A new look at cognitive functioning in pediatric MS.

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.

Familial History of Autoimmune Disorders Among Patients With Pediatric Multiple Sclerosis.

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.

Gut microbiome is associated with multiple sclerosis activity in children.

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.

Improved relapse recovery in paediatric compared to adult multiple sclerosis.

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.

Pediatric Multiple Sclerosis Severity Score in a large US cohort.

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.

Real-World Effectiveness of Initial Disease-Modifying Therapies in Pediatric Multiple Sclerosis.

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-ß, 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.

Vitamin D genes influence MS relapses in children.

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.

Cognitive processing speed in pediatric-onset multiple sclerosis: Baseline characteristics of impairment and prediction of decline.

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.

miRNA contributions to pediatric-onset multiple sclerosis inferred from GWAS.

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.

Admixture mapping reveals evidence of differential multiple sclerosis risk by genetic ancestry.

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.

Acquisition of Early Developmental Milestones and Need for Special Education Services in Pediatric Multiple Sclerosis.

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.

Several household chemical exposures are associated with pediatric-onset multiple sclerosis.

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.

Urban air quality and associations with pediatric multiple sclerosis.

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.

Heterogeneity in association of remote herpesvirus infections and 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.

Early infectious exposures are not associated with increased risk of pediatric-onset multiple sclerosis.

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.

The multiple sclerosis risk allele within the AHI1 gene is associated with relapses in children and adults.

BACKGROUND: While common variant non-HLA (human leukocyte antigen) alleles have been associated with MS risk, their role in disease course is less clear. We sought to determine whether established multiple sclerosis (MS) genetic susceptibility factors are associated with relapse rate in children and an independent cohort of adults with MS. METHODS: Genotyping was performed for 182 children with MS or clinically isolated syndrome with high risk for MS from two Pediatric MS Centers. They were prospectively followed for relapses. Fifty-two non-HLA MS susceptibility single nucleotide polymorphisms (SNPs) were evaluated for association with relapse rate. Cox regression models were adjusted for sex, genetic ancestry, disease-modifying therapy (DMT), 25-OH vitamin D level and HLA-DRB1*15:01/03 status. Investigation of pediatric subject SNP results was performed using a second cohort of 141 adult MS subjects of Northern European ancestry from the Southern Tasmanian Multiple Sclerosis Longitudinal Study. RESULTS: For pediatric subjects, 408 relapses were captured over 622 patient-years of follow-up. Four non-HLA risk SNPs (rs11154801, rs650258, rs12212193, rs2303759) were associated with relapses (p < 0.01) in the pediatric subjects. After adjustment for genetic ancestry, sex, age, vitamin D level, DMT use and HLA-DRB1*15 status, having two copies of the MS risk allele within AHI1 (rs11154801) was associated with increased relapses among children (HR = 1.75,95%CI = 1.18-2.48, p = 0.006) and this result was also observed among adults (HR = 1.81,95%CI = 1.05-3.03, p = 0.026). CONCLUSIONS: Our results suggest that the MS genetic risk variant within the gene AHI1 may contribute to disease course in addition to disease susceptibility.

Genetic risk factors for pediatric-onset multiple sclerosis.

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 (ORavg = 1.24 vs 1.13, respectively), though the difference was not significant. The wGRS was strongly associated with POMS (ORmeta = 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.

Contribution of dietary intake to relapse rate in early paediatric multiple sclerosis.

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.

Dietary factors and pediatric multiple sclerosis: A case-control study.

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.

Examining the contributions of environmental quality to pediatric multiple sclerosis.

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.