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Aim: We reviewed the clinical features of a sample of pediatric acquired demyelinating syndromes with the purpose of determining the appropriate protocol for follow-up after the first episode., Methods: A multicenter retrospective observational study was conducted on a cohort of 40 children diagnosed with a first episode of acquired demyelinating syndrome over the period 2012-2021. Patients were evaluated with clinical and neuroradiologic assessment after 3, 6, and 12 months, with a median follow-up of 4.0 years., Results: At the first acquired demyelinating syndrome episode, 18 patients (45%) were diagnosed with acute disseminated encephalomyelitis, 18 (45%) with clinical isolated syndrome, and 4 (10%) with multiple sclerosis. By month 12, 12 patients (30%) had progressed from an initial diagnosis of acute disseminated encephalomyelitis (2) or clinical isolated syndrome (10) to multiple sclerosis. Of these, 6 had clinical relapse and 6 radiologic relapse only. The first relapse occurred after a median of 3 months. Among the patients who had evolved toward multiple sclerosis, there was a prevalence of females ( P  = .014), higher oligoclonal bands positivity ( P  = .009), and older median age ( P  < .001) as compared with those who had remained stable., Interpretation: Both clinical and radiologic follow-up of children with acquired demyelinating syndromes is crucial, especially during the first year after acute onset, for early identification of multiple sclerosis and prompt initiation of disease-modifying treatment to delay axonal damage and to limit disability.