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Review
. 2025 Jul 15;272(8):513.
doi: 10.1007/s00415-025-13248-0.

Environmental risk factors for multiple sclerosis: a comprehensive systematic review and meta-analysis

Bruno Kusznir Vitturi  1 , Maria Cellerino  2 , Daniele Boccia  2 , Emmanuelle Leray  3 , Jorge Correale  4 , Ruth Dobson  5 , Ingrid van der Mei  6 , Kazuo Fujihara  7 , Matilde Inglese  2
Affiliations
Review

Environmental risk factors for multiple sclerosis: a comprehensive systematic review and meta-analysis

Bruno Kusznir Vitturi et al. J Neurol. .

Abstract

Background and objectives: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system. Its etiology may involve both genetic and environmental factors, including vitamin D levels, body mass index, infections, and smoking. This is the first comprehensive systematic review with meta-analysis that synthesizes and explore the role of many environmental risk factors in the etiology of MS.

Methods: A systematic search of MEDLINE, SciVerse ScienceDirect and Web of Science were conducted for any original peer-reviewed article that included adult subjects diagnosed with and without MS that were exposed to any environmental risk factor. We did not set any time restrictions. Data were extracted and the quality assessment was performed with the Critical Appraisal Checklist for Case Control Studies. All the information was synthesized qualitatively and quantitatively (meta-analysis). We used the random-effects model based on the binomial distribution to calculate the pooled effects sizes (ES) regarding the risk of developing MS according to each potential risk factor.

Results: One-hundred thirty-two publications met all the eligibility criteria and were included in the review. Overall, 109,626 people with MS and 16,724,390 controls from 38 countries were included in the review. A total of 42 environmental risk factors were investigated as potential risk factors for MS. Among the various statistically significant associations, the pooled ES revealed a direct association between serological evidence of contact with EBV (ES = 1.96, 95% CI = 1.53-2.51), herpes virus type 6 (HHV-6) (ES = 2.84, 95% CI = 2.08-3.89) and varicella-zoster virus (ES = 1.33, 95% CI = 1.08-1.63) and the occurrence of MS. Similarly, smoking was associated with a greater likelihood of having MS (ES = 1.43, 95% CI = 1.27-1.61). Vitamin D levels at any time were negatively associated with the proportion of cases of MS and had a moderate pooled ES (g = - 0.48, 95% CI = - 0.88-0.09). Adult BMI was not associated with MS.

Discussion: This review furnishes a broad and detailed overview of the potential environmental risk factors associated with MS. Our findings hold notable implications for public health policies, clinical practices, and the focus of future research.

Keywords: Demyelinating diseases; environmental; multiple sclerosis; neuroepidemiology; risk factors.

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Conflict of interest statement

Declarations. Conflicts of interest: None.

Figures

Fig. 1
Fig. 1
PRISMA flowchart
Fig. 2
Fig. 2
Meta-analysis of the association between EBV and MS
Fig. 3
Fig. 3
Meta-analysis of the association between infections and MS
Fig. 3
Fig. 3
Meta-analysis of the association between infections and MS
Fig. 4
Fig. 4
Meta-analysis of the association between smoking and MS
Fig. 5
Fig. 5
Meta-analysis of the association between vitamin D status and MS
Fig. 6
Fig. 6
Meta-analysis of the association between other environmental risk factors and MS
See this image and copyright information in PMC

References

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