Risk of Multiple Sclerosis Among Persons With Epstein-Barr Virus–Positive Mononucleosis

Background and Objective: Prior studies examining associations between Epstein Barr Virus (EBV)-positive infectious mononucleosis (IM) and risk of multiple sclerosis (MS) frequently lacked laboratory confirmation of EBV-positive IM or relied on billing codes to identify MS. We assessed whether laboratory-confirmed EBV-positive IM was associated with an increased risk of developing verified cases of MS. Methods: We conducted a population-based retrospective cohort study using medical records from the Rochester Epidemiology Project. We identified individuals with serologic evidence of EBV infection and an associated IM diagnosis (EBV-positive IM; exposed cohort) between 1998 and 2022. Age- (± 1 year) and sex-matched individuals without evidence of IM (3:1 match) comprised the unexposed cohort. Incident MS cases were verified through blinded expert chart review. Multivariate Cox proportional hazard models were used to assess associations between EBV-positive IM and risk of MS. Results: 4,721 persons had EBV-positive IM (exposed cohort: 55% female, 70% <20 years). The referent cohort included 14,163 persons without EBV-positive IM (55% female, 70% <20 years). During follow-up (median, 6 years for exposed; 8 years for referents), MS developed in 8 individuals with EBV-positive IM (0.17%) and 10 referents (0.07%). EBV-positive IM was associated with a >3-fold increased risk of MS (adjusted Hazard Ratio: 3.14, 95% Confidence Interval: 1.18-8.34). Discussion: EBV-positive IM was associated with a substantially higher risk of MS. Findings are consistent with prior studies and underscore the importance of preventive strategies targeting EBV to reduce the long-term burden of MS.