The optic nerve inflammation may have multiple etiologies (idiopathic, autoimmunity, infection, granulomatous diseases, vasculitides, paraneoplastic disorders, demyelination). Further prolonged follow-up studies are needed to highlight the predictors of PON evolution, its potential sequelae, and the best treatment options. A careful evaluation of the clinical and investigation findings and the natural course of PON is necessary to define its pathogenic pathway and evolution. We discuss the possible evolution of presenting ON in other ADSs, based on recent literature. We describe four pediatric cases presenting clinically with ON, with different etiopathogenetic pictures: one case had a probable infective etiology, while the others were associated with different demyelinating disorders (MS, NMO, syndrome related to MOG-IgG). These different PON phenotypes present variable clinical and radiological features, plasma and liquor biomarkers, and prognosis. PON has a high impact on the quality of life as it may or may not evolve into other acquired demyelinating syndromes (ADSs), such as multiple sclerosis (MS), neuromyelitis optica (NMO), or other syndromes related to the myelin oligodendrocyte glycoprotein IgG antibodies (MOG-IgG). Pediatric optic neuritis (PON) may be a clinically isolated and self-limiting event or may present in the context of underlying neurologic, infective, or systemic disease.
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