The association of herpes simplex virus, epstein-barr virus, and cytomegalovirus infections with multiple sclerosis: a large-scale case-control study.

BACKGROUND: The role of herpesviruses in the pathogenesis of multiple sclerosis (MS) is debated. We aimed to evaluate the association between prior documented infections with EBV, HSV, or CMV and subsequent multiple sclerosis diagnosis in a large-scale study. METHODS: A case-control study was conducted using a nationwide database (n > 370,000). All individuals with a diagnosis of multiple sclerosis and documented disease-modifying therapy were identified. For each multiple sclerosis case, five random controls were selected, based on sex, year of birth, socioeconomic status, and follow-up time. Exposure groups were defined as HSV, based on clinical diagnosis, and EBV and CMV, based on prior positive serology. RESULTS: Conditional logistic regression model demonstrated non-significant increased odds of previous HSV (adjusted odds ratio [aOR], 1.19; 95% confidence interval [CI], 0.80-1.78), significantly increased odds for EBV (aOR, 1.46; 95% CI, 1.09-1.96), and non-significant decreased odds for CMV (aOR, 0.64; 95% CI, 0.41-1.02) among multiple sclerosis patients. However, secondary CMV analysis with stricter control definitions and extended washout periods demonstrated a significant protective association (aOR, 0.51; 95% CI, 0.31-0.85). CONCLUSION: This case-control study confirmed the established association between EBV and increased multiple sclerosis risk and suggested a potential protective association between prior CMV infection and multiple sclerosis. No evidence was found linking prior HSV infection to multiple sclerosis.