Chemogenetic Activation of Hippocampal Area CA2 Promotes Acute and Chronic Seizures in a Mouse Model of Epilepsy LaFrancois JJ, Kennedy M, Rathod M, Santoro B, Lisgaras CP, Siegelbaum SA, Scharfman HE. Neurobiology of Disease . 2026;219:107256. Pyramidal cells (PCs) of hippocampal area CA2 exhibit increased excitability in temporal lobe epilepsy (TLE) and in mouse models of TLE. In epileptic mice, selective inhibition of CA2 PCs reduces chronic seizures. Here we asked if activating CA2 PCs increases seizures. Mice expressing Cre recombinase in CA2 PCs ( Amigo2 -Cre mice) were injected with the convulsant pilocarpine to induce a period of severe seizures ( status epilepticus , SE), which leads to chronic seizures after 3–4 weeks (epilepsy). Epileptic mice were injected with a Cre-dependent adeno-associated virus (AAV) to express an excitatory designer receptor exclusively activated by designer drug (eDREADD; hM3Dq) in dorsal CA2 bilaterally and implanted with subdural EEG electrodes. After recovery, mice were recorded continuously using video and EEG for 6 weeks, 3 weeks with drinking water containing the eDREADD activator clozapine-N-oxide (CNO) and 3 weeks without CNO. CA2 activation with CNO caused a significant increase in seizure frequency and duration. Seizures occurred in clusters (many seizures per day over several consecutive days) and mice given water with CNO had a greater maximum number of seizures per day during a cluster compared to water without CNO. CNO had no significant effect in control mice. In naïve Amigo2- Cre mice expressing hM3Dq, pre-treatment with CNO before pilocarpine administration shortened the latency to SE and increased EEG power at the start of SE. Taken together with prior findings, the results suggest that CA2 is a control point for regulating seizures in the pilocarpine mouse model of TLE.

Context-Dependent NMDA Receptor Dysfunction Predicts Seizure Treatment in Mice with Human GluN1 Variant Venkatesan S, Nazarkina D, Sullivan MT, Tan YF, Qu S, Ramsey AJ, Lambe EK.. iScience . 2025;29(1):114301. doi: 10.1016/j.isci.2025.114301. PMID: 41602908; PMCID: PMC12834114. Mutations in N-methyl-D-aspartate receptors (NMDARs) cause epilepsy and profound cognitive impairment, though the underlying subunit-specific vulnerabilities remain unclear. We investigate the impact of a severe human variant in the lurcher motif of obligate GluN1 NMDAR subunit using transgenic mice, revealing unexpected context-dependent phenotypes. We show that the GluN1 Y647S variant significantly reduces current flow through pharmacologically isolated synaptic NMDARs in prefrontal neurons. Yet in intact local circuits, this loss-of-function paradoxically extends NMDAR-dependent dendritic integration, causing prolonged circuit-wide excitation that promotes seizures. Mutant receptors appear deficient in engaging opposing dendritic ion channels that normally curtail NMDAR-dependent excitation. Boosting SK channel activity normalizes dendritic integration, whereas slight decreases in extracellular magnesium further extend abnormally prolonged integration in mutant mice. We find that magnesium supplementation successfully treats seizures in vivo in the transgenic mice, despite loss-of-function of NMDARs. Overall, we disentangle a GluN1 variant's receptor-level effects and its dendritic impact to treat seizures effectively.

Background: Observational studies have established a relationship between stroke and epilepsy. While most studies have reported an increased risk of epilepsy following a stroke, fewer have concluded that a diagnosis of epilepsy increases the risk of future strokes. Precisely describing the causal relationship between epilepsy and stroke has clinical and public health implications. Methods: We performed a two-sample Mendelian Randomization (MR) to analyze the relationship between epilepsy and stroke. We identified genetic instruments from the Stroke Multiancestry Genome-Wide Association Study [GCST005838 (67,162 cases and 454,450 controls)] and the International League Against Epilepsy Consortium on Complex Epilepsies [Generalized epilepsy (GE): GCST007343 (n_case=3769, n_control=29677), Focal epilepsy (FE): GCST007352 (n_case=9671, n_control=29677)]. We used a significance threshold of p -value <5 × 10 (−5) for genetic instrument identification. We included the following epilepsy phenotypes: GE, FE, childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy, GE with tonic-clonic seizures, FE with hippocampal sclerosis (focal HS), and focal lesion-negative epilepsy. Linkage disequilibrium reference panel of 1000 Genome Project pruning with Pearson correlation r 2 < 0.2 was applied to ensure that the analysis is restricted to independent variants. We used Steiger filtering for reverse causality and Z -scores for GE and FE. We employed the following methods for causal effect estimation: Inverse-variance weighted (IVW), MR-Egger, MR-RAPS, and MRPRESSO. Results: For the association between GE and stroke (GE > stroke), stroke and GE (stroke > GE), FE and stroke (FE > stroke), and stroke and FE (stroke > FE), the number of single nucleotide polymorphisms was respectively 253, 213, 187, and 210. GE was associated with an increased risk of stroke [IVW, 95% confidence interval: 0.058 (0.028-0.088)], and stroke was also associated with an increased risk of GE [IVW: 0.059 (0.026-0.092)]. FE was associated with an increased risk of stroke [IVW: 0.066 (0.029-0.102)] and stroke was associated with an increased risk of FE [IVW: 0.037(0.005-0.068)]. The analysis by epilepsy subtypes revealed an increased risk only among patients with stroke and for the following epilepsy subtypes: JAE, CAE, Focal HS, and Focal lesion negative epilepsy. Conclusion: Our findings support a bidirectional relationship between stroke and epilepsy. Studies on post-stroke epilepsy should account for this bidirectional relationship.

[This corrects the article DOI: 10.1177/15357597251342227.].

Because there are many effective treatments for epileptic seizures, there is a great need for optimal diagnostic and treatment pathways. We present national strategies to address gaps and health equity in patients with epileptic seizures, focusing on efforts in China and the USA. We outline the delay in diagnosis and treatment caused by the "treatment gap." Efforts in China to address the "treatment gap" include the National Rural Epilepsy Management Project, the establishment of the national epilepsy quality control system, and standardized tertiary epilepsy center development. In the USA, Project Extension for Community Healthcare Outcomes (ECHO) epilepsy enables specialists to partner with primary care clinicians to deliver care. The National Association of Epilepsy Centers facilitates care and contributes to the standardization of presurgical epilepsy evaluation. A major recent and ongoing development is the Epilepsy National Plan in the USA, coordinated through the American Epilepsy Society (AES) with 120 epilepsy-related organizations, to advance a comprehensive national plan that reflects the needs of the entire epilepsy community.

Anterior temporal lobectomy (ATL) remains the standard surgical treatment for drug-resistant temporal lobe epilepsy, yet 20% to 30% of patients experience persistent seizures and/or unfavorable neuropsychological outcomes. These results highlight that postoperative success is influenced not only by the technical execution of surgery but also by the accuracy with which epileptogenic networks are characterized. As such, we consider ATL failure through 2 broad mechanisms: incomplete treatment of the presumed epileptogenic network and limitations in the initial diagnostic understanding of the epileptogenic network. It is also becoming more evident that seizure outcomes alone do not fully capture surgical success, as cognitive, psychiatric, and functional consequences play a critical role in long-term quality of life. Drawing on contemporary evidence and discussions from the Temporal Lobe Club Special Interest Group at the 2025 American Epilepsy Society Annual Meeting, we present a framework for conceptualizing, reevaluating, and managing patients following ATL failure.

Social determinants of health (SDoH) are increasingly recognized as critical drivers of health outcomes, influencing care access, treatment adherence, and disease management in people with epilepsy. However, it is unclear how clinicians integrate SDoH concepts into daily practice and what needs remain unmet in the field. A mixed-methods survey was conducted among members of the American Epilepsy Society (AES) between December 2024 and February 2025 to assess current understanding, practices, challenges, and educational needs related to SDoH. Quantitative and qualitative data analyses were conducted on the survey results. A total of 189 responses were collected, with 80% from U.S.-based healthcare professionals. Approximately 69.5% reported addressing SDoH in their practice, most frequently focusing on healthcare access and quality, followed by social and community context. Common strategies for addressing SDoH commonly involve systematic screening, telemedicine expansion, and collaboration with social workers or community organizations. Benefits from addressing SDoH-related issues were reflected in improved medication adherence, appointment attendance, and patient engagement. However, effective implementation of SDoH in epilepsy care continues to be challenged by several key barriers, including limited institutional support, lack of standardized screening tools, time constraints, and inadequate access to social work services, mental-health services, and language support. While SDoH awareness among AES members is high, significant implementation gaps persist. Respondents emphasized the need for expanded education, multidisciplinary resources, and institutional alignment. These findings underscore opportunities for AES to advance advocacy, professional development, and dissemination of best practices, supporting clinicians and institutions in promoting equitable, outcomes-driven epilepsy care across diverse populations.

Decades of research have demonstrated the complex intersection between sleep and epilepsy, which significantly impacts seizure control and epilepsy-related comorbidities. However, further investigation is needed to understand the underlying mechanisms linking sleep and epilepsy. Brain exchanges are dynamic processes that include blood-to-brain transport across the blood-brain barrier (BBB), where metabolism is regulated to sustain neural activity, and brain-to-blood and cerebrospinal fluid clearance via the glymphatic system. Together, the BBB and glymphatic system maintain brain milieu homeostasis, and dysfunction at any level can contribute to neurological disorders, including epilepsy. This review highlights the dynamics of water flow within the brain and explores the interrelationship between exchange and clearance pathways across the lifespan, as presented at the 2025 American Epilepsy Society Sleep and Epilepsy Special Interest Group Session. We provide an overview of (1) sleep-related breathing disturbances, their effects on seizures and cognitive function throughout the lifespan, and their implications for sudden unexpected death in epilepsy; and (2) the role of water dynamics mediated by the BBB and the glymphatic system in modulating sleep and epilepsy. These insights deepen our understanding of epilepsy severity and the role of sleep in modifying disease progression, offering promising directions for future research to advance therapeutic strategies.

Article 1: Epileptic encephalopathies are a devastating group of severe childhood epilepsy disorders for which the cause is often unknown. Here, we report a screen for de novo mutations in patients with 2 classical epileptic encephalopathies: infantile spasms (n = 149) and Lennox-Gastaut syndrome (n = 115). We sequenced the exomes of 264 probands, and their parents, and confirmed 329 de novo mutations. A likelihood analysis showed a significant excess of de novo mutations in the ∼4000 genes that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10(-3)). Among these are GABRB3, with de novo mutations in 4 patients, and ALG13, with the same de novo mutation in 2 patients; both genes show clear statistical evidence of association with epileptic encephalopathy. Given the relevant site-specific mutation rates, the probabilities of these outcomes occurring by chance are P = 4.1 × 10(-10) and P = 7.8 × 10(-12), respectively. Other genes with de novo mutations in this cohort include CACNA1A, CHD2, FLNA, GABRA1, GRIN1, GRIN2B, HNRNPU, IQSEC2, MTOR, and NEDD4L. Finally, we show that the de novo mutations observed are enriched in specific gene sets including genes regulated by the fragile X protein (P < 10(-8)), as has been reported previously for autism spectrum disorders. Article 2: Identifying genetic risk factors for highly heterogeneous disorders such as epilepsy remains challenging. Here, we present, to our knowledge, the largest whole-exome sequencing study of epilepsy to date, with more than 54,000 human exomes, comprising 20,979 deeply phenotyped patients from multiple genetic ancestry groups with diverse epilepsy subtypes and 33,444 controls, to investigate rare variants that confer disease risk. These analyses implicate 7 individual genes, 3 gene sets and 4 copy number variants at exome-wide significance. Genes encoding ion channels show strong association with multiple epilepsy subtypes, including epileptic encephalopathies and generalized and focal epilepsies, whereas most other gene discoveries are subtype specific, highlighting distinct genetic contributions to different epilepsies. Combining results from rare single-nucleotide/short insertion and deletion variants, copy number variants and common variants, we offer an expanded view of the genetic architecture of epilepsy, with growing evidence of convergence among different genetic risk loci on the same genes. Top candidate genes are enriched for roles in synaptic transmission and neuronal excitability, particularly postnatally and in the neocortex. We also identify shared rare variant risk between epilepsy and other neurodevelopmental disorders. Our data can be accessed via an interactive browser, hopefully facilitating diagnostic efforts and accelerating the development of follow-up studies. Article 3: Background: The epilepsies are highly heritable conditions that commonly follow complex inheritance. While monogenic causes have been identified in rare familial epilepsies, most familial epilepsies remain unsolved. We aimed to determine (1) whether common genetic variation contributes to familial epilepsy risk, and (2) whether that genetic risk is enriched in familial compared with nonfamilial (sporadic) epilepsies. Methods: Using common variants derived from the largest epilepsy genome-wide association study, we calculated polygenic risk scores (PRS) for patients with familial epilepsy (n = 1818 from 1181 families), their unaffected relatives (n = 771), sporadic patients (n = 1182), and population controls (n = 15,929). We also calculated separate PRS for genetic generalized epilepsy (GGE) and focal epilepsy. Statistical analyses used mixed-effects regression models to account for familial relatedness, sex, and ancestry. Findings: Patients with familial epilepsies had higher epilepsy PRS compared to population controls (OR 1·20, padj = 5 × 10-9), sporadic patients (OR 1·11, padj = 0.008), and their own unaffected relatives (OR 1·12, padj = 0.01). The top 1% of the PRS distribution was enriched 3.8-fold for individuals with familial epilepsy when compared to the lowest decile (padj = 5 × 10-11). Familial PRS enrichment was consistent across epilepsy type; overall, polygenic risk was greatest for the GGE clinical group. There was no significant PRS difference in familial cases with established rare variant genetic etiologies compared to unsolved familial cases. Interpretation: The aggregate effects of common genetic variants, measured as PRS, play an important role in explaining why some families develop epilepsy, why specific family members are affected while their relatives are not, and why families manifest specific epilepsy types. Polygenic risk contributes to the complex inheritance of the epilepsies, including in individuals with a known genetic etiology.

First Seizure HistoryNoble AJ, Lane S, New P, Cope H, Foley C, Williams HL, Sztriha L, Powell G, Reuber M, Marson AG. How accurate are witnesses of first suspected seizures in recalling semiology at clinically relevant timepoints? A UK experimental study with a pilot intervention. Epilepsia. 2025. doi:10.1111/epi.18624. Epub ahead of print. PMID: 40913485.Objective: A key diagnostic challenge at “first seizure” clinic appointments is determining whether the reported event was epileptic. Witness accounts are often critical, yet such appointments typically occur weeks after the event. Guidelines recommend review within 2 weeks. Wait times are however often longer, with a median of 7 weeks in countries such as the UK. The accuracy of witness recall at these clinically relevant intervals and whether their confidence predicts accuracy have never been determined. This study addressed these fundamental questions. It also piloted a potential intervention: whether asking witnesses a set of systematic questions immediately after viewing a suspected seizure improves recall at follow-up, compared to the usual free recall approach used by first responders. Methods: In this UK-based experimental study, adults (≥18 years old) viewed a video of an epileptic seizure and were randomized into four conditions: A (immediate free recall + 2-week follow-up), B (immediate free recall + 7-week follow-up), C (immediate systematic questions + 2-week follow-up), and D (immediate systematic questions + 7-week follow-up). The primary outcome was accuracy on 15 standardized questions addressing key semiological features, scored against consensus ratings from five neurologists. Results: Of a representative sample of 304 participants, 295 (97%) fully viewed the video, and 94.7% completed follow-up. At 2 weeks, participants answered 54.4% of questions correctly-only 3.9% (95% confidence interval [CI] = .52-7.3) more than those at 7 weeks. Confidence was poorly correlated with accuracy. Immediate systematic questioning improved later recall by 6.7% (95% CI = 3.3-10.0). A definitive trial of this intervention would require 926 participants. Significance: This is the first evidence on the accuracy of witness recall at clinically relevant intervals. Recall is modest even within recommended timeframes and declines only slightly by 7 weeks. Witness confidence does not predict accuracy. Immediate structured questioning may enhance later recall and thus support seizure diagnoses.