Rose, John

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.

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

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.

AbstractIncomplete 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 &lt; 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 &lt; 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.

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

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.

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.

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.

AbstractBackgroundThere is limited information about the potential associations of multiple sclerosis (MS) and commonly used household chemicals.MethodsWe 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.ResultsQuestionnaire 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.ConclusionsOur 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.