Faculty Bibliography

Objective: To present baseline characteristics of the first 190 patients randomized in the PARADIGMS study. Background: The PARADIGMS study is the first global, controlled study investigating the efficacy and safety of fingolimod up to 0.5 mg vs interferon (IFN) beta-1a in pediatric patients. Approximately 3-5% of patients with multiple sclerosis (MS) experience disease onset before 18 years of age. Design/Methods: PARADIGMS is an ongoing 24-month, double-blind, double-dummy, randomized, active-controlled, parallel-group, multicenter study. Patients with MS aged between 10 to < 18 years were randomized to receive either oral fingolimod once-daily (dose adjusted for body weight) or intramuscular IFN beta-1a 30ug once weekly. Eligibility criteria include patients with active MS, with diagnosis defined by the revised consensus definition for pediatric MS consistent with the 2010 McDonald criteria and an Expanded Disability Status Scale score of <=5.5. Results: The mean+/-SD age of the patients was 15.3+/-1.82 years (41% in >14 to <16 years; 31% in>16 years and 10% in <=12 years). The majority of patients were female (63%) and Caucasian (88%). Only 6 (3%) patients were prepubertal (Tanner Stage <2). The mean+/-SD duration of MS since first symptom was 2.1+/-1.92 years; mean number of relapses in the last 12 and 12-24 months before screening was 1.5 and 0.9 respectively. Median EDSS at baseline was 1.5 (range 0.0-5.5). The mean+/-SD number of Gd+ lesions was 3.1+/-6.56 with 49% of patients free from Gd+ lesions. The majority (~59%) of patients were treatment naive prior to enrollment. Conclusions: Patients enrolled in the PARADIGMS study had a high frequency of relapses and Gd+ lesions early in their course of the disease and the majority were at post-pubertal stage. These characteristics are in line with the previously known pediatric MS cohorts. The recruitment target has been successfully met; however recruitment remains open to enroll additional eligible pre-pubertal patients

Cognitive impairment affects more than half of all individuals living with multiple sclerosis (MS). We hypothesized that training at home with an adaptive online cognitive training program would have greater cognitive benefit than ordinary computer games in cognitively-impaired adults with MS. This was a double-blind, randomized, active-placebo-controlled trial. Participants with MS were recruited through Stony Brook Medicine and randomly assigned to either the adaptive cognitive remediation (ACR) program or active control of ordinary computer games for 60 hours over 12 weeks. Training was remotely-supervised and delivered through a study-provided laptop computer. A computer generated, blocked stratification table prepared by statistician provided the randomization schedule and condition was assigned by a study technician. The primary outcome, administered by study psychometrician, was measured by change in a neuropsychological composite measure from baseline to study end. An intent-to-treat analysis was employed and missing primary outcome values were imputed via Markov Chain Monte Carlo method. Participants in the ACR (n = 74) vs. active control (n = 61) training program had significantly greater improvement in the primary outcome of cognitive functioning (mean change in composite z score+/-SD: 0.25+/-0.45 vs. 0.09+/-0.37, p = 0.03, estimated difference = 0.16 with 95% CI: 0.02-0.30), despite greater training time in the active control condition (mean+/-SD:56.9 +/- 34.6 vs. 37.7 +/-23 .8 hours played, p = 0.006). This study provides Class I evidence that adaptive, computer-based cognitive remediation accessed from home can improve cognitive functioning in MS. This telerehabilitation approach allowed for rapid recruitment and high compliance, and can be readily applied to other neurological conditions associated with cognitive dysfunction. TRIAL REGISTRATION: Clinicaltrials.gov NCT02141386.

BACKGROUND: Adverse childhood experiences (ACEs) exert a psychological and physiological toll that increases risk of chronic conditions, poorer social functioning, and cognitive impairment in adulthood. OBJECTIVE: To investigate the relationship between childhood adversity and clinical disease features in multiple sclerosis (MS). METHODS: Sixty-seven participants with MS completed the ACE assessment and neuropsychological assessments as part of a larger clinical trial of cognitive remediation. RESULTS: Adverse childhood experience scores, a measure of exposure to adverse events in childhood, significantly predicted age of MS onset (r = -0.30, p = 0.04). ACEs were also linked to reading recognition (a proxy for premorbid IQ) (r = -0.25, p = 0.04). ACE scores were not related to age, current disability, or current level of cognitive impairment measured by the Symbol Digit Modalities Test (SDMT). CONCLUSION: Childhood adversity may increase the likelihood of earlier age of onset and poorer estimated premorbid IQ in MS.

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

BACKGROUND: Genetic ancestry, sex, and individual alleles have been associated with multiple sclerosis (MS) susceptibility. OBJECTIVE: To determine whether established risk factors for disease onset are associated with relapse rate in pediatric MS. METHODS: Whole-genome genotyping was performed for 181 MS or high-risk clinically isolated syndrome patients from two pediatric MS centers. Relapses and disease-modifying therapies were recorded as part of continued follow-up. Participants were characterized for 25-hydroxyvitamin D serum status. Ancestral estimates (STRUCTURE v2.3.1), human leukocyte antigen (HLA)-DRB1*15 carrier status (direct sequencing), sex, and a genetic risk score (GRS) of 110 non-HLA susceptibility single-nucleotide polymorphisms (SNPs) were evaluated for association with relapse rate with Cox and negative binomial regression models. RESULTS: Over 622 patient-years, 408 relapses were captured. Girls had greater relapse rate than boys (incident rate ratio (IRR) = 1.40, 95% confidence interval (CI) = 1.04-1.87, p = 0.026). Participants were genetically diverse; ~40% (N = 75) had <50% European ancestry. HLA-DRB1*15 status modified the association of vitamin D status (pixn = 0.022) with relapse rate (per 10 ng/mL, in DRB1*15+ hazard ratio (HR) = 0.72, 95% CI = 0.58-0.88, p = 0.002; in DRB1*15- HR = 0.96, 95% CI = 0.83-1.12, p = 0.64). Neither European ancestry nor GRS was associated with relapse rate. CONCLUSION: We demonstrate that HLA-DRB1*15 modifies the association of vitamin D status with relapse rate. Our findings emphasize the need to pursue disease-modifying effects of MS genes in the context of environmental factors.