Fostering Education in Epilepsy: A Canadian League Against Epilepsy Teaching Initiative.

The Canadian League Against Epilepsy initiated a virtual epilepsy education program, conducting 29 webinars from March 2021 to September 2023. We report our experience, with the goal to inspire other groups to develop inclusive, equitable, and free educational spaces with a worldwide reach. Monthly sessions drew a median attendance of 118 participants, predominantly Canadian but also international, including physicians (58.9%) and trainees (22.8%). Post-webinar surveys (average 40% response rate) noted high satisfaction, a strong inclination to recommend the sessions, and an interest in clinical case-based topics. We plan to consider integrating a self-assessment section evaluating knowledge gained after each seminar.

De novo Y1460C missense variant in NaV1.1 impedes the pore region and results in epileptic encephalopathy.

Epilepsy is a common neurological disorder characterized by recurrent unprovoked seizures. SCN1A encodes NaV1.1, a neuronal voltage-gated Na+ channel that is highly expressed throughout the central nervous system. NaV1.1 is localized within the axon initial segment where it plays a critical role in the initiation and propagation of action potentials and neuronal firing, predominantly in γ-amino-butyric-acid (GABA)ergic neurons of the hippocampus. The objective of this study was to characterize a de novo missense variant of uncertain significance in the SCN1A gene of a proband presented with febrile status epilepticus characterized by generalized tonic clonic movements associated with ictal emesis and an abnormal breathing pattern. Screening a gene panel revealed a heterozygous missense variant of uncertain significance in the SCN1A gene, designated c.4379A>G, p.(Tyr1460Cys). The NaV1.1 wild-type (WT) and mutant channel reproduced in vivo and were transfected in HEK 293 cells. Na+ currents were recorded using the whole-cell configuration of the patch-clamp technique. This NaV1.1 variant (Tyr1460Cys) failed to express functional Na+ currents when expressed in HEK293 cells, most probably due to a pore defect of the channel given that the cell surface expression of the channel was normal. Currents generated after co-transfection with functional WT channels exhibited biophysical properties comparable to those of WT channels, which was mainly due to the functional WT channels at the cell surface. The NaV1.1 variant failed to express functional Na+ currents, most probably due to pore impairment and exhibited a well-established loss of function mechanism. The present study highlights the added-value of functional testing for understanding the pathophysiology and potential treatment decisions for patients with undiagnosed developmental epileptic encephalopathy.

Surgically Remediable Secondary Network Epileptic Encephalopathies With Continuous Spike Wave in Sleep: Lesions May Not Be Visible on Brain Magnetic Resonance Imaging (MRI).

BACKGROUND: Continuous spike wave in sleep (CSWS) is an electroencephalogram (EEG) pattern associated with developmental and epileptic encephalopathy with spike-and-wave activation in sleep (DEE-SWAS). This etiologically heterogeneous syndrome may occur because of genetic factors and congenital or acquired brain lesions. We studied the pattern of clinical presentation and underlying etiologies in patients with DEE-SWAS that respond to resective surgery. METHODS: We reviewed our clinical and research databases for patients who had resolution of CSWS following surgical resection of a focal lesion. RESULTS: We identified 5 patients meeting inclusion criteria. In 3 of 5, an epileptogenic structural abnormality was not apparent on brain magnetic resonance imaging (MRI). In all 3 patients, focal cortical dysplasia was identified through intracranial EEG monitoring. SIGNIFICANCE: DEE-SWAS may be a secondary bilateral network epilepsy syndrome, which can be treated with resection of the inciting focal lesion. In patients with drug-resistant CSWS, clinicians should consider a complete epilepsy presurgical workup, including intracranial EEG monitoring.

An international consortium in epilepsy surgery education: Clinical case-based discussions between Latin-American and Canadian Epilepsy Centers.

An international consortium with a focus on Epilepsy Surgery Education was established with members from different centers in Latin America and Canada. All members of the consortium and attendees from different centers in Latin America and Canada have been meeting to discuss epilepsy surgery cases in a virtual manner. We surveyed all to assess the value of the meetings. The results and description of these meetings are being presented.

SCN2A-related epilepsy of infancy with migrating focal seizures: report of a variant with apparent gain- and loss-of-function effects.

SCN2A encodes a voltage-gated sodium channel (NaV1.2) expressed throughout the central nervous system in predominantly excitatory neurons. Pathogenic variants in SCN2A are associated with epilepsy and neurodevelopmental disorders. Genotype-phenotype correlations have been described, with loss-of-function variants typically being associated with neurodevelopmental delay and later-onset seizures, whereas gain-of-function variants more often result in early infantile-onset epilepsy. However, the true electrophysiological effects of most disease-causing SCN2A variants have yet to be characterized. We report an infant who presented with migrating focal seizures in the neonatal period. She was found to have a mosaic c.2635G>A, p.Gly879Arg variant in SCN2A. Voltage-clamp studies of the variant expressed on adult and neonatal NaV1.2 isoforms demonstrated a mixed gain and loss of function, with predominantly a loss-of-function effect with reduced cell surface expression and current density. Additional small electrophysiological alterations included a decrease in the voltage dependence of activation and an increase in the voltage dependence of inactivation. This finding of a predominantly loss-of-function effect was unexpected, as the infant's early epilepsy onset would have suggested a predominantly gain-of-function effect. This case illustrates that our understanding of genotype-phenotype correlations is still limited and highlights the complexity of the underlying electrophysiological effects of SCN2A variants.NEW & NOTEWORTHY Voltage-gated sodium channels play an important role in the central nervous system, mutations in which have been reported to be responsible for epilepsy. We report here an infant presenting with epilepsy of infancy with migrating focal seizures (EIMFS) in the neonatal period with a mosaic c.2635G>A, resulting in a p.Gly879Arg missense mutation on the SCN2A gene encoding NaV1.2 sodium channels. Biophysical characterization of this variant revealed a mixture of gain- and loss-of-function effects.

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.

PURA-Related Developmental and Epileptic Encephalopathy: Phenotypic and Genotypic Spectrum.

BACKGROUND AND OBJECTIVES: Purine-rich element-binding protein A (PURA) gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients. METHODS: Data on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained. RESULTS: A cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in PURA without any clear genotype-phenotype associations. DISCUSSION: The PURA syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.

Telehealth for Children With Epilepsy Is Effective and Reduces Anxiety Independent of Healthcare Setting.

Objectives: The use of telemedicine has grown exponentially as an alternative to providing care to patients with epilepsy during the pandemic. We investigated the impact of the current pandemic among children with epilepsy from two distinct pediatric epilepsy centers. We also compared perceptions among those who received telemedicine against those who did not. Methods: We developed a questionnaire and invited families followed in Freiburg, Germany, and Calgary, Alberta, Canada, to participate during the initial 9 months of the pandemic. The survey contained 32 questions, 10 of which were stratified according to telemedicine exposure. Results: One hundred twenty-six families (80 in Freiburg, 46 in Calgary) participated, and 40.3% received telemedicine care. Most children (mean age 10.4 years, SD 5.1) had chronic epilepsy but poorly controlled seizures. Negative impacts were reported by 36 and 65% of families who had to reschedule appointments for visits and diagnostics, respectively. Nearly two-thirds of families reported no change in seizure frequency, while 18.2% reported either worsening or improvement of seizures. Although most families did not note behavioral changes, 28.2% reported behavior worsening. Families who received telemedicine care had a statistically significant reduction of parental self-reported anxiety level after virtual visits compared to those who did not experience telemedicine. Families with telemedicine consultations were more likely to consider future virtual care (84 vs. 65.2% of those without), even after the pandemic. Patient data safety, easy access to specialized services, and consistency with the same healthcare provider were graded as important in both centers, while a shorter waiting time was most relevant in Calgary. Conclusion: In our cohort, some children with epilepsy experienced increased seizures and worsening behavior during the first 9 months of the current pandemic. In addition, our data suggest that telemedicine might reduce parental anxiety symptoms, and families who experienced telehealth were more positive and open to similar appointments in the future.

Automated quantification of spike-wave activity may be used to predict the development of electrical status epilepticus in sleep (ESES) in children with perinatal stroke.

OBJECTIVE: Continuous spike and wave in slow-wave sleep (CSWS), an epileptic encephalopathy, occurs after perinatal stroke where it is associated with cognitive decline. CSWS features a distinct EEG pattern, electrical status epilepticus in sleep (ESES). Biomarkers for the prediction of ESES have not been identified but will facilitate earlier diagnosis and treatment. We hypothesized that spike-frequency and differences in power spectra would be predictive of subsequent ESES. METHODS: A cross-sectional study comparing EEG spike-frequency and Power before the development of ESES in patients with perinatal stroke, patients with focal epilepsy, and appropriate controls. RESULTS: 43 patients met the inclusion criteria; 11 stroke-ESES, 10 stroke controls, 14 epilepsy-ESES, 8 epilepsy controls. ESES patients had higher pre-diagnosis mean spike-frequency (24.0 ± 24 versus 6.6 ± 9.1 SW/min, p = 0.002) than patients that did not develop ESES; these differences present ~ 3 years before ESES diagnosis. Pre-diagnosis, normalized delta power (1-4 Hz) was higher in the stroke-ESES group (105.7 ± 58 dB/Hz) compared to stroke controls (57.4 ± 45 dB/Hz, p = 0.036). CONCLUSION: Spike-frequency and delta power may represent EEG biomarkers of the risk of developing ESES in children with perinatal stroke. SIGNIFICANCE: EEG biomarkers may be used by clinicians to assess which patients are more at-risk for ESES. Using spike-frequency, clinicians may be able to identify patients at risk of developing ESES.

Practice Guidelines for Canadian Neurophysiology Laboratories During the COVID-19 Pandemic.

The COVID-19 pandemic has had a major impact on clinical practice. Safe standards of practice are essential to protect health care workers while still allowing them to provide good care. The Canadian Society of Clinical Neurophysiologists, the Canadian Association of Electroneurophysiology Technologists, the Association of Electromyography Technologists of Canada, the Board of Registration of Electromyography Technologists of Canada, and the Canadian Board of Registration of Electroencephalograph Technologists have combined to review current published literature about safe practices for neurophysiology laboratories. Herein, we present the results of our review and provide our expert opinion regarding the safe practice of neurophysiology during the COVID-19 pandemic in Canada.

[Genetically determined epileptic encephalopathies]. / Encefalopatías epilépticas determinadas genéticamente.

Epileptic encephalopathies is a group of epileptic syndromes characterized by progressive cognitive impairment beyond the expected for the epilepsy activity. They are characterized by severe pharmaco-resistant epilepsy, severely abnormal electroencephalograms, early-age onset, neurocognitve impairment, variable phenotype and usually normal brain MRI. These syndromes are usually genetically determined. A correct and timely diagnosis could help and guide the medical counselling and the correct therapeutic approach improving the short, medium and long term outcomes. In this article we review the electroencephalographic and genetic findings along with the most recommended therapeutic options facilitating the clinical management. We include the following epileptic encephalopathy syndromes: Ohtahara, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, West, Dravet, non-progressive myoclonic status, Doose, Lennox-Gastaut, Landau-Kleffner and continuous spike-wave during sleep epilepsy.

Las encefalopatías epilépticas es un grupo de síndromes epilépticos caracterizados por el deterioro cognitivo más allá de lo esperado debido a la actividad epiléptica. Se caracterizan por presentar resistencia farmacológica grave, electroencefalogramas profundamente anormales, inicio en la niñez temprana, deterioro neurocognitivo, fenotipo variable y resonancia magnética de cerebro usualmente normal. Frecuentemente estos síndromes están genéticamente determinados. Su diagnóstico correcto y oportuno puede contribuir y guiar el consejo médico y terapia adecuada, influyendo así en el pronóstico a corto, mediano y largo plazo. En este artículo se revisan los hallazgos electroencefalográficos, genéticos y opciones terapéuticas más recomendadas, facilitando así la conducta clínica. Las encefalopatías epilépticas incluidas en este artículos abarcan los síndromes de Ohtahara, encefalopatia mioclónica temprana, epilepsia focal migratoria de la infancia, West, Dravet, estado mioclónico en encefalopatías no progresivas, Doose, Lennox-Gastaut, Landau-Kleffner y epilepsia con espiga-onda continuas durante el sueño de onda lenta.

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.

Single-center experience with Beta-propeller protein-associated neurodegeneration (BPAN); expanding the phenotypic spectrum.

Beta-propeller protein-associated neurodegeneration (BPAN) is a subtype of neurodegeneration with brain iron accumulation (NBIA) that presents with childhood developmental delay (especially speech delay), occasionally associated with epileptic encephalopathy, autism, or Rett-like syndrome. The majority of children described to date have been severely affected, with little to no expressive speech function, severe developmental delay, and cognitive impairment. Herein, five additional patients with BPAN identified in the same center in Canada are described, four with the typical severe phenotype and one with a milder phenotype. Our findings provide further evidence that a spectrum of severity exists for this rare and newly described condition. Challenges in identifying iron accumulation on brain MRI are also addressed. Additionally, the importance of including the WDR45 gene on epilepsy and Rett-like syndrome genetic panels is highlighted.

Implementation of Neonatal Neurocritical Care Program Improved Short-Term Outcomes in Neonates With Moderate-to-Severe Hypoxic Ischemic Encephalopathy.

BACKGROUND: Despite the introduction of therapeutic hypothermia, infants with moderate-to-severe hypoxic-ischemic encephalopathy remain at risk of mortality and morbidity. A dedicated service with standardized management protocols and improved communication may help improve care. We aimed to evaluate the impact of a dedicated neonatal neurocritical care service on short-term outcomes in infants with hypoxic-ischemic encephalopathy. METHODS: We performed a retrospective cohort study (July 2008 to December 2017) on term and near-term infants admitted to two tertiary neonatal intensive care units with moderate-to-severe hypoxic-ischemic encephalopathy, before and after neonatal neurocritical care service implementation. The primary outcome was brain magnetic resonance imaging findings consistent with those of hypoxic-ischemic encephalopathy. Secondary outcomes included the cooling initiation rate, hospital stay duration, antiseizure medication use, and inotrope use. Regression analysis and interrupted time series analysis were performed after adjusting for confounding factors. RESULTS: In total, 216 infants with moderate-to-severe hypoxic-ischemic encephalopathy were analyzed-109 before and 107 after neonatal neurocritical care implementation. After adjusting for confounding factors, there was a significant reduction in primary outcomes (adjusted odds ratio: 0.3, confidence interval: 0.15 to 0.57, P < 0.001) after neonatal neurocritical care implementation. Average hospital stay duration reduced by 5.2 days per infant (P = 0.03), identification of eligible infants for cooling improved (P < 0.001), antiseizure medication use reduced (P = 0.001), and early inotropes use reduced (P = 0.04). CONCLUSION: Implementation of a neonatal neurocritical care service associated with decreased brain injury shortened the hospital stay duration and improved the care of infants with moderate-to-severe hypoxic-ischemic encephalopathy.