Study of Patients With Early MS Finds Universal Positivity to Epstein-Barr Antibodies

A new analysis of patients with early multiple sclerosis (MS) suggests they universally carry antibodies for Epstein-Barr virus, a virus increasingly thought to be linked to MS.

New evidence is bolstering the already strong case that Epstein-Barr virus (EBV) is linked to multiple sclerosis (MS).

In a new study published this week in The Journal of Neurology, Neurosurgery, and Psychiatry, investigators report that every single patient selected from a database of people with early MS tested positive for antibodies to EBV.

“While this finding is consistent with the known high EBV seroprevalence in MS, the absence of any EBV-seronegative patients with early MS in our cohort appears remarkable and further strengthens the evidence for an association of EBV infection and MS,” write corresponding author Klemens Ruprecht, of Charité — Universitätsmedizin Berlin, in Germany, and colleagues.

The authors began with the premise that if MS and EBV are closely linked, it is possible that MS could be seen as a late complication of EBV. If that were the case, one would expect all patients with MS to have EBV seropositivity.

To test the premise, the team tested serum samples from 901 patients with either clinically isolated syndrome (CIS) or early relapsing-remitting multiple sclerosis (RRMS) from the German National MS cohort. The team then measured Epstein-Barr nuclear antigen-1 (EBNA-1) and viral capsid antigen (VCA) antibodies in diluted sera using chemiluminescence immunoassays (CLIAs). Of the 901 patients who were tested, 839 samples came back positive for EBNA-1 antibodies.

The investigators then looked at the 62 remaining samples and found that 45 had antibodies to VCA. That left 17 patients, all of whom subsequently tested positive for EBV antibodies via immunoblot.

In sum, all 901 patients eventually tested positive for antibodies.

Ruprecht and colleagues note that their study began with a population that went through rigorous diagnostic screening prior to being allowed into the early MS cohort. Thus, the patients in the study likely have a higher degree of certainty of diagnosis than other studies might have found.

“Assuming that there is a genuine association of EBV and MS, the high degree of diagnostic certainty in patients participating in the German National MS cohort may therefore explain the 100% EBV seropositivity observed in this cohort…” the authors write. Insofar as other research might find less than 100% seropositivity, the authors suggest it could be due to misdiagnosis of MS.

For comparison’s sake, the authors then analyzed EBV-seroprevalence among 16,000 hospitalized patients. While the rate of seropositivity increased with age among the hospital cohort, in no case did it reach 100%. For instance, within those aged 20 to 40, seropositivity was 95.2% The authors note, however, that unlike the MS group, those who tested negative in the hospital group were not routinely retested with immunoblot.

Still, Ruprecht and colleagues said, “[w]e consider it very unlikely that this could have resulted in a higher rate of EBV seronegativity in the hospital population than in patients with MS.”

Among other reasons, they say the immunoblot method is thought to have a similar reliability to CLIA testing. The group also said they re-tested 28 negative sera by immunoblot and the samples likewise came back negative.

The authors conclude that their findings affirm the potential connection between EBV and MS. They also say that if a patient is suspected of MS but had negative EBV serology, physicians ought to consider diagnoses other than MS.


Abrahamyan S, Eberspächer B, Hoshi M, et al. Complete Epstein-Barr virus seropositivity in a large cohort of patients with early multiple sclerosis [published online May 5, 2020]. J Neurol Neurosurg Psychiatry Res. doi:10.1136/jnnp-2020-322941.

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