Multiple sclerosis-related optic neuritis is an outlier in the autoimmune optic neuritis group. The 2022 International Panel Classification needs a prompt revision.

Introduction – Optic neuritis (ON) manifests in a range of demyelinating diseases of the central nervous system (DDCNS), offering crucial insights for early diagnosis and tailored treatment strategies. However, the current 2022 International Panel classification of ON fails to adequately distinguish multiple sclerosis-related ON (MSON) from other forms of immune-mediated ON (IMON).Objective – This study aims to propose a revised classification for immune-mediated ON emphasizing the distinctions between MSON and other IMON. Methods – Patients diagnosed with DDCNS presenting with ON as their initial symptom were selected. ON cases were categorized into two groups: (1) MSON, including single isolated ON and ON in MS;  (2) non-MS IMON, encompassing other IMON subtypes. Demographic, clinical, and imaging features, as well as outcomes, were compared between the groups. Results – Analysis of 271 DDCNS patients revealed 101 (37.5%) with MSON and 170 (62.5%) with non-MS IMON at disease onset. The non-MS IMON group included NMOSD-ON; MOG-ON, recurring idiopathic ON, chronic relapsing inflammatory optic neuropathy, ADEM-ON, systemic autoimmune diseases-related ON; parainfectious ON; vaccine-related ON; and IMON  of unknown etiology. Significant differences (p < 0.05) between MS-related optic neuritis (MS-ON) and non-MS optic neuritis included age at onset, race, simultaneous bilaterality, severity of visual impairment, presence of CSF-specific OCB, and MRI lesions in the brain and optic nerve. These differences  underscore the need for a revised classification, distinct from the 2022 International Panel classification. This revision proposes the classification of MS-ON as a separate entity, distinguished from other autoimmune ON (AION) forms. Additionally, the AION group should be renamed as IMON group to encompass  parainfectious ON, vaccine-related ON, and cancer-related ON.Conclusions – The proposed revision of the 2022 International Panel Classification of ON could assist clinicians in more accurately identifying MSON within the expanding spectrum of identifiable IMON etiologies, thereby facilitating tailored treatment for patients’ conditions.