Epilepsy Currents

This practice guideline from the American Epilepsy Society provides evidence-based recommendations for pharmacological, dietary, and surgical therapies for epilepsy for infants and children from 1 month of age to <36 months. The multidisciplinary panel updated an existing systematic review, which was funded by the Patient-Centered Outcomes Research Institute and conducted by ECRI (formerly the Emergency Care Research Institute) on behalf of the Agency for Healthcare Research and Quality. The updated review used the same search strategy, inclusion/exclusion criteria, and Grading of Recommendations Assessment, Development and Education methodology, and added studies from August 2021 through September 2025 that were not in the original systematic review. As with the previous review, West syndrome and infantile spasms were excluded from this guideline, as existing treatment guidance is already available for infantile epileptic spasms. While many of the recommendations are conditional due to low certainty of evidence, the panel made two strong recommendations: (1) hemispherectomy/hemispherotomy surgery is recommended for infants and children <36 months of age with drug resistant epilepsy secondary to select underlying lesional pathologies, including but not limited to hemimegaloencephaly, Rasmussen's encephalitis, Sturge-Weber syndrome, perinatal stroke, and hemispheric cortical dysplasia; and (2) intralobar, multilobar, or focal resections or posterior disconnections for drug-resistant focal or lesional epilepsy in this same age range. A treatment algorithm was developed based on evidence and expert opinion as part of the guideline to help place pharmacological, dietary, and surgical recommendations in a clinical context. The limited number of studies and low certainty of evidence in this population underscores the need for higher-quality data and etiology-specific treatments. More research is needed to evaluate effective therapies for infants with epilepsy, as well as the impact these therapies have on long-term developmental and mortality outcomes.

This brief review summarizes presentations and discussion from the Health Disparities Special Interest Group held in December 2024 at the American Epilepsy Society Annual Meeting. The session addressed known health disparities in pediatric and adult epilepsy at a national and global level. The goal of the session was not just to present the known inequities, but to also propose ideas and work together toward improving healthcare for all. Invited speakers work directly with at-risk communities in the United States and abroad and shared their experiences on how we can do better. This piece is intended to provide a brief overview of the talks given by the invited speakers and to put it all together with the goal of achieving better epilepsy care for all by working together.

Human Epilepsy Project (1) Investigators. Treatment Response to Antiseizure Medications in People With Newly Diagnosed Focal Epilepsy

Barnard SN, Chen Z, Holmes M, Kanner AM, Hegde M, Kuzniecky R, Lowenstein D, French JA. JAMA Neurol. 2025 Aug 25:e252949. doi: 10.1001/jamaneurol.2025.2949. Epub ahead of print. PMID: 40853673

Importance: Epilepsy affects approximately 65 million people worldwide, and 60% have focal seizures. Predicting seizure response and drug resistance to antiseizure medications (ASMs) in people with focal epilepsy remains difficult. Objective: To describe the expected short- and long-term response to treatment with ASMs in people with focal epilepsy using recognized definitions by the International League Against Epilepsy. Design, setting, and participants: The Human Epilepsy Project is an international, prospective, observational cohort study that followed up people with newly diagnosed focal epilepsy for up to 6 years between 2012 and 2020. Data were analyzed from 2023 to 2024. The Human Epilepsy Project was conducted at 34 tertiary epilepsy centers across the US, Australia, and Europe. Participants with confirmed diagnosis of focal epilepsy aged 12 to 60 years were enrolled within 4 months of treatment initiation with ASM(s). Data were analyzed from February 2024 to July 2024. Exposure: ASM (variable). Main outcomes and measures: The primary outcome was seizure freedom, defined as a period without seizures for 12 months or 3 times the longest pretreatment seizure-free interval, whichever was longer. Treatment response was categorized as sensitive, meaning seizure free receiving 2 or fewer adequate ASM trials; resistant, meaning having 2 or more adequate ASM trials fail; or indeterminate (neither treatment sensitive nor resistant). Results: Among 448 enrolled participants, 267 (59.6%) were female, and median (IQR) participant age was 32 (21–44) years at treatment initiation. Median (IQR) follow-up duration was 3.13 (2.33–3.55) years. Most achieved seizure freedom (267 participants of 448 [59.6%]), largely without relapse (223 [83.5%]). There were 245 treatment-sensitive participants (54.7%), 102 treatment-resistant participants (22.8%), and 101 indeterminate participants (22.5%). Among treatment-sensitive participants, most (217 [89.3%]) responded to monotherapy and half (121 [49.4%], or 27% of total cohort) became seizure free while receiving their first ASM. In the first year of treatment, 251 participants (63%) had ongoing or worsening seizures. Median time to first seizure freedom was 12.1 months (95% CI, 9.7–16.1). This occurred earlier in those who never relapsed (median, 2.2 months; 95% CI, 0.8–3.2) than those who did (median, 7.4 months; 95% CI, 4.0–10.7). Those with infrequent pretreatment seizures were 0.30-fold less likely to be treatment resistant than those with very frequent seizures (hazard ratio, 0.30; 95% CI, 0.14–0.64; P = .002; Holm–Bonferroni-corrected P = .006). Participants with self-reported comorbid psychological disorders were 1.78-fold more likely to be treatment resistant than those without (relative risk, 1.78; 95% CI, 1.26–2.52; P = .001). Conclusions and relevance: In the Human Epilepsy Project multicenter prospective cohort study, most people with newly diagnosed focal epilepsy took more than a year and more than 1 ASM to become seizure free. Drug resistance can be identified earlier in those with frequent pretreatment seizures, and a history of psychiatric comorbidities at epilepsy diagnosis is an important prognostic factor.

Lamotrigine and Cardiac Arrhythmias. A Target Trial Approach

W. S. Terman, C. B. Josephson, P. Goyal, A. Gonzalez-Izquierdo, J. Morrison, S. Denaxas, and S. Wiebe. Neurology. 2025 Jul 8;105(1):e213640. doi: 10.1212/WNL.0000000000213640. Epub 2025 Jun 11.

Background and objectives: While lamotrigine is an effective, well-tolerated antiseizure medication (ASM), a recent warning raised the possibility of ventricular arrhythmias. We compared arrhythmia incidence between patients newly treated for seizures with lamotrigine and those with levetiracetam (presumed cardiac-inert control). Methods: We included patients whose first ASM prescription fill was after the first seizure or epilepsy ICD code in the study period, with no ASM in the previous year. We conducted retrospective cohort studies to emulate a target trial using two datasets: (1) 2009 to 2018 Medicare claims (United States) and (2) Clinical Practice Research Datalink (CPRD), a population-based cohort (United Kingdom). We examined cumulative incidence curves for ventricular tachycardia or fibrillation (VT/VF) from Cox proportional hazard models. Results: We included 40 554 patients (lamotrigine: 3038; levetiracetam: 37 516) from Medicare and 13 098 (lamotrigine: 8694; levetiracetam: 4404) from CPRD. In Medicare, the median (interquartile range) age was 61 (44-74) years and 60% were female in the lamotrigine group versus 74 (65-82) years and 57% female in the levetiracetam group. In CPRD, the median (interquartile range) age was 34 (23-53) years and 63% were female in the lamotrigine group versus 48 (29-66) years and 50% female in the levetiracetam group. After adjusting for demographics, comorbidities, and medication use, the hazard ratio for VT/VF comparing patients whose first ASM was lamotrigine versus levetiracetam was 0.73 (95% confidence interval (CI) 0.50-1.08) for Medicare and 0.75 (95% CI 0.35-1.59) for CPRD, with a 2-year cumulative incidence of 1.7% (95% CI 1.0%-2.3%) versus 2.3% (95% CI 2.1%-2.4%) for Medicare and 0.2% (95% CI 0.1%-0.4%) versus 0.3% (95% CI 0.2%-0.6%) for CPRD. In both datasets, lamotrigine showed a slightly but nonsignificantly lower 2-year absolute difference in cumulative incidence of VT/VF compared with levetiracetam (Medicare: −0.6%, 95% CI −1.2% to 0.0%; CPRD: −0.1%, 95% CI −0.3% to 0.1%). Numerous sensitivity analyses modifying the outcome (atrial arrhythmias or any arrhythmias), censorship procedure (further censoring patients on discontinuing their initial ASM akin to a “per-protocol” analysis), or population (patients with existing cardiovascular diagnoses) found similar results. Discussion: These data do not support concerns regarding lamotrigine increasing arrhythmias. Limitations include possible residual confounding and lack of generalizability to other populations. Classification of evidence: This study provides Class III evidence that lamotrigine compared with levetiracetam did not significantly increase the 2-year cumulative incidence of VT/VF in adult patients with epilepsy.

First Seizure History

Noble 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.

Trends in Status Epilepticus-Related Mortality Disparities in the United States, 1999–2020.

Budd W, Law CA, Shaik NF, Camitan M, Woodward MR, Schneider ALC, Johnson EL. Neurology. 2025;105(7):e214098. doi: 10.1212/WNL.0000000000214098. Epub 2025 Sep 8. PMID: 40921023.

Objectives: Status epilepticus (SE) is a life-threatening neurologic emergency. Although health disparities in epilepsy are well-documented, disparities in SE mortality are not fully understood. This study analyzes mortality trends and demographics in the United States from 1999 through 2020. Methods: This was a retrospective study of national data from the Center for Disease Control and Prevention's Wide-Ranging Online Data for Epidemiologic Research platform. We identified annual deaths due to SE for the years 1999 through 2020, stratified by age and by race and ethnicity. Results: From 1999 through 2020, there were 16,491 deaths due to SE in the United States. Overall, there was nearly a 2-fold increase in the age-standardized mortality due to the SE rate from 1999 to 2020 (0.13 per 100,000 persons [95% CI 0.11-0.15] in 1999 to 0.25 per 100,000 persons [95% CI 0.23-0.27] in 2020). This increase was most pronounced among older individuals (aged 75 years and older, followed by ages 50-74 years), and in non-Hispanic Black or African American individuals. Discussion: Over the past 2 decades, deaths attributed to SE have increased. This increase was most pronounced among individuals aged 75 years or older and Black or African Americans. Investigation into the underlying causes of SE-related mortality and reasons for these disparities is needed.

Frequency-Specific Alterations in Brain Connectivity Induced by Pulvinar Stimulation.

Acerbo E, Jegou A, Lagarde S, Pizzo F, Makhalova J, Trébuchon A, Bénar C-G, Bartolomei F, Carron R. Epilepsia. 2025 Aug;66(8):2690-2702. doi: 10.1111/epi.18405. Epub 2025 Apr 19.

Objective: Deep brain stimulation (DBS) is emerging as a promising therapy for patients with drug-resistant epilepsy, particularly those who are either unsuitable for or unresponsive to resective surgery. The potential benefit of DBS in these patients may stem from its ability to reduce excessive brain functional connectivity (FC). Given that patients undergoing presurgical evaluation in our institution are implanted with stereoelectroencephalographic (SEEG) electrodes in the thalamus, specifically in the pulvinar medialis (PuM), our aim was to investigate the impact of different stimulation frequencies on brain FC. We sought to determine whether specific frequencies were more effective in modulating FC. Methods: SEEG was used to investigate the effects of PuM stimulation across a broad frequency range (1-200 Hz) in a cohort of 14 patients with drug-resistant focal epilepsy. FC was assessed using the nonlinear correlation coefficient (h2) and node strength calculations. Results: Our findings revealed a reduction in FC at stimulation frequencies of 10 Hz and >90 Hz, contrasting with an increase in FC in the 20–80-Hz range. This modulation of FC extended beyond the epileptogenic zone, influencing all assessed brain lobes, with the parietal, insular, and subcortical regions particularly affected by high-frequency stimulation. Within the epileptogenic zone, however, the observed FC changes were notably more complex. Significance: These results underscore the potential of high-frequency stimulation to decrease interictal FC in epilepsy patients, although intermediate frequencies may exacerbate it and warrant caution. Crucially, this study highlights the effects of PuM stimulation on FC patterns, supporting the role of high-frequency thalamic stimulation as a promising DBS parameter for improving epilepsy management strategies.

Visualizing diagnostic delays in functional/dissociative seizures using the referral odyssey plot: A retrospective cohort study

Konomatsu K, Kakisaka Y, Ogawa M, Fujikawa M, Ishida M, Kubota T, Ukishiro K, Nakasato N, Aoki M, Jin K. Seizure. 2025 Oct 13;133:61-67. PMID: 41108888. doi:10.1016/j.seizure.2025.10.009. Epub ahead of print.

Background: Functional/dissociative seizures (FDS) are often misdiagnosed as epilepsy, leading to delays in appropriate interventions. Although certain factors are associated with diagnostic delays, the overall referral trajectory remains unclear. This study aimed to illustrate the diagnostic journey with a novel visual approach, the “referral odyssey plot,” and to depict patient pathways and identify factors associated with referral delays and diagnosis. Methods: We retrospectively reviewed 50 patients diagnosed with documented FDS at Tohoku University Hospital (2014–2024). All patients underwent comprehensive inpatient evaluation, including long-term video-electroencephalogram monitoring, brain MRI, and psychosocial assessment. Four milestones were defined: seizure onset (T1), first non-epileptologist visit (T2), first epileptologist consultation (T3), and epilepsy monitoring unit admission (T4). Diagnostic pathways were visualized using a referral odyssey plot. Associations between variables and intervals were analyzed using Spearman's correlation, Friedman test, Mann–Whitney U test, and Kruskal–Wallis test. Results: The median total delay (T1‐T4) was 51 months (interquartile range [IQR]: 83.8). The longest delay occurred between T2 and T3 (median, 41 months; IQR, 74.8) and strongly correlated with total delay (ρ = 0.95, p < 0.001). Younger age at onset and a family history of epilepsy were significantly associated with longer T2‐T3 intervals. Seizure worry scores were negatively correlated with T1‐T2 intervals. Conclusion: Referral delay to an epileptologist was the main contributor to prolonged diagnosis of FDS. The referral odyssey plot visualized individual trajectories and bottlenecks, supporting earlier specialist referrals. These findings highlight the need for timely access to epileptologists experienced in the comprehensive evaluation of epilepsy and FDS.

Seizure Frequency Trends Over Time in Treatment-Resistant Focal Epilepsy

Potnis O, Biondo G, Sukonik R, Grzeskowiak C, Cutter G, Altalib H, Kuzniecky R, Lowenstein D, French J; HEP2 Investigators. JAMA Neurology. 2025; 82(12):1257-1264.

Importance: Open-label trials of antiseizure medications (ASMs) and devices suggest seizure reduction in focal treatment-resistant epilepsy (FTRE) and may demonstrate treatment-related disease-modifying effects. Understanding FTRE trends can provide insight into treatment responses. Objective: To determine whether seizure frequency in FTRE improves over time. Design, setting, and participants: The Human Epilepsy Project 2 was a prospective, observational, multicenter study of patients with FTRE from May 2018 to September 2021 who were followed-up for 18 to 36 months at 10 U.S.-based comprehensive epilepsy centers. Analysis was performed from 2021 to 2024. Study data included seizure frequency, medication use, device use, surgeries tracked using daily electronic diaries, monthly check-ins, medical record review, and case report forms. Eligibility criteria included focal epilepsy diagnosis, age between 16 and 65 years, and failure of 4 or more ASMs (≥2 due to seizure control failure). Participants were recruited as a volunteer sample. Exposures: Participants were treated with multiple interventions at their physicians’ discretion. Main outcomes and measures: The primary outcome was seizure frequency trends, evaluated by quantifying seizure freedom rates and frequency reductions. Medication and device treatment responses were assessed by tracking ASM and device changes. Results: Of 196 approached participants, 146 met eligibility criteria and were included in the study. Mean (SD) participant age was 40 (12) years, and epilepsy was diagnosed at a mean (SD) age of 19.8 (13.6) years. The cohort had 84 (57.5%) female participants. A total of 35 participants had implantable devices; 1 had epilepsy surgery during the study. Of 146 participants, 128 provided sufficient seizure data for analysis, and 2 were excluded as outliers. Seizure frequency was reduced in 86 participants (68.3%) during the second half of study participation compared to the first half. In the overall cohort, mean modeled monthly seizure frequency percentage reduction was 68.73% (95% CI, 52.92%-84.54%). From 0 to 12 months (cohort 1), mean modeled percentage reduction was 67.76% (95% CI, 19.42%-116.09%); for 12 to 24 months (cohort 2), 36.00% (95% CI, 9.27%-53.46%); and for longer than 24 months (cohort 3), 66.03% (95% CI, 48.25%-83.80%) (all P < .001). An ASM was added in 69 participants (54.7%), of whom 46 (66.7%) experienced seizure frequency reduction, including seizure freedom. Seizure trajectories in participants with devices did not significantly differ from those without devices. Conclusions and relevance: Findings from the Human Epilepsy Project 2 study imply that FTRE improves over time, ASM additions had low probability of achieving seizure freedom but contributed to seizure reduction, and device-treated participants exhibited similar seizure trajectories to those without devices. Whether improvements reflected the natural history of FTRE or active management remains unclear, but our findings suggest cautious interpretation of open-label studies positing disease-modifying effects and further research into FTRE treatment response.

Antiseizure Medications Consumption in 73 Countries and Regions from 2012 to 2022: A Longitudinal Trend Study

Chan AYL, Yuen ASC, Hsia Y, Lau WCY, Cross JH, Walker MC, Besag FMC, Hung ATF, Iessa N, Chowdhary N, Man KKC, Wong ICK. EClinicalMedicine. 2025 Oct 9;89:103558. doi: 10.1016/j.eclinm.2025.103558. PMID: 41140454; PMCID: PMC12547185.

Background: International trends in antiseizure medication use across countries from different geographical regions and income levels remain underexplored. Valproic acid (valproate) use has raised concerns due to its teratogenic risks, with World Health Organization (WHO) guidelines recommending lamotrigine or levetiracetam as first-line therapy for epilepsy in women and girls of childbearing potential, advising against valproate use in this population. This study aimed to assess multinational trends in antiseizure medication (ASM) consumption from 2012 to 2022 in the context of evolving policy and regulatory actions. Methods: In this longitudinal trend study, we used pharmaceutical sales data of antiseizure medications from the IQVIA-Multinational Integrated Data Analysis System (MIDAS) between January 1, 2012 and December 31, 2022, covering 73 countries/regions. The list of ASMs included in this study was based on the Anatomical Therapeutic Chemical (ATC) Classification, N03A. We obtained the midyear national/regional population estimates of each country from the United Nations Population Division and the total epilepsy (active idiopathic and secondary epilepsy) population from the Global Burden of Disease Collaborative Network. In total, 41 high-income, 20 upper-middle income, and 12 lower-middle-income countries/regions were included in this study. Antiseizure medication consumption rate was expressed as defined daily doses per 10 000 inhabitants per day (DDD/TID). Linear mixed models were used to estimate multinational, regional, and income-level trends in consumption over time. Findings: Multinational antiseizure medication consumption increased throughout the study period, with an average annual percentage change of +2.58% (95% CI +1.85% to +3.32%), rising from 40.96 DDD/TID (31.94-52.52) in 2012 to 52.87 DDD/TID (42.17-66.27) in 2022. The highest change in consumption was in South-eastern Asia (+5.20%, +3.41% to +7.03%), followed by Western Asia (+4.70%, +0.58% to +8.99%) and Southern Asia (+3.80%, +1.52% to +6.14%). Newer generation antiseizure medications such as levetiracetam (+21.72%, +13.86% to +30.11%) and lamotrigine (+7.48%, +6.34% to +8.63%) showed growth in consumption, while consumption of older medications such as phenobarbital (−2.85%, −9.50% to +4.29%), phenytoin (−11.19%, −17.58% to −4.30%), and carbamazepine (−1.09%, −1.95% to −0.23%) declined. In 2022, the consumption rate of high-income countries (88.36 DDD/TID, 71.69-108.90) was more than 4 times of lower-middle-income countries (15.63 DDD/TID, 8.75-27.91). Valproate remained the most widely used antiseizure medication globally (10.93 DDD/TID, 8.68-13.77) in 2022, with stronger growth observed in lower- (+4.24%, +1.73% to +6.81%) and upper-middle-income (+3.10%, +0.95% to +5.29%) countries, compared with high-income countries (+0.86%, −0.07% to +1.79%). Interpretation: Multinational antiseizure medication use increased between 2012 and 2022, particularly for newer medications like levetiracetam and lamotrigine. Disparities in access to antiseizure medications across countries of varying income levels persist, with valproate consumption remaining predominant. This underscores the urgent need to align prescribing practice with safety guidelines, in order to optimize patient outcomes. Since patient-level characteristics are not available in IQVIA-MIDAS, further research is warranted to examine consumption rates across different population groups.

The Gut Microbiome Associated with LGI1-Antibody Encephalitis

Gilbert E, Binks S, Damato V, Uy C, Colmenero P, Kelly M, Khalil MI, O'Brien M, Claesson MJ, Cryan JF, Delanty N, Irani SR, Cavalleri GL. Epilepsia. 2025;66:4411–4424.

Objective: Autoimmune encephalitis is a cause of brain inflammation characterized by auto-antibodies, which target cell surface neuronal proteins and lead to neuronal dysfunction. The most common form is associated with auto-antibodies to leucine-rich glioma-inactivated 1 (LGI1) protein, the presentation of which includes frequent focal seizures. The exact cause of these auto-antibodies remains unknown, but established predispositions include overrepresented human leukocyte antigen (HLA) alleles. Yet, these HLA alleles are themselves common in the healthy ancestry-matched population. One potential etiological hypothesis is that an environmental trigger, such as the gut microbiome, interacts with a genetically predisposed individual. Methods: To investigate this, we studied 42 patients with LGI1-antibody encephalitis (LGI1-Ab-E) and 27 familial/environmentally matched controls and performed metagenomic shotgun sequencing, to describe the compositional and functional differences in the gut microbiome. Results: We observed that LGI1-Ab-E gut microbiomes exhibited a significant reduction in the ratio of Firmicutes (or Bacillota) and Bacteroidetes phyla, which is associated with the dosage of HLA susceptibility allele count in patients with LGI1-Ab-E. Furthermore, we identified differences in functional gene profiles in the gut microbiome that led to a reduction of neuroinflammatory protective short-chain fatty acids (SCFAs) in LGI1-Ab-E patients. Significance: Taken together, our results suggest that a compositional shift in the gut microbiome of LGI1-Ab-E associates with a neuroinflammatory state, possibly through the reduction of SCFA production. Our study highlights the potential of the gut microbiome to explain some of the complex condition and unravel etiological questions. Validation studies with greater sample sizes are recommended.

Sudden unexpected death in epilepsy (SUDEP) is the most catastrophic complication associated with epileptic seizures. Despite its devastating impact, the mechanistic underpinnings of SUDEP remain poorly understood, limiting the development of effective preventive strategies. Animal models have proven indispensable in understanding the complex pathophysiology of SUDEP, offering controlled systems to dissect potential causes of these fatal events. This review provides a comprehensive overview of the current landscape of SUDEP animal models, with an emphasis on key experimental variables that impact SUDEP outcome in animal studies. In particular, this review focuses on how the animals’ genetic background, age, sex, vigilance state, and time of day influence their phenotypic variability. We also report the major discrepancies in terminal seizure characteristics between mice and humans and highlight the necessity to segregate “anti-SUDEP” effects from potential “antiseizure” effects. From a regulatory and animal welfare perspective, we discuss the challenges of studying SUDEP as an endpoint and outline the critical steps to implement the preclinical SUDEP common data element, thereby promoting consistency, reproducibility, and interoperability across preclinical studies. By synthesizing insights across critical experimental variables and remaining challenges in SUDEP preclinical studies, this review aims to promote rigorous experimental design in animal SUDEP studies, with the long-term goal of facilitating translational insights into human SUDEP prevention.

Connectomic and Behavioural Alterations in Creatine Transporter Deficiency are Partially Normalized by Gene Therapy

Montani C, Iovino L, Di Vetta F, Rene’ Pasquin Mariani J-C, De Guzman AE, Gini S, Galbusera A, D'Epifanio B, Ghirardini E, Cornuti S, Dadà L, Putignano E, Alessandrì MG, Vasirani G, Bertozzi SM, Armirotti A, Baroncelli L, Gozzi A. Brain. 2025:awaf275. doi: 10.1093/brain/awaf275. Online ahead of print.

Creatine Transporter Deficiency (CTD) is an X-linked disorder due to the loss of SLC6A8 gene and presenting with low brain creatine, intellectual disability, autistic-like behavior and seizures. No treatments are available yet for CTD, and little is known about the brain circuit alterations underlying its pathological endophenotypes. Here, we tracked brain network and behavioral dysfunction in a murine model of CTD at two stages of disease progression. fMRI mapping revealed widespread disruption of brain connectivity in Slc6a8-KO mice, with robust somatomotor hypoconnectivity in juvenile animals, and weaker and more focal alterations of cortical and subcortical connectivity in adulthood. Notably, perinatal AAV-mediated expression of human SLC6A8 in Slc6a8-KO mice robustly prevented juvenile fMRI hypoconnectivity, an effect accompanied by the regression of multiple translationally relevant phenotypes, including reduced stereotyped movements, improved declarative memory and increased body weight, all of which persisted into adulthood. However, early cognitive deficits, impairments in working memory and residual fMRI hypoconnectivity in adult mice were not ameliorated by gene therapy. Furthermore, significant cognitive impairments were observed in WT mice receiving gene therapy, highlighting a potential detrimental effect of ectopic expression of SLC6A8 in healthy brain circuits. Finally, multivariate modeling in adult mice revealed a basal forebrain network whose activity was associated with behavioral performance and modulated by brain creatine levels. This brain-behavior relationship was disrupted in Slc6a8-KO mice. Our results document robust network disruption in CTD and demonstrate that CTD pathology can be partially alleviated by perinatal genetic expression of SLC6A8, providing a foundation for the future development of experimental therapies for this genetic disorder.

Resolving Native GABA_A Receptor Structures From the Human Brain

Zhou J, Noviello CM, Teng J, Moore H, Lega B, Hibbs RE. Nature. 2025;638(8050):562–568. DOI: 10.1038/s41586-024-08454-1

Type A GABA (γ-aminobutyric acid) receptors (GABA_A receptors) mediate most fast inhibitory signalling in the brain and are targets for drugs that treat epilepsy, anxiety, depression and insomnia and for anaesthetics.^1,2 These receptors comprise a complex array of 19 related subunits, which form pentameric ligand-gated ion channels. The composition and structure of native GABA_A receptors in the human brain have been inferred from subunit localization in tissue,^1,3 functional measurements and structural analysis from recombinant expression^4–7 and in mice.⁸ However, the arrangements of subunits that co-assemble physiologically in native human GABA_A receptors remain unknown. Here we isolated α1 subunit-containing GABA_A receptors from human patients with epilepsy. Using cryo-electron microscopy, we defined a set of 12 native subunit assemblies and their 3D structures. We address inconsistencies between previous native and recombinant approaches, and reveal details of previously undefined subunit interfaces. Drug-like densities in a subset of these interfaces led us to uncover unexpected activity on the GABA_A receptor of antiepileptic drugs and resulted in localization of one of these drugs to the benzodiazepine-binding site. Proteomics and further structural analysis suggest interactions with the auxiliary subunits neuroligin 2 and GARLH4, which localize and modulate GABA_A receptors at inhibitory synapses. This work provides a structural foundation for understanding GABA_A receptor signalling and targeted pharmacology in the human brain.

Cortical Versus Hippocampal Network Dysfunction in a Human Brain Assembloid Model of Epilepsy and Intellectual Disability

McCrimmon CM, Toker D, Pahos M, Cao Q, Lozano K, Lin JJ, Parent JM, Tidball A, Zheng J, Molnár L, Mody I, Novitch BG, Samarasinghe RA. Cell Rep. 2025 Sep 23;44(9):116217. PMID: 40925365 PMCID: PMC12674601 DOI: 10.1016/j.celrep.2025.116217

Neurodevelopmental disorders often impair multiple cognitive domains. For instance, a genetic epilepsy syndrome might cause seizures due to cortical hyperexcitability and present with memory impairments arising from hippocampal dysfunction. This study examines how a single disorder differentially affects distinct brain regions using induced pluripotent stem cell (iPSC)-derived cortical- and hippocampal-ganglionic eminence assembloids to model developmental and epileptic encephalopathy 13, a condition arising from gain-of-function mutations in the SCN8A gene encoding the sodium channel Nav1.6. While cortical assembloids showed network hyperexcitability akin to epileptogenic tissue, hippocampal assembloids did not, and instead displayed network dysregulation patterns similar to in vivo hippocampal recordings from epilepsy patients. Predictive computational modeling, immunohistochemistry, and single-nucleus RNA sequencing revealed changes in excitatory and inhibitory neuron organization that were specific to hippocampal assembloids. These findings highlight the unique impacts of a single pathogenic variant across brain regions and establish hippocampal assembloids as a platform for studying neurodevelopmental disorders.

Distinct Changes to Hippocampal and Medial Entorhinal Circuits Emerge Across the Progression of Cognitive Deficits in Epilepsy

Feng Y, Diego KS, Dong Z, Christenson Wick Z, Page-Harley L, Page-Harley V, Schmipper J, Lamsifer SI, Pennington ZT, Vetere LM, Philipsberg PA, Soler I, Jurkowski A, Rosado CJ, Khan NN, Cai DJ, Shuman T. Cell Rep. 2025;44(2):115131.

Temporal lobe epilepsy (TLE) causes pervasive and progressive memory impairments, yet the specific circuit changes that drive these deficits remain unclear. To investigate how hippocampal-entorhinal dysfunction contributes to progressive memory deficits in epilepsy, we performed simultaneous in vivo electrophysiology in the hippocampus (HPC) and medial entorhinal cortex (MEC) of control and epileptic mice 3 or 8 weeks after pilocarpine-induced status epilepticus (Pilo-SE). We found that HPC synchronization deficits (including reduced theta power, coherence, and altered interneuron spike timing) emerged within 3 weeks of Pilo-SE, aligning with early-onset, relatively subtle memory deficits. In contrast, abnormal synchronization within the MEC and between HPC and MEC emerged later, by 8 weeks after Pilo-SE, when spatial memory impairment was more severe. Furthermore, a distinct subpopulation of MEC layer 3 excitatory neurons (active at theta troughs) was specifically impaired in epileptic mice. Together, these findings suggest that hippocampal-entorhinal circuit dysfunction accumulates and shifts as cognitive impairment progresses in TLE.

Original Article Citation:

Hippocampal Spreading Depolarization as a Driver of Postictal Ambulation

Mitlasóczki B, Gutiérrez Gómez A, Kamali M, Babushkina N, Baues M, Kück L, Haubrich AN, Tamiolakis T, Breuer A, Granak S, Schwering Sohnrey M, Gerhauser I, Baumgärtner W, Schwarz MK, Ewell L, Opitz T, Pitsch J, Musall S, Surges R, Mormann F, Beck H, Wenzel M. Sci Transl Med. 2025;17(816):eadv3260. doi:10.1126/scitranslmed.adv3260. PMID: 40961224

Original Article Abstract:

Postseizure (postictal) symptoms are regularly encountered in epilepsy and can be life threatening, yet their neurobiological underpinnings remain understudied. Using two-photon or widefield imaging, field potential and unit recordings, optogenetics, and basic behavioral assessment under healthy conditions or viral encephalitis, we studied seizures and postictal symptoms in mice. We show a propensity of the hippocampus for seizure-associated spreading depolarization (sSD). Through optogenetic stimulation, we provide evidence that induced isolated hippocampal spreading depolarization SD is sufficient to elicit postictal ambulation (PIA), whereas induced isolated seizure-like episodes are not. Furthermore, PIA occurred in the absence of SD progression to the neocortex. In addition, we analyzed Behnke-Fried depth-electrode recordings in four patients with focal epilepsy. Of 13 recorded seizures, we observed five slow shifts at seizure termination in the regionwise analysis that could reflect putative sSD. In support of our experiments in mice, we also found an increased vulnerability of the human temporomesial system (hippocampus and amygdala) for this phenomenon and longer recovery times of affected as compared with nonaffected brain regions. This work suggests sSD as a previously underrecognized pathoclinical entity underlying distinct postictal symptoms in epilepsy.

Distinct Manifestations of Excitatory–Inhibitory Imbalance Associated With Amyloid-β and tau in Patients With Alzheimer's Disease

Ranasinghe KG, Kudo K, Syed F, Yballa C, Kramer JH, Miller BL, Rankin KP, Garcia PA, Kirsch HE, Vossel K, Jagust W, Rabinovici GD, Nagarajan SS. Nat Commun. 2025;16(1):7957. doi:10.1038/s41467-025-62798-4

A growing body of evidence shows that epileptic activity is frequently observed in patients with Alzheimer's disease (AD), implicating underlying excitatory–inhibitory imbalance. The distinction of whether the AD-epileptic phenotype represents a subset of patients or an underdiagnosed manifestation holds major therapeutic implications. Here, we quantified the excitatory–inhibitory imbalance in AD patients using magnetoencephalography and examined the relationships to AD pathophysiology—amyloid-beta and tau, and to epileptic activity. We used two metrics to quantify regional excitatory–inhibitory imbalance distinguishing between local hyperexcitability (Neural excitability, quantified by regional aperiodic spectral slope) and aberrant long-range synaptic input integration (Neural fragility, quantified by regional linear dynamic instability). We found that amyloid-beta correlated with higher neural fragility and higher neural excitability, while tau and hypometabolism uniquely correlated with higher neural excitability. Importantly, the AD-epileptic phenotype showed a distinctive increase in neural fragility. Our findings demonstrate that AD pathophysiology is associated with diverse mechanisms of excitatory–inhibitory imbalance and that AD-epileptic phenotype represents a distinct group of patients with greater impairments in long-range synaptic input integration.

Early Microglia-Mediated Neuroinflammation After Status Epilepticus Causes Behavioral Dysfunction and Neurocognitive Deficits but not Epilepsy in Mice

Thergarajan P, Al-Hobaish G, Sutherland G, Tsantikos E, Jupp B, Haskali MB, Casillas-Espinosa PM, Hibbs ML, O’Brien TJ, Ali I, Jones NC. Brain Behav Immun. 2026 Jan;131:106183. doi: 10.1016/j.bbi.2025.106183. Epub 2025 Nov 13. PMID: 41241085.

Background: Neuroinflammation is implicated in epilepsy pathogenesis, and microglia are key immune cells of the brain that participate in neuroinflammatory responses associated with epilepsy. This study investigated the role of early microglial activation following an epileptogenic brain injury on the incidence and severity of epilepsy and associated neurobehavioral impairments in a model of acquired epilepsy. Methods: Status epilepticus (SE) was induced in male C57BL/6 mice via electrical stimulation of the ventral hippocampus, while additional mice were enrolled as sham controls (n = 125 total). Following termination of SE, mice received injections of the colony-stimulating factor 1 (CSF1) receptor inhibitor PLX5622 (PLX; 50 mg/kg IP twice daily) to suppress microglial activation caused by SE, or vehicle, for seven days. At the end of treatment, the effect of microglial suppression on the neuroinflammatory response to SE was characterised using gene expression, immunohistochemistry, and flow cytometry. Additional mice were followed for four months and underwent a series of neurobehavioral tests and epilepsy assessment. Results: PLX treatment significantly reduced Iba1 + cell counts, reduced GFAP + immunoreactivity, and downregulated the expression of proinflammatory cytokines in the hippocampus compared to vehicle following SE, intimating that the neuroinflammatory response of SE was suppressed by PLX. Flow cytometry revealed that SE significantly reduced microglial expression of CX3CR1 and CD206, but increased expression of CD16/32, shifting microglia towards a pro-inflammatory state. However, PLX treatment did not influence the relative expression of these genes. In the chronic stage, SE mice treated with PLX exhibited improved spatial memory (Y-maze test: p = 0.0016) and reduced depressive-like behavior (tail suspension test: p = 0.04; sucrose preference: p = 0.14) compared to vehicle-treated SE mice. However, PLX treatment did not alter the incidence of epilepsy after SE (58% in vehicle-treated mice vs 50% PLX treated mice; p = 0.65) or seizure frequency in epileptic animals. Conclusion: Suppression of microgliosis with PLX eliminates the neuroinflammatory response after SE, and this is associated with prevention of long-term behavioral impairment. However, this intervention does not influence the development of epilepsy. These results demonstrate that acquired epilepsy and its behavioral comorbidities have different pathogenic mechanisms after SE, with early microglial driven neuroinflammation most relevant to the latter.