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Objective: To determine the impact of pediatric-onset multiple sclerosis (MS) on age-expected brain growth.Methods: Whole brain and regional volumes of 36 patients with relapsing-remitting MS onset prior to 18 years of age were segmented in 185 longitudinal MRI scans (2-11 scans per participant, 3-month to 2-year scan intervals). MRI scans of 25 age-and sex-matched healthy normal controls (NC) were also acquired at baseline and 2 years later on the same scanner as the MS group. A total of 874 scans from 339 participants from the NIH-funded MRI study of normal brain development acquired at 2-year intervals were used as an age-expected healthy growth reference. All data were analyzed with an automatic image processing pipeline to estimate the volume of brain and brain substructures. Mixed-effect models were built using age, sex, and group as fixed effects.Results: Significant group and age interactions were found with the adjusted models fitting brain volumes and normalized thalamus volumes (p , 10 24 ). These findings indicate a failure of agenormative brain growth for the MS group, and an even greater failure of thalamic growth. In patients with MS, T2 lesion volume correlated with a greater reduction in age-expected thalamic volume. To exclude any scanner-related influence on our data, we confirmed no significant interaction of group in the adjusted models between the NC and NIH MRI Study of Normal Brain Development groups. Conclusions:Our results provide evidence that the onset of MS during childhood and adolescence limits age-expected primary brain growth and leads to subsequent brain atrophy, implicating an early onset of the neurodegenerative aspect of MS. Neurology ® 2014;83:2140-2146 GLOSSARY EDSS 5 Expanded Disability Status Scale; FOV 5 field of view; MS 5 multiple sclerosis; NC 5 normally developing controls; NIHPD 5 NIH MRI Study of Normal Brain Development; PDW 5 proton density-weighted; RF 5 radiofrequency; T1W 5 T1-weighted; T2W 5 T2-weighted; TE 5 echo time; TR 5 repetition time.In multiple sclerosis (MS), focal inflammatory white matter lesions are the most visible aspect of pathology but represent only one component of the disease. There is growing evidence that the disease is also characterized by a neurodegenerative component.1 In adult-onset MS, deep gray matter atrophy is measurable even within the first few years after the first attack. 2In cross-sectional analyses, patients with MS with disease onset prior to age 18 years have been shown to have reduced thalamic 3-5 and brain volumes 3,5,6 relative to age-and sexmatched healthy controls. As MS is a chronic progressive illness, and childhood and adolescence are key periods of brain growth, 7 longitudinal analysis is required to define the impact of MS disease on brain development, in order to determine whether these differences in brain volumes are due to failure of normal age-related brain growth or to progressive loss of volume, or both.In this study, we used longitudinal MRI data to compare the growth trajectory of the brain and ...