Although Epstein–Barr virus (EBV) is hypothesized to be a prerequisite for multiple sclerosis (MS), up to 15% of children with a diagnosis of MS were reported to be EBV‐seronegative. When re‐evaluating 25 EBV‐seronegative children out of 189 pediatric patients with a diagnosis of clinically isolated syndrome/MS, we found anti–myelin oligodendrocyte glycoprotein (MOG) antibody in 11 of 25 (44%) EBV‐seronegative but only 9 of 164 (5.5%, p < 0.001) EBV‐seropositive patients. After critical review, MS remained a plausible diagnosis in only 4 of 14 EBV‐seronegative/MOG antibody–negative patients. In children with an MS‐like presentation, EBV seronegativity should alert clinicians to consider diagnoses other than MS, especially MOG‐antibody disease. ANN NEUROL 2021;89:1234–1239

Background: Myelin oligodendrocyte glycoprotein (MOG)-IgG is increasingly detected in children with CNS demyelinating diseases. Due to the clinical overlap in children with CNS demyelination with and without MOG-IgG positivity, identifying distinct characteristics would help early diagnosis. Objective: To compare the specific features that may help differentiate MOG-IgG positive from negative children with CNS demyelinating diseases. To compare characteristics of patients with high and low MOG-IgG titers. Methods: Children with CNS demyelinating disorders with onset before 18 years of age who were tested for MOG-IgG at the University of California San Francisco were included. This retrospective study collected the following by chart review: demographic, clinical, MRI, CSF, and treatment data. Serum was tested for MOG-IgG at Mayo Clinic by live cell-based fluorescent activated cell sorting assay with titer ≥1:20 confirming positivity. Results: We assessed 65 Mog-IgG positive and 65 MOG-IgG negative patients. Median (IQR) age of onset was 7.6 (6.6) years for MOG-IgG positive and 13.8 (5.8) years for MOG-IgG negative (p<0.001). The female to male ratio was approximately 1:1 for the MOG-IgG positive group and 3:1 for the negative group (p=0.042). The most common initial diagnosis was demyelinating disease not otherwise specified (52.3%) in the positive group, compared to relapsing-remitting multiple sclerosis (41.5%) in the negative group (p<0.01). Optic nerve involvement (52.3%) was the most common clinical localization at onset for the MOG-IgG positive group, while brainstem/cerebellar (49.2%) localization predominated in the MOG-IgG negative group. The positive group also presented more often with a severe event at disease onset than the negative group (81.5% vs 60.3%; p< 0.002). MOG-IgG positive children had a lower frequency of oligoclonal bands (15.8% vs 57.4%; p<0.001). The frequency of baseline brain and spinal cord MRI abnormalities were similar in both groups; however, MOG-IgG positive patients more often had T2 hyperintense lesions in the optic nerves (26/43 vs 10/41; p<0.001). Disease-modifying medications were used in 64.6% of MOG-IgG positive patients versus 80% of negative children. Of the 32 positive patients with follow-up titers, seven reverted to negative while two who tested negative initially converted to positive. Positive titers greater than 1:160 were only observed within four months of a clinical event (disease onset or relapse). Patients with high and low MOG-IgG titers were comparable in demographic and clinical characteristics. Conclusion: Despite some clinical overlap, we report notable demographic, MRI and CSF differences between MOG-IgG positive and negative children with CNS demyelinating disorders at disease onset. High MOG-IgG titers were only observed close to a clinical event.