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Multiple Sclerosis Physical Activity in Pediatric Multiple Sclerosis— Can Lifestyle Factors Affect Disease Outcomes? E Ann Yeh, MD, FRCPC 1 and Robert Motl, PhD 2 1. Associate Professor of Paediatrics (Neurology), University of Toronto; Director, Child Neurology Residency Program; Director, Paediatric MS and Demyelinating Disorders Program; Associate Scientist, Research Institute, Hospital for Sick Children, Toronto, Ontario, Canada; 2. Associate Professor, Department of Kinesiology and Community Health; Affiliate, Neuroscience Program; Director, Exercise Neuroscience Research Laboratory, University of Illinois at Urbana-Champaign, US Abstract Currently, little to no information is available about interventions that can ameliorate symptoms such as depression and fatigue in children and adolescents with multiple sclerosis (MS), nor is there clear information on modifiable factors that can provide neuroprotection in this ­population. However, physical activity (PA) may have significant effects on disease activity, future disability, cognition, and symptoms of depression and fatigue in pediatric MS. The extent of this effect is unknown. In this paper, after providing an overview of definitions of and outcomes in pediatric MS, we provide a review of existing literature relating PA to outcomes in MS, and then turn to a review of the complex relationship between PA, neuroinflammation, and outcomes in the pediatric population. Keywords Pediatric, multiple sclerosis, physical activity, outcome, fatigue, depression, exercise, review Disclosure: E Ann Yeh receives funding from the National MS Society, the Canadian Institutes of Health Research, the Dairy Farmers of Ontario, SickKids Foundation, SickKids Innovation Fund, Canadian Multiple Sclerosis Monitoring System/Public Health Agency of Canada (CMSMS/PHAC), the Canadian Multiple Sclerosis Scientific Research Foundation, and the MS Society of Canada. Robert Motl has received speaker honoraria from EMD Serono. No funding was received for the publication of this article. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any noncommercial use, distribution, adaptation, and reproduction provided the original author(s) and source are given appropriate credit. Received: January 26, 2015 Accepted: March 6, 2015 Citation: US Neurology, 2015;11(1):19–22 Correspondence: E Ann Yeh, Division of Neurology, Hospital for Sick Children, 555 University Avenue, Toronto, ON, M5B 1X8 Canada. E: ann.yeh@sickkids.ca Demyelinating disorders of the central nervous system (CNS) occur in approximately 1/100,000 children. About one-fifth of these children will eventually receive a diagnosis of multiple sclerosis (MS). 1 These cases constitute approximately 2–5 % of all cases of MS. 2 Of these children, up to three-quarters will experience cognitive decline, depression, and/or fatigue, and irreversible motor disability occurs at a young age, on average 2 decades after disease onset, or in the fourth decade of life. Currently, little to no information is available about interventions that can ameliorate symptoms such as depression and fatigue in children and adolescents with MS. Cross-sectional studies in healthy adolescents have suggested relationships between higher levels of physical activity (PA) and cognitive outcomes, brain volumes, psychosocial outcomes, and academic achievement. Adult MS studies have shown PA to benefit cognition and psychosocial outcomes. Improvement in levels of PA in this population may provide a simple, nonpharmacologic means by which to reach this goal. In this paper, after providing background information on pediatric demyelinating disorders, we will move on to an overview of studies focused on the relationship between physical activity, neuroinflammation, and outcomes in MS and in the pediatric population. Tou ch MEd ica l MEdia Background—Pediatric Demyelinating Disorders Definitions Pediatric demyelinating disorders can be divided broadly into recurrent and monophasic entities, including acute disseminated encephalomyelitis (ADEM), clinically isolated syndrome (CIS), and MS, in addition to entities such as neuromyelitis optica and recurrent optic neuritis/chronic relapsing inflammatory optic neuropathy. Currently, magnetic resonance imaging (MRI) and clinical parameters fulfilling criteria for dissemination in space and time appear to be suitable for diagnosing MS in childhood. While the 2005 McDonald criteria were found to have poor specificity and sensitivity for pediatric MS, 3,4 the revised McDonald MRI Criteria 5 are sensitive and specific for the diagnosis of MS in children >11 years of age. 6 In brief, in children over 11 years of age, demonstration of dissemination in time can be accomplished by using a single MRI timepoint with evidence for enhancing and nonenhancing lesions in areas typical for MS, whereas dissemination in space can be demonstrated by greater or equal to one lesion in at least two of the four following regions: periventricular, juxtacortical, infratentorial, spinal cord. Younger children who present with multifocal demyelination diagnosed as ADEM should have two or more non-ADEM attacks or 19