EBV-Positive Infectious Mononucleosis Linked to Threefold Higher Risk of Multiple Sclerosis: Study
A population-based retrospective study has found that infectious mononucleosis caused by Epstein-Barr virus (EBV) is associated with a more than threefold increased risk of developing multiple sclerosis (MS). The analysis specifically included individuals with laboratory-confirmed EBV infection, strengthening the evidence for a causal link. Ongoing clinical trials are now exploring EBV-targeted vaccines and antiviral therapies as potential strategies to reduce MS risk or progression.
While previous landmark investigations suggested that EBV plays a causal role in the development of MS—noting that risk did not increase after other infections like cytomegalovirus—earlier research often relied on potentially inaccurate self-reported histories of mononucleosis or administrative billing codes for disease ascertainment, prompting Dr. Jennifer L. St. Sauver and colleagues from the Mayo Clinic to design a study aimed at closing this clinical gap through the use of laboratory-verified infection status and expert-adjudicated diagnostic cases.
Therefore, the retrospective cohort study utilized the Rochester Epidemiology Project (REP) infrastructure to analyze health records from 1998 through 2022, comparing 4,721 individuals with serologically confirmed EBV-positive IM against 14,163 age- and sex-matched referents over a median follow-up period of six to eight years. To ensure the integrity of the findings, the researchers excluded any individuals with pre-existing demyelinating conditions, focusing on the primary endpoint of new-onset MS cases, which were verified through a rigorous, blinded expert review of full medical charts.
Key Clinical Findings of the Study Include:
Significant Risk Multiplier: The study determined that patients with a history of EBV-positive IM faced a significantly elevated 3.14-fold increased hazard of developing MS (95% confidence interval [CI]: 1.18–8.34).
Incidence Disparity: Data from the study showed that MS developed in 0.17% of the exposed group (2.25 per 10,000 person-years) compared to only 0.07% in the referent population (0.77 per 10,000 person-years).
Accelerated Disease Onset: According to the study, the median time from the initial infection to an MS diagnosis was notably shorter at 9.7 years for the exposed cohort, whereas the control group experienced a median duration of 14.2 years.
Robust Adjusted Analysis: The study demonstrated that this heightened risk remained statistically significant even after adjusting for variables such as smoking status, neighborhood deprivation measured by the Area Deprivation Index (ADI), and the overall burden of illness captured by the Elixhauser Comorbidity Index.
The results suggest that laboratory-confirmed EBV-positive IM is a potent risk factor for future neurological morbidity, with the data indicating that infected individuals remain at a substantially higher risk even when accounting for diverse social and clinical determinants. These findings imply that clinicians should recognize the importance of monitoring patients with a history of mononucleosis while supporting the continued development of preventive EBV vaccination strategies to potentially lower the long-term incidence of multiple sclerosis.
While the study is limited by its focus on a predominantly White population and a relatively short follow-up window that may not capture MS cases developing later in life, it underscores that future research into how the virus triggers physiological changes before symptom onset could provide vital insights into the underlying pathogenic process of the disease.
Reference
St. Sauver JL, Hall SA, Jacobson RM, et al. Risk of Multiple Sclerosis Among Persons With Epstein-Barr Virus–Positive Mononucleosis: A Population-Based Study. Neurol Open Access 2026;2:e000082.
