Biomarker for Differentiating MS From NMOSD Identified in Study

A study published in JAMA Neurology identified a biomarker that could help to differentiate multiple sclerosis (MS) from diseases that present similarly, including myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and neuromyelitis optica spectrum disorder (NMOSD). High-level Epstein-Barr virus nuclear antigen 1 (EBNA-1) peptide antibody titers could help improve MS diagnosis accuracy.

The prognosis of MS, NMOSD, and MOGAD relies on being able to identify them and which treatment would work best. But with overlapping symptoms² and even features on imaging, it can be hard to make the right call, which can lead to losing time for treating the patient. MS pathogenesis has been linked to the herpesvirus Epstein-Barr virus (EBV), with EBNA-1 capable of triggering autoimmunity in the central nervous system. This study aimed to assess whether EBNA-1 peptide antibody responses differed between MS, MOGAD, NMOSD, and other neurological diseases to determine its ability to be used as a biomarker for diagnosis.¹

Patients from the Medical University of Vienna, Austria; the US Network of Pediatric MS Centers; and the BIOMARKER study at the Children’s Hospital Datteln in Datteln, Germany, who were diagnosed with a neuroinflammatory disease of the central nervous system between 2001 and 2023 were eligible for inclusion in the study. Patients were diagnosed with relapsing-remitting MS (RRMS) or MOGAD using established criteria or fulfilled diagnostic criteria for NMOSD, with seronegative NMOSD defined as being negative for AQP4-IgG and myelin oligodendrocyte glycoprotein. A healthy control group was included, as well as patients with other inflammatory neurological diseases who acted as the inflammatory controls.

There were 1338 patients with neuroinflammatory diseases that were included in the study, of whom 1039 were diagnosed with RRMS, 205 were diagnosed with MOGAD, and 94 fulfilled diagnostic criteria for NMOSD. A total of 318 patients with other inflammatory neurological diseases were included, and 715 patients were included with other neurological diseases. The mean (SD) age of all participants was 31.1 (18.9) years, and 52.1% were women. The 1548 patients who served as healthy controls had a mean age of 42.2 (16.3) years, and 38.4% were women.

The researchers found that high EBNA-1 peptide antibody titers were more frequently found in patients with MS compared with other disease groups and the controls. The other groups had low or absent titers (MOGAD: OR, 1.89; 95% CI, 1.39-2.55; NMOSD: OR, 1.44; 95% CI, 0.94-2.19). This pattern persisted across all subgroups, as women, men, pediatric patients, and adult patients with MS had more frequent high EBNA-1 peptide antibody titers.

The researchers also looked into whether persistent high-level EBNA-1 peptide antibody titers were representative of MS. Plasma samples taken at 3 points with mean intervals of 13.9 months after diagnosis were analyzed, with patients with MS demonstrating persistently high titers over time. Patients with MOGAD and NMOSD showed declines in titers during follow-up. Only 6 patients with MS did not have detectable titers through the analysis.

When comparing the number of follow-up samples with high-level EBNA-1 peptide antibody titers, the investigators observed that 96.2% of the patients with MS had high levels in at least 2 of 4 samples, compared with only 7.7% of those with MOGAD and 18% of those with NMOSD. The presence of high-level titers in 2 or more plasma samples was associated with a diagnosis of MS but not with a diagnosis of MOGAD or NMOSD (accuracy: 95.2% and 92.7%, respectively).

There were some limitations to this study. Detectable EBNA-1 peptide antibody responses were not developed by some patients with MS in the follow-up samples. The study was case-control and retrospective in design, which could have limited the results. The discovery cohort had a low proportion of women included.

“This case-control study highlights the diagnostic value of serial EBNA-1 peptide antibody measures to distinguish MS from other neuroinflammatory diseases,” the authors concluded. “This biomarker offers a noninvasive tool that may support early diagnosis, particularly in clinically ambiguous demyelinating presentations.…”

References

1. 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 9, 2026. doi:10.1001/jamaneurol.2026.0240
2. Mason K. New diagnostic criteria for MOGAD distinguishes the disease from MS and NMOSD. CU Anschutz. March 19, 2024. Accessed March 10, 2026. https://news.cuanschutz.edu/ophthalmology/new-diagnostic-criteria-for-mogad-distinguishes-the-disease-from-ms-and-nmosd