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.

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.

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.

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.

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.

No improvement in quality of life in children with epilepsy treated with the low glycemic index diet.

BACKGROUND: Up to 30% of children with epilepsy show a poor therapeutic response to pharmacologic treatment. Ketogenic diets, including the less strict low glycemic index treatment (LGIT), may improve seizure control in pharmacoresistant epilepsy. However, little is known about the quality of life (QoL) in children on LGIT. To explore psychosocial implications of the LGIT on pediatric patients and their caregivers, we have conducted a pilot study to explore the QoL of children and adolescents on the diet. METHODS: Pediatric patients on LGIT and their parents completed standardized, validated QoL questionnaires (Pediatric Quality of Life Epilepsy Module), one retrospectively and one while being on LGIT. An additional questionnaire included two open-ended questions in order to gain a better understanding of personal experiences of families. RESULTS: We enrolled six patients with epilepsy on LGIT between the age of 3 and 13 years. Self-reported QoL decreased in all adolescents, regardless of improvement in seizure control. Parent-reported QoL improved in three of six participants, remained stable in one, and decreased in two patients (both displayed no seizure improvement). Parents and adolescents reported positive experiences of trying new foods and being more health conscious, as well as negative themes such as social isolation and meal preparation difficulties. CONCLUSIONS: The lack of improvement in patient-reported QoL points towards an overall negative impact of the LGIT on patient well-being, despite positive effects on seizure control. Our preliminary results indicate that the benefits of seizure control may subjectively be outweighed by adverse social effects of the LGIT. Families should be made aware of psychosocial risks of the diet. Whenever possible, children should be part of the therapeutic decision-making process. Larger prospective studies are required to fully assess the overall impact of the LGIT.

Physically active children with epilepsy have good objective sleep duration and efficiency despite subjective reports of fatigue and sleep problems.

OBJECTIVE: The aim of this study was to longitudinally characterize in children with epilepsy the objective and subjective sleep quality and the relationship between increased physical activity and sleep as well as measures of psychosocial well-being. METHODS: Baseline physical activity and sleep were established in children with epilepsy over four weeks, prior to a 12-week exercise intervention (weekly meeting with exercise counselor). Participants continuously wore a wrist pedometer (Fitbit Flex®) to capture daily number of steps, sleep efficiency, and total sleep time. The Early Childhood Epilepsy Severity Scale (E-Chess) assessed baseline epilepsy severity. Subjective sleep quality (Children's Sleep Habits Questionnaire, CSHQ), quality of life (KIDSCREEN-27; Pediatric Quality of Life Inventory, PedsQL™, 4.0 Core), fatigue (PedsQL™ Multidimensional Fatigue Scale), depression (Children's Depression Inventory-Short), and anxiety (Multidimensional Anxiety Scale for Children) were assessed pre- and post-interventions. RESULTS: Our cohort of 22 children with epilepsy aged 8-14 years was similarly active to peers (11,271 ±â€¯3189 mean steps per day) and displayed normal sleeping patterns (mean sleep efficiency: 87.4% ±â€¯3.08 and mean total sleep time: 521 ±â€¯30.4). Epilepsy severity assessed by E-Chess was low to moderate (median baseline E-Chess score of 6, interquartile range: 5-7). Study outcomes did not change with the intervention. Older children and those with lower baseline activity were more likely to increase their activity during the intervention. Changes in physical activity were not associated with changes in sleep outcomes when accounting for age, sex, and baseline E-Chess score. Subjective sleep quality marginally improved with the intervention (CSHQ total score: 44.5 ±â€¯5.8 at baseline and 41.6 ±â€¯7.2 at the end of study, p = 0.05). Quality of life, fatigue, depression, and anxiety did not change with the intervention (p = 0.55, 0.60, 0.12, and 0.69, respectively). SIGNIFICANCE: Children with epilepsy who are as active as peers without epilepsy have good objective measures of sleep despite self-reported fatigue and parent-reported sleep problems. The physical activity of initially less active and older children with epilepsy may benefit from an exercise counseling intervention.

Cannabis Treatment in Children with Epilepsy: Practices of Canadian Neurologists.

BACKGROUND: Medical cannabis has recently emerged as a treatment option for children with drug-resistant epilepsy. Despite the fact that many pediatric epilepsy patients across Canada are currently being treated with cannabis, little is known about the attitudes of neurologists toward cannabinoid treatment of children with epilepsy. METHODS: A 21-item online survey was distributed via email to 148 pediatric neurologists working in hospitals and community clinics across Canada. Questions were related to clinical practice and demographics. RESULTS: This survey achieved a response rate of 38% (56 Canadian neurologists). These neurologists were treating 668 pediatric epilepsy patients with cannabinoids. While 29% of neurologists did not support cannabis treatment in their patients, 34% prescribed cannabis, and 38% referred to another authorizing physician, mostly to community-based non-neurologists. The majority of neurologists considered cannabis for patients with Dravet syndrome (68%) and Lennox-Gastaut syndrome (64%) after an average of three failed anticonvulsants. Twenty-seven percent considered it for patients with idiopathic generalized epilepsy, and 18% for focal epilepsy. No neurologist used cannabis as a first-line treatment. All neurologists had at least one hesitation regarding cannabis treatment in pediatric epilepsy. The most common one was poor evidence (66%), followed by poor quality control (52%) and high cost (50%). CONCLUSIONS: The majority of Canadian pediatric neurologists consider using cannabis as a treatment for epilepsy in children. With many gaps in evidence and high patient-driven demand for cannabis therapy, this survey provides immediate information from the "wisdom of the crowd," to aid neurologists until further evidence is available.

Higher screen time, lower muscular endurance, and decreased agility limit the physical literacy of children with epilepsy.

OBJECTIVE: The objective of this study was to determine the physical literacy (the motivation, confidence, physical competence, and knowledge contributing to the capacity for physical activity) of children with epilepsy, as compared with that of their healthy peers. METHODS: Patients age 8-12 years with epilepsy, without any disabilities interfering with their ability to answer questionnaires and perform vigorous physical activity, were recruited from the Neurology Clinic at the time of visits. They completed the Canadian Assessment of Physical Literacy (CAPL), a comprehensive battery of tests reflecting the primary domains of physical literacy (motivation/confidence, physical competence, knowledge/understanding, and daily behavior). Daily behavior was assessed by pedometer step counts, as well as self-reported moderate-to-vigorous physical activity and screen time. Physical competence included agility and movement skill measures as well as physical fitness. Children with epilepsy were matched with healthy peers from a large research database of over 6000 Canadian children. RESULTS: We tested 35 children with epilepsy, divided into those with presumed self-limiting forms of epilepsy (49%) and those with chronic disease (51%). Only a small proportion of participants (23%) were taking more than one antiepileptic medication, and only one patient was taking three anticonvulsants. Children with epilepsy including those with self-limiting forms had significantly lower total physical literacy scores, lower agility and movement skills, and lower muscular endurance, and reported more screen time than their healthy peers. Only 11% of the children with epilepsy achieved the recommended level of physical literacy. However, the children with epilepsy were knowledgeable about and highly motivated to participate in a physically active lifestyle. CONCLUSIONS: Children with epilepsy demonstrate poor physical literacy levels, with potential immediate and long-lasting negative impacts on general health and psychosocial well-being. Programs promoting physical literacy in children with epilepsy should be encouraged, specifically interventions decreasing screen time and enhancing muscular endurance and motor skills, thereby facilitating healthier lifestyles.

Can behavioral strategies increase physical activity and influence depressive symptoms and quality of life among children with epilepsy? Results of a randomized controlled trial.

PURPOSE: This study examined whether increasing physical activity (PA) through 6 months of behavioral counseling positively influenced depressive symptoms and quality of life (QoL) over 12 months among children with epilepsy (CWE). METHODS: A longitudinal multisite randomized controlled trial (RCT) was conducted with 8-14-year-old children with active epilepsy. Participants wore a pedometer to track daily PA and completed 3 measures at 4 time points to examine depressive symptoms and QoL. Stratified by site and activity level, participants were randomized to an intervention or control group. The 6-month intervention included 11 behavioral counseling sessions targeting self-regulation of PA. To assess the associations among PA, depression scores, and QoL, primary analysis involved mixed-effects models. RESULTS: We recruited 122 CWE, of whom 115 were randomized (Mage = 11 ±â€¯2; 50% female) and included in the analysis. The intervention did not increase PA in the treatment compared with the control group. No differences were found between groups over time during the subsequent 6 months, where PA decreased among all participants. Results did not show differences between the groups and over time for measures of depressive symptoms and QoL. SIGNIFICANCE: The intervention did not improve or sustain PA levels over 12 months. Both groups demonstrated declines in PA over one year, but there were no changes in depression scores or QoL. As most participants were already nearly reaching the Canadian average of step counts of children their age, with a baseline daily step count of over 9000, there may be a challenge for further increasing PA over a longer period.

Continuous Electroencephalography Monitoring for Critically Ill Neonates: A Canadian Perspective.

BACKGROUND: Continuous EEG monitoring, in the form of amplitude-integrated (aEEG) or conventional EEG (cEEG), is used in the neonatal intensive care unit (NICU) to detect subclinical central nervous system pathologies, inform management, and prognosticate neurodevelopmental outcomes. To learn more about provider attitudes and current practices in Canada, we evaluated neurologist and neonatologist opinions regarding NICU EEG monitoring. METHODS: A 15-item electronic questionnaire was distributed to 114 pediatric neurologists and 176 neonatologists working across 25 sites. RESULTS: The survey was completed by 87 of 290 physicians. Continuous EEG monitoring is utilized by 97% of pediatric neurologists and 92% of neonatologists. Neurologists and neonatologists differ in their EEG monitoring preferences. For seizure detection and diagnosis of encephalopathy, significantly more neonatologists favor aEEG alone or in combination with cEEG, whereas most neurologists prefer cEEG (p = 0.047, 0.001). There is a significant difference in the perceived gaps in monitoring patients with cEEG between neonatologists (13% would monitor more) and neurologists (41% would monitor more) (p = 0.007). Half of all respondents (53%) reported that they would be interested in attending an education session on neonatal EEG monitoring. CONCLUSIONS: Canadian neurologists and neonatologists do not agree on the best monitoring approach for critically ill neonates. Furthermore, neonatologists perceive a smaller cEEG monitoring gap as compared with neurologists. However, many participants from both specialties would like to increase long-term EEG monitoring in the NICU setting. Facilitating access to EEG monitoring and enhancing education may help to address these needs.

La surveillance continue par électroencéphalographie dans le cas de nouveau-nés gravement malades : une perspective canadienne. Contexte: La surveillance continue par électroencéphalographie (EEG), que ce soit à amplitude intégrée (EEGai) ou conventionnelle (EEGc), est utilisée dans les unités de soins intensifs néonatals (USIN) afin de détecter des pathologies sous-cliniques du système nerveux central, de fournir des indications en matière de prise en charge et d'établir des pronostics quant à l'évolution neuro-développementale de ces nouveau-nés. Afin d'en savoir plus au sujet des attitudes des prestataires de soins et des pratiques actuelles dans ce domaine au Canada, nous avons cherché à évaluer les points de vue de neurologues et de néonatologistes en ce qui regarde la surveillance continue par EEG dans les USIN. Méthodes: Un questionnaire en ligne abordant 15 aspects a été envoyé à 114 neuro-pédiatres et à 176 néonatologistes travaillant dans 25 établissements différents. Résultats: Ce sondage a été complété par 87 médecins sur 290. Il en ressort que la surveillance continue par EEG est utilisée par 97 % des neuro-pédiatres et par 92 % des néonatologistes. Cela dit, les neuro-pédiatres et les néonatologistes n'ont pas les mêmes préférences quant à l'utilisation de cet examen. Quand il s'agit de détecter des crises convulsives et de diagnostiquer des cas d'encéphalopathie, on remarque qu'un nombre nettement plus élevé de néonatologistes favorisent la seule EEGai ou la combinent avec la EEGc tandis que davantage de neurologues ont dit préférer la seule EEGc (p = 0,047 ; p = 0,001). Qui plus est, on peut dénoter une différence notable entre les néonatologistes et les neurologues en ce qui a trait aux écarts perçus de surveillance des patients au moyen de la EEGc, 13 % des premiers assurant une surveillance supérieure alors qu'ils sont 41 % parmi les deuxièmes à assurer une surveillance supérieure (p = 0,007). Enfin, plus de la moitié des répondants (53 %) ont affirmé être intéressés à assister à des séances de formation portant sur la surveillance continue par EEG destinée aux nouveau-nés. Conclusions: Les neurologues et les néonatologistes canadiens divergent quant à la meilleure approche de surveillance dans le cas de nouveau-nés gravement malades. En outre, les néonatologistes ont tendance à percevoir un écart de surveillance moins important si on les compare aux neurologues. Néanmoins, nombreux sont les répondants formés dans ces deux spécialités qui souhaiteraient augmenter à long terme la surveillance par EEG dans les USIN. Le fait de faciliter l'accès à ces examens et d'améliorer l'enseignement pourrait ainsi permettre de répondre aux besoins.

Case report of novel DYRK1A mutations in 2 individuals with syndromic intellectual disability and a review of the literature.

BACKGROUND: Chromosomal deletions encompassing DYRK1A have been associated with intellectual disability for several years. More recently, point mutations in DYRK1A have been shown to be responsible for a recognizable syndrome characterized by microcephaly, developmental delay and intellectual disability (ID) as well as characteristic facial features. Here we present 2 individuals with novel mutations in DYRK1A, and a review of the cases reported to date. CASE PRESENTATION: Both individuals presented with the well-known characteristic features, as well as rarer anomalies seen in a minority of patients. Patient 1 presented shortly after birth with an enlarged cisterna magna, distal contractures, and distinctive facies that included bitemporal narrowing and deep set eyes. A de novo splice site mutation in DYRK1A [c.951 + 4_951 + 7delAGTA; p.Val222Aspfs*22] was identified by next generation sequencing. Patient 2 presented at 7 months of age with microcephaly and dysmorphic features. She went several years without a diagnosis until a de novo DYRK1A nonsense mutation [c.787C>T; p.(Arg263*)] was identified at age 12. These individuals, and the 52 cases reviewed from the literature, show the characteristic features of the DYRK1A-related syndrome including global developmental delay, ID, microcephaly, feeding difficulties, and the facial gestalt. Other common findings include seizures, vision defects, brain abnormalities and skeletal abnormalities of the hands and feet. Less common features include optic nerve defects, contractures, ataxia, and cardiac anomalies. CONCLUSION: DYRK1A testing should be considered in individuals with the facial features, intellectual disability and post-natal microcephaly. Once diagnosed with DYRK1A-related intellectual disability, a cardiac and ophthalmologic assessment would be recommended as would routine surveillance by a pediatrician for psychomotor development, growth, and feeding.

Antibodies to MOG and AQP4 in children with neuromyelitis optica and limited forms of the disease.

OBJECTIVE: To determine the frequency and clinical-radiological associations of antibodies to myelin oligodendrocyte glycoprotein (MOG) and aquaporin-4 (AQP4) in children presenting with neuromyelitis optica (NMO) and limited forms. METHODS: Children with a first event of NMO, recurrent (RON), bilateral ON (BON), longitudinally extensive transverse myelitis (LETM) or brainstem syndrome (BS) with a clinical follow-up of more than 12 months were enrolled. Serum samples were tested for MOG- and AQP4-antibodies using live cell-based assays. RESULTS: 45 children with NMO (n=12), LETM (n=14), BON (n=6), RON (n=12) and BS (n=1) were included. 25/45 (56%) children had MOG-antibodies at initial presentation (7 NMO, 4 BON, 8 ON, 6 LETM). 5/45 (11%) children showed AQP4-antibodies (3 NMO, 1 LETM, 1 BS) and 15/45 (33%) were seronegative for both antibodies (2 NMO, 2 BON, 4 RON, 7 LETM). No differences were found in the age at presentation, sex ratio, frequency of oligoclonal bands or median EDSS at last follow-up between the three groups. Children with MOG-antibodies more frequently (1) had a monophasic course (p=0.018) after one year, (2) presented with simultaneous ON and LETM (p=0.004) and (3) were less likely to receive immunosuppressive therapies (p=0.0002). MRI in MOG-antibody positive patients (4) less frequently demonstrated periependymal lesions (p=0.001), (5) more often were unspecific (p=0.004) and (6) resolved more frequently (p=0.016). CONCLUSIONS: 67% of all children presenting with NMO or limited forms tested positive for MOG- or AQP4-antibodies. MOG-antibody positivity was associated with distinct features. We therefore recommend to measure both antibodies in children with demyelinating syndromes.

Myelin Oligodendrocyte Glycoprotein-Associated Pediatric Central Nervous System Demyelination: Clinical Course, Neuroimaging Findings, and Response to Therapy.

Under the umbrella of pediatric-acquired demyelinating syndromes, there is a multitude of disorders, including optic neuritis, transverse myelitis, acute disseminated encephalomyelitis (ADEM), multiple sclerosis (MS), and neuromyelitis optica spectrum disorders (NMOSD). Due to overlapping clinical and magnetic resonance imaging (MRI) features, it can be challenging to provide an accurate diagnosis. In view of therapeutic and prognostic implications, an early and reliable diagnosis is however of utmost importance. Recent studies of myelin oligodendrocyte glycoprotein (MOG) identify MOG, as a promising target for antibody-mediated demyelination and a biomarker for a relatively benign and non-MS disease course. We describe the clinical and MRI presentation of five children presenting with an acute, severe central nervous system inflammatory disease involving the brain and spinal cord, all of whom were positive for MOG-IgG antibody. Encephalopathy was uncommon at presentation and all had quick resolution of symptoms with intravenous steroid and intravenous immunoglobulin (IVIG) treatment. All patients recovered well, and have been treated with IVIG to potentially prevent relapses.

Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein.

The role of autoantibodies in the pathogenesis of multiple sclerosis (MS) and other demyelinating diseases is controversial, in part because widely used western blotting and ELISA methods either do not permit the detection of conformation-sensitive antibodies or do not distinguish them from conformation-independent antibodies. We developed a sensitive assay based on self-assembling radiolabeled tetramers that allows discrimination of antibodies against folded or denatured myelin oligodendrocyte glycoprotein (MOG) by selective unfolding of the antigen domain. The tetramer radioimmunoassay (RIA) was more sensitive for MOG autoantibody detection than other methodologies, including monomer-based RIA, ELISA or fluorescent-activated cell sorting (FACS). Autoantibodies from individuals with acute disseminated encephalomyelitis (ADEM) selectively bound the folded MOG tetramer, whereas sera from mice with experimental autoimmune encephalomyelitis induced with MOG peptide immunoprecipitated only the unfolded tetramer. MOG-specific autoantibodies were identified in a subset of ADEM but only rarely in adult-onset MS cases, indicating that MOG is a more prominent target antigen in ADEM than MS.

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.

Serum autoantibodies to myelin peptides distinguish acute disseminated encephalomyelitis from relapsing-remitting multiple sclerosis.

BACKGROUND AND OBJECTIVE: Acute disseminated encephalomyelitis (ADEM) and relapsing-remitting multiple sclerosis (RRMS) share overlapping clinical, radiologic and laboratory features at onset. Because autoantibodies may contribute to the pathogenesis of both diseases, we sought to identify autoantibody biomarkers that are capable of distinguishing them. METHODS: We used custom antigen arrays to profile anti-myelin-peptide autoantibodies in sera derived from individuals with pediatric ADEM (n = 15), pediatric multiple sclerosis (Ped MS; n = 11) and adult MS (n = 15). Using isotype-specific secondary antibodies, we profiled both IgG and IgM reactivities. We used Statistical Analysis of Microarrays software to confirm the differences in autoantibody reactivity profiles between ADEM and MS samples. We used Prediction Analysis of Microarrays software to generate and validate prediction algorithms, based on the autoantibody reactivity profiles. RESULTS: ADEM was characterized by IgG autoantibodies targeting epitopes derived from myelin basic protein, proteolipid protein, myelin-associated oligodendrocyte basic glycoprotein, and alpha-B-crystallin. In contrast, MS was characterized by IgM autoantibodies targeting myelin basic protein, proteolipid protein, myelin-associated oligodendrocyte basic glycoprotein and oligodendrocyte-specific protein. We generated and validated prediction algorithms that distinguish ADEM serum (sensitivity 62-86%; specificity 56-79%) from MS serum (sensitivity 40-87%; specificity 62-86%) on the basis of combined IgG and IgM anti-myelin autoantibody reactivity to a small number of myelin peptides. CONCLUSIONS: Combined profiles of serum IgG and IgM autoantibodies identified myelin antigens that may be useful for distinguishing MS from ADEM. Further studies are required to establish clinical utility. Further biological assays are required to delineate the pathogenic potential of these antibodies.

International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders: revisions to the 2007 definitions.

BACKGROUND: There has been tremendous growth in research in pediatric multiple sclerosis (MS) and immune mediated central nervous system demyelinating disorders since operational definitions for these conditions were first proposed in 2007. Further, the International Pediatric Multiple Sclerosis Study Group (IPMSSG), which proposed the criteria, has expanded substantially in membership and in its international scope. OBJECTIVE: The purpose of this review is to revise the 2007 definitions in order to incorporate advances in delineating the clinical and neuroradiologic features of these disorders. METHODS: Through a consensus process, in which input was sought from the 150 members of the Study Group, criteria were drafted, revised and finalized. Final approval was sought through a web survey. RESULTS: Revised criteria are proposed for pediatric acute disseminated encephalomyelitis, pediatric clinically isolated syndrome, pediatric neuromyelitis optica and pediatric MS. These criteria were approved by 93% or more of the 56 Study Group members who responded to the final survey. CONCLUSIONS: These definitions are proposed for clinical and research purposes. Their utility will depend on the outcomes of their application in prospective research.

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.