Despite advancements in "autoimmune epilepsy," more accurately referred to herein as seizures or epilepsy of autoimmune etiology, significant variability exists in its recognition, diagnosis, and management internationally. This study assessed clinicians' understanding, access to diagnostic tools, and treatment practices across global regions. An online survey, "Recognizing Autoimmune Seizures" was disseminated globally through professional networks including the Canadian League Against Epilepsy (CLAE), International League Against Epilepsy (ILAE), Young Epilepsy Section (YES), and American Epilepsy Society (AES). The survey included 157 respondents: adult neurologists (50%), pediatric neurologists (38%), other healthcare professionals (8%), and trainees (6%). Although 69% reported familiarity with updated ILAE definitions for seizures or epilepsy of autoimmune etiology, 43% noted difficulty with clinical identification. Familiarity varied significantly by region (p = 0.024) and was highest in Europe (76%) and Asia/South/Central America (73%) versus North America (50%). In Asia and South/Central America, 66% of respondents reported difficulty accessing neural antibody testing, compared with 22% in North America and 17% in Europe (p < 0.001), largely due to financial barriers in resource-limited regions (87%; p < 0.001). As a result, clinicians in these settings more frequently treated patients empirically with immunotherapy without confirmatory testing (72%; p < 0.001). Further, adult providers more often identified anti-GAD65 (73% vs. 52%), anti-LGI1 (83% vs. 36%), and paraneoplastic antibodies (79% vs. 31%), whereas pediatric clinicians more frequently encountered anti-MOG-associated seizures (84% vs. 58%; all p ≤ 0.015). The survey highlights a clear knowledge-to-practice gap in the recognition and diagnosis of seizures or epilepsy of autoimmune etiology. While many are familiar with conceptual definitions, a substantial proportion lack confidence in clinical identification. Respondents emphasized that both knowledge gaps and limited access to diagnostic resources contribute to ongoing disparities in care. There is a pressing need for regionally tailored international initiatives to facilitate clinician education and improve equitable access to neural antibody testing. This global survey of 157 clinicians found that while familiarity with conceptual definitions of seizures and epilepsy of autoimmune etiology was high, clinical recognition remained limited, revealing a clear knowledge-to-practice gap. Familiarity varied by region, highest in Europe and South/Central America and Asia, and lowest in North America. Access to neural antibody testing was most constrained in Asia and South/Central America, where limited public funding and high out-of-pocket costs were major barriers, leading clinicians to rely more often on empirical immunotherapy. These regional differences highlight the need for context-specific strategies rather than one-size-fits-all solutions to improve equitable care.

Cenobamate (CNB) is a highly effective antiseizure medication (ASM) for focal drug-resistant epilepsy (DRE); nevertheless, even with CNB treatment and optimized therapy, a substantial proportion of patients continued to experience seizures. Preliminary observations suggest that clobazam (CLB), a 1,5-benzodiazepine, may enhance CNB efficacy. We aimed to evaluate the real-world effectiveness and safety of adjunctive low-dose CLB in adults with focal DRE who continued to have incomplete seizure control despite CNB. We conducted a retrospective single-center study including adults with focal DRE treated with CNB ≥200 mg/day who subsequently received adjunctive CLB due to persistent seizures despite CNB therapy. Seizure outcomes, responder rates, treatment retention, adverse drug reactions (ADRs), and changes in concomitant ASM burden were assessed at approximately 3, 6, 9, and 12 months after CLB initiation. Eighty-five patients were included (median disease duration, 12 years; median of 6 prior ASM failures). Median seizure reduction from CLB initiation improved from 80.0% at 3 months to 95.8% at 12 months (p < 0.001 at all time points). Responder rates (≥50% reduction) ranged from 72.9% to 82.1%, and approximately one-third of patients achieved seizure freedom across follow-up. The 12-month retention rate was 83.1%. Modifications in concomitant ASM burden were minor and descriptive, without implying a meaningful reduction in polytherapy. ADRs were mostly mild to moderate, predominantly somnolence, with low discontinuation rates. Adjunctive low-dose clobazam was associated with rapid and sustained seizure reduction in adults with focal DRE who had incomplete seizure control on CNB. The combination was generally well tolerated and was associated with no meaningful reduction in polytherapy. These findings support a potential pharmacokinetic-pharmacodynamic interaction between CNB and CLB and highlight the role of mechanism-driven polytherapy in refractory epilepsy. This study looked at adults with hard-to-treat focal epilepsy whose seizures were not fully controlled by cenobamate. Adding a low dose of clobazam to their existing treatment helped most patients reduce the number of seizures, with many achieving near-complete control. The combination was generally well tolerated, and most patients were able to continue therapy over 1 year. These findings suggest that strategically combining these two medicines can improve seizure control in patients who remain resistant to standard treatments.

Expanded indications, diagnostic tools, and treatment options have transformed the landscape of modern pediatric epilepsy surgery. Published real-world experiences from large surgical cohorts are still needed. To close this gap, we evaluated access, indications, treatment, and outcomes in a contemporary pediatric epilepsy surgery program. We evaluated data from 100 consecutive diagnostic and therapeutic procedures in 62 pediatric and young adult patients. Data collected included demographics, diagnostics, procedures, 12-month seizure and medication outcomes, and adverse events. Primary outcome for patients who underwent treatment with the goal of cure or resection, along with the intent of palliation, was 12-month postoperative Engel/ILAE scores. For those who underwent RNS-implant (alone or in combination with a second procedure) with the goal of seizure reduction, the primary outcome was proportion seizure reduction in the prior 28 days at 12 months postoperatively. Patients largely matched state and regional demographics. Epilepsy types included unifocal (n = 33, 53.2%), multifocal (n = 15, 24.2%), generalized (n = 12, 19.4%), and combined (n = 2, 3.2%). Of the 100 procedures, 36.0% were diagnostic SEEG (n = 35) and 64.0% were treatment procedures (n = 58; note: n = 4 pending). Among patients who underwent surgical treatment with the goal of cure (n = 33), a 12-month Engel I/ILAE I or III outcome was achieved in 81.8% (n = 27). Among patients who underwent RNS implantation, 79.0% were responders (>50% reduction) and 38.0% were super-responders (>90% reduction), with a median seizure reduction of 78% at 12 months. Three treatment procedures (4.7%, n = 3 patients) had a surgical complication, none permanent. Contemporary pediatric epilepsy surgery, utilizing modern diagnostic and surgical techniques, including off-label use of RNS, provides safe, effective, accessible, and equitable treatment to children across a broad range of indications, many of whom, historically, have not been considered viable surgical candidates. "In this article by McLaren etal, 100 consecutive procedures were examined from a modern pediatric epilepsy surgery program. By utilizing advanced diagnostic and surgical techniques, they've shown that pediatric epilepsy surgery can be safe, effective, and accessible across diverse conditions and demographics. Notably, 82% of patients who underwent surgery aimed at curing their condition achieved seizure-freedom in 12 months and 79% of patients with Responsive Neurostimulation (RNS) implants experienced significant seizure reduction."

Male people with epilepsy (mPWE) are at higher risk for bilateral tonic-clonic seizures (BTCs) and sudden unexpected death in epilepsy (SUDEP) compared to female people with epilepsy (fPWE). Despite major clinical and personal implications, little is known about sex-specific differences in seizure propagation and termination. Characterization of seizure duration in men versus women with unifocal epilepsy. Adults with unifocal epilepsy and available intracranial EEG (iEEG) recordings (September 2006 to March 2022) were identified retrospectively. Up to 20 clinical seizures were analyzed per person, excluding individuals with status epilepticus or lateralized periodic discharges. Seizure duration was determined based on iEEG recordings. In focal to bilateral tonic-clonic seizures (FBTCs), durations of the focal and BTC phases were assessed based on EEG and seizure semiology. Multiple linear regression was used to assess sex-specific differences in seizure duration, adjusting for age, epileptic hemisphere, frontal lobe epilepsy (FLE), temporal lobe epilepsy (TLE), lateralizing signs, onset during sleep, and focal seizures with preserved consciousness and aura phenomena (FPC-a). A restricted-cohort sensitivity analysis was performed, excluding PWE in whom clinical seizure onset preceded iEEG onset. A total of 100 PWE (m/f = 50/50; age: 33.6 ± 12.2 years) and 758 seizures (120 FBTCs) were analyzed. While fPWE had significantly longer focal seizures (FSs) (p = 0.015), mPWE revealed significantly longer FBTCs (p < 0.001), driven by a prolonged focal phase (p = 0.002). No significant difference was observed for the BTC phase. In the restricted cohort (n = 77 PWE), the prolongation of the focal phase during FBTCs in mPWE remained robust (p = 0.006). Our findings demonstrate sex-specific differences in seizure duration, suggesting that seizure propagation may differ between men and women. This may contribute to a better pathophysiological understanding of the sex-specific differences in seizure manifestation and associated risks and underline the yet unmet need for a sex-specific approach in epilepsy research and patient management. Sex-related differences in epilepsy are increasingly recognized but remain poorly understood. In this study, we compared seizure duration between women and men with unifocal epilepsy using intracranial brain recordings. We found that women had longer focal seizures, whereas men had longer focal phases in focal to bilateral tonic-clonic seizures. Further research is needed, as these differences may be relevant for clinical care and risk assessment in epilepsy.

Drug-resistant epilepsy (DRE) imposes a significant burden on patients and their caregivers. This study aimed to explore the concerns and perceptions of healthcare providers (HCPs), patients, and caregivers regarding the burden of disease and quality of life (QoL) in patients with DRE. This was a multinational, cross-sectional, online, survey-based study. Participants were HCPs managing at least 30-50 epilepsy patients per month, including ≥10 patients with DRE; patients aged ≥18 years with DRE; and caregivers aged ≥18 years supporting patients with DRE. Data collection was carried out between March and August 2024. In total, 213 stakeholders took part in the survey (146 HCPs, 42 patients, and 25 caregivers); 58% of the HCPs were neurologists and 42% were epileptologists. Caregivers were mainly parents (79%). Patients represented by caregivers were younger (84% vs. 29% aged 18-34 years) and had a higher incidence of seizures (20 vs. 5 seizures per month; p < 0.05) than patient participants. According to all stakeholders, DRE had a significant impact on multiple components of patient QoL, with work capability, psychological well-being, and daily management and logistics the most affected. Significantly fewer HCPs regarded "achieving complete seizure freedom" as of high importance for patients compared with patient participants (p < 0.05) and caregivers (p < 0.05). High satisfaction with current treatment was reported by only 35% of HCPs, 33% of patient participants, and 4% of caregivers. Most stakeholders reported insufficient time during consultations to investigate patients' concerns, and different topics for discussion were prioritized by HCPs and patients/caregivers. This survey highlighted the continued and multifaceted burden of disease among patients with DRE. While seizure freedom is the ultimate goal of treatment, disparities exist among key stakeholders regarding aims and outcomes of treatment as well as management of expectations. Patients with DRE have epileptic seizures despite receiving medicines to reduce their seizures. This survey shows that DRE places a heavy strain on patients and their carers. Satisfaction with current treatments is low, especially among carers. Patients and carers see stopping all seizures as very important, but doctors tend to rate this as less of a priority; patients and carers are also more open than doctors to using digital tools to improve communication with their doctor. Overall, the differences in expectations and approaches between patients, carers, and doctors may create barriers to improving seizure control.

Focal epilepsy is characterized by progressive cortical thinning, particularly within limbic structures; however, whether this atrophy reflects acquired seizure-induced damage or shared genetic predisposition remains unresolved. We integrated genome-wide association study (GWAS) summary statistics from the ILAE Consortium (focal epilepsy: 15212 cases; 29 677 controls), ENIGMA (cortical thickness: N = 33 992), and COGENT (cognitive function: N = 257 841) using linkage disequilibrium score regression and genomic structural equation modeling (Genomic SEM). A latent cortical factor (F-EpiCortex) was derived and interrogated through MAGMA gene-based analysis, cell-type-specific Mendelian randomization (csMR) using brain single-cell expression quantitative trait loci, and spatial transcriptomic mapping (gsMap) across mouse embryonic and human cortical datasets. Focal epilepsy exhibited significant negative genetic correlations with cingulate cortical thickness (rg = -0.23 to -0.27; p < 0.05). Genomic SEM identified a well-fitting two-factor model (CFI = 0.916) wherein focal epilepsy genetic liability was associated with reduced cortical thickness (β = -0.30; p = 0.02), while cognitive function showed a protective association (β = 0.10; p = 0.04). GWAS of the F-EpiCortex latent factor identified nine genome-wide significant loci, with DPYSL5 (p = 1.88 × 10-11) as the lead signal. Cell-type-specific analysis revealed oligodendrocytes as the predominant cellular mediator, with DPYSL5 (β = -0.21; p = 1.3 × 10-10) and SLC16A8 (β = -0.28; p = 8.9 × 10-8) exhibiting robust protective effects predominantly within the oligodendrocyte lineage. Spatial transcriptomic validation confirmed oligodendrocyte enrichment across human cingulate and temporal cortices, with 70% concordance between csMR predictions and spatial expression patterns. Experimental validation in human oligodendrocytes under glutamate-induced excitotoxic stress demonstrated significant downregulation of the prioritized protective proteins, providing functional evidence for their susceptibility to epilepsy-associated injury. These findings implicate oligodendrocyte dysfunction as a shared genetic component linking focal epilepsy to cortical atrophy. This extends the "scars of seizures" paradigm by supporting a complementary neurodevelopmental origin model, with implications for neuroprotective therapeutic strategies. Focal epilepsy is often accompanied by a progressive thinning of the brain's cortex, which has traditionally been viewed purely as cumulative damage from repeated seizures. In this study, we investigated whether an underlying genetic predisposition also plays a role. By analyzing large-scale genetic and brain imaging datasets, we discovered a shared genetic link between focal epilepsy and cortical thinning. Furthermore, we traced this genetic vulnerability specifically to oligodendrocytes-the cells responsible for supporting and insulating nerve fibers. Our findings suggest that cortical thinning is not merely a "scar" from seizures, but partly a preexisting structural vulnerability driven by reduced protective functions of specific genes (such as DPYSL5 and SLC16A8) in these support cells. This offers a new perspective on preventing brain structural changes in epilepsy.

Verbal memory tasks differ in their cognitive demands and may rely on distinct left medial temporal structures. One model holds that verbal delayed recall is hippocampal dependent, whereas verbal paired associate learning relies on adjacent rhinal cortex. We test this by examining the relationship between task performance and regional temporal lobe volumes in individuals with temporal lobe epilepsy and hippocampal sclerosis (TLE-HS). Retrospective analysis of 99 surgically naïve TLE patients (12 bilateral TLE-HS, 35 left TLE-HS, 28 right TLE-HS, and 24 MRI-negative left TLE) with contemporaneous neuropsychological and T1-weighted MRI data. Delayed recall was operationalized using the Rey Auditory Verbal Learning Test, and arbitrary associative learning with the Paired Associates Learning subtest. Linear regressions assessed associations between memory performance and temporal lobe volumes. We also studied a cohort with nonlesional left TLE to better distinguish the relative impact on verbal memory of left temporal onset seizures versus the structural integrity of the left mesial temporal lobe. Patients with left-sided TLE-HS (unilateral/bilateral) performed significantly worse on both memory measures compared to right TLE-HS and MRI-negative left TLE (p < 0.001). Left hippocampal volume significantly predicted performance on both measures (both p < 0.001), whereasrhinal cortex volumes were not significantly associated with either. Secondary analyses revealed associations between left temporal pole volume and both memory measures, and between inferior temporal gyrus volume and delayed recall. Despite differing cognitive demands, both verbal arbitrary associative learning and delayed recall were primarily linked to left hippocampal volume, underscoring its central role in verbal memory impairment in TLE. Associations with the temporal pole and inferior temporal regions suggest additional contributions from extrahippocampal areas. Left hippocampal atrophy exacerbates verbal memory impairment beyond what would be expected from seizure activity alone. The results of this study show that the ability to learn semantically unrelated information and recall unstructured information after a period of delay is particularly compromised in individuals with left hippocampal atrophy. These impairments were strongly associated with reduced left hippocampal volume. In contrast, volumes of the adjacent rhinal cortex were not related to memory performance. These findings underscore the central role of the left hippocampus in supporting verbal memory in temporal lobe epilepsy.

Temporal lobe epilepsy (TLE) is characterized by recurrent seizures originating usually from the hippocampus, and approximately one-third of TLE patients remain refractory to pharmacological interventions. Surgical resection offers a potential cure for refractory TLE cases, with approximately 70% achieving seizure freedom. Still, the pathogenesis of TLE remains poorly understood. Electrophysiological characterization of the resected tissue with microelectrode arrays (MEAs) can help reveal the pathogenesis of TLE, but the commercially available MEAs cover only a small part of the hippocampal cross-section. The objective here is to develop a MEA that can cover a significant area of a human hippocampal slice to help understand the electrophysiology of TLE pathogenesis. The custom MEA, entitled Hippo-MEA, was designed to have 60 round electrodes, each 60 μm in diameter, in an area of 5.6 mm × 5.6 mm. The titanium nitride-coated electrodes were deposited on borosilicate glass using ion beam-assisted e-beam deposition (IBAD) process. Hippo-MEA's sample chamber, named Sample Cup, was designed large enough to hold a human hippocampal slice. Hippocampal samples were obtained from patients undergoing neurosurgical tissue resection for TLE treatment and sliced to 300 μm thick sections for Hippo-MEA recording. Data from the Hippo-MEA were recorded using the commercially available MEA2100-Mini-system. Cellular composition of the recording area was analyzed with immunohistochemistry (IHC). Extracellular action potentials (EAPs) and local field potentials (LFPs) were successfully recorded from acute human hippocampal slices. Activity was mainly localized to the dentate gyrus, whereas the CA regions found sclerotic and gliotic in IHC analysis showed little to no activity. Hippo-MEA is compatible with a commercially available and widely used data acquisition system and enables recording of EAPs and LFPs across several regions of human hippocampal tissue. This enables Hippo-MEA, in combination with other methods, to help discover the neurophysiological mechanisms of TLE. In some cases of temporal lobe epilepsy (TLE), the only treatment option is to surgically remove a part of the brain, including a structure known as the hippocampus, which is often the source of the electrical epileptic activity. Understanding hippocampal function is important to understanding the reasons behind TLE and designing the surgeries. Microelectrode arrays (MEAs) are a tool for recording the electrical function of tissues. Here we present a new MEA, named Hippo-MEA, that is big enough to measure a cross-section of the human hippocampus.

Ketogenic dietary therapies (KDTs) are increasingly used worldwide as a non-pharmacological treatment for epilepsy, including among people of childbearing potential. In many cases, KDTs allow for the reduction of antiseizure medications (ASMs) and lower drug exposure during pregnancy. However, limited evidence on maternal tolerability, fetal safety, and lactation outcomes has led to reluctance among healthcare providers to recommend KDTs during pregnancy. To inform evidence-based counseling, it is crucial to systematically collect data on maternal and offspring outcomes following KDT exposure. Over the past 25 years, international epilepsy pregnancy registries have provided robust data on the teratogenic risks of ASM exposure. Yet, no standardized dataset currently exists for documenting KDT exposure during pregnancy and lactation. The International League Against Epilepsy Ketogenic Dietary Treatments Task Force conducted a structured consensus process to develop the first international core dataset designed to capture maternal KDT exposure within existing pregnancy registries. This dataset provides a standardized, pragmatic framework for recording diet type, exposure duration, maternal-fetal outcomes, and lactation parameters. By harmonizing data collection across registries, this initiative aims to transform isolated case reports into aggregated, high-quality multicenter evidence, closing a critical knowledge gap. Incorporating these standardized questions into epilepsy pregnancy registries represents both a scientific necessity and a call to action to ensure safer, evidence-based care for women with epilepsy and their children. PLAIN LANGUAGE SUMMARY: More people are using ketogenic diets as a treatment for epilepsy around the world, including during pregnancy. It is not yet known if these diets are safe for mothers and babies during pregnancy and breastfeeding. Collecting standardized information about pregnancy outcomes in existing registries will inform us about the safety and effectiveness of these diets. The authors, who are either members of the International League Against Epilepsy dietary task force or specifically chosen by them for their expertise, followed a consensus process to suggest the addition of key standardized questions to the existing international pregnancy outcome registries for epilepsy.

Epilepsy surgery is an established treatment for drug-resistant epilepsy, offering a realistic prospect of seizure freedom in well-selected candidates. However, surgery is sometimes offered to individuals with a low probability of seizure freedom when it is framed as potentially "life-saving" on the basis of the elevated mortality associated with uncontrolled epilepsy. We examined this rationale using absolute risk reduction and number needed to treat (NNT) analyses derived from published mortality rates (deaths per 1000 person-years) in unoperated drug-resistant epilepsy, postoperative seizure-free patients, and postoperative patients who were not seizure-free. Weighted averages were used to estimate ARR and NNT for all-cause and sudden unexpected death in epilepsy (SUDEP) mortality across varying probabilities of seizure freedom and postoperative life expectancy. Compared with unoperated patients, mortality reductions were greatest in those who became seizure-free after surgery but remained modest in patients who did not. At a 50% probability of seizure freedom, the NNT to prevent one all-cause death was 146 person-years and to prevent one SUDEP was 243 person-years; with higher seizure-freedom probabilities (80%), the NNT improved to 124 and 225 person-years, respectively; at 20%, it worsened to 178 and 264 person-years. Lifetime modeling demonstrated that NNT decreases sharply with increasing life expectancy, reaching 3.5 and 4.7 at 60 years postoperative life expectancy for all-cause and SUDEP mortality, respectively. These findings highlight the complexity of invoking a "life-saving" rationale for surgery in poor candidates. Patients with the highest mortality risk, those with frequent generalized seizures, are also those least likely to achieve postoperative seizure freedom and therefore least likely to realize a mortality benefit. Our analyses underscore the need for balanced, data-driven risk-benefit discussions when surgery is considered primarily on mortality grounds. PLAIN LANGUAGE SUMMARY: This study looked at whether epilepsy surgery saves lives for people whose seizures cannot be controlled with medication. We found that surgery lowers the risk of death-especially when it stops seizures completely-but the benefit is smaller for people who continue to have seizures afterwards. Because people with the most severe forms of epilepsy have a lower chance of becoming seizure-free following surgery, the idea that surgery will be "life-saving" for them needs to be considered carefully and discussed with clear, balanced information.