ACTRIMS 2026 | MS onset precedes EBV infection in some cases: a population-based assessment

Well, we’ve known for many decades that there’s an association between EBV and infectious mononucleosis and the risk of developing MS. But it wasn’t until 2022 when compelling evidence emerged that suggested that EBV is actually a necessary previous environmental exposure for MS to develop. So this was based on a study by Alberto Ascherio and colleagues from Harvard University, which was published in Science. They had this very unique cohort from the U.S. military. And in this cohort, they had blood samples available regularly from around the age of recruitment up until the time when individuals developed MS. They identified around 800 incident cases of MS, and there were 35 who were EBV seronegative when they were first recruited into the military, and all but one had actually seroconverted to EBV positive status on that last blood sample available before MS onset. So from these results, they calculated a very high hazard ratio of greater than 32 for the risk of developing MS with EBV seroconversion compared to persistent seronegative status. And that such a high hazard ratio basically suggests an etiologic role of EBV. So we were curious to investigate this question in a general population-based setting to see if we could find cases of MS onset preceding EBV infection. So we looked in the province of Ontario in Canada, where I’m from, for any positive laboratory blood tests that suggest primary EBV infection, either the heterophile antibody or the VCA IgM antibody. And these tests rise very rapidly after positive infection, usually within two weeks, and then they neutralize within eight weeks after the primary infection. So we had over 93,000 positive lab tests in Ontario, and then we searched for individuals who met an algorithm for MS, and they had to have at least three demyelinating diagnostic codes, actually not just demyelinating, but positive codes for MS. And they had to have at least one demyelinating disease code before the first positive EBV lab tests. So we found 74 such people. We also screened to see if they had ever been positive for the aquaporin-4 and MOG antibody and removed those cases. We found 74 cases of MS onset before EBV infection that were definitively not clinically isolated syndrome or MOG antibody disease. And this is a small number, but it was greater than what we were originally expecting. I think there are several possible explanations. So one is that some of these individuals could have been misdiagnosed with MS. A second is that some people could have had false positive lab tests for EBV. But I think given the number of cases, we have to consider the probability of a third explanation, which is that there could be some etiologic diversity underlying MS, and that EBV infection may not be necessary in 100% of cases. So perhaps there could be other viruses that engender a similar immune dysregulated state, which could later give rise to MS.

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