Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:Accumulating evidence points to worse clinical outcomes among adults with multiple sclerosis (MS) belonging to minority or poverty-affected groups. By contrast, little is known about the outcomes of these populations with pediatric-onset MS (POMS). Individuals with POMS represent 5% of the MS population and are more racially diverse yet have been understudied regarding socioeconomic environment or characteristics. In this study, we investigated the association between childhood social determinants of health (SDOH) and brain MRI outcomes in patients with POMS. METHODS:This is a retrospective single-site cohort study of patients with POMS with brain MRI quantitatively analyzed using icobrain software to yield total white matter lesion, black hole, whole brain, white matter, and gray matter volumes. All patients with POMS evaluated at New York University Langone MS Center and who underwent high-quality volumetric MRI scans were included in this study. SDOH indicators of race, ethnicity, health insurance type, parental education, and childhood neighborhood social vulnerability index (SVI) were examined for association with MRI outcomes using linear least absolute shrinkage selection operator penalized regression modeling. Disease-modifying therapy (DMT) timing and DMT efficacy were compared for each SDOH category. RESULTS:= 0.39). There were no differences in DMT timing or efficacy between categories of social disadvantage. DISCUSSION/CONCLUSIONS:Individual-level and neighborhood-level indicators of social disadvantage are associated with worse brain MRI outcomes in POMS. Further investigation of race, ethnicity, and childhood disadvantage as risk factors of MS susceptibility and severity is needed to reduce MS health disparities.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Social determinants of health (SDOH) affect patient health outcomes, but the impact on patients with pediatric-onset multiple sclerosis (POMS) has not been well studied. Study objectives were to (1) describe the frequency of adverse SDOH, (2) evaluate social hardships as a potential barrier to the initiation of disease-modifying therapy (DMT), and (3) explore the association between adverse SDOH and disease outcomes in POMS, as well as study attrition. METHODS:This was a retrospective multicenter observational study conducted through the United States Network of Pediatric MS Centers database. Participants were patients diagnosed with POMS (excluding primary progressive MS). The primary outcome was time to initiation of DMT. Secondary outcomes included most recent Expanded Disability Status Scale (EDSS) score, steroid treatment for the first event, time to second event, and study attrition. Demographic variables and clinical outcomes were compared between patients with and without hardships (maternal education of high school or less, public insurance/no insurance, or single/no-income household). Multivariable regression models were used to assess the impact of social hardship on study outcomes. RESULTS:= 0.034). DISCUSSION/CONCLUSIONS:The experience of hardships is common and associated with younger age at symptom onset and diagnosis, as well as shorter time to second event. Lack of private insurance is associated with study attrition and a higher EDSS score despite no difference in time to initiating DMT. There may be differences in early disease pathophysiology related to social hardship, and future studies are needed to better understand this complex relationship.

BACKGROUND/UNASSIGNED:Cognitive decline in multiple sclerosis (MS) is common, but unpredictable, and increases with disease duration. As such, early detection of cognitive decline may improve the effectiveness of interventions. To that end, the Symbol Digit Modalities Test (SDMT) is effective in detecting slow processing speed as it relates to cognitive impairment, and intraindividual variability (IIV) observed in trials assessing continuous reaction time (RT) may be a useful indicator of early cognitive changes. Here, we will assess cognitive IIV changes in adults with early MS. METHODS/UNASSIGNED:Adults with relapsing-remitting MS (RRMS), <11 years since diagnosis, were recruited nationally. Baseline and two-year follow-up assessments included Brief International Cognitive Assessment in MS (BICAMS) and Cogstate computerized tests. Intraindividual variability in RT was calculated from psychomotor tasks and data were age-normalized. RESULTS/UNASSIGNED:= 0.05) compared to the lower SDMT group, with no significant RT or BICAMS changes. CONCLUSIONS/UNASSIGNED:In early MS, higher SDMT performance at baseline is associated with less cognitive variability but may indicate susceptibility to increased variability over time, highlighting the importance of monitoring IIV for early cognitive changes.

INTRODUCTION/UNASSIGNED:Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique with simultaneous (during stimulation) and cumulative effects (after repeated sessions) on blood flow and neuronal metabolism. These effects remain mostly unclear especially in multiple sclerosis (MS). This work aims to elucidate brain metabolic and hemodynamic underpinnings of tDCS and its potential therapeutic impact in MS patients using quantitative tDCS-MRI. METHODS/UNASSIGNED:) were obtained at pre-tDCS, during-tDCS and post-tDCS. RESULTS/UNASSIGNED:and CBF in pre-tDCS follow up, reaching the magnitudes measured at baseline during-tDCS. DISCUSSION/UNASSIGNED:TDCS induces an acute surge in metabolic activity persisting immediately after the stimulation is removed. Moreover, treatment composed of repeated tDCS-aCT paired sessions contributes to establishing long-lasting increases in neuronal activity.

BACKGROUND/UNASSIGNED:Many individuals with progressive multiple sclerosis (PMS) are challenged by reduced manual dexterity and limited rehabilitation options. Transcranial direct current stimulation (tDCS) during motor training can improve rehabilitation outcomes. We developed a protocol for remotely supervising tDCS to deliver sessions of stimulation paired with training at home. OBJECTIVE/UNASSIGNED:This study evaluated the effectiveness of at-home tDCS paired with manual dexterity training for individuals with PMS. METHODS/UNASSIGNED:Sixty-five right-hand dominant participants with PMS and hand impairment were randomized to receive either active or sham M1-SO tDCS paired with manual dexterity training over 4 weeks. Clinical outcomes were measured by the changes in Nine-Hole Peg Test (9-HPT) and Dellon-Modified-Moberg-Pick-Up Test (DMMPUT). RESULTS/UNASSIGNED:= 0.04). CONCLUSION/UNASSIGNED:At-home tDCS paired with manual dexterity training is effective for individuals with PMS, with M1-SO tDCS enhancing training outcomes and offering a promising intervention for improving and preserving hand dexterity.

BACKGROUND:Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently described demyelinating disorder, and children represent about 50% of all cases. Almost half of the patients experience relapses, but very few studies have evaluated predictors of relapse risk, challenging clinical management. The study aimed to identify predictors at MOGAD onset that are associated with a relapsing course. METHODS:Prospectively collected data from paediatric patients with MOGAD seen by the US Network of Paediatric MS Centres were leveraged. Univariable and adjusted multivariable models were used to predict recurrent disease. RESULTS:We identified 326 MOGAD cases (mean age at first event 8.9 years [SD 4.3], 57% female, 77% white and 74% non-Hispanic) and 46% relapsed during a mean follow-up of 3.9 years (SD 4.1). In the adjusted multivariable model, female sex (HR 1.66, 95% CI 1.17 to 2.36, p=0.004) and Hispanic/Latino ethnicity (HR 1.77, 95% CI 1.19 to 2.64, p=0.005) were associated with a higher risk of relapsing MOGAD. Maintenance treatment initiated before a second event with rituximab (HR 0.25, 95% CI 0.07 to 0.92, p=0.037) or intravenous immunoglobulin (IVIG) (HR 0.35, 95% CI 0.14 to 0.88, p=0.026) was associated with lower risk of a second event in multivariable analyses. Conversely, maintenance steroids were associated with a higher estimated relapse risk (HR 1.76, 95% CI 0.90 to 3.45, p=0.097). CONCLUSION/CONCLUSIONS:Sex and ethnicity are associated with relapsing MOGAD. Use of rituximab or IVIG therapy shortly after onset is associated with a lower risk of the second event. Preventive treatment after a first event could be considered for those with a higher relapse risk.

BACKGROUND AND OBJECTIVES/OBJECTIVE:Psychosocial adversity and stress, known to predispose adults to neurodegenerative and inflammatory immune disorders, are widespread among children who experience socioeconomic disadvantage, and the associated neurotoxicity and proinflammatory profile may predispose these children to multiple sclerosis (MS). We sought to determine associations of socioeconomic disadvantage and psychosocial adversity with odds of pediatric-onset MS (POMS), age at POMS onset, and POMS disease activity. METHODS:This case-control study used data collected across 17 sites in the United States by the Environmental and Genetic Risk Factors for Pediatric Multiple Sclerosis Study. Cases (n = 381) were youth aged 3-21 years diagnosed with POMS or a clinically isolated demyelinating syndrome indicating high risk of MS. Frequency-matched controls (n = 611) aged 3-21 years were recruited from the same institutions. Prenatal and postnatal adversity and postnatal socioeconomic factors were assessed using retrospective questionnaires and zip code data. The primary outcome was MS diagnosis. Secondary outcomes were age at onset, relapse rate, and Expanded Disability Status Scale (EDSS). Predictors were maternal education, maternal prenatal stress events, child separation from caregivers during infancy and childhood, parental death during childhood, and childhood neighborhood disadvantage. RESULTS:= 0.025). There were no associations of the socioeconomic variables with age at onset, relapse rate, or EDSS, or of prenatal or postnatal adverse events with risk of POMS, age at onset, relapse rate, or EDSS. DISCUSSION/CONCLUSIONS:Low socioeconomic status at the neighborhood level may increase the risk of POMS while high parental education may be protective against POMS. Although we did not find associations of other evaluated prenatal or postnatal adversities with POMS, future research should explore such associations further by assessing a broader range of stressful childhood experiences.

BACKGROUND:Observational studies looking at clinical a++nd MRI outcomes of treatments in pediatric MS, could assess current treatment algorithms, and provide insights for designing future clinical trials. OBJECTIVE:To describe baseline characteristics and clinical and MRI outcomes in MS patients initiating ocrelizumab and fingolimod under 18 years of age. METHODS:MS patients seen at 12 centers of US Network of Pediatric MS were included in this study if they had clinical and MRI follow-up and started treatment with either ocrelizumab or fingolimod prior to the age of 18. RESULTS:Eighty-seven patients initiating fingolimod and 52 initiating ocrelizumab met the inclusion criteria. Before starting fingolimod, mean annualized relapse rate was 0.43 (95 % CI: 0.29 - 0.65) and 78 % developed new T2 lesions while during treatment it was 0.12 (95 % CI: 0.08 - 1.9) and 47 % developed new T2 lesions. In the ocrelizumab group, the mean annualized relapse rate prior to initiation of treatment was 0.64 (95 % CI: 0.38-1.09) and a total of 83 % of patients developed new T2 lesions while during treatment it was 0.09 (95 % CI: 0.04-0.21) and none developed new T2 lesions. CONCLUSION/CONCLUSIONS:This study highlights the importance of evaluating current treatment methods and provides insights about the agents in the ongoing phase III trial comparing fingolimod and ocrelizumab.

IMPORTANCE/OBJECTIVE:This pilot study evaluates a remote strategy-based intervention for individuals with multiple sclerosis who experience everyday memory impairments. The intervention can potentially inform cognitive rehabilitation for this population. OBJECTIVE:To investigate the feasibility and efficacy of an intervention (TELE-Self-GEN) to determine whether it can alleviate everyday memory impairments of individuals with multiple sclerosis. DESIGN/METHODS:Pretest-posttest. SETTING/METHODS:Community. PARTICIPANTS/METHODS:Ten adults with multiple sclerosis. INTERVENTION/METHODS:Six synchronous treatment sessions were delivered online via Zoom. The treatment protocol embedded a memory strategy (self-generated learning) within a metacognitive framework, including self-awareness and self-management strategies. The treatment emphasizes when and how self-generation should be used. OUTCOME/RESULTS:Measurements assessed feasibility and participants' satisfaction with the intervention and its delivery method, as well as memory, everyday memory, and functional performance. RESULTS:Participants expressed high satisfaction with the virtual treatment, highlighting its convenience as a key factor. Treatment resulted in improvements in memory performance, perceived memory ability in daily life, and functional performance. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:Results provide initial proof of concept in the utilization of a remotely delivered, strategy-based treatment approach to improve memory performance and functional abilities. The pilot data support a larger randomized clinical trial of the TELE-self-GEN. Plain-Language Summary: The results of this pilot study highlight the promising potential of TELE-self-GEN for people with multiple sclerosis (MS), who face memory challenges every day. This remotely delivered, strategy-based occupational therapy treatment approach, TELE-self-GEN, has the potential to significantly improve functional memory. The study participants reported improvements in their memory performance, perceived memory ability in daily life, and functional performance. These encouraging results serve as a foundation for more extensive clinical trials using TELE-self-GEN for people with MS.