Mono and MS: New Research Deepens Link

Infectious mononucleosis (IM) with confirmed Epstein-Barr virus (EBV) was associated with a more than threefold increase in incident multiple sclerosis (MS), a population-based retrospective study showed.

Over follow-up periods of 6 to 8 years, MS developed in 0.17% of people with EBV-positive IM compared with 0.07% of people in a referent group without IM (adjusted HR 3.14, 95% CI 1.18-8.34), reported Jennifer St. Sauver, PhD, of the Mayo Clinic in Rochester, Minnesota, and colleagues.

The study followed 4,721 people with IM who had serologic evidence of EBV infection and 14,163 people without evidence of IM, St. Sauver and colleagues wrote in Neurology Open Evidence.

“Mononucleosis is a relatively uncommon illness, but developing strategies to prevent infection with the virus that causes this disease could help us to lower the number of MS cases in the future,” St. Sauver said in a statement.

A landmark study in 2022 showed that MS risk increased 32-fold among U.S. military recruits who had evidence of prior EBV infection. While seroprevalence studies indicate that EBV infection is nearly universal, MS remains relatively rare in the general population, St. Sauver and co-authors observed.

“Thus, EBV infection seems to be a necessary, but not sufficient, trigger for MS, with additional genetic and environmental health factors likely determining which individuals are at the highest risk of developing disease,” they wrote.

EBV infection may result in IM, a relatively uncommon respiratory illness with an estimated incidence of 42-104 cases per 100,000 people, mainly in adolescents and young adults, the researchers noted. Whether immune responses that lead to IM also play a role in MS is unknown.

Previous research has suggested that people with IM have a two- to threefold increased risk of later developing MS. However, these studies frequently lacked laboratory confirmation of EBV-positive IM or relied on billing codes to identify MS, raising concerns about misclassification.

To address this, St. Sauver and colleagues studied individuals with a diagnosis code for IM who had laboratory confirmation that EBV was the causative agent. They compared incident MS cases in this group with an age-matched and sex-matched referent population.

Participants were part of the Rochester Epidemiology Project in Minnesota and Wisconsin from 1998 to 2022. The sample included 55% females, and more than 70% of all participants were younger than 20 years old.

Median follow-up was 6 years for people with EBV-positive IM and 8 years for the referent group. All potential cases of MS were verified through expert review of medical records.

During follow-up, MS developed in eight individuals with EBV-positive IM and in 10 referents. Five additional cases of central nervous system inflammatory disorders were identified during chart review, including three in the EBV-positive IM cohort; these were not included in the analyses.

The results highlight the need for further research into ways to prevent EBV infection, St. Sauver said. “Preventing these infections could reduce the overall burden of MS,” she suggested. “While MS is relatively rare, it carries the risks of significant disability and high treatment costs, and it usually develops when people are in their prime years of working and raising families.”

The analysis had several limitations, the researchers acknowledged. The study cohort was largely from Minnesota and most participants were white. Additional cases of MS linked to EBV-IM might emerge beyond the 6- to 8-year follow-up window, they noted.

Evolving laboratory tests and coding systems meant that EBV results and IM diagnoses were not readily available before 1998. Consequently, some EBV-positive IM cases in the referent group may have been overlooked, St. Sauver and co-authors pointed out.

Clinical trials are underway to further explore the relationship between EBV and MS. One trial is testing whether an investigational EBV vaccine can reduce relapse activity in people with MS; another is assessing the effect of antiviral therapies on EBV replication in MS patients.