Channelopathies in epilepsy: an overview of clinical presentations, pathogenic mechanisms, and therapeutic insights.

Pathogenic variants in genes encoding ion channels are causal for various pediatric and adult neurological conditions. In particular, several epilepsy syndromes have been identified to be caused by specific channelopathies. These encompass a spectrum from self-limited epilepsies to developmental and epileptic encephalopathies spanning genetic and acquired causes. Several of these channelopathies have exquisite responses to specific antiseizure medications (ASMs), while others ASMs may prove ineffective or even worsen seizures. Some channelopathies demonstrate phenotypic pleiotropy and can cause other neurological conditions outside of epilepsy. This review aims to provide a comprehensive exploration of the pathophysiology of seizure generation, ion channels implicated in epilepsy, and several genetic epilepsies due to ion channel dysfunction. We outline the clinical presentation, pathogenesis, and the current state of basic science and clinical research for these channelopathies. In addition, we briefly look at potential precision therapy approaches emerging for these disorders.

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.

Removing barriers to accessing medical cannabis for paediatric patients.

Medical cannabis (MC) may offer therapeutic benefits for children with complex neurological conditions and chronic diseases. In Canada, parents, and caregivers frequently report encountering barriers when accessing MC for their children. These include negative preconceived notions about risks and benefits, challenges connecting with a knowledgeable healthcare provider (HCP), the high cost of MC products, and navigating MC product shortages. In this manuscript, we explore several of these barriers and provide recommendations to decision-makers to enable a family-centered and evidence-based approach to MC medicine and research for children.

KCTD7-related progressive myoclonic epilepsy: Report of 42 cases and review of literature.

OBJECTIVE: KCTD7-related progressive myoclonic epilepsy (PME) is a rare autosomal-recessive disorder. This study aimed to describe the clinical details and genetic variants in a large international cohort. METHODS: Families with molecularly confirmed diagnoses of KCTD7-related PME were identified through international collaboration. Furthermore, a systematic review was done to identify previously reported cases. Salient demographic, epilepsy, treatment, genetic testing, electroencephalographic (EEG), and imaging-related variables were collected and summarized. RESULTS: Forty-two patients (36 families) were included. The median age at first seizure was 14 months (interquartile range = 11.75-22.5). Myoclonic seizures were frequently the first seizure type noted (n = 18, 43.9%). EEG and brain magnetic resonance imaging findings were variable. Many patients exhibited delayed development with subsequent progressive regression (n = 16, 38.1%). Twenty-one cases with genetic testing available (55%) had previously reported variants in KCTD7, and 17 cases (45%) had novel variants in KCTD7 gene. Six patients died in the cohort (age range = 1.5-21 years). The systematic review identified 23 eligible studies and further identified 59 previously reported cases of KCTD7-related disorders from the literature. The phenotype for the majority of the reported cases was consistent with a PME (n = 52, 88%). Other reported phenotypes in the literature included opsoclonus myoclonus ataxia syndrome (n = 2), myoclonus dystonia (n = 2), and neuronal ceroid lipofuscinosis (n = 3). Eight published cases died over time (14%, age range = 3-18 years). SIGNIFICANCE: This study cohort and systematic review consolidated the phenotypic spectrum and natural history of KCTD7-related disorders. Early onset drug-resistant epilepsy, relentless neuroregression, and severe neurological sequalae were common. Better understanding of the natural history may help future clinical trials.

Proposed Pathway for the Utilization of Pediatric Ambulatory EEG.

PURPOSE: The clinical utility of pediatric ambulatory-EEG (A-EEG) has been studied for decades, but limited information exists regarding which variables influence its utility. The authors aimed to evaluate clinical/EEG variables that may influence A-EEG yields and to develop a pathway for A-EEG utilization in children. METHODS: Single-center retrospective review of A-EEGs performed from July 2019 to January 2021 in a tertiary referral center. The primary outcome was whether the A-EEG test successfully answered the referring physician's clinical question or influenced therapy. When it did, the A-EEG test was deemed useful. Clinical and EEG variables were assessed for their ability to predict utility. Further, the literature review generated 10 relevant prior studies whose details were used to generate a pathway for A-EEG utilization in children. RESULTS: One hundred forty-two A-EEG studies were included (mean age 8.8 years, 48% male patients, mean A-EEG duration 33.5 hours). Overall, A-EEG was considered useful in 106 children (75%) but heavily influenced by A-EEG indication. Specifically, it was deemed useful for 94% of patients evaluated for electrical status epilepticus in slow-wave sleep, 92% of those evaluated for interictal/ictal burden, and 63% of those undergoing spell classification. The test indication (P < 0.001), a diagnosis of epilepsy (P = 0.02), and an abnormal routine EEG (P = 0.04) were associated with A-EEG test utility, although the multivariate analysis confirmed the test indication as the only independent outcome predictor of A-EEG. CONCLUSIONS: Pediatric A-EEG is extremely useful for evaluating electrical status epilepticus in slow-wave sleep and interictal/ictal burden and is often helpful for spell classification. Among all clinical and EEG variables analyzed, the test indication was the only independent outcome predictor of obtaining a helpful A-EEG.

Early recognition of characteristic conventional and amplitude-integrated EEG patterns of seizures in SCN2A and KCNQ3-related epilepsy in neonates.

PURPOSE: Early recognition of seizures in neonates secondary to pathogenic variants in potassium or sodium channel coding genes is crucial, as these seizures are often resistant to commonly used anti-seizure medications but respond well to sodium channel blockers. Recently, a characteristic ictal amplitude-integrated electroencephalogram (aEEG) pattern was described in neonates with KCNQ2-related epilepsy. We report a similar aEEG pattern in seizures caused by SCN2A- and KCNQ3-pathogenic variants, as well as conventional EEG (cEEG) descriptions. METHODS: International multicentre descriptive study, reporting clinical characteristics, aEEG and cEEG findings of 13 neonates with seizures due to pathogenic SCN2A- and KCNQ3-variants. As a comparison group, aEEGs and cEEGs of neonates with seizures due to hypoxic-ischemic encephalopathy (n = 117) and other confirmed genetic causes affecting channel function (n = 55) were reviewed. RESULTS: In 12 out of 13 patients, the aEEG showed a characteristic sequence of brief onset with a decrease, followed by a quick rise, and then postictal amplitude attenuation. This pattern correlated with bilateral EEG onset attenuation, followed by rhythmic discharges ending in several seconds of post-ictal amplitude suppression. Apart from patients with KCNQ2-related epilepsy, none of the patients in the comparison groups had a similar aEEG or cEEG pattern. DISCUSSION: Seizures in SCN2A- and KCNQ3-related epilepsy in neonates can usually be recognized by a characteristic ictal aEEG pattern, previously reported only in KCNQ2-related epilepsy, extending this unique feature to other channelopathies. Awareness of this pattern facilitates the prompt initiation of precision treatment with sodium channel blockers even before genetic results are available.

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.

The phenotypic spectrum of KCNT1: a new family with variable epilepsy syndromes including mild focal epilepsy.

BACKGROUND AND OBJECTIVE: Pathogenic variants in KCNT1 have been associated with severe forms of epilepsy, typically sleep-related hypermotor epilepsy or epilepsy of infancy with migrating focal seizures. To show that pathogenic variants in KCNT1 can be associated with mild extra-frontal epilepsy, we report a KCNT1 family with a wide spectrum of phenotypes ranging from developmental and epileptic encephalopathy to mild focal epilepsy without cognitive regression and not consistent with sleep-related hypermotor epilepsy. METHODS: A large Canadian family of Caucasian descent including 9 affected family members was recruited. Family members were phenotyped by direct interview and review of existing medical records. Clinical epilepsy gene panel analysis and exome sequencing were performed. RESULTS: Phenotypic information was available for five family members of which two had developmental and epileptic encephalopathy and three had normal development and focal epilepsy with presumed extra-frontal onset. All three had predominantly nocturnal seizures that did not show hyperkinetic features. All three reported clusters of seizures at night with a feeling of being unable to breathe associated with gasping for air, choking and/or repetitive swallowing possibly suggesting insular or opercular involvement. Genetic analysis identified a heterozygous KCNT1 c.2882G > A, p.Arg961His variant that was predicted to be deleterious. DISCUSSION: This family demonstrates that the phenotypic spectrum associated with KCNT1 pathogenic variants is broader than previously assumed. Our findings indicate that variants in KCNT1 can be associated with mild focal epilepsy and should not be excluded during variant interpretation in such patients based solely on gene-disease validity.

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.

Creation and implementation of an electronic health record note for quality improvement in pediatric epilepsy: Practical considerations and lessons learned.

OBJECTIVE: To describe the development of the Pediatric Epilepsy Outcome-Informatics Project (PEOIP) at Alberta Children's Hospital (ACH), which was created to provide standardized, point-of-care data entry; near-time data analysis; and availability of outcome dashboards as a baseline on which to pursue quality improvement. METHODS: Stakeholders involved in the PEOIP met weekly to determine the most important outcomes for patients diagnosed with epilepsy, create a standardized electronic note with defined fields (patient demographics, seizure and syndrome type and frequency and specific outcomes- seizure type and frequency, adverse effects, emergency department visits, hospitalization, and care pathways for clinical decision support. These were embedded in the electronic health record from which the fields were extracted into a data display platform that provided patient- and population-level dashboards updated every 36 hours. Provider satisfaction and family experience surveys were performed to assess the impact of the standardized electronic note. RESULTS: In the last 5 years, 3,245 unique patients involving 13, 831 encounters had prospective, longitudinal, standardized epilepsy data accrued via point-of-care data entry into an electronic note as part of routine clinical care. A provider satisfaction survey of the small number of users involved indicated that the vast majority believed that the note makes documentation more efficient. A family experience survey indicated that being provided with the note was considered "valuable" or "really valuable" by 86% of respondents and facilitated communication with family members, school, and advocacy organizations. SIGNIFICANCE: The PEOIP serves as a proof of principle that information obtained as part of routine clinical care can be collected in a prospective, standardized, efficient manner and be used to construct filterable process/outcome dashboards, updated in near time (36 hours). This information will provide the necessary baseline data on which multiple of QI projects to improve meaningful outcomes for children with epilepsy will be based.