Is Epstein-Barr virus infection not a prerequisite for MS?

Using population-based laboratory and health claims data from Ontario, Canada (2007–2022), investigators identified cases suggesting that MS onset may precede documented primary Epstein-Barr virus (EBV) infection.

Among 95,980 individuals with laboratory-confirmed primary EBV infection, 300 (0.31%) had ≥3 MS diagnostic codes at any time. Within this subgroup, 74 patients (24.7%) had at least 1 demyelinating disease code preceding the index EBV-positive test. The mean age at MS onset in these cases was 33.3 years (SD 14.3), and 56 (75.7%) were women. Notably, 58 of the 74 patients (78.4%) fulfilled a validated MS case definition (3 MS diagnostic codes) prior to their first documented EBV-positive test.

“These findings question whether EBV infection is required in all cases for the development of MS,” said Dr Dalia Rotstein (University of Toronto, ON, Canada) [1]. The study was motivated by 3 key questions:

Is EBV infection a requisite environmental exposure for MS to develop?
Is EBV causally related to MS pathogenesis?
Could EBV seronegativity be used to exclude an MS diagnosis?

Dr Rotstein emphasised the importance of avoiding the post hoc, ergo hoc fallacy: “Although nearly all individuals with MS have evidence of prior EBV infection, this temporal association alone does not establish causality.”

The investigators concluded that, at a population level, cases of MS onset preceding documented EBV infection can be identified, and these were not limited to clinically isolated syndrome (CIS) or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD).

Potential explanations include MS misdiagnosis, misclassification of EBV infection (e.g., false-positive or delayed testing), EBV reactivation rather than primary infection, or the possibility that alternative infectious triggers, such as human herpes virus (HHV-6), may contribute to MS pathogenesis. Further research is warranted to clarify these observations and their implications for understanding MS causality.

Rotstein DL, et al. Is it possible for MS onset to precede EBV infection? A population-based assessment. CE2.2, ACTRIMS Congress 2026, 4–7 February, San Diego, California, USA.