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Update on the Epidemiology of Multiple Sclerosis

      Neuroepidemiology has been important in providing clues about the cause and pathogenesis of multiple sclerosis. In this review, we update the incidence and prevalence rates of multiple sclerosis in Olmsted County, Minnesota, and examine the potential role of viruses, exposure to animals, toxins, trauma, and diet in the development of this disease. Diseases of probable autoimmune nature have also been linked to multiple sclerosis. These descriptive data may contribute to the formulation of testable specific hypotheses about the pathogenesis and treatment of multiple sclerosis and other demyelinating diseases.
      In recent years, the incidence, prevalence, and mortality rates of numerous common and uncommon neurologic conditions have been estimated, and seasonal, regional, ethnic, and international differences in these rates have been described. Similarly, long-term sequelae, comorbidity, and survival characteristics of neurologic disease have been addressed. In many instances, these descriptive data have provided etiologic clues and have set directions for more specific hypothesis-generating and hypothesis-testing analytic studies.

      INCIDENCE AND PREVALENCE

      “The basic premise of epidemiology is that disease does not occur randomly but in patterns which reflect the operation of the underlying causes.”
      • Fox JP
      • Hall CE
      • Elveback LR
      The geographic pattern of multiple sclerosis (MS) has attracted considerable attention in recent decades, but such studies actually began soon after the formal description of the disease by Charcot,
      • Charcot JM
      who commented that the disease was prevalent in France, not well recognized in Germany, and uncommon in England. These clinical impressions finally gave way to systematic comparative studies of the prevalence of MS.
      In 1922, Davenport
      • Davenport CB
      Multiple sclerosis from the standpoint of geographic distribution and race.
      reported the distribution of MS in the United States based on diagnoses among Army inductees in World War I. He noted that the frequency of occurrence of MS was higher in urban than in rural areas and that the highest rates were among persons living near the Great Lakes and in Washington, Maine, Pennsylvania, Kansas, and Mississippi. In 1926, postal surveys of physicians in Switzerland by Bing and Reese
      • Bing R
      • Reese H
      Die multiple Sklerose in der Nordwest-schweiz.
      and a subsequent survey by Ackermann
      • Ackermann A
      Die multiple Sklerose in der Schweiz: Enquete von 1918–22.
      suggested that MS was more common in the predominantly Germanic northern Swiss cantons than in the French and Italian cantons. Allison,
      • Allison RS
      Disseminated sclerosis in North Wales: an inquiry into its incidence, frequency, distribution and other etiological factors.
      who conducted a survey in northern Wales in 1928, is credited with the first systematic study of MS morbidity in a defined population in which diagnostic criteria were described and all the suspected cases were examined.
      Many of the early reports were based on clinical impressions; nevertheless, some were useful in stimulating the intense population-based surveys that were needed to provide a geographic pattern of the distribution of the disease. In 1938, Steiner
      • Steiner G
      Multiple sclerosis. I. The etiological significance of the regional and occupational incidence.
      reported that he had noted no scarcity of MS in New York City, but during a 6-month period in New Orleans he had not seen a single clinical or autopsy case in a native-born person.
      The next major development in the effort to clarify the distribution of MS was Limburg's demonstration
      • Limburg CC
      The geographic distribution of multiple sclerosis and its estimated prevalence in the United States.
      that MS death rates increased from south to north within the United States. Subsequent work by MacLean, Kurland, Kurtzke, Alter, Dean, Acheson, and others gradually developed the global topography of the disease with the general picture of a higher prevalence in the temperate zones than in the sub-tropics and tropics and some uncertainty about the disease prevalence nearer the poles.
      • Kurland LT
      The epidemiologic characteristics of multiple sclerosis.
      • Kurtzke JF
      Epidemiology of multiple sclerosis.
      Research at the Mayo Clinic has pursued the epidemiology of MS and has expanded to a systematic study of the population features of numerous neurologic disorders. The development of neuroepidemiology as a distinct discipline began with the presentation, by MacLean and associates
      • MacLean AR
      • Berkson J
      • Woltman HW
      • Schionneman L
      Multiple sclerosis in a rural community.
      in 1950, of the first population-based study of MS in the United States; they described the incidence and prevalence of MS and survival of affected persons in the population of Rochester, Minnesota. This study, based on the Mayo Clinic records system, showed that the prevalence of MS was more than twice that previously reported anywhere else, and the prognosis, based on community experience, was far more optimistic than estimates derived from hospital-based studies.
      Two subsequent surveys of the frequency of MS have been done in Rochester. Percy and co-workers
      • Percy AK
      • Nobrega FT
      • Okazaki H
      • Glattre E
      • Kurland LT
      Multiple sclerosis in Rochester, Minn: a 60-year appraisal.
      extended the earlier study by MacLean and colleagues
      • MacLean AR
      • Berkson J
      • Woltman HW
      • Schionneman L
      Multiple sclerosis in a rural community.
      by estimating prevalence ratios in Rochester at 10-year intervals from 1935 through 1964. In addition, they calculated the mean annual incidence rates for each decade from 1905 through 1964. Kranz and associates
      • Kranz JMS
      • Kurland LT
      • Schuman LM
      • Layton D
      Multiple sclerosis in Olmsted and Mower Counties, Minnesota.
      extended the incidence estimates through 1974 and the prevalence estimates through 1978. As has been observed in other communities where surveys have been repeated, Kranz and co-workers noted an increase in prevalence rate, from 46 per 100,000 as calculated by Percy and associates for 1915 to 108 per 100,000 for 1978. They noted a mean annual incidence rate of 3.6 per 100,000 population for the interval 1965 through 1974, similar to that calculated by Percy and colleagues for the 6 earlier decades, and concluded that the incidence rate of MS was stable in the Rochester population as also had been shown in a similar study in Winnipeg, Canada.
      We recently reassessed the incidence and prevalence of MS in Rochester and in Olmsted County (of which Rochester is the county seat) for the 80-year interval 1905 through 1984.
      • Wynn DR
      • Kurland LT
      • O'Fallon WM
      • Rodriguez M
      Multiple sclerosis in Olmsted County: an 80-year review (abstract).
      On Jan. 1, 1985, 152 prevalent cases of MS were identified in Olmsted County, of which 102 were in Rochester residents. Age- and sex-adjusted prevalence rates were 171 per 100,000 for Olmsted County and 177 per 100,000 for the city of Rochester. As noted in previous studies
      • Percy AK
      • Nobrega FT
      • Okazaki H
      • Glattre E
      • Kurland LT
      Multiple sclerosis in Rochester, Minn: a 60-year appraisal.
      • Kranz JMS
      • Kurland LT
      • Schuman LM
      • Layton D
      Multiple sclerosis in Olmsted and Mower Counties, Minnesota.
      and by others elsewhere in repeated population-based studies of MS, the prevalence of MS has increased significantly in the past 10 years.
      Previous increases in MS prevalence have been attributed to increased survival of MS patients, changes in population age structure, migration, and miscellaneous effects of restudy.
      • Kranz JMS
      • Kurland LT
      • Schuman LM
      • Layton D
      Multiple sclerosis in Olmsted and Mower Counties, Minnesota.
      • Wynn DR
      • Kurland LT
      • O'Fallon WM
      • Rodriguez M
      Multiple sclerosis in Olmsted County: an 80-year review (abstract).
      • Poskanzer DC
      • Prenney LB
      • Sheridan JL
      • Kondy JY
      Multiple sclerosis in the Orkney and Shetland Islands. I. Epidemiology, clinical factors, methodology.
      Important effects of restudy include improved case-finding methods as a result of technologic advances in diagnosis and computerization of medical records, both of which increase completeness of case ascertainment. Another feature of importance in this population is the retention and availability of records since early in this century, increasing the likelihood that some cases previously regarded as “possible only” now were “probable” or “definite” because of information collected on such patients for several decades. Although these factors have likely contributed to the increased prevalence rates, they might be insufficient to explain the entire difference noted; therefore, an increase in disease incidence must also be considered.
      An intensive reevaluation of all categories that might include MS cases for the 80-year period Jan. 1, 1905, to Jan. 1, 1985, identified 208 incident cases (57 males and 151 females) fulfilling current criteria for MS in the Olmsted County population. The age-adjusted incidence rates were 3.0 and 7.0 per 100,000 for males and females, respectively; the median age at onset was 34.3 years for males, 32.4 years for females, and 32.8 years overall. The median follow-up interval was 13.8 years for males, 14.1 years for females, and 14.0 years overall; 3,472 person-years of follow-up information was available for review. Autopsy information was available for 18 of the 41 persons (44%) who died during the study interval. The diagnostic criteria were those outlined by Poser and associates
      • Poser CM
      • Paty DW
      • Scheinberg L
      • McDonald I
      • Davis FA
      • Ebers GC
      • Johnson KP
      • Sibley WA
      • Silberberg DH
      • Tourtellotte WW
      New diagnostic criteria for multiple sclerosis: guidelines for research protocols.
      from the Workshop on the Diagnosis of Multiple Sclerosis. More than 90% of the patients were in the category “clinically definite MS A1.” This high percentage of clinically definite cases probably is related to the availability of old medical records and the long period of follow-up.
      These data suggest a trend toward an increasing risk for development of MS, a finding not previously noted in Rochester or other major centers.
      • Rosati G
      Descriptive epidemiology of multiple sclerosis in Italy.
      When grouped by place of residence—metropolitan Rochester or rural Olmsted County—the MS rates were comparable.
      The increase in incidence may be real, although issues of improved case ascertainment, diagnostic improvements (especially in the milder cases), and improved study design must be considered. The increase in incidence may explain in large part the increases in prevalence noted now and previously in this community. Whether this implies a more general trend toward increasing risk of MS elsewhere awaits study in other communities.

      MIGRATION

      Since the demonstration by Limburg
      • Limburg CC
      The geographic distribution of multiple sclerosis and its estimated prevalence in the United States.
      of an increasing frequency of MS from south to north within the United States, investigations in different parts of the world have supported the hypothesis that the risk of MS is related to distance from the equator.
      • Kurland LT
      The epidemiologic characteristics of multiple sclerosis.
      • Kurtzke JF
      Epidemiology of multiple sclerosis.
      In an attempt to distinguish between the importance of environmental factors and possible genetic risk factors, the effect of migration on risk has been studied. The study of the incidence and prevalence of MS in migrant groups has been one of the most important natural experiments in the study of MS epidemiology.
      Rozanski
      • Rozanski J
      Contribution to the incidence of multiple sclerosis among Jews in Israel.
      and subsequently Alter and associates
      • Alter M
      • Halpern L
      • Kurland LT
      • Bornstein B
      • Leibowitz U
      • Silberstein J
      Multiple sclerosis in Israel: prevalence among immigrants and native inhabitants.
      reported the prevalence rate of MS among groups migrating to Israel. The prevalence rate was noted to be 5 to 10 times higher among northern European immigrants than among African or Asian immigrants or in the native population of Israel, even among those of northern European parentage. These findings suggested an environmental influence on the risk of developing MS.
      In 1967, Dean
      • Dean G
      Annual incidence, prevalence, and mortality of multiple sclerosis in white South-African-born and in white immigrants to South Africa.
      noted that the prevalence rate among South Africans who were of European stock but were born and raised in South Africa was approximately 17% of that among immigrants from England and Europe. Visscher and colleagues
      • Detels R
      • Visscher BR
      • Malmgren RM
      • Coulson AH
      • Lucia MV
      • Dudley JP
      Evidence for lower susceptibility to multiple sclerosis among Japanese-Americans.
      • Visscher BR
      • Detels R
      • Coulson AH
      • Malmgren RM
      • Dudley JP
      Latitude, migration, and the prevalence of multiple sclerosis.
      noted that the prevalence rate of MS is higher among Japanese-Americans than in the population of Japan, although this finding might be a reflection of differences in training and clinical practice. In addition, Kurtzke and Bui
      • Kurtzke JF
      • Bui QH
      Multiple sclerosis in a migrant population. 2. Half-orientals immigrating in childhood.
      noted an increased risk of MS among persons who migrated from low-risk southern zones in the United States to high-risk northern zones as well as a decreased risk in those who migrated from north to south. Similar findings in France, Hawaii, Australia, England, and other locations have led to postulates of protective factors in subtropical zones and risk factors in temperate zones.
      • Kurland LT
      The epidemiologic characteristics of multiple sclerosis.
      • Kurtzke JF
      Epidemiology of multiple sclerosis.
      Migration after adolescence has been associated with a risk of MS characteristic of the country of origin, whereas migration earlier in life has been associated with a risk characteristic of the new environment.
      • Alter M
      • Kahana E
      • Lowenston R
      Migration and risk of multiple sclerosis.
      • Detels R
      • Visscher BR
      • Haile RW
      • Malmgren RM
      • Dudley JP
      • Coulson AH
      Multiple sclerosis and age at migration.
      Studies of this important topic have been limited by the paucity of migrant groups suitable for study. The immigration policy of an admitting country may exclude disabled immigrants, or migration of patients may be relatively increased if it is thought that the climate of a particular country may favorably affect the course of the disease. As noted by Alter and co-workers,
      • Alter M
      • Kahana E
      • Lowenston R
      Migration and risk of multiple sclerosis.
      the migrant groups must be large enough to yield a sufficient number of cases for meaningful statistical analysis, medical facilities must be comparable for native and migrant populations, and the populations studied must be well defined demographically so that accurate incidence and prevalence figures can be generated.
      Several racial groups have been reported to be maintaining low MS incidence rates although living in high-risk zones for MS.
      • Dean G
      • Brady R
      • McLoughlin H
      Motor neurone disease and multiple sclerosis among immigrants to Britain.
      • Pálffy G
      MS in Hungary, including the Gipsy population.
      This result refutes a purely environmental interpretation, although those who migrated may have been the healthier members of the community and the level of medical care available in the adopted country may have been inadequate for the diagnosis and reporting of the disease when it did occur. Also, in some cases, the development of the disease may have led to their return to their homeland.
      Before definite conclusions can be drawn, a substantial population of immigrants must be observed for most of a lifetime and comparisons in frequency must be made that take into account the age at migration and the duration of residence in the host country. Because hypotheses that implicate environmental factors assume, in part, that patients with MS and geographically matched control subjects have similar racial and genetic characteristics, ideally the migrant groups should be well defined or described genetically such that further characterization of the respective roles of heredity and environment can be made.

      QUESTIONS POSED BY EPIDEMIOLOGISTS

      What are the important risk factors for development of MS? Descriptive epidemiologic studies point toward a role for environmental factors in the development of MS, but what are these factors? The following have been topics of active research and ongoing controversy.

      Infectious Agents.

      The epidemiologic data accumulated for the past 25 years implicating an environmental influence in the development of MS provide indirect evidence that MS may be caused by an infectious agent. Of particular prominence have been the reports by Kurtzke and Hyllested
      • Kurtzke JF
      • Hyllested K
      Multiple sclerosis in the Faroe Islands. I. Clinical and epidemiological features.
      • Kurtzke JF
      • Hyllested K
      Multiple sclerosis in the Faroe Islands. II. Clinical update, transmission, and the nature of MS.
      • Kurtzke JF
      • Hyllested K
      MS epidemiology in Faroe Islands.
      of cases of MS among residents of the Faroe Islands. Between 1943 and 1963, 24 cases were identified. In this ongoing study, the 32 cases of MS diagnosed between 1943 and 1973 constituted three distinct periods of increased incidence. Kurtzke and Hyllested interpreted these data to indicate a point-source epidemic with an infectious common source associated temporally with the stationing of British troops in the Faroes during World War II. Based on their observations, they suggested that MS is a widespread systemic infectious disease that most frequently is asymptomatic and only rarely affects the central nervous system in a clinically detectable manner. Their hypothesis is based on two lines of evidence: (1) the pattern of onset of the cases between 1943 and 1960 and (2) contact between these patients and British troops during World War II.
      Although these studies were performed well, some investigators have questioned their reliability.
      • Acheson ED
      The epidemiology of multiple sclerosis.
      Suspicion has been raised about the completeness of case ascertainment, particularly in the period before 1943, during which no cases of MS are known; however, this was a time when medical expertise may have been less readily available. In addition, some uncertainty exists about the reliability of the use of retrospective methods for assignment of date of diagnosis. Just as the war brought turmoil to the Faroes, so it may have introduced unresolvable recall bias among patients, causing them to date the onset of their first symptoms to 1943, the midpoint of the stationing of British troops on the island. Evaluation of the association with the British garrisons is difficult without similar information from control subjects with some other progressive disease characterized by remissions and exacerbations.
      The identity of the putative infectious agents remains unknown. Despite several observations that have raised hope,
      • Johnson RT
      Viral aspects of multiple sclerosis.
      no associated infectious agent has yet been convincingly demonstrated. As detailed elsewhere in this symposium, viruses are known to cause several demyelinating diseases, in humans and in animals, with pathologic characteristics similar to those of MS. Of the proposed infectious agents, the morbilliform viruses measles and canine distemper virus (CDV) have received the most attention during the past decade.
      In 1962, Adams and Imagawa
      • Adams JM
      • Imagawa DT
      Measles antibodies in multiple sclerosis.
      noted an increased concentration of measles antibodies in patients with MS compared with control subjects. Measles antibodies also have been found to be increased in siblings of patients with MS. Several authors have noted an increase in measles antibody in the cerebrospinal fluid of patients with MS, in part attributable to increased production of antibodies within the central nervous system. An increase in MS risk has been reported when measles infection occurs later than usual in childhood; thus, the question is raised whether MS might be an age-dependent host response to measles virus.
      • Johnson RT
      Viral aspects of multiple sclerosis.
      • Adams JM
      • Imagawa DT
      Measles antibodies in multiple sclerosis.
      • Sullivan CB
      • Visscher BR
      • Detels R
      Multiple sclerosis and age at exposure to childhood diseases and animals: cases and their friends.
      • Panelius M
      • Salmi A
      • Halonen PE
      • Kivalo E
      • Rinne UK
      • Penttinen K
      Virus antibodies in serum specimens from patients with multiple sclerosis, from siblings, and matched controls: a final report.
      • Alter M
      • Cendrowski W
      Multiple sclerosis and childhood infections.
      • Alter M
      • Zhen-xin Z
      • Davanipour Z
      • Sobel E
      • Min Lai S
      • LaRue L
      Does delay in acquiring childhood infection increase risk of multiple sclerosis? (editorial).
      Interpretation of these findings is difficult. Increased levels of antibody against viruses other than measles have been noted, although less consistently. The titer of measles virus antibody found is relatively low, and in some patients with MS, this antibody may even be absent. In a carefully performed seroepidemiologic study of MS in the Shetland and Orkney Islands—an area of very high MS incidence and prevalence—no association was noted between MS and measles or 17 other viruses.
      • Poskanzer DC
      • Sever JL
      • Sheridan JL
      • Prenney LB
      Multiple sclerosis in the Orkney and Shetland Islands. IV. Viral antibody titres and viral infections.
      In 1977, Chan
      • Chan WW-C
      Multiple sclerosis and dogs (letter to the editor).
      suggested that MS may be attributable to exposure to a virus passed in canine urine. Cook and Dowling
      • Cook SD
      • Dowling PC
      A possible association between house pets and multiple sclerosis.
      subsequently reported three cases in which MS apparently developed in sisters after a family dog suffered from an acute encephalopathy. In a subsequent case-control study, an increased relative risk was noted for contact with dogs before the onset of MS.
      • Cook SD
      • Natelson BH
      • Levin BE
      • Chavis PS
      • Dowling PC
      Further evidence of a possible association between house dogs and multiple sclerosis.
      Additional reports suggested a temporal relationship between epidemics of CDV and MS.
      • Cook SD
      • Dowling PC
      Distemper and multiple sclerosis in Sitka, Alaska.
      • Cook SD
      • Blumberg B
      • Dowling PC
      • Deans W
      • Cross R
      Multiple sclerosis and canine distemper on Key West, Florida (letter to the editor).
      The findings from these studies were interpreted to suggest that CDV is the putative agent in MS.
      Several factors suggest a relationship between CDV and MS.

      Kranz JMS: A Multiple Sclerosis Case-Control Study in Olmsted and Mower Counties, Minnesota. Thesis, University of Minnesota, Minneapolis, 1983

      Canine distemper encephalitis (CDE) and MS are characterized by demyelination and inflammatory infiltration.
      • Innes JRM
      • Saunders LZ
      • McCullough B
      • Krakowka S
      • Koestner A
      Experimental canine distemper virus-induced demyelination.
      Optic neuritis may be the sole clinical manifestation of either disease.
      • McGrath JT
      Patients with MS and dogs with CDE have increased cerebrospinal fluid γ-globulin levels and may have antimyelin antibodies.
      • Cutler RWP
      • Averill Jr, DR
      Cerebrospinal fluid gamma globulins in canine distemper encephalitis.
      CDV may remain latent for years before producing neurologic disease (old dog encephalitis).
      • Appel MJG
      • Gillespie JH
      Canine distemper virus.
      Despite these seemingly promising findings, a relationship among MS, increased exposure to dogs, and CDV has not been confirmed in case-control studies by other investigators.
      • Cook SD
      • Blumberg B
      • Dowling PC
      • Deans W
      • Cross R
      Multiple sclerosis and canine distemper on Key West, Florida (letter to the editor).
      • Bunnell DH
      • Visscher BR
      • Detels R
      Multiple sclerosis and house dogs: a case control study.
      • Poskanzer DC
      • Prenney LB
      • Sheridan JL
      House pets and multiple sclerosis (letter to the editor).
      • Sylwester DL
      • Poser CM
      The association of multiple sclerosis with domestic animals and household pets.
      • Hughes RAC
      • Russell WC
      • Froude JRL
      • Jarrett RJ
      Pet ownership, distemper antibodies and multiple sclerosis.
      • Read D
      • Nassim D
      • Smith P
      • Patterson C
      • Warlow C
      Multiple sclerosis and dog ownership: a case-control investigation.
      Other factors that also suggest that MS may not be related to CDV have been noted. For example, although neurotropic strains of CDV may exist that could infect humans, none has been found. In only a single unconfirmed case has viruslike material been noted in the brain of patients with MS, whereas intracytoplasmic and intranuclear inclusions are common in CDE. CDE and old dog encephalitis frequently affect the gray matter extensively and are associated with prominent neuronal degeneration, whereas MS is primarily demyelinative and is associated with only minor neuronal degeneration. CDV is ubiquitous throughout the world; the distribution of MS does not parallel this, and MS occurs in areas where dogs are uncommon. With widespread vaccination against CDV, CDE presumably has declined, whereas the incidence of MS has not.
      • Kurland LT
      The epidemiologic characteristics of multiple sclerosis.
      • Kurtzke JF
      Epidemiology of multiple sclerosis.
      • MacLean AR
      • Berkson J
      • Woltman HW
      • Schionneman L
      Multiple sclerosis in a rural community.
      • Percy AK
      • Nobrega FT
      • Okazaki H
      • Glattre E
      • Kurland LT
      Multiple sclerosis in Rochester, Minn: a 60-year appraisal.
      • Kranz JMS
      • Kurland LT
      • Schuman LM
      • Layton D
      Multiple sclerosis in Olmsted and Mower Counties, Minnesota.
      • Wynn DR
      • Kurland LT
      • O'Fallon WM
      • Rodriguez M
      Multiple sclerosis in Olmsted County: an 80-year review (abstract).
      • Poskanzer DC
      • Prenney LB
      • Sheridan JL
      • Kondy JY
      Multiple sclerosis in the Orkney and Shetland Islands. I. Epidemiology, clinical factors, methodology.
      • Poser CM
      • Paty DW
      • Scheinberg L
      • McDonald I
      • Davis FA
      • Ebers GC
      • Johnson KP
      • Sibley WA
      • Silberberg DH
      • Tourtellotte WW
      New diagnostic criteria for multiple sclerosis: guidelines for research protocols.
      In immunoprecipitation studies of serum specimens from patients with MS, antigens unique to CDV have not been identified.
      • Krakowka S
      • Miele JA
      • Mathes LE
      • Metzler AE
      Antibody responses to measles virus and canine distemper virus in multiple sclerosis.
      Many important methodologic problems arise
      • Kurland L
      • Brian D
      Multiple sclerosis and canine pets.
      in the analysis of Cook and Dowling's data.
      • Cook SD
      • Dowling PC
      A possible association between house pets and multiple sclerosis.
      • Cook SD
      • Natelson BH
      • Levin BE
      • Chavis PS
      • Dowling PC
      Further evidence of a possible association between house dogs and multiple sclerosis.
      • Cook SD
      • Dowling PC
      Distemper and multiple sclerosis in Sitka, Alaska.
      • Cook SD
      • Dowling PC
      MS in Iceland revisited (letter to the editor).
      • Cook SD
      • Cromarty JI
      • Tapp W
      • Poskanzer D
      • Walker JD
      • Dowling PC
      Declining incidence of multiple sclerosis in the Orkney Islands.
      • Cook SD
      • Blumberg B
      • Dowling PC
      • Deans W
      • Cross R
      Multiple sclerosis and canine distemper on Key West, Florida (letter to the editor).
      Much of their data is retrospective and subject to the problems of case-control studies. Of prime importance is the selection of a group of control subjects for those variables that may be confounding but are not causal. To help ensure comparability, multiple control groups are desirable. Why other investigators have been less successful in detecting a relationship between MS and exposure to pets is unclear.
      Attempts have been made to correlate MS with prior infections.
      • Sibley WA
      • Bamford CR
      • Clark K
      Clinical viral infections and multiple sclerosis.
      Gay and associates
      • Gay D
      • Dick G
      • Upton G
      Multiple sclerosis associated with sinusitis: case-controlled study in general practice.
      noted a fourfold increase in chronic sinusitis in patients with MS compared with age- and sex-matched control subjects; in this study, MS and chronic sinus infection were significantly associated with the timing of attacks of MS, with the age at which patients suffered their attacks, and with the seasonal pattern of attacks. These findings raise the question of whether MS may be a delayed response to an upper respiratory pathogen or an allergic antigenic challenge. Indeed, Sibley and colleagues
      • Sibley WA
      • Bamford CR
      • Clark K
      Clinical viral infections and multiple sclerosis.
      noted minor respiratory tract infections preceding 27% of MS exacerbations, although a suitable basis for comparison is not evident.
      • Gay D
      • Dick G
      • Upton G
      Multiple sclerosis associated with sinusitis: case-controlled study in general practice.
      A similar seasonal fluctuation of MS has not been observed consistently in other communities.
      • Bamford CR
      • Sibley WA
      • Thies C
      Seasonal variation of multiple sclerosis exacerbations in Arizona.
      • Hopkins CE
      • Swank RL
      Multiple sclerosis and the local weather.
      • Schapira K
      The seasonal incidence of onset and exacerbations in multiple sclerosis.
      • Prineas JW
      The etiology and pathogenesis of multiple sclerosis.
      • Sibley WA
      • Foley JM
      Infection and immunization in multiple sclerosis.
      • Sibley WA
      • Foley JM
      Seasonal variation in multiple sclerosis and retrobulbar neuritis in northeastern Ohio.
      • Wüthrich R
      • Rieder HP
      The seasonal incidence of multiple sclerosis in Switzerland.
      Kranz

      Kranz JMS: A Multiple Sclerosis Case-Control Study in Olmsted and Mower Counties, Minnesota. Thesis, University of Minnesota, Minneapolis, 1983

      noted no significant relationship between MS and infections or tonsillectomy. Several investigators have looked for but found no consistent patterns of childhood illnesses.
      • Acheson ED
      The epidemiology of multiple sclerosis.
      • Johnson RT
      Viral aspects of multiple sclerosis.
      • Adams JM
      • Imagawa DT
      Measles antibodies in multiple sclerosis.
      • Sullivan CB
      • Visscher BR
      • Detels R
      Multiple sclerosis and age at exposure to childhood diseases and animals: cases and their friends.
      • Panelius M
      • Salmi A
      • Halonen PE
      • Kivalo E
      • Rinne UK
      • Penttinen K
      Virus antibodies in serum specimens from patients with multiple sclerosis, from siblings, and matched controls: a final report.
      • Alter M
      • Cendrowski W
      Multiple sclerosis and childhood infections.
      • Alter M
      • Zhen-xin Z
      • Davanipour Z
      • Sobel E
      • Min Lai S
      • LaRue L
      Does delay in acquiring childhood infection increase risk of multiple sclerosis? (editorial).
      • Alter M
      • Zhen-xin Z
      • Davanipour Z
      • Sobel E
      • Zibulewski J
      • Schwartz G
      • Friday G
      Multiple sclerosis and childhood infections.
      Therefore, multiple modes of infection may act as nonspecific triggers for the immune system in initiating the onset or in eliciting an exacerbation of MS.

      Trauma.

      The role of trauma in precipitating, aggravating, or causing MS remains highly controversial. In 1877, Charcot
      • Charcot JM
      proposed a link between the onset of MS and exposure to cold, falling, illness, or stress. Subsequently, Mendel
      • Mendel E
      Tabes und multiple Sklerose in ihren Beziehungen zum Trauma.
      suggested that, in the absence of other etiologic factors, trauma could be considered as a cause of MS that develops within a year after severe trauma, particularly if the trauma involves the skull or the spine. In support of this hypothesis, cases occurring after major or minor injury have been reported—Von Hoesslin

      Von Hoesslin R: Über multiple Sklerose: exogen Aetiologie, Pathogenese, und Verlauf. Munich, JF Lehmans, 1934

      reported trauma in 59 of 516 cases of MS (11.4%), McAlpine
      • McAlpine D
      The problem of disseminated sclerosis.
      noted injury in 5.6% of 142 patients with MS, Adams and co-workers
      • Adams DK
      • Sutherland JM
      • Fletcher WB
      Early clinical manifestations of disseminated sclerosis.
      noted accidental or surgical trauma in 41 of 389 cases of MS (10.5%), and Bobowick and colleagues
      • Bobowick AR
      • Kurtzke JF
      • Brody JA
      • Hrubec Z
      • Gillespie M
      Twin study of multiple sclerosis: an epidemiologic inquiry.
      noted an increase in the recall of trauma by patients with MS in comparison with their discordant twin siblings.
      Bamford and associates
      • Bamford CR
      • Sibley WA
      • Thies C
      • Laguna JF
      • Smith MS
      • Clark K
      Trauma as an etiologic and aggravating factor in multiple sclerosis.
      recently pointed out that most of the data relating to the etiologic controversy were derived from retrospective and uncontrolled studies. Nevertheless, McAlpine
      • McAlpine D
      The problem of disseminated sclerosis.
      reported that trauma to a limb or any part of the body, including operation, could occasionally precipitate the disease in a predisposed person or could cause a relapse. In a retrospective and prospective study, Bamford and colleagues
      • Bamford CR
      • Sibley WA
      • Thies C
      • Laguna JF
      • Smith MS
      • Clark K
      Trauma as an etiologic and aggravating factor in multiple sclerosis.
      noted a suggestion of an increase in electrical injury preceding clinical exacerbations in patients with MS. Kurland and Westlund
      • Kurland LT
      • Westlund KB
      Epidemiologic factors in the etiology and prognosis of multiple sclerosis.
      noted no significant difference between patients with MS and control subjects in regard to a history of trauma to the spine or trauma to the head sufficient to cause unconsciousness.
      Pathologic studies have suggested a role for trauma in the pathogenesis of MS. Brain and Wilkinson
      • Brain R
      • Wilkinson M
      The association of cervical spondylosis and disseminated sclerosis.
      speculated that cervical spondylosis renders the spinal cord more susceptible to MS lesions. In patients with MS, Oppenheimer
      • Oppenheimer DR
      The cervical cord in multiple sclerosis.
      found twice as many plaques in the cervical cord as in other areas of the nervous system and thus suggested that mechanical stress may play a role in determining the site of MS lesions. Gonsette and co-workers
      • Gonsette R
      • Andre-Balisaux G
      • Delmotte P
      La perméabilité des vaisseaux cérébraux. VI. Démyélinisation expérimentale provoquée par des substances agissant sur la barrière hémato-encéphalique.
      and Riechert and associates
      • Riechert T
      • Hassler R
      • Mundinger F
      • Bronisch F
      • Schmidt K
      Pathologic-anatomical findings and cerebral localization in stereotactic treatment of extrapyramidal motor disturbances in multiple sclerosis.
      examined the brains of five patients with MS who died after thalamotomy and noted fresh demyelinating lesions adjacent to or surrounding the needle tracks in four of them. These studies, however, provided no information about injuries that were not followed by clinical MS or details about the severity of the trauma. Poser
      • Poser CM
      Trauma and multiple sclerosis: an hypothesis.
      recently postulated that alterations in the blood-brain barrier associated with trauma may result in exacerbation or recurrences of previously symptomatic plaques, in the appearance of symptoms from silent lesions, or in the formation of new plaques in areas of selected vulnerability. In addition, he suggested that, in patients whose MS develops after injury to the nervous system, MS plaques may form in areas of old trauma. Unfortunately, Poser's hypothesis is based on anecdotal reports only, and statistically valid data are lacking.
      Thus, the answer to this important clinical and medicolegal question remains uncertain. Most authorities agree that no available evidence supports the theory that trauma causes MS. Because of the unpredictable course of the disease, however, demonstrating a convincing relationship or lack of such a relationship between clinical worsening of MS and traumatic events has proved difficult. We are in the process of evaluating a large cohort of patients with head trauma in Olmsted County to determine whether the occurrence of MS was increased subsequently in comparison with what would be expected based on the local incidence rates of MS.

      Heavy Metals.

      A recent report by Stein and colleagues
      • Stein EC
      • Schiffer RB
      • Hall WJ
      • Young N
      Multiple sclerosis and the workplace: report of an industry-based cluster.
      of an increased incidence of MS among workers exposed to zinc in a manufacturing plant raises the question of a role of heavy metals and other toxins in MS. In that study, 11 cases of MS were diagnosed among workers within a 10-year period, an incidence 2 to 4 times greater than that predicted by using population-based incidence data from Rochester,
      • Percy AK
      • Nobrega FT
      • Okazaki H
      • Glattre E
      • Kurland LT
      Multiple sclerosis in Rochester, Minn: a 60-year appraisal.
      Denmark,
      • Kurtzke JF
      The risk of multiple sclerosis in Denmark.
      and a study by the National Institute of Neurological and Communicative Disorders.
      • Baum HM
      • Rothschild BB
      The incidence and prevalence of reported multiple sclerosis.
      Although expected case numbers and relative risks within the factory were estimated by using three comparison groups, no comparisons were made with other MS populations in the local community to assess the suitability of using such incidence data. Because of the lack of prior incidence estimates in this population and the apparent increase in incidence, such population data would be helpful. Our recent finding that the incidence of MS is higher than previously reported in Rochester emphasizes the need for up-to-date local rates.
      These findings may be important because abnormalities of zinc balance may affect immunoregulation.
      • Rühl H
      • Kirchner H
      Monocyte-dependent stimulation of human T cells by zinc.
      • Chandra RK
      Excessive intake of zinc impairs immune responses.
      • Prasad AS
      Clinical, biochemical and pharmacological role of zinc.
      A decrease in erythrocyte zinc levels during clinical exacerbations of MS was described recently,
      • Ho S-Y
      • Catalanotto FA
      • Lisak RP
      • Dore-Duffy P
      Zinc in multiple sclerosis. II. Correlation with disease activity and elevated plasma membrane-bound zinc in erythrocytes from patients with multiple sclerosis.
      but Stein and associates
      • Stein EC
      • Schiffer RB
      • Hall WJ
      • Young N
      Multiple sclerosis and the workplace: report of an industry-based cluster.
      failed to find specific abnormalities of zinc in blood samples from patients with MS. All plant workers were noted to have increased blood zinc levels. If, however, an increased blood zinc level leads to a substantial alteration in immune function, one might expect to find an unusually high prevalence of other immunologically based disorders among workers. Such an increase was not noted.
      Reports of clusters of patients with MS in small populations have stimulated new theories about etiologic factors. In 1947, four of seven workers investigating swayback, a demyelinating disease in sheep, were found to have MS within 3 months of one another and within 1 year of their common exposure to pathologic material from the sheep.
      • Campbell AMG
      • Daniel P
      • Porter RJ
      • Russell WR
      • Smith HV
      • Innes JRM
      Disease of the nervous system occurring among research workers on swayback in lambs.
      Swayback was subsequently presumed to be related to copper deficiency and excessive exposure to lead.
      • Butler EJ
      Chronic neurological disease as a possible form of lead poisoning.
      Follow-up studies found no increase in lead exposure among the workers and no convincing evidence of deficiency of copper or any other trace element; thus, the occurrence of the cluster was unexplained. Similar small clusters, all without final explanation, have occurred in Mansfield, Massachusetts,
      • Eastman R
      • Sheridan J
      • Poskanzer DC
      Multiple sclerosis clustering in a small Massachusetts community, with possible common exposure 23 years before onset.
      Mossyrock, Washington,
      • Koch MJ
      • Reed D
      • Stern R
      • Brody JA
      Multiple sclerosis: a cluster in a small northwestern United States community.
      Nova Scotia, Canada,
      • Murray TJ
      An unusual occurrence of multiple sclerosis in a small rural community.
      and elsewhere. A cluster of MS in the seacoast village of Duxbury, Massachusetts,
      • Deacon WE
      • Alexander L
      • Siedler HD
      • Kurland LT
      Multiple sclerosis in a small New England community.
      was found to be due to migration of persons whose cases had begun elsewhere. A recent cluster of cases of MS on Key West, Florida, was thought to be associated with both canine distemper and environmental pollution, but confirmation of these cases as MS is still awaited.
      • Cook SD
      • Blumberg B
      • Dowling PC
      • Deans W
      • Cross R
      Multiple sclerosis and canine distemper on Key West, Florida (letter to the editor).
      • Ingalls TH
      Endemic clustering of multiple sclerosis in time and place, 1934–1984: confirmation of a hypothesis.
      Clusters of MS and other diseases can be expected to occur by chance. Only independent evidence of prior or subsequent clustering in the same population can be interpreted as indicative of an association. With such clusters, the main concern is to ensure that the diagnosis is correct and that the earliest symptoms of the disease occurred during residence in the community, not before migration into the area. When these conditions are present in a cluster, opportunities are available for extensive study to identify possible risk factors.

      Diet.

      The relationship of diet to the cause of MS remains controversial. In 1950, Swank
      • Swank RL
      Multiple sclerosis: a correlation of its incidence with dietary fat.
      • Swank RL
      first suggested that MS was related to a high-fat diet. This hypothesis was based on (1) a correlation of diet and the geographic distribution of MS, on a global scale, and the observation that populations in Norway
      • Swank RL
      • Lerstad O
      • Strom A
      • Backer J
      Multiple sclerosis in rural Norway.
      and Switzerland who were consuming more animal fat had higher rates of MS, (2) a view that the disease has become more common during the past century, (3) a reported high attack rate among persons changing suddenly from a low-fat to a high-fat diet, (4) the supposed decrease in the disease in occupied countries during World War II, and (5) the alleged therapeutic effects of a low-fat diet.
      Agranoff and Goldberg
      • Agranoff BW
      • Goldberg D
      Diet and the geographical distribution of multiple sclerosis.
      noted a high correlation between consumption of milk and MS. Dean
      • Dean G
      Diet and geographic distribution of multiple sclerosis (letter to the editor).
      noted that, although this correlation may exist in Europeans and North Americans, Afrikaans-speaking white South Africans, whose diet is rich in animal fat, have a low incidence of MS. Dean thought that these findings implicated an infectious, possibly viral, cause, but the high rate among northern Europeans who migrate to South Africa after the age of 15 years could imply the importance of early dietary exposure. In the Winnipeg case-control study, no obvious association was found between MS and diet.
      • Westlund KB
      • Kurland LT
      Studies on multiple sclerosis in Winnipeg, Manitoba, and New Orleans, Louisiana. I. Prevalence: comparison between the patient groups in Winnipeg and New Orleans.
      Although some investigators have reported a beneficial effect of a low-fat diet, others have obtained equally salubrious results with high-fat diets.
      • Brickner RM
      • Brill NQ
      Dietetic and related studies on multiple sclerosis.
      • Crane JE
      Treatment of multiple sclerosis with fat-soluble vitamins: animal fat and ammonium chloride.
      Dietary fat is of particular interest in MS because the myelin sheath of nerves is composed predominantly of lipids. The results of this research have been incomplete and contradictory; thus, no consensus exists about the pathogenesis of MS or its treatment.

      Disease Associations.

      In the continuing search for clues about the cause of MS, attempts have been made to determine whether it is linked with other diseases. Of particular interest has been a question about associations between MS and autoimmune diseases and neoplasia.
      • Wynn DR
      • Codd MB
      • Kurland LT
      • Rodriguez M
      Multiple sclerosis: a population-based investigation of the association with possible autoimmune diseases and diabetes mellitus (abstract).
      • Wynn DR
      • Codd MB
      • Kurland LT
      • Rodriguez M
      Multiple sclerosis: a population-based investigation of the association with neoplastic disorders (abstract).
      Anecdotal reports and small series of cases have suggested an association between MS and myasthenia gravis, systemic lupus erythematosus, ankylosing spondylitis, ulcerative colitis, scleroderma, diabetes mellitus, or cancer.
      • Baker HWG
      • Balla JI
      • Burger HG
      • Ebeling P
      • Mackay IR
      Multiple sclerosis and autoimmune diseases.
      • Lo R
      • Feasby TE
      Multiple sclerosis and autoimmune diseases.
      • Margolis LN
      • Graves RW
      The occurrence of myasthenia gravis in a patient with multiple sclerosis.
      • Aita JF
      • Snyder DH
      • Reichl W
      Myasthenia gravis and multiple sclerosis: an unusual combination of diseases.
      • Achari AN
      • Trontelj JV
      • Campos RJ
      Multiple sclerosis and myasthenia gravis: a case report with single fiber electromyography.
      • Shakir RA
      • Hussien JM
      • Trontelj JV
      Myasthenia gravis and multiple sclerosis.
      • Dore-Duffy P
      • Donaldson JO
      • Rothman BL
      • Zurier RB
      Antinuclear antibodies in multiple sclerosis.
      • Matthews WB
      The neurological complications of ankylosing spondylitis.
      • Khan MA
      • Kushner I
      Ankylosing spondylitis and multiple sclerosis: a possible association.
      • Thomas DJ
      • Kendall MJ
      • Whitfield AGW
      Nervous system involvement in ankylosing spondylitis.
      • Devos P
      • Destée A
      • Prin L
      • Warot P
      Sclérose en plaques et maladie lupique.
      • April RS
      • Vansonnenberg E
      A case of neuromyelitis optica (Devic's syndrome) in systemic lupus erythematosus.
      • Holmes FF
      • Stubbs DW
      • Larsen WE
      Systemic lupus erythematosus and multiple sclerosis in identical twins.
      • Trostle DC
      • Helfrich D
      • Medsger Jr, TA
      Systemic sclerosis (scleroderma) and multiple sclerosis.
      • Palo J
      • Duchesne J
      • Wikström J
      Malignant diseases among patients with multiple sclerosis.
      • Reagan TJ
      • Freiman IS
      Multiple cerebral gliomas in multiple sclerosis.
      • Spaar FW
      • Wikström J
      Multiple sclerosis and malignant neoplasms of the central nervous system.
      • Warren S
      • Warren KG
      Multiple sclerosis and associated diseases: a relationship to diabetes mellitus.
      The interpretation of these reports is difficult, because of the nature of the studies and, particularly, the non-population-based selection of cases.
      In an attempt to evaluate this issue, we examined the incidence of diabetes mellitus, 17 autoimmune diseases,
      • Wynn DR
      • Codd MB
      • Kurland LT
      • Rodriguez M
      Multiple sclerosis: a population-based investigation of the association with possible autoimmune diseases and diabetes mellitus (abstract).
      and neoplasia
      • Wynn DR
      • Codd MB
      • Kurland LT
      • Rodriguez M
      Multiple sclerosis: a population-based investigation of the association with neoplastic disorders (abstract).
      in our population-based cohort of patients with MS in Olmsted County. Using, for comparison, the incidence values for these diseases based on prior surveys of them in this population,
      • Linos A
      • Worthington JW
      • O'Fallon WM
      • Kurland LT
      The epidemiology of rheumatoid arthritis in Rochester, Minnesota: a study of incidence, prevalence, and mortality.
      • Furszyfer J
      • Kurland LT
      • McConahey WM
      • Wollner LB
      • Elveback LR
      Epidemiologic aspects of Hashimoto's thyroiditis and Graves' disease in Rochester, Minnesota (1935–1967), with special reference to temporal trends.
      • Palumbo PJ
      • Elveback LR
      • Chu C-P
      • Connolly DC
      • Kurland LT
      Diabetes mellitus: incidence, prevalence, survivorship, and causes of death in Rochester, Minnesota, 1945–1970.
      we noted the following relative risks: diabetes mellitus, 2.5; rheumatoid arthritis, 1.8; autoimmune thyroid disease (Hashimoto's thyroiditis and Graves' disease), 3.3; and neoplasia, 1.4. Although a suggestion of an increased incidence of diabetes mellitus was noted, supporting the observations by Warren and Warren,
      • Warren S
      • Warren KG
      Multiple sclerosis and associated diseases: a relationship to diabetes mellitus.
      a statistically significant increased risk was noted for only autoimmune thyroid disease. Interpretation of these inconclusive findings awaits the results of studies at other medical centers. We are in the process of constructing pedigrees for incident cases of MS within Olmsted County to determine whether some variation exists in the frequency of diabetes mellitus, autoimmune diseases, or neoplastic disorders among first-degree relatives of patients with MS.

      CONCLUSION

      Current prevalence and incidence trends continue to support Limburg's hypothesis
      • Limburg CC
      The geographic distribution of multiple sclerosis and its estimated prevalence in the United States.
      that the occurrence of MS is increased in a south-to-north gradient in the northern hemisphere, the highest rates occurring in the northern temperate zones. The current trends in incidence and prevalence of MS may be dynamic, as suggested by the recent increase in Olmsted County and by the apparent decrease in the Shetland and Orkney Islands. These results and those from migration studies suggest that environmental influences are important etiologic factors in MS. Recent studies have examined the role of viruses, exposure to animals, diet, toxins, and trauma in the pathogenesis of MS. Diseases, including those of a probable autoimmune nature, have been tentatively linked to MS. Considerable controversy remains, and several lines of research are being conducted. Just as neuroepidemiology can be expected to provide important clues to the cause and pathogenesis of MS, we must likewise be certain that etiologic hypotheses are compatible with verified population patterns.

      REFERENCES

        • Fox JP
        • Hall CE
        • Elveback LR
        Epidemiology: Man and Disease. The Macmillan Company, Toronto1970: 185
        • Charcot JM
        Sigerson Lectures on the Diseases of the Nervous System. Vol 1. The New Sydenham Society, London1877: 157-222
        • Davenport CB
        Multiple sclerosis from the standpoint of geographic distribution and race.
        Res Publ Assoc Res Nerv Ment Dis Proc. 1922; 2: 8-19
        • Bing R
        • Reese H
        Die multiple Sklerose in der Nordwest-schweiz.
        Schweiz Med Wochenschr. 1926; 56: 30-34
        • Ackermann A
        Die multiple Sklerose in der Schweiz: Enquete von 1918–22.
        Schweiz Med Wochenschr. 1931; 61: 1245-1250
        • Allison RS
        Disseminated sclerosis in North Wales: an inquiry into its incidence, frequency, distribution and other etiological factors.
        Brain. 1931; 53: 391-430
        • Steiner G
        Multiple sclerosis. I. The etiological significance of the regional and occupational incidence.
        J Nerv Ment Dis. 1938; 88: 42-66
        • Limburg CC
        The geographic distribution of multiple sclerosis and its estimated prevalence in the United States.
        Res Publ Assoc Res Nerv Ment Dis Proc. 1950; 28: 15-24
        • Kurland LT
        The epidemiologic characteristics of multiple sclerosis.
        in: Vinken PJ Bruyn GW Handbook of Clinical Neurology. Vol 9: Multiple Sclerosis and Other Demyelinating Diseases. American Elsevier Publishing Company, New York1970: 63-84
        • Kurtzke JF
        Epidemiology of multiple sclerosis.
        in: Vinken PJ Bruyn GW Klawans HL Koetsier JC Handbook of Clinical Neurology. Vol 47: Demyelinating Diseases. Elsevier Science Publishing Company, New York1985: 259-287
        • MacLean AR
        • Berkson J
        • Woltman HW
        • Schionneman L
        Multiple sclerosis in a rural community.
        Res Publ Assoc Res Nerv Ment Dis Proc. 1950; 28: 25-27
        • Percy AK
        • Nobrega FT
        • Okazaki H
        • Glattre E
        • Kurland LT
        Multiple sclerosis in Rochester, Minn: a 60-year appraisal.
        Arch Neurol. 1971; 25: 105-111
        • Kranz JMS
        • Kurland LT
        • Schuman LM
        • Layton D
        Multiple sclerosis in Olmsted and Mower Counties, Minnesota.
        Neuroepidemiology. 1983; 2: 206-218
        • Wynn DR
        • Kurland LT
        • O'Fallon WM
        • Rodriguez M
        Multiple sclerosis in Olmsted County: an 80-year review (abstract).
        Neurology. 1988; 38: 138
        • Poskanzer DC
        • Prenney LB
        • Sheridan JL
        • Kondy JY
        Multiple sclerosis in the Orkney and Shetland Islands. I. Epidemiology, clinical factors, methodology.
        J Epidemiol Community Health. 1980; 34: 229-239
        • Poser CM
        • Paty DW
        • Scheinberg L
        • McDonald I
        • Davis FA
        • Ebers GC
        • Johnson KP
        • Sibley WA
        • Silberberg DH
        • Tourtellotte WW
        New diagnostic criteria for multiple sclerosis: guidelines for research protocols.
        Ann Neurol. 1983; 13: 227-231
        • Rosati G
        Descriptive epidemiology of multiple sclerosis in Italy.
        Riv Neurol. 1987; 57: 5-12
        • Rozanski J
        Contribution to the incidence of multiple sclerosis among Jews in Israel.
        Monatsschr Psychiatr Neurol. 1952; 123: 65-72
        • Alter M
        • Halpern L
        • Kurland LT
        • Bornstein B
        • Leibowitz U
        • Silberstein J
        Multiple sclerosis in Israel: prevalence among immigrants and native inhabitants.
        Arch Neurol. 1962; 7: 253-263
      1. Alter M Kurtzke JF The Epidemiology of Multiple Sclerosis. Charles C Thomas, Publisher, Springfield, Illinois1968
        • Dean G
        Annual incidence, prevalence, and mortality of multiple sclerosis in white South-African-born and in white immigrants to South Africa.
        Br Med J. 1967; 2: 724-730
        • Detels R
        • Visscher BR
        • Malmgren RM
        • Coulson AH
        • Lucia MV
        • Dudley JP
        Evidence for lower susceptibility to multiple sclerosis among Japanese-Americans.
        Am J Epidemiol. 1977; 105: 303-310
        • Visscher BR
        • Detels R
        • Coulson AH
        • Malmgren RM
        • Dudley JP
        Latitude, migration, and the prevalence of multiple sclerosis.
        Am J Epidemiol. 1977; 106: 470-475
        • Kurtzke JF
        • Bui QH
        Multiple sclerosis in a migrant population. 2. Half-orientals immigrating in childhood.
        Ann Neurol. 1980; 8: 256-260
        • Alter M
        • Kahana E
        • Lowenston R
        Migration and risk of multiple sclerosis.
        Neurology. 1978; 28: 1089-1093
        • Detels R
        • Visscher BR
        • Haile RW
        • Malmgren RM
        • Dudley JP
        • Coulson AH
        Multiple sclerosis and age at migration.
        Am J Epidemiol. 1978; 108: 386-393
        • Dean G
        • Brady R
        • McLoughlin H
        Motor neurone disease and multiple sclerosis among immigrants to Britain.
        Br J Prev Soc Med. 1977; 31: 141-147
        • Pálffy G
        MS in Hungary, including the Gipsy population.
        in: Kuroiwa Y Kurland LT Multiple Sclerosis East and West. Kyushu University Press, Fukuoka City, Japan1982: 149-157
        • Kurtzke JF
        • Hyllested K
        Multiple sclerosis in the Faroe Islands. I. Clinical and epidemiological features.
        Ann Neurol. 1979; 5: 6-21
        • Kurtzke JF
        • Hyllested K
        Multiple sclerosis in the Faroe Islands. II. Clinical update, transmission, and the nature of MS.
        Neurology. 1986; 36: 307-328
        • Kurtzke JF
        • Hyllested K
        MS epidemiology in Faroe Islands.
        Riv Neurol. 1987; 57: 77-87
        • Acheson ED
        The epidemiology of multiple sclerosis.
        in: McAlpine D Lumsden CE Acheson ED Multiple Sclerosis: A Reappraisal. Second edition. Williams & Wilkins, Baltimore1972: 3-80
        • Johnson RT
        Viral aspects of multiple sclerosis.
        in: Vinken PJ Bruyn GW Klawans HL Koetsier JC Handbook of Clinical Neurology. Vol 47: Demyelinating Diseases. Elsevier Science Publishing Company, New York1985: 319-336
        • Adams JM
        • Imagawa DT
        Measles antibodies in multiple sclerosis.
        Proc Soc Exp Biol Med. 1962; 111: 562-566
        • Sullivan CB
        • Visscher BR
        • Detels R
        Multiple sclerosis and age at exposure to childhood diseases and animals: cases and their friends.
        Neurology. 1984; 34: 1144-1148
        • Panelius M
        • Salmi A
        • Halonen PE
        • Kivalo E
        • Rinne UK
        • Penttinen K
        Virus antibodies in serum specimens from patients with multiple sclerosis, from siblings, and matched controls: a final report.
        Acta Neurol Scand. 1973; 49: 85-107
        • Alter M
        • Cendrowski W
        Multiple sclerosis and childhood infections.
        Neurology. 1976; 26: 201-204
        • Alter M
        • Zhen-xin Z
        • Davanipour Z
        • Sobel E
        • Min Lai S
        • LaRue L
        Does delay in acquiring childhood infection increase risk of multiple sclerosis? (editorial).
        Ital J Neurol Sci. 1987; 8: 23-28
        • Poskanzer DC
        • Sever JL
        • Sheridan JL
        • Prenney LB
        Multiple sclerosis in the Orkney and Shetland Islands. IV. Viral antibody titres and viral infections.
        J Epidemiol Community Health. 1980; 34: 258-264
        • Chan WW-C
        Multiple sclerosis and dogs (letter to the editor).
        Lancet. 1977; 1: 487-488
        • Cook SD
        • Dowling PC
        A possible association between house pets and multiple sclerosis.
        Lancet. 1977; 1: 980-982
        • Cook SD
        • Natelson BH
        • Levin BE
        • Chavis PS
        • Dowling PC
        Further evidence of a possible association between house dogs and multiple sclerosis.
        Ann Neurol. 1978; 3: 141-143
        • Cook SD
        • Dowling PC
        Distemper and multiple sclerosis in Sitka, Alaska.
        Ann Neurol. 1982; 11: 192-194
        • Cook SD
        • Dowling PC
        MS in Iceland revisited (letter to the editor).
        Neurology. 1982; 32: 1204-1205
        • Cook SD
        • Cromarty JI
        • Tapp W
        • Poskanzer D
        • Walker JD
        • Dowling PC
        Declining incidence of multiple sclerosis in the Orkney Islands.
        Neurology. 1985; 35: 545-551
        • Cook SD
        • Blumberg B
        • Dowling PC
        • Deans W
        • Cross R
        Multiple sclerosis and canine distemper on Key West, Florida (letter to the editor).
        Lancet. 1987; 1: 1426-1427
      2. Kranz JMS: A Multiple Sclerosis Case-Control Study in Olmsted and Mower Counties, Minnesota. Thesis, University of Minnesota, Minneapolis, 1983

        • Innes JRM
        • Saunders LZ
        Comparative Neuropathology. Academic Press, New York1962: 373-384
        • McCullough B
        • Krakowka S
        • Koestner A
        Experimental canine distemper virus-induced demyelination.
        Lab Invest. 1974; 31: 216-222
        • McGrath JT
        Neurologic Examination of the Dog: With Clinicopathologic Observations. Second edition. Lea & Febiger, Philadelphia1960: 127-136
        • Cutler RWP
        • Averill Jr, DR
        Cerebrospinal fluid gamma globulins in canine distemper encephalitis.
        Neurology. 1969; 19: 1111-1114
        • Appel MJG
        • Gillespie JH
        Canine distemper virus.
        Virol Monogr. 1972; 11: 3-96
        • Bunnell DH
        • Visscher BR
        • Detels R
        Multiple sclerosis and house dogs: a case control study.
        Neurology. 1979; 29: 1027-1029
        • Poskanzer DC
        • Prenney LB
        • Sheridan JL
        House pets and multiple sclerosis (letter to the editor).
        Lancet. 1977; 1: 1204
        • Sylwester DL
        • Poser CM
        The association of multiple sclerosis with domestic animals and household pets.
        Ann Neurol. 1979; 5: 207-208
        • Hughes RAC
        • Russell WC
        • Froude JRL
        • Jarrett RJ
        Pet ownership, distemper antibodies and multiple sclerosis.
        J Neurol Sci. 1980; 47: 429-432
        • Read D
        • Nassim D
        • Smith P
        • Patterson C
        • Warlow C
        Multiple sclerosis and dog ownership: a case-control investigation.
        J Neurol Sci. 1982; 55: 359-367
        • Krakowka S
        • Miele JA
        • Mathes LE
        • Metzler AE
        Antibody responses to measles virus and canine distemper virus in multiple sclerosis.
        Ann Neurol. 1983; 14: 533-538
        • Kurland L
        • Brian D
        Multiple sclerosis and canine pets.
        Ann Neurol. 1978; 3: 97-100
        • Sibley WA
        • Bamford CR
        • Clark K
        Clinical viral infections and multiple sclerosis.
        Lancet. 1985; 1: 1313-1315
        • Gay D
        • Dick G
        • Upton G
        Multiple sclerosis associated with sinusitis: case-controlled study in general practice.
        Lancet. 1986; 1: 815-819
        • Bamford CR
        • Sibley WA
        • Thies C
        Seasonal variation of multiple sclerosis exacerbations in Arizona.
        Neurology. 1983; 33: 697-701
        • Hopkins CE
        • Swank RL
        Multiple sclerosis and the local weather.
        Arch Neurol Psychiatry. 1955; 74: 203-207
        • Schapira K
        The seasonal incidence of onset and exacerbations in multiple sclerosis.
        J Neurol Neurosurg Psychiatry. 1959; 22: 285-286
        • Prineas JW
        The etiology and pathogenesis of multiple sclerosis.
        in: Vinken PJ Bruyn GW Handbook of Clinical Neurology. Vol 9: Multiple Sclerosis and Other Demyelinating Diseases. American Elsevier Publishing Company, New York1970: 118-120
        • Sibley WA
        • Foley JM
        Infection and immunization in multiple sclerosis.
        Ann NY Acad Sci. 1965; 122: 457-468
        • Sibley WA
        • Foley JM
        Seasonal variation in multiple sclerosis and retrobulbar neuritis in northeastern Ohio.
        Trans Am Neurol Assoc. 1965; 90: 295-297
        • Wüthrich R
        • Rieder HP
        The seasonal incidence of multiple sclerosis in Switzerland.
        Eur Neurol. 1970; 3: 257-264
        • Alter M
        • Zhen-xin Z
        • Davanipour Z
        • Sobel E
        • Zibulewski J
        • Schwartz G
        • Friday G
        Multiple sclerosis and childhood infections.
        Neurology. 1986; 36: 1386-1389
        • Mendel E
        Tabes und multiple Sklerose in ihren Beziehungen zum Trauma.
        Neurol Zentralbl. 1897; 16: 140-143
      3. Von Hoesslin R: Über multiple Sklerose: exogen Aetiologie, Pathogenese, und Verlauf. Munich, JF Lehmans, 1934

        • McAlpine D
        The problem of disseminated sclerosis.
        Brain. 1946; 69: 233-250
        • Adams DK
        • Sutherland JM
        • Fletcher WB
        Early clinical manifestations of disseminated sclerosis.
        Br Med J. 1950; 2: 431-436
        • Bobowick AR
        • Kurtzke JF
        • Brody JA
        • Hrubec Z
        • Gillespie M
        Twin study of multiple sclerosis: an epidemiologic inquiry.
        Neurology. 1978; 28: 978-987
        • Bamford CR
        • Sibley WA
        • Thies C
        • Laguna JF
        • Smith MS
        • Clark K
        Trauma as an etiologic and aggravating factor in multiple sclerosis.
        Neurology. 1981; 31: 1229-1234
        • Kurland LT
        • Westlund KB
        Epidemiologic factors in the etiology and prognosis of multiple sclerosis.
        Ann NY Acad Sci. 1954; 58: 682-701
        • Brain R
        • Wilkinson M
        The association of cervical spondylosis and disseminated sclerosis.
        Brain. 1957; 80: 456-478
        • Oppenheimer DR
        The cervical cord in multiple sclerosis.
        Neuropathol Appl Neurobiol. 1978; 4: 151-162
        • Gonsette R
        • Andre-Balisaux G
        • Delmotte P
        La perméabilité des vaisseaux cérébraux. VI. Démyélinisation expérimentale provoquée par des substances agissant sur la barrière hémato-encéphalique.
        Acta Neurol Belg. 1966; 66: 247-262
        • Riechert T
        • Hassler R
        • Mundinger F
        • Bronisch F
        • Schmidt K
        Pathologic-anatomical findings and cerebral localization in stereotactic treatment of extrapyramidal motor disturbances in multiple sclerosis.
        Confin Neurol. 1975; 37: 24-40
        • Poser CM
        Trauma and multiple sclerosis: an hypothesis.
        J Neurol. 1987; 234: 155-159
        • Stein EC
        • Schiffer RB
        • Hall WJ
        • Young N
        Multiple sclerosis and the workplace: report of an industry-based cluster.
        Neurology. 1987; 37: 1672-1677
        • Kurtzke JF
        The risk of multiple sclerosis in Denmark.
        Acta Neurol Scand. 1978; 57: 141-150
        • Baum HM
        • Rothschild BB
        The incidence and prevalence of reported multiple sclerosis.
        Ann Neurol. 1981; 10: 420-428
        • Rühl H
        • Kirchner H
        Monocyte-dependent stimulation of human T cells by zinc.
        Clin Exp Immunol. 1978; 32: 484-488
        • Chandra RK
        Excessive intake of zinc impairs immune responses.
        JAMA. 1984; 252: 1443-1446
        • Prasad AS
        Clinical, biochemical and pharmacological role of zinc.
        Ann Rev Pharmacol Toxicol. 1979; 20: 393-426
        • Ho S-Y
        • Catalanotto FA
        • Lisak RP
        • Dore-Duffy P
        Zinc in multiple sclerosis. II. Correlation with disease activity and elevated plasma membrane-bound zinc in erythrocytes from patients with multiple sclerosis.
        Ann Neurol. 1986; 20: 712-715
        • Campbell AMG
        • Daniel P
        • Porter RJ
        • Russell WR
        • Smith HV
        • Innes JRM
        Disease of the nervous system occurring among research workers on swayback in lambs.
        Brain. 1947; 70: 50-58
        • Butler EJ
        Chronic neurological disease as a possible form of lead poisoning.
        J Neurol Neurosurg Psychiatry. 1952; 15: 119-128
        • Eastman R
        • Sheridan J
        • Poskanzer DC
        Multiple sclerosis clustering in a small Massachusetts community, with possible common exposure 23 years before onset.
        N Engl J Med. 1973; 289: 793-794
        • Koch MJ
        • Reed D
        • Stern R
        • Brody JA
        Multiple sclerosis: a cluster in a small northwestern United States community.
        JAMA. 1974; 228: 1555-1557
        • Murray TJ
        An unusual occurrence of multiple sclerosis in a small rural community.
        Can J Neurol Sci. 1976; 3: 163-166
        • Deacon WE
        • Alexander L
        • Siedler HD
        • Kurland LT
        Multiple sclerosis in a small New England community.
        N Engl J Med. 1959; 261: 1059-1061
        • Ingalls TH
        Endemic clustering of multiple sclerosis in time and place, 1934–1984: confirmation of a hypothesis.
        Am J Forensic Med Pathol. 1986; 7: 3-8
        • Swank RL
        Multiple sclerosis: a correlation of its incidence with dietary fat.
        Am J Med Sci. 1950; 220: 421-430
        • Swank RL
        A Biochemical Basis of Multiple Sclerosis. Charles C Thomas, Publisher, Springfield, Illinois1961
        • Swank RL
        • Lerstad O
        • Strom A
        • Backer J
        Multiple sclerosis in rural Norway.
        N Engl J Med. 1952; 246: 721-728
        • Agranoff BW
        • Goldberg D
        Diet and the geographical distribution of multiple sclerosis.
        Lancet. 1974; 2: 1061-1066
        • Dean G
        Diet and geographic distribution of multiple sclerosis (letter to the editor).
        Lancet. 1974; 2: 1445
        • Westlund KB
        • Kurland LT
        Studies on multiple sclerosis in Winnipeg, Manitoba, and New Orleans, Louisiana. I. Prevalence: comparison between the patient groups in Winnipeg and New Orleans.
        Am J Hyg. 1953; 57: 380-396
        • Brickner RM
        • Brill NQ
        Dietetic and related studies on multiple sclerosis.
        Arch Neurol Psychiatry. 1941; 46: 16-32
        • Crane JE
        Treatment of multiple sclerosis with fat-soluble vitamins: animal fat and ammonium chloride.
        Conn Med J. 1950; 14: 40-41
        • Wynn DR
        • Codd MB
        • Kurland LT
        • Rodriguez M
        Multiple sclerosis: a population-based investigation of the association with possible autoimmune diseases and diabetes mellitus (abstract).
        Neurology. 1987; 37: 272
        • Wynn DR
        • Codd MB
        • Kurland LT
        • Rodriguez M
        Multiple sclerosis: a population-based investigation of the association with neoplastic disorders (abstract).
        Neurology. 1987; 37: 151
        • Baker HWG
        • Balla JI
        • Burger HG
        • Ebeling P
        • Mackay IR
        Multiple sclerosis and autoimmune diseases.
        Aust N Z J. 1972; 2: 256-260
        • Lo R
        • Feasby TE
        Multiple sclerosis and autoimmune diseases.
        Neurology. 1983; 33: 97-98
        • Margolis LN
        • Graves RW
        The occurrence of myasthenia gravis in a patient with multiple sclerosis.
        N C Med J. 1945; 6: 243-244
        • Aita JF
        • Snyder DH
        • Reichl W
        Myasthenia gravis and multiple sclerosis: an unusual combination of diseases.
        Neurology. 1974; 24: 72-75
        • Achari AN
        • Trontelj JV
        • Campos RJ
        Multiple sclerosis and myasthenia gravis: a case report with single fiber electromyography.
        Neurology. 1976; 26: 544-546
        • Shakir RA
        • Hussien JM
        • Trontelj JV
        Myasthenia gravis and multiple sclerosis.
        J Neuroimmunol. 1983; 4: 161-165
        • Dore-Duffy P
        • Donaldson JO
        • Rothman BL
        • Zurier RB
        Antinuclear antibodies in multiple sclerosis.
        Arch Neurol. 1982; 39: 504-506
        • Matthews WB
        The neurological complications of ankylosing spondylitis.
        J Neurol Sci. 1968; 6: 561-573
        • Khan MA
        • Kushner I
        Ankylosing spondylitis and multiple sclerosis: a possible association.
        Arthritis Rheum. 1979; 22: 784-786
        • Thomas DJ
        • Kendall MJ
        • Whitfield AGW
        Nervous system involvement in ankylosing spondylitis.
        Br Med J. 1974; 1: 148-150
        • Devos P
        • Destée A
        • Prin L
        • Warot P
        Sclérose en plaques et maladie lupique.
        Rev Neurol. 1984; 140: 513-515
        • April RS
        • Vansonnenberg E
        A case of neuromyelitis optica (Devic's syndrome) in systemic lupus erythematosus.
        Neurology. 1976; 26: 1066-1070
        • Holmes FF
        • Stubbs DW
        • Larsen WE
        Systemic lupus erythematosus and multiple sclerosis in identical twins.
        Arch Intern Med. 1967; 119: 302-304
        • Trostle DC
        • Helfrich D
        • Medsger Jr, TA
        Systemic sclerosis (scleroderma) and multiple sclerosis.
        Arthritis Rheum. 1986; 29: 124-127
        • Palo J
        • Duchesne J
        • Wikström J
        Malignant diseases among patients with multiple sclerosis.
        J Neurol. 1977; 216: 217-222
        • Reagan TJ
        • Freiman IS
        Multiple cerebral gliomas in multiple sclerosis.
        J Neurol Neurosurg Psychiatry. 1973; 36: 523-528
        • Spaar FW
        • Wikström J
        Multiple sclerosis and malignant neoplasms of the central nervous system.
        J Neurol. 1978; 218: 23-33
        • Warren S
        • Warren KG
        Multiple sclerosis and associated diseases: a relationship to diabetes mellitus.
        Can J Neurol Sci. 1981; 8: 35-39
        • Linos A
        • Worthington JW
        • O'Fallon WM
        • Kurland LT
        The epidemiology of rheumatoid arthritis in Rochester, Minnesota: a study of incidence, prevalence, and mortality.
        Am J Epidemiol. 1980; 111: 87-98
        • Furszyfer J
        • Kurland LT
        • McConahey WM
        • Wollner LB
        • Elveback LR
        Epidemiologic aspects of Hashimoto's thyroiditis and Graves' disease in Rochester, Minnesota (1935–1967), with special reference to temporal trends.
        Metabolism. 1972; 3: 197-204
        • Palumbo PJ
        • Elveback LR
        • Chu C-P
        • Connolly DC
        • Kurland LT
        Diabetes mellitus: incidence, prevalence, survivorship, and causes of death in Rochester, Minnesota, 1945–1970.
        Diabetes. 1976; 25: 566-573