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Multisystem inflammatory syndrome in children (MIS-C) (1) manifests as immune dysregulation after SARS-CoV-2 infection. (2) The syndrome has no pathognomonic features. Thus, the diagnostic criteria of the Royal College of [...], Background: SARS-CoV-2 infection can lead to multisystem inflammatory syndrome in children (MIS-C). We sought to investigate risk factors for admission to the intensive care unit (ICU) and explored changes in disease severity over time. Methods: We obtained data from chart reviews of children younger than 18 years with confirmed or probable MIS-C who were admitted to 15 hospitals in Canada, Iran and Costa Rica between Mar. 1, 2020, and Mar. 7, 2021. Using multivariable analyses, we evaluated whether admission date and other characteristics were associated with ICU admission or cardiac involvement. Results: Of 232 children with MIS-C (median age 5.8 yr), 130 (56.0%) were male and 50 (21.6%) had comorbidities. Seventy-three (31.5%) patients were admitted to the ICU but none died. We observed an increased risk of ICU admission among children aged 13-17 years (adjusted risk difference 27.7%, 95% confidence interval [CI] 8.3% to 47.2%), those aged 6-12 years (adjusted risk difference 25.2%, 95% CI 13.6% to 36.9%) or those with initial ferritin levels greater than 500 [micro]g/L (adjusted risk difference 18.4%, 95% CI 5.6% to 31.3%). Children admitted to hospital after Oct. 31, 2020, had numerically higher rates of ICU admission (adjusted risk difference 12.3%, 95% CI -0.3% to 25.0%) and significantly higher rates of cardiac involvement (adjusted risk difference 30.9%, 95% CI 17.3% to 44.4%). At Canadian sites, the risk of ICU admission was significantly higher for children admitted to hospital between December 2020 and March 2021 than those admitted between March and May 2020 (adjusted risk difference 25.3%, 95% CI 6.5% to 44.0%). Interpretation: We observed that age and higher ferritin levels were associated with more severe MIS-C. We observed greater severity of MIS-C later in the study period. Whether emerging SARS-CoV-2 variants pose different risks of severe MIS-C needs to be determined.

ABSTRACT:Background and Objectives:Neurological involvement associated with SARS-CoV-2 infection is increasingly recognized. However, the specific characteristics and prevalence in pediatric patients remain unclear. The objective of this study was to describe the neurological involvement in a multinational cohort of hospitalized pediatric patients with SARS-CoV-2.Methods:This was a multicenter observational study of children <18 years of age with confirmed SARS-CoV-2 infection or multisystemic inflammatory syndrome (MIS-C) and laboratory evidence of SARS-CoV-2 infection in children, admitted to 15 tertiary hospitals/healthcare centers in Canada, Costa Rica, and Iran February 2020–May 2021. Descriptive statistical analyses were performed and logistic regression was used to identify factors associated with neurological involvement.Results:One-hundred forty-seven (21%) of 697 hospitalized children with SARS-CoV-2 infection had neurological signs/symptoms. Headache (n= 103), encephalopathy (n= 28), and seizures (n= 30) were the most reported. Neurological signs/symptoms were significantly associated with ICU admission (OR: 1.71, 95% CI: 1.15–2.55; p= 0.008), satisfaction of MIS-C criteria (OR: 3.71, 95% CI: 2.46–5.59; p< 0.001), fever during hospitalization (OR: 2.15, 95% CI: 1.46–3.15; p< 0.001), and gastrointestinal involvement (OR: 2.31, 95% CI: 1.58–3.40; p< 0.001). Non-headache neurological manifestations were significantly associated with ICU admission (OR: 1.92, 95% CI: 1.08–3.42; p= 0.026), underlying neurological disorders (OR: 2.98, 95% CI: 1.49–5.97, p= 0.002), and a history of fever prior to hospital admission (OR: 2.76, 95% CI: 1.58–4.82; p< 0.001).Discussion:In this study, approximately 21% of hospitalized children with SARS-CoV-2 infection had neurological signs/symptoms. Future studies should focus on pathogenesis and long-term outcomes in these children.

•Larger social network size, and more individuals with post-secondary education and who regularly exercise in the social network associates with higher physical activity in children with multiple sclerosis.•More emotional support and camaraderie associates with higher physical activity in children with multiple sclerosis.•Social network characteristics may help understand physical activity behavior in children with multiple sclerosis.

•Individuals with PoMS had lower dietary whole grain intake than controls.•Higher WG intakes were associated with lower odds of being MOG+ve versus MOG-ve.•This warrants further investigation to ascertain the direction of this effect.

1 Acute flaccid myelitis is a clinical syndrome characterized by rapid onset of muscle weaknessFrom January to November 2018, there were 90 confirmed cases of acute flaccid myelitis in the [...]

Acute flaccid myelitis (AFM) is a disabling, polio-like illness mainly affecting children. Outbreaks of AFM have occurred across multiple global regions since 2012, and the disease appears to be caused by non-polio enterovirus infection, posing a major public health challenge. The clinical presentation of flaccid and often profound muscle weakness (which can invoke respiratory failure and other critical complications) can mimic several other acute neurological illnesses. There is no single sensitive and specific test for AFM, and the diagnosis relies on identification of several important clinical, neuroimaging, and cerebrospinal fluid characteristics. Following the acute phase of AFM, patients typically have substantial residual disability and unique long-term rehabilitation needs. In this Review we describe the epidemiology, clinical features, course, and outcomes of AFM to help to guide diagnosis, management, and rehabilitation. Future research directions include further studies evaluating host and pathogen factors, including investigations into genetic, viral, and immunological features of affected patients, host–virus interactions, and investigations of targeted therapeutic approaches to improve the long-term outcomes in this population.

Abstract:The Canadian Multiple Sclerosis Working Group has updated its treatment optimization recommendations (TORs) on the optimal use of disease-modifying therapies for patients with all forms of multiple sclerosis (MS). Recommendations provide guidance on initiating effective treatment early in the course of disease, monitoring response to therapy, and modifying or switching therapies to optimize disease control. The current TORs also address the treatment of pediatric MS, progressive MS and the identification and treatment of aggressive forms of the disease. Newer therapies offer improved efficacy, but also have potential safety concerns that must be adequately balanced, notably when treatment sequencing is considered. There are added discussions regarding the management of pregnancy, the future potential of biomarkers and consideration as to when it may be prudent to stop therapy. These TORs are meant to be used and interpreted by all neurologists with a special interest in the management of MS.

Treatment options in multiple sclerosis (MS) have expanded tremendously, with 23 disease-modifying therapies (DMT) approved in the United States since 1993. Along with the increasing number of approved MS DMTs, refinements to diagnostic criteria and recognition of the benefits of early treatment have led clinicians to diagnose and treat patients when they have a first demyelinating episode. Furthermore, treatment approaches have shifted to the use of more powerful, highly efficacious agents, including monoclonal antibodies (mAbs), at onset.1The newer therapies, such as natalizumab, alemtuzumab, and the anti-B-cell mAb ocrelizumab, have made “no evidence of disease activity” a realistic therapeutic target, delayed the onset of progressive disease, and led to improved quality of life of individuals with MS. Yet these agents are a double-edged sword: with higher efficacy comes potential risks, particularly with long-term use of these therapies.2

IMPORTANCE: Identifying the course of demyelinating disease associated with myelin oligodendrocyte glycoprotein (MOG) autoantibodies is critical to guide appropriate treatment choices. OBJECTIVE: To characterize serial anti-MOG antibody serologies and clinical and imaging features at presentation and during follow-up in an inception cohort of prospectively monitored children with acquired demyelination. DESIGN, SETTING, AND PARTICIPANTS: In this prospective cohort study, study participants were recruited from July 2004 to February 2017 through the multicenter Canadian Pediatric Demyelinating Disease Study. Inclusion criteria included (1) incident central nervous system demyelination, (2) at least 1 serum sample obtained within 45 days from onset, and (3) complete clinical information. Of 430 participants with acquired demyelinating syndrome recruited, 274 were included in analyses. Of 156 excluded participants, 154 were excluded owing to missing baseline samples and 2 owing to incomplete clinical information. Data were analyzed from May to October 2018. MAIN OUTCOMES AND MEASURES: Presence of anti-MOG antibodies was blindly assessed in serial samples collected over a median of 4 years. Clinical, magnetic resonance imaging, and cerebrospinal fluid features were characterized at presentation, and subsequent disease course was assessed by development of new brain magnetic resonance imaging lesions, total lesion volume at last evaluation, annualized relapse rates, Expanded Disability Status Scale score and visual functional score at 4 years, and any disease-modifying treatment exposure. RESULTS: Of the 274 included participants, 140 (51.1%) were female, and the median (interquartile range) age of all participants was 10.8 (6.2-13.9) years. One-third of children were positive for anti-MOG antibodies at the time of incident demyelination. Clinical presentations included a combination of optic neuritis, transverse myelitis, and acute disseminated encephalomyelitis for 81 of 84 anti-MOG antibody–positive children (96%). Brain lesions were present in 51 of 76 anti-MOG antibody–positive participants (67%), but magnetic resonance imaging characteristics differed with age at presentation. Complete resolution of baseline lesions was observed in 26 of 49 anti-MOG antibody–positive participants (53%). On serial serum analysis, 38 of 67 participants (57%) who were seropositive at onset became seronegative (median time to conversion, 1 year). Among all participants who were positive for anti-MOG antibodies at presentation, clinical relapses occurred in 9 of 24 children (38%) who remained persistently seropositive and in 5 of 38 children (13%) who converted to seronegative status. CONCLUSIONS AND RELEVANCE: Myelin oligodendrocyte glycoprotein antibodies are common in children with acquired demyelinating syndrome and are transient in approximatively half of cases. Even when persistently positive, most anti-MOG antibody–positive children experience a monophasic disease. The presence of anti-MOG antibodies at the time of incident demyelination should not immediately prompt the initiation of long-term immunomodulatory therapy.

Since first defined in 1998, paediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) and its later, broader iteration, paediatric acute-onset neuropsychiatric syndrome (PANS), have garnered significant attention and controversy. The role of streptococcal infection in children with explosive onset obsessive-compulsive disorder and new onset tics, the natural history of this entity, and the role of symptomatic and disease-modifying therapies, including antibiotics, immunotherapy, and psychoactive drugs, are all issues that have yet to be definitively addressed. While definitive proof of the autoimmune hypothesis of PANDAS is lacking, given the heightened attention to this entity and apparent rise in use of this diagnostic category, addressing questions around diagnosis, treatment, and etiology is imperative. In this paper, we review current working definitions of PANDAS/PANS, discuss published evidence for interventions related to this entity, and propose a clinical approach to children presenting with acute symptoms satisfying criteria for PANDAS/PANS.

•Incidental MRI lesions consistent with demyelination occur, but are rare in children.•A high rate of later clinical events may occur in children with RIS.•Risk of clinical events is higher in children classified with RIS who have spinal cord lesions or oligoclonal bands in the CSF.•The role of disease modifying therapy in RIS remains to be studied.

AbstractBackground:Medical school and residency training in ophthalmoscopic evaluation is limited, reducing diagnostic accuracy. We sought to evaluate the efficacy of self-study using an ophthalmoscopy simulator to improve the technical motor skills involved in direct funduscopy in postgraduate pediatric residents. Methods:In this randomized-controlled study, 17 pediatric residents (postgraduate years 1-3) were randomized to control (n=8) or intervention (n=9) groups. Participants were asked to correctly identify the funduscopic findings presented to them on an ophthalmoscopy simulator after being trained on its use. Each participant was asked to review 20 images of the fundus, and then record their multiple-choice response on a scantron sheet listing all possible funduscopic pathologies. Pre- and post-intervention testing was performed. Survey data assessing exposure to funduscopy skills during undergraduate and postgraduate training and overall experience with the simulator were collected. Results:Most (65% [11/17]) participants reported minimal or no formal teaching in ophthalmology during their undergraduate medical studies. Average pre-intervention score (of 20) was 10.24±1.75 (51%) for the entire group, with no statistically significant difference between average pre-score in the control (10.63±1.77) versus intervention (9.89±1.76, p=0.405) groups. Intervention subjects experienced a statistically significant improvement in scores (9.89±1.76 vs. 12.78±2.05, p=0.006 [95% confidence interval 4.80-0.98]), but control subjects did not. Conclusions:A single session with an ophthalmoscopy simulator can improve diagnostic accuracy in postgraduate pediatric trainees. Use of ophthalmoscopy simulation represents a novel addition to traditional learning methods for postgraduate pediatric residents that can help trainees to improve their confidence and accuracy in performing this challenging examination.

MRI and laboratory features have been incorporated into international diagnostic criteria for multiple sclerosis. We assessed the pattern of MRI lesions and contributions of cerebrospinal fluid (CSF) and serum antibody findings that best identifies children with multiple sclerosis, and the applicability of international diagnostic criteria in the paediatric context.

•Oculomotor metrics relate to structure, vision, and cognition in demyelination.•Number of optic neuritis episodes affects saccade and pupil response latencies.•Presaccadic pupil responses are delayed in demyelinating disorders.

•Larger social network size is associated with lower anxiety in youth with recurrent neuroinflammatory disorders.•Youth with recurrent neuroinflammatory disorders who meet screening thresholds for anxiety disorder have smaller network sizes compared to those who do not.•Social network size has the potential to shape mental health outcomes in youth with neuroinflammatory disorders.

Ethical concerns have been raised about the practice of using teriflunomide, an oral licensed disease-modifying therapy, as an active comparator in phase 3 multiple sclerosis (MS) trials. The assumption is based on the perceived low efficacy of teriflunomide as judged by its effect on relapses and focal MRI activity. However, when you look beyond focal inflammation, teriflunomide has a robust impact on disability progression and a similar effect to the anti-CD20 monoclonal antibody therapies on slowing down the accelerated brain volume loss associated with MS. Teriflunomide is also more effective when used second or third line. The other classes of disease-modifying therapies have problems with their use as active comparators in clinical trials. Using a non-inferiority or equivalence trial design has its own unique set of regulatory and ethical challenges and is not necessarily a solution. There are also economic, altruistic and pragmatic reasons for continuing to use teriflunomide as an active comparator in MS clinical trials. An online survey indicates that the majority of the MS community feels it is still ethical to randomise subjects to teriflunomide and that procedures can be put in place to protect trial subjects randomised to teriflunomide. Therefore, we still have equipoise, and teriflunomide comparator trials are ethical.

Resilience; Progressive multiple sclerosis; Genomics

Hyperphosphorylation of signal transducer and activator of transcription 3 (STAT3) has been found in various types of human cancers, including head and neck cancer (HNC). Although smoking is critical in the development and progression of HNC, how tobacco components activate STAT3 is unclear. We demonstrated that exposure of HNC cell lines to a tobacco extract induced a rapid Y705 phosphorylation of STAT3 and a rapid increase in the SUMO protease SENP3 that depended on a simultaneous increase in reactive oxygen species. We identified that SUMOylation at the lysine 451 site facilitated STAT3 binding to the phosphatase TC45 through an SUMO-interacting motif of TC45. SENP3 could thus enhance STAT3 phosphorylation by de-conjugating the SUMO2/3 modification of STAT3. Knocking-down of SENP3 greatly impaired basal and induced STAT3 phosphorylation by tobacco extract or interleukin 6. A correlation between SENP3 protein levels and STAT3 Y705 phosphorylation levels in human laryngeal carcinoma specimens was found, which was more significant in the specimens derived from the smoker patients and with poor clinicopathological parameters. Our data identified SUMOylation as a previously undescribed post-translational modification of STAT3 and SENP3 as a critical positive modulator of tobacco- or cytokine-induced STAT3 activation. These findings provide novel insights into the hyperphosphorylation of STAT3 in development of HNC.

Knowledge regarding physical activity (PA) and its benefits in pediatric onset multiple sclerosis (POMS) is growing and suggests high levels of inactivity. The utility of a validated screening tool for clinical settings is unknown. This study evaluated the Godin Leisure-Time Exercise Questionnaire (GLTEQ) as a measure of PA in POMS.

The clinical and MRI presentation differs between earlier- and later-onset pediatric multiple sclerosis (MS), whereas the effect of age on the CSF inflammatory profile is unknown and may contribute to delayed diagnosis.

Importance of the field:Pediatric multiple sclerosis is an acquired inflammatory, demyelinating CNS disorder associated with recurrent episodes of neurologic dysfunction. Precise diagnosis is increasingly important as disease modifying therapies have been developed in adults and introduced into pediatric practice.Areas covered in this review:Literature published over the past two decades relating to pharmacologic treatment of multiple sclerosis (MS) in adults and children is reviewed, with emphasis on current publications.What the reader will gain:This article reviews available research and clinical experience regarding treatment of acute episodes of CNS demyelination in children and adolescents, strategies for introduction and modification of disease-modifying therapies depending on disease course, and use of medication for symptomatic improvement in quality of life.Take home message:Pharmacotherapy for MS has been studied in adults but to a significantly lesser extent in children or adolescents. However, children and adolescents have different biology than adults in terms of drug metabolism, immune mechanisms and incomplete maturity of CNS myelin. Effectiveness as well as long-term safety needs to be studied in children and adolescents.

Pediatric multiple sclerosis (MS) accounts for up to 5% of all MS cases. Work conducted over the past 5 years has provided new information about the treatment, pathogenesis, demographics, and natural history of this disorder. Genetic and environmental factors seem to exert critical influences on its development. Clinical, MRI and laboratory data from prepubertal and postpubertal children suggest differences between the immune response and/or CNS environment in younger compared with older children and adults with MS. Randomized, controlled treatment trials for pediatric MS have not yet been performed, but therapies used in adult MS have been evaluated in this population, and their use seems to be safe. This article provides a comprehensive review of current knowledge regarding pediatric MS, highlighting new advances in the field.

•Cognitive outcomes of relapsing MOGAD, POMS, and controls were compared.•Relapsing MOGAD participants showed deficits in reasoning relative to HCs.•Relapsing MOGAD and POMS groups performed more slowly overall relative to HCs.•EF and overall PCNB score were significantly lower in POMS compared to relapsing MOGAD.•Cognitive deficits in relapsing MOGAD are milder relative to POMS.

To meet the demands of developing lead drugs for the profusion of human genes being sequenced as part of the human genome project, we developed a high-throughput assay construction method in yeast. A set of optimized techniques allows us to rapidly transfer large numbers of heterologous cDNAs from nonyeast plasmids into yeast expression vectors. These high- or low-copy yeast expression plasmids are then converted quickly into integration-competent vectors for phenotypic profiling of the heterologous gene products. The process was validated first by testing proteins of diverse function, such as p38, poly(ADP-ribose) polymerase-1, and PI 3-kinase, by making active-site mutations and using existing small molecule inhibitors of these proteins. For less well-characterized genes, a novel random mutagenesis scheme was developed that allows a combination selection/screen for mutations that retain full-length expression and yet reverse a growth phenotype in yeast. A broad range of proteins in different functional classes has been profiled, with an average yield for growth interference phenotypes of approximately 30%. The ease of manipulation of the yeast genome affords us the opportunity to approach drug discovery and exploratory biology on a genomic scale and shortens assay development time significantly.