Faculty Bibliography

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.

[This corrects the article DOI: 10.1371/journal.pone.0177177.].

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.

Background: Fatigue is known for being one of the most debilitating and common symptoms of multiple sclerosis (MS). Despite its prevalence, though, reliable treatment options are lacking. Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation treatment that uses low amperage (2.0 mA) electric current to stimulate cortical regions. tDCS has been shown to improve fatigue in MS following consecutive daily treatment sessions. We have recently developed and shown the feasibility of a remotely supervised tDCS (RS-tDCS) protocol to ease the burden of daily sessions and allow patients to complete the treatment at home. We aim to evaluate the efficacy of RS-tDCS in fatigue management for patients with MS. Methods: We enrolled n = 31 patients with MS (all subtypes) into a randomly controlled, double-blind trial; n = 27 patients provided data for analysis with n = 15 randomized to the active group and n = 12 in the placebo or "sham" group. Participants came to the clinic for baseline and follow-up measures including self-report forms on fatigue. At baseline they were also trained in operating the tDCS headset. Participants then took the device home where they complete 20 sessions of tDCS (20 minutes, 2.0 mA, dorsolateral prefrontal cortex montage, left anodal) paired with cognitive training. Results: Our primary outcome measure was the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue scale. When comparing change in PROMIS Fatigue between the active and sham tDCS groups we found that active tDCS participants had significantly greater reductions in fatigue (mean change in Active =-5.6 +/- 8.9 vs. Sham = 0.9 +/- 1.9, p = 0.02 conditions). We analyzed the within-subject effect tDCS had and found a significant, beneficial effect in the active group (pre-treatment mean = 26.6 +/- 9.2, post-treatment mean = 21.0 +/- 6.4, p = 0.04) and no such effect in the sham group (pre-treatment mean = 22.9 +/- 7.9, post-treatment mean = 23.8 +/- 8.4, p = 0.15). Finally, we calculated Cohen's d effect size (Active d =-0.71, Sham d = 0.11). Conclusions: These data suggest that RS-tDCS provides significant reduction in MS-related fatigue

The neuropsychological aspects of multiple sclerosis (MS) have evolved over the past three decades. What was once thought to be a rare occurrence, cognitive dysfunction is now viewed as one of the most disabling symptoms of the disease, with devastating effects on patients' quality of life. This selective review will highlight major innovations and scientific discoveries in the areas of neuropathology, neuroimaging, diagnosis, and treatment that pertain to our understanding of the neuropsychological aspects of MS. Specifically, we focus on the recent discovery that MS produces pathogical lesions of gray matter (GM) that have consequences for cognitive functions. Methods for imaging these GM lesions in MS are discussed along with multimodal imaging studies that integrate structural and functional imaging methods to provide a better understanding of the relationship between cognitive test performance and functional reserve. Innovations in the screening and comprehensive assessment of cognitive disorders are presented along with recent research that examines cognitive dysfunction in pediatric MS. Results of innovative outcome studies in cognitive rehabilitation are discussed. Finally, we highlight trends for potential future innovations over the next decade. (JINS, 2017, 23, 832-842).

Objective: To confirm our preliminary findings of association between EBV, CMV and HSV-1 remote infections, serum 25(OH)vitamin D levels and pediatric-MS in a large national case-control study. Background: Prior studies have suggested possible associations between viral infections acquired during childhood and development of MS. Moreover, vitamin D deficiency and genetic polymorphisms in the vitamin D pathway may alter the immune response and are associated with increased risk of pediatric and adult MS. Design/Methods: Patients with pediatric-onset MS or CIS and frequency-matched controls were recruited at 16 pediatric MS centers across the US. Batched Epstein-Barr virus(EBV)-viral capsid antigen(VCA), Epstein-Barr nuclear antigen-1(EBNA-1), EBV-early antigen(EA), CMV, HSV-1 and -2 serostatus were tested by ELISA.25(OH)vitamin D levels were determined by chemoluminescence. The rates of viral seropositivity and serum levels of vitamin D were compared between cases and controls in analyses adjusted for possible confounders such as age, sex, race and ethnicity. DRB1*1501 status was determined using SNP typing. Results: Serum samples from 360 pediatric cases(mean age: 15.2+/-3.2 years, 64% females, mean disease duration 354+/-321 days)and 496 healthy controls(mean age:14.3+/-3.8 years, 52% females)were tested for EBV, CMV and HSV antibodies and 25(OH)vitamin D. In a model adjusting for age, sex, race and ethnicity, a remote infection with EBV(anti-EBNA1 IgG positive)was strongly associated with higher risk of developing pediatric-onset MS(OR:3.6, 95%CI 2.1-6.3). HSV-1 seropositivity was also associated with pediatric-onset MS(OR:1.4, 95%CI 1.001-2.011). There was no association between serostatus for CMV and HSV-2 and risk of pediatric MS. For vitamin D analyses, we compared controls with 42 cases who were recruited within 45 days of disease onset as serum levels could not yet be substantially altered by vitamin D supplementation. There was a trend towards an association between lower serum levels of vitamin D and the risk of developing pediatric MS. For each 1 ng increase in 25(OH)vitamin D serum levels, there was a 3% reduction in the risk of pediatric MS onset(OR:0.77, 95%CI 0.93-1.01). Analyses stratifying by DRB1*1501 status are ongoing. Conclusions: Our preliminary results support an association between prior EBV and HSV-1 infection, and vitamin D deficiency and development of pediatric-onset MS

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

Objective: To test the relation between intra-individual variability (IIV) and cognition across the lifespan in multiple sclerosis (MS). Background: The Symbol Digit Modalities Test (SDMT) is a widely-used screen of cognitive functioning in MS across the lifespan. IIV in reaction time is a novel index of consistency across sustained performance. IIV been shown to be highly sensitive to general CNS integrity and global morbidity, and may serve as a cognitive biomarker in MS. Design/Methods: Patients with clinically-definite MS were recruited through the Lourie Center for Pediatric Multiple Sclerosis and the NYU Langone MS Comprehensive Care Center. Healthy controls were recruited for comparison purposes and utilized for the creation of the linear model that is necessary to calculate IIV scores. The SDMT and Cogstate Brief Battery were administered to all participants. The Cogstate Brief Battery consists of simple and choice reaction time tasks from which reaction time IIV was calculated. Results: A total of 187 MS participants completed the assessments ranging in age from 8 to 68 years (mean 32.9+/-17.6 years). Mean detection and identification IIV was calculated across the Cogstate reaction time measures, and predicted performance on the SDMT (r= -0.394, p<0.001). When compared to healthy controls, the effect sizes were nearly equivalent (Cohen's d = 0.53 and SDMT = 0.55, respectively). Conclusions: IIV in reaction time tasks may be used as a sensitive measure of performance variability in patients with MS and is related to cognitive performance as well. IIV is impaired in MS across the lifespan, including pediatric patients. IIV is a novel and sensitive marker of cognitive involvement in patients with MS, and may predict future cognitive decline as in other diseases