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Background and Objectives: Recent studies suggest that the choroid plexus (CP) may function as a site of access of inflammatory cells into the CNS in multiple sclerosis (MS). Pediatric-onset MS (POMS) is characterized by a high inflammatory burden, as evidenced by a high relapse rate and volume of T2 lesions, making patients with POMS an informative population to evaluate choroid plexus volume (CPV). The objectives of the study were (1) to evaluate CPV at symptom onset in participants with POMS compared with healthy controls (HCs); (2) to evaluate changes in CPV in the first year of disease in participants with POMS; and (3) to evaluate associations between CPV, brain volumes, relapse activity, and disability in participants with POMS., Methods: Baseline 1.5T MRI scans were acquired from 23 participants with POMS and 23 age-matched and sex-matched HCs; 18 participants with POMS also had 12-month follow-up MRI scans. The CP of the lateral ventricles was segmented manually. CP and brain structure volumes were normalized for total intracranial volume. The number of relapses, T2 and gadolinium-enhancing T1 lesion counts, and Expanded Disability Status Scale (EDSS) scores at 12 months were also analyzed. Baseline CPVs were compared between groups using the Wilcoxon exact test, and CPV change from baseline to 12 months in participants with POMS was compared using the Wilcoxon signed-rank test. The relationship between CPV and brain volumetric measures, T2 lesion volumes, lesion count, number of relapses, and EDSS scores was assessed through Spearman correlation., Results: The median normalized CPV was 1.51 × 10 -3 (interquartile range [IQR]: 1.32-1.76) in POMS baseline scans and 1.21 × 10 -3 (IQR: 1.1-1.47) in HC scans ( p = 0.001). CPV did not significantly change at 12 months in the 18 participants with POMS with follow-up scans ( p = 0.352). CPV in participants with POMS and HCs correlated with lateral ventricular volume ( p = 0.012 for both groups) but did not correlate with brain and T2 lesion volumes or lesion count at baseline, nor with relapse activity or EDSS scores at 12 months in participants with POMS., Discussion: CPV measured at baseline is greater in participants with POMS than in HCs. Baseline CPV did not predict higher disease activity or worse neurologic outcomes over 1 year. While higher CPV may be an early feature of inflammation in MS, its strong correlation with ventricular volumes could also reflect enlargement secondary to the mechanical attachment of CP to the ventricular wall.

The differential diagnosis of multiple sclerosis can present specific challenges in patients from Latin America, Africa, the Middle East, eastern Europe, southeast Asia, and the Western Pacific. In these areas, environmental factors, genetic background, and access to medical care can differ substantially from those in North America and western Europe, where multiple sclerosis is most common. Furthermore, multiple sclerosis diagnostic criteria have been developed primarily using data from North America and western Europe. Although some diagnoses mistaken for multiple sclerosis are common regardless of location, a comprehensive approach to the differential diagnosis of multiple sclerosis in Latin America, Africa, the Middle East, eastern Europe, southeast Asia, and the Western Pacific regions requires special consideration of diseases that are prevalent in those locations. A collaborative effort has therefore assessed global differences in multiple sclerosis differential diagnoses and proposed recommendations for evaluating patients with suspected multiple sclerosis in regions beyond North America and western Europe., Competing Interests: Declaration of interests JC declares receiving grants or research contracts from Biogen and Merck; personal compensation for consulting from Merck; payment or honoraria for lectures from Biogen, Merck, Bristol Myers Squibb, Novartis, and Roche; and support for attending meetings and travel from Merck. JC is a deputy chair International Medical and Scientific Board of Multiple sclerosis International Federation (MSIF), unpaid; and has received equipment, materials, drugs, medical writing, gifts, or other services from Novartis (Investigator initiated award). AJS declares receiving grant funding from National Institute of Neurological Disorders and Stroke, National Institutes of Health and Bristol Myers Squibb (investigator initiated award); has done contracted research with Sanofi, Biogen, Novartis, Actelion, and Genentech; has received personal compensation for consulting from Emmanuel Merck, Darmstadt, Serono and Octave Bioscience; has received payments or honoraria for lectures from Emmanuel Merck, Darmstadt, Serono; has received expert testimony from The Jacob D Fuchsberg Law Firm and Koskoff Koskoff & Bieder; is a participant on a Data Safety Monitoring Board for the Patient Centered Research Institute, and Yale University; declares participation on an advisory board for Genentech, Biogen, Alexion, Celgene, Greenwich Biosciences, TG Therapeutics, and Horizon Therapeutics; and is a content Chair for the American Academy of Neurology (AAN) Institute Multiple Sclerosis Quality Measure Development Work Group and Section Editor for Multiple Sclerosis and Related Disorders. JAC declares personal compensation for consulting from Astoria, Bristol-Myers Squibb, Convelo, EMD Serono, FiND Therapeutics, INMune, and Sandoz; and serving as an editor of Multiple Sclerosis Journal. BLB is funded by the National Multiple Sclerosis Society, and National Institute of Health; is a consultant for Roche, and Sanofi; and is a Board Director AAN (unpaid). TG has served as a consultant and received compensation from Genentech, Horizon, Sanofi, Alexion, and Greenwich Biosciences. BH declares grants from the European Union, Bundesministerium für Bildung und Forschung, and Deutsche Forschungsgemeinschaft; received personal compensation for consulting from Sandoz, Novartis, and GLG consulting; holds patents for antibodies against KIR4·1 in a subpopulation of patients with multiple sclerosis (2012) and genetic determinants of neutralising antibodies to interferon (filed 2010); and participated in a Data Safety and Monitoring Board for Novartis, Allergy Care DSMB, TG Therapeutics, and Polpharma, and Advisory Board for Novartis. HJK declares a research grant from the National Research Foundation of Korea and research support from Aprilbio, UCB, and Eisai; has received consultancy fees from Altos Biologics, AstraZeneca, Biogen, Daewoong, Kaigene, Kolon Life Science, MDimune, Merck Serono, and Roche; declares honoraria for lectures from Alexion, Eisai, GCPharma, Handok, Mitsubishi Tanabe Pharma, and Sanofi Genzyme; has received personal compensation for participation on a Data Safety Monitoring Board from Sanofi-Genzyme; has received compensation as Co-editor for the Multiple Sclerosis Journal and Associate Editor for the Journal of Clinical Neurology; and is a Vice President of Pan-Asian Committee on Treatment and Research in Multiple Sclerosis (unpaid). RAM declares grants or contracts from Biogen, Idec, and Roche. FM has received research funding to her institution from Sumaira Foundation, Genentech, Biogen, Horizon Therapeutics, US National Histitute Institute of Health, US Department of State, Foundation Pierre Fabre, and Novartis; has received consulting fees from Alexion, EMD Serono, Genentech, TG Therapeutics, and Horizon Therapeutics; and declares shares of the startup company Brain Capture (not related to the content of this manuscript). SDN declares grants or contracts (paid directly to institution) from Biogen, Roche, Genentech, National MS Society, Department of Defense, and Patient Centered Outcomes Research Institute; has received personal compensation for consulting from Biogen, Roche, Genentech, Bristol Myers Squibb, EMD Serono, Greenwich Biosciences, Novartis, Horizon Therapeutics, and TG Therapeutics; and is a study lead principal investigator for a Roche clinical trial programme. MAS declares personal honoraria for lectures from Roche, Biogen, Cinnagen, NanoAlvand, Merck, Novartis, and Abidi. DKS declares grants or research contracts from CNPq / Brazil 425331/2016–4 and 308636/2019–8, and Brazilian National Council for Scientific and Technological Development; has received investigator initiated awards from TEVA, Merck, and Biogen; has received personal compensation for consulting from Roche, and Alexion; declares personal honoraria for lectures from Roche, Alexion, Horizon, Merck, Americas Health Foundation; and is a member of International Society of Neuroimmunology, International Advisory Board (unpaid), and Academia Brasileira de Neurologia, Educational Committee (unpaid). DS declares a pilot research grant from the National MS Society paid to the Institution; declares receipt of personal honoraria for lecturing from Roche Pharmaceuticals; declares travel support from Roche Pharmaceutical; and is a Committee member and chair of Multiple Sclerosis International Federation (unpaid). AS has received grants or contracts from the Turkish MS Society, Istanbul University-Cerrahpasa Research Support Funds, and The Scientific and Technological Research Council of Türkiye Health Sciences Research Grants; has received consulting fees from Roche, Merck-Serono, Biogen Idec/Gen Pharma of Turkey , Sanofi-Genzyme, Novartis, and Alexion; has received honoraria for lectures from Sanofi-Genzyme, Novartis, TEVA, and Roche; and has received support for attending meetings from Sanofi-Genzyme, Roche, Merck-Serono, and Alexion. KT declares personal consulting fees from Merck and Eisai; declares payment for lectures from Merck, Eisai, Roche, and Terumo Blood and Cell Technology; and is a member of the Organizing Committee Pan-Asian Committee for Treatment and Research in Multiple Sclerosis (unpaid). MW has received publication royalties from Springer and Elsevier; has received consultancy honoraria from Icometrix, Imcyse, Novartis, Sanofi, Merck, and Biologix; declares personal compensation for lectures or presentations from Alexion, Bayer Healthcare, Biogen, Biologix, Bristol Myers Squibb, Celgene, Genilac, Imcyse, Icometrix, Merck-Serono, Novartis, Roche, and Sanofi-Genzyme; and declares support for attending meetings from Merck-Serono. BGW declares royalties from RSR, Hospices Civils de Lyon, MVZ Labor PD Dr Volkmann und Kollegen GbR , and Oxford University; declares personal consulting fees from Roche, Horizon Therapeutics, Cambridge Pharmaceuticals, and Mitsubishi Tanabe; has received payments for lecture presentations from Roche and Horizon; has a patent planned for NMO-IgG for diagnosis of neuromyelitis optica; and declares participation on a Data Safety Monitoring Board and Advisory borads for Alexion MedImmune/VielaBio/Horizon, and UCB Biosciences. KF declares grants from Ministry of Education, Culture, Sports, Science and Technology of Japan and Ministry of Health, Welfare and Labor of Japan; has received personal compensation for consulting from Merck Biopharma, Japan Tobacco, and Abbvie; has received payment or honoraria forlectures and presentations from Biogen, Eisai, Mitsubishi Tanabe, Novartis, Chugai/Roche, Alexion, VielaBio/Horizon Therapeutics, Teijin, Asahi Kasei Medical, Merck, and Takeda; declares participation in an Advisory Board for Biogen, Mitsubishi Tanabe, Novartis, Chugai/Roche, Alexion, VielaBio/Horizon Therapeutics, and UCB; serves as President of the Pan-Asian Committee for Treatment and Research in Multiple Sclerosis (unpaid), President of the Japanese Society of Neuroimmunology (unpaid), is a Board Member of the Japan Multiple Sclerosis Society (unpaid), is a board member of theEuropean Charcot Foundation (unpaid), and is a Member of the International Medical and Scientific Board, MSIF (unpaid). All other authors declared no competing interest., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Abstract: Immune effector cell-associated neurotoxicity syndrome (ICANS) is a common but potentially severe adverse event associated with chimeric antigen receptor T-cell (CART) therapy, characterized by the development of acute neurologic symptoms following CART infusion. ICANS encompasses a wide clinical spectrum typified by mild to severe encephalopathy, seizures, and/or cerebral edema. As more patients have been treated with CART, new ICANS phenomenology has emerged. We present the clinical course of 5 children who developed acute onset of quadriparesis or paraparesis associated with abnormal brain and/or spine neuroimaging after infusion of CD19- or CD22-directed CART, adverse events not previously reported in children. Orthogonal data from autopsy studies, cerebrospinal fluid (CSF) flow cytometry, and CSF proteomics/cytokine profiling demonstrated chronic white matter destruction, but a notable lack of inflammatory pathologic changes and cell populations. Instead, children with quadriparesis or paraparesis post-CART therapy had lower levels of proinflammatory cytokines, such as interferon gamma, CCL17, CCL23, and CXCL10, than those who did not develop quadriparesis or paraparesis. Taken together, these findings imply a noninflammatory source of this newly described ICANS phenomenon in children. The pathophysiology of some neurologic symptoms following CART may therefore have a more complex etiology than exclusive T-cell activation and excessive cytokine production., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Multiple sclerosis is a chronic immune-mediated disease of the central nervous system affecting nearly 3 million people worldwide. Although much progress has been made in the understanding and treatment of MS, cures remain elusive., Objectives: To accelerate the development of cures for MS by updating the Pathways to Cures Research Roadmap based on a contemporary understanding of disease. The refined Roadmap will help to promote research in scientific areas with great potential to reveal insights leading to cures and inspire greater coordination of global resources., Methods: Refinements to the Roadmap were achieved during a Global Summit that included close to 200 academic and industry scientists, health care providers, policy makers, funders, and people with MS from 15 countries., Results: The refined Roadmap describes three pathways that target opportunities for generating scientific insights leading to cures. Recommendations for accelerating research progress include, lowering barriers for global data sharing, enhancing collaboration and coordination among research supporters, committing to sustained funding, considering implications for implementation, engaging PwMS and committing to diversity, equity, and inclusion in the global MS movement., Conclusion: The refined roadmap provides a strategic framework for tackling the complexities of MS and advancing prevention strategies, effective treatments, and cures., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: BFB has as no relevant conflicts. BLB serves as a consultant to Novartis, UCB, Roche, and Sanofi for work unrelated to the present manuscript. BLB receives funding for research grants from the NIH and National MS Society. CCW has no relevant conflicts. TC has received travel support from Sanofi. UD has no relevant conflicts. PLD has received research support from Biogen and Merck Serono. AKP has no relevant conflicts. VWY is funded by research grants from MS Canada, the Canadian Institutes of Health Research, USA Department of Defense Multiple Sclerosis Research Program, Genentech and Novartis. He has received speaker honoraria from Biogen, EMD Serono, Novartis, Roche, Sanofi-Genzyme and Teva Canada. He is the recipient of unrestricted educational grants from Biogen, EMD Serono, Novartis, Roche, Sanofi-Genzyme and Teva Canada to support educational activities of the Alberta MS Network, which he directs. ENB has no relevant conflicts. AJT is Co-Chair, UCL-Eisai Steering Committee drug discovery collaboration (paid to institution), Member, National MS Society (USA) Scientific Advisory Committee (receive support for travel), Clinical Trials Committee, Progressive MS Alliance (receive support for travel), Board member, European Charcot Foundation (receive support for travel), Editor in Chief, Multiple Sclerosis Journal (receiving honorarium from SAGE Publishers), Editorial Board Member, The Lancet Neurology (receiving free subscription).

Background: Aquaporin-4 (AQP4) antibody-associated neuromyelitis optica spectrum disorder (NMOSD) is an antibody-mediated inflammatory disease of the central nervous system. We have undertaken a systematic review and meta-analysis to ascertain the sex ratio and mean age of onset for AQP4 antibody associated NMOSD. We have also explored factors that impact on these demographic data., Methods: A systematic search of databases was conducted according to the PRISMA guidelines. Articles reporting sex distribution and age of onset for AQP4 antibody-associated NMSOD were reviewed. An initially inclusive approach involving exploration with regression meta-analysis was followed by an analysis of just AQP4 antibody positive cases., Results: A total of 528 articles were screened to yield 89 articles covering 19,415 individuals from 88 population samples. The female:male sex ratio was significantly influenced by the proportion of AQP4 antibody positive cases in the samples studied (p < 0.001). For AQP4 antibody-positive cases the overall estimate of the sex ratio was 8.89 (95% CI 7.78-10.15). For paediatric populations the estimate was 5.68 (95% CI 4.01-8.03) and for late-onset cases, it was 5.48 (95% CI 4.10-7.33). The mean age of onset was significantly associated with the mean life expectancy of the population sampled (p < 0.001). The mean age of onset for AQP4 antibody-positive cases in long-lived populations was 41.7 years versus 33.3 years in the remainder., Conclusions: The female:male sex ratio and the mean age of onset of AQP4 antibody-associated NMOSD are significantly higher than MS. The sex ratio increases with the proportion of cases that are positive for AQP4 antibodies and the mean age of onset increases with population life expectancy., (© 2024. Crown.)

Dysregulated B cell cytokine production contributes to pathogenesis of immune-mediated diseases including multiple sclerosis (MS); however, the underlying mechanisms are poorly understood. In this study we investigated how cytokine secretion by pro-inflammatory (GM-CSF-expressing) and anti-inflammatory (IL-10-expressing) B cells is regulated. Pro-inflammatory human B cells required increased oxidative phosphorylation (OXPHOS) compared with anti-inflammatory B cells. OXPHOS reciprocally modulated pro- and anti-inflammatory B cell cytokines through regulation of adenosine triphosphate (ATP) signaling. Partial inhibition of OXPHOS or ATP-signaling including with BTK inhibition resulted in an anti-inflammatory B cell cytokine shift, reversed the B cell cytokine imbalance in patients with MS, and ameliorated neuroinflammation in a myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalitis mouse model. Our study identifies how pro- and anti-inflammatory cytokines are metabolically regulated in B cells and identifies ATP and its metabolites as a "fourth signal" that shapes B cell responses and is a potential target for restoring the B cell cytokine balance in autoimmune diseases.

Objective: The relationship between multiple sclerosis and the gut microbiome has been supported by animal models in which commensal microbes are required for the development of experimental autoimmune encephalomyelitis. However, observational study findings in humans have only occasionally converged when comparing multiple sclerosis cases and controls which may in part reflect confounding by comorbidities and disease duration. The study of microbiome in pediatric-onset multiple sclerosis offers unique opportunities as it is closer to biological disease onset and minimizes confounding by comorbidities and environmental exposures., Methods: A multicenter case-control study in which 35 pediatric-onset multiple sclerosis cases were 1:1 matched to healthy controls on age, sex, self-reported race, ethnicity, and recruiting site. Linear mixed effects models, weighted correlation network analyses, and PICRUSt2 were used to identify microbial co-occurrence networks and for predicting functional abundances based on marker gene sequences., Results: Two microbial co-occurrence networks (one reaching significance after adjustment for multiple comparisons; q < 0.2) were identified, suggesting interdependent bacterial taxa that exhibited association with disease status. Both networks indicated a potentially protective effect of higher relative abundance of bacteria observed in these clusters. Functional predictions from the significant network suggested a contribution of short-chain fatty acid producers through anaerobic fermentation pathways in healthy controls. Consistent family-level findings from an independent Canadian-US study (19 case/control pairs) included Ruminococaccaeae and Lachnospiraceae (p < 0.05). Macronutrient intake was not significantly different between cases and controls, minimizing the potential for dietary confounding., Interpretation: Our results suggest that short-chain fatty acid producers may be important contributors to multiple sclerosis onset., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Accurate diagnosis of multiple sclerosis requires careful attention to its differential diagnosis-many disorders can mimic the clinical manifestations and paraclinical findings of this disease. A collaborative effort, organised by The International Advisory Committee on Clinical Trials in Multiple Sclerosis in 2008, provided diagnostic approaches to multiple sclerosis and identified clinical and paraclinical findings (so-called red flags) suggestive of alternative diagnoses. Since then, knowledge of disorders in the differential diagnosis of multiple sclerosis has expanded substantially. For example, CNS inflammatory disorders that present with syndromes overlapping with multiple sclerosis can increasingly be distinguished from multiple sclerosis with the aid of specific clinical, MRI, and laboratory findings; studies of people misdiagnosed with multiple sclerosis have also provided insights into clinical presentations for which extra caution is warranted. Considering these data, an update to the recommended diagnostic approaches to common clinical presentations and key clinical and paraclinical red flags is warranted to inform the contemporary clinical evaluation of patients with suspected multiple sclerosis., Competing Interests: Declaration of interests AJS reports grant funding from National Institute of Neurological Disorders and Stroke, National Institutes of Health, and Bristol Myers Squibb; contracted research with Sanofi, Biogen, Novartis, Actelion, and Genentec; personal compensation for consulting from EMD Serono and Octave Bioscience; payment or honoraria for lectures from EMD Serono; expert testimony from The Jacob D Fuchsberg Law Firm and Koskoff Koskoff & Bieder; participation on a Data Safety Monitoring Board for Patient Centered Research Institute and Yale University; participation on an advisory board for Genentech, Biogen, Alexion, Celgene, Greenwich Biosciences, TG Therapeutics, and Horizon Therapeutics. AJS is also content Chair for the American Academy of Neurology Institute Multiple Sclerosis Quality Measure Development Work Group and Section Editor for Multiple Sclerosis and Related Disorders. GA reports a grant from FIS PI19/01590 from Instituto de Salud Carlos III, Spain; personal compensation for consulting from Sanofi; payment or honoraria for lectures from Merck, Roche, and Novartis; support for attending meetings or travel from Merck, Novartis, European Committee for Treatment and Research in Multiple Sclerosis, and European Academy of Neurology; participation on a Data Safety Monitoring Board or Advisory Board for Merck, Roche, Horizon Therapeutics. GA is editor for Europe of Multiple Sclerosis Journal—Experimental, Translational and Clinical. GA is also executive committee member of International Women in Multiple Sclerosis network and steering committee member of European Biomarkers in Multiple Sclerosis consortium. WJB reports personal compensation for consulting from Biogen, Jannsen, Merck, Novartis, Roche, Sanofi, and Viatris; and payment or honoraria for lectures from Biogen, Jannsen, Merck, Novartis and Roche. EPF reports grant funding from the National Institutes of Health; personal compensation for consulting from Alexion, Genentech, UCB, and Horizon Therapeutics; and payment or honoraria for lectures from Pharmacy Times. EPF also served as site primary investigator in a randomised clinical trial on inebilizumab in neuromyelitis optica spectrum disorder sponsored by Medimmune/Viela-Bio/Horizon Therapeutics. EPF is also employed at the Mayo Clinic where commercial MOG-IgG, aquaporin-4-IgG and other antibodies are tested but does not receive any royalties from this testing. MPA reports grants or contracts with Biogen, Merck, Sanofi, Genzyme, Roche, Novartis, and Celgene/Bristol Myers Squibb; payment or honoraria for lectures from Biogen, Merck, Sanofi, Genzyme, Roche, Novartis, and Celgene/Bristol Myers Squibb; and participation on a Data Safety Monitoring Board or Advisory Board for Biogen, Merck, Sanofi, Genzyme, Roche, Novartis, and Celgene/Bristol Myers Squibb. BLB reports a grant from the National Multiple Sclerosis Society; personal compensation for consulting from Roche, Sanofi, Novartis, and UCB; and serves on the American Academy of Neurology Board of Directors and the International Medical and Scientific Advisory Board for the Multiple Sclerosis International Federation (MSIF). FB reports a grant from EU-IMI; personal compensation for consulting from Merck, Biogen, Roche, Combinostics, and IXICO; participation on a Data Safety Monitoring Board or Advisory Board for Prothena and EISAI; and stock options for QSA LTD. QSA is a contract research organization that provides imaging analysis services to the pharmaceutical industry. FB notes that his work with QSA has no relationship with his work as a diagnostic neuroradiologist nor with the content of the Personal View. JRC reports grants or contracts from the National Multiple Sclerosis Society, Patient Centered Outcomes Research Institute, EMD Serono, and Med Day; payment or honoraria for lectures from ECTRIMS European Charcot Foundation, Emory University, University of Chicago, MS XChange, and The Ohio State University. JRC also reports expert testimony for Mylan; participation on a Data Safety Monitoring Board or Advisory Board for Bristol Myers Squibb; and serves as Medical Director of Rocky Mountain Multiple sclerosis Center. JC reports grants or contracts from Biogen and Merck; payment or honoraria for lectures from Biogen, Merck, Sanofi, Bristol Myers Squibb, Novartis, Roche, and Jansen; and receipt of equipment, materials, drugs, medical writing, gifts, or other services from Novartis. KF reports grants from Ministry of Education, Culture, Sports, Science and Technology of Japan, and from Ministry of Health, Welfare and Labor of Japan. KF also reports personal compensation for consulting from Merck Biopharma, Japan Tobacco, and Abbvie; payment or honoraria for lectures and presentations from Biogen, Eisai, Mitsubishi Tanabe, Novartis, Chugai/Roche, Alexion, VielaBio/Horizon, Therapeutics, Teijin, Asahi Kasei Medical, Merck, and Takeda; participation on an Advisory Board for Biogen, Mitsubishi Tanabe, Novartis, Chugai/Roche, Alexion, VielaBio/Horizon Therapeutics, and UCB. KF serves as President of Pan-Asian Committee for Treatment and Research in Multiple Sclerosis, President of the Japanese Society of Neuroimmunology, Board Member of Japan Multiple Sclerosis Society and European Charcot Foundation, and Committee and Board member Executive Committee, International Medical and Scientific Board, MSIF. BH reports support from the European Union, Bundesministerium für Bildung und Forschung, and Deutsche Forschungsgemeinschaft; personal compensation for consulting from Sandoz and Biocom; patents for antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis (2012) and genetic determinants of neutralizing antibodies to interferon (filed 2010); and participation on a Data Safety Monitoring Board for TG Therapeutics and Polpharma and an Advisory Board for Novartis. RAM reports grants or contracts from Biogen Idec and Roche. SDN reports grants or contracts from Biogen, Roche, Genentech, National Multiple Sclerosis Society, Department of Defense, and Patient Centered Outcomes Research Institute; personal compensation for consulting from Biogen, Roche, Genentech, Bristol Myers Squibb, EMD Serono, Greenwich Biosciences, Novartis, and Horizon Therapeutics; and participation on a Data Safety Monitoring Board or Advisory Board for MedDay Pharmaceuticals. SDN also reports support from the Stiff Person Syndrome Research Foundation. MAR reports grants or contracts from Multiple Sclerosis Society of Canada and Fondazione Italiana Sclerosi Multipla; personal compensation for consulting from Biogen, Bristol Myers Squibb, Eli Lilly, Janssen, and Roche; payment or honoraria for lectures from Bayer, Biogen, Bristol Myers Squibb, Bromatech, Celgene, Genzyme, Merck Healthcare Germany, Merck Serono SpA, Novartis, Roche, and Teva. MAR also serves as Associate Editor for Multiple Sclerosis and Related Disorders. BY serves on the MSIF scientific advisory board and as President of MENACTRIMS. BY also reports personal compensation for consulting from Merck, Biogen, Novartis, Roche, Sanofi, and Bayer. JAC reports personal compensation for consulting from Biogen, Convelo, EMD Serono, Gossamer Bio, and PSI; serves as President of the Americas Committee on Treatment and Research in Multiple Sclerosis; and receives personal compensation for working as the Editor of Multiple Sclerosis Journal. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: The presence of subclinical optic nerve (ON) injury in youth living with pediatric-onset MS has not been fully elucidated. Magnetization transfer saturation (MTsat) is an advanced magnetic resonance imaging (MRI) parameter sensitive to myelin density and microstructural integrity, which can be applied to the study of the ON., Objective: The objective of this study was to investigate the presence of subclinical ON abnormalities in pediatric-onset MS by means of magnetization transfer saturation and evaluate their association with other structural and functional parameters of visual pathway integrity., Methods: Eleven youth living with pediatric-onset MS (ylPOMS) and no previous history of optic neuritis and 18 controls underwent standardized brain MRI, optical coherence tomography (OCT), Magnetoencephalography (MEG)-Visual Evoked Potentials (VEPs), and visual battery. Data were analyzed with mixed effect models., Results: While ON volume, OCT parameters, occipital MEG-VEPs outcomes, and visual function did not differ significantly between ylPOMS and controls, ylPOMS had lower MTsat in the supratentorial normal appearing white matter (-0.26 nU, p  = 0.0023), and in both in the ON (-0.62 nU, p  < 0.001) and in the normal appearing white matter of the optic radiation (-0.56 nU, p  = 0.00071), with these being positively correlated (+0.57 nU, p  = 0.00037)., Conclusions: Subclinical microstructural injury affects the ON of ylPOMS. This may appear as MTsat changes before being detectable by other currently available testing.

Background: Pediatric-onset multiple sclerosis (POMS) represents the earliest stage of disease pathogenesis. Investigating the cerebrospinal fluid (CSF) proteome in POMS may provide novel insights into early MS processes., Objective: To analyze CSF obtained from children at time of initial central nervous system (CNS) acquired demyelinating syndrome (ADS), to compare CSF proteome of those subsequently ascertained as having POMS versus monophasic acquired demyelinating syndrome (mADS)., Methods: Patients were selected from two prospective pediatric ADS studies. Liquid chromatography-mass spectrometry (LC-MS) was performed in a Dutch discovery cohort (POMS n = 28; mADS n = 39). Parallel reaction monitoring-mass spectrometry (PRM-MS) was performed on selected proteins more abundant in POMS in a combined Dutch and Canadian validation cohort (POMS n = 48; mADS n = 106)., Results: Discovery identified 5580 peptides belonging to 576 proteins; 58 proteins were differentially abundant with ⩾2 peptides between POMS and mADS, of which 28 more abundant in POMS. Fourteen had increased abundance in POMS with ⩾8 unique peptides. Five selected proteins were all confirmed within validation. Adjusted for age, 2 out of 5 proteins remained more abundant in POMS, that is, Carboxypeptidase E (CPE) and Semaphorin-7A (SEMA7A) ., Conclusion: This exploratory study identified several CSF proteins associated with POMS and not mADS, potentially reflecting neurodegeneration, compensatory neuroprotection, and humoral response in POMS. The proteins associated with POMS highly correlated with age at CSF sampling.

Purpose: We implemented a video ambulatory EEG (VA-EEG) Program as an alternative to inpatient video EEG monitoring for some patients given potential benefits related to quicker access, greater convenience, and lower cost. To evaluate the newly initiated program, we performed a quality improvement study to assess whether VA-EEG yielded studies with interpretable EEG and video quality that generated clinically beneficial data., Methods: This was a single-center prospective quality improvement study. We surveyed ordering clinicians, electroencephalographers, and caregivers regarding consecutive children who underwent clinically indicated VA-EEG. The primary outcome was the percentage of VA-EEG studies in which the ordering clinician reported that the study had answered the question of interest., Results: We evaluated 74 consecutive children selected to undergo clinically indicated VA-EEG by their clinicians and caregivers. Ordering clinicians reported that 77% of studies answered the question of interest. Electroencephalographers reported that the quality of the EEG and video was excellent or adequate in 100% and 92% of patients, respectively. Additionally, 84% of caregivers reported preferring VA-EEG if EEG data were needed in the future., Conclusions: Video ambulatory EEG may be an effective diagnostic modality among children selected by clinicians and caregivers to undergo long-term EEG monitoring. Given it is effective as well as convenient, accessible, and lower cost than inpatient EEG monitoring, all of which align with our institution's quality goals, we intend to expand our VA-EEG Program., Competing Interests: The authors have no funding or conflicts of interest to disclose., (Copyright © 2020 by the American Clinical Neurophysiology Society.)

Inhibition of Bruton's Tyrosine Kinase (BTKi) is now viewed as a promising next-generation B-cell-targeting therapy for autoimmune diseases including multiple sclerosis (MS). Surprisingly little is known; however, about how BTKi influences MS disease-implicated functions of B cells. Here, we demonstrate that in addition to its expected impact on B-cell activation, BTKi attenuates B-cell:T-cell interactions via a novel mechanism involving modulation of B-cell metabolic pathways which, in turn, mediates an anti-inflammatory modulation of the B cells. In vitro, BTKi, as well as direct inhibition of B-cell mitochondrial respiration (but not glycolysis), limit the B-cell capacity to serve as APC to T cells. The role of metabolism in the regulation of human B-cell responses is confirmed when examining B cells of rare patients with mitochondrial respiratory chain mutations. We further demonstrate that both BTKi and metabolic modulation ex vivo can abrogate the aberrant activation and costimulatory molecule expression of B cells of untreated MS patients. Finally, as proof-of-principle in a Phase 1 study of healthy volunteers, we confirm that in vivo BTKi treatment reduces circulating B-cell mitochondrial respiration, diminishes their activation-induced expression of costimulatory molecules, and mediates an anti-inflammatory shift in the B-cell responses which is associated with an attenuation of T-cell pro-inflammatory responses. These data collectively elucidate a novel non-depleting mechanism by which BTKi mediates its effects on disease-implicated B-cell responses and reveals that modulating B-cell metabolism may be a viable therapeutic approach to target pro-inflammatory B cells., (© 2022. The Author(s).)

Introduction: Myelin oligodendrocyte glycoprotein antibodies are identified in approximately 30-50% of youth with pediatric-onset acquired demyelinating syndromes. Little is known about the cognitive sequelae of relapsing myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) with onset in childhood or adolescence.Overall, adults had 41% more risk than children to relapse over the whole disease course Overall, adults had 41% more risk than children to relapse over the whole disease course OBJECTIVE: To compare cognitive performance in participants with pediatric-onset relapsing MOGAD, pediatric-onset multiple sclerosis (POMS), and age-matched healthy controls., Methods: The Penn Computerized Neurocognitive Battery (PCNB) was administered to 12 individuals with relapsing MOGAD (age = 16.3 ± 4.8 years; 75% female; disease duration = 8.1 ± 2.7 years), 68 individuals with POMS (age = 18.3 ± 4.0 years; 72% female; disease duration = 3.8 ± 3.9 years), and 108 healthy controls (age = 17.0 ± 4.9 years; 68.5% female). Accuracy was assessed on four domains: Executive Function, Episodic Memory, Complex Cognition, Social Cognition; and overall response time (RT) and RT across three factors (i.e., Time Constrained, Open-Window, Memory). Global performance was determined by a composite score. Multiple linear regression was used to examine group differences on PCNB domain and factor z-scores, controlling for age and sex. We also covaried disease duration for relapsing MOGAD vs. POMS analyses., Results: Relative to healthy controls, relapsing MOGAD participants were less accurate on the Complex Cognition domain (B=-0.28, SE=0.11, p=.02), and had slower overall response time (B=-0.16, SE=0.07, p=.02). Relative to POMS, relapsing MOGAD participants were more accurate on the Executive Function domain (B = 0.70, SE=0.30, p=.02) and on the battery overall (B = 0.41, SE=0.18, p=.02). Relative to controls, overall PCNB score was significantly lower in the POMS group (B=-0.28, SE=0.06, p<.001) whereas the relapsing MOGAD participants did not differ from controls (p=.06) on the overall PCNB score., Conclusions: The relapsing MOGAD group demonstrated reduced reasoning skills and slower overall response time, relative to controls. A broad pattern of deficits was observed among POMS participants relative to controls. Overall, cognitive difficulties in the MOGAD group were milder relative to the POMS group., (Copyright © 2022. Published by Elsevier B.V.)

The impact of multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) - associated disorders (MOGAD) on brain structure in youth remains poorly understood. Reductions in cortical mantle thickness on structural MRI and abnormal diffusion-based white matter metrics (e.g., diffusion tensor parameters) have been well documented in MS but not in MOGAD. Characterizing structural abnormalities found in children with these disorders can help clarify the differences and similarities in their impact on neuroanatomy. Importantly, while MS and MOGAD affect the entire CNS, the visual pathway is of particular interest in both groups, as most patients have evidence for clinical or subclinical involvement of the anterior visual pathway. Thus, the visual pathway is of key interest in analyses of structural abnormalities in these disorders and may distinguish MOGAD from MS patients. In this study we collected MRI data on 18 MS patients, 14 MOGAD patients and 26 age- and sex-matched typically developing children (TDC). Full-brain group differences in fixel diffusion measures (fibre-bundle populations) and cortical thickness measures were tested using age and sex as covariates. Visual pathway analysis was performed by extracting mean diffusion measures within lesion free optic radiations, cortical thickness within the visual cortex, and retinal nerve fibre layer (RNFL) and ganglion cell layer thickness measures from optical coherence tomography (OCT). Fixel based analysis (FBA) revealed MS patients have widespread abnormal white matter within the corticospinal tract, inferior longitudinal fasciculus, and optic radiations, while within MOGAD patients, non-lesional impact on white matter was found primarily in the right optic radiation. Cortical thickness measures were reduced predominately in the temporal and parietal lobes in MS patients and in frontal, cingulate and visual cortices in MOGAD patients. Additionally, our findings of associations between reduced RNFLT and axonal density in MOGAD and TORT in MS patients in the optic radiations imply widespread axonal and myelin damage in the visual pathway, respectively. Overall, our approach of combining FBA, cortical thickness and OCT measures has helped evaluate similarities and differences in brain structure in MS and MOGAD patients in comparison to TDC., (Copyright © 2022. Published by Elsevier Inc.)

Aim to perform a systematic review of the literature on treatment of paediatric patients with MOG-IgG associated disease (MOGAD). Method We followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. The search was conducted in Pubmed (MEDLINE) seeking articles of treatment of MOGAD in patients ≤ 18 years published between January 2012 and April 25th, 2020. Results We found 72 non-controlled studies (observational studies, case reports and expert recommendations). There were no randomized controlled trials (RCTs). The most commonly reported acute phase treatment was intravenous methylprednisolone in 88% followed by oral steroids in 67%, intravenous human immunoglobulin (IVIG) in 66% and plasma exchange in 33% of the studies. Long-term maintenance treatment was described by 53 studies mainly in relapsing disease course. The most frequently reported treatments were prolonged oral corticosteroids in 53% of the studies followed by azathioprine (51%), mycophenolate mofetil (45%), rituximab (41%) and periodic intravenous immunoglobulin (26%). Interpretation long-term treatment was reported mainly in relapsing MOGAD paediatric patients. However, the most frequently used medications are not those that have shown higher reduction in the annualised relapse rate in observational studies. RCTs with standardized outcomes are needed to confirm the safety and efficacy of current and new treatments., (Copyright © 2021. Published by Elsevier B.V.)

Purpose: Thalamic nuclei are largely invisible in conventional MRI due to poor contrast. Thalamus Optimized Multi-Atlas Segmentation (THOMAS) provides automatic segmentation of 12 thalamic nuclei using white-matter-nulled (WMn) Magnetization Prepared Rapid Gradient Echo (MPRAGE) sequence at 7T, but increases overall scan duration. Routinely acquired, bias-corrected Magnetization Prepared 2 Rapid Gradient Echo (MP2RAGE) sequence yields superior tissue contrast and quantitative T1 maps. Application of THOMAS to MP2RAGE has been investigated in this study., Methods: Eight healthy volunteers and five pediatric-onset multiple sclerosis patients were recruited at Children's Hospital of Philadelphia and scanned at Siemens 7T with WMn-MPRAGE and multi-echo-MP2RAGE (ME-MP2RAGE) sequences. White-matter-nulled contrast was synthesized (MP2-SYN) from T 1 maps from ME-MP2RAGE sequence. Thalamic nuclei were segmented using THOMAS joint label fusion algorithm from WMn-MPRAGE and MP2-SYN datasets. THOMAS pipeline was modified to use majority voting to segment bias corrected T1-weighted uniform (MP2-UNI) images. Thalamic nuclei from MP2-SYN and MP2-UNI images were evaluated against corresponding nuclei obtained from WMn-MPRAGE images using dice coefficients, volume similarity indices (VSIs) and distance between centroids., Results: For MP2-SYN, dice > 0.85 and VSI > 0.95 was achieved for five larger nuclei and dice > 0.6 and VSI > 0.7 was achieved for seven smaller nuclei. The dice and VSI were slightly higher, whereas the distance between centroids were smaller for MP2-SYN compared to MP2-UNI, indicating improved performance using the MP2-SYN image., Conclusions: THOMAS algorithm can successfully segment thalamic nuclei in MP2RAGE images with essentially equivalent quality as WMn-MPRAGE, widening its applicability in studies focused on thalamic involvement in aging and disease., (© 2020 International Society for Magnetic Resonance in Medicine.)

Objective: We evaluated performance on the Penn Computerized Neurocognitive Battery (PCNB), a tool assessing accuracy and response time across four cognitive domains, alongside the Symbol Digit Modalities Test (SDMT), a measure of processing speed commonly used in MS. We determined whether performance decrements are more likely to be detected on measures of accuracy versus response time in pediatric-onset multiple sclerosis (POMS)., Methods: Performance on the SDMT, accuracy on PCNB tests belonging to four domains (executive function, episodic memory, complex cognition, social cognition), and response time on the PCNB were compared for 65 POMS patients (age range: 8-29 years) and 76 healthy controls (HCs) by ANCOVA. Associations between the Overall PCNB score and SDMT were examined for both groups, and their agreement in classifying impairment was assessed using Cohen's kappa., Results: POMS patients (age at testing = 18.3 ± 4.0 years; age at POMS onset = 14.9 ± 2.3 years) demonstrated reduced accuracy relative to HCs on tests of working memory, attention/inhibition, verbal memory, and visuospatial processing, after adjusting for response time (p ≤ .002). Patients demonstrated slower overall response time on the PCNB (p = .003), while group differences on the SDMT did not meet significance (p = .03). Performance on the PCNB and SDMT were correlated (MS: r = 0.43, HC: r = 0.50, both p < .001), however, the degree of agreement for impairment was minimal (k = 0.22, p = .14)., Conclusion: Specific cognitive deficits exist independently of slowed information processing speed in POMS, and may represent more significant areas of dysfunction. Delineation of accuracy and response time in neuropsychological assessment is important to identify areas of cognitive deficit in POMS. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Objective: The objective of this study was to validate the computerized Symbol Digit Modalities Test (c-SDMT) in a Swiss pediatric cohort, in comparing the Swiss sample to the Canadian norms. Secondly, we evaluated sex effects, age-effects, and test-retest reliability of the c-SDMT in comparison to values obtained for the paper and pencil version of the Symbol Digit Modalities Test (SDMT)., Methods: This longitudinal observational study was conducted in a single-center setting at the University Children's Hospital of Bern. Our cohort consisted of 86 children (45 male and 41 female) aged from 8 to 16 years. The cohort included both healthy participants ( n = 38) and patients ( n = 48) hospitalized for a non-neurological disease. Forty eight participants were assessed during two testing sessions with the SDMT and the c-SDMT., Results: Test-retest reliability was high in both tests (SDMT: ICC = 0.89, c-SDMT: ICC = 0.90). A reliable change index was calculated for the SDMT (RCIp = -3.18, 14.01) and the c-SDMT (RCIp = -5.45, 1.46) corrected for practice effects. While a significant age effect on information processing speed was observed, no such effect was found for sex. When data on the c-SDMT performance of the Swiss cohort was compared with that from a Canadian cohort, no significant difference was found for the mean time per trial in any age group. Norm values for age groups between 8 and 16 years in the Swiss cohort were established., Conclusion: Norms for the c-SDMT between the Swiss and the Canadian cohort were comparable. The c-SDMT is a valid alternative to the SDMT. It is a feasible and easy to administer bedside tool due to high reliability and the lack of motor demands., 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 Hochstrasser, Rieder, Jufer-Riedi, Klein, Feinstein, Banwell, Steiner, Cao, Lidzba and Bigi.)

Importance: Although magnetic resonance imaging (MRI) is useful for monitoring disease dissemination in space and over time and excluding multiple sclerosis (MS) mimics, there has been less application of MRI to progressive MS, including diagnosing primary progressive (PP) MS and identifying patients with relapsing-remitting (RR) MS who are at risk of developing secondary progressive (SP) MS. This review addresses clinical application of MRI for both diagnosis and prognosis of progressive MS., Observations: Although nonspecific, some spinal cord imaging features (diffuse abnormalities and lesions involving gray matter [GM] and ≥2 white matter columns) are typical of PPMS. In patients with PPMS and those with relapse-onset MS, location of lesions in critical central nervous system regions (spinal cord, infratentorial regions, and GM) and MRI-detected high inflammatory activity in the first years after diagnosis are risk factors for long-term disability and future progressive disease course. These measures are evaluable in clinical practice. In patients with established MS, GM involvement and neurodegeneration are associated with accelerated clinical worsening. Subpial demyelination and slowly expanding lesions are novel indicators of progressive MS., Conclusions and Relevance: Diagnosis of PPMS is more challenging than diagnosis of RRMS. No qualitative clinical, immunological, histopathological, or neuroimaging features differentiate PPMS and SPMS; both are characterized by imaging findings reflecting neurodegeneration and are also impacted by aging and comorbidities. Unmet diagnostic needs include identification of MRI markers capable of distinguishing PPMS from RRMS and predicting the evolution of RRMS to SPMS. Integration of multiple parameters will likely be essential to achieve these aims.

Objective: The limbic system is involved in memory and in processing of emotional stimuli. We measured volume of the hippocampus, amygdala, and thalamus, and assessed their relative contribution to episodic memory and emotion identification in POMS., Method: Sixty-five POMS participants (M age  = 18.3 ± 3.9 years; 48 female (73.8%)), average disease duration = 3.8 ± 3.8 years) and 76 age- and sex-matched controls (M age  = 18.1 ± 4.6 years; 49 female (64.5%)) completed the Penn Computerized Neurocognitive Battery (PCNB); 59 of 65 POMS participants and 69 out of 76 controls underwent 3 T MRI scanning. We derived age-adjusted Z-scores on accuracy and response time (RT) measures of episodic memory and emotion identification of the PCNB. Magnetic resonance imaging (MRI) volumetrics were normalized using the scaling factor computed by SIENAx. On PCNB tests that differed between groups, we used multiple linear regression to assess relationships between regional brain volumes and either episodic memory or emotion identification outcomes controlling for age, sex, accuracy/RT, and parental education., Results: POMS participants were slower and less accurate than controls on the episodic memory domain but did not differ from controls on emotion outcomes. At the subtest level, POMS participants showed reduced accuracy on Word Memory (p = .002) and slower performance on Face Memory (p = .04) subtests. POMS participants had smaller total and regional brain volumes of the hippocampus, amygdala, and thalamus (p values ≤ 0.01). Collapsing across groups, both hippocampal and thalamic volume were significant predictors of Word Memory accuracy; hippocampal volume (B = 0.24, SE = 0.10, p = .02) was more strongly associated with Word Memory performance than thalamic volume (B = 0.16, SE = 0.05, p = .003), though the estimate with was less precise., Conclusions: POMS participants showed reduced episodic memory performance compared to controls. Aspects of episodic memory performance were associated with hippocampal and thalamic volume. Emotion identification was intact, despite volume loss in the amygdala., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: While monophasic and relapsing forms of myelin oligodendrocyte glycoprotein antibody associated disorders (MOGAD) are increasingly diagnosed world-wide, consensus on management is yet to be developed., Objective: To survey the current global clinical practice of clinicians treating MOGAD., Method: Neurologists worldwide with expertise in treating MOGAD participated in an online survey (February-April 2019)., Results: Fifty-two responses were received (response rate 60.5%) from 86 invited experts, comprising adult (78.8%, 41/52) and paediatric (21.2%, 11/52) neurologists in 22 countries. All treat acute attacks with high dose corticosteroids. If recovery is incomplete, 71.2% (37/52) proceed next to plasma exchange (PE). 45.5% (5/11) of paediatric neurologists use IV immunoglobulin (IVIg) in preference to PE. Following an acute attack, 55.8% (29/52) of respondents typically continue corticosteroids for ≥ 3 months; though less commonly when treating children. After an index event, 60% (31/51) usually start steroid-sparing maintenance therapy (MT); after ≥ 2 attacks 92.3% (48/52) would start MT. Repeat MOG antibody status is used by 52.9% (27/51) to help decide on MT initiation. Commonly used first line MTs in adults are azathioprine (30.8%, 16/52), mycophenolate mofetil (25.0%, 13/52) and rituximab (17.3%, 9/52). In children, IVIg is the preferred first line MT (54.5%; 6/11). Treatment response is monitored by MRI (53.8%; 28/52), optical coherence tomography (23.1%; 12/52) and MOG antibody titres (36.5%; 19/52). Regardless of monitoring results, 25.0% (13/52) would not stop MT., Conclusion: Current treatment of MOGAD is highly variable, indicating a need for consensus-based treatment guidelines, while awaiting definitive clinical trials.

BACKGROUNDInitial reports from the severe acute respiratory coronavirus 2 (SARS-CoV-2) pandemic described children as being less susceptible to coronavirus disease 2019 (COVID-19) than adults. Subsequently, a severe and novel pediatric disorder termed multisystem inflammatory syndrome in children (MIS-C) emerged. We report on unique hematologic and immunologic parameters that distinguish between COVID-19 and MIS-C and provide insight into pathophysiology.METHODSWe prospectively enrolled hospitalized patients with evidence of SARS-CoV-2 infection and classified them as having MIS-C or COVID-19. Patients with COVID-19 were classified as having either minimal or severe disease. Cytokine profiles, viral cycle thresholds (Cts), blood smears, and soluble C5b-9 values were analyzed with clinical data.RESULTSTwenty patients were enrolled (9 severe COVID-19, 5 minimal COVID-19, and 6 MIS-C). Five cytokines (IFN-γ, IL-10, IL-6, IL-8, and TNF-α) contributed to the analysis. TNF-α and IL-10 discriminated between patients with MIS-C and severe COVID-19. The presence of burr cells on blood smears, as well as Cts, differentiated between patients with severe COVID-19 and those with MIS-C.CONCLUSIONPediatric patients with SARS-CoV-2 are at risk for critical illness with severe COVID-19 and MIS-C. Cytokine profiling and examination of peripheral blood smears may distinguish between patients with MIS-C and those with severe COVID-19.FUNDINGFinancial support for this project was provided by CHOP Frontiers Program Immune Dysregulation Team; National Institute of Allergy and Infectious Diseases; National Cancer Institute; the Leukemia and Lymphoma Society; Cookies for Kids Cancer; Alex's Lemonade Stand Foundation for Childhood Cancer; Children's Oncology Group; Stand UP 2 Cancer; Team Connor; the Kate Amato Foundations; Burroughs Wellcome Fund CAMS; the Clinical Immunology Society; the American Academy of Allergy, Asthma, and Immunology; and the Institute for Translational Medicine and Therapeutics.

We have previously demonstrated that pediatric-onset multiple sclerosis (POMS) negatively impacts the visual pathway as well as motor processing speed. Relationships between MS-related diffuse structural damage of gray and white matter (WM) tissue and cortical responses to visual and motor stimuli remain poorly understood. We used magnetoencephalography in 14 POMS patients and 15 age- and sex-matched healthy controls to assess visual gamma (30-80 Hz), motor gamma (60-90 Hz), and motor beta (15-30 Hz) cortical oscillatory responses to a visual-motor task. Then, 3T MRI was used to: (a) calculate fractional anisotropy (FA) of the posterior visual and corticospinal motor WM pathways and (b) quantify volume and thickness of the cuneus and primary motor cortex. Visual gamma band power was reduced in POMS and was associated with reduced FA of the optic radiations but not with loss of cuneus volume or thickness. Activity in the primary motor cortex, as measured by postmovement beta rebound amplitude associated with peak latency, was decreased in POMS, although this reduction was not predicted by structural metrics. Our findings implicate loss of WM integrity as a contributor to reduced electrical responses in the visual cortex in POMS. Future work in larger cohorts will inform on the cognitive implications of this finding in terms of visual processing function and will determine whether the progressive loss of brain volume known to occur in POMS ultimately contributes to both progressive dysfunction in such tasks as well as progressive reduction in cortical electrical responses in the visual cortex., (© 2020 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)

Objective: Prevalence and characteristics of fractures and factors related to loss of ambulation after lower limb fractures were investigated., Design: Chart review included height, weight, dual-energy x-ray absorptiometry, corticosteroid use, vitamin D, fracture history, muscle strength, range of motion, and timed performance tests (10 meter walk/run, Gowers, and four steps). Patients were grouped by fracture location and ambulation loss after fracture., Results: Two hundred eighty-seven patients with Duchenne muscular dystrophy were identified, 53 of these had experienced fracture. Eighty-one percent were older than 9 yrs at first fracture and 36.4% became nonambulatory after fracture. Dorsiflexion range of motion (fracture side, P = 0.021), quadriceps strength (right side, P = 0.025), and shoulder abduction strength (right, left, and fracture side; P = 0.028, P = 0.027, and P = 0.016) were significantly different within the groups. Patients who became nonambulatory after fracture initially had less dorsiflexion (right, left, fracture side; 2.25 vs. -7.29, P = 0.004; 2.67 vs. -12, P = 0.001; and 2.41 vs. -7.42, P = 0.002) and slower 10-meter walk/run times (7.43 secs vs. 14.7 secs, P = 0.005)., Conclusions: Fracture represents a significant risk in patients with Duchenne muscular dystrophy; both slower walking speed and ankle contracture confer an increased risk of ambulation loss after fracture., To Claim Cme Credits: Complete the self-assessment activity and evaluation online at http://www.physiatry.org/JournalCME CME OBJECTIVES: Upon completion of this article, the reader should be able to: (1) Identify the main factors that are associated with ambulation loss after fracture in patients with Duchenne muscular dystrophy; (2) Identify the risk of fracture in the Duchenne muscular dystrophy population; and (3) Articulate the characteristics associated with fracture in patients with Duchenne muscular dystrophy., Level: Advanced., Accreditation: The Association of Academic Physiatrists is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.The Association of Academic Physiatrists designates this Journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Objective: To assess the rapid implementation of child neurology telehealth outpatient care with the onset of the coronavirus disease 2019 (COVID-19) pandemic in March 2020., Methods: This was a cohort study with retrospective comparison of 14,780 in-person encounters and 2,589 telehealth encounters, including 2,093 audio-video telemedicine and 496 scheduled telephone encounters, between October 1, 2019 and April 24, 2020. We compared in-person and telehealth encounters for patient demographics and diagnoses. For audio-video telemedicine encounters, we analyzed questionnaire responses addressing provider experience, follow-up plans, technical quality, need for in-person assessment, and parent/caregiver satisfaction. We performed manual reviews of encounters flagged as concerning by providers., Results: There were no differences in patient age and major ICD-10 codes before and after transition. Clinicians considered telemedicine satisfactory in 93% (1,200 of 1,286) of encounters and suggested telemedicine as a component for follow-up care in 89% (1,144 of 1,286) of encounters. Technical challenges were reported in 40% (519 of 1,314) of encounters. In-person assessment was considered warranted after 5% (65 of 1,285) of encounters. Patients/caregivers indicated interest in telemedicine for future care in 86% (187 of 217) of encounters. Participation in telemedicine encounters compared to telephone encounters was less frequent among patients in racial or ethnic minority groups., Conclusions: We effectively converted most of our outpatient care to telehealth encounters, including mostly audio-video telemedicine encounters. Providers rated the vast majority of telemedicine encounters to be satisfactory, and only a small proportion of encounters required short-term in-person follow-up. These findings suggest that telemedicine is feasible and effective for a large proportion of child neurology care. Additional strategies are needed to ensure equitable telemedicine use., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: High-contrast visual acuity (HCVA) changes with age, yet little is known about pediatric-specific age- and sex-normative values for low-contrast letter acuity (LCLA). We define maturational changes in monocular and binocular HCVA and LCLA in childhood and adolescence., Methods: Normally sighted youth (ages 5-20 years, without neurologic or ophthalmologic disease and best-corrected HCVA of 20/25 or better in each eye) were recruited. Mean monocular and binocular scores using Early Treatment Diabetic Retinopathy Study (for HCVA) and 2.5% and 1.25% Sloan (for LCLA) charts and the magnitude of binocular summation were calculated using 2-year bins. Relationships between scores and age were explored using scatterplots with Locally Weighted Scatterplot Smoothing (LOWESS) and analysis of variance that accounts for intereye correlation, followed by test of linear trend for age effect., Results: Among 101 (202 eyes) healthy participants (mean age 13 years, 42% males), monocular and binocular scores varied by age, with highest mean scores achieved in the 13 to 14-year age group for both HCVA and LCLA. Between the ages of 5 and 14.9 years, monocular scores increased linearly with age (0.76 letter/year for HCVA, 1.11 letters/year for 2.5% LCLA, and 0.97 letter/year for 1.25% LCLA; all P < 0.0001). Binocular HCVA scores also increased with age between 5 and 14.9 years (0.71 letters/year, P < 0.0001). The magnitude of binocular summation for HCVA or LCLA did not change with age., Conclusions: HCVA and LCLA abilities mature into adolescence, peak between 13 and 14.9 years of age, and then plateau into adulthood. Evaluation of patients with visual deficits should consider age-expected normal visual acuity.

Background and Purpose: Pediatric-onset multiple sclerosis (POMS) is associated with focal inflammatory lesions and the loss of cortical and deep gray matter. Optic neuritis (ON) and white matter (WM) lesions in the visual pathway can directly contribute to visual cortical mantle thinning. We determine the relative contributions of MS insult on anterior and posterior visual pathway integrity., Methods: High- and low-contrast visual acuity, optical coherence tomography (OCT), and 3T MRI scans were obtained from 20 POMS patients (10 with remote ON) and 22 age- and sex-matched healthy controls. Cortical mantle thickness was measured using FreeSurfer. Fractional anisotropy (FA) and mean diffusivity were calculated for postchiasmal optic radiations (with and without WM lesions). Groups were compared using Student's t-test (adjusted for multiple comparisons), and simple linear regression was used to investigate interrelationships between measures., Results: Mean cortical thickness of the whole brain was reduced in patients (2.49 mm) versus controls (2.58 mm, P = .0432) and in the visual cortex (2.07 mm vs. 2.17 mm, P = .0059), although the foveal confluence was spared. Mean FA of the optic radiations was reduced in POMS (.40) versus controls (.43, P = .0042) and correlated with visual cortical mantle thickness in POMS (P = .017). Visual acuity, OCT measures, and lesion volumes in the optic radiations were not associated with cortical mantle thickness., Conclusions: POMS negatively impacts the integrity of the anterior visual pathway, but it is the loss of WM integrity that drives anterograde loss of the cortical mantle. Preserved visual acuity and foveal sparing imply some degree of functional and structural resilience., (© 2019 by the American Society of Neuroimaging.)

MRI has improved the diagnostic work-up of multiple sclerosis, but inappropriate image interpretation and application of MRI diagnostic criteria contribute to misdiagnosis. Some diseases, now recognized as conditions distinct from multiple sclerosis, may satisfy the MRI criteria for multiple sclerosis (e.g. neuromyelitis optica spectrum disorders, Susac syndrome), thus making the diagnosis of multiple sclerosis more challenging, especially if biomarker testing (such as serum anti-AQP4 antibodies) is not informative. Improvements in MRI technology contribute and promise to better define the typical features of multiple sclerosis lesions (e.g. juxtacortical and periventricular location, cortical involvement). Greater understanding of some key aspects of multiple sclerosis pathobiology has allowed the identification of characteristics more specific to multiple sclerosis (e.g. central vein sign, subpial demyelination and lesional rims), which are not included in the current multiple sclerosis diagnostic criteria. In this review, we provide the clinicians and researchers with a practical guide to enhance the proper recognition of multiple sclerosis lesions, including a thorough definition and illustration of typical MRI features, as well as a discussion of red flags suggestive of alternative diagnoses. We also discuss the possible place of emerging qualitative features of lesions which may become important in the near future., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Pediatric onset multiple sclerosis (POMS) is a rare disease with an incidence of 0.07 to 2.9/100'000 children per year. It follows a relapsing-remitting disease course and is characterized by rapid accrual of inflammatory lesions, high relapse frequency, and early cognitive impairment. Magnetic resonance imaging (MRI) plays a pivotal role in the diagnosis of POMS, and in the exclusion of other disorders mimicking POMS. Furthermore, MRI aids in disease monitoring, and in the evaluation of therapeutic efficacy in both clinical practice and clinical trials. Volumetric MRI studies, diffusion tensor imaging, resting-state, and task-based functional MRI provide deeper insight into the impact of POMS on maturing neural networks. This review article aims to highlight the importance of MRI in the care of POMS patients and to provide an overview on the different MRI techniques used in the management of POMS., Competing Interests: Dr. Parmar received travel support from Novartis Switzerland unrelated to this work. Dr. Banwell receives financial compensation for work as a consultant to Novartis on clinical trial work unrelated to this work. Dr. Akbar and Dr. Bigi declare that they have no conflict of interest., (Georg Thieme Verlag KG Stuttgart · New York.)

The clinicaltrials.gov identifying number for the article titled "Impact of an electronic monitoring device and behavioral feedback on adherence to multiple sclerosis therapies in youth: results of a randomized trial" is NCT02234713 (https://clinicaltrials.gov/ct2/show/NCT02234713).

Background: Adherence to disease-modifying therapies (DMTs) in pediatric multiple sclerosis (MS) is not well understood. We examined the prevalence and risk factors for poor adherence in pediatric MS., Methods: This cross-sectional study recruited youth with MS from 12 North American pediatric MS clinics. In addition to pharmacy-refill data, patients and parents completed self-report measures of adherence and quality of life. Additionally, patients completed measures of self-efficacy and well-being. Factor analysis and linear regression methods were used., Results: A total of 66 youth (mean age, 15.7 years) received MS DMTs (33% oral, 66% injectable). Estimates of poor adherence (i.e. missing >20% of doses) varied by source: pharmacy 7%, parent 14%, and patient 41%. Factor analysis yielded two composites: adherence summary and parental involvement in adherence. Regressions revealed that patients with better self-reported physical functioning were more adherent. Parents were more likely to be involved in adherence when their child had worse parent-reported PedsQL School Functioning and lower MS Self-Efficacy Control. Oral DMTs were associated with lesser parental involvement in adherence., Conclusion: Rates of non-adherence varied by information source. Better self-reported physical functioning was the strongest predictor of adherence. Parental involvement in adherence was associated with worse PedsQL School Functioning and lower MS Self-Efficacy-measured confidence in controlling MS.

The 2010 McDonald criteria for the diagnosis of multiple sclerosis are widely used in research and clinical practice. Scientific advances in the past 7 years suggest that they might no longer provide the most up-to-date guidance for clinicians and researchers. The International Panel on Diagnosis of Multiple Sclerosis reviewed the 2010 McDonald criteria and recommended revisions. The 2017 McDonald criteria continue to apply primarily to patients experiencing a typical clinically isolated syndrome, define what is needed to fulfil dissemination in time and space of lesions in the CNS, and stress the need for no better explanation for the presentation. The following changes were made: in patients with a typical clinically isolated syndrome and clinical or MRI demonstration of dissemination in space, the presence of CSF-specific oligoclonal bands allows a diagnosis of multiple sclerosis; symptomatic lesions can be used to demonstrate dissemination in space or time in patients with supratentorial, infratentorial, or spinal cord syndrome; and cortical lesions can be used to demonstrate dissemination in space. Research to further refine the criteria should focus on optic nerve involvement, validation in diverse populations, and incorporation of advanced imaging, neurophysiological, and body fluid markers., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Youth with multiple sclerosis (MS) often experience cognitive impairment and psychosocial disturbances. We describe the relationship between memory function, psychosocial skills, and brain volume in 32 patients with pediatric-onset MS and 30 controls. Amygdala volume was significantly lower in patients compared with controls. In general, poorer memory was associated with reduced functional communication skills and reduced amygdala volume. Greater amygdala volume in patients correlated with parent-reported functional communication and social skills. Adjusting for whole-brain volume, right amygdala volume was positively associated with visual memory; left amygdala volume was a stronger predictor of parent-reported social skills.

Purpose: To report the results of a randomized controlled trial using an electronic monitoring device (EM) plus a motivational interviewing (MI) intervention to enhance adherence to disease-modifying therapies (DMT) in pediatric MS., Methods: Fifty-two youth with MS (16.03 ± 2.2 years) were randomized to receive either MI (n = 25) (target intervention) or a MS medication video (n = 27) (attention control). Primary endpoint was change in adherence. Secondary outcomes included changes in quality of life, well-being and self-efficacy. Random effects modeling and Cohen's effect size computation evaluated intervention impact., Results: Longitudinal random effect models revealed that the MI group decreased their EM adherence (GroupxTime interaction = -0.19), while increasing frequency of parental DMT reminder (26.01)/administration (11.69). We found decreased EM use in the MI group at 6 months (Cohen's d = -0.61), but increased pharmacy refill adherence (d = 0.23). Parental reminders about medication increased in MI subjects vs controls (d = 0.59 at 3 months; d = 0.70 at 6 months). We found increases in self-reported adherence (d = 0.21) at 3 but not 6 months, fewer barriers to adherence at three (d = -0.58) and six months (d = -0.31), better physical (d = 0.23 at 3 months; d = 0.45 at 6 months), emotional (d = 0.25 at 3 months) and self-efficacy function (d = 0.55 at 3 months; 0.48 at 6 months), but worse well-being, including self-acceptance (d = -0.53 at 6 months) and environmental mastery (d = -0.42 at 3 and 6 months) in intervention as compared to control patients., Conclusions: Participants receiving MI + EM experienced worsening on objective measures of adherence and increased parental involvement, but improved on some self- and parent-reported measures. MI participants reported improvements in quality of life and self-efficacy, but worsened well-being.

Background: Intravenous lipid emulsion (ILE) has gained favor as a rescue treatment for cardiovascular collapse due to intravenous local anesthetic overdose, however, goals of ILE therapy are still being defined. We describe a case of a girl given 66 mL/kg of 20% lipid emulsion (ILE) in the treatment of presumed mepivacaine toxicity., Case Report: An 11-year-old girl weighing 55.6 kg developed pallor, rolling back of the eyes, and rhythmic muscle twitching after receiving a mandibular nerve block injection with a 1.8 mL ampule of 3% mepivacaine. With concern for persistent seizures she was given three 1 mL/kg boluses of ILE, followed by an infusion of 0.25 mL/kg/min. The total dose ultimately administered was 3670 mL (66 mL/kg) over 7 h. A serum triglyceride concentration, drawn 2 h after cessation of ILE infusion, was estimated to be 16,583 mg/dL (429 mmol/L) after several dilutions; her blood was grossly lipemic. Notable signs included hypersomnolence, tachypnea, and tachycardia. Other complications included apparent metabolic acidosis (serum bicarbonate of 5 mmol/L) with hyperlactatemia (lactate 7.0 mmol/L), difficulty with serum laboratory interpretation, and a non-contrast brain magnetic resonance imaging showing high signal in the dural venous sinuses. The lipemia cleared over three days and the patient recovered uneventfully. Case discussion: This case demonstrates a unique neurologic and metabolic toxicity associated with ILE given as an antidote in a high total dose, and highlights the need for cautious antidotal application of lipid emulsion infusions. Until more data is available, clinicians are advised to take great care if considering a dose in excess of 12.5 mL/kg/day, the maximum daily dosage recommended by the U.S. Food and Drug Administration for nutritional supplementation. Careful monitoring of total doses administered across institutions and hospital wards during transfers is paramount to avoid inadvertent overdose of antidotes.

Objective: To determine the relative ability of optical coherence tomography (OCT) and pattern-reversal visual evoked potentials (pVEPs) to detect visual pathway involvement in pediatric-onset MS., Methods: Pediatric-onset MS participants (onset <18 years) and healthy controls (HCs) underwent OCT (Cirrus HD-OCT) and pVEPs. Retinal nerve fiber layer (RNFL), ganglion cell layer to inner plexiform layer (GCL-IPL), and P100 pVEP latency were measured. Generalized estimating equation models were used to compare the groups, adjusting for age and intereye correlations., Results: Twenty-four pediatric MS participants, 14 with a history of remote (>6 months) optic neuritis (ON) in one eye (8 participants) or both the eyes (6 participants), and 24 HCs were enrolled. RNFL thinning (<83 μm, 2 SDs below HC eyes) occurred in 50% of ON eyes vs 5% of non-ON eyes. Prolonged VEP latency (>109 msec) occurred in 58% of ON eyes and 55% of non-ON eyes. A clinical history of ON predicted RNFL ( p < 0.001) and GCL-IPL thinning ( p = 0.011), whereas prolonged pVEP latency in children with MS occurred independent of ON history., Conclusions: OCT and pVEPs provide complementary but distinct insights. OCT is sensitive to retinal changes in the context of clinical ON, whereas pVEPs are useful to detect disseminated lesions of the visual pathway in children with MS.

Decreased information processing speed (IPS) is frequently reported in pediatric multiple sclerosis (MS) patients. The computerized version of the Symbol Digit Modalities Test (c-SDMT) measures IPS over eight consecutive trials per session and additionally captures changes in performance within the session. Here, we establish normative c-SDMT performance and test-retest reliability in healthy children (HC) and explore differences in the overall c-SDMT-performance between HC and MS patients. This cross-sectional study included 478 HC (237 female, 49.5%) divided into five age groups (2 years each), and 27 MS patients (22 female, 81.5%) aged 8-18 years. The average time to complete the c-SDMT increased with age (|r| 0.70, 95% CI -0.74, -0.64). Test-retest reliability was high (ICC = 0.91) in HC. The total time to complete the c-SDMT did not differ between children with MS and sex- and age- matched HC (p = 0.23). However, MS patients were less likely to show faster performance across all the successive eight trials compared to HC (p = 0.0001). Healthy children demonstrate faster IPS with increasing age, as well as during successive trials of the c-SDMT. The inability of pediatric MS patients to maintain the increase in processing speed over successive trials suggests a reduced capacity for procedural learning, possibly resulting from cognitive fatigue.

Objective: We aimed to determine the prevalence and risk factors for electrographic seizures in neonates and children requiring extracorporeal membrane oxygenation support., Design: Prospective quality improvement project., Setting: Quaternary care pediatric institution., Patients: Consistent with American Clinical Neurophysiology Society electroencephalographic monitoring recommendations, neonates and children requiring extracorporeal membrane oxygenation support underwent clinically indicated electroencephalographic monitoring., Interventions: We performed a 2-year quality improvement study from July 2013 to June 2015 evaluating electrographic seizure prevalence and risk factors., Main Results: Ninety-nine of 112 patients (88%) requiring extracorporeal membrane oxygenation support underwent electroencephalographic monitoring. Electrographic seizures occurred in 18 patients (18%), of whom 11 patients (61%) had electrographic status epilepticus and 15 patients (83%) had exclusively electrographic-only seizures. Electrographic seizures were more common in patients with low cardiac output syndrome (p = 0.03). Patients with electrographic seizures were more likely to die prior to discharge (72% vs 30%; p = 0.01) and have unfavorable outcomes (54% vs 17%; p = 0.004) than those without electrographic seizures., Conclusions: Electrographic seizures occurred in 18% of neonates and children requiring extracorporeal membrane oxygenation support, often constituted electrographic status epilepticus, and were often electrographic-only thereby requiring electroencephalographic monitoring for identification. Low cardiac output syndrome was associated with an increased risk for electrographic seizures. Electrographic seizures were associated with higher mortality and unfavorable outcomes. Further investigation is needed to determine whether electrographic seizures identification and management improves outcomes.

Background: Outcome measures to capture disability, such as the Multiple Sclerosis Functional Composite (MSFC), were developed to enhance outcome measurements for clinical trials in adults with multiple sclerosis (MS). The MSFC initially included three components: a timed 25-foot walk [T25FW], 9-hole peg test [9HPT], and the Paced Auditory Serial Addition Task [PASAT]. Modifications to the original MSFC, such as adding binocular low-contrast letter acuity (LCLA) or substituting the symbol digit modalities test (SDMT) for the PASAT, improved the capacity to capture neurologic impairment in adults. Similar outcome scales for pediatric MS have not yet been established., Objective: To determine whether the three-component MSFC or a modified MSFC with LCLA and the SDMT better identifies neurological deficits in pediatric MS., Methods: We evaluated 5 measures (T25FW, 9HPT, Children's PASAT [ChiPASAT], SDMT, and binocular LCLA [Sloan charts, 1.25% contrast]) in children with MS (disease onset <18 years) and healthy controls. To be able to compare measures whose scores have different scales, Z-scores were also created for each test based on the numbers of standard deviations from a control group mean, and these individual scale scores were combined to create composite scores. Logistic regression models, accounting for age, were used to determine whether the standard 3-component MSFC or modified versions (including 4 or 5 metrics) best distinguished children with MS from controls., Results: Twenty pediatric-onset MS subjects, aged 6-21 years, and thirteen healthy controls, aged 6-19 years, were enrolled. MS subjects demonstrated worse scores on the 9HPT (p=0.004) and SDMT (p=0.001), but not the 25FTW (adjusted for height, p=0.63) or the ChiPASAT (p=0.10): all comparisons adjusted for age. Decreased (worse) binocular LCLA scores were associated with MS (vs. control status, p=0.03, logistic regression; p=0.08, accounting for age). The MSFC composite score for the traditional 3 components did not differ between the groups (p=0.28). Replacing the ChiPASAT with the SDMT (OR 0.72, p=0.05) better distinguished MS from controls. A modified MSFC-4 with the SDMT replacing the ChiPASAT and including binocular 1.25% LCLA had the greatest capacity to distinguish pediatric MS from controls (OR 0.89, p=0.04, logistic regression). Including all 5 metrics as a composite MSFC-5 did not improve the model (p=0.18)., Conclusions: A modified MSFC (25FTW, 9HPT, SMDT, and binocular 1.25% LCLA) is more sensitive than the traditional MSFC or its components to capture the subtle impairments that characterize pediatric MS and should be validated in order to be considered for future pediatric MS trials., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objectives: The aim of this study was to describe cognitive, academic, and psychosocial outcomes after an incident demyelinating event (acquired demyelinating syndromes, ADS) in childhood and to investigate the contribution of brain lesions and confirmed MS diagnosis on outcome., Methods: Thirty-six patients with ADS (mean age=12.2 years, SD=2.7, range: 7-16 years) underwent brain MRI scans at presentation and at 6-months follow-up. T2-weighted lesions on MRI were assessed using a binary classification. At 6-months follow-up, patients underwent neuropsychological evaluation and were compared with 42 healthy controls., Results: Cognitive, academic, and behavioral outcomes did not differ between the patients with ADS and controls. Three of 36 patients (8.3%) were identified with cognitive impairment, as determined by performance falling ≤1.5 SD below normative values on more than four independent tests in the battery. Poor performance on a visuomotor integration task was most common, observed among 6/32 patients, but this did not differ significantly from controls. Twelve of 36 patients received a diagnosis of MS within 3 years post-ADS. Patients with MS did not differ from children with monophasic ADS in terms of cognitive performance at the 6-months follow-up. Fatigue symptoms were reported in 50% of patients, irrespective of MS diagnosis. Presence of brain lesions at onset and 6 months post-incident demyelinating event did not associate with cognitive outcome., Conclusions: Children with ADS experience a favorable short-term neurocognitive outcome, even those confirmed to have MS. Longitudinal evaluations of children with monophasic ADS and MS are required to determine the possibility of late-emerging sequelae and their time course. (JINS, 2016, 22, 1050-1060).

Introduction: Infantile neuroaxonal dystrophy (INAD), an autosomal recessive neurodegenerative disorder due to PLA2G6 mutation, is classified both as a PLA2G6-associated neurodegeneration (PLAN) disorder and as one of the neurodegeneration with brain iron accumulation (NBIA) disorders. Age of onset and clinical presentation in INAD is variable. Typically described imaging features of cerebellar atrophy, cerebellar cortex bright FLAIR signal, and globus pallidus iron deposition are variable or late findings. We characterize clinical and neuroimaging phenotypes in nine children with confirmed PLA2G6 mutations and show a useful imaging feature, clava hypertrophy, which may aid in earlier identification of patients. Measurements of the clava confirm actual enlargement, rather than apparent enlargement due to volume loss of the other brain stem structures., Methods: A retrospective clinical and MRI review was performed. Brain stem measurements were performed and compared with age-matched controls., Results: We identified nine patients, all with novel PLA2G6 gene mutations. MRI, available in eight, showed clava hypertrophy, regardless of age or the absence of other more typically described neuroimaging findings. Brain autopsy in our cohort confirmed prominent spheroid bodies in the clava nuclei., Conclusion: Clava hypertrophy is an important early imaging feature which may aid in indentification of children who would benefit from specific testing for PLA2G6 mutations.

Background: The onset of multiple sclerosis (MS) during childhood or adolescence is increasingly recognized in the United States. Administrative databases quantify healthcare utilization as measured by hospital admissions, providing insight into the impact of MS in the pediatric population., Objective: We examine the frequency of hospital admissions for pediatric MS in the US using the Pediatric Health Information System (PHIS) database., Methods: Data was extracted from the PHIS database using the ICD-9 code for MS (340.00) and reviewed to verify case ascertainment. Mean, median, and range values were determined for the number of inpatient hospitalizations per patient, number of days in the hospital, and cost of each encounter. A trend analysis was performed to evaluate the annual frequency of MS-related admissions over the study period., Results: After case verification, the PHIS database extraction reported 2068 hospital inpatient encounters for 1422 unique pediatric MS patients between 2004 and 2013. The median number of hospitalizations per patient was 2 with a median hospital stay of 4 days. Admission rates for MS increased from 2.37 per 10,000 in 2004 to 4.13 per 10,000 in 2013., Conclusion: The number of admissions due to pediatric MS has increased since the start of the PHIS database collection, concurrent with increased disease awareness and the establishment of dedicated pediatric MS centers., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Acquired pediatric demyelinating diseases manifest acutely with optic neuritis, transverse myelitis, acute disseminated encephalomyelitis, or with various other acute deficits in focal or polyfocal areas of the central nervous system. Patients may experience a monophasic illness (as in the case of acute disseminated encephalomyelitis) or one that may manifest as a chronic, relapsing disease [e.g., multiple sclerosis (MS)]. The diagnosis of pediatric MS and other demyelinating disorders of childhood has been facilitated by consensus statements regarding diagnostic definitions. Treatment of pediatric MS has been modeled after data obtained from clinical trials in adult-onset MS. There are now an increasing number of new therapeutic agents for MS, and many will be formally studied for use in pediatric patients. There are important efficacy and safety concerns regarding the use of these therapies in children and young adults. This review will discuss acute management as well as chronic immunotherapies in acquired pediatric demyelination., Competing Interests: Compliance with Ethical Standards Required Author Forms Disclosure forms provided by the authors are available with the online version of this article.

Objective: To evaluate the association between physical activity (PA) and multiple sclerosis (MS) disease activity, depression, and fatigue in a cohort of children with MS and monophasic acquired demyelinating syndrome (mono-ADS)., Methods: In this cross-sectional study of consecutive patients attending a specialized pediatric MS clinic, we administered the PedsQL Multidimensional Fatigue Scale, Center for Epidemiological Studies Depression Scale, and Godin Leisure-Time Exercise Questionnaire. Quantitative MRI analysis was performed to obtain whole brain and T2 lesion volume in a subset of participants (n = 60)., Results: A total of 110 patients (79 mono-ADS; 31 MS; 5-18 years; M:F 1:1.2) were included. Patients with MS reported less strenuous (33.21 ± 31.88 metabolic equivalents [METs] vs 15.97 ± 22.73 METs, p = 0.002) and total (44.48 ± 39.35 METs vs 67.28 ± 59.65 METs; p = 0.0291) PA than those with mono-ADS. Patients with MS who reported greater amounts of moderate PA METs had fewer sleep/rest fatigue symptoms (r = -0.4). Participation in strenuous PA was associated with smaller T2 lesion volumes (r = -0.66) and lower annualized relapse rate (r = -0.66). No associations were found between total brain volume and participation in PA., Conclusions: Children with MS are less physically active than children with mono-ADS. Reasons for this are unclear, but may be related to ongoing disease activity, perceived limitations, or symptoms such as depression or fatigue. Children with MS reporting higher levels of strenuous PA had lower T2 lesion volumes and lower relapse rates, suggesting a potential protective effect of strenuous PA in this population. Further longitudinal studies are needed to establish the relationship of PA to MS symptoms and disease activity in this population., (© 2015 American Academy of Neurology.)

Background: For reasons that remain unclear, three times more women develop multiple sclerosis (MS) than men. This preponderance among women is evident only after 12 years of age, implicating pubertal factors in the risk of MS., Objective: To investigate the influence of female puberty on central nervous system (CNS) autoimmunity., Methods: We examined the relationship between age of menarche on MS outcomes in 116 female children (< 16 years old) whom presented with incident 'acquired demyelinating syndromes' (ADS) and were followed prospectively in the national Canadian Pediatric Demyelinating Disease Study, from 2004-2013. Furthermore, we directly investigated the effects of puberty on susceptibility to experimental autoimmune encephalomyelitis (EAE) in two groups of female mice that differed only in their pubertal status., Results: In the ADS children, a later age of menarche was associated with a decreased risk of subsequent MS diagnosis. This relationship persisted, after accounting for patient age at ADS presentation and the presence of ≥1 T2 lesions on brain magnetic resonance imaging (MRI), with a hazard ratio (HR) of 0.64; and additional factors that associate with MS outcomes in ADS children, including low vitamin D levels. Furthermore, we found female mice that had transitioned through puberty were more susceptible to EAE than age-matched, pre-pubertal mice., Conclusion: Puberty in females enhances CNS autoimmune mechanisms that lead to MS in humans and EAE in mice., (© The Author(s), 2014.)

Since its initial reports in the 19th century, neuromyelitis optica (NMO) had been thought to involve only the optic nerves and spinal cord. However, the discovery of highly specific anti-aquaporin-4 antibody diagnostic biomarker for NMO enabled recognition of more diverse clinical spectrum of manifestations. Brain MRI abnormalities in patients seropositive for anti-aquaporin-4 antibody are common and some may be relatively unique by virtue of localization and configuration. Some seropositive patients present with brain involvement during their first attack and/or continue to relapse in the same location without optic nerve and spinal cord involvement. Thus, characteristics of brain abnormalities in such patients have become of increased interest. In this regard, MRI has an increasingly important role in the differential diagnosis of NMO and its spectrum disorder (NMOSD), particularly from multiple sclerosis. Differentiating these conditions is of prime importance because early initiation of effective immunosuppressive therapy is the key to preventing attack-related disability in NMOSD, whereas some disease-modifying drugs for multiple sclerosis may exacerbate the disease. Therefore, identifying the MRI features suggestive of NMOSD has diagnostic and prognostic implications. We herein review the brain, optic nerve, and spinal cord MRI findings of NMOSD., (© 2015 American Academy of Neurology.)

Cognitive impairment is often reported in pediatric-onset multiple sclerosis (MS). Using serial cognitive data from 35 individuals with pediatric-onset MS, this study examined how age at disease-onset and proxies of cognitive reserve may impact cognitive maturation over the course of childhood and adolescence. Neuropsychological evaluations were conducted at baseline and up to four more assessments. Of the 35 participants, 7 completed only one assessment, 5 completed two assessments, 13 completed three assessments, 10 completed four or more assessments. Growth curve modeling was used to assess longitudinal trajectories on the Trail Making Test-Part B (TMT-B) and the Symbol Digit Modalities (SDMT; oral version) and to examine how age at disease onset, baseline Full Scale IQ, and social status may moderate rate of change on these measures. Mean number of evaluations completed per patient was 2.8. Younger age at disease onset was associated with a greater likelihood of cognitive decline on both the TMT-B (p=.001) and SDMT (p=.005). Baseline IQ and parental social status did not moderate any of the cognitive trajectories. Findings suggest that younger age at disease-onset increases the vulnerability for disrupted performance on measures of information processing, visual scanning, perceptual/motor speed, and working memory. Proxies of cognitive reserve did not protect against the progression of decline on these measures. Young patients with MS should be advised to seek follow-up cognitive evaluation to assess cognitive maturation and to screen for the potential late emergence of cognitive deficits. (JINS, 2014, 20, 1-9).

Tumefactive demyelinating lesions can be difficult to distinguish from tumors. Clinical and magnetic resonance imaging features of children with tumefactive demyelination and supratentorial brain tumors were compared. Patients were identified through a 23-site national demyelinating disease study, and from a single-site neuroradiology database. For inclusion, lesions met at least 1 of 3 criteria: maximal cross-sectional diameter >20 mm, local or global cerebral mass effect, or presence of perilesional edema. Thirty-one children with tumefactive demyelination (5 with solitary lesions) were identified: 27 of 189 (14.3%) from the demyelinating disease study and 4 from the database. Thirty-three children with tumors were identified. Children with tumefactive demyelination were more likely to have an abnormal neurologic examination and polyfocal neurologic deficits compared to children with tumors. Tumefactive demyelination was distinguished from tumor by the presence of multiple lesions, absence of cortical involvement, and decrease in lesion size or detection of new lesions on serial imaging.

Impairments in visuospatial abilities are commonly reported in children and adolescents with multiple sclerosis (MS). Corpus callosum (CC) pathology occurs in patients with MS and may contribute to impairment in visuospatial perception, particularly when interhemispheric information transfer is required. This study used a global-local hierarchical letter paradigm to examine the relationship between interhemispheric information transfer and white matter integrity in the CC assessed using diffusion tensor imaging. Thirteen cognitively preserved pediatric-onset MS patients and 15 age-matched healthy controls were asked to determine whether a target letter E appeared at the attended level of the stimulus. As expected, both groups processed global and local information more slowly under divided than selective attention conditions. The MS group performed similarly to the control group with respect to reaction time and accuracy on selective and divided attention conditions, with one exception. Specifically, the presence of a global target when attending to a local target caused greater response conflict in the MS group than in controls (p = .01). Pooling both the patient and control data, greater response conflict was associated with reduced white matter integrity as indicated by lower fractional anisotropy in the anterior body of the CC (r = -.33, p < .05). Results suggest that reduced white matter integrity in anterior regions of the CC may lead to less efficient inhibition of task-irrelevant global information in the hierarchal processing of visual information.