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BACKGROUND: Multiple sclerosis (MS) and allergies are both considered to be related to imbalanced Th1 and Th2 immune responses. Previous studies evaluating the relationship between MS and allergies provide conflicting results. OBJECTIVE: To assess allergies and asthma as risk factors for MS and as predictors of MS relapses in a pediatric cohort. METHODS: The environment and genetic risk factors for pediatric MS study is a national case-control project with 16 participating US sites. An environmental questionnaire is used that includes history of allergies in the first five years of life. Case-control data are entered in the pediatric MS Network database and cases at 12 of the 16 sites enter relapse data prospectively. Annualized relapse rate was calculated for patients with follow-up and adjusted for age at disease onset, gender, race, ethnicity, and use of disease-modifying therapy (DMT). RESULTS: We included 271 cases (mean age at disease onset of 15.7years and 62% female) and 418 controls. Relapse data were available for 193 cases. There was no difference in prevalence of allergies or asthma between cases and controls. Patients with food allergies had fewer relapses compared to patients without food allergies (0.14 vs 0.48, p=0.01). CONCLUSIONS: While allergies and asthma are not associated with pediatric MS, cases with food allergies have fewer relapses compared to those without food allergies.

Background: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently described demyelinating disorder, and children represent about 50% of all cases. Almost half of the patients experience relapses, but very few studies have evaluated predictors of relapse risk, challenging clinical management. The study aimed to identify predictors at MOGAD onset that are associated with a relapsing course., Methods: Prospectively collected data from paediatric patients with MOGAD seen by the US Network of Paediatric MS Centres were leveraged. Univariable and adjusted multivariable models were used to predict recurrent disease., Results: We identified 326 MOGAD cases (mean age at first event 8.9 years [SD 4.3], 57% female, 77% white and 74% non-Hispanic) and 46% relapsed during a mean follow-up of 3.9 years (SD 4.1). In the adjusted multivariable model, female sex (HR 1.66, 95% CI 1.17 to 2.36, p=0.004) and Hispanic/Latino ethnicity (HR 1.77, 95% CI 1.19 to 2.64, p=0.005) were associated with a higher risk of relapsing MOGAD. Maintenance treatment initiated before a second event with rituximab (HR 0.25, 95% CI 0.07 to 0.92, p=0.037) or intravenous immunoglobulin (IVIG) (HR 0.35, 95% CI 0.14 to 0.88, p=0.026) was associated with lower risk of a second event in multivariable analyses. Conversely, maintenance steroids were associated with a higher estimated relapse risk (HR 1.76, 95% CI 0.90 to 3.45, p=0.097)., Conclusion: Sex and ethnicity are associated with relapsing MOGAD. Use of rituximab or IVIG therapy shortly after onset is associated with a lower risk of the second event. Preventive treatment after a first event could be considered for those with a higher relapse risk., Competing Interests: Competing interests: AV is supported by Fellowship Grants from Biogen, EMD Serono and Novartis (2022-2024) and is a recipient of National Multiple Sclerosis Society (NMSS) Sylvia Lawry Fellowship Award (Grant#FP-2307-41848, 2024-2025).JR is supported by NMSS Grant SI-2110-38420, a grant awarded to the Utah DCAC which in turn provides funding for my contributions.CEM is supported by a National Multiple Sclerosis Society Clinician Scientist Development Award # FAN-2107-38301 and is listed on a patent application related to autoimmune aquaporinopathy.SSZ is supported by the National Institutes of Health (Grants 1 R01 AI131624-01A1 and 1 R01 AI170863-01A1), Race to Erase MS, The Sumaira Foundation and the Weill Institute of Neurosciences; received fees for consultation with Amgen/Horizon Therapeutics, Genentech, Genzyme and Merck; received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Amgen/Horizon Therapeutics, Genzyme and Merck and Co; received payments from Krakow for expert testimony; received support for attending meetings and/or travel from Horizon Therapeutics/Amgen, EMD Serono and Alexion; listed on a patent application related to autoimmune aquaporinopathy; participated on a Data Safety Monitoring Board or Advisory Board Horizon Therapeutics/Amgen, EMD Serono and Alexion; and serves in the leadership or fiduciary role in other boards, societies, committees or advocacy groups for NMSS, as deputy editor for Neurology, Neuroimmunology and Neuroinflammation, and ACTRIMS advisory committee.TCC has received research funding (for his institution) from NMSS Grant # SI-210-38420, Hoffmann-La Roche, Biogen and UCB.JR has research support from NMSS, NIH, Guthy Jackson Foundation, PCORI, Friends of MS, Biogen and VA.EPF is supported by the National Institutes of Health/National Institute of Neurological Disorders and Stroke (R01NS113828) and funded this work; received research support from UCB; receives royalties for an article on UpToDate on MOGAD; a patent pending on DACH1-IgG as a biomarker of paraneoplastic autoimmunity; and participates on a Data Safety Monitoring Board or Advisory Board for Alexion, Horizon Therapeutics, UCB and Roche.J-MT serves as the site PI and collaborates with the NPMSC, which is supported by NMSS (SI-2110-38420, multisite funding: PI University of Utah, T.C. Casper), NINDS (R01NS117541) Institution (multisite funding; PI UCSF E. Waubant), NMSS (RG4861A3/1, multisite funding: PI University of Utah T.C. Casper) and NINDS (R01NS113828) Institution (PI Mayo Clinic E.P. Flanagan).TC is supported by grant funding from NIH, NMSS, Massachusetts Life Sciences Center, Department of Defense, Novartis Pharmaceuticals Corporation, Tiziana Therapeutics, Wesley Clover International, Genentech, Celgene Corp, Sumaira Foundation, Brainstorm Cell Therapeutics, Bristol Myers Squibb, EMD Serono, I-Mab Biopharma, Mallinckrodt ARD, Octave Bioscience, Sanofi and Genzyme; received consulting fees (payment made to the institution) from Genentech, Janssen Research & Development, Novartis Pharmaceuticals Corporation and Siemens Healthcare Diagnostics, Banner Life Sciences, Biogen, Bristol Myers Squibb, Octave Bioscience, Sandoz, Siemens, TG Therapeutics, UCB and Vida Ventures; received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Genentech, MJH Life Sciences, Prime Education and Novartis Pharmaceuticals Corporation; and participates in on a Data Safety Monitoring Board or Advisory Board for Bristol Myers Squibb, Genentech, Novartis Pharmaceuticals Corporation, Octave Bioscience, Roche, Sanofi US Services.MPG serves as the site PI and collaborates with the NPMSC, which is supported by NMSS (SI-2110-38420, multisite funding: PI University of Utah, T.C. Casper), NINDS (R01NS117541) Institution (multisite funding; PI UCSF E. Waubant), NMSS (RG4861A3/1, multisite funding: PI University of Utah T.C. Casper) and NINDS (R01NS113828) Institution (PI Mayo Clinic E.P. Flanagan).JSG has received research funding from NMSS, the Department of Defence, Sanofi Pharmaceuticals, Octave Bioscience and EMD Serono.LAB has participated in multicenter clinical trials funded by Roche, Alexion and Biogen; received support from ROHHAD Fight, NIH and Rosamund Stone Zander Translational Neuroscience Center; received an honorarium for talks from Novartis; consultant to the National Vaccine Injury Compensation Program and the Massachusetts Department of Public Health; and received travel support from NMSS.MR has received research funding (Roche, Novartis, Biogen, Genentech, Connor B. Judge (CBJ) Foundation and National Multiple Sclerosis) and patient education funds (Genzyme, CBJ Foundation); served on the Data Safety Monitoring Committee (DSMC) for Biogen, Horizon, TG Theraeutics, Novartis, Cycle and EMD Serono; speaker or consultant for EMD Serono, Novartis, Genentech, Genzyme, Horizon, TG Therapeutics, Bristol Myers Squibb, (BMS), Cycle and Sanofi and is the Founder of Brain Fresh LLC and Co-Founder of Brain Ops Group; and involved in the leadership or fiduciary roles in other board, societies, committee or advocacy group for AAN, NMSS, Ohio Board Member.LK has received research funding from NMSS (#HC-1509-06233); additional research support was received from Novartis grant, NMSS grant #RG150705285, Biogen, NIH and Department of Defense; royalties received from various biopharmaceutical entities for use of the Fatigue Severity Scale; received consulting fees from Eisai, Gerson Lehrman, Peer View, WebMD/Medscape, F. Hoffman/LaRoche, CME Outfitters and General Dynamics Information; received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Bristol Myers Squibb and At the Limits; received payment for expert testimony from MCIC Vermont Individual; received travel support from Celgene; and participated on a Data Safety Monitoring Board or Advisory Board for Novartis and Biogen.GA has received research support from the NIH and NMSS.TS has received grants from the National MS Society, consulting fees from Hoffman LaRoche, honoraria from Cycle Pharmaceuticals, participated in a DSMB for Biogen and received travel support from AAN.SM is the site PI for clinical trials for paediatric MS, supported by Biogen and Roche.EW has not received any pharmaceutical company honorarium and is the site PI for Biogen, Alexion and Roche trials and is volunteering on a DSMB for a BMS trial; received funding from the NIH, the DoD and the Race to Erase MS; and received honoraria for talks for Advanced Curriculum and NeurologyLive.VAS, MW, SS, ZN, CMG, AS, AA, TEL, YW, AW and JC have no conflicts of interest to report., (© Author(s) (or their employer(s)) 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.)

Background and Objectives: This survey study aimed to (1) identify patient/family research priorities in pediatric-onset multiple sclerosis (POMS), and (2) delineate optimized methods for research study/clinical trials design, engagement, and implementation., Methods: Participants were as follows: (1) parents of a child (<18 years) with POMS enrolled in a national registry, (2) adolescents (13-17 years) with POMS in the registry, and (3) adults (18-40 years) with POMS receiving care at a registry affiliated clinic. Of 293 eligible participants, 192 completed surveys., Results: Experiences with health care and medications were generally positive but there remain areas of priority improvement. Incentives to participate in clinical trials included medications previously tested and in pill form, bloodwork/study visits required ⩾ every 3 months, cognitive testing ⩽1 hour, compensation for travel and time, ability to continue current multiple sclerosis (MS) medication, option to take study medication if on placebo, and individualized study feedback. Priorities for clinical research were (1) psychosocial impact, (2) cognitive/academic impact, (3) environmental risk, and (4) nutrition., Conclusions: Results highlighted the importance of a holistic approach to study design and a focus on the impact of disease on daily life to best engage patients and families in POMS clinical trials and research., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: T.C. has received compensation for consulting from Banner Life Sciences*, Biogen, Bristol Myers Squibb, Janssen, Genentech, Novartis Pharmaceuticals, Octave Bioscience, Sandoz, Siemens, TG Therapeutics*, UCB Biopharma, and Vida Ventures*. He has received compensation for speaking engagements from Prime Education, LLC*. He has received research support from the National Institutes of Health, National MS Society, US Department of Defense, Sumaira Foundation, Brainstorm Cell Therapeutics, Bristol Myers Squibb, Genentech, EMD Serono, I-Mab Biopharma, Mallinckrodt ARD, Massachusetts Life Sciences Center, Novartis Pharmaceuticals, Octave Bioscience, Sanofi Genzyme, Tiziana Life Sciences, and Wesley Clover International. All activities and funding have occurred within the past 24 months (*relationship has since ended), and disclosures do not conflict with the work being presented.

Background: Lipids are of particular interest for the study of neuroinjury and neuroinflammation as structural lipids are major components of myelin, and a variety of lipid species modulate inflammation. In this study, we performed an in-depth lipidomics analysis to identify lipids associated with injury and disease activity., Methods: Plasma samples were collected from paediatric-onset multiple sclerosis (MS) cases within 4 years of disease onset from 17 sites. The lipidome was measured using untargeted and targeted mass spectrometry. For cross-sectional analyses, the agreement between multiple machine learning models was used to predict neurofilament light chain (NfL) levels. In longitudinal analyses, the association between clinical (relapse count) and imaging (MRI count with ≥1 enhancing or new T2 lesion) outcomes with each metabolite was estimated using adjusted negative binomial regression., Results: At sample collection, 68% of the 435 included individuals were treatment-naive, with a median disease duration of 0.8 years (IQR 0.3-1.7). For longitudinal analyses, 381 and 335 subjects had at least 1 year of clinical and imaging follow-up, respectively. In cross-sectional analyses, NfL chain levels identified structural lipids (phosphatidylcholines and phosphatidylethanolamines) as the highest-performing predictors, including external validation. In contrast, longitudinal analyses found polyunsaturated fatty acids (PUFAs) and their derivatives to be protective from subsequent disease activity (q<0.001, multiple outcomes)., Conclusion: There are two categories of lipids associated with MS processes. First, structural lipids strongly associated with NfL levels may result from cell lysis secondary to acute inflammation. In contrast, PUFAs, especially ω-3, had a protective effect on subsequent disease activity., Competing Interests: Competing interests: VAS, KB, JC, DCL, GA, AA, SM, LFB, MRodriguez, TEL, J-MT, SP and JN have no conflicts of interest to report. PB has received honoraria from Genentech and EMD-Serono, grants from Genentech, EMD-Serono, GSK and Amylyx Pharmaceuticals. AV has received a Fellowship Grant from Biogen, Novartis and EMD Serono. CM is supported by a Clinician Scientist Development Award, Grant # FAN-2107-38301 from the National Multiple Sclerosis Society. JSG has received research support from NMSS, Octave, Biogen, EMD Serono, Novartis, ATARA Biotherapeutics and ABM. She has served on advisory boards for TG therapeutics and a Horizon and a paediatric clinical trial steering committee for Novartis. She has consulted for Google. LB has participated in multicentre clinical trials funded by Roche, Alexion and Biogen. She has current support from ROHHAD Fight, NIH and Rosamund Stone Zander Translational Neuroscience Center. She has received speakers honorarium from Novartis. MPG has received research funding paid to his institution from Biogen, Genentech Roche and Pfizer and personal compensation from Arialys for medical advisory board work. MRensel has received grant funding from the National MS Society (NMSS) and Genzyme. She has served as a consultant and or speaker for; EMD Serono, Horizon, Genzyme, Sanofi and Genentech. She serves on a data safety monitoring board for Biogen. She serves on the Ohio Board of NMSS. JR has received research funding from NMSS, NIH, Biogen and VATS has received speakers fees from Cycle Pharmaceutics and Hoffman La Roche. She participates in research funded by Roche and the National MS Society. TC has consulted for Genentech-Roche and Novartis. She has received research support from Bristol Myers Squibb, Genentech-Roche, Novartis, Octave Biosciences, Sanofi and Tiziana Life Sciences. AW has received research funding from the National Multiple Sclerosis Society, Genentech and Novartis. LK has received research or programmatic funding or has received compensation for consulting, speaking, travel and meal allowances or serving on DSMB committees from Eisai, Peer View, Gerson Lehrman, WebMD, CME Outfitters, General Dynamics Information, At the Limits, Novartis, Biogen, F. Hoffman/LaRoche. She also receives royalties for use of the Fatigue Severity Scale by various biopharmaceutical entities. FQ is an employee of Octave Bioscience. TCC has received funding for research unrelated to this work from Hoffmann La Roche and Biogen. EW has participated in multicentre clinical trials funded by Genentech, Alexion and Biogen. She has current support from the NIH, NMSS, DoD, PCORI, CMSC and Race to Erase MS. She has received honorarium for talks from Advanced Curriculum, Yoga Moves MS and NeurologyLive., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Understanding nutrition's role in multiple sclerosis (MS) can guide recommendations and intervention-based studies., Objective: Evaluate the association between nutrition and pediatric-onset MS outcomes., Methods: Prospective longitudinal multicenter study conducted as part of the US Network of Pediatric MS centers. Predictors were collected using a food screener estimating intake of various dietary food groups (e.g. dairy and fruits) and additional calculated indices (e.g. Healthy Eating Index (HEI)). Outcomes included time-from-enrollment to clinical relapse, new magnetic resonance imaging (MRI) T2 lesions, and Expanded Disability Status Scale (EDSS) increase., Results: 353 children with MS were enrolled (mean ± SD age 15.4 ± 2.9, follow-up 3.9 ± 2.6 years). Multivariable analysis demonstrated that increased dairy by 50% of recommended intake was associated with increased relapse risk by 41% (adjusted hazard ratio (HR) 1.41, 95% CI 1.07-1.86), and risk of T2 progression by 40% (1.40, 1.12-1.74). Increased intake of fruit or vegetable above recommended, and every five-point HEI increase decreased relapse risk by 25% (0.75, 0.60-0.95), 45% (0.55, 0.32-0.96), and 15% (0.84, 0.74-0.96), respectively. No associations were found with EDSS., Conclusion: This work supports the influence of dietary intake on MS course, particularly with dairy intake. Future prospective study is required to establish causation., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Objective: Prior Epstein-Barr virus (EBV) infection is associated with an increased risk of pediatric-onset multiple sclerosis (POMS) and adult-onset multiple sclerosis (MS). It has been challenging to elucidate the biological mechanisms underlying this association. We examined the interactions between candidate human leukocyte antigen (HLA) and non-HLA variants and childhood EBV infection as it may provide mechanistic insights into EBV-associated MS., Methods: Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. Participants were categorized as seropositive and seronegative for EBV-viral capsid antigen (VCA). The association between prior EBV infection and having POMS was estimated with logistic regression. Interactions between EBV serostatus, major HLA MS risk factors, and non-HLA POMS risk variants associated with response to EBV infection were also evaluated with logistic regression. Models were adjusted for sex, age, genetic ancestry, and the mother's education. Additive interactions were calculated using relative risk due to interaction (RERI) and attributable proportions (APs)., Results: A total of 473 POMS cases and 702 controls contributed to the analyses. Anti-VCA seropositivity was significantly higher in POMS cases compared to controls (94.6% vs 60.7%, p  < 0.001). There was evidence for additive interaction between childhood EBV infection and the presence of the HLA-DRB1*15 allele (RERI = 10.25, 95% confidence interval (CI) = 3.78 to 16.72; AP = 0.61, 95% CI = 0.47 to 0.75). There was evidence for multiplicative interaction ( p  < 0.05) between childhood EBV infection and the presence of DRB1*15 alleles (odds ratio (OR) = 3.43, 95% CI = 1.06 to 11.07). Among the pediatric MS variants also associated with EBV infection, we detected evidence for additive interaction ( p  = 0.02) between prior EBV infection and the presence of the GG genotype in risk variant (rs2255214) within CD86 (AP = 0.30, 95% CI = 0.03 to 0.58)., Conclusion: We report evidence for interactions between childhood EBV infection and DRB1*15 and the GG genotype of CD86 POMS risk variant. Our results suggest an important role of antigen-presenting cells (APCs) in EBV-associated POMS risk., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

ADEM is an inflammatory disease, with new onset polyfocal neurologic symptoms, encephalopathy and multifocal demyelination, typically in childhood. Initial diagnosis of ADEM is challenging and up to 20 % of children with MS or NMOSD are initially diagnosed with ADEM. We describe characteristics of patients with monophasic ADEM vs. recurrent demyelinating syndromes at onset and identify features consistent with monophasic course. This is a multicenter observational study of children with demyelinating disease, followed at 12 regional pediatric MS centers. Descriptive statistics were used to report patient characteristics, clinical/imaging features and outcomes. Logistic regression was used to predict features associated with monophasic course. As of July 2019, 837 children with final diagnosis of ADEM (n = 79), MS (n = 646) or NMOSD (n = 112) were identified. The mean follow-up was 5·7 +/- 3·2 years. ADEM patients were youngest with mean age at first event 5·2 +/- 3·8 years (p < 0.001) and male predominant (66 %) (p < 0·001). After 2 years of follow-up, 83 % of patients initially diagnosed with monophasic ADEM retained this diagnosis. In multivariable analysis, older age (OR 1·16 [95 % CI 1·02 - 1·33] for 1-year increase, p = 0·02), presenting with optic neuritis (OR 8.18 [95 % CI 1.88 - 35.64], p = 0·005) and presence of gadolinium enhancement (OR 4.08 [95 % CI 1.38 - 12.08], p = 0·011) were associated with reclassification of ADEM to MS, NMOSD or DDNOS within 2 years. Children with monophasic ADEM vs. those reclassified as other demyelinating disorders are younger at onset, and less likely to have optic neuritis or gadolinium-enhancing lesions at onset., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interests., (Copyright © 2023. Published by Elsevier B.V.)

Background: Treatment of pediatric-onset multiple sclerosis (POMS) is challenging given the lack of safety and efficacy data in the pediatric population for many of the disease-modifying treatments (DMTs) approved for use in adults with MS. Our objective was to describe the demographic features and clinical and radiologic course of patients with POMS treated with the commonly used newer DMTs within the US Network of Pediatric MS Centers (NPMSC)., Methods: This is an analysis of prospectively collected data from patients who initiated treatment before age 18 with the DMTs listed below at the 12 regional pediatric MS referral centers participating in the NPMSC., Results: One hundred sixty-eight patients on dimethyl fumarate, 96 on fingolimod, 151 on natalizumab, 166 on rituximab, and 37 on ocrelizumab met criteria for analysis. Mean age at DMT initiation ranged from 15.2 to 16.5 years. Disease duration at the time of initiation of index DMT ranged from 1.1 to 1.6 years with treatment duration of 0.9-2.0 years. Mean annualized relapse rate (ARR) in the year prior to initiating index DMT ranged from 0.4 to 1.0. Mean ARR while on index DMT ranged from 0.05 to 0.20. New T2 and enhancing lesions occurred in 75%-88% and 55%-73% of the patients, respectively, during the year prior to initiating index DMT. After initiating index DMT, new T2 and enhancing lesions occurred in 0%-46% and 11%-34% patients, respectively. Rates of NEDA-2 (no evidence of disease activity) ranged from 76% to 91% at 6 months of treatment with index DMTs and 66% to 84% at 12 months of treatment with index DMTs., Conclusions: Though limited by relatively short treatment duration with the index DMTs, our data suggest clinical and MRI benefit, as well as high rates of NEDA-2, in a large number of POMS patients, which can be used to guide future studies in this population., Competing Interests: Declaration of competing interest No conflicts of interest noted., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: We previously reported an association between household chemical exposures and an increased risk of paediatric-onset multiple sclerosis., Methods: Using a case-control paediatric multiple sclerosis study, gene-environment interaction between exposure to household chemicals and genotypes for risk of paediatric-onset multiple sclerosis was estimated.Genetic risk factors of interest included the two major HLA multiple sclerosis risk factors, the presence of DRB1*15 and the absence of A*02, and multiple sclerosis risk variants within the metabolic pathways of common household toxic chemicals, including IL-6 (rs2069852), BCL-2 (rs2187163) and NFKB1 (rs7665090)., Results: 490 paediatric-onset multiple sclerosis cases and 716 controls were included in the analyses. Exposures to insect repellent for ticks or mosquitos (OR 1.47, 95% CI 1.06 to 2.04, p=0.019), weed control products (OR 2.15, 95% CI 1.51 to 3.07, p<0.001) and plant/tree insect or disease control products (OR 3.25, 95% CI 1.92 to 5.49, p<0.001) were associated with increased odds of paediatric-onset multiple sclerosis. There was significant additive interaction between exposure to weed control products and NFKB1 SNP GG (attributable proportions (AP) 0.48, 95% CI 0.10 to 0.87), and exposure to plant or disease control products and absence of HLA-A*02 (AP 0.56; 95% CI 0.03 to 1.08). There was a multiplicative interaction between exposure to weed control products and NFKB1 SNP GG genotype (OR 2.30, 95% CI 1.00 to 5.30) but not for other exposures and risk variants. No interactions were found with IL-6 and BCL-2 SNP GG genotypes., Conclusions: The presence of gene-environment interactions with household toxins supports their possible causal role in paediatric-onset multiple sclerosis., Competing Interests: Competing interests: EW has current support from the NIH, NMSS, PCORI, CMSC and Race to Erase MS., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Rare genetic variants are emerging as important contributors to the heritability of multiple sclerosis (MS). Whether rare variants also contribute to pediatric-onset multiple sclerosis (POMS) is unknown., Objective: To test whether genes harboring rare variants associated with adult-onset MS risk ( PRF1, PRKRA, NLRP8 , and HDAC7 ) and 52 major histocompatibility complex (MHC) genes are associated with POMS., Methods: We analyzed DNA samples from 330 POMS cases and 306 controls from the US Network of Pediatric MS Centers and Kaiser Permanente Northern California for which Illumina ExomeChip genotypes were available. Using the gene-based method "SKAT-O," we tested the association between candidate genes and POMS risk., Results: After correction for multiple comparisons, one adult-onset MS gene ( PRF1, p = 2.70 × 10 -3 ) and two MHC genes ( BRD2, p = 5.89 × 10 -5 and AGER, p = 7.96 × 10 -5 ) were significantly associated with POMS. Results suggest these are independent of HLA-DRB1*1501., Conclusion: Findings support a role for rare coding variants in POMS susceptibility. In particular, rare minor alleles within PRF1 were more common among individuals with POMS compared to controls while the opposite was true for rare variants within significant MHC genes, BRD2 and AGER . These genes would not have been identified by common variant studies, emphasizing the merits of investigating rare genetic variation in complex diseases.

Background and Objectives: Limited data is available on children with evidence of silent central nervous system demyelination on MRI. We sought to characterize the population in a US cohort and identify predictors of clinical and radiologic outcomes., Methods: We identified 56 patients such patients who presented with incidental MRI findings suspect for demyelination, enrolled through our US Network of Pediatric Multiple Sclerosis Centers, and conducted a retrospective review of 38 patients with MR images, and examined risk factors for development of first clinical event or new MRI activity. MRI were rated based on published MS and radiologically isolated syndrome (RIS) imaging diagnostic criteria., Results: One-third had a clinical attack and ¾ developed new MRI activity over a mean follow-up time of 3.7 years. Individuals in our cohort shared similar demographics to those with clinically definite pediatric-onset MS. We show that sex, presence of infratentorial lesions, T1 hypointense lesions, juxtacortical lesion count, and callosal lesions were predictors of disease progression. Interestingly, the presence of T1 hypointense and infratentorial lesions typically associated with worse outcomes were instead predictive of delayed disease progression on imaging in subgroup analysis. Additionally, currently utilized diagnostic criteria (both McDonald 2017 and RIS criteria) did not provide statistically significant benefit in risk stratification., Conclusion: Our findings underscore the need for further study to determine if criteria currently used for pediatric patients with purely radiographic evidence of demyelination are sufficient., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: The purpose of this study was to determine the frequency of myelin oligodendrocyte glycoprotein (MOG)-IgG and aquaporin-4 (AQP4)-IgG among patients with pediatric-onset multiple sclerosis (POMS) and healthy controls, to determine whether seropositive cases fulfilled their respective diagnostic criteria, to compare characteristics and outcomes in children with POMS versus MOG-IgG-associated disease (MOGAD), and identify clinical features associated with final diagnosis., Methods: Patients with POMS and healthy controls were enrolled at 14 US sites through a prospective case-control study on POMS risk factors. Serum AQP4-IgG and MOG-IgG were assessed using live cell-based assays., Results: AQP4-IgG was negative among all 1,196 participants, 493 with POMS and 703 healthy controls. MOG-IgG was positive in 30 of 493 cases (6%) and zero controls. Twenty-five of 30 patients positive with MOG-IgG (83%) had MOGAD, whereas 5 of 30 (17%) maintained a diagnosis of multiple sclerosis (MS) on re-review of records. MOGAD cases were more commonly in female patients (21/25 [84%] vs 301/468 [64%]; p = 0.044), younger age (mean = 8.2 ± 4.2 vs 14.7 ± 2.6 years; p < 0.001), more commonly had initial optic nerve symptoms (16/25 [64%] vs 129/391 [33%]; p = 0.002), or acute disseminated encephalomyelitis (ADEM; 8/25 [32%] vs 9/468 [2%]; p < 0.001), and less commonly had initial spinal cord symptoms (3/20 [15%] vs 194/381 [51%]; p = 0.002), serum Epstein-Barr virus (EBV) positivity (11/25 [44%] vs 445/468 [95%]; p < 0.001), or cerebrospinal fluid oligoclonal bands (5/25 [20%] vs 243/352 [69%]; p < 0.001)., Interpretation: MOG-IgG and AQP4-IgG were not identified among healthy controls confirming their high specificity for pediatric central nervous system (CNS) demyelinating disease. Five percent of those with prior POMS diagnoses ultimately had MOGAD; and none had AQP4-IgG positivity. Clinical features associated with a final diagnosis of MOGAD in those with suspected MS included initial ADEM phenotype, younger age at disease onset, and lack of EBV exposure. ANN NEUROL 2023;93:271-284., (© 2022 American Neurological Association.)

Objective: Cognitive involvement in pediatric multiple sclerosis (MS) relative to adult MS is less defined. This study advances our understanding by measuring cognitive performances in pediatric MS, adult MS, and pediatric healthy controls., Methods: Consecutive relapsing pediatric MS participants from the United States Network of Pediatric MS Centers were compared with pediatric healthy controls and adults with relapsing MS. Participants were compared on two screening batteries: the Brief International Cognitive Assessment for MS and the Cogstate Brief Battery. Results were transformed to age-normative z scores., Results: The pediatric groups (MS vs. Healthy Controls) did not differ on either battery's composite mean score or individual test scores ( p s > 0.32), nor in the proportions impaired on either battery, Brief International Cognitive Assessment for MS (26% vs. 24%, p  = 0.83); Cogstate Brief Battery (26% vs. 32%, p  = 0.41). The pediatric versus adult MS group even after controlling for differences in disease duration performed better on the Brief International Cognition Assessment for MS composite ( p  = 0.03), Symbol Digit Modalities Test ( p  = 0.02), Rey Auditory Verbal Learning Test ( p  = 0.01), and Cogstate choice reaction time ( p  < 0.001)., Conclusion: Pediatric MS patients do not differ from healthy pediatric controls on cognitive screens but perform better than adults with MS.

Background: We previously reported a relationship between air pollutants and increased risk of pediatric-onset multiple sclerosis (POMS). Ozone is an air pollutant that may play a role in multiple sclerosis (MS) pathoetiology. CD86 is the only non-HLA gene associated with POMS for which expression on antigen-presenting cells (APCs) is changed in response to ozone exposure., Objectives: To examine the association between county-level ozone and POMS, and the interactions between ozone pollution, CD86 , and HLA - DRB1*15 , the strongest genetic variant associated with POMS., Methods: Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. County-level-modeled ozone data were acquired from the CDC's Environmental Tracking Network. Participants were assigned ozone values based on county of residence. Values were categorized into tertiles based on healthy controls. The association between ozone tertiles and having MS was assessed by logistic regression. Interactions between tertiles of ozone level and the GG genotype of the rs928264 (G/A) single nucleotide polymorphism (SNP) within CD86 , and the presence of DRB1*15:01 ( DRB1*15 ) on odds of POMS were evaluated. Models were adjusted for age, sex, genetic ancestry, and mother's education. Additive interaction was estimated using relative excess risk due to interaction (RERI) and attributable proportions (APs) of disease were calculated., Results: A total of 334 POMS cases and 565 controls contributed to the analyses. County-level ozone was associated with increased odds of POMS (odds ratio 2.47, 95% confidence interval (CI): 1.69-3.59 and 1.95, 95% CI: 1.32-2.88 for the upper two tertiles, respectively, compared with the lowest tertile). There was a significant additive interaction between high ozone tertiles and presence of DRB1*15 , with a RERI of 2.21 (95% CI: 0.83-3.59) and an AP of 0.56 (95% CI: 0.33-0.79). Additive interaction between high ozone tertiles and the CD86 GG genotype was present, with a RERI of 1.60 (95% CI: 0.14-3.06) and an AP of 0.37 (95% CI: 0.001-0.75) compared to the lowest ozone tertile. AP results indicated that approximately half of the POMS risk in subjects can be attributed to the possible interaction between higher county-level ozone carrying either DRB1*15 or the CD86 GG genotype., Conclusions: In addition to the association between high county-level ozone and POMS, we report evidence for additive interactions between higher county-level ozone and DRB1*15 and the CD86 GG genotype. Identifying gene-environment interactions may provide mechanistic insight of biological processes at play in MS susceptibility. Our work suggests a possible role of APCs for county-level ozone-induced POMS risk.

Background: Pediatric multiple sclerosis (MS) is rare: only 1.5-5% of MS cases are diagnosed before 18 years of age, and data on disease-modifying therapies (DMTs) for pediatric MS are limited. The CONNECTED study assessed the long-term safety and efficacy of treatment with delayed-release dimethyl fumarate (DMF), an oral MS DMT, in pediatric patients with MS. Methods: CONNECTED is the 96-week extension to FOCUS, a 24-week phase 2 study of patients aged 13-17 years; participants received DMF 240 mg twice daily. Endpoints included (primary) incidence of adverse events (AEs), serious AEs, and DMF discontinuations due to an AE, and (secondary) T2 hyperintense lesion incidence by magnetic resonance imaging and annualized relapse rate (ARR). Results: Twenty participants [median (range) age, 17 (14-18) years; 65% female] who completed FOCUS enrolled into CONNECTED; 17 (85%) completed CONNECTED. Eighteen participants (90%) experienced AEs: the most frequent was flushing (25%). None experienced infections or fever related to low lymphocyte counts. Three participants experienced four serious AEs; none led to DMF discontinuation. Twelve of 17 participants (71%) had no new/newly enlarged T2 lesions from weeks 16-24, two (12%) had one, and one each (6%) had two, three, or five or more lesions [median (range), 0 (0-6)]. Over the full 120-week treatment period, ARR was 0.2, an 84.5% relative reduction ( n = 20; 95% confidence interval: 66.8-92.8; p < 0.0001) vs. the year before DMF initiation. Conclusions: The long-term safety and efficacy observed in CONNECTED was consistent with adults, suggesting pediatric and adolescent patients with MS might benefit from DMF treatment., Competing Interests: RA reports receiving personal compensation for serving on speaker/advisory boards for Bayer, Biogen, Merck, Novartis, Roche, and Sanofi, and receiving research support from Biogen, Merck, Novartis, and Roche for the establishment of regional multiple sclerosis registries and the conduct of clinical trials. PH reports receiving speaker/consulting fees from Bayer, Merck, and Novartis. AB reports receiving speaker/consulting fees from AveXis, Biogen, Genzyme, and Merck. MV reports receiving speaker/consulting fees from Biogen, Genzyme, Merck, Novartis, Roche, and Teva. JP is a contractor for Biogen. XP and VB are employees of and hold stock/stock options in Biogen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Alroughani, Huppke, Mazurkiewicz-Beldzinska, Blaschek, Valis, Aaen, Pultz, Peng and Beynon.)

Background: Cognitive impairment occurs in approximately one-third of pediatric-onset multiple sclerosis (POMS) patients. The Symbol Digit Modalities Test (SDMT), a widely used cognitive screen in adults, has yet to be incorporated early into the standard care of POMS., Objective: To screen for cognitive impairment early in the course of POMS and analyze predictive factors., Methods: Of the 955 POMS or clinically isolated syndrome (CIS) patients prospectively assessed from March 2014 to July 2018, 500 POMS and 116 CIS patients met inclusion criteria (disease onset before the age of 18, one or more SDMTs, and 8 years or older at the time of testing). Those with relapse were analyzed separately from those who were relapse-free., Results: At initial assessment, the mean (interquartile range (IQR)) age at symptom onset was 13.5 years (12.0, 15.9) and the mean (±SD) disease duration was 3.0 ± 2.9 years. Impaired processing speed occurred in 23.4% of POMS and in 16.4% of CIS. On serial testing ( n  = 383, mean follow-up: 1.8 years), 14.1% had clinically meaningful decline predicted by older age of multiple sclerosis (MS) onset and male gender. Disease relapse or steroid use led to transient worsening on the SDMT., Conclusion: Early in the disease, some POMS and CIS patients are at risk for cognitive impairment and subsequent decline.

Objective: To characterize disease severity and distribution of disability in pediatric-onset multiple sclerosis (POMS) and to develop an optimized modeling scale for measuring disability, we performed a multicenter retrospective analysis of disability scores in 873 persons with POMS over time and compared this to previously published data in adults with multiple sclerosis (MS)., Methods: This was a retrospective analysis of prospectively collected data collected from 12 centers of the US Network of Pediatric MS Centers. Patients were stratified by the number of years from first symptoms of MS to Expanded Disability Status Scale (EDSS) assessment and an MS severity score (Pediatric Multiple Sclerosis Severity Score [Ped-MSSS]) was calculated per criteria developed by Roxburgh et al. in 2005., Results: In total, 873 patients were evaluated. In our cohort, 52%, 19.4%, and 1.5% of all patients at any time point reached an EDSS of 2.0, 3.0, and 6.0. Comparison of our Ped-MSSS scores and previously published adult Multiple Sclerosis Severity Scores (MSSS) showed slower progression of Ped-MSSS with increasing gaps between higher EDSS score and years after diagnosis. Decile scores in our POMS cohort for EDSS of 2.0, 3.0, and 6.0 were 8.00/9.46/9.94, 7.86/9.39/9.91, and 7.32/9.01/9.86 at 2, 5, and 10 years, respectively. Notable predictors of disease progression in both EDSS and Ped-MSSS models were ever having a motor relapse and EDSS at year 1. Symbol Digit Modalities Test (SDMT) scores were inversely correlated with duration of disease activity and cerebral functional score., Conclusions: Persons with POMS exhibit lower EDSS scores compared to persons with adult-onset MS. Use of a Ped-MSSS model may provide an alternative to EDSS scoring in clinical assessment of disease severity and disability accrual., (© 2020 American Academy of Neurology.)

Incomplete relapse recovery contributes to disability accrual and earlier onset of secondary progressive multiple sclerosis. We sought to investigate the effect of age on relapse recovery. We identified patients with multiple sclerosis from two longitudinal prospective studies, with an Expanded Disability Status Scale (EDSS) score within 30 days after onset of an attack, and follow-up EDSS 6 months after attack. Adult patients with multiple sclerosis (n = 632) were identified from the Comprehensive Longitudinal Investigations in Multiple Sclerosis at Brigham study (CLIMB), and paediatric patients (n = 132) from the US Network of Paediatric Multiple Sclerosis Centers (NPMSC) registry. Change in EDSS was defined as the difference in EDSS between attack and follow-up. Change in EDSS at follow-up compared to baseline was significantly lower in children compared to adults (P = 0.001), as were several functional system scores. Stratification by decade at onset for change in EDSS versus age found for every 10 years of age, EDSS recovery is reduced by 0.15 points (P < 0.0001). A larger proportion of children versus adults demonstrated improvement in EDSS following an attack (P = 0.006). For every 10 years of age, odds of EDSS not improving increase by 1.33 times (P < 0.0001). Younger age is associated with improved recovery from relapses. Age-related mechanisms may provide novel therapeutic targets for disability accrual in multiple sclerosis., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: The aim of this study was to determine whether a vitamin D genetic risk score (vitDGRS) is associated with 25-hydroxyvitamin D (25(OH)D) level and multiple sclerosis (MS) relapses in children., Methods: DNA samples were typed for single nucleotide polymorphisms (SNPs) from four genes previously identified to be associated with 25(OH)D levels. SNPs with strong associations with 25(OH)D after multiple comparison correction were used to create a genetic risk score (vitDGRS). Cox regression models tested associations of vitDGRS with relapse hazard., Results: Two independent SNPs within or near GC and NADSYN1/DHCR7 genes were strongly associated with 25(OH)D levels in the discovery cohort ( n  = 182) after Bonferroni correction. The vitDGRS of these SNPs explained 4.5% of the variance of 25(OH)D level after adjustment for genetic ancestry. Having the highest versus lowest vitDGRS was associated with 11 ng/mL lower 25(OH)D level (95% confidence interval (CI) = -17.5, -4.5, p  = 0.001) in the discovery cohort. Adjusting for ancestry, sex, disease-modifying therapy (DMT), and HLA-DRB1*15 carrier status, the highest versus lowest vitDGRS was associated with 2.6-fold (95% CI = 1.37, 5.03, p  = 0.004) and 2.0-fold (95% CI = 0.75, 5.20, p  = 0.16) higher relapse hazard in the discovery and replication cohorts, respectively., Conclusion: The vitDGRS identifies children at greater risk of relapse. These findings support a causal role for vitamin D in MS course.

Objective: To assess real-world effectiveness of initial treatment with newer compared to injectable disease-modifying therapies (DMTs) on disease activity in pediatric multiple sclerosis (MS) and clinically isolated syndrome (CIS)., Methods: This is a cohort study of children with MS/CIS followed at 12 clinics in the US Network of Pediatric MS Centers, who received initial therapy with newer (fingolimod, dimethyl fumarate, teriflunomide, natalizumab, rituximab, ocrelizumab) or injectable (interferon-β, glatiramer acetate) DMTs. Propensity scores (PSs) were computed, including preidentified confounders. Relapse rate while on initial DMT was modeled with negative binomial regression, adjusted for PS-quintile. Time to new/enlarging T2-hyperintense and gadolinium-enhancing lesions on brain magnetic resonance imaging were modeled with midpoint survival analyses, adjusted for PS-quintile., Results: A total of 741 children began therapy before 18 years, 197 with newer and 544 with injectable DMTs. Those started on newer DMTs were older (15.2 vs injectable 14.4 years, p = 0.001) and less likely to have a monofocal presentation. In PS-quintile-adjusted analysis, those on newer DMTs had a lower relapse rate than those on injectables (rate ratio = 0.45, 95% confidence interval (CI) = 0.29-0.70, p < 0.001; rate difference = 0.27, 95% CI = 0.14-0.40, p = 0.004). One would need to treat with newer rather than injectable DMTs for 3.7 person-years to prevent 1 relapse. Those started on newer DMTs had a lower rate of new/enlarging T2 (hazard ratio [HR] = 0.51, 95% CI = 0.36-0.72, p < 0.001) and gadolinium-enhancing lesions (HR = 0.38, 95% CI = 0.23-0.63, p < 0.001) than those on injectables., Interpretation: Initial treatment of pediatric MS/CIS with newer DMTs led to better disease activity control compared to injectables, supporting greater effectiveness of newer therapies. Long-term safety data for newer DMTs are required. ANN NEUROL 2020 ANN NEUROL 2020;88:42-55., (© 2020 American Neurological Association.)

Objective: Onset of multiple sclerosis (MS) occurs in childhood for approximately 5% of cases (pediatric MS, or ped-MS). Epigenetic influences are strongly implicated in MS pathogenesis in adults, including the contribution from microRNAs (miRNAs), small noncoding RNAs that affect gene expression by binding target gene mRNAs. Few studies have specifically examined miRNAs in ped-MS, but individuals developing MS at an early age may carry a relatively high burden of genetic risk factors, and miRNA dysregulation may therefore play a larger role in the development of ped-MS than in adult-onset MS. This study aimed to look for evidence of miRNA involvement in ped-MS pathogenesis., Methods: GWAS results from 486 ped-MS cases and 1362 controls from the U.S. Pediatric MS Network and Kaiser Permanente Northern California membership were investigated for miRNA-specific signals. First, enrichment of miRNA-target gene network signals was evaluated using MIGWAS software. Second, SNPs in miRNA genes and in target gene binding sites (miR-SNPs) were tested for association with ped-MS, and pathway analysis was performed on associated target genes., Results: MIGWAS analysis showed that miRNA-target gene signals were enriched in GWAS ( P  = 0.038) and identified 39 candidate biomarker miRNA-target gene pairs, including immune and neuronal signaling genes. The miR-SNP analysis implicated dysregulation of miRNA binding to target genes in five pathways, mainly involved in immune signaling., Interpretation: Evidence from GWAS suggests that miRNAs play a role in ped-MS pathogenesis by affecting immune signaling and other pathways. Candidate biomarker miRNA-target gene pairs should be further studied for diagnostic, prognostic, and/or therapeutic utility., Competing Interests: E. Waubant is site PI for a Novartis and Roche trial. She has volunteered on an advisory board for a Novartis trial. She is a nonremunerated advisor for clinical trial design to Novartis, Biogen‐IDEC, Sanofi, Genentech, Serono, and Celgene. She has funding from the NMSS, PCORI, and the Race to Erase MS. She is the section editor for Annals of Clinical and Translational Neurology, and co‐Chief editor for MS And Related Disorders. A. Waldman reports grants from NIH (NINDS) NS071463 and from NMSS during the conduct of the study, as well as funds for investigator‐initiated study from Ionis Pharmaceuticals and Biogen Idec and grants from United Leukodystrophy Foundation outside the submitted work. She is a consultant for Optum and has received royalties from UpToDate. B. Greenberg has received grant funding from Chugai, Medimmune, Medday, National Institutes of Health (NIH), NMSS, Guthy Jackson Charitable Foundation, and Transverse Myelitis Association. He has received consulting fees from Novartis, EMD Serono, Celgene, and Alexion. L. Benson reports BG12 clinical trial support from Biogen, grants from Boston Children's Hospital Office of Faculty Development, travel funds from National MS Society, and personal fees from National Vaccine Compensation Program outside the submitted work. T.C. Casper reports grants from National MS Society. J. Graves reports speaking honoraria from Novartis outside the submitted work. B. Weinstock‐Guttman reports grants and personal fees from Biogen, EMD Serono, Novartis, and Genentech, and personal fees from Mallinckrodt outside the submitted work.

Children with pediatric-onset multiple sclerosis and pediatric controls were enrolled across 16 pediatric multiple sclerosis centers in the United States and completed questionnaires that addressed time of first unaided walking and acquisition of 2-word phrases. A total of 467 (308 female) cases and 428 (209 female) controls were enrolled. Pediatric multiple sclerosis (n = 467) were not delayed in walking or using 2-word phrases compared to healthy controls (n = 428) (2.2% vs 5.7%, respectively). Children with disease onset before age 11 versus onset at 11 years or after were more likely to need an individualized education plan ( P = .002), reading assistance ( P = .0003), and math assistance ( P = .001). Children with multiple sclerosis onset prior to age 18 are not delayed in meeting the 2 major early developmental milestones but do have a significantly increased use of special services or learning assistance at school. Further research will need to address whether other measures of development (eg, rate of language acquisition or fine motor skills) differ between pediatric multiple sclerosis and controls.

Multiple sclerosis (MS) is an autoimmune disease with high prevalence among populations of northern European ancestry. Past studies have shown that exposure to ultraviolet radiation could explain the difference in MS prevalence across the globe. In this study, we investigate whether the difference in MS prevalence could be explained by European genetic risk factors. We characterized the ancestry of MS-associated alleles using RFMix, a conditional random field parameterized by random forests, to estimate their local ancestry in the largest assembled admixed population to date, with 3,692 African Americans, 4,915 Asian Americans, and 3,777 Hispanics. The majority of MS-associated human leukocyte antigen (HLA) alleles, including the prominent HLA-DRB1*15:01 risk allele, exhibited cosmopolitan ancestry. Ancestry-specific MS-associated HLA alleles were also identified. Analysis of the HLA-DRB1*15:01 risk allele in African Americans revealed that alleles on the European haplotype conferred three times the disease risk compared to those on the African haplotype. Furthermore, we found evidence that the European and African HLA-DRB1*15:01 alleles exhibit single nucleotide polymorphism (SNP) differences in regions encoding the HLA-DRB1 antigen-binding heterodimer. Additional evidence for increased risk of MS conferred by the European haplotype were found for HLA-B*07:02 and HLA-A*03:01 in African Americans. Most of the 200 non-HLA MS SNPs previously established in European populations were not significantly associated with MS in admixed populations, nor were they ancestrally more European in cases compared to controls. Lastly, a genome-wide search of association between European ancestry and MS revealed a region of interest close to the ZNF596 gene on chromosome 8 in Hispanics; cases had a significantly higher proportion of European ancestry compared to controls. In conclusion, our study established that the genetic ancestry of MS-associated alleles is complex and implicated that difference in MS prevalence could be explained by the ancestry of MS-associated alleles., Competing Interests: The authors have declared that no competing interests exist.

Background: Strong evidence supports the role of both genetic and environmental factors in pediatric-onset multiple sclerosis (POMS) etiology., Objective: We comprehensively investigated the association between established major histocompatibility complex (MHC) and non-MHC adult multiple sclerosis (MS)-associated variants and susceptibility to POMS., Methods: Cases with onset <18 years ( n  = 569) and controls ( n  = 16,251) were included from the United States and Sweden. Adjusted logistic regression and meta-analyses were performed for individual risk variants and a weighted genetic risk score (wGRS) for non-MHC variants. Results were compared to adult MS cases ( n  = 7588)., Results: HLA-DRB1*15:01 was strongly associated with POMS (odds ratio (OR) meta  = 2.95, p  < 2.0 × 10 -16 ). Furthermore, 28 of 104 non-MHC variants studied (23%) were associated ( p  < 0.05); POMS cases carried, on average, a higher burden of these 28 variants compared to adults (OR avg  = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (OR meta  = 2.77, 95% confidence interval: 2.33, 3.32, p  < 2.0 × 10 -16 ) and higher, on average, when compared to adult cases. Additional class III risk variants in the MHC region associated with POMS were revealed after accounting for HLA-DRB1*15:01 and HLA-A*02 ., Conclusion: Pediatric and adult MS share many genetic variants suggesting similar biological processes are present. MHC variants beyond HLA-DRB1*15:01 and HLA-A*02 are also associated with POMS.

Objective: To characterize the use and safety of newer disease-modifying therapies (DMTs) in children with multiple sclerosis (MS) and clinically isolated syndrome (CIS) treated under 18 years of age., Methods: This is a cohort study including children with MS or CIS followed at 12 outpatient practices participating in the US Network of Pediatric MS Centers. DMT use, including duration, dose, and side effects, was analyzed. Newer DMTs were defined as agents receiving Food and Drug Administration approval or with increased use in adult MS after 2005., Results: As of July 2017, 1,019 pediatric patients with MS (n = 748) or CIS (n = 271) were enrolled (65% female, mean onset 13.0 ± 3.9 years, mean follow-up 3.5 ± 3.1 years, median 1.6 visits per year). Of these, 78% (n = 587) with MS and 11% (n = 31) with CIS received DMT before 18 years of age. This consisted of at least one newer DMT in 42%, including dimethyl fumarate (n = 102), natalizumab (n = 101), rituximab (n = 57), fingolimod (n = 37), daclizumab (n = 5), and teriflunomide (n = 3). Among 17%, the initial DMT prescribed was a newer agent (36 dimethyl fumarate, 30 natalizumab, 22 rituximab, 14 fingolimod, 2 teriflunomide). Over the last 10 years, the use of newer agents has increased, particularly in those ≥12 years and to lesser extent in those <12 years. The short-term side effect profiles of newer DMTs did not differ from those reported in adults., Conclusion: Newer DMTs are often used in pediatric MS, and have similar short-term safety, tolerability, and side effect profiles as in adults. These findings may help inform pediatric MS management., (© 2018 American Academy of Neurology.)

Background: There is limited information about the potential associations of multiple sclerosis (MS) and commonly used household chemicals., Methods: We performed a case-control study of exposures to common household chemicals during childhood in children with MS and healthy pediatric controls. Exposures to household products were collected from a comprehensive questionnaire (http://www.usnpmsc.org/Documents/EnvironmentalAssessment.pdf) completed by parents at the time of enrollment in the study. Cases included children diagnosed with MS or clinically isolated syndrome with at least two silent T2 bright lesions on MRI, recruited within 4 years of disease onset from 16 pediatric MS clinics in the USA. Multivariate analyses using logistic regression were adjusted for possible confounders including age, sex, race, ethnicity, mother's highest level of education, and urban versus rural living., Results: Questionnaire responses to household chemicals were available for 312 eligible cases (median age 15.7 years, 63% girls) and 490 healthy controls (median age 15.0, 57% girls). Exposure to rodenticides (odds ratio [OR] 2.10, 95% confidence interval [CI] 1.35-3.26, P  ≤ 0.001), weed control agents (OR 1.99, 95% CI 1.36-2.92, P  ≤ 0.001) and products for plant/tree disease control (OR 2.72, 95% CI 1.54-4.82, P  ≤ 0.001) anytime during childhood were associated with an increased risk for pediatric-onset MS in adjusted and multiple comparisons analyses., Conclusions: Our findings suggest that exposure to specific household chemicals during early childhood is associated with the risk of developing pediatric-onset MS. Future studies are needed to elucidate a causal relationship and the exact agents involved.

Background: We previously identified air quality as a risk factor of interest for pediatric multiple sclerosis. The purpose of this study is to more closely examine the association between the six criteria air pollutants and pediatric MS as well as identify specific areas of toxic release using data from the Toxic Release Inventory., Methods: Pediatric MS cases ( N = 290) and healthy controls ( N = 442) were included as part of an ongoing case-control study. We used the National Emissions Inventory system to estimate particulate exposure by county of residence for each participant. Proximity to Toxic Release Inventory (TRI) sites was also assessed using ArcGIS mapping tools. Risk-Screening Environmental Indicators (RSEI) classified counties at risk to exposure of environmental toxic releases., Results: Fine particulate matter (PM 2.5 ), carbon monoxide (CO), sulfur dioxide (SO 2 ), and lead air emissions were associated with increased odds for pediatric MS ( P < 0.01) for those residing within 20 miles of an MS center. Most study participants (75%) resided within 5 miles of at least one TRI site; however, the mean total pounds of stack air releases was higher for sites near MS cases (81,000 tons) compared to those near healthy controls (35,000 tons, P = 0.002). Average RSEI scores did not differ significantly between cases and controls., Conclusion: Out of several air pollutants examined, we show that fine particulate matter and three other criteria pollutants (SO 2 , CO, and lead) were statistically associated with higher odds for pediatric MS.

Objective: While prior Epstein-Barr virus (EBV) infection has been consistently associated with subsequent risk of developing multiple sclerosis (MS), the association with other common herpesviruses has been more controversial. Our objectives were to determine whether remote infection with EBV and other common herpesviruses affect the susceptibility to pediatric MS and if there are interactions between genetic and demographic factors and viral infections., Methods: Cases with pediatric-onset MS or clinically isolated syndrome within 4 years of disease onset, and controls were recruited from 16 American pediatric MS centers. Logistic regression models adjusted for potential confounders assessed the association between case status and serological evidence for past infection with EBV, cytomegalovirus (CMV), Herpes Simplex viruses-1 (HSV-1) and -2. We determined the heterogeneity of the effect of viral infection on the risk of having MS according to race, ethnicity and HLA-DRB1:1501 status., Results: A total of 356 pediatric cases and 493 controls were recruited. In multivariable models, EBV-viral capsid antigen (VCA) seropositivity was associated with increased odds of having MS by 7.4 times (95% CI: 4.5-12.0, P < 0.001). Seropositivity for HSV-1 was also associated with increased odds of having MS (OR 1.54, 95% CI: 1.06-2.25, P = 0.025) but this increase was seen only in Whites (OR = 2.18, 95% CI 1.35-3.52, P < 0.001) and those negative for HLA-DRB1*1501 (OR = 1.89, 95% CI 1.17-3.03, P = 0.009). The effect of remote EBV infection on the risk of pediatric MS depended on race and HLA-DRB1*15:01 status., Interpretation: EBV seropositivity is strongly associated with pediatric MS, as is HSV-1 seropositivity in subjects negative for HLA-DRB1*15:01 . Our report of interactions between select viral exposures, and age, race and DRB1 status suggests a complex effect of environmental and genetic risk factors on MS development.

Background: The role of diet in multiple sclerosis (MS) is largely uncharacterized, particularly as it pertains to pediatric-onset disease., Objective: To determine the association between dietary factors and MS in children., Methods: Pediatric MS patients and controls were recruited from 16 US centers (MS or clinically isolated syndrome onset before age 18, <4 years from symptom onset and at least 2 silent lesions on magnetic resonance imaging). The validated Block Kids Food Screener questionnaire was administered 2011-2016. Chi-squared test compared categorical variables, Kruskal-Wallis test compared continuous variables, and multivariable logistic regression analysis was performed., Results: In total, 312 cases and 456 controls were included (mean ages 15.1 and 14.4 years). In unadjusted analyses, there was no difference in intake of fats, proteins, carbohydrates, sugars, fruits, or vegetables. Dietary iron was lower in cases ( p = 0.04), and cases were more likely to consume below recommended guidelines of iron (77.2% of cases vs 62.9% of controls, p < 0.001). In multivariable analysis, iron consumption below recommended guidelines was associated with MS (odds ratio = 1.80, p < 0.01)., Conclusion: Pediatric MS cases may be less likely to consume sufficient iron compared to controls, and this warrants broader study to characterize a temporal relationship. No other significant difference in intake of most dietary factors was found.

Objective: We sought to determine if early infectious exposures such as daycare, early use of antibiotics, vaccinations and other germ exposures including pacifier use and playing on grass are associated with multiple sclerosis (MS) risk in children., Methods: This was a case-control study of children with MS or clinically isolated syndrome (CIS) and healthy controls enrolled at sixteen clinics participating in the US Network of Pediatric MS Centers. Parents completed a comprehensive environmental questionnaire that captured early infectious exposures, habits, and illnesses in the first five years of life. A panel of at least two pediatric MS specialists confirmed diagnosis of participants. Association of early infectious variables with diagnosis was assessed via multivariable logistic regression analyses, adjusting for age, sex, race, ethnicity, US birth region, and socioeconomic status (SES)., Results: Questionnaire responses for 326 eligible cases (mean age 14.9, 63.5% girls) and 506 healthy pediatric subjects (mean age 14.4, 56.9% girls) were included in analyses. History of flu with high fever before age five (p = 0.01), playing outside in grass and use of special products to treat head lice or scabies (p = 0.04) were associated with increased risk of MS in unadjusted analyses. In the multivariable model adjusted for age, sex, race, ethnicity, and mother's highest educational attainment, these results were not statistically significant. Notably, antibiotic use (p = 0.22) and regular daycare attendance before age 6 (p = 0.09) were not associated with odds of developing MS., Conclusion: Early infectious factors investigated in this study were not associated with MS risk., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objective: The role of diet in multiple sclerosis (MS) course remains largely unknown. Children with MS have a higher relapse rate compared with MS in adults. Thus, studying the effect of diet on relapse rate in this age group is likely to provide more robust answers., Methods: This is a multicentre study done at 11 paediatric MS centres in the USA. Patients with relapsing-remitting MS (RRMS) or clinically isolated syndrome (CIS) with disease onset before 18 years of age and duration of less than 4 years were included in this study. Dietary intake during the week before enrolment was assessed with the validated Block Kids Food Screener. The outcome of the study was time from enrolment to the next relapse. 219 patients with paediatric RRMS or CIS were enrolled. Each 10% increase in energy intake from fat increased the hazard of relapse by 56% (adjusted HR 1.56, 95% CI 1.05 to 2.31, p=0.027), and in particular each 10% increase in saturated fat tripled this hazard (adjusted HR: 3.37, 95% CI 1.34 to 8.43, p=0.009). In contrast, each additional one cup equivalent of vegetable decreased the hazard of relapse by 50% (adjusted HR: 0.50, 95% CI 0.27 to 0.91, p=0.024). These associations remained with mutual adjustment and persisted when adjusting for baseline 25(OH) vitamin D serum level. Other studied nutrients were not associated with relapse., Conclusions: This study suggests that in children with MS, high energy intake from fat, especially saturated fat, may increase the hazard to relapse, while vegetable intake may be independently protective., Competing Interests: Competing interests: Dr JG was supported by grants from Race to Erase MS, NMSS, Biogen and Genentech during this work. Dr AW is funded by the NIH (NINDS, K23NS069806) and has received research funding from Biogen Idec. Dr CTC has been supported by the National MS Society and the NIH (R01NS071463). He is an ad hoc consultant for Biovest International, Inc. Dr EW is funded by the National MS Society, the NIH and the Race to Erase MS. She volunteers on an advisory board for a clinical trial of Novartis. Dr LK is supported by the National MS Society, NIH, Robert and Lisa Lourie Foundation, Department of Defense. She has received honoraria, consulting payments, grant support or royalties from Biogen, Medimmune, Novartis, Teva Neuroscience, Sanofi-Aventis and EMD Serono. Dr BWG received honoraria for serving in advisory boards and educational programmes from Teva Pharmaceuticals, Biogen Idec, Novartis, Acorda EMD Serono, Novartis, Genzyme and Sanofi. She also received support for research activities from the National Institutes of Health, National Multiple Sclerosis Society, National Science Foundation, Department of Defense, EMD Serono, Biogen Idec, Teva Neuroscience, Novartis, Acorda, Genzyme and the Jog for the Jake Foundation. Dr TC has served as a consultant for Biogen Idec, Teva Neurosciences, Novartis and Sanofi-Aventis and has received grant support from NIH, National MS Society, Guthy-Jackson Charitable Foundation, CMSC and Merck-Serono, Novartis, and Biogen and Verily. Dr JR has research funding from Teva Neuroscience and Biogen. He is a member of the Medical Advisory Board for the DECIDE trial, which is funded by Biogen and AbbVie. Dr GA has received research support from Biogen-Idec. Drs AB, JN, MG, TL, MR and GA have no disclosures. JH has no disclosures. Dr J-MT received funding from the NIH (NCATS) during this work., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Multiple sclerosis (MS) is a presumed autoimmune disease caused by genetic and environmental factors. It is hypothesized that environmental exposures (such as air and water quality) trigger the innate immune response thereby activating a pro-inflammatory cascade., Objective: To examine potential environmental factors in pediatric MS using geographic information systems (GIS)., Methods: Pediatric MS cases and healthy controls were identified as part of an ongoing multicenter case-control study. Subjects' geographic locations were mapped by county centroid to compare to an Environmental Quality Index (EQI). The EQI examines 5 individual environmental components (air, land, water, social, built factors). A composite EQI score and individual scores were compared between cases and controls, stratified by median proximity to enrollment centers (residence <20 or ≥20 miles from the recruiting center), using logistic regression., Results: Of the 287 MS cases and 445 controls, 46% and 49% respectively live in areas where the total EQI is the highest (worst environmental quality). Total EQI was not significantly associated with the odds for MS (p = 0.90 < 20 miles from center; p = 0.43 ≥ 20 miles); however, worsening air quality significantly impacted the odds for MS in those living near a referral center (OR = 2.83; 95%CI 1.5, 5.4) and those who reside ≥ 20 miles from a referral center (OR = 1.61; 95%CI 1.2, 2.3)., Conclusion: Among environmental factors, air quality may contribute to the odds of developing MS in a pediatric population. Future studies will examine specific air constituents and other location-based air exposures and explore potential mechanisms for immune activation by these exposures., (Copyright © 2017. Published by Elsevier B.V.)

Objective: To utilize Mendelian randomization to estimate the causal association between low serum vitamin D concentrations, increased body mass index (BMI), and pediatric-onset multiple sclerosis (MS) using genetic risk scores (GRS)., Methods: We constructed an instrumental variable for vitamin D (vitD GRS) by computing a GRS for 3 genetic variants associated with levels of 25(OH)D in serum using the estimated effect of each risk variant. A BMI GRS was also created that incorporates the cumulative effect of 97 variants associated with BMI. Participants included non-Hispanic white individuals recruited from over 15 sites across the United States (n = 394 cases, 10,875 controls) and Sweden (n = 175 cases, 5,376 controls; total n = 16,820)., Results: Meta-analysis findings demonstrated that a vitD GRS associated with increasing levels of 25(OH)D in serum decreased the odds of pediatric-onset MS (odds ratio [OR] 0.72, 95% confidence interval [CI] 0.55, 0.94; p = 0.02) after controlling for sex, genetic ancestry, HLA-DRB1*15:01 , and over 100 non-human leukocyte antigen MS risk variants. A significant association between BMI GRS and pediatric disease onset was also demonstrated (OR 1.17, 95% CI 1.05, 1.30; p = 0.01) after adjusting for covariates. Estimates for each GRS were unchanged when considered together in a multivariable model., Conclusions: We provide evidence supporting independent and causal effects of decreased vitamin D levels and increased BMI on susceptibility to pediatric-onset MS., (© 2017 American Academy of Neurology.)

Background: Salt intake was reported to be associated with increased clinical and MRI activity in adult patients with relapsing-remitting multiple sclerosis (MS)., Objective: To determine if salt intake is associated with time to relapse in patients with paediatric-onset MS., Methods: Paediatric-onset MS and patients with clinically isolated syndrome (CIS) within 4 years of disease onset were recruited from 15 paediatric MS centres in the USA as part of a case-control study. Patients with available prospective relapse data subsequent to enrolment were included in this project. Dietary sodium intake was assessed by self-report questionnaire using the validated Block Kids Food Screener. Cox proportional-hazards regression models were employed to determine the association of sodium density, excess sodium intake and sodium density tertiles with time to relapse following study enrolment, adjusting for several confounders., Results: 174 relapsing-remitting MS/CIS patients were included in this analysis (mean age of 15.0 years, and 64.9% females). Median duration of follow-up was 1.8 years. In an unadjusted analysis, density of daily sodium intake was not associated with time to relapse, and patients with excess sodium intake had no decrease in time to relapse as compared with patients with non-excess sodium intake. The multivariable analysis demonstrated that patients in the medium and high tertile of sodium density had a HR of 0.69 (95% CI 0.37 to 1.30, p=0.25) and 1.37 (95% CI 0.74 to 2.51, p=0.32) compared with patients in the lowest tertile, respectively., Conclusions: Higher salt intake was not associated with decreased time to relapse in patients with paediatric-onset MS., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Objective: The aim of this study was to examine the relative contributions of body mass index (BMI) and pubertal measures for risk and age of onset of pediatric MS., Methods: Case-control study of 254 (63% female) MS cases (onset<18 years of age) and 420 (49% female) controls conducted at 14 U.S. Pediatric MS Centers. Sex- and age-stratified BMI percentiles were calculated using CDC growth charts from height and weight measured at enrollment for controls, and within 1 year of onset for MS cases. Sex-stratified associations between MS risk and age at symptom onset with both BMI and pubertal factors were estimated controlling for race and ethnicity., Results: Only 11% of girls and 15% of boys were prepubertal (Tanner stage I) at MS onset. 80% of girls had onset of MS after menarche. BMI percentiles were higher in MS cases versus controls (girls: P < 0.001; boys: P = 0.018). BMI was associated with odds of MS in multivariate models in postpubertal girls (OR = 1.60, 95% confidence interval [CI]: 1.12, 2.27, P = 0.009) and boys (OR = 1.43, 95% CI: 1.08, 1.88, P = 0.011). In girls with MS onset after menarche, higher BMI was associated with younger age at first symptoms ( P = 0.031). Younger menarche was associated with stronger effects of BMI through mediation and interaction analysis. In pubertal/postpubertal boys, 89% of whom were obese/overweight, earlier sexual maturity was associated with earlier onset of MS ( P < 0.001)., Interpretation: Higher BMI in early adolescence is a risk factor for MS in girls and boys. Earlier age at sexual maturity contributes to earlier age at MS onset, particularly in association with obesity.

Objectives: To describe the demographic and clinical characteristics of pediatric multiple sclerosis (MS) in the United States., Methods: This prospective observational study included children and adolescents with MS. Cases were evaluated across 9 geographically diverse sites as part of the US Network of Pediatric MS Centers., Results: A total of 490 children and adolescents (324 girls, 166 boys) were enrolled; 28% developed symptoms before 12 years of age. The proportion of girls increased with age from 58% (<12 years) to 70% (≥12 years). Race and ethnicity as self-identified were: white, 67%; African American, 21%; and non-Hispanic, 70%. Most (94%) of the cases were born in the United States, and 39% had 1 or both foreign-born parents. Fifty-five percent of cases had a monofocal presentation; 31% had a prodrome (most frequently infectious), most often among those aged <12 years (P < .001). Children aged <12 years presented more commonly with encephalopathy and coordination problems (P < .001). Sensory symptoms were more frequently reported by older children (ie, those aged ≥12 years) (P < .001); 78% of girls had MS onset postmenarche. The initial Expanded Disability Status Scale score for the group was <3.0, and the annualized relapse rate was 0.647 for the first 2 years. Interval from symptom onset to diagnosis and from diagnosis to initiation of disease-modifying therapy was longer among those <12 years of age., Conclusions: Pediatric MS in the United States is characterized by racial and ethnic diversity, a high proportion of children with foreign-born parents, and differences in clinical features and timing of treatment among those <12 years of age compared with older children., (Copyright © 2016 by the American Academy of Pediatrics.)

Background: High salt intake may be associated with pro-inflammatory changes in the immune response, and increased clinical and MRI activity in adults with relapsing-remitting multiple sclerosis., Objective: We sought to determine if dietary salt intake is associated with pediatric-onset MS risk in a multicenter, case-control study., Methods: Pediatric-onset CIS/MS cases within four years of onset and controls less than 22 years old recruited from 14 pediatric-MS centers were studied. Dietary sodium intake was assessed using the validated Block Kids Food Screener (NutritionQuest). Sodium intake, excess sodium, and sodium terciles were compared between cases and controls. Logistic regression models were adjusted for age, gender, ethnicity, body mass index, and socioeconomic status., Results: Among 170 cases (mean age=15.2±3.5) and 331 controls (mean age=14.0±3.7), no significant difference in unadjusted mean sodium intake was found between cases (2044mg/d) and controls (2030mg/d, p=0.99). The proportion of subjects consuming excess sodium, based on the adequate intake for age and gender, was similar between cases and controls (65% versus 69%, p=0.34). There were no increased odds of higher sodium intake among cases as compared to controls (for each 100mg/d increase in sodium, OR=1.00, 95% CI 0.98, 1.02; p=0.93, for excess sodium intake, OR=1.05, 95% CI 0.67, 1.64; p=0.84)., Conclusions: Our results show no strong association between dietary salt intake and pediatric-onset MS risk, suggesting that salt intake may not play a prominent role in susceptibility to MS in children., (Copyright © 2016. Published by Elsevier B.V.)

Objective: To compare clinical features of pediatric neuromyelitis optica (NMO) to other pediatric demyelinating diseases., Methods: Review of a prospective multicenter database on children with demyelinating diseases. Case summaries documenting clinical and laboratory features were reviewed by an adjudication panel. Diagnoses were assigned in the following categories: multiple sclerosis (MS), acute disseminated encephalomyelitis, NMO, and recurrent demyelinating disease not otherwise specified., Results: Thirty-eight cases of NMO were identified by review panel, 97% of which met the revised International Panel on NMO Diagnosis NMO-SD 2014 criteria, but only 49% met 2006 Wingerchuk criteria. Serum or CSF NMO immunoglobulin G (IgG) was positive in 65% of NMO cases that were tested; however, some patients became seropositive more than 3 years after onset despite serial testing. No patient had positive CSF NMO IgG and negative serum NMO IgG in contemporaneous samples. Other than race (p = 0.02) and borderline findings for sex (p = 0.07), NMO IgG seropositive patients did not differ in demographic, clinical, or laboratory features from seronegatives. Visual, motor, and constitutional symptoms (including vomiting, fever, and seizures) were the most common presenting features of NMO. Initiation of disease-modifying treatment was delayed in NMO vs MS. Two years after onset, patients with NMO had higher attack rates, greater disability accrual measured by overall Expanded Disability Status Scale score, and visual scores than did patients with MS., Conclusion: The new criteria for NMO spectrum disorders apply well to the pediatric setting, and given significant delay in treatment of NMO compared to pediatric MS and worse short-term outcomes, it is imperative to apply these to improve access to treatment., (© 2015 American Academy of Neurology.)

Multiple sclerosis and other demyelinating diseases in the pediatric population have received an increasing level of attention by clinicians and researchers. The low incidence of these diseases in children creates a need for the involvement of multiple clinical centers in research efforts. The Network of Pediatric Multiple Sclerosis Centers was created initially in 2006 to improve the diagnosis and care of children with demyelinating diseases. In 2010, the Network shifted its focus to multicenter research while continuing to advance the care of patients. The Network has obtained support from the National Multiple Sclerosis Society, the Guthy-Jackson Charitable Foundation, and the National Institutes of Health. The Network will continue to serve as a platform for conducting impactful research in pediatric demyelinating diseases of the central nervous system. This article provides a description of the history and development, organization, mission, research priorities, current studies, and future plans of the Network., (© The Author(s) 2014.)

Objective: To determine whether early environmental factors, such as cesarean delivery, breastfeeding, and exposure to smoking or herpes viruses, are associated with neuromyelitis optica (NMO) risk in children., Methods: This is a case-control study of pediatric NMO, multiple sclerosis (MS), and healthy subjects. Early-life exposures were obtained by standardized questionnaire. Epstein-Barr virus, cytomegalovirus, and herpes simplex virus 1 antibody responses were determined by ELISA. Multivariate logistic regression models were used to adjust for age at sampling, sex, race, and ethnicity., Results: Early-life exposures were obtained from 36 pediatric subjects with NMO, 491 with MS, and 224 healthy controls. Daycare (odds ratio [OR] 0.33, 95% confidence interval [CI] 0.14, 0.78; p < 0.01) and breastfeeding (OR 0.42, 95% CI 0.18, 0.99; p = 0.05) were associated with lower odds of having NMO compared with healthy subjects. Cesarean delivery tended to be associated with 2-fold-higher odds of NMO compared with having MS/clinically isolated syndrome (OR 1.98, 95% CI 0.88, 4.59; p = 0.12) or with being healthy (OR 1.95, 95% CI 0.81, 4.71; p = 0.14). Sera and DNA were available for 31 subjects with NMO, 189 with MS, and 94 healthy controls. Epstein-Barr virus, herpes simplex virus 1, cytomegalovirus exposure, and being HLA-DRB1*15 positive were not associated with odds of having NMO compared with healthy subjects., Conclusions: Exposure to other young children may be an early protective factor against the development of NMO, as previously reported for MS, consistent with the hypothesis that infections contribute to disease risk modification. Unlike MS, pediatric NMO does not appear to be associated with exposures to common herpes viruses., (© 2014 American Academy of Neurology.)

Cerebral folate deficiency presents during infancy with irritability, deceleration of head growth, seizures, and progressive cognitive and motor impairment. Although low serum folate levels have been found in patients with schizophrenia, we describe the first case of cerebral folate deficiency presenting as catatonic schizophrenia. A 13-year-old previously healthy boy presented to our hospital with a 17-month history of schizophrenic symptoms with progressively worsening catatonia. On admission, he demonstrated near-complete mutism, frequent enuresis and encopresis, and severe psychomotor retardation. Our initial diagnostic evaluations, including brain magnetic resonance imaging, electroencephalogram, and routine metabolic tests, were normal. A lumbar puncture done to look for neurotransmitter defects or cerebral folate deficiency revealed low levels of 5-methyltetrahydrofolate (31 nmol/L; reference range, 40-150 nmol/L). He also had elevated titers of folate receptor-blocking antibodies. He was treated for the next 9 months with 5-formyltetrahydrofolate (folinic acid), but his catatonia was unchanged.