Faculty Bibliography

ADEM is an inflammatory disease, with new onset polyfocal neurologic symptoms, encephalopathy and multifocal demyelination, typically in childhood. Initial diagnosis of ADEM is challenging and up to 20 % of children with MS or NMOSD are initially diagnosed with ADEM. We describe characteristics of patients with monophasic ADEM vs. recurrent demyelinating syndromes at onset and identify features consistent with monophasic course. This is a multicenter observational study of children with demyelinating disease, followed at 12 regional pediatric MS centers. Descriptive statistics were used to report patient characteristics, clinical/imaging features and outcomes. Logistic regression was used to predict features associated with monophasic course. As of July 2019, 837 children with final diagnosis of ADEM (n = 79), MS (n = 646) or NMOSD (n = 112) were identified. The mean follow-up was 5·7 +/- 3·2 years. ADEM patients were youngest with mean age at first event 5·2 +/- 3·8 years (p < 0.001) and male predominant (66 %) (p < 0·001). After 2 years of follow-up, 83 % of patients initially diagnosed with monophasic ADEM retained this diagnosis. In multivariable analysis, older age (OR 1·16 [95 % CI 1·02 - 1·33] for 1-year increase, p = 0·02), presenting with optic neuritis (OR 8.18 [95 % CI 1.88 - 35.64], p = 0·005) and presence of gadolinium enhancement (OR 4.08 [95 % CI 1.38 - 12.08], p = 0·011) were associated with reclassification of ADEM to MS, NMOSD or DDNOS within 2 years. Children with monophasic ADEM vs. those reclassified as other demyelinating disorders are younger at onset, and less likely to have optic neuritis or gadolinium-enhancing lesions at onset.

A workshop titled "Beyond the Symptom: The Biology of Fatigue" was held virtually September 27-28, 2021. It was jointly organized by the Sleep Research Society and the Neurobiology of Fatigue Working Group of the NIH Blueprint Neuroscience Research Program. For access to the presentations and video recordings, see: https : //neuroscienceblueprint.nih.gov/about/event/beyond-symptom-biology-fatigue. The goals of this workshop were to bring together clinicians and scientists who use a variety of research approaches to understand fatigue in multiple conditions and to identify key gaps in our understanding of the biology of fatigue. This workshop summary distills key issues discussed in this workshop and provides a list of promising directions for future research on this topic. We do not attempt to provide a comprehensive review of the state of our understanding of fatigue, nor to provide a comprehensive reprise of the many excellent presentations. Rather, our goal is to highlight key advances and to focus on questions and future approaches to answering them.

BACKGROUND:Treatment of pediatric-onset multiple sclerosis (POMS) is challenging given the lack of safety and efficacy data in the pediatric population for many of the disease-modifying treatments (DMTs) approved for use in adults with MS. Our objective was to describe the demographic features and clinical and radiologic course of patients with POMS treated with the commonly used newer DMTs within the US Network of Pediatric MS Centers (NPMSC). METHODS:This is an analysis of prospectively collected data from patients who initiated treatment before age 18 with the DMTs listed below at the 12 regional pediatric MS referral centers participating in the NPMSC. RESULTS:One hundred sixty-eight patients on dimethyl fumarate, 96 on fingolimod, 151 on natalizumab, 166 on rituximab, and 37 on ocrelizumab met criteria for analysis. Mean age at DMT initiation ranged from 15.2 to 16.5 years. Disease duration at the time of initiation of index DMT ranged from 1.1 to 1.6 years with treatment duration of 0.9-2.0 years. Mean annualized relapse rate (ARR) in the year prior to initiating index DMT ranged from 0.4 to 1.0. Mean ARR while on index DMT ranged from 0.05 to 0.20. New T2 and enhancing lesions occurred in 75%-88% and 55%-73% of the patients, respectively, during the year prior to initiating index DMT. After initiating index DMT, new T2 and enhancing lesions occurred in 0%-46% and 11%-34% patients, respectively. Rates of NEDA-2 (no evidence of disease activity) ranged from 76% to 91% at 6 months of treatment with index DMTs and 66% to 84% at 12 months of treatment with index DMTs. CONCLUSIONS:Though limited by relatively short treatment duration with the index DMTs, our data suggest clinical and MRI benefit, as well as high rates of NEDA-2, in a large number of POMS patients, which can be used to guide future studies in this population.

BACKGROUND:We previously reported an association between household chemical exposures and an increased risk of paediatric-onset multiple sclerosis. METHODS:(rs7665090). RESULTS:SNP GG genotypes. CONCLUSIONS:The presence of gene-environment interactions with household toxins supports their possible causal role in paediatric-onset multiple sclerosis.

BACKGROUND:Pediatric patients with multiple sclerosis (POMS) and related disorders, clinically isolated syndrome (CIS), myelin oligodendrocyte glycoprotein antibody disorder (MOGAD), and neuromyelitis optica spectrum disorder (NMOSD), are commonly treated with immunosuppressants. Understanding the impact of SARS-CoV-2 infection in patients may inform treatment decisions. OBJECTIVE:Characterize SARS-CoV-2 infection prevalence and severity among a cohort of patients with POMS and related disorders, as well as the impact of disease-modifying therapies (DMTs). METHODS:POMS and related disorders patients enrolled in a large, prospective registry were screened for COVID-19 during standard-of-care neurology visits. If confirmed positive of having infection, further analysis was undertaken. RESULTS: = 0.016). CONCLUSIONS:B-cell-depleting treatment was associated with a higher risk of COVID-19, higher rates of hospitalization, and ICU admission, suggesting this therapy carries a higher risk of severe infection in POMS and related disorders.

OBJECTIVES:Intra-individual variability (IIV), measured across repeated response times (RT) during continuous psychomotor tasks, is an early marker of cognitive change in the context of neurodegeneration. To advance IIV towards broader application in clinical research, we evaluated IIV from a commercial cognitive testing platform and compared it to the calculation approaches used in experimental cognitive studies. METHODS:-transformed standard deviation or "LSD"). We calculated IIV from the raw RTs using coefficient of variation (CoV), regression-based, and ex-Gaussian methods. The IIV from each calculation was then compared by rank across participants. RESULTS:A total of n = 120 participants with MS aged 20-72 (Mean ± SD, 48.99 ± 12.09) completed the baseline cognitive measures. For each task, the interclass correlation coefficient was generated. Each ICC showed that LSD, CoV, ex-Gaussian, and regression methods clustered strongly (Average ICC for DET: 0.95 with 95% CI [0.93, 0.96]; Average ICC for IDN: 0.92 with 95% CI [0.88 to 0.93]; Average ICC for ONB: 0.93 with 95% CI [0.90 to 0.94]). Correlational analyses indicated the strongest correlation between LSD and CoV for all tasks (rs ≥ 0.94). CONCLUSION:The LSD was consistent with research-based methods for IIV calculations. These findings support the use of LSD for the future measurement of IIV for clinical studies.

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.

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.

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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