most important, perhaps, is that epidemiological studies, in general, are inconsistent because they utilize different methodological procedures to measure prevalence. This is characteristic of epidemiological studies of the mentally ill (Gallagher, 1987, pp. 214-215), and is apparently a pattern which also prevails in MS studies (Kurtzke, 1985, pp. 262-263). Nowhere are the methodological problems raised by epidemiological studies of MS, and the role played by methodology in influencing the nature of results, better illustrated than in the investigative methodology used to study the relationship between MS and animals (Kurland and Brian, 1978; Alter et al., 1979). Much of the data, for example, tends to be observational, retrospective, and subject to the limitations of case-control studies (Kurland and Brian, 1978).

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Perhaps the most severe limitation is that the validity of the data depends on how representative it is of the disease and control samples and, typically, case-control studies tend not to be representative (Kurland and Brian, 1978). Other limitations include the fact that data collection methods tend to vary from use of a procedure whereby subjects are interviewed directly, by telephone, or written questionnaires, thereby making comparative generalizations less than uniform and unsystematic. Also, since there is no definitive laboratory test for MS, and the only certain diagnosis is made at autopsy, the date of onset of MS and the criteria of diagnosis are frequently problematic (Kurland and Brian, 1978). It is, therefore, not too surprising that a number of epidemiologists continue to argue that, although it is difficult to accept an association between MS and contact with, and exposure to, animals and animal illness, these issues are not clearly resolved and further investigation continues to be warranted (Kurland and Brian, 1978; Alter et al., 1979; Anderson et al., 1984; Cook et al., 1985). Earlier we stated that there were at least three possible explanations for the contradictory nature of MS epidemiological data. All of these, it is suggested, may play a role in influencing the nature of results in studies dealing with socioeconomic status. First, MS may be more common among the upper socioeconomic groups, since people occupying these class statuses may more readily report initial symptoms of the disease, such as minor visual and motor disturbances, emotional changes, and numbness of body parts, than might persons in the classes below them. Next, data in these studies may be an underestimate of the actual socioeconomic distribution in a population since they tend to be uncorrected; i.e. they do not take into consideration the fact that MS is a chronic, disabling and costly disease that often moves patients downward in socioeconomic status. Finally, there is no uniformity of methodological usage in these studies regarding the stratification classification for determining socioeconomic status. One or more of these criteria have been used singularly or in combination: income, education, occupation, standard of living, and self-rating. In the Beebe et al. (1967) study, for example, socioeconomic status is explicitly represented by the composite score of educational level and occupation. In the Miller et al. (1960) and Russell (1971) investigations, however, occupation is the common variable used, but in different and confusing ways. Occupation of the patient at the time of onset of disease is used to determine what Miller et al. (1960) call social class level. Occupational data are also used by Russell (1971), but his mode of classification is one in which the population is placed into a social class status of high and low dimensions and a socioeconomic grouping based on various occupational categories. Future research should address the problem associated with the tendency of MS researchers to use case-control studies which are not representative of the disease and control samples in the population. Only studies in which a sufficiently large random sample of the population with MS is compared with a random sample of the general population without MS would satisfy this representativeness criterion. Furthermore, the question of whether researchers

182 h a v e i n t h e p a s t u s e d a d e q u a t e m e t h o d s of i d e n t i f y i n g t h e s i c k p o p u l a t i o n i n d e t e r m i n i n g p r e v a l e n c e m u s t be a d d r e s s e d . I n d e e d , o n e r e s e a r c h e r h a s a l r e a d y suggested t h a t there may be m a j o r problems in c a s e - a s c e r t a i n m e n t in I t a l i a n e p i d e m i o l o g i c a l s t u d i e s ( K u r t z k e , 1985, p. 263). I t a l y , for e x a m p l e , h a s t r a d i t i o n a l l y b e e n i d e n t i f i e d as a m e d i u m - p r e v a l e n c e zone. R e c e n t l y , h o w e v e r , n u m e r o u s i n v e s t i g a t o r s , b y c o n c e n t r a t i n g o n s m a l l p o p u l a t i o n s w i t h i n comm u n i t i e s , h a v e r e p o r t e d h i g h M S p r e v a l e n c e r a t e s for a l l s e c t i o n s ( n o r t h a n d s o u t h ) of t h i s c o u n t r y . T h i s o b v i o u s l y r e p r e s e n t s a m e t h o d o l o g i c a l p r o b l e m , a n d c a s t s s e r i o u s d o u b t o n m a n y of t h e e m p i r i c a l g e n e r a l i z a t i o n s t h u s f a r offered a b o u t t h e e p i d e m i o l o g y o f m u l t i p l e s c l e r o s i s . ACKNOWLEDGEMENT This work was s u p p o r t e d by a S k i d m o r e College r e s e a r c h grant. REFERENCES Acheson, E.D., 1972. The epidemiology of multiple sclerosis. In: D. McAlpine, C.E. Lumsden and E.D. Acheson (Eds), Multiple Sclerosis, A Reappraisal. Churchill Livingstone, Edinburgh, pp. 1-80. Acheson, E.D., 1977. Epidemiology of multiple sclerosis. Br. Med. Bull., 33: 9~14. Acheson, E.D. and C.A. Bachrach, 1960. The distribution of multiple sclerosis in United States veterans by birthplace. Am. J. Hyg., 72: 88-99. Adams, D.K., J. Sutherland and W. Fletcher, 1950. Early clinical manifestations of multiple sclerosis. Br. Med. J., 2: 431-445. Agranoff, B.W. and D. Goldberg, 1974. Diet and the geographical distribution of multiple sclerosis. Lancet, 2: 106~1066. Alter, M., 1962. Multiple sclerosis in the negro. Arch. Neurol., 7: 83-91. Alter, M., 1968. Etiologic considerations based on the epidemiology of multiple sclerosis. Am. J. Epidemiol., 88: 318-322. Alter, M., 1972. The distribution of multiple sclerosis and environmental sanitation. In: U. Leibowitz (Ed.), Progress in Multiple Sclerosis, Research & Treatment. Academic Press, New York, pp. 99-131. Alter, M., 1973. Multiple sclerosis in migrant populations. Triangle, 12:25 30. Alter, M., 1978. The epidemiology of multiple sclerosis. In: W.A. den Hartog Jager, G.W. Bruyn and A.P.J. Heijstee (Eds), Neurology, Proceedings of the Eleventh World Congress of Neurology. Elsevier, Amsterdam, Holland, pp. 330-350. Alter, M. and B. Bornstein, 1962. Multiple sclerosis among Yemenite Jews in Israel, a clinical appraisal. World Neurol., 3: 561-565. Alter, M. and M. Harshe, 1975. Racial prediliction in multiple sclerosis. J. Neurol., 210: 1-20. Alter, M. and M. Okihiro, 1971. When is multiple sclerosis acquired? Neurology, 21: 1030-1036. Alter, M. and L. Olivares, 1970. Multiple sclerosis in Mexico. Arch. Neurol., 23: 451-459. Alter, M. and J. Speer, 1968. Clinical evaluation of possible etiologic factors in multiple sclerosis. Neurology, 18: 109-116. Alter, M., L. Halpern, L.T. Kurland, B. Bornstein, U. Leibowitz and J. Silberstein, 1962. Multiple sclerosis in Israel. Arch. Neurol., 7: 253-263. Alter, M., U. Leibowitz and L. Halpern, 1964. Clinical studies of multiple sclerosis in Israel. Part II A comparison between European and Afro-Asian patients. J. Neurol., Neurosurg. Psychiatry, 27: 522-529. Alter, M., U. Leibowitz and J. Speer, 1966. Risk of multiple sclerosis related to age at immigration to Israel. Arch. Neurol., 15: 234-237. -

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