Background: Antibodies against aquaporin-4 (AQP4-ab) have diagnostic and prognostic value. However, little is known to date about their utility in the first event of optic neuritis (ON). Objective: To evaluate the utility of systematic AQP4-ab determination in a retrospective cohort of patients with a first onset of ON. Patients and Methods: All patients (n = 42) were tested for AQP4-ab in the following context: typical ON (TON) and atypical ON (AON). Clinical, radiological and biochemical data were collected; patients with TON vs. AON and AQP4-ab positive vs. negative were compared. Results: The proportion of AQP4-ab seropositive patients was 40% in the TON group vs. 40.9% in the AON group. Visual acuity (VA) at baseline was poor in AON patients (p = 0.02) and these patients were associated with worse VA outcome (p < 0.001) at 6 months compared with TON patients, with a median follow-up of 3.27 ± 1.79 years. Brain MRI with dissemination in space criteria (p < 0.001), spinal cord partial lesions (p < 0.001) and oligoclonal bands (p = 0.02) were associated with the initial stages of TON. VA severity, number of myelitis attacks and ON relapses did not differ significantly between seropositive and seronegative patients. AQP4-ab were detected only in neuromyelitis optica spectrum disorders patients. Conclusion: This study showed a high seropositivity for AQP4-ab in TON patients, suggesting that it could diagnostic utility at the onset of ON.

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