BACKGROUND AND OBJECTIVES:Sex steroid hormones have been demonstrated to affect the immune system in multiple sclerosis (MS), and puberty may trigger MS activity. We aimed to evaluate the association between menarche and disease course in pediatric MS through comparison of relapse rates across premenarche, perimenarche, and postmenarche periods. METHODS:This is a retrospective analysis of a prospectively followed female cohort with pediatric-onset MS in the US Network of Pediatric MS Centers database. Perimenarche was considered the period from 1 year before to 1 year after the estimated menarche date based on menarche integer age. Relapses were collected prospectively. Negative binomial and repeated-measures Cox regression models were used to assess the association of pubertal development stage with relapse rate, adjusted for race, body mass index, and disease-modifying therapy (DMT). RESULTS:Of 736 participants (all female; mean onset age 14.4 ± 2.8 years; mean menarche age 11.6 ± 1.4 years), onset was in premenarche in 73, perimenarche in 112 (± 1 year of menarche), and postmenarche in 551. The median time of MS onset was 2.8 years after menarche. Most (86%) were exposed to DMT in follow-up. In adjusted negative binomial analysis, the annualized relapse rate during premenarche was 0.43, perimenarche was 0.65, and postmenarche was 0.43 (premenarche rate ratio [RR] 1.00 (95% CI 0.70-1.43) and perimenarche RR 1.52 (95% CI 1.16-1.99), compared with reference of postmenarche, p = 0.0049. In adjusted repeated-events Cox regression analysis, there was increased hazard to relapse in perimenarche and postmenarche compared with premenarche (perimenarche hazard ratio [HR] 1.78 [95% CI 1.17-2.70] and postmenarche HR 1.67 [95% CI 1.12-2.50], compared with reference of premenarche, p = 0.025). In this analysis, use of oral and infusion DMTs significantly lowered the relapse hazard compared with periods of no DMT use (injectable HR 0.98 [95% CI 0.83-1.15], oral HR 0.48 [95% CI 0.37-0.61], and infusion HR 0.24 [95% CI 0.18-0.31], compared with no DMT, p < 0.001). DISCUSSION:Onset of puberty may be a time of increase in disease activity and may require consideration of a change in therapeutic approach. Menarche age was used as a surrogate for puberty, and future studies measuring sex steroid hormones may be informative.

BACKGROUND AND OBJECTIVES:Psychosocial adversity and stress, known to predispose adults to neurodegenerative and inflammatory immune disorders, are widespread among children who experience socioeconomic disadvantage, and the associated neurotoxicity and proinflammatory profile may predispose these children to multiple sclerosis (MS). We sought to determine associations of socioeconomic disadvantage and psychosocial adversity with odds of pediatric-onset MS (POMS), age at POMS onset, and POMS disease activity. METHODS:This case-control study used data collected across 17 sites in the United States by the Environmental and Genetic Risk Factors for Pediatric Multiple Sclerosis Study. Cases (n = 381) were youth aged 3-21 years diagnosed with POMS or a clinically isolated demyelinating syndrome indicating high risk of MS. Frequency-matched controls (n = 611) aged 3-21 years were recruited from the same institutions. Prenatal and postnatal adversity and postnatal socioeconomic factors were assessed using retrospective questionnaires and zip code data. The primary outcome was MS diagnosis. Secondary outcomes were age at onset, relapse rate, and Expanded Disability Status Scale (EDSS). Predictors were maternal education, maternal prenatal stress events, child separation from caregivers during infancy and childhood, parental death during childhood, and childhood neighborhood disadvantage. RESULTS:MS cases (64% female, mean age 15.4 years, SD 2.8) were demographically similar to controls (60% female, mean age 14.9 years, SD 3.9). Cases were less likely to have a mother with a bachelor's degree or higher (OR 0.42, 95% CI 0.22-0.80, p = 0.009) and were more likely to experience childhood neighborhood disadvantage (OR 1.04 for each additional point on the neighborhood socioeconomic disadvantage score, 95% CI 1.00-1.07; p = 0.025). There were no associations of the socioeconomic variables with age at onset, relapse rate, or EDSS, or of prenatal or postnatal adverse events with risk of POMS, age at onset, relapse rate, or EDSS. DISCUSSION:Low socioeconomic status at the neighborhood level may increase the risk of POMS while high parental education may be protective against POMS. Although we did not find associations of other evaluated prenatal or postnatal adversities with POMS, future research should explore such associations further by assessing a broader range of stressful childhood experiences.

BACKGROUND AND OBJECTIVES:Psychosocial adversity and stress, known to predispose adults to neurodegenerative and inflammatory immune disorders, are widespread among children who experience socioeconomic disadvantage, and the associated neurotoxicity and proinflammatory profile may predispose these children to multiple sclerosis (MS). We sought to determine associations of socioeconomic disadvantage and psychosocial adversity with odds of pediatric-onset MS (POMS), age at POMS onset, and POMS disease activity. METHODS:This case-control study used data collected across 17 sites in the United States by the Environmental and Genetic Risk Factors for Pediatric Multiple Sclerosis Study. Cases (n = 381) were youth aged 3-21 years diagnosed with POMS or a clinically isolated demyelinating syndrome indicating high risk of MS. Frequency-matched controls (n = 611) aged 3-21 years were recruited from the same institutions. Prenatal and postnatal adversity and postnatal socioeconomic factors were assessed using retrospective questionnaires and zip code data. The primary outcome was MS diagnosis. Secondary outcomes were age at onset, relapse rate, and Expanded Disability Status Scale (EDSS). Predictors were maternal education, maternal prenatal stress events, child separation from caregivers during infancy and childhood, parental death during childhood, and childhood neighborhood disadvantage. RESULTS:MS cases (64% female, mean age 15.4 years, SD 2.8) were demographically similar to controls (60% female, mean age 14.9 years, SD 3.9). Cases were less likely to have a mother with a bachelor's degree or higher (OR 0.42, 95% CI 0.22-0.80, p = 0.009) and were more likely to experience childhood neighborhood disadvantage (OR 1.04 for each additional point on the neighborhood socioeconomic disadvantage score, 95% CI 1.00-1.07; p = 0.025). There were no associations of the socioeconomic variables with age at onset, relapse rate, or EDSS, or of prenatal or postnatal adverse events with risk of POMS, age at onset, relapse rate, or EDSS. DISCUSSION:Low socioeconomic status at the neighborhood level may increase the risk of POMS while high parental education may be protective against POMS. Although we did not find associations of other evaluated prenatal or postnatal adversities with POMS, future research should explore such associations further by assessing a broader range of stressful childhood experiences.

Background: Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease of the central nervous system (CNS), characterized by new onset polyfocal neurologic symptoms with encephalopathy and multifocal demyelination, typically occurring in early childhood. The initial diagnosis of ADEM can be challenging, as up to 20% of children with multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD) are initially diagnosed with ADEM. Objective:To describe characteristics of patients with ADEM vs. recurrent demyelinating syndromes (MS, NMOSD, other) at the time of initial presentation and identify features at disease onset of presentations consistent with ADEM associated with monophasic demyelinating disease. Methods: This is a multicenter observational cohort study of children with a demyelinating disease diagnosis of ADEM, multiphasic ADEM, MS, and NMOSD who were followed at 12 regional pediatric MS referral centers in the US Network of Pediatric MS Centers. Descriptive statistics were used to report patient characteristics, clinical/imaging presenting features and subsequent outcomes. Logistic regression was used to predict features associated with a monophasic course. Results: As of July 2019, 872 pediatric patients with a final diagnosis of ADEM (n=89), MS (n= 664) or NMOSD (n=119) were identified. The mean +/- standard deviation follow-up for all patients was 5·7 +/- 3·1 years. ADEM patients were the youngest with mean age at first event 5·4 +/- 3·7 years (p < 0.001) and male predominance (62%) (p < 0·001). Severe clinical symptoms at onset were more frequent in ADEM (55% vs. 35% NMOSD and 15% MS, p < 0·001). After 2 years of follow-up, 78% (93/119) of patients initially diagnosed with ADEM retained this diagnosis (ADEM to ADEM), while 9·2% were later reclassified as MS, 3·3% as NMOSD and 7·5% as demyelinating disease not otherwise specified (DDNOS). In univariable logistic regression, younger age at first event was associated with retaining ADEM diagnosis, while presentation with optic neuritis and gadolinium enhancement on brain MRI were associated with ADEM reclassification to MS, NMOSD, or DDNOS at 2 years of follow-up. In multivariable analysis, older age at first event (OR 1·16 [95% CI 1·00 – 1·33] for 1-year increase, p = 0·04), presenting with optic neuritis (OR 15·31 [95% CI 3·27 – 71·66], p <0·001) and presence of gadolinium enhancement on brain MRI at onset (OR 6·80 [95% CI 2·03 – 22·78], p = 0·0019) were associated with reclassification of ADEM to MS, NMOSD or DDNOS within 2 years. Conclusion: Children who remain classified as ADEM vs. those who are reclassified as other demyelinating disorders are younger at onset, and less likely to have optic neuritis or gadolinium-enhancing lesions at disease onset. Funding: None to declare. Declaration of Interest: None to declare. Ethical Approval: The ethics committees of participating institutions approved this study. Parents and participants signed consent forms and assent forms when required by each center’s institutional review board prior to enrollment.

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 (ps > 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 AND OBJECTIVE:The objective of this study was to determine whether family members of patients with pediatric multiple sclerosis (MS) have an increased prevalence of autoimmune conditions compared with controls.METHODS:Data collected during a pediatric MS case-control study of risk factors included information about various autoimmune diseases in family members. The frequency of these disorders was compared between cases and controls.RESULTS:There was an increased rate of autoimmune diseases among family members of pediatric MS cases compared with controls with first-degree history of MS excluded (OR = 2.27, 95% CI 1.71-3.01, p < 0.001). There was an increased rate of MS among second-degree relatives of pediatric MS cases compared with controls (OR = 3.47, 95% CI 1.36-8.86, p = 0.009). The OR for MS was 2.64 when restricted to maternal relatives and 6.37 when restricted to paternal relatives.DISCUSSION:The increased rates of autoimmune disorders, including thyroid disorders and MS among families of patients with pediatric MS, suggest shared genetic factors among families with children diagnosed with pediatric MS.

Abstract Objective To identify features of the gut microbiome associated with multiple sclerosis activity over time. Methods We used 16S ribosomal RNA sequencing from stool of 55 recently diagnosed pediatric‐onset multiple sclerosis patients. Microbiome features included the abundance of individual microbes and networks identified from weighted genetic correlation network analyses. Prentice‐Williams‐Peterson Cox proportional hazards models estimated the associations between features and three disease activity outcomes: clinical relapses and both new/enlarging T2 lesions and new gadolinium‐enhancing lesions on brain MRI. Analyses were adjusted for age, sex, and disease‐modifying therapies. Results Participants were followed, on average, 2.1 years. Five microbes were nominally associated with all three disease activity outcomes after multiple testing correction. These included butyrate producers Odoribacter (relapse hazard ratio = 0.46, 95% confidence interval: 0.24, 0.88) and Butyricicoccus (relapse hazard ratio = 0.49, 95% confidence interval: 0.28, 0.88). Two networks of co‐occurring gut microbes were significantly associated with a higher hazard of both MRI outcomes (gadolinium‐enhancing lesion hazard ratios (95% confidence intervals) for Modules 32 and 33 were 1.29 (1.08, 1.54) and 1.42 (1.18, 1.71), respectively; T2 lesion hazard ratios (95% confidence intervals) for Modules 32 and 33 were 1.34 (1.15, 1.56) and 1.41 (1.21, 1.64), respectively). Metagenomic predictions of these networks demonstrated enrichment for amino acid biosynthesis pathways. Interpretation Both individual and networks of gut microbes were associated with longitudinal multiple sclerosis activity. Known functions and metagenomic predictions of these microbes suggest the important role of butyrate and amino acid biosynthesis pathways. This provides strong support for future development of personalized microbiome interventions to modify multiple sclerosis disease activity.

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.

ObjectiveTo 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).MethodsThis 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.ResultsA 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.InterpretationInitial 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

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.

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.

Objective: Investigate the distribution of disease severity in pediatric-onset multiple sclerosis (MS). Background: Previous studies indicate pediatric-onset MS has a slower progression to disability than adult-onset MS; however, these studies account for disability as measured by the EDSS scale, which focuses largely on locomotor deficits, which are less prominent in children. There is a need to better characterize disability distribution and accrual in this population. Design/Methods: Data collected prospectively by the U.S. Network of Pediatric MS Centers was reviewed. Patients were stratified by the number of years from first symptoms of MS to EDSS assessment and an MS severity score (MSSS) was calculated per Roxburgh et al. criteria. For each year, the lowest and highest EDSS scores were calculated and then normalized by dividing 1+the number of available assessments. Scores from +/− one year were used to avoid stochastic fluctuations. This value was then multiplied by 10 to provide a range from 0–10 (MSSS = (Rank Average/N+1) ×10). Pediatric MSSS scores represented percentiles amongst patients who had the disease for the same disease duration. Results: In total, 994 patients were reviewed, consisting of 4,349 unique data points. Range of disability in our pediatric cohort at one year from diagnosis was narrower than data published by Roxburgh et al., with EDSS of 0, 1, 1.5, and 2.0, corresponding to the 14th, 40th, 60th, and 76thpercentiles compared to adults (7th, 24th, 43rd, 59th). This pattern was maintained at 2, 5, and 10 year’s disease duration (2 years: 14th/5th, 42nd/20th, 64th/37th, and 80th/52nd; 5 years: 13th/3rd, 38th/13th, 60th/26th, and 78th/39th; 10 years: 14th/2nd, 38th/8th, 56nd/15th, and 72nd/21st). Conclusions: The distribution of disease severity by MSSS scoring in pediatric patients with MS is much more narrow than adults. This could have significant implications on clinical intervention analysis utilizing EDSS scoring alone. Disclosure: Dr. Santoro has nothing to disclose. Dr. Waltz has nothing to disclose. Dr. Casper has nothing to disclose. Dr. Chitnis has received personal compensation for advisory boards/consulting with F. Hoffman-La Roche, Biogen and Novartis. Dr Chitnis has received research support from Biogen, Merck Serono, Verily and Novartis. Dr. Aaen has received research support from Biogen. Dr. Belman has nothing to disclose. Dr. Benson has nothing to disclose. Dr. Candee has nothing to disclose. Dr. Gorman has received research support from Biogen. Dr. Goyal has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities as a neuroradiology consultant. Dr. Goyal holds stock and/or stock options in IBM. Dr. Graves has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Genentech, Inc. and S3 Group. Dr. Graves has received research support from Biogen and Genentech. Dr. Greenberg has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Novartis, Alexion, EMD Serono. Dr. Greenberg has received research support from Chugai, Medimmune, Genentech, MedDay, PCORI, NIH, NMSS and Guthy Jackson Charitable Foundation for NMO. Dr. Harris has nothing to disclose. Dr. Kahn has nothing to disclose. Dr. Krupp has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Everyday Health, Gerson Lehman, Novartis, RedHill Biopharma, Roche, Shire, and Sanofi-Aventis. Dr. Krupp has received royalty, license fees, or contractual rights payments from Biogen, Reata Pharma, AbbVie Pharmaceuticals, Amicus Therapeutics, SA Inventions, Finkhar Health, Janssen Pharmaceuticals, Eisai, IPSOS, Octapharma, Atara Biotherapeutics, Merck, Research Tech, and ERT Inc. Dr. Krupp has received research support from Biogen and Novartis Pharmaceuticals. Dr. Lotze has received research support from PTC Therapeutics, Serepta Therapeutics and Catalyst Therapeutics. Dr. Mar has nothing to disclose. Dr. Moodley has nothing to disclose. Dr. Ness has nothing to disclose. Dr. Rensel has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Teva, Genzyme and Novartis. Dr. Rensel has received research support from Medimmune. Dr. Rodriguez has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with MedDay. Dr. Rose has received research support from the National Multiple Sclerosis Society, the Guthy Jackson Foundation, the Western Institute for Biomedical Research, Teva Neuroscience and Biogen. Dr. Rubin has nothing to disclose. Dr. Schreiner has received research support from Biogen and MSDx. Dr. Tillema has nothing to disclose. Dr. Waldman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with UpToDate, Optum Inc. Dr. Waldman holds stock and/or stock options in Spark, Thermo Fisher, and Pfizer. Dr. Waldman has received research support from Ionis Pharmaceuticals. Dr. Waubant has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with AAN for Frontiers in neurology talk, The Corpus for talks, compensation for editorial work for Annals of Clinical and Translational Neurology and MS and Related Disorders. Site PI for clinical trials with Roche, Biogen Idec and Novartis Dr. Weinstock-Guttman has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen Idec, EMD Serono, Genentech, Novartis, Mallinckrodt, and Celgene. Dr. Weinstock-Guttman has received research support from Biogen Idec, Novartis, and Genentech.

AbstractObjectiveOnset of multiple sclerosis (MS) occurs in childhood for approximately 5% of cases (pediatricMS, or ped‐MS). Epigenetic influences are strongly implicated inMSpathogenesis in adults, including the contribution from microRNAs (miRNAs), small noncodingRNAs that affect gene expression by binding target genemRNAs. Few studies have specifically examined miRNAs in ped‐MS, but individuals developingMSat an early age may carry a relatively high burden of genetic risk factors, and miRNAdysregulation may therefore play a larger role in the development of ped‐MSthan in adult‐onsetMS. This study aimed to look for evidence of miRNAinvolvement in ped‐MSpathogenesis.MethodsGWASresults from 486 ped‐MScases and 1362 controls from the U.S. PediatricMSNetwork and Kaiser Permanente Northern California membership were investigated for miRNA‐specific signals. First, enrichment of miRNA‐target gene network signals was evaluated usingMIGWASsoftware. Second,SNPs in miRNAgenes and in target gene binding sites (miR−SNPs) were tested for association with ped‐MS, and pathway analysis was performed on associated target genes.ResultsMIGWASanalysis showed that miRNA‐target gene signals were enriched inGWAS(P = 0.038) and identified 39 candidate biomarker miRNA‐target gene pairs, including immune and neuronal signaling genes. The miR‐SNPanalysis implicated dysregulation of miRNAbinding to target genes in five pathways, mainly involved in immune signaling.InterpretationEvidence fromGWASsuggests that miRNAs play a role in ped‐MSpathogenesis by affecting immune signaling and other pathways. Candidate biomarker miRNA‐target gene pairs should be further studied for diagnostic, prognostic, and/or therapeutic utility.

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.

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.

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.

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.

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.

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.

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.