Reexamining the EBV-Multiple Sclerosis Causality Hypothesis: Dalia Rotstein, MD, MPH

WATCH TIME: 4 minutes

“I think it raises a question about whether EBV is 100% necessary in all cases of MS. Based on the number of cases we saw, we need to at least entertain the possibility that there may be etiologic diversity underlying what we clinically define as MS.”

The relationship between Epstein–Barr virus (EBV) infection and multiple sclerosis (MS) has been one of the most consequential developments in neuroimmunology over the past decade. While epidemiologic links between infectious mononucleosis and MS risk have been recognized for years, a landmark 2022 study using U.S. military serum samples suggested that EBV seroconversion may be a necessary environmental trigger for MS.¹ That analysis reported a hazard ratio exceeding 30 for MS following EBV infection, reshaping discussions around MS pathogenesis and fueling interest in EBV-targeted prevention strategies.

At the 2026 Americas Committee for Treatment & Research in Multiple Sclerosis (ACTRIMS) Forum in San Diego, Dalia Rotstein, MD, MPH, presented new population-based data examining whether MS onset can precede documented EBV infection. Using province-wide laboratory records from Ontario, Canada, Rotstein and colleagues identified individuals with confirmed primary EBV infection based on heterophile antibody or viral capsid antigen IgM testing and cross-referenced these with cases of MS onset. The analysis aimed to assess whether instances of MS occurring before documented EBV seroconversion could be identified outside of the military cohort studied in 2022.

During the meeting, Rotstein, a neurologist at the Barlo MS Clinic at St. Michael’s Hospital in Toronto, sat down to discuss how her findings contrast with prior assumptions about EBV as a universal prerequisite for MS. In the conversation, she outlined the limitations of earlier datasets, explained the identification of cases in which MS onset appeared to precede EBV infection, and explored possible interpretations, including misclassification, testing limitations, or etiologic heterogeneity within clinically defined MS.

Click here for more 2026 ACTRIMS Forum coverage.

REFERENCE
1. Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022;375(6578):296-301. doi:10.1126/science.abj8222