FURTHER STUDIES ON THE EPIDEMIOLOGY OF MULTIPLE SCLEROSIS IN FINLAND

The places of birth of 1,000 Finnish patients with multiple sclerosis (MS) were located according to the population statistics of 1930. The highest frequency of the disease was found in a small district, Jalasjärvi, composed of 6 rural communes in the western high-risk area of the country. One animal disease, nutritional muscular dystrophy of the cattle (NMD), appeared to be very common in the same western area and, in 1970, its highest frequency was also found in the Jalasjärvi district. Some western accumulation was found in the cases of two viruses of cereals, European wheat striate mosaie virus (EWSMV) and oat sterile dwarf virus (OSDV), but both of them were rare in the southwestern part of Finland where the prevalence of MS was high.     

THE EPIDEMIOLOGY OF OPTIC NEURITIS IN FINLAND

Evidence has been presented that optic neuritis partially reflects benign cases of MS which are lost in the epidemiological investigation of the disease. As part of a large epidemiological investigation of MS, 221 patients with pure optic neuritis were identified during the period from January 1, 1967 to December 31, 1971. The mean annual incidence for the whole of Finland was 0.94 per 100,000 population. The female to male ratio was 1.7. The mean age at onset was 31.2 years. The distribution of optic neuritis by counties showed the highest mean annual incidence in the southwestern county of Turku and Pori (1.69) and in the western county of Vaasa (1.68). The prevalence data for MS were highest in these counties. A highly significant deviation from a random distribution according to place at onset and place of birth was obtained. Even the geographical distribution by smaller units, i.e. the combined clerical districts, revealed a firm accumulation to the western districts in the county of Vaasa and to the southwestern districts in the county of Turku and Pori. Thus, optic neuritis showed a similar geographical distribution to MS. The appearance of optic neuritis in the high-risk district of Jalasjarvi with several familial cases of MS did not increase the familial percentage when both conditions were considered as a single group. The risk of getting optic neuritis seems to depend on the influence of factors present during childhood. The epidemiological data point to a common factor in the aetiology of optic neuritis and MS.     

STUDIES ON THE CLUSTERING OF MULTIPLE SCLEROSIS IN FINLAND I: COMPARISON BETWEEN THE DOMICILES AND PLACES OF BIRTH IN SELECTED SUBPOPULATIONS

Further studies on the epidemiology of multiple sclerosis (MS) in Finland were carried out in three different types of geographical unit: in counties, combined clerical districts, and single clerical districts. For longitudinal studies, the prevalence of MS by present domicile was compared to that by place of birth, and also to the number of MS cases in relation to the number of births. The analysis was based on 1,866 living MS patients. The highest prevalence by present domicile was recorded in the southwestern county of Turku and Pori (52.3 cases per 100,000 inhabitants). It was 39.6 for the whole country. Two separate clusters were found at the level of combined and single clerical districts: one in the western county of Vaasa, and another in the south-western county of Turku and Pori. The highest prevalences by present domicile were found in two clerical districts of Vaasa (83.5 and 79.7). They also had very high prevalences by place of birth. They lie close to each other, but are not immediate neighbours. Another high-risk focus was revealed in an area of the neighbouring districts of Turku and Pori. In fact, the two highest prevalences by place of birth were found in this region (123.1 and 95.0). The focus extended from the coastal area to the more central region of the county, and further to the western districts of the otherwise medium-risk county of Häme. Thus, two separate foci were found in Finland: one in the western and another in the southwestern part of the country. The clustering became even more pronounced when the prevalences by place of birth were analysed. Considering that the Finnish population still largely originates from genetic isolates of varying degrees, gene enrichment explains the clustering at least partly.     

THE EPIDEMIOLOGY OF MULTIPLE SCLEROSIS AND TUBERCULOSIS IN FINLAND. A Study based on Mortality Statistics

Mortality statistics were used to check the previously observed uneven geographical distribution of multiple sclerosis (MS) in Finland, and also to compare the distribution of tuberculosis and MS with each other. In total, 331 MS deaths which could be regarded as deaths primarily due to MS were registered during the period from 1963 to 1971. The mean age at death was 49.9 years. The mean annual mortality rate was 0.8 per 100,000 population. The highest rates due to MS were registered in the western county of Vaasa. The cumulative mortality and birth rates showed a significant accumulation of MS cases to the western county of Vaasa and the southwestern county of Turku and Pori. A previous study revealed a high percentage of familial cases of first-degree kinship in the selected district of Jalasjarvi in the county of Vaasa. The mortality material revealed one additional MS case which raised the familial percentage to 13 among the living patients in this district. Statistics of tuberculosis have shown a constant accumulation of the disease in the western part of the country for more than 100 years. The mean annual mortality rate for tuberculosis was 17.1. The highest rate (23.0) was found in the western county of Vaasa, where the mortality rate (1.34) for MS was highest. Previous immigrant studies in Finland suggest that the uneven geographical distribution of tuberculosis is due to hereditary factors. The population of Finland consists of varying degrees of isolates, and the similarity of the distributions of MS and tuberculosis may thus reflect a common genetic factor in their aetiology.     

Studies on the clustering of multiple sclerosis in Finland.

The epidemiological investigation of multiple sclerosis (MS) in Finland revealed a prevalence rate of 40.3 per 100.000 inhabitants. The geographic distribution of MS was uneven in the country. MS seemed to occur more often in the western and southwestern parts of the country, where the prevalences varied between 51.7 and 62.1 This phenomenon became even more pronounced when the distribution of the disease was investigated in small geographic units. Optic neuritis showed a geographic distribution similar to that of MS, with clustering in the same parts of the country and even in the same narrow districts. The correlation between the birthplaces of MS and optic neuritis patients was very significant (p less than 0.001), which suggest that they share a common aetiology. The possible aetiological role of genetic and exogenous factors was discussed in the western cluster of MS, where the percentage of familial cases was 13 and an accumulation of muscular dystrophy of cattle was observed.     

The incidence of optic neuritis and its prognosis for multiple sclerosis

An incidence study of idiopathic optic neuritis (ON) was carried out in 2 geographic areas of Finland for the 9-year period 1970 to 1978. The southern province of Uusimaa composes a medium-risk and the western province of Vaasa a high-risk area for multiple sclerosis (MS). The risk for subsequent MS was determined. A total of 315 attacks on ON were recorded in 296 patients. The mean annual age-adjusted incidence for ON in Uusimaa was 2.2 and in Vaasa 2.5 per 100,000 population. The incidence figures remained unchanged all the time. The mean age at onset was 30 years. 19% of ON patients developed MS during the mean follow-up period of 5.1 years. When the life-table method of analysis was used, the probability of developing MS was 38% in Uusimaa and 24% in Vaasa 9 years after acute optic neuritis. In Uusimaa the risk of women for MS was significantly higher than in men. In 47%, the MS symptoms and signs developed within 1 year and in 90% within 5 years after the initial bout of ON. It is possible that only one part of idiopathic ON cases do have a relationship with MS.     

Genetic factors and the founder effect explain familial MS in Sardinia.

OBJECTIVE: To estimate the presence of familial aggregation and determine the contribution of genetic factors to familial clustering of MS in patients coming from Sardinia, a Mediterranean island considered a genetically homogeneous, isolated area having high disease incidence and prevalence. METHODS: Recurrence risk in siblings of 901 Sardinian patients and factors influencing risk (patient and sibling sex, patient age at onset, sibling birth cohort, and presence of affected relatives other than siblings) were examined. The presence of distant familial relationships among patients was evaluated by tracing the extended pedigrees of all patients with MS born in one Sardinian village. RESULTS: Twenty-three brothers and 36 sisters of the 2,971 siblings were affected with MS. Recurrence risk was greater in siblings of index patients with onset age less than 30 years (p < 0.01, increased risk 2.33 times) and having a relative with MS other than a sibling or parent (p < 0.01, increased risk 2.90 times). Pedigree analysis of patients from the village of L. showed that all 11 patients descended from 3 pairs of ancestors, whereas no cases occurred in the remaining 2,346 inhabitants. In descendants from the 3 couples, MS prevalence was dramatically greater than the regional average and 1.5 times greater than that observed in siblings of affected cases. CONCLUSIONS: Data from this study indicate that MS familial aggregation in Sardinians is influenced by genetic factors and that founder effect and the isolation of Sardinia can be considered causes of the enrichment of "etiologic" MS genes.     

Sex ratio of multiple sclerosis in persons born from 1930 to 1979 and its relation to latitude in Norway

A remarkable increase in female to male ratio of multiple sclerosis (MS) is recognised in high incidence areas. Norway is a high-risk area for MS, spanning latitudes 58–71°N. We studied whether the sex ratio has changed over time and whether it differs by clinical phenotype or by latitude. Population-based epidemiological data and data from the Norwegian MS Registry on patients born from 1930 to 1979 were combined in this study. Place of birth was retrieved from the Norwegian Population Registry and information on clinical subtypes was obtained from the Norwegian MS Registry. The female to male ratio ranged from 1.7 to 2.7 (median 2.0) in 5,469 patients born in Norway, and increased slightly by 5-year blocks of year of birth (p = 0.043). The sex ratio was 2.6:1 in 825 patients born 1970–1979, which is significantly higher than in those born 1930–1969 (p < 0.001). In patients with relapsing remitting onset, the sex ratio was 2.4:1, while it was 1.1:1 in those with primary progressive disease. The sex ratio did not differ between the south, the middle and the north of the country. The overall sex ratio of MS is strongly determined by cases with relapsing remitting onset. We did not observe the remarkable increase in sex ratios of MS reported from other high-risk areas. The high sex ratio in the youngest birth cohorts may change as an increasing proportion of cases in this age group is being diagnosed. Sex ratio was not associated with latitude.     

The epidemiology of multiple sclerosis in Finland: increase of prevalence and stability of foci in high-risk areas

ABSTRACT- Reliable data on the epidemiology of multiple sclerosis (MS) in Finland are available from 1964 and 1972. They show that the whole country is a high-risk area of MS with clustering in the western part. A reassessment of the prevalence data was carried out in the southern province of Uusimaa and in the western province of Vaasa, the prevalence day being January 1, 1979. The age-adjusted prevalence was 52.9 per 100,000 in Uusimaa and 92.9 per 100,000 in Vaasa, figures that were three times higher than those recorded for the same areas in 1964. The communities with the highest prevalence rates in the province of Vaasa were the same as those in the survey of 1972; some rates exceeded 200 per 100,000. The increase in the prevalence rates may be due to a better registration of MS cases, but it may also represent a true increase, a possibility that only can be answered by further incidence studies.     

Parental causes of death in primary intracerebral haemorrhage.

There are many reports of familial aggregation in stroke. Previously, examining parental causes of death, we found no evidence for familial risk in stroke once socioeconomic and socioenvironmental factors were controlled for. However, the number of patients with primary intracerebral haemorrhage (PICH) was small in this sample and we could not exclude a moderate effect of familial factors in this important subgroup. We therefore matched all cases with PICH on the Lothian Stroke Register with 2 controls per case of the same sex, born in the same year, district, and whose fathers had the same occupation. Presence on parental death certificates of cerebrovascular disease, other vascular disease, bronchial carcinoma, hypertension, diabetes mellitus and other causes of death was recorded. No significant difference in risk was found for cases with parental cerebrovascular disease (OR 0.75, 95% CI 0.40-1.40). Other forms of vascular disease in parents were not associated with significant risk either (OR 0.93, 95% CI 0.51-1.68). We conclude that familial factors do not contribute substantially to risk in most cases of PICH.     

SELENIUM, VITAMIN E AND COPPER IN MULTIPLE SCLEROSIS

There has been accumulation of the nutritional muscular dystrophy of the cattle in a certain western district of Finland where the prevalence of multiple sclerosis (MS) is also highest. This animal disease is due to lack of selenium (Se) and vitamin E. The Se content of whole blood was low (52.8 ± 11.3 ng/ml) in MS patients from this high-risk area compared to the controls (68.8 ± 11.0). The data for serum failed to confirm this tendency. All Se values appeared to he lower than international values suggested. The values for hoth vitamin E and copper were within the international normal range.     

The clustering of multiple sclerosis in various administrative subunits of western Poland

Summary A survey of multiple sclerosis was made in the western part of Poland, with special attention being paid to the distribution of the disease in various administrative subunits. The prevalence of MS for the 35 counties (mean 45.08 per 100,00 for definite and possible cases taken together) revealed significant differences between particular regions, with clusters of high prevalence rates occurring in two towns (Leszno, 130.97; Gniezno, 122.83). Local uneven distribution of multiple sclerosis was also found within 198 communes covering the territory of the 35 counties. There were four clusters in eight neighbouring towns and communes with a high prevalence ranging from 74.37 to 141.54, and several with a very low prevalence.     

Region with persistent high frequency of multiple sclerosis in Croatia and Slovenia

OBJECTIVE: The aim of this study was to evaluate the prevalence of multiple sclerosis (MS), and to determine the clinical characteristics and the occurrence of familial MS in the Gorski kotar-Kocevje region, which was previously considered to be a region of high prevalence of MS. METHODS: All clinically and laboratory supported definite cases of MS according to Poser's criteria, living residents of the chosen area on June 1, 1999 were included in the study. The patients were ascertained through national case registers for MS at the University Medical Centers (Rijeka and Ljubljana), registries of the national associations of MS patients, as well as from the medical records of regional outpatient clinics. RESULTS: The crude annual prevalence per 100,000 population was 151.9 (95% CI 123.2-187.4). 28.7% of patients had a history of MS among first-, second-, or third-degree relatives. The frequency of primary progressive course of disease was 23.5%. The sex ratio (F/M) was 1.41. CONCLUSION: A stable high prevalence of MS as well as a high number of familial MS cases was identified in the neighbouring regions of Slovenia and Croatia.     

Epidemiology of multiple sclerosis in London and Middlesex County, Ontario, Canada

A case-controlled epidemiologic study of multiple sclerosis (MS) was carried out in London, Ontario, and its surrounding Middlesex County for the period 1974-1983. The prevalence rates for clinically definite/probable MS on January 1, 1984 were 94/100,000 for the city and 91/100,000 for the county. The estimated annual incidence rate for the decade 1974-83 was 3.4/100,000. The female-to-male sex ratio was 2.5:1. A familial history of MS was recorded in 14.4% of close relatives and a total of 17% when distant relatives are included. The MS group is predominantly of British (70%) and European (23%) origin. The urban-rural residence pattern analysis indicates no significant regional influence on the risk of developing MS.     

Migration and multiple sclerosis in Alaskan military veterans

The objective is to provide the first estimates of the prevalence of multiple sclerosis (MS) in Alaskan white males including those migrant to and from the state. A case–control cohort design was utilized with a nationwide series of United States (US) veterans service-connected for MS and matched to pre-illness controls who had entered military service between 1960 and 1994. Among 3,758 white male MS cases and their 7,426 controls were 7 MS and 28 controls resident in Alaska at service entry, who provided an adjusted case/control (C/C) risk ratio for developing MS of 0.47 and an estimated prevalence rate of 22/100,000 population, but only 1 of the 7 had also been born in Alaska, for an estimated prevalence rate of 3.2 per 100,000 (95% confidence interval (CI): 0.08–17.80). The other 6 MS patients and their 26 controls, who migrated from another state to Alaska before onset, had an adjusted C/C ratio of 0.44 for a prevalence rate of 20.6 (95% CI: 7.56–44.90), significantly lower than the reported rate of 45.23 per 100,000 for all US white males in 1976. Another 9 MS patients and 7 controls born in Alaska, who had migrated to another state before entering service, provided an adjusted C/C risk ratio for developing MS of 2.44, with a highly significant elevated prevalence rate of 115 per 100,000 (95% CI: 52.6–218.1). In conclusion, these data suggest that Alaska is not a high-risk area for MS and indicate that migration before onset to Alaska from the high-risk coterminous US decreases the risk of MS and the opposite migration increases it. A formal prevalence survey of MS in Alaska is needed to support or refute these findings.     

A nationwide survey of the influence of month of birth on the risk of developing multiple sclerosis in Sweden and Iceland

Previous studies have shown that the risk of multiple sclerosis (MS) is associated with season of birth with a higher proportion of MS patients being born in spring. However, this relationship has recently been questioned and may be due to confounding factors. Our aim was to assess the influence from season or month of birth on the risk of developing MS in Sweden and Iceland. Information about month of birth, gender, and phenotype of MS for patients born 1940–1996 was retrieved from the Swedish MS registry (SMSR), and their place of birth was retrieved from the Swedish Total Population Registry (TPR). The corresponding information was retrieved from medical journals of Icelandic MS patients born 1981–1996. The control groups consisted of every person born in Sweden 1940–1996, their gender and county of birth (TPR), and in Iceland all persons born between 1981 and 1996 and their gender (Statistics Iceland). We calculated the expected number of MS patients born during each season and in every month and compared it with the observed number. Adjustments were made for gender, birth year, and county of birth. We included 12,020 Swedish and 108 Icelandic MS patients in the analyses. There was no significant difference between expected and observed MS births related to season or month of birth in Sweden or Iceland. This was even the results before adjustments were made for birth year and birth place. No significant differences were found in subgroup analyses including data of latitude of birth, gender, clinical phenotype, and MS onset of 30 years or less. Our results do not support the previously reported association between season or month of birth and MS risk. Analysis of birth place and birth year as possible confounding factors showed no major influence of them on the seasonal MS risk in Sweden and Iceland.     

Distribution of multiple sclerosis in Sweden based on mortality and disability compensation statistics

Previous studies have shown the Fennoscandian region to be a high-risk area for multiple sclerosis (MS). In order to investigate the distribution of MS in Sweden, mortality (1952-1992) and disability pensioning statistics (1971-1994) were studied. A total of 11,414 cases with a disability pension and 5,421 cases with MS on their death certificate were analysed according to county and time period and the results were compared with the mortality figures for amyotrophic lateral sclerosis (ALS) and disability pensioning statistics for Parkinson's disease. We found increasing rates of both MS mortality and disability pensioning. Disability pensioning correlated well with mortality 10 years later (r = 0.42, p = 0.04). We also found a marked geographical variation. V?rmland county had the highest mortality, with 14 out of its 16 municipalities having higher rates than the national mean. Unexpectedly, we found a high correlation between mortality due to MS and ALS (r = 0.60, p = 0.002).     

Multiple sclerosis in Oslo, Norway: prevalence on 1 January 1995 and incidence over a 25-year period

The Oslo Multiple Sclerosis (MS) Registry was established in 1990, and this is the first report on the prevalence and incidence of MS in the city of Oslo, Norway. The prevalence rate of definite MS on 1 January 1995 was 120.4/10(5). Inclusion of patients of native Norwegian ancestry only and exclusion of non-Norwegian immigrants yielded a prevalence rate of 136.0/10(5). A similar prevalence rate (136.5/10(5)) was found when patients and immigrants from the other Nordic countries (Finland, Sweden, Denmark) were included. Segregation of the native Norwegian patients according to the counties where they were born showed no significant differences except for a disproportionate increase of patients born in the inland county of Oppland. A total of 794 cases were resident in Oslo at the time of a diagnosis of definite MS in the period 1972-99. The crude average annual incidence rate for each 5-year period, between 1972 and 1996, increased significantly from 3.7/10(5) in the 1972-76 to 8.7/10(5) in the 1992-96 period. The increase was more marked in relapsing-remitting (RR) than in primary progressive disease and in female cases.     

A cluster of multiple sclerosis cases in Lysvik in the Swedish county of Värmland

Objectives – When surveying the county of Värmland in Sweden in order to determine the prevalence of multiple sclerosis (MS), we observed an aggregation of MS cases originating from the parish of Lysvik in the local region called Fryksdalen. Our intention was to analyse this cluster thoroughly, confirming the MS diagnosis and seeing if a hereditary or environmental background was plausible. Methods – The medical files were studied and the cases were classified by a neurologist according to Poser's criteria. Hereditary factors were analysed. Results – Sixteen living cases of MS were found, either living in the parish (n = 6) or born or raised there and had later moved to another place (n = 10). All patients had clinically definite MS. Eleven patients had relatives with MS, all of these being descendants of the Suhoinen family. Another two cases were Suhoinen descendants who did not have relatives with MS. Other common ancestors were also identified. Two cases were adopted. Eleven deceased MS patients from Lysvik were found, 10 of them had Suhoinen ancestry. Conclusion – We report a cluster of MS cases with a common ancestry indicating heredity for MS in 85% of the cases. Lysvik is a parish where Finnish immigration was pronounced in the 17th century and there has been inbreeding to a certain extent through marriage between cousins. Thus, we interpret this aggregation as possibly being genetically based, and neurogenetic studies are now being performed. However, as two of the cases were adopted environmental factors must also be considered.     

Multiple sclerosis distribution in northern Sardinia: spatial cluster analysis of prevalence.

BACKGROUND: A heterogeneous geographic distribution of MS has been reported among different ethnic groups, and also within small communities. Epidemiologic studies conducted over the past two decades using repeated assessments clearly show that Sardinia is at high risk for MS, with a prevalence of 150 per 100,000 in 1997. OBJECTIVE: To present spatial analysis of the disease prevalence to disclose possible "hot" or "cold" spots of disease, further allowing correlations with risk factors. METHODS: A spatial analysis of the whole province of Sassari, in northern Sardinia, at a microgeographic level (i.e., in the 89 administrative communes and 6 linguistic areas) was conducted. Because of the small number of cases per commune and to overcome random variability, a hierarchical Bayesian approach was adopted. The distribution of prevalent cases by commune of residence on December 31, 1997 and from age 5 to 15 years was analyzed. RESULTS: A clustering pattern was found in the southwestern communes of the province based on geographic distribution by both prevalence and residence at age 5 to 15 years. A west-to-east gradient also was observed. CONCLUSIONS: This study highlights a hot spot of MS in the southwestern part of Sassari province, bordering with the commune of Macomer, where MS was once hypothesized as having occurred as an epidemic. Interestingly, these areas of MS clustering comprise the Common Logudorese linguistic domain. The Catalan area, linguistically and genetically distant from the remaining Sardinian domains, does not show such high estimates. Because MS is not a single-source infectious disease, this study may help test the hypothesis that a widely and evenly spread environmental (infectious?) agent may produce disease in subgroups of genetically more susceptible individuals in areas at higher inbreeding rates, wherein a disease mode of inheritance could be better investigated.