Graves, Jennifer

Background: Epstein–Barr virus (EBV) is a key environmental risk factor for multiple sclerosis (MS), and tonsils and adenoids serve as a primary viral reservoir. This study investigates the potential role of adenotonsillectomy in pediatric-onset multiple sclerosis (POMS) risk and relapse rate. Objectives: POMS participants and controls were recruited from 16 pediatric MS clinics between 1 November 2011 and 1 July 2017. Clinical and demographic information, including history of adenotonsillectomy, EBV serostatus, and HLA-DRB1*15:01:01 status, were collected. Multivariable logistic regression assessed the association between adenotonsillectomy and MS risk. In addition, negative binomial regression offset by follow-up time was used to assess the relationship between adenotonsillectomy and relapse rate in POMS participants with available follow-up data. Results: The case-control analysis included 359 POMS participants and 560 pediatric controls. Individuals with a history of adenotonsillectomy had a 63% increased odds of MS (adjusted odds ratio (OR) = 1.63, 95% confidence interval (CI) = 1.01–2.64, p = 0.046). Among the 239 POMS participants with available follow-up data, adenotonsillectomy was associated with a twofold increase in annualized relapse rate (adjusted incidence rate ratio (IRR) = 2.00, 95% CI = 1.15–3.48, p = 0.013). Conclusions: Prior adenotonsillectomy was associated with increased risk of MS and greater relapse rate in pediatric patients, suggesting a potential interplay between EBV, immune regulation, and MS pathogenesis.

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.

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

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.