Not all cases of multiple sclerosis (MS) are preceded by exposure to Epstein-Barr virus (EBV) infection, according to new data presented at the ACTRIMS Forum.
A population-based study in Ontario, Canada, found 74 patients with MS that had developed before a positive EBV test. They had characteristics similar to those in the rest of the MS population.
Dalia Rotstein, MD, MPH, a neurologist at the Barlo MS Centre at St. Michael’s Hospital in Toronto, Canada, noted that there is strong biological and epidemiologic evidence linking EBV infection and MS, including from a seminal 2022 study that suggested EBV is a necessary environmental exposure for MS to develop. She added that some clinics have started using EBV-seronegative status to rule out a diagnosis of MS.
“Our findings raise the question of whether EBV infection is required in all cases for the development of MS,” she told meeting attendees, cautioning that “it is premature to use EBV serostatus to rule out an MS diagnosis.”
Dr. Rotstein and her colleagues looked for cases of MS preceding a primary EBV infection using province-wide health claims data from Ontario, which is home to 16 million people. Hospital and community laboratory data from 2007 to 2022 were examined for positive serum test results for primary EBV infection.
The researchers identified 74 individuals who met criteria for MS (having at least three MS diagnosis codes) and had at least one demyelinating disease code recorded before the first positive EBV test.
“This is still a small number but greater than what we were expecting to see based on the theory that EBV is absolutely necessary for MS to occur,” Dr. Rotstein told Doximity.
The patients’ mean age at MS onset was 33.3 years and their mean age at the time of a positive EBV test was 42.5 years. Three-quarters were women.
Dr. Rotstein said there are several possible explanations for these cases of MS coming before evidence of EBV exposure. It’s possible that MS was misdiagnosed, that EBV infection was misclassified due to false-positive test results, or that EBV was reactivated.
“But given the number of cases, I think we need to entertain the probability of a fourth hypothesis, which is that there is some etiologic diversity underlying MS pathogenesis,” she said, suggesting that it’s possible other infections could “engender the same immune dysregulated state.”
There were some limitations of the analysis, including the likelihood of missing some cases of EBV seroconversion after MS onset, the lack of blood samples to directly assess EBV seroconversion status before MS onset, and the inability to review medical records, MRIs, or cerebrospinal fluid findings.
“We need to carefully investigate cases of MS onset preceding EBV infection in other cohorts where blood samples and full clinical and biomarker data are available,” Dr. Rotstein said.
She underscored during a Q&A period after her presentation that this new study “doesn’t undercut the evidence of a strong association between EBV and MS. We’re just suggesting that there may be exceptions and there may be some heterogeneity in terms of etiology.”
That should be kept in mind, she told Doximity, “as we develop therapeutic and preventative strategies targeting EBV.”
Todd Neale has no conflicts of interest.
Illustration by April Brust
