The diagnostic workup of children with the radiologically isolated syndrome differs by age and by sex.

BACKGROUND: Cerebrospinal fluid (CSF) and spinal MRIs are often obtained in children with the radiologically isolated syndrome (RIS) for diagnosis and prognosis. Factors affecting the frequency and timing of these tests are unknown. OBJECTIVE: To determine whether age or sex were associated with (1) having CSF or spinal MRI obtained or (2) the timing of these tests. METHODS: We analyzed children (≤ 18 y) with RIS enrolled in an international longitudinal study. Index scans met 2010/2017 multiple sclerosis (MS) MRI criteria for dissemination in space (DIS). We used Fisher's exact test and multivariable logistic regression (covariates = age, sex, MRI date, MRI indication, 2005 MRI DIS criteria met, and race). RESULTS: We included 103 children with RIS (67% girls, median age = 14.9 y). Children ≥ 12 y were more likely than children < 12 y to have CSF obtained (58% vs. 21%, adjusted odds ratio [AOR] = 4.9, p = 0.03). Pre-2017, girls were more likely than boys to have CSF obtained (n = 70, 79% vs. 52%, AOR = 4.6, p = 0.01), but not more recently (n = 30, 75% vs. 80%, AOR = 0.2, p = 0.1; p = 0.004 for interaction). Spinal MRIs were obtained sooner in children ≥ 12 y (median 11d vs. 159d, p = 0.03). CONCLUSIONS: Younger children with RIS may be at continued risk for misdiagnosis and misclassification of MS risk. Consensus guidelines are needed.

Quick, Effective Screening Tasks Identify Children With Medical Conditions or Disabilities Needing Physical Literacy Support.

PURPOSE: This study evaluated screening tasks able to identify children with medical conditions or disabilities who may benefit from physical literacy. METHOD: Children completed ≤20 screening tasks during their clinic visit and then the Canadian Assessment of Physical Literacy (2nd edition) at a separate visit. Total Canadian Assessment of Physical Literacy scores <30th percentile were categorized as potentially needing physical literacy support. Receiver operator characteristic curves identified assessment cut points with 80% sensitivity and 40% specificity relative to total physical literacy scores. RESULTS: 223 children (97 girls; 10.1 [2.6] y) participated. Physical activity adequacy, predilection, and physical competence achieved ≥80% sensitivity and ≥40% specificity in both data sets. Adequacy ≤ 6.5 had 86% to 100% sensitivity and 48% to 49% specificity. Daily screen time >4.9 hours combined with Adequacy ≤6.15 had 88% to 10% sensitivity and 53% to 56% specificity. CONCLUSIONS: Activity adequacy, alone or with screen time, most effectively identified children likely to benefit from physical literacy support. Adequacy and screen time questionnaires are suitable for clinical use. Similar results regardless of diagnosis suggest physical competence deficits are not primary determinants of active lifestyles. Research to enhance screening specificity is required.

Does E-learning Facilitate Medical Education in Pediatric Neurology?

BACKGROUND: E-learning has become commonplace in medical education. Incorporation of multimedia, clinical cases, and interactive elements has increased its attractiveness over textbooks. Although there has been an expansion of e-learning in medicine, the feasibility of e-learning in pediatric neurology is unclear. This study evaluates knowledge acquisition and satisfaction using pediatric neurology e-learning compared to conventional learning. METHODS: Residents of Canadian pediatrics, neurology, and pediatric neurology programs and medical students from Queens University, Western University, and the University of Ottawa were invited to participate. Learners were randomly assigned two review papers and two ebrain modules in a four-topic crossover design. Participants completed pre-tests, experience surveys, and post-tests. We calculated the median change in score from pre-test to post-test and constructed a mixed-effects model to determine the effect of variables on post-test scores. RESULTS: In total, 119 individuals participated (53 medical students; 66 residents). Ebrain had a larger positive change than review papers in post-test score from pre-test score for the pediatric stroke learning topic but a smaller positive change for Duchenne muscular dystrophy, childhood absence epilepsy, and acute disseminated encephalomyelitis. Learning topics showed statistical relationship to post-test scores (p = 0.04). Depending on topic, 57-92% (N = 59-66) of respondents favored e-learning over review article learning. CONCLUSIONS: Ebrain users scored higher on post-tests than review paper users. However, the effect is small and it is unclear if it is educationally meaningful. Although the difference in scores may not be substantially different, most learners preferred e-learning. Future projects should focus on improving the quality and efficacy of e-learning modules.

Craniofacial features of POLR3-related leukodystrophy caused by biallelic variants in POLR3A, POLR3B and POLR1C.

BACKGROUND: RNA polymerase III-related or 4H leukodystrophy (POLR3-HLD) is an autosomal recessive hypomyelinating leukodystrophy characterized by neurological dysfunction, hypodontia and hypogonadotropic hypogonadism. The disease is caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C or POLR3K. Craniofacial abnormalities reminiscent of Treacher Collins syndrome have been originally described in patients with POLR3-HLD caused by biallelic pathogenic variants in POLR1C. To date, no published studies have appraised in detail the craniofacial features of patients with POLR3-HLD. In this work, the specific craniofacial characteristics of patients with POLR3-HLD associated with biallelic pathogenic variants in POLR3A, POLR3B and POLR1C are described. METHODS: The craniofacial features of 31 patients with POLR3-HLD were evaluated, and potential genotype-phenotype associations were evaluated. RESULTS: Various craniofacial abnormalities were recognized in this patient cohort, with each individual presenting at least one craniofacial abnormality. The most frequently identified features included a flat midface (61.3%), a smooth philtrum (58.0%) and a pointed chin (51.6%). In patients with POLR3B biallelic variants, a thin upper lip was frequent. Craniofacial anomalies involving the forehead were most commonly associated with biallelic variants in POLR3A and POLR3B while a higher proportion of patients with POLR1C biallelic variants demonstrated bitemporal narrowing. CONCLUSION: Through this study, we demonstrated that craniofacial abnormalities are common in patients with POLR3-HLD. This report describes in detail the dysmorphic features of POLR3-HLD associated with biallelic variants in POLR3A, POLR3B and POLR1C.

Cognitive Behavioral Therapy for Children With Headaches: Will an App Do the Trick?

Participants were enrolled into a pilot randomized-controlled 4-week trial comparing the efficacy and feasibility of app-based cognitive behavioral therapy (CBT) to a stretching program. Headache-related disability and quality of life were assessed using the Pediatric Migraine Disability Scale (PedMIDAS), Kidscree27, and Pediatric Quality of Life Inventory. Multivariable regression analysis were performed to assess the group effects in the presence of adherence and other covariates. Twenty participants completed the study. Adherence was significantly higher in the stretching than in the CBT app group (100% vs 54%, P < .034). When controlling for adherence and baseline scores, the stretching group showed greater reduction in PedMIDAS score (average: 29.2, P < .05) as compared to the CBT app group. However, in terms of the Quality-of-Life Indicators, pre- and postintervention raw scores were not significantly different between groups (P > .05). App-based CBT was not superior to a stretching program in reducing headache-related disability in a select population of pediatric headache patients. Future studies should assess if implementing features to the CBT app, like tailoring to pediatric age groups, would improve outcomes.

Being physically active with epilepsy: Insights from young people and their parents.

INTRODUCTION: Researchers have called for innovative tailored interventions to address specific challenges to physical activity (PA) engagement for young people with epilepsy (YPE). Working with YPE and their parents, this study aimed to identify barriers and facilitators to adoption and maintenance of PA among YPE prior to and during the COVID-19 pandemic. METHODS: Ten YPE (all female) and their 13 caregivers, and five additional caregivers to males (N = 18; 72% mothers), completed virtual focus group sessions prior to and during the COVID-19 pandemic. Trained Child Life specialists asked questions about barriers and facilitators of PA engagement experienced by YWE, which included a specific focus on the impact of epilepsy. RESULTS: Thematic analysis of the data identified both epilepsy-specific and generic themes that impact PA participation among YPE. These included: (i) epilepsy experience/impact and accommodation; (ii) safety precautions; (iii) concern about seizures; (iv) social connections and acceptance; (v) parent and family support; (vi) intrapersonal self-regulation and motivation; (vii) health benefits; and (viii) key factors in common with all youth. CONCLUSION: This study provides valuable insight into diverse social-ecological health factors that impact PA participation among YPE from two key stakeholder perspectives (YPE and their caregivers). By understanding these lived experiences, providers can better tailor individual support for YPE and their families to foster and maintain a healthy active lifestyle.

Temporal Dynamics of MOG Antibodies in Children With Acquired Demyelinating Syndrome.

BACKGROUND AND OBJECTIVE: The spectrum of myelin oligodendrocyte glycoprotein (MOG) antibody-associated disorder (MOGAD) comprises monophasic diseases such as acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), and transverse myelitis and relapsing courses of these presentations. Persistently high MOG antibodies (MOG immunoglobulin G [IgG]) are found in patients with a relapsing disease course. Prognostic factors to determine the clinical course of children with a first MOGAD are still lacking. The objective of the study is to assess the clinical and laboratory prognostic parameters for a risk of relapse and the temporal dynamics of MOG-IgG titers in children with MOGAD in correlation with clinical presentation and disease course. METHODS: In this prospective multicenter hospital-based study, children with a first demyelinating attack and complete data set comprising clinical and radiologic findings, MOG-IgG titer at onset, and clinical and serologic follow-up data were included. Serum samples were analyzed by live cell-based assay, and a titer level of ≥1:160 was classified as MOG-IgG-positive. RESULTS: One hundred sixteen children (f:m = 57:59) with MOGAD were included and initially diagnosed with ADEM (n = 59), unilateral ON (n = 12), bilateral ON (n = 16), myelitis (n = 6), neuromyelitis optica spectrum disorder (n = 8) or encephalitis (n = 6). The median follow-up time was 3 years in monophasic and 5 years in relapsing patients. There was no significant association between disease course and MOG-IgG titers at onset, sex, age at presentation, or clinical phenotype. Seroconversion to MOG-IgG-negative within 2 years of the initial event showed a significant risk reduction for a relapsing disease course. Forty-two/one hundred sixteen patients (monophasic n = 26, relapsing n = 16) had serial MOG-IgG testing in years 1 and 2 after the initial event. In contrast to relapsing patients, monophasic patients showed a significant decrease of MOG-IgG titers during the first and second years, often with seroconversion to negative titers. During the follow-up, MOG-IgG titers were persistently higher in relapsing than in monophasic patients. Decrease in MOG-IgG of ≥3 dilution steps after the first and second years was shown to be associated with a decreased risk of relapses. In our cohort, no patient experienced a relapse after seroconversion to MOG-IgG-negative. DISCUSSION: In this study, patients with declining MOG-IgG titers, particularly those with seroconversion to MOG-IgG-negative, are shown to have a significantly reduced relapse risk.

The Benefit of Multigene Panel Testing for the Diagnosis and Management of the Genetic Epilepsies.

With the increasing use of genetic testing in pediatric epilepsy, it is important to describe the diagnostic outcomes as they relate to clinical care. The goal of this study was to assess the diagnostic yield and impact on patient care of genetic epilepsy panel testing. We conducted a retrospective chart review of patients at the Children's Hospital of Eastern Ontario (CHEO) who had genetic testing between the years of 2013-2020. We identified 227 patients that met criteria for inclusion. The majority of patients had their testing performed as "out-of-province" tests since province-based testing during this period was limited. The diagnostic yield for multi-gene epilepsy panel testing was 17% (39/227) and consistent with the literature. Variants of unknown significance (VUS) were reported in a significant number of undiagnosed individuals (77%; 128/163). A higher diagnostic rate was observed in patients with a younger age of onset of seizures (before one year of age; 32%; 29/90). A genetic diagnosis informed prognosis, recurrence risk counselling and expedited access to resources in all those with a diagnosis. A direct change in clinical management as a result of the molecular diagnosis was evident for 9% (20/227) of patients. The information gathered in this study provides evidence of the clinical benefits of genetic testing in epilepsy and serves as a benchmark for comparison with the current provincial Ontario Epilepsy Genetic Testing Program (OEGTP) that began in 2020.

Current international trends in the treatment of multiple sclerosis in children-Impact of the COVID-19 pandemic.

BACKGROUND: Only recently has the first disease-modifying therapy been approved for children with multiple sclerosis (MS) and practice patterns including substantial off-label use have evolved. Understanding attitudes towards treatment of paediatric MS and whether this has changed due to the ongoing COVID-19 pandemic is vital to guide future therapeutic trials and for developing guidelines that reflect practice. METHODS: We performed an online survey within the International Paediatric Multiple Sclerosis Study Group between July and September 2020. The survey was sent to 130 members from 25 countries and consisted of five sections: demographic data, treatment, disease modifying therapies and COVID-19, outcome and three patient cases. RESULTS: The survey was completed by 66 members (51%), both paediatric neurologists and adult neurologists. Fingolimod and ß-interferons were the most frequently used disease-modifying therapies, especially among paediatric neurologists. Almost a third (31%) of respondents had altered their prescribing practice due to COVID-19, in particular at the beginning of the pandemic. CONCLUSIONS: The survey results indicate a tendency of moving from the traditional escalation therapy starting with injectables towards an early start with newer, highly effective disease modifying therapies. The COVID-19 pandemic only slightly affected prescribing patterns and treatment choices in paediatric MS.

Characterization of physical literacy in children with chronic medical conditions compared with healthy controls: a cross-sectional study.

To determine the physical literacy, defined as the capability for a physically active lifestyle, of children with medical conditions compared with healthy peers, this multicenter cross-sectional study recruited children with medical conditions from cardiology, neurology (including concussion), rheumatology, mental health, respirology, oncology, hematology, and rehabilitation (including cerebral palsy) clinics. Participants aged 8-12 years (N = 130; mean age: 10.0 ± 1.44 years; 44% female) were randomly matched to 3 healthy peers from a normative database, based on age, gender, and month of testing. Total physical literacy was assessed by the Canadian Assessment of Physical Literacy, a validated assessment of physical literacy measuring physical competence, daily behaviour, knowledge/understanding, and motivation/confidence. Total physical literacy mean scores (/100) did not differ (t(498) = -0.67; p = 0.44) between participants (61.0 ± 14.2) and matched healthy peers (62.0 ± 10.7). Children with medical conditions had lower mean physical competence scores (/30; -6.5 [-7.44 to -5.51]; p < 0.001) but higher mean motivation/confidence scores (/30; 2.6 [1.67 to 3.63]; p < 0.001). Mean daily behaviour and knowledge/understanding scores did not differ from matches (/30; 1.8 [0.26 to 3.33]; p = 0.02;/10; -0.04 [-0.38 to 0.30]; p = 0.81; respectively). Children with medical conditions are motivated to be physically active but demonstrate impaired movement skills and fitness, suggesting the need for targeted interventions to improve their physical competence. Novelty: Physical literacy in children with diverse chronic medical conditions is similar to healthy peers. Children with medical conditions have lower physical competence than healthy peers, but higher motivation and confidence. Physical competence (motor skill, fitness) interventions, rather than motivation or education, are needed for these youth.

Pediatric Hyperacute Arterial Ischemic Stroke Pathways at Canadian Tertiary Care Hospitals.

BACKGROUND: Childhood acute arterial ischemic stroke (AIS) is diagnosed at a median of 23 hours post-symptom onset, delaying treatment. Pediatric stroke pathways can expedite diagnosis. Our goal was to understand the similarities and differences between Canadian pediatric stroke protocols with the aim of optimizing AIS management. METHODS: We contacted neurologists at all 16 Canadian pediatric hospitals regarding AIS management. Established protocols were analyzed for similarities and differences in eight domains. RESULTS: Response rate was 100%. Seven (44%) centers have an established AIS protocol and two (13%) have a protocol under development. Seven centers do not have a protocol; two redirect patients to adult neurology, five rely on a case-by-case approach for management. Analysis of the seven protocols revealed differences in: 1) IV-tPA dosage: age-dependent 0.75-0.9 mg/kg (N = 1) versus age-independent 0.9 mg/kg (N = 6), with maximum doses of 75 mg (N = 1) or 90 mg (N = 6); 2) IV-tPA lower age cut-off: 2 years (N = 5) versus 3 or 10 years (each N = 1); 3) IV-tPA exclusion criteria: PedNIHSS score <4 (N = 3), <5 (N = 1), <6 (N = 3); 4) first choice of pre-treatment neuroimaging: computed tomography (CT) (N = 3), magnetic resonance imaging (MRI) (N = 2) or either (N = 2); 5) intra-arterial tPA use (N = 3) and; 6) mechanical thrombectomy timeframe: <6 hour (N = 3), <24 hour (N = 2), unspecified (N = 2). CONCLUSIONS: Although 44% of Canadian pediatric hospitals have established AIS management pathways, several differences remain among centers. Some criteria (dosage, imaging) reflect adult AIS literature. Canadian expert consensus regarding IV-tPA and endovascular treatment should be established to standardize and implement AIS protocols across Canada.

Poor adherence to sleep and physical activity guidelines among children with epilepsy.

OBJECTIVE: To assess physical activity and sleep rates in a cohort of children with epilepsy (CWE) and determine if there is a relationship between physical activity and sleep time. METHODS: Children aged 8-14 years with a diagnosis of epilepsy and at least one seizure in the past 12 months were monitored via a wrist-worn activity tracker for 16 weeks, to objectively measure daily physical activity, as assessed by step counts, and sleep time. Adherence to physical activity (≥12,000 steps/day) and sleep recommendations (≥9 h for children aged 8-12 years, or ≥8 h for children aged 13-15 years) was determined. To predict daily activity or nightly sleep, a series of multivariable models incorporating age, sex, day-type (all combinations of weekday or weekend and summer holiday or school), participant (as a random effect), daily physical activity (for models predicting sleep), nightly sleep (for models predicting physical activity), and autoregressive terms of previous sleep or physical activity were constructed, and the best-performing models were selected with Akaike information criterion analysis. RESULTS: Twenty-two children with mild to moderate epilepsy were recruited (54.5% female, median (IQR) age 11 (10, 13) years) and monitored for 16 weeks. They met the recommended level of physical activity only in 38.0% (21.7%, 59.4%), and sleep in 49.1% (30.0%, 68.5%) of days. They met both physical activity and sleep guidelines on the same day in only 17.8% (95% CI 7.1%, 38.0%). There was no association between meeting the recommended levels of daily physical activity and sleep time (p = 0.86, ρ = 0.03). In the best-performing model, age, sex, day type, and participant explained 28.9% of the variance in daily physical activity, with no additional insight provided by measures of sleep time. Age, sex, day type, participant, and daily physical activity explained 17.3% of the variance in nightly sleep time, with a statistically discernable but small association between physical activity and sleep time (1.79 ±â€¯0.53, p = 0.001). CONCLUSION: Our cohort of children with mild to moderate epilepsy showed poor adherence to sleep and physical activity guidelines. There was no clinically relevant association between daily physical activity and sleep among these children who were similarly active to healthy peers. Future studies should assess the effect of increased sleep hygiene and physical activity on overall well-being and seizure control in CWE.

Continuous EEG in a Pediatric Intensive Care Unit: Adherence to Monitoring Criteria and Barriers to Adequate Implementation.

BACKGROUND: Subclinical seizures are common in critically ill children and are best detected by continuous EEG (cEEG) monitoring. Timely detection of seizures requires pediatric intensive care unit (PICU) physicians to identify patients at risk of seizures and request cEEG monitoring. A recent consensus statement from the American Clinical Neurophysiology Society (ACNS) outlines the indications for cEEG monitoring in critically ill patients. However, adherence to these cEEG monitoring criteria among PICU physicians is unknown. Our project had two goals: 1. To assess adherence to cEEG monitoring indications and barriers toward their implementation; 2. To improve compliance with the ACNS cEEG monitoring criteria in our PICU. METHODS: This is a single-institution study. A total of 234 PICU admissions (183 unique patients) were studied. A 6-month retrospective chart review identified PICU patients meeting ACNS criteria for cEEG monitoring, and patients for whom monitoring was requested. This was followed by an 8-week quality improvement project. During this mentorship period, a didactic 15-min lecture and summary handouts regarding the ACNS indications for cEEG monitoring were provided to all PICU physicians. Requests for cEEG monitoring during the mentorship period were compared to baseline adherence to cEEG monitoring recommendations, and barriers toward timely cEEG monitoring were assessed. RESULTS: Nearly every fifth PICU patient met cEEG monitoring indications, and prevalences of patients meeting those indications were similar in the retrospective and the prospective mentorship period (18% vs. 19%). Almost all patients (98%) requiring cEEG as per ACNS criteria met the indication for monitoring already at the time of their PICU admission. During the retrospective period, 23% of patients meeting ACNS criteria had a request for cEEG monitoring, which increased to 83% during the mentorship period. The median delay to cEEG initiation was 16.7 h during the mentorship period, largely due to limited hours of EEG technician availability. Electrographic seizures were identified in 36% of patients monitored, all within the first 120 min of cEEG recording. The majority (79%) of cEEGs informed clinical management. CONCLUSIONS: A brief teaching intervention supplemented by pictographic handouts significantly increased adherence to cEEG monitoring recommendations, and cEEGs guided clinical management. However, there were long delays to cEEG initiation. In order to promptly recognize subclinical seizures in critically ill children, we strongly advocate for a routine screening for cEEG monitoring indications as part of the PICU admission process, and a care model allowing for cEEG initiation around-the-clock.

Endocrine and Growth Abnormalities in 4H Leukodystrophy Caused by Variants in POLR3A, POLR3B, and POLR1C.

CONTEXT: 4H or POLR3-related leukodystrophy is an autosomal recessive disorder typically characterized by hypomyelination, hypodontia, and hypogonadotropic hypogonadism, caused by biallelic pathogenic variants in POLR3A, POLR3B, POLR1C, and POLR3K. The endocrine and growth abnormalities associated with this disorder have not been thoroughly investigated to date. OBJECTIVE: To systematically characterize endocrine abnormalities of patients with 4H leukodystrophy. DESIGN: An international cross-sectional study was performed on 150 patients with genetically confirmed 4H leukodystrophy between 2015 and 2016. Endocrine and growth abnormalities were evaluated, and neurological and other non-neurological features were reviewed. Potential genotype/phenotype associations were also investigated. SETTING: This was a multicenter retrospective study using information collected from 3 predominant centers. PATIENTS: A total of 150 patients with 4H leukodystrophy and pathogenic variants in POLR3A, POLR3B, or POLR1C were included. MAIN OUTCOME MEASURES: Variables used to evaluate endocrine and growth abnormalities included pubertal history, hormone levels (estradiol, testosterone, stimulated LH and FSH, stimulated GH, IGF-I, prolactin, ACTH, cortisol, TSH, and T4), and height and head circumference charts. RESULTS: The most common endocrine abnormalities were delayed puberty (57/74; 77% overall, 64% in males, 89% in females) and short stature (57/93; 61%), when evaluated according to physician assessment. Abnormal thyroid function was reported in 22% (13/59) of patients. CONCLUSIONS: Our results confirm pubertal abnormalities and short stature are the most common endocrine features seen in 4H leukodystrophy. However, we noted that endocrine abnormalities are typically underinvestigated in this patient population. A prospective study is required to formulate evidence-based recommendations for management of the endocrine manifestations of this disorder.