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This chapter reviews the spectrum of inflammatory, infectious, metabolic, and neurodegenerative disorders that can overlap or simulate the phenotype of demyelinating disorders in children, including its relapsing-remitting nature. Careful clinical documentation, serum and cerebrospinal fluid (CSF) testing and neuroimaging will likely provide the diagnostic specificity desired to differentiate between acquired demyelinating disorders of the CNS in children and the other disorders. Careful but preliminary studies looking at MRI characteristics are attempting to identify reliable findings to differentiate between pediatric multiple sclerosis and other, clinically relapsing neurologic disorders. Validation of these early findings as well as studies to define additional risk factors, clinical features and biomarkers are needed to further improve our ability to recognize acquired CNS demyelinating disease and to differentiate it from other types of CNS lesions in children. Newer imaging modalities such as diffusion tensor imaging, magnetization transfer ratios, and volumetric analysis will likely play a future role.