The EnvIMS Study: Design and Methodology of an International Case-Control Study of Environmental Risk Factors in Multiple Sclerosis.

BACKGROUND: Multiple sclerosis (MS) is a chronic disease of the central nervous system, often resulting in significant neurological disability. The causes of MS are not known; however, the incidence of MS is increasing, thereby suggesting that changes in lifestyle and/or environmental factors may be responsible. On this background, the Environmental Risk Factors in MS Study or EnvIMS study was designed to further explore the etiology of MS. The design and methodology are described, providing details to enable investigators to (i) use our experiences to design their own studies; (ii) take advantage of, and build on the methodological work completed for, the EnvIMS study; (iii) become aware of this data source that is available for use by the research community. METHODS: EnvIMS is a multinational case-control study, enrolling 2,800 cases with MS and 5,012 population-based controls in Canada, Italy, Norway, Serbia and Sweden. The study was designed to investigate the most commonly implicated risk factors for MS etiology using a self-report questionnaire. RESULTS/CONCLUSIONS: The use of a common methodology to study MS etiology across several countries enhances the comparability of results in different geographic regions and research settings, reduces the resources required for study design and enhances the opportunity for data harmonization.

Body size and the risk of multiple sclerosis in Norway and Italy: the EnvIMS study.

BACKGROUND: Obesity may be a risk factor for developing multiple sclerosis (MS). OBJECTIVE: We examined if body size influences the risk of MS in a population-based, case control study. METHODS: A total of 953 cases and 1717 controls from Norway and 707 cases and 1333 controls from Italy reported their body size by choosing a silhouette 1 to 9 (largest) every fifth year from age 5 to 30 and at time of study. The body size-related MS risk was defined by odds ratios (ORs) in logistic regression analyses adjusting for age, smoking and outdoor activity. RESULTS: In Norway a large body size (silhouettes 6-9) compared to silhouette 3 increased the risk of MS, especially at age 25 (OR 2.21; 95% CI 1.09-4.46 for men and OR 1.43; 95% CI 0.90-2.27 for women). When comparing silhouette 9 to 1, we found a significant dose-response from age 10 until age 30 peaking at age 25 (sex-adjusted OR 2.83; 95% CI 1.68-4.78). The association was present for at least 15 years prior to disease onset. No significant associations were found in Italy. CONCLUSIONS: Obesity from childhood until young adulthood is a likely risk factor for MS with a seemingly stronger effect in Norway than in Italy.

Notes on the epidemiology of multiple sclerosis, with special reference to dietary habits.

A hypothesis, based primarily on the occurrence of multiple sclerosis (MS) in the Faroe Islands and supported by numerous analytical epidemiological studies, is described. It proposes that MS is caused by the interaction of a virus disease with intestinal pathology, e.g., infectious mononucleosis, and application of smoked and nitrate/nitrite-cured meat products in the diet during circumscribed time intervals. The biological mechanisms might involve a break of tolerance by an alteration of self within the central nervous system, by nitrophenylated compounds conjugated to animal tissue, in particular to proteins occurring in the central nervous system. Further research is needed.

Sun exposure and multiple sclerosis risk in Norway and Italy: The EnvIMS study.

OBJECTIVES: The objective of this paper is to estimate the association between multiple sclerosis (MS) and measures of sun exposure in specific age periods in Norway and Italy. METHODS: A total of 1660 MS patients and 3050 controls from Italy and Norway who participated in a multinational case-control study (EnvIMS) reported sun habits during childhood and adolescence. RESULTS: A significant association between infrequent summer outdoor activity and increased MS risk was found in Norway and in Italy. The association was strongest between the ages of 16 and 18 years in Norway (odds ratio (OR) 1.83, 95% confidence interval (CI) 1.30-2.59), and between birth and age 5 years in Italy (OR 1.56, 95% CI 1.16-2.10). In Italy a significant association was also found during winter (OR 1.42, 95% CI 1.03-1.97). Frequent sunscreen use between birth and the age of 6 years was associated with MS in Norway (OR 1.44, 95% CI 1.08-1.93) after adjusting for outdoor activity during the same period. Red hair (OR 1.67, 95% CI 1.06-2.63) and blonde hair (OR 1.36, 95% CI 1.09-1.70) were associated with MS after adjusting for outdoor activity and sunscreen use. CONCLUSION: Converging evidence from different measures underlines the beneficial effect of sun exposure on MS risk.

Season of infectious mononucleosis and risk of multiple sclerosis at different latitudes; the EnvIMS Study.

BACKGROUND: Seasonal fluctuations in solar radiation and vitamin D levels could modulate the immune response against Epstein-Barr virus (EBV) infection and influence the subsequent risk of multiple sclerosis (MS). METHODS: Altogether 1660 MS patients and 3050 controls from Norway and Italy participating in the multinational case-control study of Environmental Factors In Multiple Sclerosis (EnvIMS) reported season of past infectious mononucleosis (IM). RESULTS: IM was generally reported more frequently in Norway (p=0.002), but was associated with MS to a similar degree in Norway (odds ratio (OR) 2.12, 95% confidence interval (CI) 1.64-2.73) and Italy (OR 1.72, 95% CI 1.17-2.52). For all participants, there was a higher reported frequency of IM during spring compared to fall (p<0.0005). Stratified by season of IM, the ORs for MS were 1.58 in spring (95% CI 1.08-2.31), 2.26 in summer (95% CI 1.46-3.51), 2.86 in fall (95% CI 1.69-4.85) and 2.30 in winter (95% CI 1.45-3.66). CONCLUSIONS: IM is associated with MS independently of season, and the association is not stronger for IM during spring, when vitamin D levels reach nadir. The distribution of IM may point towards a correlation with solar radiation or other factors with a similar latitudinal and seasonal variation.

An ecological study of industry in a high-risk region of multiple sclerosis.

The county of Värmland, Sweden, has shown a high frequency of multiple sclerosis in several investigations. It has been presented in three studies; a period prevalence study in 1925-1934, a mortality study during 1952-1992 and a prevalence investigation in 2002. The aim of this study was to investigate the pattern of industry in this high-risk area for multiple sclerosis. The three investigations were correlated with industry in 1913 and in the 1950s, all analyzed by the Kruskall-Wallis test. Select industries from wood-pulp, paper and iron/mechanical sectors were tested also in whole Sweden. The Spearman rank correlation was used for these data and forestry data in Värmland. In Värmland, industrial data from 1913 revealed that large sawmills were associated with the period prevalence in 1925-1934 and there was a possible correlation with the prevalence for 2002. Wood-pulp factories showed a possible association with the prevalence 1925-1934 and the mortality 1952-1992. Some industries in the 1950s were correlated with the prevalence 2002. Wood and paper industries in Sweden 1913 showed an association with the MS mortality 1952-1992. In summary, data on MS prevalence in Värmland and mortality both in Värmland and all Sweden from the past 100 years suggest an association with wood-related industries in 1913 and in the 1950s, whereas no consistent association was found for other industries.

Prevalence and incidence of multiple sclerosis in Oppland County: a cross-sectional population-based study in a landlocked county of Eastern Norway.

OBJECTIVES - We report the prevalence and incidence rates of multiple sclerosis (MS) in Oppland County, Norway. METHODS - Records from all patients diagnosed with MS at the two Oppland County hospitals, Gjøvik and Lillehammer during 1989-2001 were evaluated. In addition, all general practitioners in Oppland County reported their patients into the study. RESULTS - The age-adjusted prevalence rate of definite MS was 174.4/ 100 000 on the prevalence day 1 January 2002. When the probable cases were included, the prevalence rate rose to 185.6/100 000. The highest prevalence rates were detected in the northern mountain areas, thus corroborating the results from previous local surveys 30-50 years ago. The prevalence of MS was statistically significantly associated with climatic, socioeconomic and geographic variables in the county. The age-adjusted incidence of definite and probable MS in Oppland County was 6.6/100 000 during 1989-1993 increasing to 7.6/100 000 during 1994-1998. DISCUSSION - We found the highest prevalence rates of MS ever reported in Norway. Our findings indicate a possible influence of environmental factors.

Environmental risk factors in multiple sclerosis.

The etiology of multiple sclerosis is, at present, not definitely known, but genetic and environmental factors play a role in its causation. Environmental causes have a predominant impact. Epidemiologic research has contributed considerably to the identification of external risk factors in this multifactorial setting, but methodological constraints still play a major part. Viral and other microbial agents have drawn much attention, although none of them is a necessary condition for the disease. This is true also for the Epstein-Barr virus, for which most data, including prospective data, supports a role in the majority of multiple sclerosis patients. In parallel, the hypothesis is still attractive in that it is not the virus per se, but rather more the age when it infects the human being that is the crucial matter. Other risk factors, such as tobacco smoking and vitamin D deficiency, which have immunomodulating properties, may also play some role, although the latter is not compatible with all data of the descriptive epidmiology of multiple sclerosis. Diet might be of considerable importance, all the more since multiple sclerosis can be ecologically attributed to a certain food patterns and is inversely associated with others (e.g., the 'Mediterranean diet'). The hypothesis that the preservation of meat by nitrite and wood smoke plays a role, and the protective influence of a fish and, possibly, a vegetable diet, are supported by some studies, but methodological constraints limit, at present, definite conclusions. A new avenue is the search for an interaction between genetic and environmental causes, and also between several environmental factors that might lead to new approaches for prevention and, perhaps, for the treatment of multiple sclerosis.

Divergent risk of multiple sclerosis in two anabaptist communities in America.

A lowered risk of multiple sclerosis (MS) has been reported in the Hutterite community residing mainly in southern Canada. In another anabaptist community, the Old Colony Mennonites (OCM), settled in Canada and spread to Latin America, only a large pedigree with an increased risk of autoimmune diseases, including type I diabetes and three cases of MS, was reported. The prevalence of MS in the pedigree (3,158 per 100,000), even when observing its confidence interval, seems rather high, and the MS prevalence in the Mennonite general population is assumed at least to be equal to the Canadian rates. Based upon an extended study of the literature, the hypothesis that smoking and curing with nitrate/nitrite plays any role, by interaction with inflammatory intestinal changes in childhood infections, is supported. In addition, tobacco smoking and short-term breast-feeding as possible risk factors are also in line with a higher MS risk in OCM, whereas insecticides and herbicides can be excluded as risk factors in MS.