ArticlesEnvironmental risk factors and multiple sclerosis: an umbrella review of systematic reviews and meta-analyses
Introduction
Multiple sclerosis is the most common demyelinating disease in high-income countries1 and, according to a report by the Multiple Sclerosis International Federation,2 the global median prevalence of multiple sclerosis has increased from 30 per 100 000 in 2008 to 33 per 100 000 in 2013. Prevalence varies considerably between countries3, 4 and is highest in North America (140 per 100 000) and Europe (108 per 100 000) and lowest in sub-Saharan Africa (2·1 per 100 000) and east Asia (2·2 per 100 000).2 The cause of multiple sclerosis is multifactorial; both genetic and environmental factors contribute to disease risk. In particular, several environmental risk factors, such as Epstein-Barr virus infection,5 smoking,6 and latitude,7 have been proposed; however, the causes of multiple sclerosis are still largely unknown and there are at present no well-established risk factors to assist disease prevention.8
Numerous meta-analyses and systematic reviews for environmental risk factors associated with multiple sclerosis have been published. However, to our knowledge, there has been no effort to summarise the evidence from these meta-analyses and their associated limitations, such as the presence of diverse biases. We did the first umbrella review of the evidence across existing systematic reviews and meta-analyses of observational studies, to provide an overview of the range and validity of the reported associations of diverse environmental risk factors with multiple sclerosis. We summarise the risk factors that have been associated with multiple sclerosis in meta-analyses, assess whether there is evidence for diverse biases in these meta-analyses, and finally assess which of the previously studied associations that have been synthesised in meta-analyses have robust evidence.
Section snippets
Search strategy and eligibility criteria
We did an umbrella review (a systematic collection and assessment of multiple systematic reviews and meta-analyses done on a specific research topic).9 We systematically searched PubMed from inception to Nov 22, 2014 to identify systematic reviews and meta-analyses of observational studies examining associations between environmental (non-genetic) factors and multiple sclerosis. The search strategy used the keywords “multiple sclerosis” AND (“systematic review” OR “meta-analysis”). The full
Results
Overall, 609 articles were searched and 20 articles were deemed eligible (figure). 17 of the 20 eligible articles had a quantitative synthesis providing a summary estimate. 13 of 33 articles screened at full text were excluded because a larger meta-analysis that examined the same risk factors and population was found. These articles pertained to chronic cerebrospinal venous insufficiency,28, 29 Epstein-Barr virus infection30 and seronegativity,31 hepatitis B vaccination,32, 33 immunisations,34
Discussion
We provide an overview and appraisal of environmental risk factors that have been associated with multiple sclerosis. Overall, 44 risk factors have been studied for an association with the disease, including infections and vaccinations, comorbid diseases, surgeries, traumatic events and accidents, exposure to toxic environmental agents, and biochemical biomarkers. Only three of these risk factors (anti-EBNA IgG seropositivity, infectious mononucleosis, and smoking) were supported by evidence
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