Margitta T. Kampman

Outdoor activities and diet in childhood and adolescence relate to MS risk above the Arctic Circle

BackgroundA relationship between the latituderelated distribution of multiple sclerosis (MS) and exposure to sunlight has long been considered. Higher sun exposure during early life has been associated with decreased risk of MS.ObjectiveSince Norway is an exception to the latitude gradient of MS prevalence, we tested here whether sunlight exposure or vitamin D-related dietary factors in childhood and adolescence are associated with the risk of MS.MethodsRetrospective recall questionnaire data from 152 MS patients and 402 population controls born at and living at latitudes 66–71°N were analysed by means of conditional logistic regression analysis accounting for the matching variables age, sex, and place of birth.ResultsIncreased outdoor activities during summer in early life were associated with a decreased risk of MS, most pronounced at ages 16–20 years (odds ratio (OR) 0.55, 95% CI 0.39–0.78, p = 0.001, adjusted for intake of fish and cod-liver oil). A protective effect of supplementation with cod-liver oil was suggested in the subgroup that reported low summer outdoor activities (OR 0.57, 95% CI 0.31–1.05, p = 0.072). Consumption of fish three or more times a week was also associated with reduced risk of MS (OR 0.55, 95% CI 0.33–0.93, p = 0.024).ConclusionSummer outdoor activities in childhood and adolescence are associated with a reduced risk of MS even north of the Arctic Circle. Supplemental cod-liver oil may be protective when sun exposure is less, suggesting that both climate and diet may interact to influence MS risk at a population level.

Effect of vitamin D3 supplementation on relapses, disease progression, and measures of function in persons with multiple sclerosis: exploratory outcomes from a double-blind randomised controlled trial

Background: High vitamin D levels may reduce the risk of relapses and disease progression in multiple sclerosis. Methods: This 96-week randomised controlled trial was designed to assess the effect of vitamin D3 supplementation on bone mineral density in persons with multiple sclerosis. Supplementation with 20,000 IU vitamin D3 weekly raised median serum 25-hydroxy vitamin D (25[OH]D) to 121 nmol/L. The modified intention to treat analysis included 35 persons in the vitamin D3 group and 33 in the placebo group. Participants were age 21 to 50 years and fully ambulatory (median Expanded Disability Status Scale (EDSS) 2.5). We studied the effect of supplementing vitamin D3 on the exploratory outcomes annualised relapse rate (ARR), EDSS, multiple sclerosis functional composite (MSFC) components, grip strength, and fatigue. Results: After 96 weeks, there was no significant difference between groups in ARR (absolute difference 0.10, 95% CI -0.07 to 0.27; p = 0.25), EDSS (absolute difference -0.01, 95% CI -0.35 to 0.35; p = 0.97), MSFC components, grip strength, or fatigue. Conclusion: Supplementation with 20,000 IU vitamin D3 weekly did not result in beneficial effects on the measured multiple sclerosis-related outcomes. This study was not powered to address clinical outcomes, but none of the results were suggestive of an effect in this unselected population of fully ambulatory persons with multiple sclerosis.

Environmental risk factors in multiple sclerosis

Objectives –  Multiple sclerosis (MS) likely results from an interaction between genetic and exogenous factors. While genetics shapes the overall population MS susceptibility, observed epidemiological patterns strongly suggest a role for the environment in disease initiation and modulation.

Vitamin D: a candidate for the environmental effect in multiple sclerosis - observations from Norway.

Multiple sclerosis (MS) is a chronic disease of the central nervous system, pathologically characterized by inflammation, demyelination, and axonal damage, presumably auto-immune in nature. Complex interactions between genetic susceptibility and environmental factors, such as vitamin D status and primary Epstein-Barr virus infection in adolescence or later in life, probably determine the MS risk. Norway at a latitude 58–71°N is a discrete exception to the hypothesis that solar UV radiation exposure, mediated by vitamin D, coheres with the latitude gradient seen for MS prevalence. Where UV radiation exposure is low in Norway,vitamin D sufficiency is maintained through a traditional diet providing vitamin D as well as marine omega–3 polyunsaturated fatty acids. This observation supports an environmental interaction between diet and latitude, with vitamin D as the common mediator. The potential roles of vitamin D, other environmental exposures, and genes in the complex aetiology of MS are discussed in this review.

Late Onset Myasthenia Gravis Is Associated with HLA DRB1*15:01 in the Norwegian Population

Background Acquired myasthenia gravis (MG) is a rare antibody-mediated autoimmune disease caused by impaired neuromuscular transmission, leading to abnormal muscle fatigability. The aetiology is complex, including genetic risk factors of the human leukocyte antigen (HLA) complex and unknown environmental factors. Although associations between the HLA complex and MG are well established, not all involved components of the HLA predisposition to this heterogeneous disease have been revealed. Well-powered and comprehensive HLA analyses of subgroups in MG are warranted, especially in late onset MG. Methodology/Principal Findings This case-control association study is of a large population-based Norwegian cohort of 369 MG patients and 651 healthy controls. We performed comprehensive genotyping of four classical HLA loci (HLA-A, -B, -C and -DRB1) and showed that the DRB1*15:01 allele conferred the strongest risk in late onset MG (LOMG; onset ≥60years) (OR 2.38, pc7.4×10−5). DRB1*13:01 was found to be a protective allele for both early onset MG (EOMG) and LOMG (OR 0.31, pc 4.71×10−4), a finding not previously described. No significant association was found to the DRB1*07:01 allele (pnc = 0.18) in a subset of nonthymomatous anti-titin antibody positive LOMG as reported by others. HLA-B*08 was mapped to give the strongest contribution to EOMG, supporting previous studies. Conclusion The results from this study provide important new information concerning the susceptibility of HLA alleles in Caucasian MG, with highlights on DRB1*15:01 as being a major risk allele in LOMG.

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.

Month of birth as a risk factor for multiple sclerosis: an update

Several studies have indicated month of birth as a risk factor for multiple sclerosis (MS) susceptibility and disease progression.

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.

Month of birth as a latitude-dependent risk factor for multiple sclerosis in Norway.

Objective: We aimed to determine if the risk of Multiple Sclerosis (MS) is associated with month of birth in Norway and to explore a possible latitudinal gradient. Methods: All patients with MS born between 1930 and 1979 registered in the Norwegian MS Registry or ascertained in Norwegian prevalence studies were included (n = 6649). The latitude gradient was divided in Southern, Middle and Northern Norway, according to the estimated regional yearly mean vitamin D effective UV dose. Results: Risk of MS was 11% higher for those born in April (p = 0.045), and 5% higher for those born in May (p = 0.229), 5% lower for those born in November (p = 0.302) and 12% lower for those born in February (p = 0.053) compared with the corresponding population, unaffected mothers and siblings. In Southern Norway the odds ratio of MS births in April and May was 1.05 (0.98 – 1.24), in Middle Norway 1.11 (0.97 – 1.27) and in Northern Norway 1.28 (1.0 – 1.63) compared with the other months. Conclusions: This study confirms previous reports of increased MS births in spring and decreased MS births in the winter months. This could support the role of decreased sunlight exposure during pregnancy and vitamin D deficiency in prenatal life in MS.

A questionnaire for multinational case–control studies of environmental risk factors in multiple sclerosis (EnvIMS-Q)

The increasing incidence of multiple sclerosis (MS) worldwide, especially in women, points to the crucial role of environmental and lifestyle risk factors in determining the disease occurrence. An international multicentre case–control study of Environmental Risk Factors In Multiple Sclerosis (EnvIMS) has been launched in Norway, Sweden, Italy, Serbia and Canada, aimed to examine MS environmental risk factors in a large study population and disclose reciprocal interactions. To ensure equivalent methodology in detecting age‐related past exposures in individuals with and without MS across the study sites, a new questionnaire (EnvIMS‐Q) is presented.