Faculty Bibliography

BACKGROUND:Myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is a demyelinating disorder that most commonly presents with optic neuritis (ON) and affects children more often than adults. We report 8 pediatric patients with MOG-associated ON and characterize focal optical coherence tomography (OCT) abnormalities over time that help distinguish this condition from the trajectories of other demyelinating disorders. These OCT findings are examined in the context of longitudinal visual function testing. METHODS:This is a retrospective case series of 8 pediatric patients with MOG-associated ON who were referred for neuro-ophthalmic evaluation. Longitudinal data for demographics, clinical history, physical examination, and OCT obtained in the course of clinical evaluations were collected through retrospective medical record review. RESULTS:Patients demonstrated acute peripapillary retinal nerve fiber layer (RNFL) thickening in one or both eyes, consistent with optic disc swelling. This was followed by steady patterns of average RNFL thinning, with 9 of 16 eyes reaching significantly low RNFL thickness using OCT platform reference databases (P < 0.01), accompanied by paradoxical recovery of high-contrast visual acuity (HCVA) in every patient. There was no correlation between HCVA and any OCT measures, although contrast sensitivity (CS) was associated with global thickness, PMB thickness, and nasal/temporal (N/T) ratio, and color vision was associated with PMB thickness. There was a lower global and papillomacular bundle (PMB) thickness (P < 0.01) in clinically affected eyes compared with unaffected eyes. There was also a significantly higher N:T ratio in clinically affected eyes compared with unaffected eyes in the acute MOG-ON setting (P = 0.03), but not in the long-term setting. CONCLUSIONS:MOG shows a pattern of prominent retinal atrophy, as demonstrated by global RNFL thinning, with remarkable preservation of HCVA but remaining deficits in CS and color vision. These tests may be better clinical markers of vision changes secondary to MOG-ON. Of the OCT parameters measured, PMB thickness demonstrated the most consistent correlation between structural and functional measures. Thus, it may be a more sensitive marker of clinically significant retinal atrophy in MOG-ON. The N:T ratio in acute clinically affected MOG-ON eyes in our study was higher than the N:T ratio of neuromyelitis optica (NMO)-ON eyes and similar to the N:T ratio in multiple sclerosis (MS)-ON eyes as presented in the prior literature. Therefore, MOG may share a more similar pathophysiology to MS compared with NMO.

BACKGROUND AND OBJECTIVE/UNASSIGNED:Prior Epstein-Barr virus (EBV) infection is associated with an increased risk of pediatric-onset multiple sclerosis (POMS) and adult-onset multiple sclerosis (MS). It has been challenging to elucidate the biological mechanisms underlying this association. We examined the interactions between candidate human leukocyte antigen (HLA) and non-HLA variants and childhood EBV infection as it may provide mechanistic insights into EBV-associated MS. METHODS/UNASSIGNED:Cases and controls were enrolled in the Environmental and Genetic Risk Factors for Pediatric MS study of the US Network of Pediatric MS Centers. Participants were categorized as seropositive and seronegative for EBV-viral capsid antigen (VCA). The association between prior EBV infection and having POMS was estimated with logistic regression. Interactions between EBV serostatus, major HLA MS risk factors, and non-HLA POMS risk variants associated with response to EBV infection were also evaluated with logistic regression. Models were adjusted for sex, age, genetic ancestry, and the mother's education. Additive interactions were calculated using relative risk due to interaction (RERI) and attributable proportions (APs). RESULTS/UNASSIGNED:(AP = 0.30, 95% CI = 0.03 to 0.58). CONCLUSION/UNASSIGNED:POMS risk variant. Our results suggest an important role of antigen-presenting cells (APCs) in EBV-associated POMS risk.

A 16-year-old adolescent boy presented with recurrent episodes of weakness and numbness. Brain MRI demonstrated subcortical, juxtacortical, and periventricular white matter T2 hyperintensities with gadolinium enhancement. CSF was positive for oligoclonal bands that were not present in serum. Despite treatment with steroids, IV immunoglobulins, plasmapheresis, and rituximab, he continued to have episodes of weakness and numbness and new areas of T2 hyperintensity on imaging. Neuro-ophthalmologic examination revealed a subclinical optic neuropathy with predominant involvement of the papillomacular bundle. Genetic evaluation and brain biopsy led to an unexpected diagnosis.

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.

BACKGROUND:Our previous study identified a significant association between lower time spent outdoors, as a proxy of sun exposure, and a higher risk of pediatric-onset multiple sclerosis (POMS). UV radiation modulates the expression of several genes, but it is unknown whether these genes modify the effect of sun exposure on POMS risk. METHODS:In an age- and sex-matched case-control study, we evaluated the additive and multiplicative interactions between time spent outdoors and genetic non-HLA risk variants for developing POMS within the metabolic pathways of UV radiation, including CD28(rs6435203), CD86(rs9282641), and NFkB1(rs7665090) and the top two HLA risk factors (presence of DRB1×15 and absence of A*02). RESULTS:In an adjusted model (332 POMS cases, 534 healthy controls), greater time compared to <30 min/day spent outdoors during the prior summer and higher UV radiation dose were associated with decreased odds of POMS (OR 0.66, 95% CI 0.56-0.78, p < 0.001; OR 0.78, 95 % CI 0.62-0.98, p = 0.04, respectively). No significant additive or multiplicative interactions were found between risk factors. CONCLUSIONS:The exploration of gene-environment interactions in the risk of developing MS can unravel the underlying mechanisms involved. Although we do not have evidence that our candidate genes contribute to interactions, other genes may.

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.

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.

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: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.