This chapter focuses on the clinical features of the pathophysiology of acute disseminated encephalomyelitis (ADEM) in children. ADEM can occur at any age, but is more common in pediatric patients than in adults. Few systematic population-based studies have been performed to address the incidence and geographic distribution of ADEM. ADEM was more frequently associated with pediatric exanthematous infections. ADEM is usually a monophasic illness presenting with neurological symptoms and signs within 2 days to 4 weeks after an antecedent event. Neuroimaging studies are useful and essential tools in establishing the diagnosis of ADEM. Fever, encephalopathy, and neurological signs and symptoms are by nature frequent presenting features of ADEM. Many inflammatory and non-inflammatory disorders of the central nervous system (CNS) may have similar clinical and neuroimaging presentation. Patients who do not have encephalopathy are categorized as having a clinical isolated syndrome (CIS).