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BackgroundApproximately one-third of those with pediatric-onset multiple sclerosis (MS) experience cognitive impairment. Less is known concerning their change in cognitive functioning over time.ObjectiveChanges in cognitive function over time were measured in the largest pediatric cohort to date through the US Network of Pediatric MS Centers.MethodsA total of 67 individuals with pediatric MS (n=62) or clinically isolated syndrome (CIS, n=5), ranging from 8-17 years of age (mean age ± standard deviation (SD)=14.37 ± 2.02) completed initial and follow-up neuropsychological testing after an average of 1.64 ± 0.63 years apart. The nine tests administered measure general intellect, attention and working memory, verbal memory, visuomotor integration, language, and executive functioning.ResultsRate of impairment (having one-third or more scores in the impaired range) was 37% at baseline and 33% at follow-up. Tests commonly impaired were measures of visuomotor integration, speeded processing, and attention. Most tested did not decline over two years. There was no clear pattern of change on any specific measure.ConclusionFindings suggest that, over short timeframes, stable or even improved performances on measures of cognitive ability can occur. Pediatric MS may instead prevent expected age-related cognitive gains.

BackgroundPediatric onset multiple sclerosis (MS) accounts for 2-4% of all MS. It is unknown whether the disease shares the same underlying pathophysiology found in adult patients or an extreme early onset phenotype triggered by distinct biological mechanisms. It has been hypothesized that copy number variations (CNVs) may result in extreme early onset diseases because CNVs can have major effects on many genes in large genomic regions.Objectives and methodsThe objective of the current research was to identify CNVs, with a specific focus on de novo CNVs, potentially causing early onset MS by competitively hybridizing 30 white non-Hispanic pediatric MS patients with each of their parents via comparative genomic hybridization (CGH) analysis on the Agilent 1M CGH array.Results and discussionWe identified 10 CNVs not overlapping with any CNV regions currently reported in the Database of Genomic Variants (DGV). Fifty-five putatively de novo CNVs were also identified: all but one common in the DGV. We found the single rare CNV was a private variation harboring the SACS gene. SACS mutations cause autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) disease. Additional clinical review revealed that the patient with the SACS gene CNV shared some features of both MS and ARSACS.ConclusionsThis is the first reported study analyzing pediatric MS CNVs. While not yielding causal variation in our initial pediatric dataset, our approach confirmed diagnosis of an ARSACS-like disease in addition to MS in the affected individual, which led to a more complete understanding of the patient's disease course and prognosis.

The article presents a study which examines the association of pediatric-onset multiple sclerosis (MS) patients with social cognitive deficits. Facial affect recognition of participants with pediatric-onset MS compared to a group of age- and gender matched healthy controls was measured on Theory of Mind (ToM) task performance. The study concludes that social cognition may represent an area of cognitive functioning that MS has affected in the pediatric-onset population.

Approximately half of all patients with multiple sclerosis (MS) experience cognitive impairment, most commonly with regard to new learning and memory. Cognitive dysfunction is a leading cause of disability in MS and it can have profound social and economic consequences for patients and their families. Research on treatment for cognitive impairment in MS is still in the early stages, as it is for most neurological conditions. The available disease-modifying therapies in MS may provide some modest benefit to cognition, but patients with MS clearly need better treatment for cognitive dysfunction. A number of studies have assessed symptomatic treatments of cognition in MS, and the results of these small, underpowered studies have been mixed. Regardless, acetylcholinesterase inhibitors (AChEIs) have been the most promising class of medications tested in MS to date. Seven of eight studies on AChEIs have shown positive results, although it is difficult to assess their adequacy since only three of the studies have been published in peer reviewed journals, with the rest appearing only as abstracts. The earliest AChEI studies in MS examined physostigmine, but the short half-life and prominent adverse effects of this medication may have limited its use compared with other AChEIs. All of the more recent AChEI studies have used donepezil, which, from the limited data available to date, appears to have been relatively well tolerated among MS patients. The largest randomized controlled trial of donepezil included 69 subjects and found that donepezil improved verbal learning and memory compared with placebo during neuropsychological testing. That study also found that patients receiving donepezil were more likely to report memory improvement than those receiving placebo, and the study clinician also noted a cognitive benefit among those on donepezil as opposed to placebo. There are still many unanswered questions regarding the use of AChEIs in MS, including the effects of their long-term use in a chronic disease such as MS. On the whole, to date the research on AChEIs in MS must be considered preliminary, and it is premature to recommend the clinical use of this class of medications at the present time. [ABSTRACT FROM AUTHOR]

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disorder that occurs in children and adults., Case: 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: 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., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background and Objectives: 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: A total of 138 patients with POMS (70% female) were included with a mean age of 19.86 years and median disease duration of 4 years at time of scan. Public health insurance, Black race, Hispanic ethnicity, low parental education, and high SVI (greater neighborhood disadvantage) were each associated with white matter lesion and black hole volume. SVI was the strongest individual predictor of total white matter lesion (β = 4.63, p = 0.002) and black hole volume (β = 2.91, p = 0.003). In models incorporating all SDOH variables, public health insurance was the strongest predictor of total lesion (β = 2.48, p = 0.01) and black hole volume (β = 1.50, p = 0.02), attenuating the effect of SVI (β = 1.66, p = 0.33 and β = 1.00, p = 0.39). There were no differences in DMT timing or efficacy between categories of social disadvantage., Discussion: 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: 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: There were 996 total participants (69% female, mean age at symptom onset and EDSS score [±SD] were 14.2 ± 3 and 1.2 ± 1.1, respectively). Of 768 patients with complete demographic information, 66% reported a hardship. Hardship was associated with younger age at symptom onset and diagnosis. While there was no difference in time to DMT initiation, patients with hardship were more likely to receive steroids for the first event (odds ratio [OR] 1.66, 95% CI 1.21-2.26, p = 0.002). Lack of private insurance was associated with increased risk of study attrition (OR 1.85, 95% CI 1.14-3.00, p = 0.012) and higher EDSS score (β = 0.15, 95% CI 0.01, 0.28). Living in a no-income household (vs dual-income) was associated with a shorter time to second event (hazard ratio 1.33, 95% CI 1.02-1.74, p = 0.034)., Discussion: 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 and Objectives: 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: MS cases (64% female, mean age 15.4 years, SD 2.8) were demographically similar to controls (60% female, mean age 14.9 years, SD 3.9). Cases were less likely to have a mother with a bachelor's degree or higher (OR 0.42, 95% CI 0.22-0.80, p = 0.009) and were more likely to experience childhood neighborhood disadvantage (OR 1.04 for each additional point on the neighborhood socioeconomic disadvantage score, 95% CI 1.00-1.07; p = 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: 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.

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.

Objectives: To examine the agreement between published reference resources for neurofilament light chain (NfL) applied to a large population of people with multiple sclerosis (MS)., Methods: Six published reference resources were used to classify NfL in participants in the Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network as elevated or normal and to derive age-specific NfL Z -scores. NfL values were classified as elevated if they exceeded the >95th percentile (i.e., Z -score >1.645) of the age-specific reference range. Furthermore, age-specific NfL Z -scores could be derived for 4 of 6 reference resources., Results: NfL measurements were assessed from 12,855 visits of 6,687 people with MS (median 2 samples per individual [range 1-7]). The mean ± SD age was 47.1 ± 11.7 years, 72.1% of participants were female, disease duration was 15.0 ± 10.6 years, body mass index was 28.6 ± 6.9 kg/m 2 , and serum NfL was 12.87 ± 12.86 pg/mL. Depending on the selection of the reference resource, the proportion of NfL measurements classified as elevated varied from 3.7% to 30.9%. The kappa coefficient across the 6 reference resources used was 0.576 (95% CI 0.571-0.580) indicating moderate agreement. Spearman correlations between Z -scores derived from the various reference resources exceeded 0.90; however, concordance coefficients were lower, ranging from 0.72 to 0.89., Discussion: Interpretation of blood NfL values may vary markedly depending on the selection of the reference resource. Borderline elevated values should be interpreted with caution, and future studies should focus on standardizing NfL measurement and reporting across laboratories/platforms, better characterizing the effects of confounding/influencing factors, and defining the performance of NfL (including as part of multimodal predictive algorithms) for prediction of disease-specific outcomes., (© 2023 American Academy of Neurology.)

Objective: Evaluation of serum neurofilament light chain (sNfL), measured using high-throughput assays on widely accessible platforms in large, real-world MS populations, is a critical step for sNfL to be utilized in clinical practice., Methods: Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) is a network of healthcare institutions in the United States and Europe collecting standardized clinical/imaging data and biospecimens during routine clinic visits. sNfL was measured in 6974 MS and 201 healthy control (HC) participants, using a high-throughput, scalable immunoassay., Results: Elevated sNfL levels for age (sNfL-E) were found in 1238 MS participants (17.8%). Factors associated with sNfL-E included male sex, younger age, progressive disease subtype, diabetes mellitus, impaired renal function, and active smoking. Higher body mass index (BMI) was associated with lower odds of elevated sNfL. Active treatment with disease-modifying therapy was associated with lower odds of sNfL-E. MS participants with sNfL-E exhibited worse neurological function (patient-reported disability, walking speed, manual dexterity, and cognitive processing speed), lower brain parenchymal fraction, and higher T2 lesion volume. Longitudinal analyses revealed accelerated short-term rates of whole brain atrophy in sNfL-E participants and higher odds of new T2 lesion development, although both MS participants with or without sNfL-E exhibited faster rates of whole brain atrophy compared to HC. Findings were consistent in analyses examining age-normative sNfL Z-scores as a continuous variable., Interpretation: Elevated sNfL is associated with clinical disability, inflammatory disease activity, and whole brain atrophy in MS, but interpretation needs to account for comorbidities including impaired renal function, diabetes, and smoking., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Objective: 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: 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: The pediatric groups (MS vs. Healthy Controls) did not differ on either battery's composite mean score or individual test scores ( p s > 0.32), nor in the proportions impaired on either battery, Brief International Cognitive Assessment for MS (26% vs. 24%, p  = 0.83); Cogstate Brief Battery (26% vs. 32%, p  = 0.41). The pediatric versus adult MS group even after controlling for differences in disease duration performed better on the Brief International Cognition Assessment for MS composite ( p  = 0.03), Symbol Digit Modalities Test ( p  = 0.02), Rey Auditory Verbal Learning Test ( p  = 0.01), and Cogstate choice reaction time ( p  < 0.001)., Conclusion: Pediatric MS patients do not differ from healthy pediatric controls on cognitive screens but perform better than adults with MS.

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: 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., (Copyright © 2022. Published by Elsevier B.V.)

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., (Copyright © 2022. Published by Elsevier B.V.)

Introduction: Emotional health is important dimension of care for patients living with pediatric onset multiple sclerosis (POMS), but few options are available for stress and anxiety reduction. The high burden of interventions requiring regular in person and onsite visits for treatment are less feasible. Attention bias modification training (ABMT) is effective for anxiety reduction in adult and adolescent populations. We tested the feasibility and preliminary efficacy of ABMT delivered through a mobile gamified version as a digital emotional health tool for patients with POMS. Methods: Participants with POMS were consecutively recruited from the NYU Langone Pediatric MS Care Center and enrolled to complete a 1-month intervention with use of the Personal Zen ABMT app on their mobile personal device. Feasibility was evaluated by use of the 1-month intervention and efficacy was measured by changes in depression, anxiety, and affect. Results: A total n = 35 patients with POMS were enrolled in the study ( M age = 17.7, SD = 2.2 years, range 14-23). Feasibility criteria were met with 74% completing the full intervention time, and 100% of the sample completing at least 50% of targeted intervention use. Initial efficacy was found for a reduction in negative affect from baseline to intervention end [ M = 22.88, SD = 9.95 vs. M = 19.56, SD = 7.37; t (33) = 2.47, p = 0.019]. Anxiety also significantly decreased from pre to post-intervention in adults [ M = 11.82, SD = 9.90 vs. M = 7.29, SD = 7.17; t (16) = 3.88, p = 0.001] and youth [ M = 51.14, SD = 19.66 vs. M = 40.86, SD = 27.48; t (13) = 3.17, p = 0.007]. Conclusion: Mobile ABMT with the Personal Zen app is a feasible and accessible digital emotional health tool for patients with POMS and may have broader application for managing distress across chronic neurological conditions., Competing Interests: TD-T has equity in Wise Therapeutics, Inc., which owns Personal Zen, and is on the advisory board of Lil Space Inc. TD-T is an inventor, with IP under patent review, on a digital therapeutics system and cognitive training method related to Personal Zen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Charvet, George, Cho, Krupp and Dennis-Tiwary.)

Pediatric-onset multiple sclerosis (POMS), representing approximately 5% of all MS cases, affects the central nervous system during its ongoing development. POMS is most commonly diagnosed during adolescence but can occur in younger children as well. For pediatric patients with MS, it is critical to manage the full impact of the disease and monitor for any effects on school and social functioning. Disease management includes not only disease-modifying therapies but also strategies to optimize wellbeing. We review the interventions with the highest evidence of ability to improve the disease course and quality of life in POMS. High levels of vitamin D and a diet low in saturated fat are associated with lower relapse rates. Exercise ameliorates fatigue and sleep. Behavioral strategies for sleep hygiene and mood regulation can also improve fatigue and perceived health. POMS management should be addressed holistically, including assessing overall symptom burden as well as the psychological and functional impact of the disease., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Background: Cognitive impairment due to multiple sclerosis (MS) is common and often limits occupational functioning, contributes to disability, and reduces quality of life. Early detection of cognitive involvement in MS is critical for treatment planning and intervention, and frequent, regular cognitive monitoring may provide insight into subtle changes in disease progression., Objective: To compare the sensitivity and specificity of clinical, computer-based and experimental measures to early cognitive involvement in MS., Methods: Cognitive functioning was compared in MS participants early in the disease course to matched healthy controls using conventional, computer-based and functional assessments: the Brief International Cognitive Assessment in MS (BICAMS); the computer-based Cogstate Brief Battery (CBB); the Attention Network Test-Interaction (ANT-I), including intra-individual variability; and the Test of Everyday Cognitive Ability (TECA), a functional measure of instrumental activities of daily living., Results: MS participants (n = 25, mean disease duration= 5.82 ± 3.65 years) and demographically matched healthy controls (n = 29) completed the cognitive assessments. The Cogstate measure of choice reaction time (AUC = 0.73, p = .004), intra-individual variability on the ANT-I (AUC = 0.79, p = .001), and TECA (AUC = 0.78, p = .001) scores were the most sensitive and specific markers of cognitive involvement in MS., Conclusions: Brief, repeatable, computer-based measures of reaction time and variability detect early MS associated cognitive involvement., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: The Symbol Digit Modalities Test (SDMT) is the gold standard for cognitive screening in multiple sclerosis (MS)., Objective: Due to the recent COVID-19 pandemic and the increased need for virtual clinical visits, we examined the reliability of remote administration of the SDMT vs. standard in-person administration to individuals with MS., Methods: Pearson's correlation analysis was performed between SDMT scores on the in-person and remote administrations., Results: For n = 132 participants, remote and in-person SDMT scores were strongly correlated (r = .80, p  = .000)., Conclusion: Remote administration of the SDMT is a reliable cognitive screening approach in MS., (© The Author(s) 2021.)

Background: Cognitive impairment is a common feature of multiple sclerosis (MS). A semi-structured interview, including informant input, can characterize the experience of individuals living with MS and cognitive involvement. Objective: We administered the Cognitive Assessment Interview (CAI), a patient- and informant-based semi-structured interview, to characterize the experience of cognitive impairments in those living with MS. Methods: Trained raters administered the CAI to a sample of MS participants and their informants enrolled for a trial of cognitive remediation. Cognitive impairments on the CAI were characterized and compared to those captured by neuropsychological and self-report measures. Results: A total of n = 109 MS participants (mean age = 50.3 ± 12.2) and their available informants ( n = 71) were interviewed. Participants reported experiencing processing speed (90/106, 85%), working memory (87/109, 80%), and learning and memory (79/109, 72%) problems most commonly. CAI-based ratings were moderately correlated with a self-report measure (Multiple Sclerosis Neuropsychological Screening Questionnaire, r s = 0.52, p < 0.001) and only mildly correlated with objective neuropsychological measures specific to executive functions ( r s = 0.21, p = 0.029). For those with informant interviews, ratings were overall consistent, suggesting that the CAI is valid even in cases in which an informant is unavailable and the interview is conducted with the patient alone (as is often the case in clinical and research settings). Conclusions: The CAI provides a semi-structured interview to characterize the experience of cognitive impairment in MS, with findings representing real-world functioning, adding valuable information to both self-report measures and neuropsychological assessment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Eilam-Stock, Best, Sherman, Shaw, Ventura, Krupp and Charvet.)

Background: Cognitive impairment occurs in approximately one-third of pediatric-onset multiple sclerosis (POMS) patients. The Symbol Digit Modalities Test (SDMT), a widely used cognitive screen in adults, has yet to be incorporated early into the standard care of POMS., Objective: To screen for cognitive impairment early in the course of POMS and analyze predictive factors., Methods: Of the 955 POMS or clinically isolated syndrome (CIS) patients prospectively assessed from March 2014 to July 2018, 500 POMS and 116 CIS patients met inclusion criteria (disease onset before the age of 18, one or more SDMTs, and 8 years or older at the time of testing). Those with relapse were analyzed separately from those who were relapse-free., Results: At initial assessment, the mean (interquartile range (IQR)) age at symptom onset was 13.5 years (12.0, 15.9) and the mean (±SD) disease duration was 3.0 ± 2.9 years. Impaired processing speed occurred in 23.4% of POMS and in 16.4% of CIS. On serial testing ( n  = 383, mean follow-up: 1.8 years), 14.1% had clinically meaningful decline predicted by older age of multiple sclerosis (MS) onset and male gender. Disease relapse or steroid use led to transient worsening on the SDMT., Conclusion: Early in the disease, some POMS and CIS patients are at risk for cognitive impairment and subsequent decline.

Objective: To report outcomes on patients with multiple sclerosis (MS) and related disorders with coronavirus disease 2019 (COVID-19) illness., Methods: From March 16 to April 30, 2020, patients with MS or related disorders at NYU Langone MS Comprehensive Care Center were identified with laboratory-confirmed or suspected COVID-19. The diagnosis was established using a standardized questionnaire or by review of in-patient hospital records., Results: We identified 76 patients (55 with relapsing MS, of which 9 had pediatric onset; 17 with progressive MS; and 4 with related disorders). Thirty-seven underwent PCR testing and were confirmed positive. Of the entire group, 64 (84%) patients were on disease-modifying therapy (DMT) including anti-CD20 therapies (n = 34, 44.7%) and sphingosine-1-phosphate receptor modulators (n = 10, 13.5%). The most common COVID-19 symptoms were fever and cough, but 21.1% of patients had neurologic symptom recrudescence preceding or coinciding with the infection. A total of 18 (23.7%) were hospitalized; 8 (10.5%) had COVID-19 critical illness or related death. Features more common among those hospitalized or with critical illness or death were older age, presence of comorbidities, progressive disease, and a nonambulatory status. No DMT class was associated with an increased risk of hospitalization or fatal outcome., Conclusions: Most patients with MS with COVID-19 do not require hospitalization despite being on DMTs. Factors associated with critical illness were similar to the general at-risk patient population. DMT use did not emerge as a predictor of poor COVID-19 outcome in this preliminary sample., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Walking impairments are a debilitating feature of multiple sclerosis (MS) because of the direct interference with daily activity. The management of motor symptoms in those with MS remains a therapeutic challenge. Transcranial direct current stimulation (tDCS) is a type of non-invasive brain stimulation that is emerging as a promising rehabilitative tool but requires further characterization to determine its optimal therapeutic use. In this randomized, sham-controlled proof-of-concept study, we tested the immediate effects of a single tDCS session on walking and functional mobility in those with MS. Seventeen participants with MS completed one 20-min session of aerobic exercise, randomly assigned to be paired with either active (2.5 mA, n = 9) or sham ( n = 8) tDCS over the primary motor cortex (M1). The groups (active vs. sham) were matched according to gender (50% vs. 60% F), age (52.1 ± 12.85 vs. 54.2 ± 8.5 years), and level of neurological disability (median Expanded Disability Status Scale score 5.5 vs. 5). Gait speed on the 10-m walk test and the Timed Up and Go (TUG) time were measured by a wearable inertial sensor immediately before and following the 20-min session, with changes compared between conditions and time. There were no significant differences in gait speed or TUG time changes following the session in the full sample or between the active vs. sham groups. These findings suggest that a single session of anodal tDCS over M1 is not sufficient to affect walking and functional mobility in those with MS. Instead, behavioral motor response of tDCS is likely to be cumulative, and the effects of multiple tDCS sessions require further study. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT03658668., (Copyright © 2020 Pilloni, Choi, Coghe, Cocco, Krupp, Pau and Charvet.)

Pediatric multiple sclerosis is associated with challenges in prompt diagnosis and uncertainty regarding optimal treatment. This review aimed to identify treatment guidelines or consensus statements for pediatric patients with multiple sclerosis, US Food and Drug Administration (FDA)-approved treatment options for pediatric multiple sclerosis, and any randomized controlled trials and observational studies examining available pharmacologic treatments in the pediatric multiple sclerosis population. Literature searches were performed in MEDLINE (1946-2016), EMBASE (1974-2016), and the Cochrane Central Register of Controlled Trials to identify treatment guidelines or consensus statements, pediatric multiple sclerosis treatment approvals, and randomized controlled trials and observation studies that examine the safety and effectiveness of available disease-modifying therapies. Only 3 consensus statements provided recommendations for pharmacologic treatments for children, all 3 published before the most recent revisions of the pediatric multiple sclerosis diagnostic guidelines. Despite the changes to the clinical landscape of pediatric multiple sclerosis with the introduction of diagnostic guidelines, fingolimod is the only FDA-approved treatment for pediatric multiple sclerosis in the United States. The effectiveness and safety of other disease-modifying therapies suggested by consensus statements have been reported in relatively small prospective and retrospective observational studies. Clinical evidence from a recently completed randomized controlled trial and future global registries can inform treatment decisions for the pediatric multiple sclerosis population.

Introduction: In the clinic, the assessment of patients with multiple sclerosis (MS) is typically qualitative and non-standardized., Objectives: To describe the MS Performance Test (MSPT), an iPad Air ® 2 (Apple, Cupertino, CA, USA)-based neurological assessment platform allowing patients to input relevant information without the aid of a medical technician, creating a longitudinal, clinically meaningful, digital medical record. To report results from human factor (HF) and usability studies, and the initial large-scale implementation in a practice setting., Methods: The HF study examined use-error patterns in small groups of MS patients and healthy controls (n = 14), the usability study assessed the effectiveness of patient interaction with the tool by patients with a range of MS disability (n = 60) in a clinical setting, and the implementation study deployed the MSPT across a diverse population of patients (n = 1000) in a large MS center for routine clinical care., Results: MSPT assessments were completed by all users in the HF study; minor changes to design were recommended. In the usability study, 73% of patients with MS completed the MSPT, with an average administration time of 32 min; 85% described their experience with the tool as satisfactory. In the initial implementation for routine care, 84% of patients with MS completed the MSPT, with an average administration time of 28 min., Conclusion: Patients with MS with varying disability levels completed the MSPT with minimal or no supervision, resulting in comprehensive, efficient, standardized, quantitative, clinically meaningful data collection as part of routine medical care, thus allowing for large-scale, real-world evidence generation., Funding: Biogen., Trial Registration: NCT02664324.

The prevalence of nocturia in patients with multiple sclerosis (MS) is high, ranging from 20.9% to 48.8% in this population. Its underlying pathophysiology is complex and different from the non-neurogenic population. In the MS population, the pathophysiology may involve neurogenic lower urinary tract dysfunction (NLUTD) such as detrusor overactivity (NDO), detrusor-sphincter dyssynergia, or detrusor underactivity resulting in reduced bladder capacity. Nocturnal polyuria is also a significant contributor to the pathogenesis of nocturia in MS patients and may be the result of specific mechanisms such as nocturnal hypertension through autonomic cardiovascular dysfunction or lack of diurnal variation of antidiuretic hormone production (ADH) due to demyelinating lesions of the spinal cord. Nocturia might be particularly burdensome in MS patients by contributing to fatigue, a common and highly debilitating symptom in this population. There is likely a complex and multidirectional relationship between nocturia, other sleep disorders, and fatigue in the MS population that has yet to be explored. The assessment of nocturia in MS should rely upon a thorough history and physical examination. Urinalysis should be done to rule out urinary tract infection, a frequency-volume chart might help elucidating the underlying mechanisms, and post-void residual volume may be of interest to screen for urinary retention that could be asymptomatic in MS patients. Other tests such as urodynamics or polysomnography are indicated in selected patients. The treatment should be tailored to the underlying cause. The first steps involve behavioral interventions and treatment of cofactors. When possible, the predominant mechanism should be addressed first. In case of predominant NDO, antimuscarinics and beta-3 agonists should be offered as a first-line treatment and intradetrusor injections of botulinum toxin as a second-line treatment. In cases of incomplete bladder emptying, clean-intermittent self-catheterization is often used as part of multiple other interventions. In cases of nocturnal polyuria, desmopressin may be offered, inclusive of use of newer formulations (desmopressin acetate nasal spray, desmopressin orally disintegrated tablet) in countries where they are approved., (© 2019 MedReviews®, LLC.)

Background and Purpose: Pediatric-onset multiple sclerosis (POMS) is a demyelinating disorder with unique clinical challenges. A brief computer-administered cognitive screening battery measuring processing speed (Cogstate) and the Brief International Cognitive Assessment in MS (BICAMS) detect cognitive impairment in POMS. The neuroanatomic correlates of these deficits are incompletely understood. The purpose of this study is to define the neuroanatomic underpinnings of deficits identified with cognitive screening batteries in POMS., Methods: Participants with POMS and age-matched healthy controls (HCs) were screened with Cogstate and BICAMS. Diffusion tensor imaging assessed region-wise and tractography-based fractional anisotropy (FA)., Results: The POMS (n = 15) and HC (n = 21) groups were matched on age (mean ages 17.9 ± 3.2 vs. 17.8 ± 3.3 years, respectively) and on an estimate of general intellectual functioning. The Cogstate composite revealed significant slowing in POMS relative to HCs (P = .004), but the BICAMS composite did not significantly distinguish the groups (P = .10). The Cogstate composite showed moderate-to-strong correlations with regional FA (r = -.67 to -.82) and significantly associated with uncinate fasciculus FA following multiple comparisons correction (P = .002) in POMS. However, the BICAMS composite measure showed only weak-to-moderate correlations with FA in POMS (r = -.19 to -.57), with none surviving multiple comparisons correction., Conclusions: Computer-administered measures of cognitive processing are particularly sensitive in POMS and are closely linked to white matter FA., (© 2018 by the American Society of Neuroimaging.)