Faculty Bibliography

Fatigue is a common and often debilitating feature of multiple sclerosis (MS) that lacks reliably effective treatment options for most patients. Transcranial direct current stimulation (tDCS), a safe and well-tolerated type of noninvasive brain stimulation, is a low-cost and home-based approach with the potential to reduce fatigue in MS. We conducted a double-blind, sham-controlled, randomized clinical trial to compare active vs. low-dose (sham) tDCS paired with computer-based cognitive training, delivered as a home-based intervention, to reduce MS-related fatigue. Participants with MS-related fatigue, but without depression, were stratified by neurologic disability using the Extended Disability Status Scale (EDSS) and randomized to complete 30 daily sessions over six weeks of either active or sham tDCS paired with online cognitive training (BrainHQ). The primary outcome was the change in PROMIS Fatigue score from baseline to the end of the intervention. A total of 117 participants were randomized, with 92% completing all treatment sessions. Both groups showed significant reductions in fatigue, with no significant difference between them. This suggests that tDCS does not provide any additional benefit over cognitive training alone in reducing fatigue, but confirms the feasibility and tolerance of this home-based intervention.

BACKGROUND/UNASSIGNED:Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disorder that occurs in children and adults. CASE/UNASSIGNED:We report a case of a 10-year-old female with AQP4+ NMOSD who presented with paraparesis from longitudinally extensive transverse myelitis (LETM) from C2 to the conus medullaris. The patient showed gradual improvement in strength and sensation with solumedrol and plasma exchange therapy. Given her severe presentation, eculizumab therapy was also initiated acutely. She had near complete recovery, although she developed a myelitis relapse during transition to rituximab treatment. CONCLUSION/UNASSIGNED:This case demonstrates the role of eculizumab as a safe and effective treatment option in treating an acute attack of pediatric AQP4+ NMOSD. More data are needed to understand the risk of relapse if transitioning off of these highly effective medications.

BACKGROUND:Lipids are of particular interest for the study of neuroinjury and neuroinflammation as structural lipids are major components of myelin, and a variety of lipid species modulate inflammation. In this study, we performed an in-depth lipidomics analysis to identify lipids associated with injury and disease activity. METHODS:Plasma samples were collected from paediatric-onset multiple sclerosis (MS) cases within 4 years of disease onset from 17 sites. The lipidome was measured using untargeted and targeted mass spectrometry. For cross-sectional analyses, the agreement between multiple machine learning models was used to predict neurofilament light chain (NfL) levels. In longitudinal analyses, the association between clinical (relapse count) and imaging (MRI count with ≥1 enhancing or new T2 lesion) outcomes with each metabolite was estimated using adjusted negative binomial regression. RESULTS:At sample collection, 68% of the 435 included individuals were treatment-naive, with a median disease duration of 0.8 years (IQR 0.3-1.7). For longitudinal analyses, 381 and 335 subjects had at least 1 year of clinical and imaging follow-up, respectively. In cross-sectional analyses, NfL chain levels identified structural lipids (phosphatidylcholines and phosphatidylethanolamines) as the highest-performing predictors, including external validation. In contrast, longitudinal analyses found polyunsaturated fatty acids (PUFAs) and their derivatives to be protective from subsequent disease activity (q<0.001, multiple outcomes). CONCLUSION/CONCLUSIONS:There are two categories of lipids associated with MS processes. First, structural lipids strongly associated with NfL levels may result from cell lysis secondary to acute inflammation. In contrast, PUFAs, especially ω-3, had a protective effect on subsequent disease activity.

This scientific commentary refers to 'Fatigue in early multiple sclerosis: MRI metrics of neuroinflammation, relapse and neurodegeneration', by Meijboom et al. (https://doi.org/10.1093/braincomms/fcae278).

BACKGROUND/UNASSIGNED:Cognitive impairment is common in multiple sclerosis (MS). Transcranial direct current stimulation (tDCS) combined with adaptive cognitive training (aCT) may improve clinical outcomes. OBJECTIVE/UNASSIGNED:To evaluate the effect of active vs. sham home-based tDCS + aCT on cognitive function. METHODS/UNASSIGNED:-scores. RESULTS/UNASSIGNED: = .411). CONCLUSIONS/UNASSIGNED:Active vs. sham tDCS + aCT resulted in significantly better cognitive outcomes, with the greatest benefit in those with high neurologic disability.CLINICALTRIALS.GOV; https://clinicaltrials.gov/study/NCT03838770; IDENTIFIER: NCT03838770.

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: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: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: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.