Elsevier

The Lancet Neurology

Volume 14, Issue 3, March 2015, Pages 263-273
The Lancet Neurology

Articles
Environmental risk factors and multiple sclerosis: an umbrella review of systematic reviews and meta-analyses

https://doi.org/10.1016/S1474-4422(14)70267-4Get rights and content

Summary

Background

The cause of multiple sclerosis is believed to involve environmental exposure and genetic susceptibility. We aimed to summarise the environmental risk factors that have been studied in relation to onset of multiple sclerosis, assess whether there is evidence for diverse biases in this literature, and identify risk factors without evidence of biases.

Methods

We searched PubMed from inception to Nov 22, 2014, to identify systematic reviews and meta-analyses of observational studies that examined associations between environmental factors and multiple sclerosis. For each meta-analysis we estimated the summary effect size by use of random-effects and fixed-effects models, the 95% CI, and the 95% prediction interval. We estimated the between-study heterogeneity expressed by I2 (defined as large for I2≥50%), evidence of small-study effects (ie, large studies had significantly more conservative results than smaller studies), and evidence of excess significance bias (ie, more studies than expected with significant results).

Findings

Overall, 44 unique meta-analyses including 416 primary studies of different risk factors and multiple sclerosis were examined, covering a wide range of risk factors: vaccinations, comorbid diseases, surgeries, traumatic events and accidents, exposure to environmental agents, and biochemical, infectious, and musculoskeletal biomarkers. 23 of 44 meta-analyses had results that were significant at p values less than 0·05 and 11 at p values less than 0·001 under the random-effects model. Only three of the 11 significant meta-analyses (p<0·001) included more than 1000 cases, had 95% prediction intervals excluding the null value, and were not suggestive of large heterogeneity (I2<50%), small-study effects (p for Egger's test >0·10), or excess significance (p>0·05). These were IgG seropositivity to Epstein-Barr virus nuclear antigen (EBNA) (random effects odds ratio [OR] 4·46, 95% CI 3·26–6·09; p for effect size=1·5 × 10−19; I2=43%), infectious mononucleosis (2·17, 1·97–2·39; p=3·1 × 10−50; I2=0%), and smoking (1·52, 1·39–1·66; p=1·7 × 10−18; I2=0%).

Interpretation

Many studies on environmental factors associated with multiple sclerosis have caveats casting doubts on their validity. Data from more and better-designed studies are needed to establish robust evidence. A biomarker of Epstein-Barr virus (anti-EBNA IgG seropositivity), infectious mononucleosis, and smoking showed the strongest consistent evidence of an association.

Funding

None.

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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