On the geoepidemiology of multiple sclerosis and environmental and infectious determinants of its clinical course

Multiple sclerosis (MS) is a chronic, demyelinating condition of the central nervous system, manifesting in alteration or loss of motor, sensory and cognitive function. The causes of MS are unclear but include genetic and environmental factors. This thesis presents several epidemiologic analyses, examining MS geoepidemiology, locally and globally, as well as evaluating key environmental and infectious determinants of clinical course. The first analysis chapter examines MS epidemiology in the Greater Hobart region of Tasmania over the interval 1951 to 2009. This analysis found a significant increase in prevalence, this mediated by a significantly decreased mortality and increased longevity, as well as evidence of an increasing female/male sex ratio. Next is a meta-analysis of MS prevalence and its association with latitude. This work, utilising the largest collection of MS prevalence studies, found a significant positive association between MS prevalence and latitude. This provides evidence in favour of the latitudinal gradient hypothesis and for environmental factors underlying the gradient, most particularly personal ultraviolet radiation (UVR) exposure and vitamin D. The association between serum 25-hydroxyvitamin D (25(OH)D) and relapse was examined in a prospective cohort with clinically-definite MS followed for 2.3 years. This analysis found a significant inverse association between higher levels of 25(OH)D and subsequent hazard of relapse. This study provides key evidence that is needed to justify conducting randomised clinical trials of vitamin D supplementation in reducing relapse frequency in MS. In this MS cohort, it was also found that persons on interferon-β (IFN-β) therapy had significantly higher 25(OH)D levels and that the association between personal sun exposure and 25(OH)D was stronger compared to those not on IFN-β. Importantly, the above association between 25(OH)D and relapse was only observed for those on IFN-β therapy. Last is an examination of the role of antibodies to Human Herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) in MS clinical course. This analysis found a significant positive association between anti-HHV-6 I\(_g\)G and relapse. This effect persisted on adjustment for the anti-EBV I\(_g\)Gs, indicating the effect was specific for HHV-6 antigen, or host antigen resembling it. There was no evidence of frequent serological HHV-6 reactivation, suggesting that the observed association between anti-HHV-6 I\(_g\)G and relapse was not being mediated by serologically-detectable peripheral reactivation of HHV-6. No associations were observed between anti-HHV-6 and anti-EBV I\(_g\)Gs and progression in clinical disability. This thesis presents a range of studies which add significantly to the literature on MS geoepidemiology, as well as the associations of environmental and infectious factors on MS clinical course. This work will be useful in the scientific community; both for hypothesis generation and providing strong evidence in support of existing hypotheses, and hopefully be of benefit to people with this debilitating disease