Where there is no genetic counselor: An online decision-aid supports the majority of parents' diagnostic genomic testing choices for their children.

PURPOSE: We evaluated DECIDE, an online pretest decision-support tool for diagnostic genomic testing, in nongenetics specialty clinics where there are no genetic counselors (GCs). METHODS: Families of children offered genomic testing were eligible to participate. Fifty-six parents/guardians completed DECIDE at home, at their convenience. DECIDE includes an integrated knowledge quiz and decisional conflict screen. Six months later, parents were offered follow-up questionnaires and interviews about their experiences. RESULTS: Forty parents (71%) had sufficient knowledge and no decisional conflict surrounding their testing decision, but 6 of this group had residual questions. These 6, plus 16 with decisional conflict or insufficient knowledge, saw a GC. At follow-up, little-to-no decisional regret and few negative emotions were identified in any parents. Most chose testing and described their decision as easy, yet stressful, and described many motivations for sequencing. Parents appreciated the simple comprehensive information DECIDE provided and the ability to view it in a low-stress environment. CONCLUSION: DECIDE provides adequate decision-support to enable most parents to make value-consistent choices about genetic testing for their child. Parents reported that DECIDE helped to clarify motivations for pursuing (or declining) testing. DECIDE is a timely, well-tested, and accessible tool in clinical settings without GCs.

Epilepsy in Legius syndrome: Coincidence or causation?

Legius syndrome is a rare genetic disorder, caused by heterozygous SPRED1 pathogenic variants, which shares phenotypic features with neurofibromatosis type 1 (NF1). Both conditions typically involve café-au-lait macules, axillary freckling, and macrocephaly; however, patients with NF1 are also at risk for tumors, such as optic nerve gliomas and neurofibromas. Seizure risk is known to be elevated in NF1, but there has been little study of this aspect of Legius syndrome. The reported epilepsy incidence is 3.3%-5%, well above the general population incidence of ~0.5%-1%, but the few reports in the literature have very little data regarding epilepsy phenotype. We identified two unrelated individuals, both with Legius syndrome and epilepsy, and performed thorough phenotyping. One individual's mother also had Legius syndrome and now-resolved childhood epilepsy, as well as reports of more distant relatives who also had multiple café-au-lait macules and seizures. Both probands had experienced childhood-onset focal seizures, with normal brain MRI. In one patient, EEG later showed apparently generalized epileptiform abnormalities. Based on the data from this small case series and literature review, seizure risk is increased in people with Legius syndrome, but the epilepsy prognosis appears to be generally good, with patients having either self-limited or pharmacoresponsive courses.

Expanding the genotype-phenotype spectrum in SCN8A-related disorders.

BACKGROUND: SCN8A-related disorders are a group of variable conditions caused by pathogenic variations in SCN8A. Online Mendelian Inheritance in Man (OMIM) terms them as developmental and epileptic encephalopathy 13, benign familial infantile seizures 5 or cognitive impairment with or without cerebellar ataxia. METHODS: In this study, we describe clinical and genetic results on eight individuals from six families with SCN8A pathogenic variants identified via exome sequencing. RESULTS: Clinical findings ranged from normal development with well-controlled epilepsy to significant developmental delay with treatment-resistant epilepsy. Three novel and three reported variants were observed in SCN8A. Electrophysiological analysis in transfected cells revealed a loss-of-function variant in Patient 4. CONCLUSIONS: This work expands the clinical and genotypic spectrum of SCN8A-related disorders and provides electrophysiological results on a novel loss-of-function SCN8A variant.

Rapid Implementation of Virtual Health in a Pediatric Neurology Practice During COVID-19.

During the COVID-19 pandemic, the Division of Neurology at BC Children's Hospital rapidly transitioned to almost exclusively virtual health. In April 2020, 96% of outpatient visits were done virtually (64%) or by telephone, and only 4.2% were in-person. Total clinic visit numbers were unchanged compared to previous months. Neurologists reported high satisfaction with the virtual history and overall assessment, while the physical examination was less reliable. Additional in-person visits were rarely required. Rapid, sustained adoption of virtual health is possible in a pediatric neurology setting, providing reliable care that is comparable to in-person consultations when physical distancing is necessary.

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.

Global characterization of copy number variants in epilepsy patients from whole genome sequencing.

Epilepsy will affect nearly 3% of people at some point during their lifetime. Previous copy number variants (CNVs) studies of epilepsy have used array-based technology and were restricted to the detection of large or exonic events. In contrast, whole-genome sequencing (WGS) has the potential to more comprehensively profile CNVs but existing analytic methods suffer from limited accuracy. We show that this is in part due to the non-uniformity of read coverage, even after intra-sample normalization. To improve on this, we developed PopSV, an algorithm that uses multiple samples to control for technical variation and enables the robust detection of CNVs. Using WGS and PopSV, we performed a comprehensive characterization of CNVs in 198 individuals affected with epilepsy and 301 controls. For both large and small variants, we found an enrichment of rare exonic events in epilepsy patients, especially in genes with predicted loss-of-function intolerance. Notably, this genome-wide survey also revealed an enrichment of rare non-coding CNVs near previously known epilepsy genes. This enrichment was strongest for non-coding CNVs located within 100 Kbp of an epilepsy gene and in regions associated with changes in the gene expression, such as expression QTLs or DNase I hypersensitive sites. Finally, we report on 21 potentially damaging events that could be associated with known or new candidate epilepsy genes. Our results suggest that comprehensive sequence-based profiling of CNVs could help explain a larger fraction of epilepsy cases.

Case reports: novel TUBG1 mutations with milder neurodevelopmental presentations.

BACKGROUND: Tubulinopathies result from mutations in tubulin genes, including TUBG1, responsible for cell microtubules, are characterized by brain development abnormalities, microcephaly, early-onset epilepsy, and motor impairment. Only eleven patients with TUBG1 mutations have been previously described in literature to our knowledge. Here we present two new patients with novel de novo TUBG1 mutations and review other cases in the literature. CASE PRESENTATIONS: Both patients have microcephaly and intellectual disability. Patient B further fits a more typical presentation, with well-controlled epilepsy and mild hypertonia, whereas Patient A's presentation is much milder without these other features. CONCLUSION: This report expands the spectrum of TUBG1 mutation manifestations, suggesting the possibility of less severe phenotypes for patients and families, and influencing genetic counselling strategies.

Position Statement on the Use of Medical Cannabis for the Treatment of Epilepsy in Canada.

In Canada, recreational use of cannabis was legalized in October 2018. This policy change along with recent publications evaluating the efficacy of cannabis for the medical treatment of epilepsy and media awareness about its use have increased the public interest about this agent. The Canadian League Against Epilepsy Medical Therapeutics Committee, along with a multidisciplinary group of experts and Canadian Epilepsy Alliance representatives, has developed a position statement about the use of medical cannabis for epilepsy. This article addresses the current Canadian legal framework, recent publications about its efficacy and safety profile, and our understanding of the clinical issues that should be considered when contemplating cannabis use for medical purposes.

Énoncé de position quant à l'utilisation du cannabis médical dans le traitement de l'épilepsie. L'utilisation du cannabis à des fins récréatives a été légalisée au Canada en octobre 2018. Parallèlement à ce changement de politique, de récentes publication visant à évaluer l'efficacité du cannabis dans le traitement de l'épilepsie, de même qu'une sensibilisation médiatique accrue en ce qui concerne son utilisation, ont eu pour effet d'augmenter l'intérêt du grand public à son égard. Le Comité médical thérapeutique de la Ligue canadienne contre l'épilepsie (LCCE), de concert avec un groupe multidisciplinaire d'experts et des représentants de l'Alliance canadienne de l'épilepsie, a ainsi élaboré un énoncé de position en ce qui regarde l'utilisation du cannabis médical dans le traitement de l'épilepsie. Cet article entend donc aborder le cadre légal qui prévaut actuellement au Canada et examiner de récentes publications s'étant penchées sur le profil sécuritaire et sur l'efficacité du cannabis. De plus, nous voulons apporter un éclairage au sujet des aspects cliniques dont il faudrait tenir compte au moment d'envisager l'utilisation du cannabis à des fins médicales.

Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test.

PurposeGenetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use.MethodsWe prospectively recruited 103 patients from pediatric non-genetic subspecialty clinics, each with a clinical phenotype suggestive of an underlying genetic disorder, and compared the diagnostic yield and coverage of WGS with those of conventional genetic testing.ResultsWGS identified diagnostic variants in 41% of individuals, representing a significant increase over conventional testing results (24%; P = 0.01). Genes clinically sequenced in the cohort (n = 1,226) were well covered by WGS, with a median exonic coverage of 40 × ±8 × (mean ±SD). All the molecular diagnoses made by conventional methods were captured by WGS. The 18 new diagnoses made with WGS included structural and non-exonic sequence variants not detectable with whole-exome sequencing, and confirmed recent disease associations with the genes PIGG, RNU4ATAC, TRIO, and UNC13A.ConclusionWGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort.

Increased subcortical oligodendroglia-like cells in pharmacoresistant focal epilepsy in children correlate with extensive epileptogenic zones.

OBJECTIVE: Cortical resections in epilepsy surgery tend to involve multiple lobes in children, compared to adults, partly due to underlying pathology. Oligodendroglia-like cells (OLCs) have been observed in surgical specimens from children with pharmacoresistant epilepsy. We hypothesize that OLCs recruit multiple-lobe epileptogenic zones in pediatric pharmacoresistant focal epilepsy. METHODS: We examined the surgical specimens from 30 children who underwent epilepsy surgery (1.8- to 16.9-years-old; mean age 9.7 years). Immunohistochemical assays of OLCs were performed using Olig2, which is a marker of OLC. OLC populations in three sites (gray matter, gray-white matter junction, and white matter) were counted. We also performed immunohistochemical staining with neuronal nuclear antigen (NeuN) and glial fibrillary acidic protein (GFAP) for neuronal and astroglial markers, respectively. NeuN- and GFAP-positive cells were distinguished from OLCs. OLC results were compared with seizure types, scalp and intracranial video-electroencephalography (EEG), magnetic resonance imaging (MRI), surgical resection area, histopathologic diagnosis, and seizure outcome. RESULTS: Histopathologic diagnosis consisted of 14 cases of focal cortical dysplasia (FCD; type I; 4, type II; 9, type III; one); 6 cases of oligodendrogliosis; 6 cases of astrocytic gliosis; 2 cases of hyaline protoplasmic astrocytopathy; and 2 cases of tuberous sclerosis. Fifteen children (50%) underwent multiple-lobe resections after intracranial video-EEG. There was a positive correlation between the number of resected electrodes and the OLC population in the white matter (correlation coefficient 0.581, p = 0.001) and at the gray-white matter junction- (correlation coefficient 0.426, p = 0.027). OLC populations in both areas were increased significantly in nine children with epileptic spasms (ES) (gray-white matter junction [p = 0.021] and white matter [p = 0.025]), and nine nonfocal ictal scalp EEG findings (gray-white matter junction [p = 0.04] and white matter [p = 0.042]). The OLC population in white matter was significantly increased in children with 11 nonfocal interictal scalp EEG findings (p = 0.01), with 15 multiple-lobe resections (p = 0.028). SIGNIFICANCE: Pharmacoresistant epilepsy in children with increased OLCs presented with nonfocal epileptiform discharges on scalp EEG and ES, and they required multiple-lobe resections. We found increased populations of subcortical OLCs in the extensive epileptogenic zone.

Faulty cardiac repolarization reserve in alternating hemiplegia of childhood broadens the phenotype.

Alternating hemiplegia of childhood is a rare disorder caused by de novo mutations in the ATP1A3 gene, expressed in neurons and cardiomyocytes. As affected individuals may survive into adulthood, we use the term 'alternating hemiplegia'. The disorder is characterized by early-onset, recurrent, often alternating, hemiplegic episodes; seizures and non-paroxysmal neurological features also occur. Dysautonomia may occur during hemiplegia or in isolation. Premature mortality can occur in this patient group and is not fully explained. Preventable cardiorespiratory arrest from underlying cardiac dysrhythmia may be a cause. We analysed ECG recordings of 52 patients with alternating hemiplegia from nine countries: all had whole-exome, whole-genome, or direct Sanger sequencing of ATP1A3. Data on autonomic dysfunction, cardiac symptoms, medication, and family history of cardiac disease or sudden death were collected. All had 12-lead electrocardiogram recordings available for cardiac axis, cardiac interval, repolarization pattern, and J-point analysis. Where available, historical and prolonged single-lead electrocardiogram recordings during electrocardiogram-videotelemetry were analysed. Half the cohort (26/52) had resting 12-lead electrocardiogram abnormalities: 25/26 had repolarization (T wave) abnormalities. These abnormalities were significantly more common in people with alternating hemiplegia than in an age-matched disease control group of 52 people with epilepsy. The average corrected QT interval was significantly shorter in people with alternating hemiplegia than in the disease control group. J wave or J-point changes were seen in six people with alternating hemiplegia. Over half the affected cohort (28/52) had intraventricular conduction delay, or incomplete right bundle branch block, a much higher proportion than in the normal population or disease control cohort (P = 0.0164). Abnormalities in alternating hemiplegia were more common in those ≥16 years old, compared with those <16 (P = 0.0095), even with a specific mutation (p.D801N; P = 0.045). Dynamic, beat-to-beat or electrocardiogram-to-electrocardiogram, changes were noted, suggesting the prevalence of abnormalities was underestimated. Electrocardiogram changes occurred independently of seizures or plegic episodes. Electrocardiogram abnormalities are common in alternating hemiplegia, have characteristics reflecting those of inherited cardiac channelopathies and most likely amount to impaired repolarization reserve. The dynamic electrocardiogram and neurological features point to periodic systemic decompensation in ATP1A3-expressing organs. Cardiac dysfunction may account for some of the unexplained premature mortality of alternating hemiplegia. Systematic cardiac investigation is warranted in alternating hemiplegia of childhood, as cardiac arrhythmic morbidity and mortality are potentially preventable.

Antithrombotic therapy for secondary stroke prevention in bacterial meningitis in children.

OBJECTIVE: To assess the safety and efficacy of antithrombotic therapy (ATT) for secondary stroke prevention of childhood bacterial meningitis. STUDY DESIGN: A retrospective study of cases of stroke associated with bacterial meningitis in 2 pediatric hospitals during a period of 15 years. Patients were included in the study if they were between 28 days and 18 years of age and had at least 2 serial neuroimaging studies during the acute phase of their illness. The safety of ATT was assessed by the presence or absence of intracranial hemorrhage. Efficacy was assessed by the failure in preventing stroke recurrence. Neurologic outcome was determined by the last documented Pediatric Stroke Outcome Measure score. RESULTS: Twenty-two cases of childhood bacterial meningitis complicated by stroke were identified. Six cases were treated with heparin after either initial or recurrent infarction. None of the cases receiving heparin had further recurrence. Aspirin (acetylsalicylic acid [ASA]) was started after the initial or after recurrent infarction in 10 cases. Four (40%) had infarctions on ASA; 3 of these patients subsequently received heparin. In the 14 cases in which no ATT was begun, 8 (57%) had further recurrence of infarction. None of the patients, whether receiving heparin or ASA, had intracranial hemorrhage. CONCLUSION: In this small sample, heparin and ASA appeared to be safe in childhood bacterial meningitis complicated by stroke and may be effective in improving outcome. Heparin may be more effective than aspirin in preventing recurrent infarction.

Preictal surrender of post-spike slow waves to spike-related high-frequency oscillations (80-200 Hz) is associated with seizure initiation.

OBJECTIVE: Spike and slow waves consist of a "spike" including high-frequency oscillations (HFOs), which are linked to epileptogenicity and a "post-spike slow wave (PSS)" related to inhibitory activity. The aim of this study was to elucidate the spatiotemporal relationship between spike-related HFOs and PSS in patients with focal cortical dysplasia (FCD) type II. METHODS: We studied 10 pediatric patients with FCD type II, who underwent extraoperative video-electroencephalography (EEG). We selected spike and slow waves, which included HFOs (80-200 Hz), and performed spike peak-locked averaging 10 times during both 30 s interictal (>1 h apart from seizures) and 30 s preictal periods. We calculated the power of spike-related HFOs and PSS during both periods for the following three areas: (1) inside the seizure-onset zone (SOZ), (2) inside the resection area (RA) but outside SOZ (RA-SOZ), and (3) outside the RA. Between the interictal and preictal periods we performed correlation (Spearman's coefficient) and simple linear regression analyses comparing HFO and PSS power within each area. RESULTS: A total of 1,614 averaged spike and slow waves were analyzed during both periods. During the interictal periods, there were significant positive correlations between HFO and PSS power in all areas (inside SOZ, r = 0.568; RA-SOZ, r = 0.700; outside RA, r = 0.320). During the preictal periods, the correlation became weaker inside SOZ (r = 0.149) and remained unchanged both inside the RA-SOZ (r = 0.704) and outside RA (r = 0.346). From the interictal to preictal period, the slope (ΔPSS power/ΔHFO power) of the simple regression line decreased inside SOZ (0.349 to 0.051) but increased in RA-SOZ (0.534 to 0.734) and outside RA (0.267 to 0.435). SIGNIFICANCE: Relative power reduction of PSS to spike-related HFOs in SOZ is relevant for seizure initiation. Our analysis will contribute to future studies of seizure prediction and distinction between pathologic and physiologic HFOs. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Interictal high frequency oscillations correlating with seizure outcome in patients with widespread epileptic networks in tuberous sclerosis complex.

OBJECTIVE: Multiple tubers in patients with tuberous sclerosis complex (TSC) often are responsible for drug-resistant epilepsy. The complexity of the epileptic network formed by multiple tubers complicates localization of the epileptogenic zone that is needed to design a surgical treatment strategy. High frequency oscillations (HFOs) on intracranial video-electroencephalography (IVEEG) may be a valuable surrogate marker for the localization of the epileptogenic zone. The purpose of this study was to test the hypothesis that high occurrence rate (OR) of interictal HFOs can guide the localization of the epileptogenic zone. METHODS: We analyzed the OR of interictal HFOs at 80-200 Hz (ripples) and >200 Hz (fast ripples, FRs). We divided OR of interictal HFOs between high and low rates by thresholding. We analyzed the correlation between seizure outcomes using Engel classification and the resection ratio of the seizure onset zone (SOZ), and high-OR HFOs using ordinal logistic regression analysis. RESULTS: We collected 10 patients. The seizure outcomes resulted in Engel classification I in three patients, II in four, III in one, and IV in two. High-OR ripples (5-57 [mean 29] channels, 1-4 [2.8] lobes) and high-OR FRs (9-66 [mean 27] channels, 1-4 [2.6] lobes) were widely distributed. The resection ratio of SOZ did not show statistically significant correlation with the seizure outcome. The resection ratio of high-OR ripples showed statistically significant correlation with the seizure outcome (p = 0.038). The resection ratio of high-OR FRs showed statistically significant correlation with the seizure outcome (p = 0.048). SIGNIFICANCE: The multiple extensive zones with high-OR HFOs suggest a complex and widespread epileptic network in patients with TSC. In a subset of TSC patients with drug-resistant epilepsy, resection of cortex with both interictal high-OR FRs and ripples on IVEEG correlated with a good seizure outcome.

Rhythmic high-amplitude delta with superimposed spikes (RHADS): a treatment dilemma.

Pathognomonic EEG patterns have been described in genetic conditions such as Angelman and Rett syndromes. EEG patterns along the ictal-interictal continuum have been increasingly recognized with the greater availability of continuous EEG monitoring; however, treatment decisions may be difficult with unpredictable clinical implications. Rhythmic High-Amplitude Delta Activity with Superimposed (Poly) Spikes (RHADS) has been described as a particular EEG pattern in POLG1 Alpers Syndrome. The balance between treating subclinical seizures and managing encephalopathy in these patients is challenging.

Gain-of-function MARK4 variant associates with pediatric neurodevelopmental disorder and dysmorphism.

Microtubule affinity-regulating kinase 4 (MARK4) is a serine/threonine kinase that plays a key role in tau phosphorylation and regulation of the mammalian target of rapamycin (mTOR) pathway. Abnormal tau phosphorylation and dysregulation of the mTOR pathway are implicated in neurodegenerative and neurodevelopmental disorders. Here, we report a gain-of-function variant in MARK4 in two siblings with childhood-onset neurodevelopmental disability and dysmorphic features. The siblings carry a germline heterozygous missense MARK4 variant c.604T>C (p.Phe202Leu), located in the catalytic domain of the kinase, which they inherited from their unaffected, somatic mosaic mother. Functional studies show that this amino acid substitution has no impact on protein expression but instead increases the ability of MARK4 to phosphorylate tau isoforms found in the fetal and adult brain. The MARK4 variant also increases phosphorylation of ribosomal protein S6, indicating upregulation of the mTORC1 pathway. In this study, we link a germline monoallelic MARK4 variant to a childhood-onset neurodevelopmental disorder characterized by global developmental delay, intellectual disability, behavioral abnormalities, and dysmorphic features.

STXBP1-Related Disorders: Clinical Presentation, Molecular Function, Treatment, and Future Directions.

In recent years, the affordability and availability of genetic testing have led to its increased use in clinical care. The increased frequency of testing has led to STXBP1 variants being identified as one of the more common variants associated with neurological disorders. In this review, we aim to summarize the common clinical phenotypes associated with STXBP1 pathogenic variants, provide an overview of their known natural history, and discuss current research into the genotype to phenotype correlation. We will also provide an overview of the suspected normal function of the STXBP1-encoded Munc18-1 protein, animal models, and experimental techniques that have been developed to study its function and use this information to try to explain the diverse phenotypes associated with STXBP1-related disorders. Finally, we will explore current therapies for STXBP1 disorders, including an overview of treatment goals for STXBP1-related disorders, a discussion of the current evidence for therapies, and future directions of personalized medications for STXBP1-related disorders.

Expanding the genotype-phenotype spectrum in SCN8A-related disorders.

Background: SCN8A-related disorders are a group of variable conditions caused by pathogenic variations in SCN8A. Online Mendelian Inheritance in Man (OMIM) terms them as developmental and epileptic encephalopathy 13, benign familial infantile seizures 5 or cognitive impairment with or without cerebellar ataxia. Methods: In this study, we describe clinical and genetic results on eight individuals from six families with SCN8A pathogenic variants identified via exome sequencing. Results: Clinical findings ranged from normal development with well-controlled epilepsy to significant developmental delay with treatment-resistant epilepsy. Three novel and three reported variants were observed in SCN8A. Electrophysiological analysis in transfected cells revealed a loss-of-function variant in Patient 4. Conclusions: This work expands the clinical and genotypic spectrum of SCN8A-related disorders and provides electrophysiological results on a novel loss-of-function SCN8A variant.

Movement Disorders Secondary to Novel Antiseizure Medications in Pediatric Populations: A Systematic Review and Meta-analysis of Risk.

Novel antiseizure medications are thought to be safer than their conventional counterparts, though no dedicated analysis of movement disorder risk among pediatric populations using novel antiseizure medications has been completed. We report a systematic review with meta-analysis describing the relationship between novel antiseizure medications and movement disorders in pediatrics.MEDLINE, EMBASE, and the World Health Organization's International Clinical Trials Registry Platform were searched up to October 2020 for randomized controlled trials investigating novel antiseizure medications in pediatric populations. Antiseizure medications included lacosamide, perampanel, eslicarbazepine, rufinamide, fenfluramine, cannabidiol, and brivaracetam. Outcomes were pooled using random effects models; risk difference (RD) and 95% confidence intervals (CIs) were calculated.Twenty-three studies were selected from 1690 nonredundant manuscripts (n = 1912 total). There was a significantly increased risk of movement disorders associated with perampanel (RD 0.07, 95% CI 0.01-0.13; n = 133), though only 1 relevant trial was found. No increased risk of movement disorders was found with other antiseizure medications.Our findings indicate most novel antiseizure medications are safe to use in pediatric populations with respect to movement disorders. However, findings were limited by quality of adverse event reporting.

Effect of Training on Visual Identification of High Frequency Oscillations-A Delphi-Style Intervention.

OBJECTIVE: We examined the effect of a simple Delphi-method feedback on visual identification of high frequency oscillations (HFOs) in the ripple (80-250 Hz) band, and assessed the impact of this training intervention on the interrater reliability and generalizability of HFO evaluations. METHODS: We employed a morphology detector to identify potential HFOs at two thresholds and presented them to visual reviewers to assess the probability of each epoch containing an HFO. We recruited 19 board-certified epileptologists with various levels of experience to complete a series of HFO evaluations during three sessions. A Delphi-style intervention was used to provide feedback on the performance of each reviewer relative to their peers. A delayed-intervention paradigm was used, in which reviewers received feedback either before or after the second session. ANOVAs were used to assess the effect of the intervention on the reviewers' evaluations. Generalizability theory was used to assess the interrater reliability before and after the intervention. RESULTS: The intervention, regardless of when it occurred, resulted in a significant reduction in the variability between reviewers in both groups (p GroupDI = 0.037, p GroupEI = 0.003). Prior to the delayed-intervention, the group receiving the early intervention showed a significant reduction in variability (p GroupEI = 0.041), but the delayed-intervention group did not (p GroupDI = 0.414). Following the intervention, the projected number of reviewers required to achieve strong generalizability decreased from 35 to 16. SIGNIFICANCE: This study shows a robust effect of a Delphi-style intervention on the interrater variability, reliability, and generalizability of HFO evaluations. The observed decreases in HFO marking discrepancies across 14 of the 15 reviewers are encouraging: they are necessarily associated with an increase in interrater reliability, and therefore with a corresponding decrease in the number of reviewers required to achieve strong generalizability. Indeed, the reliability of all reviewers following the intervention was similar to that of experienced reviewers prior to intervention. Therefore, a Delphi-style intervention could be implemented either to sufficiently train any reviewer, or to further refine the interrater reliability of experienced reviewers. In either case, a Delphi-style intervention would help facilitate the standardization of HFO evaluations and its implementation in clinical care.