Faculty Bibliography

Background: Approximately 3-5% of multiple sclerosis (MS) cases manifest in childhood and adolescence, characteristically with highly active inflammatory disease course. Paediatric-onset MS (POMS) has an impact on brain integrity and may increase brain volume loss (BVL) above age-expected rates. This study assessed the effect of oral fingolimod up to 0.5mg daily versus intramuscular interferon (IFN) beta-1a 30 micro g once weekly on MRI outcomes in POMS patients. Method(s): In this double-blind, double-dummy, active-controlled, multicentre study, patients with POMS (aged 10-<18 Years) received either fingolimod (dose adjusted for body weight; n = 107) or IFN beta-1a (n = 107) for up to 2 years. MRI was performed at baseline and every 6 months until the end of the study (EOS) core phase. Key MRI outcomes were the number of new/newly enlarging T2 (N/NET2) lesions and gd-enhancing T1 (Gd+T1) lesions, annual rate of brain volume change (ARBVC), annualised rate of number of new T1 hypointense lesions, change in total T2 hyperintense lesion volume (T2LV) and the number of combined unique active lesions (CUAL). Result(s): At the EOS, compared with IFN beta-1a, fingolimod significantly reduced the annualised rate of N/NET2 lesions (52.6%; p < 0.001), number of Gd+T1 lesions per scan (66.0%; p < 0.001), ARBVC (-0.48% vs. -0.80%, p = 0.014), annualised rate of number of new T1 hypointense lesions (62.8%; p < 0.001), T2LV (percent change from baseline: 18.4% vs. 32.4%, p < 0.001) and CUAL per scan (60.7%; p < 0.001). Conclusion(s): Fingolimod significantly reduced MRI activity and slowed BVL for up to 2 years vs. IFN beta-1a in paediatric-onset MS.

BACKGROUND:/UNASSIGNED:Fatigue is one of the most common and distressing symptoms among persons with multiple sclerosis (pwMS). OBJECTIVE:/UNASSIGNED:The aim of this study is to evaluate fatigue as a predictor for disease worsening among pwMS. METHODS:/UNASSIGNED:, categorized participants into two groups: those with stable/improved outcomes and those who worsened. In a subgroup of patients with longitudinal data ( n = 1951), sustained EDSS worsening was analyzed using Cox proportional hazards modeling to explore the effect of fatigue. RESULTS:/UNASSIGNED:The median survival time from study enrollment to sustained EDSS worsening was 8.7 years (CI: 7.2-10.1). Participants who reported fatigue at baseline were more likely to experience sustained EDSS worsening during follow-up (HR: 1.4, 95% CI: 1.2-1.7). Patients who were fatigued at baseline were also more likely to report worsening psychosocial limitations (all ps ⩽ 0.01). CONCLUSION:/UNASSIGNED:In addition to being a common symptom of MS, severe fatigue was a significant predictor for EDSS worsening in the NYSMSC.

Background/UNASSIGNED: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/UNASSIGNED:= 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/UNASSIGNED:= 0.002). Average RSEI scores did not differ significantly between cases and controls. Conclusion/UNASSIGNED:, CO, and lead) were statistically associated with higher odds for pediatric MS.

OBJECTIVE:To characterize the use and safety of newer disease-modifying therapies (DMTs) in children with multiple sclerosis (MS) and clinically isolated syndrome (CIS) treated under 18 years of age. METHODS:This is a cohort study including children with MS or CIS followed at 12 outpatient practices participating in the US Network of Pediatric MS Centers. DMT use, including duration, dose, and side effects, was analyzed. Newer DMTs were defined as agents receiving Food and Drug Administration approval or with increased use in adult MS after 2005. RESULTS:As of July 2017, 1,019 pediatric patients with MS (n = 748) or CIS (n = 271) were enrolled (65% female, mean onset 13.0 ± 3.9 years, mean follow-up 3.5 ± 3.1 years, median 1.6 visits per year). Of these, 78% (n = 587) with MS and 11% (n = 31) with CIS received DMT before 18 years of age. This consisted of at least one newer DMT in 42%, including dimethyl fumarate (n = 102), natalizumab (n = 101), rituximab (n = 57), fingolimod (n = 37), daclizumab (n = 5), and teriflunomide (n = 3). Among 17%, the initial DMT prescribed was a newer agent (36 dimethyl fumarate, 30 natalizumab, 22 rituximab, 14 fingolimod, 2 teriflunomide). Over the last 10 years, the use of newer agents has increased, particularly in those ≥12 years and to lesser extent in those <12 years. The short-term side effect profiles of newer DMTs did not differ from those reported in adults. CONCLUSION/CONCLUSIONS:Newer DMTs are often used in pediatric MS, and have similar short-term safety, tolerability, and side effect profiles as in adults. These findings may help inform pediatric MS management.

PURPOSE/OBJECTIVE:To promote understanding of cognitive impairment in multiple sclerosis (MS), recommend optimal screening, monitoring, and treatment strategies, and address barriers to optimal management. METHODS:The National MS Society ("Society") convened experts in cognitive dysfunction (clinicians, researchers, and lay people with MS) to review the published literature, reach consensus on optimal strategies for screening, monitoring, and treating cognitive changes, and propose strategies to address barriers to optimal care. RECOMMENDATIONS/CONCLUSIONS:Based on current evidence, the Society makes the following recommendations, endorsed by the Consortium of Multiple Sclerosis Centers and the International Multiple Sclerosis Cognition Society: Increased professional and patient awareness/education about the prevalence, impact, and appropriate management of cognitive symptoms. For adults and children (8+ years of age) with clinical or magnetic resonance imaging (MRI) evidence of neurologic damage consistent with MS: As a minimum, early baseline screening with the Symbol Digit Modalities Test (SDMT) or similarly validated test, when the patient is clinically stable; Annual re-assessment with the same instrument, or more often as needed to (1) detect acute disease activity; (2) assess for treatment effects (e.g. starting/changing a disease-modifying therapy) or for relapse recovery; (3) evaluate progression of cognitive impairment; and/or (4) screen for new-onset cognitive problems. For adults (18+ years): more comprehensive assessment for anyone who tests positive on initial cognitive screening or demonstrates significant cognitive decline, especially if there are concerns about comorbidities or the individual is applying for disability due to cognitive impairment. For children (<18 years): neuropsychological evaluation for any unexplained change in school functioning (academic or behavioral). Remedial interventions/accommodations for adults and children to improve functioning at home, work, or school.

BACKGROUND:Treatment of patients younger than 18 years of age with multiple sclerosis has not been adequately examined in randomized trials. We compared fingolimod with interferon beta-1a in this population. METHODS:In this phase 3 trial, we randomly assigned patients 10 to 17 years of age with relapsing multiple sclerosis in a 1:1 ratio to receive oral fingolimod at a dose of 0.5 mg per day (0.25 mg per day for patients with a body weight of ≤40 kg) or intramuscular interferon beta-1a at a dose of 30 μg per week for up to 2 years. The primary end point was the annualized relapse rate. RESULTS:-weighted magnetic resonance imaging (MRI) was 4.39 with fingolimod and 9.27 with interferon beta-1a (absolute difference, 4.88 lesions; relative difference, 53%; P<0.001). Adverse events, excluding relapses of multiple sclerosis, occurred in 88.8% of patients who received fingolimod and 95.3% of those who received interferon beta-1a. Serious adverse events occurred in 18 patients (16.8%) in the fingolimod group and included seizures (in 4 patients), infection (in 4 patients), and leukopenia (in 2 patients). Serious adverse events occurred in 7 patients (6.5%) in the interferon beta-1a group and included infection (in 2 patients) and supraventricular tachycardia (in 1 patient). CONCLUSIONS:Among pediatric patients with relapsing multiple sclerosis, fingolimod was associated with a lower rate of relapse and less accumulation of lesions on MRI over a 2-year period than interferon beta-1a but was associated with a higher rate of serious adverse events. Longer studies are required to determine the durability and safety of fingolimod in pediatric multiple sclerosis. (Funded by Novartis Pharma; PARADIG MS ClinicalTrials.gov number, NCT01892722 .).

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.

Background and aims: Approximately 3-5% of Multiple Sclerosis (MS) cases manifest in childhood and adolescence, characteristically with highly active inflammatory disease course. Paediatric-onset MS (POMS) has an impact on brain integrity and may increase Brain Volume Loss (BVL) above age-expected rates. This study assessed the effect of oral Fingolimod up to 0.5mg daily versus intramuscular interferon (IFN) beta-1a 30mug once weekly on MRI outcomes in POMS patients. Methods: In this double-blind, double-dummy, activecontrolled, multicentre study, patients with POMS (aged 10-<18 years) received either Fingolimod (dose adjusted for body weight; N=107) or IFN beta-1a (N=107) for up to 2 years. MRI was performed at baseline and every 6 months until the End Of The Study (EOS) core phase. Key MRI outcomes were the number of new/newly enlarging T2 (n/ neT2) lesions and Gd-enhancing T1 (Gd+T1) lesions, Annual Rate Of Brain Volume Change (ARBVC), annualised rate of number of new T1 hypointense lesions, change in total T2 Hyperintense Lesion Volume (T2LV) and the number of Combined Unique Active Lesions (CUAL). Results: At the EOS, compared with IFN beta-1a, fingolimod significantly reduced the annualised rate of n/ neT2 lesions (52.6%; p<0.001), number of Gd+T1 lesions per scan (66.0%; p<0.001), ARBVC (-0.48% vs. -0.80%, p=0.014), annualised rate of number of new T1 hypointense lesions (62.8%; p<0.001), T2LV (percent change from baseline: 18.4% vs. 32.4%, p<0.001) and CUAL per scan (60.7%; p<0.001). Conclusion: Fingolimod significantly reduced MRI activity and slowed BVL for up to 2 years vs. IFN beta-1a in paediatric-onset MS