Abstract This review highlights the most common presentations of demyelination of the central nervous system (CNS, termed acquired demyelinating syndrome) in children, the difficulty in determining whether the first episode represents a monophasic/transient illness or relapsing disease, and the potential underlying etiologies that must be considered, including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and disorders associated with antibodies to myelin oligodendrocyte glycoprotein (MOG) antibodies. The initial clinical and magnetic resonance imaging (MRI) features, as well as those observed over time, are highlighted, emphasizing the distinct and overlapping features of each of these disorders.