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This chapter covers the nature and course of pediatric-onset multiple sclerosis (POMS) related cognitive impairment, its clinical correlates, assessment considerations, impact on functional activities, and future directions directed towards improving our detection of cognitive impairment, the potential for treatments, and management of POMS-related cognitive impairment in clinical practice. Psychological distress, including depression and anxiety, is quite common in adults with MS and an important factor influencing neuropsychological performance. Cognitive functioning may be a functional result of depressive symptomatology. The onset of POMS can occur during very important developmental stages critical for social, academic, and daily functioning. Cognitive dysfunction clearly represents a major problem in children with MS. These children are at risk for poor academic performance and this could adversely affect their future ability to achieve their academic potential, go on to gainful employment, and be fully independent.