Some individuals exhibit clinical signs of multiple sclerosis (MS) before a laboratory diagnosis of Epstein-Barr virus (EBV) infection, according to research presented at the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2026, held in San Diego, California.
The study, a population-based assessment, investigated whether clinical indicators suggestive of MS could appear prior to documented primary EBV infection. Researchers analyzed linked laboratory and health administrative data from Ontario, Canada, covering approximately 16 million residents between and . The laboratory data encompassed over 80% of EBV testing performed across hospital, community, and public health settings.
Participants with serological evidence of primary EBV infection were identified through positive heterophile antibody or viral capsid antigen immunoglobulin M results. MS cases were determined using a validated claims-based algorithm, requiring multiple MS diagnostic codes and at least one demyelinating disease-related diagnosis preceding the EBV index date.
Among 95,980 individuals with laboratory-confirmed primary EBV infection, 0.31% (n=300) met the criteria for MS. Notably, 24.7% of these individuals (n=74) had documentation of at least one demyelinating disease-related code recorded before their documented EBV infection. In this subgroup, the average age at MS onset was 33.3 years (standard deviation 14.3 years), and 75.7% (n=56) were women.
The average age at the first positive EBV test among these patients was 42.5 years (standard deviation 16.1 years), significantly higher than the 21.5 years (standard deviation 10.6 years) observed among all individuals with positive EBV testing. A substantial 78.4% (n=58) of patients with a demyelinating disease-related code prior to their EBV index date ultimately met the criteria for MS before their first documented EBV test. 93.2% (n=69) of these patients had a demyelinating disease-related claim at least 90 days before EBV detection.
These findings add to a growing body of evidence suggesting a complex relationship between EBV and MS. Previous research has consistently linked EBV infection to an increased risk of developing MS. A review published in Cells highlighted strong epidemiological evidence connecting EBV infection and altered immune control to MS development, noting that clinical MS onset typically occurs years after initial EBV infection. The mechanisms underlying this connection, however, remain largely unclear.
Recent studies have begun to explore the role of EBV reactivation in MS relapses. Research presented at ACTRIMS , indicated that immune cells exhibit distinct gene activity just before a relapse in MS patients, consistent with the body’s response to EBV reactivation. This suggests that the virus may not only contribute to the initial development of MS but also to the exacerbation of symptoms.
The UCSF research, published in in Nature Immunology, further refines our understanding by identifying specific CD8+ “killer” T cells that target EBV and appear more abundant in individuals with MS. This suggests that the immune response to EBV may be directly involved in the damaging autoimmune processes seen in MS.
Despite these findings, researchers emphasize the need for caution in interpreting the data. Dalia Rotstein, MD, MPH, cautioned at ACTRIMS that “This proves premature to use EBV serostatus to rule out an MS diagnosis.” The study authors acknowledge several potential explanations for the observed findings, including the possibility of misdiagnosis of MS, misclassification of EBV infection, or EBV reactivation occurring after MS onset. They also highlight the possibility that other infections or environmental exposures may contribute to some cases of MS.
The researchers underscore the importance of further investigation to elucidate the precise mechanisms linking EBV to MS. Understanding these mechanisms could pave the way for novel therapeutic strategies targeting EBV to prevent or treat the disease. As Dr. Rotstein’s statement indicates, however, EBV status alone is not currently sufficient to definitively diagnose or exclude MS.
The ongoing research into the interplay between EBV and MS represents a significant step forward in our understanding of this complex autoimmune disease. While a definitive causal link remains to be established, the accumulating evidence strongly suggests that EBV plays a crucial role in the development and progression of MS in many individuals.
