Epstein-Barr Virus Antibodies May Aid in the Differential Diagnosis of Multiple Sclerosis
KEY TAKEAWAYS
- Persistently elevated EBNA-1 peptide antibody titers strongly differentiated MS from MOGAD and NMOSD across independent cohorts.
- Serial measurements were more specific than single time-point testing, with repeated high titers observed almost exclusively in MS.
Serial measurement of Epstein-Barr virus (EBV)–derived Epstein-Barr nuclear antigen 1 (EBNA-1) peptide antibodies may help distinguish multiple sclerosis (MS) from myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD), according to a multicenter case-control study published in JAMA Neurology. The findings suggest that persistently high EBNA-1 peptide titers could serve as an adjunct biomarker to support diagnosis, particularly clinically ambiguous cases, including in aquaporin 4 immunoglobulin G (AQP4-IgG)–seronegative NMOSD.
Investigators retrospectively analyzed plasma samples from 2 independent cohorts assembled in Austria, Germany, and the United States, with recruitment spanning 2001 to 2023 and longitudinal follow-up extending 2 years. Samples came from 2091 participants with neuroinflammatory disease and 1976 healthy controls; the longitudinal test cohort included 184 participants with MS, 65 with MOGAD, and 61 with NMOSD, while the validation cohort included 142 participants with MS, 24 with MOGAD, and 17 with NMOSD. EBNA-1 peptide antibodies were quantified by enzyme-linked immunosorbent assay (ELISA) at diagnosis and 3 follow-up time points, and the main metric was persistence of high-level titers in at least 2 of 4 samples.
Key Findings
- In the test cohort, 96.2% of participants with MS had high-level EBNA-1 peptide titers in at least 2 of 4 samples vs 7.7% of those with MOGAD (odds ratio [OR], 303.4; 95% CI, 94.4 to 908.6) and 18.0% of those with NMOSD (OR, 114.9; 95% CI, 43.0 to 280.0).
- Among patients with AQP4-IgG–seronegative NMOSD, only 11.1% showed persistent high titers vs 96.7% of matched patients with MS (OR, 236.0; 95% CI, 18.6 to 2588.0).
- In the validation cohort, the pattern held: 95.1% of patients with MS met the persistent-high-titer threshold vs 16.7% with MOGAD (OR, 96.4; 95% CI, 26.6 to 293.0) and 17.6% with NMOSD (OR, 90.0; 95% CI, 19.7 to 319.7).
- High-level titers present in 3 or 4 serial samples were observed only in MS, and the authors reported diagnostic accuracies generally exceeding 92% using the repeated high-titer definition for distinguishing MS from comparator groups using the repeated-high-titer approach.
Source
Vietzen H, Kühner LM, Berger SM, et al. Epstein-Barr virus antibodies to differentiate multiple sclerosis from other neuroinflammatory diseases. JAMA Neurol. Published online March 09, 2026. doi:10.1001/jamaneurol.2026.0240