Faculty Bibliography

BACKGROUND AND OBJECTIVE/OBJECTIVE:Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune condition, which can lead to significant disability, and up to 3% to 5% of the cases have a pediatric onset. There are limited studies to guide physicians in disease-modifying treatment (DMT) choices for children with NMOSD. METHODS:This retrospective cohort study evaluated children with NMOSD cases followed at 12 clinics in the US Network of Pediatric MS Centers. Cases were classified as Aquaporin-4 antibody positive (AQP4+) and double-seronegative (DS) when negative for AQP4+ and for myelin oligodendrocyte glycoprotein (MOG) antibody. Effect of initial DMTs including rituximab, mycophenolate, azathioprine, and intravenous immunoglobulin (IVIg) on annualized relapse rate (ARR) was assessed by negative binomial regression. Time to disability progression (EDSS increase ≥1.0 point) was modeled with a Cox proportional-hazards model. RESULTS:91 children with NMOSD were identified: 77 AQP4+ and 14 DS (85.7% females; 43.2% Caucasian, 46.6% African American). 81 patients were started on a DMT and 10 were treatment naïve at the time of the analysis. The ARR calculated in all serogroups was 0.25 (95% CI 0.13-0.49) for rituximab, 0.33 (95% CI 0.19-0.58) for mycophenolate, 0.40 (95% CI 0.13-1.24) for azathioprine and 0.54 (95% CI 0.28-1.04) for IVIg. The ARR in the AQP4+ subgroup was 0.28 (95% CI 0.14-0.55) for rituximab, 0.39 (95% CI 0.21-0.70) for mycophenolate, 0.41 (95% CI 0.13-1.29) for azathioprine and 0.54 (95% CI 0.23-1.26) for IVIg. The ARR in the treatment naïve group was 0.97 (95% CI 0.58-1.60) in all serogroups and 0.91 (95% CI 0.53-1.56) in the AQP4+ subgroup. None of the initial DMT had a statistically significant effect on EDSS progression. DISCUSSION/CONCLUSIONS:The use of DMTs, in particular rituximab, is associated with a lowered annualized relapse rate in children with NMOSD AQP4+. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class IV evidence that use of disease-modifying treatments is associated with a lowered annualized relapse rate in children with NMOSD AQP4+.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Limited data is available on children with evidence of silent central nervous system demyelination on MRI. We sought to characterize the population in a US cohort and identify predictors of clinical and radiologic outcomes. METHODS:We identified 56 patients such patients who presented with incidental MRI findings suspect for demyelination, enrolled through our US Network of Pediatric Multiple Sclerosis Centers, and conducted a retrospective review of 38 patients with MR images, and examined risk factors for development of first clinical event or new MRI activity. MRI were rated based on published MS and radiologically isolated syndrome (RIS) imaging diagnostic criteria. RESULTS:One-third had a clinical attack and ¾ developed new MRI activity over a mean follow-up time of 3.7 years. Individuals in our cohort shared similar demographics to those with clinically definite pediatric-onset MS. We show that sex, presence of infratentorial lesions, T1 hypointense lesions, juxtacortical lesion count, and callosal lesions were predictors of disease progression. Interestingly, the presence of T1 hypointense and infratentorial lesions typically associated with worse outcomes were instead predictive of delayed disease progression on imaging in subgroup analysis. Additionally, currently utilized diagnostic criteria (both McDonald 2017 and RIS criteria) did not provide statistically significant benefit in risk stratification. CONCLUSION/CONCLUSIONS:Our findings underscore the need for further study to determine if criteria currently used for pediatric patients with purely radiographic evidence of demyelination are sufficient.

Abstract Background: Loss of hand dexterity is disabling and reduces quality of life. People living with progressive forms of MS have marked neurologic disabilities but limited rehabilitation options. Transcranial direct current stimulation (tDCS) is a method of noninvasive brain stimulation in which stimulation delivered during motor training can strengthen outcomes. We have established a remotely supervised tDCS (RS-tDCS) protocol that delivers multiple stimulation sessions paired with training to participants at home.
Objective(s): To evaluate a blinded randomized sham-controlled clinical trial of active vs. sham tDCS paired with manual dexterity training for people with progressive MS.
Method(s): We recruited right-hand dominant individuals with progressive MS and hand dexterity impairment. Participants completed 20 sessions of daily (M-F) manual dexterity and were randomized to either active (2.0 mA) or sham primary motor cortex (M1-SO) tDCS. Manual dexterity was measured with the Nine-Hole Peg Test (9HPT) and Dellon-Modified Moberg Pick-Up test (MMPUT) at baseline and study end and transformed to normative z-scores for comparison.
Result(s): Participants were n=60 with primary (32%) or secondary (68%) progressive MS (52% female, ages 37-72 years, and a median Expanded Disability Status Scale (EDSS) score of 5.0 [1.5-7.5]). The intervention was safe and well tolerated, with n=59/60 (98%) completing 18/20 daily sessions. Combining hands and tasks, the full group improved following the manual dexterity training (mean z-score improvement 1.64+/-9.53, p=0.016). Active tDCS led to greater improvement (mean z-score improvement 4.51+/-8.78, p=0.001). Analyzing those with right- or left-hand impairment at baseline, the active tDCS group had significant improvement on the 9HPT (Right: p=0.036, Left: p=0.028) and trended towards significant improvement for the MMPUT (Right: p=0.071, Left: p=0.079).
Conclusion(s): At-home manual dexterity training paired with tDCS is a safe, tolerable, and feasible intervention for people with progressive MS and hand impairment. Training outcomes are augmented with simultaneous M1-SO tDCS. Research Category and Technology and Methods Clinical Research: 9. Transcranial Direct Current Stimulation (tDCS) Keywords: tDCS, motor training, multiple sclerosis, teleintervention
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BACKGROUND: Multiple sclerosis (MS) is a degenerative disease with typical onset between 20 and 50 years of age. An increase in MS cases has been found in the adolescent US population. Adolescents require fine motor manipulation skills for their functional and academic performance. Deficits in the major components of manipulation skills may result in insufficient function. This study examined the 2-point, 3-point, and lateral pinch strength of adolescents diagnosed as having MS. METHODS: Seventy-four adolescents, 37 with a diagnosis of relapsing-remitting MS and a control group of 37 age-matched peers, participated in this study. Data on 2-point, 3-point, and lateral pinch strength in both hands were collected using a pinch meter. Analyses of covariance were used to describe differences across the 2 groups, and effect sizes (Cohen d) were calculated by finding the mean difference between the study groups divided by the pooled SD. RESULTS: A significant difference was found in the 2-point pinch strength of the right hand of participants with pediatric MS compared with age- and sex-matched control participants. There were no significant differences in 2-point pinch strength of the left hand or in 3-point or lateral pinch strength of the right and left hands. CONCLUSIONS: Pinch grasp strength was differentially affected in adolescents with MS. Pinch strength should be assessed and considered in adolescents with MS for a better understanding of their functional performance of fine motor tasks in activities of daily living and academics.

B-cell depleting therapies such as rituximab and ocrelizumab are widely used for the treatment of Multiple Sclerosis but have increased risks of adverse reactions compared to earlier MS therapies. One rarely reported reaction is pyoderma gangrenosum (PG), an inflammatory, ulcerative, skin disease of unclear etiology. Here we describe a male and female patient, each with Relapsing-Remitting Multiple Sclerosis, and both of whom developed PG while on rituximab. Both PG diagnoses were supported by persistent fever, biopsy reports of sterile neutrophilia, and leukocytosis in the absence of an identifiable infectious agent. The diagnoses were further confirmed by dramatic clinical improvement following initiation of high dose steroids and intravenous immunoglobulins, and discontinuation of rituximab.

OBJECTIVE/UNASSIGNED: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/UNASSIGNED: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/UNASSIGNED: < 0.001). CONCLUSION/UNASSIGNED:Pediatric MS patients do not differ from healthy pediatric controls on cognitive screens but perform better than adults with MS.

Introduction: Treatment of pediatric MS is challenging as most disease-modifying therapies (DMT) lack efficacy data in children, including switching from first-line platform DMT. Objectives/Aims: To assess real-world effectiveness of switching DMT in patients initially treated with platform injectable DMT on disease activity in pediatric MS and CIS.
Method(s): This is a cohort study of children with MS/CIS at 12 clinics in the US Network of Pediatric MS Centers, who received initial therapy with platform injectable (interferon-beta, glatiramer acetate) and switched to the other class of injectable, oral (dimethyl fumarate, fingolimod, teriflunomide) or infusion (natalizumab, rituximab, ocrelizumab, alemtuzumab) DMT. Relapse rate after switch to platform injectable, oral or infusion DMT was modeled with negative binomial regression, adjusted for pre-identified confounders (age at onset, disease duration, sex, race/ethnicity, body mass index, first event severity and localization, baseline annualized relapse rate (ARR), MRI new T2 lesions, MRI gadolinium-enhancing lesions, EDSS).
Result(s): 212 children switched DMT before 18 years (67% female, 95% MS). Of these, 93 switched from injectable to injectable, 76 injectable to oral and 43 injectable to infusion. Compared to switching to another injectable, switchers to oral or infusion were older at onset (injectable 12.3 years vs oral 13.5, infusion 14.2) and switch date (injectable 14.6 years vs oral 16, infusion 15.7), and switchers to infusion were more likely to have new enhancing lesions prior to switch (injectable 45% vs oral 28%, infusion 67%). Other baseline characteristics were not significantly different between groups. In adjusted analysis, compared to switchers from injectable to injectable (ARR 0.59, 95%CI 0.28-1.26), relapse rates were lower for switchers from injectable to oral (ARR 0.22, 95%CI 0.10-0.48; rate ratio 0.38, 95%CI 0.21-0.69) and injectable to infusion (ARR 0.15, 95%CI 0.06-0.35; rate ratio 0.25, 95%CI 0.11-0.53) (p < 0.001). The adjusted number needed to treat to prevent 1 relapse with oral over injectable was 2.70 and infusion over injectable was 2.22.
Conclusion(s): Switching from platform injectable to oral or infusion as opposed to another injectable DMT led to better disease activity control of pediatric MS. Long-term safety data for oral and infusion DMTs are required

BACKGROUND:Transcranial direct current stimulation (tDCS) is a safe and well-tolerated noninvasive technique used for cortical excitability modulation. tDCS has been extensively investigated for its clinical applications; however further understanding of its underlying in-vivo physiological mechanisms remains a fundamental focus of current research. OBJECTIVES/OBJECTIVE:) using simultaneous MRI in healthy adults to provide a reference frame for its neurobiological mechanisms. METHODS:at three time points: pre-, during- and post- 15 minutes of 2.0 mA tDCS on left anodal dorsolateral prefrontal cortex. RESULTS:significantly increased by 5.9 % during-tDCS (175.68 ± 30.78 µmol/100g/min) compared to pre-tDCS (165.84 ± 25.32 µmol/100g/min; p = 0.0015), maintaining increased levels in post-tDCS (176.86 ± 28.58 µmol/100g/min). CONCLUSIONS:changes due to tDCS in healthy adults that may be incorporated in clinical studies to evaluate its therapeutic potential.

INTRODUCTION/BACKGROUND:The ability to deploy transcranial direct current stimulation (tDCS) at home is a key usability advantage to support scaling for pivotal clinical trials. We have established a home-based tDCS protocol for use in clinical trials termed remotely supervised (RS)-tDCS. OBJECTIVE:To report the tolerability and feasibility of tDCS sessions completed to date using RS-tDCS in clinical trials. METHODS:We analyzed tolerability (i.e., adverse events, AEs) reported in six Class I/II/III trials using RS-tDCS to study symptom outcomes over 10 to 60 daily applications. Across the six clinical trials, 308 participants (18-78 years old) completed an average of 23 sessions for a total of 6779 RS-tDCS administrations. The majority of participants were diagnosed with multiple sclerosis, and open-label trials included those diagnosed with a range of other conditions (e.g., Parkinson's disease, post-stroke aphasia, traumatic brain injury, cerebellar ataxia), with minimum-to-severe neurologic disability. Clinical trial feasibility (i.e., treatment fidelity and blinding integrity) was examined using two Class I randomized controlled trials (RCTs). RESULTS:No serious AEs occurred. Across administrations, three sessions (0.04%) were aborted due to discomfort, but no participant discontinued due to tolerability. The AEs most commonly reported by participants were tingling (68%), itching (41%) and warmth sensation (42%) at the electrode site, and these were equally reported in active and sham tDCS conditions. The two Class I RCTs resulted in rapid enrollment, high fidelity to treatment completion, and blinding integrity. CONCLUSIONS:At-home RS-tDCS is tolerable, including when used over extended periods of time. Home-based RS-tDCS is feasible and can enable Class I tDCS clinical trial designs.

BACKGROUND:The risk of SARS-CoV-2 infection and severity with disease modifying therapies (DMTs) in multiple sclerosis (MS) remains unclear, with some studies demonstrating increased risks of infection with B-cell-depleting (anti-CD20) therapies and severity, while others fail to observe an association. Most existing studies are limited by a reliance on 'numerator' data (i.e., COVID-19 cases) only. OBJECTIVE:To assess the risks of COVID-19 by DMT, this study aimed to assess both 'numerator' (patients with SARS-CoV-2 infection) and 'denominator' data (all patients treated with DMTs of interest) to determine if any DMTs impart an increased risk of SARS-CoV-2 infection or disease severity. METHODS:We systematically reviewed charts and queried patients during clinic encounters in the NYU MS Comprehensive Care Center (MSCCC) for evidence of COVID-19 in all patients who were on the most commonly used DMTs in our clinic (sphingosine-1-phosphate receptor (S1P) modulators (fingolimod/siponimod), rituximab, ocrelizumab, fumarates (dimethyl fumarate/diroximel fumarate), and natalizumab). COVID-19 status was determined by clinical symptoms (CDC case definition) and laboratory testing where available (SARS-CoV-2 PCR, SARS-CoV-2 IgG). Multivariable analyses were conducted to determine predictors of infection and severe disease (hospitalization or death) using SARS-CoV-2 infected individuals per DMT group and all individuals on a given DMT as denominator. RESULTS:We identified 1,439 MS patients on DMTs of interest, of which 230 had lab-confirmed (n = 173; 75.2%) or suspected (n = 57; 24.8%) COVID-19. Infection was most frequent in those on rituximab (35/138; 25.4%), followed by fumarates (39/217; 18.0%), S1P modulators (43/250; 17.2%), natalizumab (36/245; 14.7%), and ocrelizumab (77/589; 13.1%). There were 14 hospitalizations and 2 deaths. No DMT was found to be significantly associated with increased risk of SARS-CoV-2 infection. Rituximab was a predictor of severe SARS-CoV-2 infection among patients with SARS-CoV-2 infection (OR 6.7; 95% CI 1.1-41.7) but did not reach statistical significance when the entire patient population on DMT was used (OR 2.8; 95% CI 0.6-12.2). No other DMT was associated with an increased risk of severe COVID-19. CONCLUSIONS:Analysis of COVID-19 risk among all patients on the commonly used DMTs did not demonstrate increased risk of infection with any DMT. Rituximab was associated with increased risk for severe disease.