Faculty Bibliography

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.

Transcranial direct current stimulation (tDCS) is a safe and well-tolerated noninvasive method for stimulating the brain that is rapidly developing into a treatment method for various neurological and psychiatric conditions. In particular, there is growing evidence of a therapeutic role for tDCS in ameliorating or delaying the cognitive decline in Alzheimer's disease (AD). We provide a brief overview of the current development and application status of tDCS as a nonpharmacological therapeutic method for AD and mild cognitive impairment (MCI), summarize the levels of evidence, and identify the improvements needed for clinical applications. We also suggest future directions for large-scale controlled clinical trials of tDCS in AD and MCI, and emphasize the necessity of identifying the mechanistic targets to facilitate clinical applications.

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.

BACKGROUND:Fatigue is among the most frequent and disabling symptoms in patients with relapsing multiple sclerosis (RMS). OBJECTIVE:To measure MS fatigue and its impact on daily life in a real-world US population using an MS-specific patient-reported outcome (PRO) instrument, the Fatigue Symptoms and Impacts Questionnaire-RMS (FSIQ-RMS). METHODS:This ongoing prospective study recruited RMS patients from an online patient community (Carenity) across US. Baseline assessment data are reported. Participants completed questionnaires, including the 20-item FSIQ-RMS questionnaire, with the first seven symptom-related items collected daily for seven days, and the other 13 items on the seventh day assessing impacts of fatigue. The FSIQ-RMS scores range from 0 to 100 (higher score=greater severity). The impact of fatigue on several aspects of patients' lives was rated from 0 (no impact) to 10 (very high impact). Data on disease history, disease status, sleep, social and emotional functioning were also captured. Baseline assessment data of 300 RMS patients are reported while follow-up assessments up to 18 months are planned. RESULTS:300 RMS participants completed the 7-day assessment (mean age 43.0 years, 88% women). Fatigue was rated as severe, with a mean score of 57.3 for the FSIQ-RMS symptom domain; 3 impact sub-domain scores were 42.3, 43.4 and 50.1 (physical, cognitive/emotional, and coping). Participants who were not in relapse (78%) reported less severe fatigue than those in relapse (22%): mean±SD symptom score of 54.6 ± 17.8 vs. 67.0 ± 19.7, p< 0.001. Fatigue had a higher intensity among those with depression than without (49% vs. 51%, with mean ± SD symptom score of 62.8 ± 16.9 vs. 52.1 ± 19.3, p< 0.001), and among those with sleep disorder than without (27% vs. 73%, 61.2 ± 19.2 vs. 55.9 ± 18.6; p< 0.05). The most common factor associated with increased fatigue was heat exposure (82%). Most participants (52%) reported experiencing fatigue before their MS diagnosis. CONCLUSION/CONCLUSIONS:Fatigue influences daily functioning for most patients with RMS. The FSIQ-RMS is a novel and MS-specific PRO measure that can advance the understanding and management of fatigue.

BACKGROUND:Persistent cognitive symptoms have been reported following COVID-19 hospitalization. We investigated the relationship between demographics, social determinants of health (SDOH) and cognitive outcomes 6-months after hospitalization for COVID-19. METHODS:We analyzed 6-month follow-up data collected from a multi-center, prospective study of hospitalized COVID-19 patients. Demographic and SDOH variables (age, race/ethnicity, education, employment, health insurance status, median income, primary language, living arrangements, and pre-COVID disability) were compared between patients with normal versus abnormal telephone Montreal Cognitive Assessments (t-MOCA; scores<18/22). Multivariable logistic regression models were constructed to evaluate predictors of t-MoCA. RESULTS:Of 382 patients available for 6-month follow-up, 215 (56%) completed the t-MoCA (n = 109/215 [51%] had normal and n = 106/215 [49%] abnormal results). 14/215 (7%) patients had a prior history of dementia/cognitive impairment. Significant univariate predictors of abnormal t-MoCA included older age, ≤12 years of education, unemployment pre-COVID, Black race, and a pre-COVID history of cognitive impairment (all p < 0.05). In multivariable analyses, education ≤12 years (adjusted OR 5.21, 95%CI 2.25-12.09), Black race (aOR 5.54, 95%CI 2.25-13.66), and the interaction of baseline functional status and unemployment prior to hospitalization (aOR 3.98, 95%CI 1.23-12.92) were significantly associated with abnormal t-MoCA scores after adjusting for age, history of dementia, language, neurological complications, income and discharge disposition. CONCLUSIONS:Fewer years of education, Black race and unemployment with baseline disability were associated with abnormal t-MoCA scores 6-months post-hospitalization for COVID-19. These associations may be due to undiagnosed baseline cognitive dysfunction, implicit biases of the t-MoCA, other unmeasured SDOH or biological effects of SARS-CoV-2.

BACKGROUND:Extended interval dosing (EID; average dosing interval approximately every 6 weeks) of natalizumab is associated with significantly lower risk of progressive multifocal leukoencephalopathy than standard interval dosing (SID; every 4 weeks) in patients with relapsing-remitting multiple sclerosis (MS). Real-world studies, though limited, suggest that natalizumab effectiveness is generally maintained in patients who switch to EID after initiation of stable treatment with SID. MS PATHS (Multiple Sclerosis Partners Advancing Technology and Health Solutions) is a collaborative, multicenter learning health system that generates real-world clinical and MRI data using highly standardized acquisition protocols. We compared MRI outcomes in MS PATHS patients treated with natalizumab EID versus SID. We also compared MRI outcomes in patients treated with natalizumab (EID and/or SID) versus injectable MS platform therapy. METHODS:Natalizumab infusion data from the TOUCH Prescribing Program database and MS PATHS MRI assessment data from seven US sites as of July 23, 2020, were used to identify patients with relapsing-remitting MS who had received natalizumab EID or SID in the interval between two MRI scans (an MRI segment). Patients who received injectable platform MS therapy between two MRI scans were also identified. MRI data were used to determine the incidence rate and odds of developing new or enlarging T2 lesions, annualized percentage change in T2 lesion volume (T2LV), and annualized percentage change in brain parenchymal fraction (BPF). MRI outcomes were compared for 1) natalizumab EID treatment versus natalizumab SID treatment, 2) natalizumab treatment (EID + SID) versus platform therapy, and 3) natalizumab EID versus platform therapy. Propensity score-based weighting or matching were used to balance covariates at the start of MRI segments for all comparisons. RESULTS:The MRI outcomes observed with natalizumab EID treatment did not differ significantly from those observed with natalizumab SID treatment. The odds ratio for any new or enlarging T2 lesion was 1.07 (95% confidence interval [CI]: 0.93, 1.24; p = 0.355), and the rate ratio (95% CI) for new or enlarging T2 lesions was 1.62 (0.93, 2.82; p = 0.090). Differences (95% CI) between EID and SID patients in mean annualized percentage change in T2LV and BPF were 1.56% (-3.77%, 6.90%; p = 0.566) and -0.11% (-0.25%, -0.10%; p = 0.096), respectively. Conversely, when MRI outcomes in natalizumab and platform therapy patients were compared, there were significant differences favoring natalizumab in all assessments: the odds of any new or enlarging T2 lesion (odds ratio: 0.69 [95% CI: 0.64, 0.75]; p<0.001), the incidence rate of new or enlarging T2 lesions (rate ratio: 0.47 [95% CI: 0.37, 0.61]; p<0.001), annualized percentage change (decrease) in T2LV (difference: -3.68% [95% CI: -7.06%, -0.30%]; p = 0.033), and annualized percentage change (increase) in BPF (difference: 0.22% [95% CI: 0.16%, 0.29%]; p<0.001). Results of the subgroup comparison of natalizumab EID patients with platform therapy patients were similar to those of the overall-natalizumab-group-versus-platform-therapy comparison. CONCLUSIONS:The results indicate that natalizumab EID and SID provide comparable real-world effectiveness on quantitative MRI metrics. These data further demonstrate that natalizumab EID can provide superior real-world effectiveness to injectable platform therapy on quantitative MRI metrics.